Compositions and methods for treating inflammasome-associated diseases or conditions

Abstract

Compositions and methods for detecting inflammasome components in a sample from a subject as markers of an inflammasome-associated disease or disorder, such as multiple sclerosis, stroke, mild cognitive impairment, Alzheimer's disease, age-related macular degeneration, NASH, inflammatory aging, or traumatic brain injury. Methods of using such inflammasome markers to determine prognosis, prescribe treatment, and monitor response to treatment for subjects with an inflammasome-associated disease or disorder, such as multiple sclerosis, stroke, mild cognitive impairment, Alzheimer's disease, age-related macular degeneration, NASH, inflammatory aging, or traumatic brain injury, are also described.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 062,622, filed August 7, 2020, and U.S. Provisional Patent Application No. 63 / 016,033, filed April 27, 2020, each of which is incorporated by reference in its entirety for all purposes.

[0002] STATEMENT REGARDING FEDERALLY FUNDED RESEARCH This invention was made with U.S. government support under Grant No. 4R42NS086274-02 awarded by the National Institute of Neurological Disorders and Stroke (NINDS) and Grant No. 5R42NS086274-03 awarded by the National Institutes of Health. The U.S. government has certain rights in this invention.

[0003] The present invention relates generally to the fields of immunology and medicine. More particularly, the present invention relates to compositions and methods for detecting ASC (apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (CARD)) activity, caspase-1, IL-18, IL-1β, NOD-like receptors (NLRs), absent-in-melanoma 2 (AIM2)-like receptors (ALRs), and other inflammasome proteins, alone or in combination with control biomarker proteins, in samples obtained from mammals as biomarkers for diseases, conditions, or disorders, such as multiple sclerosis (MS), stroke, mild cognitive impairment (MCI), Alzheimer's disease (AD), age-related macular degeneration (AMD), age-related inflammation, or traumatic brain injury (TBI). Finally, the present invention relates to methods for treating neurological diseases, disorders, and / or conditions with agents directed against the inflammasome proteins, alone or in combination with assessing the expression levels of the inflammasome proteins.

[0004] Sequence Listing Description The Sequence Listing associated with this application is provided in text format in lieu of a paper copy and is incorporated herein by reference. The text file containing the Sequence Listing is named UNMI_015_03WO_SeqList_ST25.txt. The text file is approximately 43 KB, was created on April 27, 2021, and has been submitted electronically via EFS-Web. [Background technology]

[0005] Multiple sclerosis (MS) is a progressive autoimmune disorder that affects the central nervous system (CNS). Pathologically, it is characterized by demyelination and the presence of inflammatory lesions in the spinal cord and brain (Compston A. The pathogenesis and basis for treatment in multiple sclerosis. Clin Neurol Neurosurg. 2004;106:246-8). Clinically, MS patients present with blurred vision, muscle weakness, fatigue, dizziness, and balance and gating problems (Compston A. The pathogenesis and basis for treatment in multiple sclerosis. Clin Neurol Neurosurg. 2004;106:246-8). There are 400,000 MS patients in the United States alone, and approximately 2 million patients worldwide (Compston A. The pathogenesis and basis for treatment in multiple sclerosis. Clin Neurol Neurosurg. 2004;106:246-8).

[0006] Since the 1960s, immunoglobulin (Ig) G oligoclonal bands (OCBs) have been used as a classic biomarker for the diagnosis of MS (Stangel M, Fredrikson S, Meinl E, Petzold A, Stuve O and Tumani H. The utility of cerebrospinal fluid analysis in patients with multiple sclerosis. Nat Rev Neurol. 2013;9:267-76). However, the specificity of IgG-OCB is only 61%, and as a result, other diagnostic criteria are required to clinically determine the diagnosis of MS (Teunissen CE, Malekzadeh A, Leurs C, Bridel C and Killestein J. Body fluid biomarkers for multiple sclerosis—the long road to clinical application. Nat Rev Neurol. 2015;11:585-96). Nevertheless, CSF-restricted IgG-OCB is a good predictor of progression from CIS to CDMS, independent of MRI (Tintore M, Rovira A, Rio J, Tur C, Pelayo R, Nos C, Tellez N, Perkal H, Comabella M, Sastre-Garriga J and Montalban X. Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology. 2008;70:1079-83).Similar results have been obtained when analyzing IgM-OCB (Villar LM, Masjuan J, Gonzalez-Porque P, Plaza J, Sadaba MC, Roldan E, Bootello A and Alvarez-Cermeno JC. Intrathecal IgM synthesis predicts the onset of new relapses and a worse disease course in MS. Neurology. 2002;59:555-9). An important area of ​​research in the field of MS is the identification of suitable biomarkers to predict who is at risk of developing MS, biomarkers of disease progression or exacerbation, and biomarkers of treatment response and prognosis.

[0007] There are 17.5 million cardiovascular disease-related deaths each year, of which 6.7 million result from stroke (Mendis S, Davis S and Norrving B. Organizational update: the world health organization global status report on noncommunicable diseases 2014; one more landmark step in the combat against stroke and vascular disease. Stroke. 2015;46:e121-2). Although several large-scale trials of stroke biomarkers have been conducted, there is still no gold standard biomarker for use in the care of stroke patients. There remains a need for biomarkers that exhibit high sensitivity and specificity for stroke.

[0008] The US Center for Disease Control (CDC) defines traumatic brain injury (TBI) as "a disruption of the normal function of the brain that may result from a bump, blow, or impact to the head or a penetrating head injury." As of 2010, the CDC recorded 823.7 TBI-related emergency room visits, hospitalizations, and deaths per 100,000 individuals in the United States. (Centers for Disease Control's "Traumatic Brain Injury and Concussion" website: www.cdc.gov / traumaticbraininjury / index.html (as of June 21, 2018)) An important area of ​​research in the field of TBI is the identification of suitable biomarkers for TBI risk, disease diagnosis, progression or exacerbation, and treatment response and prognosis. Previous research on inflammasomes has suggested that inflammasome proteins could be used as biomarkers after traumatic brain injury. Inflammasomes are multiprotein complexes responsible for the innate immune response, involved in the activation of caspase-1 and the processing of the inflammatory cytokines IL-1beta and IL-18. Inflammasomes contribute to the inflammatory response, particularly after brain and spinal cord injury.

[0009] During aging, chronic sterile low-grade inflammation (called inflammaging) develops and contributes to the pathogenesis of age-related diseases. From an evolutionary perspective, various stimuli, including pathogens (non-self), endogenous cellular debris and misplaced molecules (self), and nutrients and gut microbiota (quasi-self), perpetuate inflammaging. These stimuli are sensed by a limited number of receptors, whose degeneracy allows for the recognition of many signals and the activation of innate immune responses. However, there is a lack of biomarkers that can aid in the diagnosis of inflammaging, as well as therapeutic targets and / or agents that can be used to treat inflammaging and / or age-related diseases. Summary of the Invention [Problem to be solved by the invention]

[0010] There has been much interest in the topic of the borderline or transitional state between normal aging and dementia, or Alzheimer's disease (AD). Several descriptions of these conditions have been made, including mild cognitive impairment (MCI), incipient dementia, and isolated memory impairment. Subjects with mild cognitive impairment (MCI) have memory impairment beyond that expected for their age and education in the absence of dementia. These subjects are becoming the focus of many predictive tests and early intervention trials. However, diagnostic criteria for MCI are generally unclear, and biomarkers are lacking. Furthermore, diagnosing subjects with early stages of AD compared with more advanced stages is essential to improve treatment outcomes.

[0011] Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population, affecting 11 million people in the United States alone and over 170 million people worldwide. AMD is a progressive degenerative disease that can cause irreversible vision loss. Patients with early-stage AMD often experience no symptoms, and the disease typically goes undetected until later stages, when vision loss begins to occur. Currently, AMD is incurable, so it is essential to find observable biomarkers that facilitate disease screening in order to diagnose early stages of AMD and slow its progression. (Zarbin MA.Current concepts in the pathogenesis of age-related macular degeneration.Arch Ophthalmol 2004;122:598-614., Ozaki E,Campbell M,Kiang AS,Humphries M,Doyle SL,Humphries P.Inflammation in age-related macular degeneration.Adv Exp Med Biol 2014;801:229-235.) [Means for solving the problem]

[0012] Therefore, to address the needs identified above, presented herein are inflammasome components useful as biomarkers with high sensitivity and specificity for a variety of inflammatory pathologies and methods for treating such pathologies by targeting the inflammasome components.

[0013] In one aspect, provided herein is a method for evaluating a patient suspected of having multiple sclerosis (MS), the method comprising measuring the level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with MS, the protein signature comprising an elevated level of at least one inflammasome protein, and selecting the patient as having MS if the patient exhibits the presence of the protein signature. In some cases, the patient exhibits clinical symptoms consistent with MS. In some cases, the MS is relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), or progressive relapsing MS (PRMS). In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay using one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1 beta, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes each of caspase-1, IL-18, IL-1 beta, and ASC. In some cases, the at least one inflammasome protein includes ASC. In some cases, the antibody binds to a PYRIN-PAAD-DAPIN domain (PYD), a C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to the level of at least one inflammasome protein in a biological sample obtained from a control.In some cases, the biological sample obtained from the control is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the control is a healthy individual, and the healthy individual is an individual who does not exhibit clinical symptoms consistent with MS. In some cases, the at least one inflammasome protein includes ASC, and the level of ASC is at least about 50% higher than the level of ASC in the biological sample obtained from the control. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to a predetermined reference value or range of reference values. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MS with a sensitivity of at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% and a specificity of at least about 90%. In some cases, the biological sample is serum, and the patient is selected as having MS with a specificity of at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100%. In some cases, the biological sample is serum, and the patient is selected as having MS with a sensitivity of at least 90% and a specificity of at least 80%. In some cases, the at least one inflammasome protein includes ASC. In some cases, cutoff values ​​for determining sensitivity, specificity, or both are selected from Table 7. In some cases, sensitivity and / or sensitivity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval.

[0014] In another aspect, provided herein is a method for evaluating a patient suspected of having a stroke, the method comprising: measuring the level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with stroke or stroke-related injury, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having a stroke if the patient exhibits the presence of the protein signature. In some cases, the patient exhibits clinical symptoms consistent with stroke, and the stroke is an ischemic stroke, transient ischemic stroke, or hemorrhagic stroke. In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay using one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1 beta, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes each of caspase-1, IL-18, IL-1 beta, and ASC. In some cases, the at least one inflammasome protein includes ASC. In some cases, the antibody binds to a PYRIN-PAAD-DAPIN domain (PYD), a C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to the level of at least one inflammasome protein in a biological sample obtained from a control.In some cases, the biological sample obtained from the control is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the control is a healthy individual, and the healthy individual is an individual who does not exhibit clinical symptoms consistent with MS. In some cases, at least one inflammasome protein includes ASC, and the level of ASC in a serum sample obtained from the subject is at least 70% higher than the level of ASC in a serum sample obtained from the control. In some cases, at least one inflammasome protein includes ASC, and the level of ASC in a serum-derived EV sample obtained from the subject is at least 110% higher than the level of ASC in a serum-derived EV sample obtained from the control. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to a predetermined reference value or range of reference values. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least about 90% specificity. In some cases, the biological sample is serum, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having had a stroke with at least 100% sensitivity and at least 95% specificity. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 8. In some cases, the biological sample obtained from the patient is serum-derived EVs, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least about 90% specificity. In some cases, the biological sample is serum-derived EVs, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity.In some cases, the biological sample is serum-derived EVs, and the patient is selected as having stroke with at least 100% sensitivity and at least 100% specificity. In some cases, the at least one inflammasome protein includes ASC. In some cases, cutoff values ​​for determining sensitivity, specificity, or both are selected from Table 9. In some cases, sensitivity and / or sensitivity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval.

[0015] In yet another aspect, provided herein are methods of treating a patient diagnosed with multiple sclerosis (MS), the methods comprising administering to the patient a standard of care treatment for MS, wherein the diagnosis of MS is made by detecting elevated levels of at least one inflammasome protein in a biological sample obtained from the patient. In some cases, the MS is relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), or progressive relapsing MS (PRMS). In some cases, the standard of care treatment is selected from therapies aimed at modifying disease outcome, managing relapses, managing symptoms, or any combination thereof. In some cases, the therapeutic agent aimed at modifying disease outcome is selected from beta-interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, mitoxantrone, ocrelizumab, alemtuzumab, daclizumab, and natalizumab.

[0016] In yet another aspect, provided herein are methods of treating a patient diagnosed with stroke or stroke-related injury, the methods comprising administering to the patient a standard of care treatment for stroke or stroke-related injury, wherein the diagnosis of stroke or stroke-related injury is made by detecting elevated levels of at least one inflammasome protein in a biological sample obtained from the patient. In some cases, the stroke is an ischemic stroke, a transient ischemic stroke, or a hemorrhagic stroke. In some cases, the stroke is an ischemic stroke or a transient ischemic stroke, and the standard of care treatment is selected from tissue plasminogen activator (tPA), an antiplatelet medication, an anticoagulant, carotid angioplasty, carotid endarterectomy, intra-arterial thrombolysis, and mechanical clot removal for cerebral ischemia (MERCI), or a combination thereof. In some cases, the stroke is a hemorrhagic stroke, and the standard of care treatment is aneurysm clipping, coil embolization, or arteriovenous malformation (AVM) repair. In some cases, the elevated level of at least one inflammasome protein is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein. In some cases, the level of at least one inflammasome protein is elevated relative to the level of at least one inflammasome protein in a control sample. In some cases, the level of at least one inflammasome protein is elevated relative to a predetermined reference value or range of reference values. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein is caspase-1, IL-18, and ASC. In some cases, the at least one inflammasome protein is ASC. In some cases, the antibody binds to the PYRIN-PAAD-DAPIN domain (PYD), the C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein.In some cases, the biological sample is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs).

[0017] In yet a further aspect, provided herein is a method for evaluating a patient suspected of having a traumatic brain injury (TBI), the method comprising: measuring the level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with TBI, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having TBI if the patient exhibits the presence of the protein signature. In some cases, the patient exhibits clinical symptoms consistent with TBI. In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes caspase-1. In some cases, the at least one inflammasome protein includes ASC. In some cases, the antibody binds to a PYRIN-PAAD-DAPIN domain (PYD), a C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein. In some cases, the level of at least one inflammasome protein in the protein signature is enhanced relative to the level of at least one inflammasome protein in a biological sample obtained from a control. In some cases, the at least one inflammasome protein includes caspase-1, and the level of caspase-1 is at least about 50% higher than the level of caspase-1 in a biological sample obtained from a control.In some cases, at least one inflammasome protein comprises ASC, and the level of ASC is at least 50% higher than the level of ASC in a biological sample obtained from a control. In some cases, the biological sample obtained from the control is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the control is a healthy individual, and a healthy individual is an individual who does not exhibit clinical symptoms consistent with TBI. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to a predetermined reference value or range of reference values. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having TBI with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least about 90% specificity. In some cases, the biological sample is serum, and the patient is selected as having TBI with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having TBI with at least 90% sensitivity and at least 80% specificity. In some cases, the sensitivity and / or specificity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining the sensitivity, specificity, or both is selected from Tables 11B, 12B, 14A, 16, 17, or 19. In some cases, the at least one inflammasome protein includes caspase-1. In some cases, the cutoff value for determining the sensitivity, specificity, or both is selected from Tables 11A or 15.

[0018] In yet another aspect, provided herein is a method for evaluating a patient suspected of having brain injury, the method comprising: measuring the level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with brain injury, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having brain injury if the patient exhibits the presence of the protein signature. In some cases, the patient exhibits clinical symptoms consistent with brain injury. In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes ASC. In some cases, the antibody binds to the PYRIN-PAAD-DAPIN domain (PYD), the C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein. In some cases, the at least one inflammasome protein includes caspase-1. In some cases, the level of the at least one inflammasome protein in the protein signature is elevated relative to the level of the at least one inflammasome protein in a biological sample obtained from a control. In some cases, the at least one inflammasome protein includes ASC, and the level of ASC is at least 50% higher than the level of ASC in a biological sample obtained from a control.In some cases, the at least one inflammasome protein comprises caspase-1, and the level of caspase-1 is at least about 50% higher than the level of caspase-1 in a biological sample obtained from a control. In some cases, the biological sample obtained from the control is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the control is a healthy individual, and a healthy individual is an individual who does not exhibit clinical symptoms consistent with brain injury. In some cases, the brain injury is selected from traumatic brain injury, stroke, mild cognitive impairment, or multiple sclerosis. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to a predetermined reference value or range of reference values. In some cases, the brain injury is traumatic brain injury (TBI). In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having TBI with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least about 90% specificity. In some cases, the biological sample is serum, and the patient is selected as having TBI with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having TBI with at least 90% sensitivity and at least 80% specificity. In some cases, the sensitivity and / or sensitivity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Tables 11B, 12B, 14A, 16, 17, or 19. In some cases, the at least one inflammasome protein includes caspase-1. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Tables 11A or 15. In some cases, the brain injury is mild cognitive impairment (MCI).In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MCI with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In some cases, the biological sample is serum, and the patient is selected as having MCI with at least about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having MCI with at least 90% sensitivity and at least 70% specificity. In some cases, the sensitivity and / or sensitivity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 22 or 23. In some cases, the at least one inflammasome protein includes IL-18. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 22 or 25. In some cases, the brain injury is multiple sclerosis (MS). In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MS with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least about 90% specificity. In some cases, the biological sample is serum, and the patient is selected as having MS with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having MS with at least 90% sensitivity and at least 80% specificity. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 7. In some cases, the sensitivity and / or specificity is determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the brain injury is a stroke.In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least 90% specificity. In some cases, the biological sample is serum, and the patient is selected as having had a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum, and the patient is selected as having had a stroke with at least 100% sensitivity and at least 95% specificity. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 8. In some cases, the biological sample obtained from the patient is serum-derived EVs, and the patient is selected as having a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% sensitivity and at least 90% specificity. In some cases, the biological sample is serum-derived EVs, and the patient is selected as having a stroke with at least about 80%, about 85%, about 90%, about 95%, about 99%, or about 100% specificity. In some cases, the biological sample is serum-derived EVs, and the patient is selected as having a stroke with at least 100% sensitivity and at least 100% specificity. In some cases, the at least one inflammasome protein includes ASC. In some cases, the cutoff value for determining sensitivity, specificity, or both is selected from Table 9. In some cases, sensitivity and / or sensitivity are determined using the area under the curve (AUC) from a receiver operating characteristic (ROC) curve with a 95% confidence interval.

[0019] In yet a further aspect, provided herein is a method for evaluating a patient suspected of having mild cognitive impairment (MCI), the method comprising: measuring the level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with MCI, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having MCI if the patient exhibits the presence of the protein signature. In some cases, the patient exhibits clinical symptoms consistent with MCI. In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes ASC. In some cases, the at least one inflammasome protein includes IL-18. In some cases, the antibody binds to a PYRIN-PAAD-DAPIN domain (PYD), a C-terminal caspase recruitment domain (CARD) domain, or a portion of the PYD or CARD domain of the ASC protein. In some cases, the level of at least one inflammasome protein in the protein signature is enhanced relative to the level of at least one inflammasome protein in a biological sample obtained from a control. In some cases, the at least one inflammasome protein includes ASC, and the level of ASC is at least 50% higher than the level of ASC in a biological sample obtained from a control.In some cases, the at least one inflammasome protein includes IL-18, and the level of IL-18 is at least about 25% greater than the level of IL-18 in a biological sample obtained from a control.

[0020] In one aspect, provided herein is a method for evaluating a patient suspected of having mild cognitive impairment (MCI), the method comprising: measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient; comparing the expression level of the at least one inflammasome protein in the biological sample with the expression level of one or more control MCI biomarkers; and selecting the patient as having MCI if the expression level of the at least one inflammasome protein in the biological sample is similar to the expression level of the one or more control MCI biomarkers. In some cases, the expression level of at least one inflammasome protein is similar to the expression level of one or more control MCI biomarkers if the expression level or a parameter representing the expression level of the at least one inflammasome protein is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the expression level or a parameter representing the expression level of the one or more control MCI biomarkers. In some cases, the expression levels of one or more control MCI biomarkers are measured in a biological sample obtained from the patient. In some cases, the expression level of one or more control MCI biomarkers is measured in a biological sample obtained from an individual previously diagnosed with MCI. In some cases, the biological sample obtained from an individual previously diagnosed with MCI is the same type of biological sample as that obtained from a patient suspected of having MCI. In some cases, the expression level of at least one inflammasome protein and the expression level of one or more control MCI biomarkers are elevated relative to the expression level of at least one inflammasome protein and the expression level of one or more control MCI biomarkers in a biological sample obtained from the control. In some cases, the biological sample obtained from the control is the same type of biological sample as that obtained from a patient suspected of having MCI. In some cases, the control is a healthy individual, and the healthy individual is an individual who does not exhibit clinical symptoms consistent with MCI.In some cases, the expression level of at least one inflammasome protein and the expression level of one or more control MCI biomarkers are elevated relative to a predetermined reference value or range of reference values ​​for at least one inflammasome protein and one or more control MCI biomarkers. In some cases, the parameter representing the expression level of at least one inflammasome protein and the parameter representing the expression level of one or more control MCI biomarkers are areas under the curve (AUC). In some cases, the patient exhibits clinical symptoms consistent with MCI. In some cases, the biological sample obtained from the patient suspected of having MCI is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the expression level of at least one inflammasome protein and / or one or more control MCI biomarkers is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein and / or one or more control MCI biomarkers. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes ASC. In some cases, the at least one inflammasome protein includes IL-18. In some cases, the one or more control MCI biomarkers are neurofilament light polypeptide (NFL), soluble APP-alpha (sAPPα), and / or soluble APP-beta (sAPPβ). In some cases, the at least one inflammasome protein is ASC and the one or more control MCI biomarkers are soluble APP-alpha (sAPPα), and the AUC for ASC is 0.974, and the AUC for sAPP-alpha is 0.9687.In some cases, the at least one inflammasome protein is ASC and the one or more control MCI biomarkers is soluble APP-beta (sAPPβ), the AUC for ASC is 0.974, and the AUC for sAPP-beta is 0.9068. In some cases, the at least one inflammasome protein is ASC and the one or more control MCI biomarkers is neurofilament light polypeptide (NFL), the AUC for ASC is 0.974, and the AUC for NFL is 0.7734. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MCI with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity and at least 55% specificity. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MCI with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having MCI with at least 70% sensitivity and at least 55% specificity. In some cases, the specificity and / or sensitivity are determined using a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the method further includes assessing the presence of one or more symptoms associated with MCI to select the patient as having MCI. In some cases, the one or more symptoms associated with MCI are forgetfulness, difficulty concentrating, anxiety, difficulty making decisions, difficulty understanding instructions, difficulty planning, difficulty navigating familiar environments, impulsive or questionable judgment, and judging the time or sequence of steps required to complete a complex task or visual perception.

[0021] In another aspect, provided herein is a method for evaluating a patient suspected of having Alzheimer's disease (AD), the method comprising: measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient; comparing the expression level of the at least one inflammasome protein in the biological sample with the expression level of one or more control AD ​​biomarkers; and selecting the patient as having AD if the expression level of the at least one inflammasome protein in the biological sample is similar to the expression level of the one or more control AD ​​biomarkers. In some cases, the expression level of at least one inflammasome protein is similar to the expression level of one or more control AD ​​biomarkers if the expression level or a parameter representing the expression level of the at least one inflammasome protein is within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, or 1% of the expression level or a parameter representing the expression level of the one or more control AD ​​biomarkers. In some cases, the expression level of one or more control AD ​​biomarkers is measured in a biological sample obtained from the patient. In some cases, the expression levels of one or more control AD ​​biomarkers are measured in a biological sample obtained from an individual previously diagnosed with AD. In some cases, the biological sample obtained from an individual previously diagnosed with AD is the same type of biological sample as that obtained from a patient suspected of having AD. In some cases, the expression levels of at least one inflammasome protein and one or more control AD ​​biomarkers are elevated relative to the expression levels of at least one inflammasome protein and one or more control AD ​​biomarkers in a biological sample obtained from the control. In some cases, the biological sample obtained from the control is the same type of biological sample as that obtained from a patient suspected of having AD. In some cases, the control is a healthy individual, and the healthy individual is an individual who does not exhibit clinical symptoms consistent with AD.In some cases, the expression level of at least one inflammasome protein and the expression level of one or more control AD ​​biomarkers are elevated relative to a predetermined reference value or range of reference values ​​for at least one inflammasome protein and one or more control AD ​​biomarkers. In some cases, the parameter representing the expression level of at least one inflammasome protein and the parameter representing the expression level of one or more control AD ​​biomarkers are areas under the curve (AUC). In some cases, the patient exhibits clinical symptoms consistent with AD. In some cases, the biological sample obtained from the patient suspected of having AD is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the expression level of at least one inflammasome protein and / or one or more control AD ​​biomarkers is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein and / or one or more control AD ​​biomarkers. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes ASC. In some cases, the at least one inflammasome protein includes IL-18. In some cases, the one or more control AD ​​biomarkers are neurofilament light polypeptide (NFL), soluble APP-alpha (sAPPα), and / or soluble APP-beta (sAPPβ). In some cases, the at least one inflammasome protein is ASC and the one or more control AD ​​biomarkers are soluble APP-alpha (sAPPα), and the AUC for ASC is 0.833, and the AUC for sAPPα is 0.956.In some cases, the at least one inflammasome protein is ASC and the one or more control AD ​​biomarkers is soluble APPβ (sAPPβ), the AUC for ASC is 0.833, and the AUC for sAPPβ is 0.919. In some cases, the at least one inflammasome protein is ASC and the one or more control AD ​​biomarkers is neurofilament light polypeptide (NFL), the AUC for ASC is 0.833, and the AUC for NFL is 0.717. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having AD with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity and at least 55% specificity. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having AD with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having AD with at least 70% sensitivity and at least 55% specificity. In some cases, the specificity and / or sensitivity are determined using a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the method further includes assessing the presence of one or more symptoms associated with AD to select the patient as having AD. In some cases, one or more symptoms associated with AD are forgetfulness, difficulty concentrating, anxiety, feeling uneasy or confused when making decisions, difficulty understanding directions or planning things, difficulty navigating familiar environments, difficulty performing tasks, forgetting material immediately after reading, losing or misplacing valuable items, difficulty organizing, confusion about time or place, difficulty with bladder or bowel control, personality or behavioral changes, such as mood or personality changes, changes in sleep patterns, difficulty communicating, such as vocabulary problems when speaking or writing, vulnerability to infections, impulsive or questionable judgment, difficulty understanding visual images and spatial relationships, misplacing things and losing the ability to backtrack, poor or impaired judgment, and withdrawal from work or social activities.In some cases, the parameter representing the expression level of at least one inflammasome protein and the parameter representing the expression level of one or more control MCI biomarkers are cutoff values. In some cases, the at least one inflammasome protein is ASC, and the cutoff value is greater than 264.9 pg / ml and less than 560 pg / ml. In some cases, the parameter representing the expression level of at least one inflammasome protein and the parameter representing the expression level of one or more control MCI biomarkers are cutoff values. In some cases, the at least one inflammasome protein is ASC, and the cutoff value is greater than 560 pg / ml.

[0022] In one aspect, provided herein is a method for determining whether a patient has mild cognitive impairment (MCI) or Alzheimer's disease (AD), the method comprising: measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient; comparing the expression level of the at least one inflammasome protein in the biological sample with a predetermined reference value or range of reference values ​​for the at least one inflammasome protein; and selecting the patient as having AD if the expression level of the at least one inflammasome protein is within the predetermined reference value range, or as having MCI if the expression level is above the predetermined reference value. In some cases, the at least one inflammasome protein is ASC. In some cases, the predetermined reference value range is 264.9 pg / ml to 560 pg / ml. In some cases, the predetermined reference value is above 560 pg / ml.

[0023] In another aspect, provided herein is a method for evaluating a patient suspected of having age-related macular degeneration (AMD), the method comprising: measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with AMD, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having AMD if the patient exhibits the presence of the protein signature. In some cases, the biological sample obtained from the patient is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the level of at least one inflammasome protein in the protein signature is measured by an immunoassay utilizing one or more antibodies directed against at least one inflammasome protein in the protein signature. In some cases, the level of at least one inflammasome protein in the protein signature is elevated relative to the level of at least one inflammasome protein in a biological sample obtained from a control. In some cases, the biological sample obtained from the control is cerebrospinal fluid (CSF), CNS microdialysate, saliva, serum, plasma, urine, or serum-derived extracellular vesicles (EVs). In some cases, the control is a healthy individual without clinical symptoms of AMD. In some cases, the at least one inflammasome protein is interleukin-18 (IL-18), IL-1β, apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, or a combination thereof. In some cases, the at least one inflammasome protein includes ASC, and the AUC for ASC is 0.9823. In some cases, the at least one inflammasome protein includes IL-18, and the AUC for IL-18 is 0.7286. In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having AMD with a sensitivity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%.In some cases, the biological sample obtained from the patient is serum, and the patient is selected as having AMD with a sensitivity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% and a specificity of at least 55%. In some cases, the specificity and / or sensitivity are determined using a receiver operating characteristic (ROC) curve with a 95% confidence interval. In some cases, the method further includes assessing the presence of one or more symptoms associated with AMD to select patients with AMD. In some cases, the one or more symptoms associated with AMD are blurred vision, unclear vision, straight lines appearing wavy or distorted, blurred areas on printed pages, difficulty reading or seeing details at low light levels, extra perception of bright, dark, or blurred areas in the central visual field, whiteout in the central visual field, or changes in color perception. In some cases, the parameter representing the expression level of at least one inflammasome protein is a cutoff value. In some cases, the at least one inflammasome protein is ASC and the cutoff value is greater than 365.6 pg / mL. In some cases, the at least one inflammasome protein is IL-18 and the cutoff value is greater than 242.4 pg / mL.

[0024] In one aspect, provided herein is a method of treating inflammatory senescence in a subject, the method comprising administering to the subject a therapeutically effective amount of a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8, or a variant thereof having at least one amino acid substitution in HCDR1, HCDR2, and / or HCDR3, and the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 14, or a variant thereof having at least one amino acid substitution in LCDR1, LCDR2, and / or LCDR3, thereby treating inflammatory senescence in the subject. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18, 19, 20, 21, 22 or SEQ ID NO: 18, 19, 20, 21 or 22, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28, 29, 30, 31 or SEQ ID NO: 28, 29, 30 or 31. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:18 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:18, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:28 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:28.In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18 or the amino acid sequence of SEQ ID NO: 18, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or the amino acid sequence of SEQ ID NO: 29. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18 or the amino acid sequence of SEQ ID NO: 18, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 30 or the amino acid sequence of SEQ ID NO: 30. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 18 or the amino acid sequence of SEQ ID NO: 18, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 31 or the amino acid sequence of SEQ ID NO: 31. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 19 or the amino acid sequence of SEQ ID NO: 19, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 28 or the amino acid sequence of SEQ ID NO: 28.In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence set forth in SEQ ID NO: 19 or at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19, and the VL region amino acid sequence comprises an amino acid sequence set forth in SEQ ID NO: 29 or at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 29. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence set forth in SEQ ID NO: 19 or at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence set forth in SEQ ID NO: 30 or at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 30. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO: 19 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO: 31 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 31. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 20 or the amino acid sequence of SEQ ID NO: 20, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 28 or the amino acid sequence of SEQ ID NO: 28. In some cases, the VH region amino acid sequence comprises SEQ ID NO:20 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:20, and the VL region amino acid sequence comprises SEQ ID NO:29 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:29.In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:20 or the amino acid sequence of SEQ ID NO:20, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:30 or the amino acid sequence of SEQ ID NO:30. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:20 or the amino acid sequence of SEQ ID NO:20, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:31 or the amino acid sequence of SEQ ID NO:31. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 21 or the amino acid sequence of SEQ ID NO: 21, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 28 or the amino acid sequence of SEQ ID NO: 28. In some cases, the VH region amino acid sequence comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 21 or the amino acid sequence of SEQ ID NO: 21, and the VL region amino acid sequence comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or the amino acid sequence of SEQ ID NO: 29. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:21 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:21, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:30 or an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:30.In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:21 or the amino acid sequence of SEQ ID NO:21, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:31 or the amino acid sequence of SEQ ID NO:31. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:22 or the amino acid sequence of SEQ ID NO:22, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:28 or the amino acid sequence of SEQ ID NO:28. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 22 or the amino acid sequence of SEQ ID NO: 22, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 29 or the amino acid sequence of SEQ ID NO: 29. In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 22 or the amino acid sequence of SEQ ID NO: 22, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises an amino acid sequence at least 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 30 or the amino acid sequence of SEQ ID NO: 30.In some cases, the VH region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:22 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:22, and the VL region amino acid sequence of the monoclonal antibody or antibody fragment thereof comprises SEQ ID NO:31 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:31. In some cases, the ASC is a human ASC protein. In some cases, the antibody fragment is a Fab, F(ab')2, Fab', scFv, single domain antibody, diabody, or single chain camelid antibody. In some cases, the monoclonal antibody or antibody fragment thereof is human, humanized, or chimeric. In some cases, administering the monoclonal antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. In some cases, administering the monoclonal antibody or antibody fragment thereof results in inhibition of inflammasome activation in a subject. In some cases, administration of the monoclonal antibody or antibody fragment thereof results in a reduction in the activity of ASC compared to a control. In some cases, the control is an untreated subject. In some cases, administration is intracerebroventricular, intraperitoneal, intravenous, or by inhalation. [Brief explanation of the drawings]

[0025] [Figures 1A-1D] Figure 1 illustrates that inflammasome proteins are elevated in the serum of MS patients. Protein levels in pg / ml of caspase-1 (Figure 1A), ASC (Figure 1B), IL-1β (Figure 1C), and IL-18 (Figure 1D) in serum samples from MS patients and healthy donors are shown. p-values ​​for significance are indicated above each box plot. Boxes and whiskers represent the 5th and 95th percentiles. Caspase-1: N = 9 controls and 19 MS; ASC: N = 115 controls and 32 MS; IL-1β: N = 21 controls and 8 MS; and IL-18: N = 119 controls and 32 MS. [Figures 2A-2D]Illustrated are ROC curves for caspase-1 (FIG. 2A), ASC (FIG. 2B), IL-1β (FIG. 2C), and IL-18 (FIG. 2D) from serum samples of MS and healthy donors. [Figure 3] Figure 1 illustrates serum inflammasome proteins as biomarkers for MS. ROC curves for caspase-1, ASC, IL-1 beta, and IL-18. Caspase-1: N = 9 controls and 19 MS patients; ASC: N = 115 controls and 32 MS patients; IL-1 beta: N = 21 controls and 8 MS patients; and IL-18: N = 119 controls and 32 MS patients. [Figure 4] 1 illustrates a table containing characteristics of multiple sclerosis (MS) subjects from Example 1. [Figures 5A-5D] Figure 5 illustrates that inflammasome proteins are elevated in the serum of stroke patients. Protein levels in pg / ml of caspase-1 (Figure 5A), ASC (Figure 5B), IL-1 beta (Figure 5C), and IL-18 (Figure 5D) in serum samples from stroke patients and healthy donors. p-values ​​for significance are indicated above each box plot. Boxes and whiskers represent the 5th and 95th percentiles. NS = not significant. Caspase-1: N = 8 controls and 13 strokes; ASC: N = 75 controls and 16 strokes; IL-1 beta: N = 9 controls and 8 strokes; and IL-18: N = 79 controls and 15 strokes. [Figure 6] Figure 1 illustrates serum inflammasome proteins as biomarkers for stroke. ROC curves for caspase-1, ASC, IL-1 beta, and IL-18. Caspase-1: N=8 controls and 13 strokes, ASC: N=75 controls and 16 strokes, IL-1 beta: N=9 controls and 8 strokes, and IL-18: N=79 controls and 15 strokes. [Figure 7A-7C]Figure 7A illustrates a comparison of total protein levels from serum-derived extracellular vesicles (EVs). A Bradford assay was performed after EV isolation from serum to determine total protein concentration in isolates using the Invitrogen kit (INVTR) and the ExoQuick kit (EQ). Data are presented as mean ± SEM. N = 6 per group. Figure 7B depicts a representative image of total loaded protein. A stain-free image of serum-derived EV protein. Equal amounts of protein lysate (10 ml) were loaded onto each lane of the Criterion gel. Figure 7C depicts a bar graph showing quantification of total lanes corresponding to loaded EVs isolated using the Invitrogen kit (INVTR) and the ExoQuick kit (EQ). [Figures 8A-8F] EV characterization in serum from stroke patients is illustrated. Figure 8A depicts a representative immunoblot of CD81- and NCAM-positive EVs isolated using the Invitrogen kit (IN) and the ExoQuick kit (EQ). + Control: Positive control for isolated EVs. Quantification of CD81 (Figure 8B) and NCAM (Figure 8C)-positive EVs isolated from serum using the Invitrogen kit (INV) and the ExoQuick kit (EQ). Figure 8D depicts electron microscopy images of EVs isolated by the two different techniques. Bar = 100 nm. Nanoparticle tracking analysis / particle size distribution of isolated serum-derived EVs. Nanoparticle tracking analysis predicts particle size distribution and concentration in serum-derived EV samples isolated using the Invitrogen kit (Figure 8E) and the ExoQuick kit (Figure 8F). [Figures 9A-9C] Figure 9 illustrates that ASC is elevated in serum-derived EVs from stroke patients. Protein levels in pg / ml of ASC (Figure 9A), IL-1 beta (Figure 9B), and IL-18 (Figure 9C) in serum-derived EVs from stroke patients and healthy donors. p-values ​​for significance are indicated above each box plot. Boxes and whiskers represent the 5th and 95th percentiles. NS = not significant. ASC: N = 16 control and 16 stroke, IL-1 beta: N = 10 control and 9 stroke, and IL-18: N = 16 control and 13 stroke. [Figure 10]Figure 1 illustrates inflammasome proteins in serum-derived EVs as biomarkers of stroke. ROC curves for ASC, IL-1 beta, and IL-18. ASC: N=16 controls and 16 strokes, IL-1 beta: N=10 controls and 9 strokes, and IL-18: N=16 controls and 13 strokes. [Figure 11] 1 illustrates a table containing characteristics of stroke subjects from Example 2. [Figures 12A-12D] Illustrated are ROC curves for caspase-1 (FIG. 12A), ASC (FIG. 12B), IL-1 beta (FIG. 12C), and IL-18 (FIG. 12D) from serum samples of stroke and healthy donors. [Figures 13A-13F] Figure 13 illustrates the characterization of inflammasome proteins in serum-derived EVs. Figure 13A depicts a representative image of immunoblot analysis of inflammasome proteins in serum-derived EVs. Quantification of immunoblot analysis of (Figure 13B) NLRP3, (Figure 13C) caspase-1, (Figure 13D) ASC, (Figure 13E) IL-1 beta, and (Figure 13F) IL-18 in serum-derived EVs using the Invitrogen kit (IN) and the ExoQuick kit (EQ). Data presented as mean ± SEM. N=6 / group. *p<0.05. [Figures 14A-14C] Illustrated are ROC curves for ASC (FIG. 14A), IL-1 beta (FIG. 14B), and IL-18 (FIG. 14C) from serum-derived extracellular vesicles of stroke and healthy donors. [Figures 15A-15D] Figure 15 illustrates how inflammasome proteins are elevated in the serum of TBI patients. Protein levels in pg / ml of ASC (Figure 15A), caspase-1 (Figure 15B), IL-18 (Figure 15C), and IL-1β (Figure 15D) in serum samples from TBI patients and healthy donors (controls). ASC: N = 120 control, 20 TBI. Caspase-1: N = 11 control, 19 TBI. IL-18: N = 120 control, 21 TBI. IL-1β: N = 25 control, 10 TBI. Boxes and whiskers represent the 5th and 95th percentiles. *p<0.05. [Figures 16A-16D]Illustrated are ROC curves for caspase-1 (FIG. 16A), ASC (FIG. 16B), IL-1β (FIG. 16C), and IL-18 (FIG. 16D) from serum samples of TBI patients and healthy donors. [Figures 17A-17B] Figure 17 illustrates how inflammasome proteins are elevated in the CSF of TBI patients. Protein levels in pg / ml of ASC (Figure 17A) and IL-18 (Figure 17B) in CSF samples from TBI patients and healthy donors (controls). ASC: N=21 control, 15 TBI. IL-18: N=24 control, 16 TBI. Boxes and whiskers indicate the 5th and 95th percentiles. *p<0.05. [Figures 18A-18B] Illustrated are ROC curves for ASC (FIG. 18A) and IL-18 (FIG. 18B) from CSF samples of TBI patients and healthy donors. [Figures 19A-19C] Figure 19 illustrates inflammasome proteins as predictive biomarkers for TBI. Protein levels in pg / ml of caspase-1 (Figure 19A), ASC (Figure 19B), and IL-18 (Figure 19C) in serum samples from TBI patients. Groups were divided into good and poor outcomes based on GOSE. p-values ​​for significance are shown above each box plot. Boxes and whiskers represent the 5th and 95th percentiles. Caspase-1: N=4 good and 16 poor; ASC: N=5 good and 16 poor; and IL-18: N=5 good and 16 poor. [Figures 20A-20B] 2 illustrates ROC curves for ASC outcome (good vs. poor) for the second (FIG. 20A) and fourth (FIG. 20B) harvests. [Figures 21A-21D]Figure 21 illustrates that inflammasome proteins are elevated in the serum of MCI and AD patients. Protein levels in pg / ml of ASC (Figure 21A), caspase-1 (Figure 21B), IL-18 (Figure 21C), and IL-1 beta (Figure 21D) in serum samples from MCI and AD patients and age-matched healthy donors (controls). * represents the p-value of significance compared to controls, and ** represents the p-value of significance between MCI and AD. ASC: N = 66 controls, 32 MCI, 31 AD. Caspase-1: N = 7 controls, 23 MCI, 15 AD. IL-18: N = 69 controls, 31 MCI, 32 AD. IL-1 beta: N = 9 controls, 9 MCI, 8 AD. Boxes and whiskers indicate the 5th and 95th percentiles. ***p<0.05. [Figures 22A-22D] 22A and 22B illustrate ROC curves for ASC (FIG. 22A), caspase-1 (FIG. 22B), IL-18 (FIG. 22C), and IL-1 beta (FIG. 22D) from serum samples of MCI and age-matched healthy donors. [Figure 23A] 22A-22D illustrate inflammasome proteins in serum as biomarkers of MCI. ROC curves for caspase-1, ASC, IL-1 beta, and IL-18 from Figures 22A-22D are overlaid on a single graph. [Figure 23B] Figure 1 illustrates serum inflammasome proteins as biomarkers for AD. ROC curves for caspase-1, ASC, IL-1 beta, and IL-18 from serum samples of AD and age-matched healthy donors are overlaid on a single graph. [Figure 23C] Figure 1 illustrates serum inflammasome proteins as biomarkers of MCI. ROC curves for caspase-1, ASC, IL-1 beta, and IL-18 from AD and MCI serum samples are overlaid on a single graph. [Figures 24A-24C]24A-C illustrate proteins elevated in the serum of MCI and AD patients. Protein levels in pg / ml of sAPPα (FIG. 24A), sAPPβ (FIG. 24B), and NFL (FIG. 24C) in serum samples from MCI, AD patients, and age-matched healthy donors (controls). [Figure 25A] Figure 1 illustrates serum inflammasome proteins as biomarkers of MCI. ROC curves for NFL, sAPPα, sAPPβ, and ASC from serum samples of MCI and age-matched healthy donors are overlaid on a single graph. [Figure 25B] Figure 1 illustrates serum inflammasome proteins as biomarkers of AD. ROC curves for NFL, sAPPα, sAPPβ, and ASC from serum samples of MCI and age-matched healthy donors are overlaid on a single graph. [Figure 25C] Figure 1 illustrates serum inflammasome proteins as biomarkers of MCI. ROC curves for NFL, sAPPα, sAPPβ, and ASC from serum samples of MCI and AD are overlaid on a single graph. [Figure 26A] 1 illustrates a linear regression analysis between IL-18 and ASC protein levels. [Figure 26B] 1 illustrates the logarithmic transformation of the linear regression analysis between IL-18 and ASC protein levels. [Figure 26C] 1 illustrates a linear regression analysis between levels of sAPPα and sAPPβ. [Figure 26D] 1 illustrates the logarithmic transformation of the linear regression analysis between sAPPα and sAPPβ protein levels. [Figure 26E] 1 illustrates the fit of a linear regression analysis between IL-18 and ASC protein levels. [Figure 26F] 1 illustrates the fitting of a logarithmic transformation of a linear regression analysis between IL-18 and ASC protein levels. [Figure 26G] 1 illustrates the results of residual analysis of linear regression analysis between the protein levels of IL-18 and ASC. [Figure 26H]1 illustrates the results of residual analysis of logarithmic transformation of linear regression analysis between IL-18 and ASC protein levels. [Figure 26I] 1 illustrates the fit of a linear regression analysis between sAPPα and sAPPβ protein levels. [Figure 26J] 1 illustrates the fitting of a logarithmic transformation of a linear regression analysis between sAPPα and sAPPβ protein levels. [Figure 26K] 1 illustrates the results of residual analysis of linear regression analysis between sAPPα and sAPPβ protein levels. [Figure 26L] 1 illustrates the results of residual analysis of logarithmic transformation of linear regression analysis between sAPPα and sAPPβ protein levels. [Figure 27A] 1 illustrates cluster analysis using ASC protein levels in controls, MCI, and AD patients. Clustering is shown using Gaussian mixture modeling. [Figure 27B] 1 illustrates cluster analysis using ASC protein levels in controls, MCI, and AD patients. Cluster dendrograms are shown. [Figure 27C] 1 illustrates cluster analysis using ASC protein levels in controls, MCI, and AD patients. Coordinate plots are shown. [Figures 28A-28D] 28A and 28B illustrate that inflammasome proteins are elevated in the serum of AMD patients. Protein levels in pg / ml of ASC (FIG. 28A), caspase-1 (FIG. 28B), IL-18 (FIG. 28C), and IL-1 beta (FIG. 28D) in serum samples from AMD patients are shown. [Figures 29A-29D] 29A and 29B illustrate ROC curves for ASC (FIG. 29A), caspase-1 (FIG. 29B), IL-18 (FIG. 29C), and IL-1 beta (FIG. 29D) from serum samples of AMD donors. [Figures 30A-30D] 30A illustrates the expression of inflammasome proteins ASC (FIG. 30A), caspase-1 (FIG. 30B), IL-18 (FIG. 30C), and IL-1 beta (FIG. 30D) in wet and dry AMD patients. [Figure 31]1 illustrates the results of residual analysis of linear regression analysis between protein levels of ASC and IL-18 in AMD patients. [Figure 32] 1 illustrates a binary logistic regression of ASC protein levels in serum of patients with and without an AMD diagnosis. [Figure 33] 1 illustrates a binary logistic regression of IL-18 protein levels in serum of patients with and without an AMD diagnosis. [Figure 34] Figure 1 illustrates that a monoclonal antibody against ASC (i.e., IC-100 (mAb)) inhibits IL-1beta activation in the cortex of aged mice. Mice were treated (ip) with IC-100 (5 mg / kg) and saline control and sacrificed 3 days later. Immunoblot of cortical protein lysates from young (3-month-old) and aged (18-month-old) mice blotted for IL-1beta. Data presented as mean ± SEM. 3m: 3 months old, 18m: 18 months old. Sal: saline. N=6 / group. *p<0.05. [Figures 35A-35D] This figure illustrates that a monoclonal antibody against ASC (i.e., IC-100 (MAb)) inhibits NLRP1 inflammasome activation in the cortex of aged mice. Mice were treated (ip) with IC-100 (5 mg / kg) and saline control and sacrificed 3 days later. Figure 35A shows representative immunoblots of cortical protein lysates from young (3-month-old) and aged (18-month-old) mice blotted for NLRP1, caspase-1, and ASC, while Figures 35B-35D depict the relative concentration units of NLRP1 (Figure 35B), caspase-1 (Figure 35C), and ASC (Figure 35D) as determined from representative immunoblots such as the immunoblot depicted in Figure 35A. Data presented as mean ± SEM. 3m: 3-month-old; 18m: 18-month-old. Sal: saline. N=6 / group. *p<0.05. [Figures 36A-36C]These figures illustrate that a monoclonal antibody against ASC (i.e., IC-100 (MAb)) inhibits noncanonical inflammasome activation in the cortex of aged mice. Mice were treated (ip) with IC-100 (5 mg / kg) and saline control and sacrificed 3 days later. Figure 36A shows representative immunoblots of cortical protein lysates from young (3-month-old) and aged (18-month-old) mice blotted for caspase-8 and caspase-11, while Figures 36B-36C depict the relative concentration units of caspase-8 (Figure 36B) and caspase-11 (Figure 35C) as determined from representative immunoblots such as the immunoblot depicted in Figure 36A. Data presented as mean ± SEM. 3m: 3-month-old, 18m: 18-month-old. Sal: saline. N=6 / group. *p<0.05. [Figure 37] This figure illustrates the formation of the non-canonical NLRP1-ASC-caspase-8 inflammasome in the cortex of aged mice. Cortical protein lysates from aged (18-month-old, saline- and IC-100-treated) and young (3-month-old) mice were co-immunoprecipitated (IP) with IC-100 (anti-ASC) and blotted for ASC, caspase-8, NLRP1, and caspase-1, suggesting protein-protein interactions between these proteins. 3m: 3-month-old, 18m: 18-month-old. Sal: saline. [Figure 38] 1 shows the results of a linear regression analysis between ASC and the pro-inflammatory cytokine IL-18. [Figure 39] The results of the analysis of residuals to assess the fit of the linear model are shown. [Figure 40] Figure 1 shows the estimated coefficient of ASC according to a binary logistic regression of ASC protein levels in serum of patients with and without AMD diagnosis. [Figure 41] Figure 1 shows the estimated coefficient of IL-18 according to a binary logistic regression of ASC protein levels in serum of patients with and without AMD diagnosis. [Figures 42A-42D]Illustrated are the expression of inflammasome proteins ASC (FIG. 42A) and IL-18 (FIG. 42B) and known NASH biomarkers Gal-3 (FIG. 42C) and C-reactive protein (CRP, FIG. 42D) from serum samples of NASH patients. [Figures 43A-43D] 43A, 43B, 43C, and 43D illustrate ROC curves for ASC (FIG. 43A), IL-18 (FIG. 43B), Gal-3 (FIG. 43C), and C-reactive protein (FIG. 43D) from serum samples of NASH donors. [Figure 44] 43A-43C illustrate inflammasome proteins in serum as biomarkers of NASH. The ROC curves for IL-18, ASC, and Gal-3 from Figures 43A-43C are overlaid on a single graph. DETAILED DESCRIPTION OF THE INVENTION

[0026] definition Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0027] The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described. All references or portions of references cited herein, including but not limited to patents, patent applications, articles, books, and treatises, are expressly incorporated herein by reference in their entirety for all purposes. In the event that one or more of the incorporated references or portions of references defines a term that conflicts with the definition of that term in this application, the definition set forth in this application shall control. However, none of the references, articles, publications, patents, patent publications, and patent applications cited herein constitute pertinent prior art or form part of the common general knowledge anywhere in the world, and their inclusion is not to be construed as an admission or suggestion in any way. Although compositions and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred compositions and methods are described below.

[0028] The term "a" or "an" refers to one or more of that entity; that is, it is possible to refer to a plurality of referents. Thus, the terms "a" or "an," "one or more," and "at least one" are used interchangeably herein. In addition, reference to an "element" by the indefinite article "a" or "an" does not exclude the possibility that more than one element is present, unless the context clearly requires that only one element be present.

[0029] Unless otherwise required by context, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," are to be interpreted in their open, inclusive sense, i.e., "including but not limited to." The use of alternatives (e.g., "or") should be understood to mean either one, all, or any combination thereof of the alternatives. As used herein, the terms "about" and "consisting essentially of" mean ±20% of the indicated range, value, or structure, unless otherwise indicated.

[0030] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in the context of this embodiment can be included in at least one embodiment of the present disclosure. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. The specific embodiments discussed below are merely exemplary and are not intended to be limiting. It will be understood that certain features of the present disclosure, which are for clarity described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are for brevity described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

[0031] Throughout this disclosure, various aspects of the methods and compositions provided herein may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This is true regardless of the breadth of the range.

[0032] As used herein, "protein" and "polypeptide" are used interchangeably to refer to any peptide-linked amino acid chain, regardless of length or post-translational modification, e.g., glycosylation or phosphorylation.

[0033] As used herein, the term "antibody" generally and broadly refers to immunoglobulin (Ig) molecules and immunologically active portions or fragments of immunoglobulin molecules, i.e., molecules that contain an antigen-binding site that specifically binds to (immunoreacts with) an antigen (e.g., ASC, NLRP1, AIM2, etc.). Antibodies provided herein can be polyclonal antibodies, monoclonal antibodies (mAbs), chimeric antibodies, humanized antibodies, anti-idiotypic antibodies (anti-Ids) to antibodies, and active fragments, regions, or derivatives thereof, in soluble or conjugated form and can be labeled. Antibodies for use herein can be chimeric, humanized, or human.

[0034] "Specifically binds to" or "immunoreacts with" means that an antibody reacts with one or more antigenic determinants of a desired antigen and does not react with other polypeptides. In certain embodiments, an antibody is said to specifically bind to an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. The term "antibody" broadly refers to an immunoglobulin (Ig) molecule, which generally comprises four polypeptide chains, i.e., two heavy (H) chains and two light (L) chains, or any functional fragment, mutant, variant, or derivative thereof that retains the essential target-binding features of an Ig molecule. Such mutant, variant, or derivative antibody formats are known in the art. Such anti-ASC and anti-NLRP1 antibodies of the present invention are capable of binding to portions of ASC and NLRP1, respectively, and interfere with caspase-1 activation.

[0035] As used herein, the term "humanized antibody" refers to an antibody in which minimal parts of a non-human antibody have been introduced into an otherwise human antibody.

[0036] As used herein, the term "human antibody" means an antibody that has only minor sequence changes or variations such that substantially all portions of the protein are substantially non-immunogenic in humans.

[0037] In full-length antibodies, each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity-determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2) or subclass. IgG, IgD, and IgE antibodies generally contain two identical heavy chains and two identical light chains and two antigen-binding domains, each composed of a heavy chain variable region (VH) and a light chain variable region (VL). IgA antibodies generally are composed of two monomers (as in IgG, IgD, and IgE antibodies), each composed of two heavy chains and two light chains; thus, an IgA molecule has four antigen-binding domains, again composed of a VH and a VL, respectively. Certain IgA antibodies are monomeric in that they are composed of two heavy chains and two light chains. Secreted IgM antibodies are generally composed of five monomers, each composed of two heavy chains and two light chains (as in IgG and IgE antibodies). Thus, an IgM molecule has 10 antigen-binding domains, again composed of a VH and a VL. Cell surface forms of IgM also exist, which have a two heavy chain / two light chain structure similar to IgG, IgD, and IgE antibodies.

[0038] As used herein, the terms "antigen-binding fragment" or "antigen-binding portion" or "antigen-binding site" or "binding domain" or "binding region" can refer to a protein, polypeptide, oligopeptide, or peptide domain, region, portion, or portion of an antibody that retains the ability to specifically bind to an antigen (e.g., an ASC protein), i.e., a binding domain derived from an antibody. Exemplary binding domains include single-chain antibody variable regions (e.g., domain antibodies sFv, scFv, scFab), fusion proteins comprising antibody portions (e.g., domain antibodies), receptor ectodomains, and ligands (e.g., cytokines, chemokines). In one embodiment, the fusion protein comprises one or more CDRs. In another embodiment, the fusion protein comprises CDR H3 (VH CDR3) and / or CDR L3 (VL CDR3). For purposes of the present invention, a fusion protein contains one or more antibodies and additional amino acid sequences, such as heterologous or homologous sequences from another region attached to the N-terminus or C-terminus of an antibody or antibody fragment thereof. Exemplary heterologous sequences include, but are not limited to, "tags" such as FLAG tags or 6His tags, or enzymes or polypeptides that increase the half-life of antibodies in the blood. Tags are well known in the art. Additional amino acid sequences can include amino- and / or carboxyl-terminal fusions, which can range in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues.

[0039] An antigen-binding site can generally be formed by heavy chain variable region (VH) and light chain variable region (VL) immunoglobulin domains, which contain an antigen-binding interface formed by six surface polypeptide loops called complementarity-determining regions (CDRs). Three CDRs are present in each of the VH (HCDR1, HCDR2, HCDR3) and VL (LCDR1, LCDR2, LCDR3) along with the framework regions (FRs). In certain embodiments, a binding domain comprises or consists of an antigen-binding site (e.g., comprising variable heavy and light chain sequences, or comprising three light chain complementarity-determining regions (CDRs) and three heavy chain CDRs of an antibody arranged within alternative framework regions (FRs) (e.g., human FRs optionally containing one or more amino acid substitutions)).

[0040] The term "CDR region" or "CDR" can refer to the hypervariable region of an immunoglobulin heavy or light chain as defined by Kabat et al., 1991 (Kabat, E. A. et al., (1991) Sequences of Proteins of Immunological Interest, 5th Edition. U.S. Department of Health and Human Services, Public Service, NIH, Washington) and subsequent editions. Antibodies typically contain three heavy chain CDRs and three light chain CDRs.

[0041] It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Antibody and antibody fragment embodiments may also be bispecific, trispecific, dual-specific, or multispecific formats that specifically bind to two or more different antigens. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include: (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains (Ward, ES et al., (1989) Nature 341, 544-546); (ii) a Fd fragment consisting of the VH and CH1 domains (McCafferty et al., (1990) Nature 348, 552-554); (iii) a Fv fragment consisting of the VL and VH domains of a single antibody (Holt et al., (2003) Trends in Biotechnology 21, 484-490); and (iv) a dAb fragment consisting of the VH or VL domain (Ward, ES et al., Nature 341, 544-546 (1989), McCafferty et al., (1990) Nature 348, 552-554, Holt et al. al., (2003) Trends in Biotechnology 21, 484-490], (v) isolated CDR regions, (vi) F(ab')2 fragments, which are bivalent fragments containing two linked Fab fragments, and (vii) single-chain Fv molecules (scFv) in which the VH and VL domains are linked by a peptide linker that allows the association of the two domains to form an antigen-binding site (Bird et al., (1988) Science, 242, 423-426; Huston et al., (1988) PNAS USA, 85, 5879-5883). The present invention also encompasses Fab' fragments. Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows for the creation of a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv)). Such single-chain antibodies are also intended to be encompassed by the term "antigen-binding fragment" of an antibody.In certain embodiments of the invention, scFv molecules may be incorporated into fusion proteins. In some embodiments, the invention includes single-chain camelid antibodies, (viii) bispecific single-chain Fv dimers (PCT / US92109965), and (ix) "diabodies," multivalent or multispecific fragments constructed by genetic fusion (WO 94 / 13804; Holliger, P. (1993) et al., Proc. Natl. Acad. Sci. USA 90 6444-6448). Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but with a linker that is too short to allow pairing between the two domains on the same chain, thereby forcing pairing with complementary domains on another chain to form two antigen-binding sites (see, e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123). Such antibody-binding fragments are known in the art (Kontermann and Dubel eds., Antibody Engineering (2001) Springer-Verlag. New York. 790 pp.). In some embodiments, the present invention includes single-domain antibodies. In general, the term "antibody" as used herein encompasses "antibody fragments." Antibody fragments generally retain the antigen-binding properties of the full-length antibody.

[0042] Fv, scFv, or diabody molecules can be stabilized by the incorporation of disulfide bridges linking the VH and VL domains (Reiter, Y. et al., Nature Biotech, 14, 1239-1245, 1996). Minibodies containing scFv linked to CH3 domains can also be produced (Hu, S. et al., (1996) Cancer Res., 56, 3055-3061). Other examples of binding fragments are Fab', which differs from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region, and Fab'-SH, a Fab' fragment in which the cysteine ​​residues in the constant domains bear free thiol groups.

[0043] As used herein, "Fv" may refer to the minimum fragment of an antibody that retains both the antigen-recognition and antigen-binding sites. As used herein, "Fab" may refer to an antibody fragment that contains the constant domain of the light chain and the CH1 domain of the heavy chain. The term "mAb" refers to a monoclonal antibody.

[0044] "Fc region" or "Fc domain" refers to a polypeptide sequence corresponding to or derived from the portion of a source antibody involved in binding to the antibody receptor on cells and the C1q component of complement. Fc stands for "fragment crystallizable," an antibody fragment that readily forms protein crystals. Originally described by proteolytic digestion, distinct protein fragments can define the entire general structure of an immunoglobulin protein. As originally defined in the literature, the Fc fragment consists of the disulfide-linked heavy chain hinge region, CH2, and CH3 domains. However, more recently, the term has been applied to a single chain consisting of CH3, CH2, and at least a portion of the hinge sufficient to form a disulfide-linked dimer with a second such chain. For a review of immunoglobulin structure and function, see Putnam, The Plasma Proteins, Vol. V (Academic Press, Inc., 1987), pp. 49-140, and Padlan, Mol. Immunol. 31:169-217, 1994. As used herein, the term Fc includes variants of naturally occurring sequences. In one embodiment, the antibodies or antibody fragments derived therefrom (e.g., anti-ASC monoclonal antibodies or antibody fragments thereof) provided herein have a modified Fc region or domain. In some cases, the modified Fc region or domain can confer increased thermal stability to the resulting antibody or antibody fragment derived therefrom. Increased thermal stability can result in increased serum half-life. The Fc region or domain can be modified as described in U.S. Patent No. 20160193295, the contents of which are incorporated herein by reference. As described in U.S. Patent No. 20160193295, the Fc region or domain can be modified to have one or more cysteine ​​residues in the hinge region deleted and one or more CH3 interface amino acids replaced with sulfhydryl-containing residues.In another embodiment, the Fc region or domain of an antibody provided herein or antibody fragment derived therefrom (e.g., an anti-ASC monoclonal antibody or antibody fragment thereof) can be stabilized by engineering the Fc region to have intradomain disulfide bonds as described in Wozniak-Knopp G, Stadlmann J, Rukuer F (2012) Stabilization of the Fc Fragment of Human IgG1 by Engineered Intradomain Disulfide Bonds. PLoS ONE 7(1):e30083, the contents of which are incorporated herein by reference. In yet another embodiment, the antibody has an Fc region modified as described in WO 99 / 58572, the contents of which are incorporated herein by reference. In yet another embodiment, the Fc region or domain can be modified as described in U.S. Pat. No. 9,574,010, the contents of which are incorporated herein by reference.

[0045] As used herein, the term "epitope" includes any protein determinant capable of specific binding to an immunoglobulin or immunoglobulin fragment. Epitopic determinants usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and usually have specific three-dimensional structural characteristics, as well as specific charge characteristics. The term "epitope" also refers to the unit of structure conventionally bound by an immunoglobulin heavy chain variable (VH) and light chain variable (VL) region pair. An epitope can define the minimal binding site for an antibody and thus is the target of antibody specificity.

[0046] The terms "apoptosis-associated speck-like protein containing a caspase-activatable recruitment domain (CARD)" and "ASC" refer to the expression product of the ASC gene or an isoform thereof, or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with ASC (e.g., NP_037390 (Q9ULZ3-1), NP_660183 (Q9ULZ3-2), or Q9ULZ3-3 in humans or NP_758825 (BAC43754) in rats) and exhibits the functional activity of ASC. A "functional activity" of a protein is any activity related to the physiological function of the protein. Functional activity of ASC includes, for example, activation of caspase-1 and recruitment of proteins for the initiation of cell death.

[0047] The term "ASC gene" or "ASC nucleic acid" refers to a native ASC-encoding nucleic acid sequence, an ASC cDNA transcribable genomic sequence, and / or allelic variants and homologs of the above. The term encompasses double-stranded DNA, single-stranded DNA, and RNA.

[0048] As used herein, the term "inflammasome" or "canonical inflammasome" refers to a multi-protein (e.g., at least two protein) complex that activates caspase-1. Furthermore, the term "inflammasome" refers to a multi-protein complex that activates caspase-1 activity, which in turn regulates the processing and activation of IL-1β, IL-18, and IL-33. See Arend et al. 2008, Li et al. 2008, and Martinon et al. 2002 (each of which is incorporated by reference in its entirety). The terms "NLRP1 inflammasome," "NALP1 inflammasome," "NLRP2 inflammasome," "NALP2 inflammasome," "NLRP3 inflammasome," "NALP3 inflammasome," "NLRC4 inflammasome," "IPAF inflammasome," or "AIM2 inflammasome" refer to a protein complex of at least caspase-1 and one adaptor protein, such as ASC. For example, the terms "NLRP1 inflammasome" and "NALP1 inflammasome" can refer to a multiprotein complex containing NLRP1, ASC, caspase-1, caspase-11, XIAP, and pannexin-1 for activating caspase-1 and processing interleukin-1β, interleukin-18, and interleukin-33. The terms "NLRP2 inflammasome" and "NALP2 inflammasome" can refer to a multiprotein complex containing NLRP2 (also known as NALP2), ASC, and caspase-1. Meanwhile, the terms "NLRP3 inflammasome" and "NALP3 inflammasome" can refer to a multiprotein complex containing NLRP3 (also known as NALP3) and ASC, and the terms "NLRC4 inflammasome" and "IPAF inflammasome" can refer to a multiprotein complex containing NLRC4 (also known as IPAF), ASC, and caspase-1. In addition, the term "AIM2 inflammasome" may refer to a multi-protein complex comprising AIM2, ASC, and caspase-1.

[0049] As used herein, the term "noncanonical inflammasome" refers to a multiprotein (e.g., at least two protein) complex that activates caspases other than caspase-1. Noncanonical inflammasomes can be composed of NLRs, such as NLRP1 and NLRP3, that interact with caspases other than caspase-1. For example, the noncanonical NLRP1-caspase-8 inflammasome is composed of NLRP1, caspase-8, and ASC.

[0050] As used interchangeably herein, "amyloid precursor protein" and "APP" can refer to an expression product of the APP gene or isoform, a cleavage product of APP, or a protein sharing at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to APP (e.g., Accession Nos. NP001129603.1, NP_001129601.1, P05067). Non-limiting examples of cleavage products of APP (SEQ ID NO: 36) include soluble amyloid precursor protein α (sAPPα) (SEQ ID NO: 37), soluble amyloid precursor protein β (sAPPβ) (SEQ ID NO: 38), amyloid-β1-42 (Aβ (1-42) ) (SEQ ID NO: 39) or amyloid-β1-40 (Aβ (1-40) ) (SEQ ID NO: 40).

[0051] As used interchangeably herein, "neurofilament light chain," "NfL," and "NFL" can refer to an expression product of the NFL gene or isoform, a cleavage product of NFL, or a protein sharing at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity to NFL (e.g., Accession No. P07196) (SEQ ID NO: 41).

[0052] As used herein, "control biomarker" or "control biomarker protein" can refer to any gene, expression product of a gene, or protein utilized in the compositions and methods of the present disclosure that is known in the art to be associated with, indicative of, or diagnostic of brain injury. For example, the brain injury can be MCI and / or AD, and the control biomarker or control biomarker protein can be NFL, amyloid-β (Aβ), or amyloid-β (Aβ). (1-42) ), T-Tau, sAPPα, or sAPPβ. In some cases, a control biomarker for a specific brain injury may be referred to as a control biomarker for that specific brain injury. For example, a control biomarker for MCI or AD may be referred to as a control MCI biomarker or a control AD ​​biomarker, respectively.

[0053] As used herein, the phrase "sequence identity" refers to the percentage of identical subunits at corresponding positions in two sequences (e.g., nucleic acid sequences, amino acid sequences) when the two sequences are aligned to maximize subunit matching, i.e., taking into account gaps and insertions. Sequence identity can be measured using sequence analysis software (e.g., sequence analysis software packages from Accelrys CGC, San Diego, CA).

[0054] The phrases "therapeutically effective amount" and "effective dosage" refer to an amount sufficient to produce a therapeutically (e.g., clinically) desired result. The exact nature of the result will vary depending on the nature of the disorder being treated. For example, if the disorder being treated is SCI, the result may be improved motor skills and locomotor function, a reduction in spinal cord pathology, and the like. The compositions described herein can be administered one or more times daily to one or more times weekly. One of skill in the art will recognize that certain factors, including but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other conditions present, can influence the dosage and timing required to effectively treat a subject. Moreover, treatment of a subject with a therapeutically effective amount of a composition of the invention can include a single treatment or a series of treatments.

[0055] As used herein, the term "treatment" is defined as the application or administration of a therapeutic agent as described herein to a patient, or to a tissue or cell line identified by the methods described herein, or isolated from a patient having a disease, a symptom of a disease, or a predisposition to a disease, for the purpose of curing, ameliorating, alleviating, altering, treating, ameliorating, improving, or affecting a disease, a symptom of a disease, or a predisposition to a disease.

[0056] The terms "patient," "subject," and "individual" are used interchangeably herein to refer to a mammalian subject to be treated, such as a human patient. In some cases, the methods of the invention are used in laboratory animals, veterinary applications, and the development of animal models for disease, including rodents, including but not limited to mice, rats, and hamsters, and primates.

[0057] As used interchangeably herein, "absentee melanoma 2" and "AIM2" can refer to the expression product of the AIM2 gene or isoform or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with AIM2 (e.g., Accession Nos. NX_014862, NP004824, XP016858337, XP005245673, AAB81613, BAF84731, AAH10940) and exhibits the functional activity of AIM2.

[0058] As used interchangeably herein, "NALP1" and "NLRP1" refer to the expression product of the NALP1 or NLRP1 gene or isoform, or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NALP1 (e.g., Accession Nos. AAH51787, NP_001028225, NP_127500, NP_127499, NP_127497, NP055737) and exhibits the functional activity of NALP1.

[0059] As used interchangeably herein, "NALP2" and "NLRP2" refer to the expression product of the NALP2 or NLRP2 gene or isoform, or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NALP2 (e.g., Accession Nos. NP_001167552, NP_001167553, NP_001167554, or NP_060322) and exhibits the functional activity of NALP2.

[0060] As used interchangeably herein, "NALP3" and "NLRP3" refer to the expression product of the NALP3 or NLRP3 gene or isoform, or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NALP3 (e.g., Accession Nos. NP_001073289, NP_001120933, NP_001120934, NP_001230062, NP_004886, NP_899632, XP_011542350, XP_016855670, XP_016855671, XP_016855672, or XP_016855673) and exhibits the functional activity of NALP3.

[0061] As used interchangeably herein, "NLRC4" and "IPAF" refer to the expression product of the NLRC4 or IPAF gene or isoform, or a protein that shares at least 65%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with NLRC4 (e.g., Accession Nos. NP_001186067, NP_001186068, NP_001289433, or NP_067032) and exhibits the functional activity of NLRC4.

[0062] The terms "stroke" and "ischemic stroke" mean when blood flow to a part of the brain or spinal cord is interrupted. The terms "ischemic stroke" and "transient ischemic stroke" mean when blood flow to a part of the brain or spinal cord is interrupted by a blockage in an artery that supplies oxygen-rich blood to the brain or spinal cord. The term "hemorrhagic stroke" means when blood flow to a part of the brain or spinal cord is interrupted when an artery in the brain or spinal cord leaks or ruptures.

[0063] "Traumatic injury to the CNS" means any injury to the CNS by mechanical force that may result in permanent or temporary impairment of CNS function.

[0064] As used herein, the term "inflammatory aging" may refer to chronic low-grade inflammation that can occur as an organism ages. Inflammatory aging is macrophage-centered, involves several tissues and organs, including the gut microbiota, and can be characterized by a complex balance between pro- and anti-inflammatory responses. In some cases, inflammatory aging may refer to a chronic pro-inflammatory state. The main inflammatory stimuli that can be characterized or linked to inflammation may be represented by endogenous / self, mislocated, or modified molecules that arise from damaged and / or dead cells and organelles (cellular debris) and are recognized by receptors of the innate immune system. While their production is physiological and increases with age, their disposal by the proteasome via autophagy and / or mitophagy progressively declines. This "autoreactive / autoimmune" process can amplify the onset or progression of chronic diseases that can accelerate and propagate the aging process locally and systemically.

[0065] Methods involving conventional molecular biology techniques are described herein. Such techniques are widely known in the art and are described in detail (and regularly updated) in methodological treatises such as "Molecular Cloning: A Laboratory Manual, 3rd ed., vol. 1-3, ed. Sambrook et al., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 2001" and "Current Protocols in Molecular Biology, ed. Ausubel et al., Greene Publishing and Wiley-Interscience, New York, 1992." Immunological techniques are widely known in the art and are described in detail in methodological treatises such as Advances in Immunology, volume 93, ed. Frederick W. Alt, Academic Press, Burlington, MA, 2007; Making and Using Antibodies: A Practical Handbook, eds. Gary C. Howard and Matthew R. Kaser, CRC Press, Boca Raton, FL, 2006; Medical Immunology, 6th ed., edited by Gabriel Virella, Informa Healthcare Press, London, England, 2007; and Harlow and Lane ANTIBODIES: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988.

[0066] exterior Provided herein are compositions and methods for evaluating or diagnosing a patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation. The method may include measuring the level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with inflammation or a disease, disorder, or condition caused by or associated with inflammation, where the protein signature includes an elevated level of at least one inflammasome protein. If the patient exhibits the presence of the protein signature, selecting the patient as having inflammation or a disease, disorder, or condition caused by or associated with inflammation. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, where the protein signature further includes an elevated expression level of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with inflammation or a disease, disorder, or condition caused by or associated with inflammation. The inflammation may be innate immune inflammation. The inflammation may be inflammasome-associated inflammation. The disease, disorder, or condition can be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmune, autoinflammatory, metabolic, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury can be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease can be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS weakness, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS).The metabolic disease can be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorders, glycogen storage disorders, medium-chain acyl-coenzyme A dehydrogenase deficiency, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease can be cryopyrin-associated periodic syndromes (CAPS). CAPS can include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). In one embodiment, the brain injury is MS. In another embodiment, the brain injury is stroke. In yet another embodiment, the brain injury is TBI. In yet another embodiment, the brain injury is MCI. In yet another embodiment, the brain injury is AD. In embodiments where the brain injury is MCI or AD, the control biomarker protein is NFL, amyloid-β (Aβ). (1-42) ), T-Tau, sAPPα, sAPPβ, or any combination thereof. The disease, disorder, or condition can be inflammatory aging or an age-related disease. In another embodiment, the age-related disease is age-related macular degeneration (AMD).

[0067] Also provided herein are methods of treating a patient suffering from or suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation. The inflammation can be innate immune inflammation. The inflammation can be inflammasome-associated inflammation. The disease, disorder, or condition can be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmune, autoinflammatory, metabolic, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury can be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease can be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS wasting, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS). The metabolic disease can be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorders, glycogen storage diseases, medium-chain acyl-coenzyme A dehydrogenase deficiency, nonalcoholic fatty liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease can be cryopyrin-associated periodic syndromes (CAPS). CAPS can include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). Any of the treatment methods provided herein can require administering treatment to a patient suffering from or suspected of suffering from an inflammation-related disease, disorder, or condition. Administering treatment with a method for treating an inflammation-related disease, disorder, or condition as provided herein can reduce inflammation in the patient. The reduction can be compared to a control (e.g., an untreated patient and / or a patient prior to treatment). In some cases, the treatment is a standard of care treatment. In some cases, the treatment is a neuroprotective treatment. Such neuroprotective treatment can include agents that reduce excitotoxicity, oxidative stress, and inflammation.Therefore, suitable neuroprotective treatments include, but are not limited to, methylprednisolone, 17alpha-estradiol, 17beta-estradiol, ginsenosides, progesterone, simvastatin, deprenyl, minocycline, resveratrol, and other glutamate receptor antagonists (e.g., NMDA receptor antagonists) and antioxidants. In some embodiments, the treatment is an antibody or binding fragment thereof directed against an inflammasome protein, such as an antibody directed against an inflammasome protein provided herein.

[0068] Also provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to apoptosis-associated speck-like protein (ASC) containing a caspase activating recruitment domain. The monoclonal antibody or fragment thereof is capable of specifically binding to an antigenic fragment of ASC comprising, consisting of, or consisting essentially of the amino acid sequence KKFKLKLLSVPLREGYGRIPR (SEQ ID NO: 5). Further to this embodiment, the present invention contemplates the use of the monoclonal antibody or antibody fragment thereof in a method for treating inflammation in a subject. The inflammation can be caused by a patient suffering from an inflammation-associated disease, disorder, or condition. The inflammation can be innate immune inflammation. The inflammation can be inflammasome-associated inflammation. The disease, disorder, or condition can be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmune, autoinflammatory, metabolic, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury can be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease can be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS wasting, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS). The metabolic disease can be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorder, glycogen storage disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, non-alcoholic fatty liver disease (e.g., non-alcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease may be cryopyrin-associated periodic syndromes (CAPS), which can include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID).In one embodiment, the monoclonal antibody or antibody fragment thereof provided herein can be used in a method for reducing inflammation in a mammal, as described in U.S. Patent No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. The monoclonal antibody or antibody fragment thereof of this embodiment can be present in a composition, such as, for example, a pharmaceutical composition, provided herein. In some cases, the monoclonal antibody or fragment thereof is used in combination with one or more other agents in the treatment methods provided herein. The other agents can be any of the agents provided herein (e.g., EV uptake inhibitors) and / or antibodies or antibody fragments against other inflammasome components (e.g., IL-18, caspase-1, NALP1, AIM2, etc.).

[0069] Diagnostic methods In some cases, provided herein are methods for diagnosing or evaluating a patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation, which may include detecting the expression level of at least one inflammasome protein in a biological sample obtained from a patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation, detecting the expression level of at least one control protein in a control biological sample, comparing the expression level of at least one inflammasome protein in the biological sample obtained from the patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation with the expression level of the at least one control protein in the control biological sample, and selecting the patient as having inflammation or a disease, disorder, or condition caused by or associated with inflammation based on the comparison. In some cases, the patient is selected as having inflammation or a disease, disorder, or condition caused by or associated with inflammation due to an increased expression level of the detected expression level of at least one inflammasome protein in the biological sample obtained from the patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation, compared to the expression level of the at least one control protein in the control biological sample. In some cases, the patient is selected as having inflammation or a disease, disorder, or condition caused by or associated with inflammation due to a decreased level of expression of the detected expression level of at least one inflammasome protein in a biological sample obtained from the patient suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation compared to the expression level of at least one control protein in a control biological sample.In some cases, the control biological sample may be a biological sample obtained from a subject not suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation, and the at least one control protein may be at least one inflammasome protein detected in a biological sample obtained from a patient suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation. In some cases, the control biological sample may be a biological sample obtained from a patient suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation, and the at least one control protein may be a control biomarker protein. The control biomarker protein may be any protein whose expression level has previously been shown to be associated with inflammation or a disease, disorder, or condition caused by or associated with inflammation. In one embodiment, elevated expression levels of the control biomarker protein have previously been shown to be associated with or diagnostic of inflammation or a disease, disorder, or condition caused by or associated with inflammation. In one embodiment, the disease, disorder, or condition caused by or associated with inflammation is MCI or AD, and the at least one control protein is NFL, amyloid-β (Aβ). (1-42)), T-Tau, sAPPα, and sAPPβ. In one embodiment, the disease, disorder, or condition caused by or associated with inflammation is NASH, and the at least one control protein is a control biomarker protein selected from Gal-3 and CRP (hs-CRP). In one embodiment, any of the methods provided herein for assessing or diagnosing a disease, disorder, or condition caused by or associated with inflammation in a patient suspected of suffering from such a disease, disorder, or condition by measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient can be performed in combination with determining the expression level of a biomarker whose altered expression level is known or suspected to be associated with such a disease, disorder, or condition. In one embodiment, any of the methods provided herein for assessing or diagnosing a disease, disorder, or condition caused by or associated with inflammation in a patient suspected of suffering from such a disease, disorder, or condition by measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient can be performed in combination with one or more additional diagnostic assessments. Detection of altered expression levels of at least inflammasome proteins in a biological sample obtained from a patient can be used to confirm a diagnosis of a particular disease, disorder, or condition caused by or associated with inflammation, as determined using one or more additional diagnostic assessments. Detection of altered expression levels of at least inflammasome proteins in a biological sample obtained from a patient can be used to increase the certainty of or strengthen the diagnosis of a particular disease, disorder, or condition caused by or associated with inflammation, as determined using one or more additional diagnostic assessments. The one or more additional diagnostic assessments can be selected from the group consisting of evaluation of clinical parameters, examination of morphological indicators in tissue biopsies, and evaluation or assessment of symptoms associated with a particular disease, disorder, or condition caused by or associated with inflammation.Any of the diagnostic methods provided herein in connection with determining the level of inflammasome proteins in a biological sample obtained from a patient can be used as an adjunct to known diagnostic methods for particular diseases, disorders or conditions caused by or associated with inflammation.

[0070] In another case, provided herein is a method of diagnosing or evaluating a patient suspected of having inflammation, or a disease, disorder, or condition caused by or associated with inflammation, which may include detecting the expression levels of at least one inflammasome protein and at least one control biomarker protein in a biological sample obtained from the patient suspected of having inflammation, or a disease, disorder, or condition caused by or associated with inflammation; detecting the expression levels of at least one inflammasome protein and at least one control biomarker protein in the control biological sample; comparing the expression levels of the at least one inflammasome protein and at least one control biomarker protein in the biological sample obtained from the patient suspected of having inflammation, or a disease, disorder, or condition caused by or associated with inflammation, with those of the control biological sample; and selecting the patient as having inflammation, or a disease, disorder, or condition caused by or associated with inflammation, based on the comparison. In some cases, a patient is selected as having inflammation or a disease, disorder, or condition caused by or associated with inflammation due to an increased expression level of the detected expression level of at least one inflammasome protein and at least one control biomarker protein in a biological sample obtained from the patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation compared to the expression level in a control biological sample. In some cases, a patient is selected as having inflammation or a disease, disorder, or condition caused by or associated with inflammation due to a decreased expression level of the detected expression level of at least one inflammasome protein and at least one control biomarker protein in a biological sample obtained from the patient suspected of having inflammation or a disease, disorder, or condition caused by or associated with inflammation compared to the expression level in a control biological sample.In some cases, the control biological sample may be a biological sample obtained from a subject not suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation, and the at least one control protein may be at least one inflammasome protein detected in a biological sample obtained from a patient suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation. The control biomarker protein may be any protein whose expression level has previously been shown to be associated with inflammation or a disease, disorder, or condition caused by or associated with inflammation. In one embodiment, elevated expression levels of the control biomarker protein have previously been shown to be associated with or diagnostic of inflammation or a disease, disorder, or condition caused by or associated with inflammation. In one embodiment, the disease, disorder, or condition caused by or associated with inflammation is MCI or AD, and the at least one control protein is NFL, amyloid-β (Aβ). (1-42) In one embodiment, the disease, disorder, or condition caused by or associated with inflammation is NASH, and the at least one control protein is a control biomarker protein selected from Gal-3 and CRP (hs-CRP).

[0071] In one embodiment, provided herein is a method for diagnosing or evaluating a patient with multiple sclerosis (MS), comprising measuring the level of at least one inflammasome protein in a biological sample obtained from the patient, determining the presence or absence of a protein signature associated with MS, the protein signature comprising an elevated level of at least one inflammasome protein, and selecting the patient as having MS if the patient exhibits the presence of the protein signature. The patient may exhibit clinical symptoms consistent with MS. Through the use of the methods and compositions provided herein, the patient can be diagnosed with any type of MS known in the art. The MS may be relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), or progressive relapsing MS (PRMS). In some cases, the method further comprises measuring the expression level of a control biomarker, such as NFL, whose altered expression levels have been shown to be associated with MS, in a sample obtained from the patient, and using the detection of the altered expression level of the control biomarker in combination with the detection of the altered expression level of one or more inflammasome proteins to reliably diagnose MS in the patient. In some cases, the method further comprises assessing the patient's clinical characteristics / symptoms in relation to MS, and using the detection of the altered expression level of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose MS in the patient.

[0072] In another embodiment, provided herein is a method for diagnosing or evaluating a patient suspected of having a stroke, the method comprising: measuring the level of at least one inflammasome protein in a biological sample obtained from the patient; determining the presence or absence of a protein signature associated with stroke or stroke-related injury, the protein signature comprising an elevated level of at least one inflammasome protein; and selecting the patient as having a stroke if the patient exhibits the presence of the protein signature. The patient may exhibit any clinical symptoms consistent with stroke known in the art. The stroke may be an ischemic stroke, a transient ischemic stroke, or a hemorrhagic stroke. In some cases, the method further comprises measuring the expression level of a control biomarker, whose altered expression level has been shown to be associated with stroke, in the sample obtained from the patient; and using the detection of the altered expression level of the control biomarker in combination with the detection of the altered expression level of one or more inflammasome proteins to reliably diagnose stroke in the patient. In some cases, the method further includes assessing the patient's clinical characteristics / symptoms in relation to stroke and using detection of altered expression levels of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose stroke in the patient.

[0073] In one embodiment, provided herein is a method for diagnosing or evaluating a patient with traumatic brain injury (TBI), comprising measuring the level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with TBI, wherein the protein signature comprises elevated levels of at least one inflammasome protein, and selecting the patient as having TBI if the patient exhibits the presence of the protein signature. The patient may exhibit clinical symptoms consistent with TBI. Through the use of the methods and compositions provided herein, the patient can be diagnosed with any type of TBI known in the art. In some cases, the method further comprises measuring the expression level of a control biomarker, whose altered expression level has been shown to be associated with TBI, in a sample obtained from the patient, and using the detection of the altered expression level of the control biomarker in combination with the detection of the altered expression level of one or more inflammasome proteins to reliably diagnose TBI in the patient. In some cases, the method further includes assessing the patient's clinical characteristics / symptoms in relation to TBI and using detection of altered expression levels of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose TBI in the patient.

[0074] In one embodiment, provided herein is a method for diagnosing or assessing a patient with cognitive impairment. The cognitive impairment can be mild or severe. In one embodiment, the cognitive impairment is mild cognitive impairment (MCI). The method includes measuring the level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with cognitive impairment (e.g., MCI), wherein the protein signature comprises an elevated level of at least one inflammasome protein, and selecting the patient as having cognitive impairment (e.g., MCI) if the patient exhibits the presence of the protein signature. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, wherein the protein signature further comprises an elevated expression level of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with brain injury. The at least one control biomarker protein can be NFL, amyloid-β (Aβ), or amyloid-β (Aβ). (1-42) ), T-Tau, sAPPα, or sAPPβ. Patients may exhibit clinical symptoms consistent with cognitive impairment (e.g., MCI). Through use of the methods and compositions provided herein, patients can be diagnosed with any type of cognitive impairment known in the art, such as MCI. Examples of symptoms often exhibited by subjects suffering from MCI may include amnesia (more frequent forgetting things and / or forgetting important events), difficulty concentrating (losing train of thought), anxiety or confusion when making decisions, understanding directions, or planning things, difficulty navigating familiar environments, and / or impulsivity and questionable judgment. MCI subjects may also experience depression, irritability, anxiety, or apathy. In some cases, the methods involve the use of control biomarkers whose altered expression levels have been shown to be associated with MCI, such as NFL, amyloid-β (Aβ), or sAPPβ. (1-42)In some cases, the method further comprises measuring expression levels of one or more inflammasome proteins, such as sAPPα, sAPPβ, T-Tau, sAPPα, sAPPβ, or the like, in a sample obtained from the patient, and using the detection of altered expression levels of the control biomarker in combination with the detection of altered expression levels of one or more inflammasome proteins to reliably diagnose MCI in the patient. In some cases, the method further comprises assessing the patient's clinical characteristics / symptoms in relation to MCI, and using the detection of altered expression levels of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose MCI in the patient.

[0075] In one embodiment, provided herein is a method of diagnosing or evaluating a patient with Alzheimer's disease (AD). In some embodiments, Alzheimer's disease causes dementia. In some embodiments, the patient has AD classified as early stage (mild), mid-stage (moderate), or late stage (severe). In one embodiment, the AD is early stage. In some embodiments, the AD is mid-stage. In some embodiments, the AD is late stage. The method includes measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with cognitive impairment (e.g., AD), wherein the protein signature comprises elevated levels of at least one inflammasome protein, and selecting the patient as having cognitive impairment (e.g., AD) if the patient exhibits the presence of the protein signature. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, wherein the protein signature further comprises elevated expression levels of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with brain injury. The at least one control biomarker protein may be NFL, amyloid-β (Aβ), or amyloid-β protein. (1-42)), T-Tau, sAPPα, or sAPPβ. Patients may exhibit clinical symptoms consistent with AD. Through the use of the methods and compositions provided herein, patients can be diagnosed with any type of AD known in the art, such as mild stage, moderate stage, or late stage. Examples of symptoms often exhibited by subjects with AD may include amnesia (more frequent forgetting things and / or forgetting important events), difficulty concentrating (losing train of thought), anxiety or confusion when making decisions, understanding instructions, or planning things, difficulty navigating familiar environments, difficulty performing tasks, forgetting material immediately after reading, losing or misplacing valuable items, experiencing increased difficulty with planning or organization, confusion, difficulty with bladder or bowel control, personality and behavioral changes, changes in sleep patterns, difficulty communicating, vulnerability to infections, and / or impulsiveness and questionable judgment. AD subjects may also experience depression, irritability, anxiety, or apathy. In some cases, the methods include detecting a control biomarker whose altered expression levels have been shown to be associated with AD, such as NFL, amyloid-β (Aβ (1-42) ), T-Tau, sAPPα, sAPPβ, etc., in a sample obtained from the patient, and using the detection of altered expression levels of the control biomarker in combination with the detection of altered expression levels of one or more inflammasome proteins to reliably diagnose AD in the patient. In some cases, the method further includes evaluating the patient's clinical characteristics / symptoms in relation to AD, and using the detection of altered expression levels of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose AD in the patient.

[0076] In one embodiment, provided herein is a method for diagnosing or assessing a patient for age-related inflammation or inflammatory senescence. The method includes measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with inflammatory senescence, where the protein signature includes an elevated level of at least one inflammasome protein. If the patient exhibits the presence of the protein signature, selecting the patient as having inflammatory senescence. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, where the protein signature further includes an elevated expression level of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with inflammatory senescence. The patient may exhibit clinical symptoms consistent with inflammatory senescence.

[0077] In one embodiment, provided herein are methods for diagnosing or evaluating patients with age-related macular degeneration (AMD). In some embodiments, AMD patients have a damaged macula. The macula is part of the retina. In some embodiments, AMD patients experience loss of central vision and fine detail, but retain peripheral vision. There are two types of AMD: dry AMD and wet AMD. Dry AMD is characterized by the presence of insoluble extracellular aggregates, or drusen, in the macula. Drusen affect the retinal pigment epithelium (RPE) and photoreceptor layer, and as they progress, can eventually lead to RPE atrophy and severe vision loss. A rare form of AMD is wet AMD, which is characterized by choroidal neovascularization (CNV), which, if left untreated, can rapidly progress to blindness. In some embodiments, the methods herein are used to diagnose patients with wet AMD. In some embodiments, the methods herein are used to diagnose patients with dry AMD. In some embodiments, the methods described herein are used to diagnose patients with wet AMD and dry AMD. In some embodiments, the methods described herein are used to distinguish between patients with wet AMD and dry AMD. Such a distinction is important because treatments effective for wet AMD, such as anti-vascular endothelial growth factor (anti-VEGF) therapy, are ineffective for dry AMD. The method includes measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with AMD, where the protein signature includes an elevated level of at least one inflammasome protein. If the patient exhibits the presence of the protein signature, the patient is selected as having AMD. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, where the protein signature further includes an elevated expression level of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with AMD.Patients may exhibit clinical symptoms consistent with AMD. Patients may exhibit abnormal changes in the macular region, such as the presence of drusen or fluid in the macula, pigment epithelial detachment, as revealed by a comprehensive eye examination including optical coherence tomography (OCT) of the macula. Through the use of the methods and compositions provided herein, patients can be diagnosed with any type of AMD known in the art, such as wet AMD or dry AMD. Examples of symptoms often exhibited by subjects with AMD may include blurred or "fuzzy" vision, straight lines such as lines on a page appearing wavy or distorted, blurred areas on printed pages, difficulty reading or seeing details at low light levels, extra perception of bright, dark, or blurred areas, or whiteouts appearing in the center of vision, or changes in color perception. In some cases, the method further comprises measuring the expression level of a control biomarker in a sample obtained from the patient, whose altered expression level has been shown to be associated with AMD, and using the detection of the altered expression level of the control biomarker in combination with the detection of the altered expression level of one or more inflammasome proteins to reliably diagnose AMD in the patient. In some cases, the method further comprises evaluating the patient's clinical characteristics / symptoms in relation to AMD, and using the detection of the altered expression level of one or more inflammasome proteins in a sample obtained from the patient to reliably diagnose AMD in the patient.

[0078] In one embodiment, provided herein is a method for diagnosing or evaluating a patient with non-alcoholic fatty liver disease (NAFLD). The method includes measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient and determining the presence or absence of a protein signature associated with NAFLD, where the protein signature includes an elevated level of at least one inflammasome protein. If the patient exhibits the presence of the protein signature, selecting the patient as having NAFLD. In some cases, the method further includes measuring the expression level of at least one control biomarker protein, where the protein signature further includes an elevated expression level of at least one control biomarker protein. The at least one control biomarker protein is any protein whose expression level has previously been shown to be associated with NAFLD. The patient may exhibit clinical symptoms consistent with NAFLD. Using the methods and compositions provided herein, patients can be diagnosed with any type of NAFLD known in the art, such as fatty liver or non-alcoholic steatohepatitis (NASH).

[0079] In one embodiment, provided herein is a method for diagnosing or evaluating a patient suspected of having NASH by measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient with or suspected of having NASH in combination with determining the expression level of a biomarker whose altered expression level is known or suspected to be associated with NASH. In one embodiment, provided herein is a method for diagnosing or evaluating a patient suspected of having NASH by measuring the expression level of at least one inflammasome protein in a biological sample obtained from the patient in combination with one or more additional diagnostic assessments. Detection of an altered expression level of at least an inflammasome protein in a biological sample obtained from the patient can be used to confirm a NASH diagnosis determined using one or more additional diagnostic assessments. Detection of an altered expression level of at least an inflammasome protein in a biological sample obtained from the patient can be used to increase the certainty or strengthen a NASH diagnosis determined using one or more additional diagnostic assessments. The one or more additional diagnostic evaluations can be selected from the group consisting of evaluation of clinical parameters, examination of morphological indicators in liver biopsies, determination of inflammatory cytokine and chemokine levels, evaluation of adipokines, evaluation of liver fibrosis biomarkers, evaluation of oxidative stress, evaluation of mitochondrial dysfunction, and evaluation of apoptosis biomarkers. Examples of inflammatory cytokines and chemokines used as biomarkers for NASH include TNF-alpha, IL-6, chemokine CC-chemokine ligand-2 (chemoattractant protein-1), and high-sensitivity C-reactive protein (hs-CRP). Examples of apoptosis biomarkers include CK-18, sFas, and hyaluronic acid. Examples of adipokines include leptin, adiponectin, resistin, retinol-binding protein 4, and ghrelin. Examples of oxidative stress biomarkers include 13-hydroxyoctadecadienoic acid, SOD2, and cytochrome p450 2E1 (CYP2E1).Examples of mitochondrial dysfunction biomarkers include CK-7 and CK-18. Liver fibrosis markers may include galectin-3 (Gal-3), hyaluronic acid, procollagen III N-terminal peptide, TGF-β, and TIMP1. Examples of clinical parameters may be selected from body mass index, waist circumference, blood or serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, low-density lipoprotein, triglycerides, glucose, insulin resistance, and metabolic and proteomic profile analysis.

[0080] In one aspect of the invention, a method for diagnosing or evaluating a patient suspected of having inflammation or an inflammation-related disease, disorder, or condition (e.g., NASH, MCI, TBI, AD, AMD, inflammatory aging, stroke, or MS) comprises determining the presence or absence of a protein signature associated with inflammation or an inflammation-related disease, disorder, or condition based on the measured level, abundance, or concentration of one or more inflammasome proteins, alone or in combination with one or more control biomarker proteins, in a biological sample obtained from the patient. In certain embodiments, the protein signature comprises elevated levels of at least one inflammasome protein and / or elevated levels of at least one control biomarker protein. The level of at least one inflammasome protein and / or control biomarker protein in the protein signature can be elevated compared to the level or percentage of at least one inflammasome protein and / or at least one control biomarker protein in a biological sample obtained from a control subject, or compared to a predetermined reference value or range of reference values ​​as further described herein. The control subject can be a healthy individual. A healthy individual may be an individual who does not exhibit symptoms associated with inflammation or an inflammation-related disease, disorder, or condition (e.g., NASH, MCI, AMD, TBI, AD, inflammatory aging, stroke, or MS). The protein signature may, in certain embodiments, comprise elevated levels of at least one inflammasome protein. The at least one control biomarker protein is any protein whose expression levels have previously been shown to be associated with inflammation or an inflammation-related disease, disorder, or condition. In some embodiments, the control biomarker proteins include Gal-3, CRP (hs-CRP), NFL, amyloid-β (Aβ), or inflammatory cytokines (e.g., IL-1, IL-2, IL-3, IL-6, IL-1, IL-2, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-1, IL-1, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-1, IL-2, IL-1, IL-2, IL-3, IL-4, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-1, IL-1, IL-2, IL-1, IL-2, IL-3, IL-4 ...1, IL-2, IL-1, IL-2, IL-3, IL-1, IL-1, IL-2, IL-1, IL-2, IL-1, IL-1, IL-2, IL-1, IL-2, IL-1, IL-1, IL (1-42) ), T-Tau, sAPPα or sAPPβ. Patients exhibiting the protein signature may be selected or identified as having inflammation or an inflammation-related disease, disorder or condition (e.g., NASH, MCI, AD, TBI, AMD, inflammatory aging, stroke or MS).

[0081] In some embodiments, the measured level, concentration, or abundance of one or more inflammasome proteins, alone or in combination with one or more control biomarker proteins in the biological sample, is used to generate a protein profile or signature indicative of the severity of inflammation or an inflammation-related disease, disorder, or condition (e.g., NASH, MCI, TBI, AD, AMD, inflammatory aging, stroke, or MS). In some cases, the protein profile may include the level, abundance, percentage, or concentration of one or more inflammasome proteins measured in a patient's biological sample relative to the level, abundance, percentage, or concentration of one or more inflammasome proteins in a biological sample obtained from a control subject, or relative to a predetermined value or range of reference values ​​described herein. In some cases, the protein profile may include the level, abundance, percentage, or concentration of one or more inflammasome proteins and one or more control biomarker proteins measured in a biological sample from a patient relative to the level, abundance, percentage, or concentration of one or more inflammasome proteins and one or more control biomarker proteins in a biological sample obtained from a control subject, or relative to a predetermined value or range of reference values ​​described herein. The control subject may be a healthy individual. A healthy individual may be an individual who does not exhibit symptoms associated with inflammation or an inflammation-related disease, disorder, or condition (e.g., NASH, MCI, TBI, AD, AMD, inflammatory aging, stroke, or MS). The one or more control biomarker proteins may be any protein whose expression level has previously been shown to be associated with inflammation or an inflammation-related disease, disorder, or condition. In some embodiments, the control biomarker protein is Gal-3, CRP (hs-CRP), NFL, amyloid-β (Aβ), or amyloid-β (Aβ). (1-42) ), T-Tau, sAPPα or sAPPβ.

[0082] The level, percentage or concentration of at least one inflammasome protein and / or control biomarker protein can be assessed at a single time point and compared to a predetermined reference value or range of reference values, or can be assessed at multiple time points and compared to a predetermined reference value or pre-assessed value.

[0083] As used herein, a "predetermined reference value" or a reference value range can refer to a predetermined value or a range of reference values ​​for the level or concentration of an inflammasome protein and / or a control biomarker protein determined from a known sample. For example, the predetermined reference value or reference value range can reflect the level or concentration of an inflammasome protein and / or a control biomarker protein in a biological sample obtained from a control subject (i.e., a healthy subject). In some embodiments, the control subject can be age-matched to the patient being evaluated. The biological samples obtained from the patient and the control subject can both be the same type of sample (e.g., serum or serum-derived extracellular vesicles (EVs)). Thus, in certain embodiments, the measured level, percentage, or concentration of at least one inflammasome protein and / or control biomarker protein is compared or determined to the level, percentage, or concentration of the at least one inflammasome protein and / or control biomarker protein in a control sample (i.e., obtained from a healthy subject). A control or healthy subject can be a subject who does not exhibit symptoms associated with a disease, disorder, or condition associated with inflammation or inflammatory brain injury (e.g., NASH, MCI, TBI, AD, stroke, inflammatory aging, AMD, or MS). The control biomarker protein can be any protein whose expression levels have previously been shown to be associated with brain injury. In some embodiments, the control biomarker protein is GAL-3, CRP (hs-CRP), NFL, amyloid-β (Aβ), or amyloid-β (Aβ). (1-42) ), T-Tau, sAPPα or sAPPβ.

[0084] In other embodiments, the predetermined reference value or range of reference values ​​can reflect the level or concentration of inflammasome proteins and / or control biomarker proteins in samples obtained from patients with a known severity of inflammation or inflammation-related disease, disorder, or condition (e.g., NASH, MCI, TBI, AD, AMD, inflammatory aging, stroke, or MS) as assessed by clinical scale or postmortem analysis. The predetermined reference value can also be a known amount or concentration of inflammasome proteins and / or control biomarker proteins. Such known amount or concentration of inflammasome and / or control biomarker proteins can be correlated to the mean level or concentration of inflammasome and / or control biomarker proteins from a population of control subjects or patients with a known level of inflammation or said inflammation-related disease, disorder, or condition. In another embodiment, the predetermined reference value can be a range of values ​​and can represent, for example, a mean ± standard deviation or confidence interval. A range of reference values ​​may also refer to individual reference values ​​for a particular inflammasome and / or control biomarker protein across various levels of inflammation or the severity of inflammation-related diseases, disorders, or conditions (e.g., NASH, AD, MCI, TBI, AMD, inflammatory senescence, stroke, or MS). The control biomarker protein may be any protein whose expression levels have previously been shown to be associated with brain injury. In some embodiments, the control biomarker protein is selected from Gal-3, CRP (hs-CRP), NFL, amyloid-β (Aβ), and / or α-amyloid-β (αβ). (1-42) ), T-Tau, sAPPα, or sAPPβ. In certain embodiments, the level of one or more inflammasome proteins (e.g., ASC, caspase-1, or IL-18) and / or control biomarker proteins (e.g., Gal-3, CRP (hs-CRP), NFL, sAPPα, sAPPβ, T-Tau, or AB) is compared to a predetermined reference value or range of reference values. (1-42) Increased levels of ) are indicative of more severe forms of inflammation or inflammation-related diseases, disorders or conditions (e.g., brain injury).

[0085] The at least one inflammasome protein detected or measured by any of the methods provided herein can be one or more inflammasome proteins. In one embodiment, the at least one inflammasome protein is a plurality of inflammasome proteins. The plurality can be at least or at most 2, 3, 4, or 5 inflammasome proteins. The at least one inflammasome protein or the plurality of inflammasome proteins can be components of any inflammasome known in the art, such as, for example, NAPL1 / NLRP1, NALP2 / NLRP2, NALP3 / NLRP3, IPAF / NLRC4, or AIM2 inflammasome. In some cases, the at least one inflammasome protein or the plurality of inflammasome proteins can be components of a canonical inflammasome or a non-canonical inflammasome. In one embodiment, the at least one inflammasome protein is apoptosis-associated speck-like protein (ASC), which contains a caspase recruitment domain, caspase-1, interleukin-18 (IL-18), or interleukin-1 beta (IL-1 beta). In one embodiment, the at least one inflammasome protein is apoptosis-associated speck-like protein (ASC), which contains a caspase recruitment domain. In one embodiment, the at least one inflammasome protein is caspase-1. In one embodiment, the at least one inflammasome protein is IL-18. The at least one control biomarker protein detected or measured in any of the methods provided herein can be any protein whose expression levels have previously been shown to be associated with brain injury. In one embodiment, the at least one control biomarker protein is Gal-3. In one embodiment, the at least one control biomarker protein is CRP (hs-CRP). In one embodiment, the at least one control biomarker protein is NFL. In some embodiments, the at least one control biomarker protein is sAPPα.In some embodiments, the at least one control biomarker protein is sAPPβ. In some embodiments, the at least one control biomarker protein is Aβ. (1-42) In some embodiments, the at least one control biomarker protein is Aβ (1-40) In some embodiments, the at least one control biomarker protein is APP. In some embodiments, the at least one control biomarker protein is T-Tau.

[0086] The inflammasome proteins and / or control biomarker proteins (e.g., Gal-3, CRP (hs-CRP), NFL, sAPPα, sAPPβ, AB) of the methods provided herein (1-42) Biomarker proteins (e.g., control biomarker proteins) can be measured in biological samples by a variety of methods known to those of skill in the art. For example, proteins can be measured by methods including, but not limited to, liquid chromatography, gas chromatography, mass spectrometry, immunoassays, radioimmunoassays, immunofluorescence assays, FRET-based assays, immunoblots, ELISA, liquid chromatography followed by mass spectrometry (e.g., MALDI MS). Those of skill in the art will be able to identify other methods suitable for measuring and quantifying any particular biomarker protein of the invention.

[0087] In one embodiment, at least one inflammasome protein or multiple inflammasome proteins detected or measured in any of the methods provided herein can be detected or measured using an immunoassay. In one embodiment, at least one control biomarker protein detected or measured in any of the methods provided herein can be detected or measured using an immunoassay. The immunoassay can be any immunoassay known in the art. For example, the immunoassay can be an immunoblot, an enzyme-linked immunosorbent assay (ELISA), or a microfluidic immunoassay. An example of a microfluidic immunoassay for use in the methods provided herein is the Simple Plex™ Platform (Protein Simple, San Jose, California).

[0088] Any immunoassay for use in the methods provided herein can utilize antibodies directed against inflammasome proteins. Inflammasome components can be any canonical or non-canonical inflammasome component known in the art, such as, for example, NAPL1, NALP2, NALP3, NLRC4, or AIM2 inflammasome. In one embodiment, the inflammasome protein is apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain, caspase-1, interleukin-18 (IL-18), or interleukin-1 beta (IL-1 beta). In one embodiment, the inflammasome protein is apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain. In one embodiment, the inflammasome protein is caspase-1. In one embodiment, the inflammasome protein is IL-18. In one embodiment, the inflammasome protein is IL-1 beta.

[0089] Any immunoassay for use in the methods provided herein can utilize an antibody directed against a control biomarker protein, such as Gal-3, CRP (hs-CRP), NFL, sAPPα, sAPPβ, or Aβ. (1-42) It could be.

[0090] Any suitable antibody that specifically binds to ASC can be used, for example, custom or commercially available ASC antibodies can be used in the methods provided herein. The anti-ASC antibody can be, for example, an antibody that specifically binds to a domain or portion of a mammalian ASC protein, such as a human or rat ASC protein. Examples of anti-ASC antibodies for use in the methods herein can be those found in U.S. Patent No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. Examples of commercially available anti-ASC antibodies for use in the methods provided herein include, but are not limited to, 04-147 anti-ASC, clone 2EI-7 mouse monoclonal antibody (Millipore Sigma), AB3607-anti-ASC antibody (Millipore Sigma), orb194021 anti-ASC (Biorbyt), LS-C331318-50 anti-ASC (LifeSpan Biosciences), AF3805 anti-ASC (R&D Systems), NBP1-78977 anti-ASC (Novus Biologicals), 600-401-Y67 anti-ASC (Rockland Immunochemicals), D086-3 anti-ASC (MBL International), AL177 anti-ASC (Adipogen), monoclonal anti-ASC (clone o93E9) antibody, anti-ASC antibody (F-9) (Santa Cruz Biosciences), and the like. Examples of antibodies include anti-ASC antibody (B-3) (Santa Cruz Biotechnology), anti-ASC antibody (B-3) (Santa Cruz Biotechnology), ASC polyclonal antibody-ADI-905-173 (Enzo Life Sciences), and A161 anti-human ASC (Leinco Technologies). Human ASC proteins can have accession numbers NP_037390.2 (Q9ULZ3-1), NP_660183 (Q9ULZ3-2), or Q9ULZ3-3. Rat ASC proteins can have accession number NP_758825 (BAC43754). Mouse ASC proteins can have accession number NP_075747.3.In one embodiment, the antibody binds to the PYRIN-PAAD-DAPIN domain (PYD) of a mammalian ASC protein (e.g., human or rat ASC), or a portion or fragment thereof. In this embodiment, the antibody described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the PYD domain of human or rat ASC, or a fragment thereof. In one embodiment, the antibody binds to the C-terminal caspase recruitment domain (CARD) of a mammalian ASC protein (e.g., human or rat ASC), or a portion or fragment thereof. In this embodiment, the antibody described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the CARD domain of human or rat ASC, or a fragment thereof. In another embodiment, the antibody specifically binds to a region of rat ASC, e.g., the amino acid sequence ALRQTQPYLVTDLEQS (SEQ ID NO: 1) (i.e., residues 178-193 of rat ASC, Accession No. BAC43754). In this embodiment, the antibody described herein specifically binds to an amino acid sequence that has at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the amino acid sequence ALRQTQPYLVTDLEQS (SEQ ID NO: 1) of rat ASC. In another embodiment, the antibody specifically binds to a region of human ASC, e.g., the amino acid sequence RESQSYLVEDLERS (SEQ ID NO: 2). In this embodiment, the antibody described herein specifically binds to an amino acid sequence that has at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the amino acid sequence RESQSYLVEDLERS (SEQ ID NO: 2) of human ASC.

[0091] Any suitable anti-NLRP1 antibody (e.g., commercially available or custom) can be used in the methods provided herein. Examples of anti-NLRP1 antibodies for use in the methods herein can be those found in U.S. Patent No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. Examples of commercially available anti-NLRP1 antibodies for use in the methods provided herein include, but are not limited to, human NLRP1 polyclonal antibody AF6788 (manufactured by R&D Systems), EMD Millipore rabbit polyclonal anti-NLRP1 ABF22, Novus Biologicals rabbit polyclonal anti-NLRP1 NB100-56148, Sigma-Aldrich mouse polyclonal anti-NLRP1 SAB1407151, Abcam rabbit polyclonal anti-NLRP1 ab3683, Biorbyt rabbit polyclonal anti-NLRP1 orb325922, myBioSource rabbit polyclonal anti-NLRP1 MBS7001225, R&D systems sheep polyclonal AF6788, Aviva Systems mouse monoclonal anti-NLRP1 oaed00344, Aviva Systems heron polyclonal anti-NLRP1 ARO54478_P050, and Origene rabbit polyclonal anti-NLRP1 APO7775PU-N, Antibodies online rabbit polyclonal anti-NLRP1 ABIN768983, Prosci rabbit polyclonal anti-NLRP1 3037, Proteintech rabbit polyclonal anti-NLRP1 12256-1-AP, Enzo mouse monoclonal anti-NLRP1 ALX-804-803-C100, Invitrogen mouse monoclonal anti-NLRP1 MA1-25842, GeneTex mouse monoclonal anti-NLRP1 GTX16091, Rockland rabbit polyclonal anti-NLRP1 200-401-CX5, or Cell Signaling Technology rabbit polyclonal anti-NLRP1 4990. The human NLRP1 protein can be accession number AAH51787, NP_001028225, NP_055737, NP_127497, NP_127499 or NP_127500.In one embodiment, the antibody binds to the Pyrin, NACHT, LRR1-6, FIIND, or CARD domain of a mammalian NLRP1 protein (e.g., human NLRP1), or a portion or fragment thereof. In this embodiment, the antibody described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65%, 70%, 75%, 80%, 85%) sequence identity to a specific domain of human NLRP1 (e.g., Pyrin, NACHT, LRR1-6, FIIND, or CARD) or a fragment thereof. In one embodiment, a chicken anti-NLRP1 polyclonal antibody custom-designed and manufactured by Ayes Laboratories can be used. This antibody may be directed against the following amino acid sequence of human NLRP1: CEYYTEIREREREKSEKGR (SEQ ID NO: 3). In one embodiment, the antibody specifically binds to an amino acid sequence having at least 85% sequence identity to the amino acid sequence SEQ ID NO: 3 or MEE SQS KEE SNT EG-cys (SEQ ID NO: 4).

[0092] Any suitable antibody that specifically binds to caspase-1, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-caspase-1 antibodies for use in the methods provided herein include R&D Systems: Cat# MAB6215 or Cat# AF6215, Cell Signaling: Cat# 3866, #225, or #4199, Novus Biologicals: Cat# NB100-56565, #NBP1-45433, #NB100-56564, #MAB6215, #AF6215, #NBP2-67487, #NBP2-15713, #NBP2-15712, #NBP1-87680, #NB120-1872, #NBP1-76605, or #H00000834-M01.

[0093] Any suitable antibody that specifically binds to caspase-8, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-caspase-8 antibodies for use in the methods provided herein include Abcam: Cat# ab25901, ab227430, ab108333, ab220171, ab4052, ab231948, ab32397, ab61755, ab138485, ab 208774, ab32125, ab231475, ab247233, ab2553, ab232046, ab194145, or ab119809; Novus: Cat# ab25901, ab227430, ab108333, ab220171, ab4052, ab231948, ab32397, ab61755, ab138485, ab 208774, ab32125, ab231475, ab247233, ab2553, ab232046, ab194145, or ab119809; Examples of such products include: Santa Cruz Biotechnology Cat. #8CSP03; and Cell Signaling Technology Cat. #4790 or #9746.

[0094] Any suitable antibody that specifically binds to caspase-11, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-caspase-11 antibodies for use in the methods provided herein include Abcam: Cat# ab180673, ab240991, ab22684, or ab69540, Novus Biological Cat# NB120-10454, Cell Signaling Technology Cat# 14340, or ThermoFisher Cat# 14-9935-82.

[0095] Any suitable antibody that specifically binds to IL-18, including custom-made and commercially available antibodies, can be used in the methods provided herein. Examples of commercially available anti-IL-18 antibodies for use in the methods provided herein include R&D Systems: Cat#D044-3, Cat#D045-3, #MAB646, #AF2548, #D043-3, #MAB2548, MAB9124, #MAB91241, #MAB91243, MAB91244, or #MAB91242; Novus Biologicals: Cat#AF2548, #D043-3, #MAB2548, #MAB9124, #MAB91243, #MAB91244, #MAB91241, #D045-3, #MAB91242, or #D044-3.

[0096] Any suitable antibody that specifically binds to IL-1 beta, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-IL-18 antibodies for use in the methods provided herein include R&D Systems: Cat#MAB601, Cat#MAB201, #MAB6964, #MAB601R, #MAB8406, or #MAB6215; Cell Signaling: Cat#31202, #63124, #12426, or #12507; Novus Biologicals: Cat# AF-201-NA, #NB600-633, #MAB201, #MAB601, #NBP1-19775, #NBP2-27345, #AB-201-NA, #NBP2-27342, #NBP2-67865, #NBP2-27343, #NBP2-27340, #NBP2-27340, #NB120-8319, #23600002, #MAB8406, #NB100-73053, #NB120-10749 or #MAB601R.

[0097] Any suitable antibody that specifically binds to NFL, including custom-made and commercially available antibodies, can be used in the methods provided herein. Examples of commercially available anti-NFL antibodies for use in the methods provided herein include Boster Bio: Cat#MA1070; BioLegend: Cat#837801; R&D Systems: Cat#MAB2216, #MAB22162, and Novus Biologicals: #NB300-131 or #NBP2-31201. Other examples of anti-NFL antibodies for use in the methods provided herein include anti-NFL antibodies prepared by Uman Diagnostics.

[0098] Any suitable antibody that specifically binds to APP, including custom-made or commercially available antibodies, can be used in the methods provided herein. Examples of commercially available anti-APP antibodies for use in the methods provided herein include United States Biological: Cat#303112; St. John's Laboratory: Cat#STJ113456; Biobyt: Cat#orb223652, Cat#orb223651, United States Biological: Cat#253944 (Cat#253943).

[0099] Any suitable antibody that specifically binds to Gal-3, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-Gal-3 antibodies for use in the methods provided herein include Abcam Cat# ab209344, ab76466, ab76245, ab2785, and ab31707; Santa Cruz Biotechnology: Cat# sc-23938; Novus Biological: Cat# AF1197, Cat# AF1154, Cat# NB300-538, Cat# NBP1-92690, Cat# MAB1197, Cat# NBP2-16589, and Cat# MAB11541.

[0100] Any suitable antibody that specifically binds to CRP, whether custom or commercially available, can be used in the methods provided herein. Examples of commercially available anti-CRP antibodies for use in the methods provided herein include Abcam Cat# ab32412, ab256492, ab256525, ab207756, and ab51016, HyTest Ltd cat# 4C28-C6, Genescript cat# hsCRP(11C2).

[0101] Methods for determining the specificity and affinity of monoclonal antibodies by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993); and Muller, Meth. Enzymol. 92:589-601, 1983 (these references are incorporated herein by reference in their entirety).

[0102] Anti-inflammasome (e.g., anti-ASC and anti-NLRP1) and / or anti-control biomarker protein antibodies of the present invention can be routinely produced according to methods such as, but not limited to, inoculation of appropriate animals with polypeptides or antigenic fragments, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and / or recombinant cells expressing nucleic acids encoding such anti-ASC, anti-NFL, anti-sAPPα / β, and anti-NLRP1 antibodies. Immunization of animals with purified recombinant ASC or a peptide fragment thereof, such as residues 178-193 (SEQ ID NO: 1) of rat ASC (e.g., accession number BAC43754) or SEQ ID NO: 2 of human ASC, is an example of a method for preparing anti-ASC antibodies. Similarly, immunization of animals with purified recombinant NLRP1 or a peptide fragment thereof, such as residues MEE SQS KEE SNT EG-CYS (SEQ ID NO: 4) of rat NALP1 or SEQ ID NO: 3 of human NALP1, is an example of a method for preparing anti-NLRP1 antibodies.

[0103] Monoclonal antibodies that specifically bind to ASC, NLRP1, sAPPα, sAPPβ, or NFL can be obtained by methods known to those skilled in the art (see, for example, Kohler and Milstein, Nature 256:495-497, 1975; U.S. Patent No. 4,376,110; Ausubel et al., eds., Current Protocols in Molecular Biology, Greene Publishing Assoc. and Wiley Interscience, NY, (1987, 1992); Harlow and Lane ANTIBODIES: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1988; Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc. and Wiley Interscience, NY, (1992, 1993) (the contents of which are incorporated herein by reference in their entirety). Such antibodies may be of any immunoglobulin class, including IgG, IgM, IgE, IgA, GILD, and any subclass thereof. Hybridomas producing monoclonal antibodies of the invention may be cultivated in vitro, in situ, or in vivo.

[0104] In some cases, the methods provided herein may be capable of diagnosing or detecting inflammation or a disease, disorder, or condition resulting from or associated with inflammation (e.g., NASH, AD, MCI, AMD, inflammatory aging, stroke, MS, or TBI) with a predicted success rate of at least about 70%, at least about 71%, at least about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, up to 100%.

[0105] In some cases, the methods provided herein may be capable of diagnosing or detecting inflammation or a disease, disorder, or condition caused by or associated with inflammation (e.g., NASH, MCI, stroke, MS, AMD, inflammatory aging, AD, or TBI) with a sensitivity and / or specificity of at least about 70%, at least about 71%, at least about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or up to 100%.

[0106] In one embodiment, the disease, disorder, or condition caused by or associated with inflammation is brain injury. In one embodiment, the brain injury is MS, and detection of elevated levels of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MS with at least 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the brain injury is MS, and detection of elevated levels of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MS with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. In these embodiments, the predetermined reference value may be the cutoff value shown in Table 7. In yet another embodiment, the brain injury is MS, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MS with at least 90% sensitivity and at least 80% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 7. In some cases, the range of reference values ​​may be from about 300 pg / ml to about 340 pg / ml to achieve at least 90% sensitivity and at least 80% specificity.

[0107] In one embodiment, the brain injury is a stroke, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has suffered from a stroke with a sensitivity of at least 75%, 80%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is a stroke, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MS with a specificity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 8. In another embodiment, the brain injury is a stroke, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has suffered from a stroke with at least 100% sensitivity and at least 90% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 8. In some cases, the range of reference values ​​may be from about 380 pg / ml to about 405 pg / ml to achieve at least 100% sensitivity and at least 90% specificity. The stroke may be ischemic or hemorrhagic, as provided herein.

[0108] In one embodiment, the brain injury is a stroke, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has suffered from a stroke with a sensitivity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is a stroke, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MS with a specificity of at least 75%, 80%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 9. In another embodiment, the brain injury is a stroke, and detection of elevated levels of ASC in serum-derived EVs obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has suffered from a stroke with at least 100% sensitivity and at least 90% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 9. In some cases, the range of reference values ​​may be from about 70 pg / ml to about 90 pg / ml to achieve at least 100% sensitivity and at least 90% specificity. The stroke may be ischemic or hemorrhagic, as provided herein.

[0109] In one embodiment, the brain injury is TBI, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has TBI with at least 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the brain injury is TBI, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has TBI with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cutoff value shown in Table 16. In yet another embodiment, the brain injury is TBI, and detection of an elevated level of ASC in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has TBI with at least 90% sensitivity and at least 80% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 16. In some cases, the range of reference values ​​may be from about 275 pg / ml to about 450 pg / ml to achieve a sensitivity of at least 80% and a specificity of at least 70%.

[0110] In one embodiment, the brain injury is TBI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has TBI with at least 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the brain injury is TBI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has TBI with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cutoff value shown in Table 15. In yet another embodiment, the brain injury is TBI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has TBI with at least 90% sensitivity and at least 80% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 15. In some cases, the range of reference values ​​may be from about 2.812 pg / ml to about 1.853 pg / ml to achieve a sensitivity of at least 70% and a specificity of at least 75%.

[0111] In one embodiment, the brain injury is MCI, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a sensitivity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a specificity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Tables 22A and 23. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 90% sensitivity and at least 70% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Tables 22A and 23. In some cases, the range of reference values ​​may be from about 257 pg / ml to about 342 pg / ml to achieve at least 90% sensitivity and at least 70% specificity. In some cases, the cutoff value is greater than 560 pg / ml.

[0112] In one embodiment, the brain injury is MCI, and detection of elevated levels of IL-18 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a sensitivity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of IL-18 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a specificity of at least 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​set forth in Tables 22A and 25. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of IL-18 in serum obtained from the patient relative to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 70% sensitivity and at least 55% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Tables 22A and 25. In some cases, the range of reference values ​​is from about 200 pg / ml to about 214 pg / ml to achieve at least 70% sensitivity and at least 50% specificity.

[0113] In one embodiment, the brain injury is MCI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a sensitivity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22A. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 65% sensitivity and at least 40% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22A. In some cases, a reference value of about 1.75 pg / ml is used to achieve at least 65% sensitivity and at least 40% specificity.

[0114] In one embodiment, the brain injury is MCI, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a sensitivity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22A. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 65% sensitivity and at least 55% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22A. In some cases, a reference value of about 0.684 pg / ml is used to achieve at least 65% sensitivity and at least 50% specificity.

[0115] In one embodiment, the brain injury is MCI, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MCI with a sensitivity of at least 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MCI with a specificity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22A. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 95% sensitivity and at least 70% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22A. In some cases, a reference value of about 1.39 ng / mL is used to achieve at least 95% sensitivity and at least 70% specificity.

[0116] In one embodiment, the brain injury is MCI, and detection of elevated levels of sAPPβ in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MCI with a sensitivity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of sAPPβ in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has MCI with a specificity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22A. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of sAPPβ in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines the patient to have MCI with at least 90% sensitivity and at least 75% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22A. In some cases, a reference value of about 0.26 ng / mL is used to achieve at least 90% sensitivity and at least 75% specificity.

[0117] In another embodiment, the brain injury is MCI, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a sensitivity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is MCI, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with a specificity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22A. In yet another embodiment, the brain injury is MCI, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has MCI with at least 70% sensitivity and at least 75% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22A. In some cases, a reference value of about 24 pg / mL is used to achieve at least 70% sensitivity and at least 75% specificity.

[0118] In one embodiment, the brain injury is AD, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is AD, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22B. In yet another embodiment, the brain damage is AD, and detection of elevated levels of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with at least 80% sensitivity and at least 70% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22B. In some cases, a reference value of about 259 pg / mL can achieve at least 80% sensitivity and at least 70% specificity. In some cases, the cutoff value for diagnosing AD versus MCI is greater than 264.9 pg / mL and less than 560 pg / mL.

[0119] In one embodiment, the brain injury is AD, and detection of elevated levels of IL-18 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a sensitivity of at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is AD, and detection of elevated levels of IL-18 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of elevated levels of IL-18 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with at least 70% sensitivity and at least 40% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22B. In some cases, a reference value of about 196 pg / ml is used to achieve at least 70% sensitivity and at least 40% specificity.

[0120] In one embodiment, the brain injury is AD, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a sensitivity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is AD, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of elevated levels of caspase-1 in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with at least 65% sensitivity and at least 55% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22B. In some cases, a reference value of about 1.78 pg / ml is used to achieve at least 65% sensitivity and at least 55% specificity.

[0121] In one embodiment, the brain injury is AD, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a sensitivity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is AD, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of elevated levels of IL-1β in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with at least 65% sensitivity and at least 55% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22B. In some cases, a reference value of about 0.693 pg / ml is used to achieve at least 75% sensitivity and at least 40% specificity.

[0122] In one embodiment, the brain injury is AD, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. In another embodiment, the brain injury is AD, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cut-off value shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of elevated levels of sAPPα in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 90% sensitivity and at least 90% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 22B. In some cases, a reference value of about 2.5 ng / mL is used to achieve a sensitivity of at least 90% and a specificity of at least 90%.

[0123] In another embodiment, the brain injury is AD, and detection of an elevated level of sAPPβ in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. In another embodiment, the brain injury is AD, and detection of an elevated level of sAPPβ in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cut-off value shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of an elevated level of sAPPβ in serum obtained from the patient compared to a control provided herein (e.g., a predetermined reference value or range of reference values) determines that the patient has AD with at least 80% sensitivity and at least 80% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 22B. In some cases, a reference value of about 0.29 ng / mL is used to achieve a sensitivity of at least 80% and a specificity of at least 80%.

[0124] In one embodiment, the brain injury is AD, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the brain injury is AD, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with a specificity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​in these embodiments may be the cutoff values ​​shown in Table 22B. In yet another embodiment, the brain injury is AD, and detection of elevated levels of NFL in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) provided herein determines that the patient has AD with at least 60% sensitivity and at least 55% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22B. In some cases, a reference value of about 21.4 pg / mL is used to achieve at least 60% sensitivity and at least 55% specificity.

[0125] In one embodiment, the brain injuries MCI and AD can be distinguished by comparing the level of ASC in serum obtained from MCI patients versus AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain injury (e.g., AD or MCI) in a patient with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cutoff value shown in Table 22C. In yet another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient based on the level of ASC with at least 70% sensitivity and at least 60% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22C. In some cases, a sensitivity of at least 70% and a specificity of at least 60% can be achieved with a reference value of about 560 pg / mL.

[0126] In one embodiment, the brain injuries MCI and AD can be distinguished by comparing the level of caspase-1 in serum obtained from MCI patients versus AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain injury (e.g., AD or MCI) in a patient with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cutoff value shown in Table 22C. In yet another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient based on the level of caspase-1 with at least 70% sensitivity and at least 60% specificity. The predetermined reference value in this embodiment may be the cutoff value shown in Table 22C. In some cases, a sensitivity of at least 70% and a specificity of at least 60% can be achieved with a reference value of about 1.94 pg / mL.

[0127] In one embodiment, the brain injuries MCI and AD can be distinguished by comparing the levels of IL-18 in serum obtained from MCI patients versus AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain injury (e.g., AD or MCI) in a patient with a sensitivity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient with a specificity of at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference value in these embodiments may be the cutoff value shown in Table 22C. In yet another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient based on the level of IL-18 with a sensitivity of at least 70% and a specificity of at least 45%. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 22C. In some cases, a reference value of about 290 pg / mL may achieve a sensitivity of at least 70% and a specificity of at least 45%.

[0128] In one embodiment, the brain injuries MCI and AD can be distinguished by comparing the level of IL-1β in serum obtained from MCI patients versus AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain injury (e.g., AD or MCI) in a patient with at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value in these embodiments may be the cutoff value shown in Table 22C. In yet another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient based on the level of IL-1β with at least 75% sensitivity and at least 40% specificity. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 22C. In some cases, a reference value of about 0.46 pg / mL may achieve a sensitivity of at least 75% and a specificity of at least 40%.

[0129] In one embodiment, the brain injuries MCI and AD can be distinguished by comparing the level of sAPPα in serum obtained from MCI patients versus AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain injury (e.g., AD or MCI) in a patient with a sensitivity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference value in these embodiments may be the cutoff value shown in Table 22C. In yet another embodiment, the method determines brain injury (e.g., AD or MCI) in a patient based on the level of sAPPα with a sensitivity of at least 70% and a specificity of at least 55%. The predetermined reference values ​​in this embodiment may be the cutoff values ​​shown in Table 22C. In some cases, a sensitivity of at least 70% and a specificity of at least 55% may be achieved with a reference value of about 8.84 ng / mL.

[0130] In one embodiment, the brain damages MCI and AD can be differentiated by comparing the level of sAPPβ in serum obtained from MCI patients with that of AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines brain damage (e.g., AD or MCI) in a patient with at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the method determines brain damage (e.g., AD or MCI) in a patient with at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference values ​​for these embodiments may be the cutoff values ​​shown in Table 22C. In yet another embodiment, the method determines brain damage (e.g., AD or MCI) in a patient based on the level of sAPPβ with at least 60% sensitivity and at least 45% specificity. The predetermined reference values ​​for this embodiment may be the cutoff values ​​shown in Table 22C. In some cases, a reference value of about 0.63 ng / ml may achieve a sensitivity of at least 60% and a specificity of at least 45%.

[0131] In one embodiment, the brain injuries MCI and AD can be differentiated by comparing the level of NFL in serum obtained from MCI patients with that of AD patients (e.g., a predetermined reference value or range of reference values). In some embodiments, the method determines the patient's brain injury (e.g., AD or MCI) with a sensitivity of at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. In another embodiment, the method determines the patient's brain injury (e.g., AD or MCI) with a specificity of at least 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100%. The predetermined reference values ​​for these embodiments can be the cutoff values ​​shown in Table 22C. In yet another embodiment, the method determines the patient's brain injury (e.g., AD or MCI) based on the level of NFL with a sensitivity of at least 70% and a specificity of at least 40%. The predetermined reference values ​​for this embodiment may be the cutoff values ​​shown in Table 22C. In some cases, a reference value of about 33.9 pg / ml may achieve a sensitivity of at least 70% and a specificity of at least 40%.

[0132] In another embodiment, the inflammation-associated disease, disorder, or condition is an age-related disease. In one embodiment, the age-related disorder is AMD, such that detecting an elevated ASC level in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the age-related disease is AMD, such that detecting an elevated ASC level in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference values ​​for these embodiments may be the cutoff values ​​shown in Table 29. In yet another embodiment, the age-related disease is AMD, such that detection of elevated ASC levels in serum obtained from the patient, compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein, determines that the patient has AMD with at least 90% sensitivity and at least 80% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 29. In some cases, a reference value of about 365.6 pg / mL may achieve at least 90% sensitivity and at least 85% specificity.

[0133] In one embodiment, the age-related disease is AMD, such that detection of elevated caspase-1 levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 60%, 65%, 70%, 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the age-related disease is AMD, such that detection of elevated caspase-1 levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 25%, 30%, 35%, 40%, 45%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value for these embodiments may be the cutoff value shown in Table 29. In yet another embodiment, the age-related disease is AMD, such that detection of elevated caspase-1 levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 75% sensitivity and at least 30% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 29. In some cases, a reference value of about 6.136 pg / mL may achieve at least 75% sensitivity and at least 30% specificity.

[0134] In one embodiment, the age-related disease is AMD, such that detecting an elevated level of IL-18 in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 70%, 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the age-related disease is AMD, such that detecting an elevated level of caspase-1 in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference values ​​for these embodiments may be the cutoff values ​​shown in Table 29. In yet another embodiment, the age-related disease is AMD, such that detection of elevated IL-18 levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 70% sensitivity and at least 50% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 29. In some cases, a reference value of about 242.4 pg / mL may achieve at least 70% sensitivity and at least 50% specificity.

[0135] In one embodiment, the age-related disease is AMD, such that detecting an elevated IL-1β level in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the age-related disease is AMD, such that detecting an elevated IL-1β level in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference values ​​for these embodiments may be the cutoff values ​​shown in Table 29. In yet another embodiment, the age-related disease is AMD, such that detection of elevated IL-1β levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 55% sensitivity and at least 50% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 29. In some cases, a reference value of 0.842 pg / ml may achieve at least 55% sensitivity and at least 50% specificity.

[0136] In another embodiment, the inflammation-associated disease, disorder, or condition is a type of non-alcoholic fatty liver disease (NAFLD). In one embodiment, the type of NAFLD is NASH, such that detecting an elevated level of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has NASH with at least 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the inflammation-associated disease is NASH, such that detecting an elevated level of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has NASH with at least 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference values ​​for these embodiments may be the cutoff values ​​shown in Table 34. In another embodiment, the inflammation-associated disease is NASH, wherein detecting an elevated level of ASC in serum obtained from the patient compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has AMD with at least 80% sensitivity and at least 60% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 34. In some cases, a reference value of about 394.9 pg / mL may achieve at least 80% sensitivity and at least 60% specificity.

[0137] In one embodiment, the disease associated with inflammation is NASH, such that detection of elevated levels of IL-18 in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has NASH with at least 60%, 65%, 70%, 75%, 80%, 90%, 95%, 99%, or 100% sensitivity. In another embodiment, the disease associated with inflammation is NASH, such that detection of elevated levels of IL-18 in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has NASH with at least 25%, 30%, 35%, 40%, 45%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% specificity. The predetermined reference value for these embodiments may be the cutoff value shown in Table 34. In yet another embodiment, the disease associated with inflammation is NASH, such that detection of elevated IL-18 levels in serum obtained from the patient as compared to a control (e.g., a predetermined reference value or range of reference values) as provided herein determines that the patient has NASH with at least 75% sensitivity and at least 60% specificity. The predetermined reference value for this embodiment may be the cutoff value shown in Table 34. In some cases, a reference value of about 269.2 pg / ml may achieve at least 75% sensitivity and at least 60% specificity. In any of the methods provided herein, the sensitivity and / or specificity of an inflammasome protein (e.g., ASC) for predicting or diagnosing an inflammation-associated disease, disorder, or condition (e.g., NASH, MCI, AD, AMD, inflammatory senescence, stroke, MS, or TBI) is determined by calculating the area under the curve (AUC) value along with a confidence interval (e.g., 95%). The area under the curve (AUC) can be determined from the receiver operating characteristic (ROC) curve along with the 95% confidence interval.

[0138] In one embodiment, the inflammation-associated disease, disorder, or condition is brain injury. In one embodiment, the brain injury is MS, such that detecting a level or concentration of at least one inflammasome protein in a biological sample obtained from a patient that is elevated by a predetermined percentage above the level of the same at least one inflammasome protein in a biological sample obtained from a control indicates that the patient has MS. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from caspase-1, IL-18, IL-1 beta, and ASC. In one embodiment, the brain damage is MS, such that detecting a level or concentration of ASC in serum obtained from the patient that is at least 50% higher than the level of ASC in a serum sample obtained from a control indicates that the patient has MS. In one embodiment, the brain damage is MS, such that detecting a level or concentration of ASC in a sample obtained from the patient that is higher than the level of ASC in a sample obtained from a control, when the patient also has an altered level or concentration of a known MS biomarker in a sample obtained from the patient, compared to the level of a known MS biomarker in a sample obtained from a control known not to be AD, indicates that the patient has MS.

[0139] In one embodiment, the brain injury is a stroke, such that detecting a level or concentration of at least one inflammasome protein in a biological sample obtained from a patient that is elevated by a predetermined percentage compared to the level of the same at least one inflammasome protein in a biological sample obtained from a control indicates that the patient has a stroke. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from caspase-1, IL-18, IL-1 beta, and ASC. In one embodiment, the brain injury is a stroke, where detecting a level or concentration of ASC in serum obtained from the patient that is at least 70% higher than the ASC level in a serum sample obtained from a control indicates that the patient has suffered a stroke. In one embodiment, the brain injury is a stroke, where detecting a level or concentration of ASC in serum-derived EVs obtained from the patient that is at least 110% higher than the ASC level in a serum-derived EV sample obtained from a control indicates that the patient has suffered a stroke. In one embodiment, the brain injury is a stroke, where detecting a level or concentration of ASC in a sample obtained from the patient that is higher than the ASC level in a sample obtained from a control indicates that the patient has suffered a stroke, when the patient also has an altered level or concentration of a known stroke biomarker in the sample obtained from the patient compared to the level of the known stroke biomarker in a sample obtained from a control known not to have suffered a stroke.

[0140] In one embodiment, the brain injury is TBI, such that detecting a level or concentration of at least one inflammasome protein in a biological sample obtained from the patient that is elevated by a predetermined percentage compared to the level of the same at least one inflammasome protein in a biological sample obtained from a control indicates that the patient has TBI. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from caspase-1, IL-18, IL-1 beta, and ASC. In one embodiment, the brain injury is a TBI such that detection of a level or concentration of AS in serum obtained from the patient that is at least 50% higher than the level of ASC in a serum sample obtained from a control indicates that the patient has TBI. In one embodiment, the brain injury is a TBI such that detection of a level or concentration of ASC in a sample obtained from the patient that is higher than the level of ASC in a serum sample obtained from a control indicates that the patient has TBI, when the patient also has an altered level or concentration of a known TBI biomarker in a sample obtained from the patient compared to the level of the known TBI biomarker in a sample obtained from a control known not to have TBI.

[0141] In one embodiment, the brain injury is MCI, such that detecting a level or concentration of at least one inflammasome protein alone or in combination with at least one control biomarker protein in a biological sample obtained from the patient that is elevated by a predetermined percentage compared to the level of the same at least one inflammasome protein in a biological sample obtained from a control indicates that the patient has MCI. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from caspase-1, IL-18, IL-1 beta, and ASC. At least one control biomarker protein is AB (1-42) , A.B. (1-40) , sAPPα, sAPPβ, T-Tau, or NFL. In one embodiment, the brain injury is MCI, such that detection of a level or concentration of AS in serum obtained from the patient that is at least 50% higher than the level of ASC in a serum sample obtained from a control indicates that the patient has MCI. In one embodiment, the brain injury is MCI, such that detection of a level or concentration of ASC in a sample obtained from the patient that is higher than the level of ASC in a sample obtained from a control indicates that the patient has MCI, when the patient also has an altered level or concentration of a known MCI biomarker in a sample obtained from the patient, when compared to the level of the known MCI biomarker in a sample obtained from a control known not to have MCI.

[0142] In one embodiment, the brain injury is AD, such that detecting a level or concentration of at least one inflammasome protein alone or in combination with at least one control biomarker protein in a biological sample obtained from the patient that is elevated by a predetermined percentage above the level of the same at least one inflammasome protein and / or control biomarker protein in a biological sample obtained from a control indicates that the patient has AD. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from caspase-1, IL-18, IL-1 beta, and ASC. At least one control biomarker protein is AB (1-42) , A.B. (1-40) , sAPPα, sAPPβ, T-Tau, or NFL. In one embodiment, the brain damage is AD, such that detection of a level or concentration of AS in serum obtained from the patient that is at least 50% higher than the level of ASC in a serum sample obtained from a control indicates that the patient has AD. In one embodiment, the brain damage is AD, such that detection of a level or concentration of ASC in a sample obtained from the patient that is higher than the level of ASC in a sample obtained from a control indicates that the patient has AD, when the patient also has an altered level or concentration of a known AD biomarker in the sample obtained from the patient compared to the level of the known AD biomarker in a sample obtained from a control known not to have AD.

[0143] In another embodiment, the inflammation-associated disease, disorder, or condition is an age-related disease. In one embodiment, the age-related disease is AMD, such that detecting a level or concentration of at least one inflammasome protein in a biological sample obtained from a patient that is elevated by a predetermined percentage compared to the level of the same at least one inflammasome protein in a biological sample obtained from a control indicates that the patient has AMD. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein may be selected from caspase-1, IL-18, IL-1β, and ASC. In one embodiment, the age-related disease is AMD, where detecting a level or concentration of AS in serum obtained from a patient that is at least 50% higher than the ASC level in a serum sample obtained from a control indicates that the patient has AMD. In one embodiment, the inflammation-associated disease, disorder, or condition is AMD, where detecting a level or concentration of ASC in a sample obtained from a patient that is higher than the ASC level in a sample obtained from a control indicates that the patient has AMD, when the patient also has an altered level or concentration of a known AMD biomarker in the sample obtained from the patient, compared to the level of a known AMD biomarker in a sample obtained from a control known to be free of AMD.

[0144] In one embodiment, the inflammation-associated disease, disorder, or condition is NASH, such that detecting a level or concentration of at least one inflammasome protein alone or in combination with at least one control biomarker protein in a biological sample obtained from a patient that is elevated by a predetermined percentage compared to the level of the same at least one inflammasome protein and / or control biomarker protein in a biological sample obtained from a control indicates that the patient has NASH. The biological samples obtained from the patient and the control can be of the same type (e.g., serum or serum-derived EVs). The predetermined percentage can be at most or at least about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, or 200%. The at least one inflammasome protein can be selected from IL-18 and ASC. The at least one control biomarker protein can be CRP (hs-CRP) or Gal-3. In one embodiment, the inflammation-associated disease, disorder, or condition is NASH, such that detecting a level or concentration of ASC in serum obtained from the patient that is at least 50% higher than the ASC level in a serum sample obtained from a control indicates that the patient has NASH. In one embodiment, the inflammation-associated disease, disorder, or condition is NASH, such that detecting a level or concentration of ASC in a sample obtained from the patient that is higher than the ASC level in a sample obtained from a control indicates that the patient has NASH, when the patient also has an elevated level or concentration of a known NASH biomarker, such as Gal-3 or CRP (hs-CRP), in the sample obtained from the patient, when compared to the level of the known NASH biomarker in a sample obtained from a control known not to have NASH.

[0145] The present invention also provides methods for determining a prognosis for a patient with inflammation or a disease, disorder, or condition caused by or associated with inflammation (e.g., MCI, AD, AMD, inflammatory aging, stroke, MS, or TBI). In one embodiment, the method includes providing a biological sample from the patient and measuring the level of at least one inflammasome protein, alone or in combination with at least one control biomarker protein, in the biological sample to prepare a protein profile as described above, wherein the inflammasome protein profile or the control biomarker protein profile is indicative of the patient's prognosis. In some embodiments, an increase in the level of one or more inflammasome proteins (e.g., IL-18, NLRP1, ASC, caspase-1, or a combination thereof) compared to a predetermined reference value or range of reference values ​​indicates a poorer prognosis. For example, an increase of about 20% to about 300% in the level of one or more inflammasome proteins compared to a predetermined reference value or range of reference values ​​indicates a poorer prognosis. In some cases, the inflammasome protein is ASC, and the predetermined reference value can be from Tables 7-9, 16, 22A-C, or 23. In some embodiments, the predetermined reference value or range of reference values ​​is compared to one or more control biomarker proteins (e.g., AB (1-42) , A.B. (1-40) , sAPPα, sAPPβ, or NFL, or a combination thereof, indicates a poorer prognosis. For example, an increase of about 20% to about 300% in the level of one or more control biomarker proteins compared to a predetermined reference value or range of reference values ​​indicates a poorer prognosis. In some embodiments, an increase of about 20% to about 300% in the level of one or more control biomarker proteins (e.g., AB, sAPPβ, or NFL, or a combination thereof) compared to a predetermined reference value or range of reference values ​​indicates a poorer prognosis. (1-42) , A.B. (1-40)Elevated levels of one or more control biomarker proteins (sAPPα, sAPPβ, or NFL, or a combination thereof) and elevated levels of one or more inflammasome proteins indicate a poorer prognosis. For example, an increase of about 20% to about 300% in the level of one or more control biomarker proteins and an increase of about 20% to about 300% in the level of one or more inflammasome proteins compared to a predetermined reference value or range of reference values ​​indicates a poorer prognosis.

[0146] In one embodiment, the expression of ASC levels in a biological sample obtained from a patient in any of the diagnostic methods provided herein is determined or detected through the use of any anti-ASC antibody known in the art and / or provided herein. In one embodiment, the anti-ASC is a monoclonal antibody or fragment thereof provided herein. In one embodiment, the anti-ASC antibody is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable (VH) region and a light or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 19 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19; and the VL region amino acid sequence comprises SEQ ID NO: 30 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 30. In some cases, a monoclonal antibody or antibody fragment derived therefrom comprising a VH region amino acid sequence comprising SEQ ID NO: 19 and a VL region amino acid sequence comprising SEQ ID NO: 30 may be referred to as IC-100.

[0147] Treatment method In one embodiment, provided herein are methods of treating a patient suffering from or suspected of suffering from inflammation or a disease, disorder, or condition caused by or associated with inflammation. Any of the methods of treatment provided herein can involve administering a treatment to a patient suffering from or suspected of suffering from a disease, disorder, or condition caused by or associated with inflammation. In some cases, administering a treatment in a method as provided herein can reduce inflammation in the patient. The reduction can be compared to a control (e.g., an untreated patient and / or a patient prior to treatment). In some cases, the treatment is a standard of care treatment. In some cases, the treatment is a neuroprotective treatment. Such neuroprotective treatment can include drugs that reduce excitotoxicity, oxidative stress, and inflammation. Therefore, suitable neuroprotective treatments include, but are not limited to, methylprednisolone, 17alpha-estradiol, 17beta-estradiol, ginsenosides, progesterone, simvastatin, deprenyl, minocycline, resveratrol, and other glutamate receptor antagonists (e.g., NMDA receptor antagonists), and antioxidants. In some embodiments, the treatment is an antibody or binding fragment thereof directed against an inflammasome protein, such as an antibody directed against an inflammasome protein provided herein. In some cases, the treatment can be an extracellular vesicle (EV) uptake inhibitor. The EV uptake inhibitor can be any EV uptake inhibitor known in the art. In some cases, the EV uptake inhibitor can be selected from those found in Table 30. In some cases, the treatment is any combination of standard of care treatment, neuroprotective treatment, an antibody directed against an inflammasome protein or a fragment thereof, and an EV uptake inhibitor.

[0148] In other embodiments, the method of diagnosing or evaluating a patient experiencing inflammation or having a disease, disorder, or condition caused by or associated with inflammation further comprises administering a treatment to the patient for the inflammation or the disease, disorder, or condition caused by or associated with inflammation based on the measured level of the at least one inflammasome protein or at least one control biomarker protein, or if a protein signature associated with inflammation or a disease, disorder, or condition caused by or associated with inflammation is identified. Methods of diagnosing or evaluating a patient as having inflammation or a disease, disorder, or condition caused by or associated with inflammation (e.g., NASH, MCI, stroke, inflammatory aging, AMD, MS, AD, or TBI) can be confirmed using the methods described herein. In some embodiments, the method of diagnosing or evaluating a patient experiencing inflammation-associated diseases, disorders, or conditions further comprises administering a treatment to the patient based on the measured level of the at least one inflammasome protein, or if a protein signature associated with inflammation-associated diseases, disorders, or conditions or more severe inflammation-associated diseases, disorders, or conditions is identified. In some cases, the treatment is a standard of care treatment. In some cases, the treatment is a neuroprotective treatment. In some cases, the treatment is an antibody or binding fragment thereof directed against an inflammasome protein, such as an antibody directed against an inflammasome protein provided herein. In some cases, the treatment can be an extracellular vesicle (EV) uptake inhibitor. The EV uptake inhibitor can be any EV uptake inhibitor known in the art. In some cases, the EV uptake inhibitor can be selected from those found in Table 30. In some cases, the treatment is a standard of care treatment, a neuroprotective treatment, or any combination of an antibody or fragment thereof directed against an inflammasome protein and an EV uptake inhibitor. In some cases, administration of a treatment in a method as provided herein can reduce inflammation in a patient. This reduction can be compared to a control (e.g., an untreated patient and / or a patient before treatment).

[0149] Regarding any of the methods of treatment embodiments provided herein for treating inflammation or a disease, disorder, or condition caused by or associated with inflammation. The inflammation can be innate immune inflammation. The inflammation can be inflammasome-associated inflammation. The disease, disorder, or condition can be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmune, autoinflammatory, metabolic, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the disease, disorder, or condition is NASH. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury can be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease may be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS collapse, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS). The metabolic disease may be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorders, glycogen storage diseases, medium-chain acyl-coenzyme A dehydrogenase deficiency, nonalcoholic fatty liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease may be cryopyrin-associated periodic syndromes (CAPS). CAPS can encompass familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0150] In one embodiment, the brain injury (e.g., AD, MCI, TBI, stroke, or MS) is MS, and the standard of care treatment is selected from a treatment for modifying disease outcome, managing relapses, managing symptoms, or any combination thereof. The treatment for modifying disease outcome may be selected from beta-interferon, glatiramer acetate, fingolimod, teriflunomide, dimethyl fumarate, mitoxantrone, ocrelizumab, alemtuzumab, daclizumab, and natalizumab. The stroke may be an ischemic stroke, a transient ischemic stroke, or a hemorrhagic stroke.

[0151] In another embodiment, the brain injury (e.g., AD, MCI, TBI, stroke, or MS) is ischemic stroke or transient ischemic stroke, and the standard of care treatment is selected from tissue plasminogen activator (tPA), antiplatelet agents, anticoagulants, carotid angioplasty, carotid endarterectomy, intra-arterial thrombolysis and mechanical clot removal in cerebral ischemia (MERCI), or a combination thereof. In yet another embodiment, the brain injury (e.g., TBI, stroke, or MS) is hemorrhagic stroke, and the standard of care treatment is aneurysm clipping, coil embolization, or arteriovenous malformation (AVM) repair.

[0152] In another embodiment, the brain injury (e.g., AD, MCI, TBI, stroke, or MS) is TBI, and the standard of care treatment is selected from diuretics, anti-seizure medications, coma-inducing drugs, surgery, and / or rehabilitation. Diuretics can be used to reduce the amount of fluid in tissues and increase urine output. Diuretics administered intravenously to those with traumatic brain injury can help reduce pressure inside the brain. Anti-seizure medications can be given during the first week to avoid any further brain damage that may be caused by seizures. Continuous anti-seizure treatment is used only if a seizure occurs. Coma-inducing drugs can be drugs used to put a person into a temporary coma, as a comatose brain requires less oxygen to function. This can be particularly beneficial when increased pressure within the brain compresses blood vessels and prevents normal amounts of nutrients and oxygen from reaching brain cells. The severity of TBI can be assessed using the Glasgow Coma Scale. This 15-point test can help doctors or other emergency medical personnel assess the initial severity of brain injury by checking a person's ability to follow commands and move their eyes and limbs. Speech integrity can also provide important clues. Ability is scored on the Glasgow Coma Scale, ranging from 3 to 15. Higher scores indicate less severe injury.

[0153] In yet another embodiment, the brain injury (e.g., AD, MCI, TBI, stroke, or MS) is MCI, and the standard of care treatment is selected from computerized cognitive training, grouped memory training, individual error-free learning sessions, family memory strategy intervention, DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), Ginkgo biloba, donepezil, rivastigmine, triflusal, Huannao Yicong capsules, piribedil, nicotine patch, vitamin E, vitamins B12 and B6, folic acid, rofecoxib, galantamine, the cholinesterase inhibitor memantine, lithium, Wuzi Yanzong Granules, ginseng, and exercise.

[0154] In another embodiment, the brain injury (e.g., AD, MCI, TBI, stroke, or MS) is AD, and the standard of care treatment is selected from computerized cognitive training, grouped memory training, individual error-free learning sessions, family memory strategy intervention, DHA (docosahexaenoic acid), EPA (eicosapentaenoic acid), Ginkgo biloba, donepezil, rivastigmine, triflusal, Huannao Yicong capsules, piribedil, nicotine patches, vitamin E, vitamins B12 and B6, folic acid, rofecoxib, galantamine, the cholinesterase inhibitor memantine, lithium, Wuzi Yanzong granules, ginseng, and exercise. The standard of care treatment may be selected from a cholinesterase inhibitor and memantine (Namenda). The cholinesterase inhibitor may be selected from donepezil (Aricept), galantamine (Razadyne) and rivastigmine (Exelon).

[0155] In one embodiment, the autoimmune disease is RA, and the standard of care treatment may be selected from nonsteroidal anti-inflammatory drugs (NSAIDs), steroids (e.g., prednisone), disease-modifying antirheumatic drugs (DMARDs), and biologics. NSAIDs may include ibuprofen (Advil, Motrin IB) and naproxen sodium (Aleve). DMARDs may include methotrexate (Trexall, Otrexup, etc.), leflunomide (Arava), hydroxychloroquine (Plaquenil), and sulfasalazine (Azulfidine). Biologics may include abatacept (Orencia), adalimumab (Humira), anakinra (Kineret), baricitinib (Olumient), certolizumab (Cimzia), etanercept (Enbrel), golimumab (Simponi), infliximab (Remicade), rituximab (Rituxan), sarilumab (Kevzara), tocilizumab (Actemra), and tofacitinib (Xeljanz).

[0156] In one embodiment, the autoimmune disease is lupus nephritis, and standard of care treatments may include blood pressure-regulating medications and / or a special diet low in protein and salt. Furthermore, standard of care treatments for lupus nephritis may include treatments for lupus, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids (e.g., prednisone; methylprednisolone), immunosuppressants, or biologics. Examples of NSAIDs may include naproxen sodium (Aleve) and ibuprofen (Advil, Motrin IB, and others). An example of an antimalarial drug may be hydroxychloroquine (Plaquenil). Examples of immunosuppressants may include azathioprine (Imuran, Azasan), mycophenolate mofetil (Cellcept), and methotrexate (Trexall). Examples of biologics may include belimumab (Benlysta) or rituximab (Rituxan).

[0157] In one embodiment, the metabolic disease is NASH, and standard treatment may include lifestyle changes such as weight loss, increased exercise, avoidance of liver-damaging drugs, cholesterol reduction, and / or diabetes management. NASH is a type of nonalcoholic fatty liver disease (NAFLD). NAFLD is a general term for a range of liver conditions that affect people who drink little or no alcohol. The main feature of NAFLD is excessive fat storage in liver cells, characterized by liver inflammation, which can progress to scarring and irreversible damage. This damage may be similar to that caused by heavy alcohol consumption. In its most severe form, nonalcoholic steatohepatitis can progress to cirrhosis and liver failure.

[0158] In one embodiment, the metabolic disease is diabetic neuropathy, and standard of care treatments may include lifestyle changes such as weight loss, increased exercise, lowering cholesterol, regulating urinary protein, promoting bone health, controlling high blood pressure, managing diabetes, kidney dialysis or transplantation. Diabetic nephropathy, which may also be called diabetic kidney disease (DKD), is a serious kidney-related complication of type 1 and type 2 diabetes.

[0159] In one embodiment, the autoimmune disease is IBD, and standard of care treatments may include anti-inflammatory drugs, immune system suppressants, antibiotics, antidiarrheal medications, painkillers, iron supplements, and calcium and vitamin D supplements. Antibiotics may include ciprofloxacin (Cipro) and metronidazole (Flagyl). Examples of immunosuppressants may include azathioprine (Azasan, Imuran), mercaptopurine (Purinethol, Purixan), cyclosporine (Gengraf, Neoral, Sandimmune), and methotrexate (Trexall). Other examples of immunosuppressants may include tumor necrosis factor (TNF)-alpha inhibitors or biologics, such as infliximab (Remicade), adalimumab (Humira), golimumab (Simponi), natalizumab (Tysabri), vedolizumab (Entyvio), and ustekinumab (Stelara). Anti-inflammatory agents may include corticosteroids and aminosalicylates, such as mesalamine (Asacol HD, Delzicol), balsalazide (Colazar), and olsalazine (Dipentum). IBD is a general term used to describe disorders involving chronic inflammation of an individual's digestive tract. IBD may include ulcerative colitis and Crohn's disease. Ulcerative colitis is persistent inflammation and pain (ulcers) in the innermost lining of a person's large intestine (colon) and rectum, while Crohn's disease is characterized by inflammation of the lining of the digestive tract, which often spreads deep into the affected tissue.

[0160] In one embodiment, the autoinflammatory disease is CAPS, and standard treatments may include biologics targeting interleukin-1, physical therapy, splints to treat joint deformities, and nonsteroidal anti-inflammatory drugs, corticosteroids, or methotrexate to relieve symptoms. Cryopyrin-associated periodic syndromes (CAPS), also known as cryopyrin-associated autoinflammatory syndromes, consist of three autoinflammatory diseases associated with deletion of the same gene (i.e., NLRP3): neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome (MWS), and familial cold autoinflammatory syndrome (FCAS). NOMID is characterized by fever accompanied by inflammation in multiple organs. Early symptoms of NOMID may include a nonitchy, hives-like rash; inflammation of the membranes surrounding the brain causing headache, blindness, or hearing loss; the appearance of bulging eyes; and episodes of vomiting. After age 1, half of children with NOMID may develop joint pain and swelling. MWS is characterized by symptoms that come and go, including skin rash, bloodshot eyes, joint pain, and severe headaches accompanied by vomiting. Episodes last one to three days. Hearing loss, which can be complete, often occurs by the teenage years. FCAS is characterized by fever, chills, nausea, extreme dry mouth, headache, and joint pain.

[0161] In one embodiment, the present invention contemplates the use of an antibody or an active fragment thereof in a method for treating inflammation or a disease, disorder, or condition caused by or associated with inflammation in a subject, wherein the antibody or active fragment thereof is directed against a component of a mammalian inflammasome or an antigen or epitope derived therefrom. In another embodiment, the agent to be administered is an antisense RNA or siRNA directed against a component of a mammalian inflammasome. The inflammasome component can be any inflammasome component known in the art, such as NAPL1, NALP2, NALP3, NLRC4, or AIM2 inflammasome. In typical embodiments, the antibody specifically binds to ASC or an antigen or epitope derived therefrom. However, antibodies directed against any other component of a mammalian inflammasome (e.g., NALP1, NALP2, NALP3, NLRC4, or AIM2 inflammasome) can also be used.

[0162] Antibodies as described herein can be monoclonal or polyclonal antibodies or active fragments thereof. The antibodies or active fragments can be chimeric, human or humanized as described herein.

[0163] In one embodiment, the antibody or active fragment thereof is directed against a component of a mammalian inflammasome or an antigen or epitope therefrom that specifically binds to at least one component (e.g., ASC, AIM2) of the mammalian inflammasome (e.g., the AIM2 inflammasome). Representative antibodies directed against a component of a mammalian inflammasome for use in the methods herein may be those found in U.S. Pat. No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. In one embodiment, the antibodies or antibody fragments thereof provided herein may be used in methods for reducing inflammation in a mammal, such as those described in U.S. Pat. No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. Use of the antibody or antibody fragment thereof in methods for treating inflammation may reduce inflammation. Use of the antibody or antibody fragment thereof (in methods for treating inflammation) may reduce innate immune or inflammasome-associated inflammation in a patient. Reduction may be relative to a control (e.g., an untreated patient and / or a patient prior to treatment). In one embodiment, the antibody or antibody fragment thereof is used to treat inflammation or a disease, disorder, or condition caused by or associated with inflammation. The inflammation can be innate immune inflammation. The inflammation can be inflammasome-associated inflammation. The disease, disorder, or condition can be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmune, autoinflammatory, metabolic, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury can be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease may be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS collapse, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS).The metabolic disease may be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorders, glycogen storage disorders, medium-chain acyl-coenzyme A dehydrogenase deficiency, nonalcoholic fatty liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease may be cryopyrin-associated periodic syndromes (CAPS). CAPS may include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). The antibody or antibody fragment derived therefrom may be a monoclonal antibody or may be derived from a monoclonal antibody. The antibody or antibody fragment derived therefrom may be a polyclonal antibody or may be derived from a polyclonal antibody. The antibody fragment may be a Fab, F(ab')2, Fab', scFv, single domain antibody, diabody, or single chain camelid antibody. The antibody or antibody fragment derived therefrom (e.g., a monoclonal antibody or antibody fragment thereof) may be human, humanized, or chimeric.

[0164] In one embodiment, the antibody or antibody fragment thereof is used to treat MS by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from MS. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof can result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof can be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control can be an untreated subject. Administration can be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof can be a monoclonal antibody or derived from a monoclonal antibody. The antibody or antibody fragment thereof can be a polyclonal antibody or derived from a polyclonal antibody. The antibody fragment can be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibody or antibody fragment derived therefrom (eg, a monoclonal antibody or antibody fragment thereof) can be human, humanized, or chimeric.

[0165] In one embodiment, the antibody or antibody fragment thereof is used to treat PD by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from PD. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof can result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof can be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control can be an untreated subject. Administration can be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof can be a monoclonal antibody or derived from a monoclonal antibody. The antibody or antibody fragment thereof can be a polyclonal antibody or derived from a polyclonal antibody. The antibody fragment can be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibody or antibody fragment derived therefrom (eg, a monoclonal antibody or antibody fragment thereof) can be human, humanized, or chimeric.

[0166] In one embodiment, the antibody or antibody fragment thereof is used to treat lupus nephritis by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from lupus nephritis. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof can result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof can be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in a decrease in ASC activity compared to a control. The control can be an untreated subject. Administration can be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof can be a monoclonal antibody or derived from a monoclonal antibody. The antibody or antibody fragment thereof can be a polyclonal antibody or derived from a polyclonal antibody. The antibody fragment can be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibody or antibody fragment derived therefrom (eg, a monoclonal antibody or antibody fragment thereof) can be human, humanized, or chimeric.

[0167] In one embodiment, the antibody or antibody fragment thereof is used to treat diabetic nephropathy by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from diabetic nephropathy. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof may result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof may be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control may be an untreated subject. Administration may be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof may be a monoclonal antibody or may be derived from a monoclonal antibody. The antibody or antibody fragment thereof may be a polyclonal antibody or may be derived from a polyclonal antibody. The antibody fragment may be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibodies or antibody fragments derived therefrom (eg, monoclonal antibodies or antibody fragments thereof) can be human, humanized, or chimeric.

[0168] In one embodiment, the antibody or antibody fragment thereof is used to treat NASH by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from NASH. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof may result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof may be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in a decrease in ASC activity compared to a control. The control may be an untreated subject. Administration may be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof may be a monoclonal antibody or may be derived from a monoclonal antibody. The antibody or antibody fragment thereof may be a polyclonal antibody or may be derived from a polyclonal antibody. The antibody fragment may be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibody or antibody fragment derived therefrom (eg, a monoclonal antibody or antibody fragment thereof) can be human, humanized, or chimeric.

[0169] In one embodiment, the antibody or antibody fragment thereof is used to treat CAPS by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from CAPS. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof can result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof can be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control can be an untreated subject. Administration can be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof can be a monoclonal antibody or derived from a monoclonal antibody. The antibody or antibody fragment thereof can be a polyclonal antibody or derived from a polyclonal antibody. The antibody fragment can be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibody or antibody fragment derived therefrom (eg, a monoclonal antibody or antibody fragment thereof) can be human, humanized, or chimeric.

[0170] In one embodiment, the antibody or antibody fragment thereof is used to treat AMD by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from AMD. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of pro-inflammatory cytokines. Administration of the antibody or antibody fragment thereof can result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof can be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control can be an untreated subject. Administration can be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof can be a monoclonal antibody or derived from a monoclonal antibody. The antibody or antibody fragment thereof can be a polyclonal antibody or derived from a polyclonal antibody. The antibody fragment can be a Fab, F(ab')2, Fab', scFv, single-domain antibody, diabody, or single-chain camelid antibody. The antibodies or antibody fragments derived therefrom (eg, monoclonal antibodies or antibody fragments thereof) can be human, humanized, or chimeric.

[0171] In one embodiment, the antibody or antibody fragment thereof is used to treat inflammatory senescence or age-related inflammation by administering the antibody or antibody fragment thereof to a patient suffering from or suspected of suffering from inflammatory senescence or age-related inflammation. In some cases, administration of the antibody or antibody fragment thereof reduces at least the level of inflammatory cytokines. Administration of the antibody or antibody fragment thereof may result in inhibition of inflammasome activation in a subject. In some cases, the antibody or antibody fragment thereof may be directed against ASC. In some cases, administration of the antibody or antibody fragment thereof results in reduced ASC activity compared to a control. The control may be an untreated subject. Administration may be intracerebroventricularly, intraperitoneally, intravenously, or by inhalation. The antibody or antibody fragment thereof may be a monoclonal antibody or may be derived from a monoclonal antibody. The antibody or antibody fragment thereof may be a polyclonal antibody or may be derived from a polyclonal antibody. The antibody fragment may be a Fab, F(ab')2, Fab', scFv, single domain antibody, diabody, or single chain camelid antibody. The antibody or antibody fragment derived therefrom (e.g., a monoclonal antibody or antibody fragment thereof) may be human, humanized, or chimeric.

[0172] The antibody or antibody fragment thereof of this embodiment can be present in a composition, such as a pharmaceutical composition as provided herein. The composition can further comprise at least one pharmaceutically acceptable carrier or diluent. In one embodiment, a method provided herein for treating inflammation or a disorder, disease, or condition caused by or associated with inflammation includes providing a therapeutically effective amount of a composition comprising an antibody or active fragment thereof as provided herein that specifically binds to at least one component (e.g., ASC) of a mammalian inflammasome (e.g., the AIM2 inflammasome); and administering the composition to a mammal suffering from inflammation, wherein administration of the composition to the mammal results in reduced caspase-1 activation in the mammal. In some cases, the antibody or fragment thereof is used in combination with one or more other agents in the methods of treatment provided herein. The other agent can be any of the agents provided herein (e.g., an extracellular vesicle (EV) uptake inhibitor) and / or an antibody or antibody fragment against other inflammasome components (e.g., IL-18, caspase-1, NALP1, AIM2, etc.). EV uptake inhibitors may be selected from those found in Table 30.

[0173] In one embodiment, the agent to be administered in the methods of treatment provided herein is an EV uptake inhibitor, which can be a compound, an antisense RNA, an siRNA, a peptide, an antibody or an active fragment thereof as provided herein, or a combination thereof. The compound or peptide can be one or more compounds selected from heparin, α-difluoromethylornithine (DFMO), enoxaparin, asialofetuin, human receptor-associated protein (RAP), RGD (Arg-Gly-Asp) peptide, cytochalasin D, cytochalasin B, ethylenediaminetetraacetic acid (EDTA), latrunculin A, latrunculin B, NSC23766, Dynasoa, chlorpromazine, 5-(N-ethyl-N-isopropyl) amiloride (EIPA), amiloride, bafilomycin A, monensin, and chloroquine, annexin-V, wortmannin, LY294002, methyl-β-cyclodextrin (MβCD), filipin, simvastatin, fumonisin B1, and N-butyldeoxynojirimycin hydrochloride, U0126, or a proton pump inhibitor. The EV uptake inhibitor antibodies or active fragments thereof as provided herein can be one or more antibodies or active fragments thereof against the protein targets listed in Table 30. The compositions for treating and / or reducing inflammation using an EV uptake inhibitor can further comprise at least one pharmaceutically acceptable carrier or diluent.

[0174] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0175] In one embodiment, the antibody or active fragment thereof for use in the treatment methods provided herein is an antibody or active fragment thereof that specifically binds to an apoptosis-associated Spec-like protein containing a caspase activation recruitment domain (ASC) or a domain or portion thereof. Any suitable anti-ASC antibody may be used, and some are commercially available. An example of an anti-ASC antibody for use in the methods herein may be found in U.S. Patent No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. Examples of commercially available anti-ASC antibodies for use in the methods provided herein include 04-147 anti-ASC from Millipore Sigma, clone 2EI-7 mouse monoclonal antibody, AB3607-anti-ASC antibody from Millipore Sigma, orb194021 anti-ASC from Biorbyt, LS-C331318-50 anti-ASC from LifeSpan Biosciences, AF3805 anti-ASC from R&D Systems, NBP1-78977 anti-ASC from Novus Biologicals, 600-401-Y67 anti-ASC from Rockland Immunochemicals, D086-3 anti-ASC from MBL International, AL177 anti-ASC from Adipogen, monoclonal anti-ASC (clone o93E9) antibody, anti-ASC antibody (F-9) from Santa Cruz Biotechnology, anti-ASC antibody (B-3) from Santa Cruz Biotechnology, Enzo Life Examples of antibodies include, but are not limited to, ASC polyclonal antibody ADI-905-173 from Biosciences or A161 anti-human ASC from Leinco Technologies. Human ASC proteins can have accession numbers NP_037390.2 (Q9ULZ3-1), NP_660183 (Q9ULZ3-2), or Q9ULZ3-3. Rat ASC proteins can have accession numbers NP_758825 (BAC43754). Mouse ASC proteins can have accession numbers NP_075747.3.In one embodiment, the antibody binds to the PYRIN-PAAD-DAPIN domain (PYD) or a portion or fragment thereof of a mammalian ASC protein (e.g., human, mouse, or rat ASC). In this embodiment, the antibody as described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the PYD domain of human, mouse, or rat ASC, or a fragment thereof. In one embodiment, the antibody binds to the C-terminal caspase recruitment domain (CARD) of a mammalian ASC protein (e.g., human, mouse, or rat ASC), or a portion or fragment thereof. In this embodiment, the antibody as described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the CARD domain of human, mouse, or rat ASC, or a fragment thereof. In yet another embodiment, the antibody binds to a portion or fragment thereof of a mammalian ASC protein sequence (e.g., human, mouse, or rat ASC) located between the PYD and CARD domains. In another embodiment, a composition for treating and / or reducing inflammation in the CNS and / or lungs of a mammal includes an antibody that specifically binds to a region of rat ASC, such as the amino acid sequence ALRQTQPYLVTDLEQS (SEQ ID NO: 1) (i.e., residues 178-193 of rat ASC, Accession No. BAC43754). In this embodiment, an antibody as described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65, 70, 75, 80, 85%) sequence identity to the amino acid sequence ALRQTQPYLVTDLEQS (SEQ ID NO: 1) of rat ASC. In another embodiment, a composition for treating and / or reducing inflammation in the CNS and / or lungs of a mammal includes an antibody that specifically binds to a region of human ASC, such as the amino acid sequence RESQSYLVEDLERS (SEQ ID NO: 2).In yet another embodiment, a composition for treating and / or reducing inflammation in the CNS and / or lungs of a mammal includes an antibody that specifically binds to a region of human ASC, such as the amino acid sequence KKFKLKLLSVPLREGYGRIPR (SEQ ID NO: 5; i.e., residues 21-41 of human ASC), or amino acids 5-10, 10-15, or 15-20 of SEQ ID NO: 5. In one embodiment, the antibody specifically binds to an amino acid sequence having at least 85% sequence identity to the amino acid sequence SEQ ID NO: 1 or SEQ ID NO: 2. In another embodiment, the antibody or fragment thereof binds to an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence KKFKLKLLSVPLREGYGRIPR (SEQ ID NO: 5). In yet another embodiment, the antibody or fragment thereof binds to the amino acid sequence KKFKLKLLSVPLREGYGRIPR (SEQ ID NO: 5), or 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids of SEQ ID NO: 5. In further embodiments, the antibody or fragment thereof binds to amino acids 2-5, 5-10, 10-15, or 15-20 of SEQ ID NO: 5. In some embodiments, the epitope of ASC to which the antibody or antibody fragment binds (e.g., the epitope having amino acid SEQ ID NO: 5) is contiguous. In some embodiments, the epitope of ASC to which the antibody or antibody fragment binds (e.g., the epitope having amino acid SEQ ID NO: 5) is discontinuous. In some cases, the antibodies or antibody fragments thereof provided herein inhibit or reduce the activity of ASC. The antibodies or antibody fragments derived therefrom may be monoclonal antibodies or may be derived from monoclonal antibodies. The antibody or antibody fragment derived therefrom may be a polyclonal antibody or may be derived from a polyclonal antibody. The antibody fragment may be a Fab, F(ab')2, Fab', scFv, single domain antibody, diabody, or single chain camelid antibody. The antibody or antibody fragment derived therefrom (e.g., a monoclonal antibody or antibody fragment thereof) may be human, humanized, or chimeric.

[0176] In certain embodiments, antibodies and antibody fragments that specifically bind to ASC are or are derived from monoclonal antibodies comprising one or more amino acid sequences set forth in Table 31. Also provided herein are isolated nucleic acid molecules encoding monoclonal antibodies or antibody fragments thereof comprising a nucleic acid sequence set forth in Table 31. In some cases, provided herein are expression vectors comprising a nucleic acid molecule of Table 31. The expression vector may comprise a heavy or light chain constant region. An example of a light and heavy chain expression vector system for use in the compositions and methods provided herein is Antitope's pANT expression vector system for IgG4(S241P) heavy chain and kappa light chain. The nucleic acid molecule for the heavy or light chain may be operably linked to appropriate control sequences for expression of the nucleic acid segment in a host cell.

[0177] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4]

[0178] In one embodiment, the antibody or antibody fragment thereof specifically binds to ASC, and the antibody or antibody fragment thereof comprises a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18, 19, 20, 21, 22 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18, 19, 20, 21 or 22.

[0179] In one embodiment, the antibody or antibody fragment thereof specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, and the VL region amino acid sequence comprises SEQ ID NO: 28, 29, 30, 31, or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28, 29, 30 or 31.

[0180] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18, 19, 20, 21, 22, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18, 19, 20, 21, or 22; and the VL region amino acid sequence comprises SEQ ID NO: 28, 29, 30, 31, or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28, 29, 30, or 31.

[0181] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, wherein the antibody or antibody fragment thereof comprises a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 18; and the VL region amino acid sequence comprises SEQ ID NO: 28 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 28.

[0182] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18; and the VL region amino acid sequence comprises SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 29.

[0183] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18; and the VL region amino acid sequence comprises SEQ ID NO: 30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 30.

[0184] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 18 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 18; and the VL region amino acid sequence comprises SEQ ID NO: 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 31.

[0185] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 19 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and the VL region amino acid sequence comprises SEQ ID NO: 28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 28.

[0186] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 19 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and the VL region amino acid sequence comprises SEQ ID NO: 29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 29.

[0187] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 19 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 19; and the VL region amino acid sequence comprises SEQ ID NO: 30 or an amino acid sequence at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO: 30. In some cases, a monoclonal antibody or antibody fragment derived therefrom comprising a VH region amino acid sequence comprising SEQ ID NO: 19 and a VL region amino acid sequence comprising SEQ ID NO: 30 may be referred to as IC-100.

[0188] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO: 19 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 19; and the VL region amino acid sequence comprises SEQ ID NO: 31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO: 31.

[0189] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:20 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:20; and the VL region amino acid sequence comprises SEQ ID NO:28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:28.

[0190] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:20 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:20; and the VL region amino acid sequence comprises SEQ ID NO:29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:29.

[0191] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:20 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:20; and the VL region amino acid sequence comprises SEQ ID NO:30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:30.

[0192] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:20 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:20; and the VL region amino acid sequence comprises SEQ ID NO:31 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:31.

[0193] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:21 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:21; and the VL region amino acid sequence comprises SEQ ID NO:28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:28.

[0194] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:21 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:21; and the VL region amino acid sequence comprises SEQ ID NO:29 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:29.

[0195] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:21 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:21; and the VL region amino acid sequence comprises SEQ ID NO:30 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:30.

[0196] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:21 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:21; and the VL region amino acid sequence comprises SEQ ID NO:31 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:31.

[0197] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:22 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:22; and the VL region amino acid sequence comprises SEQ ID NO:28 or an amino acid sequence that is at least 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence of SEQ ID NO:28.

[0198] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:22 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:22; and the VL region amino acid sequence comprises SEQ ID NO:29 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:29.

[0199] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:22 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:22; and the VL region amino acid sequence comprises SEQ ID NO:30 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:30.

[0200] In one embodiment, provided herein is a monoclonal antibody or antibody fragment thereof that specifically binds to ASC, the antibody or antibody fragment thereof comprising a heavy chain variable (VH) region and a light chain or kappa chain variable (VL) region, wherein the VH region amino acid sequence comprises SEQ ID NO:22 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:22; and the VL region amino acid sequence comprises SEQ ID NO:31 or an amino acid sequence that is at least 95%, 96%, 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:31.

[0201] Further to the above embodiments, the present invention contemplates the use of an antibody or antibody fragment thereof (e.g., a monoclonal antibody or antibody fragment thereof that binds to ASC) in a method for treating inflammation or a disorder, disease, or condition caused by or associated with inflammation in a subject, as provided herein. The antibody or antibody fragment thereof that specifically binds to ASC may be a monoclonal antibody or antibody fragment thereof that may comprise a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8, or variants thereof having at least one amino acid substitution in HCDR1, HCDR2, and / or HCDR3. In some embodiments, a monoclonal antibody or antibody fragment thereof that specifically binds to ASC may comprise a light chain variable (VL) region and a heavy chain variable (VH) region, wherein the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 14, or variants thereof having at least one amino acid substitution in LCDR1, LCDR2, and / or LCDR3. In other embodiments, a monoclonal antibody or antibody fragment thereof that specifically binds to ASC may comprise a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region amino acid sequence comprises HCDR1 of SEQ ID NO: 6, HCDR2 of SEQ ID NO: 7, and HCDR3 of SEQ ID NO: 8, or variants thereof having at least one amino acid substitution in HCDR1, HCDR2, and / or HCDR3; and the VL region amino acid sequence comprises LCDR1 of SEQ ID NO: 12, LCDR2 of SEQ ID NO: 13, and LCDR3 of SEQ ID NO: 14, or variants thereof having at least one amino acid substitution in LCDR1, LCDR2, and / or LCDR3. The antibody or fragment thereof may be in a composition. The composition may be administered in a therapeutically effective amount. The therapeutically effective amount may be a dose as provided herein. The composition may be administered by any appropriate route, for example, by inhalation, intravenously, intraperitoneally, or intracerebroventricularly. The composition may further comprise at least one pharmaceutically acceptable carrier or diluent. The composition may further comprise an additional therapeutic agent.The additional therapeutic agent may be an extracellular vesicle (EV) uptake inhibitor and / or an antibody or active fragment thereof as provided herein that binds to an inflammasome component, or a combination thereof. The EV uptake inhibitor may be selected from Table 30. The inflammation may be innate immune inflammation. The inflammation may be inflammasome-associated inflammation. The disease, disorder, or condition may be selected from the group consisting of brain injury, age-related disease, inflammatory aging, autoimmunity, autoinflammatory, metabolic disease, or neurodegenerative disease. In some cases, the disease, disorder, or condition is inflammatory aging. In some cases, the age-related disease is age-related macular degeneration (AMD). In some cases, the disease, disorder, or condition is brain injury. The brain injury may be selected from the group consisting of traumatic brain injury (TBI), stroke, and spinal cord injury (SCI). The autoimmune or neurodegenerative disease may be selected from amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease (PD), muscular dystrophy (MD), immune dysfunction muscle CNS collapse, systemic lupus erythematosus, lupus nephritis, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), and multiple sclerosis (MS). The metabolic disease may be selected from metabolic syndrome, obesity, diabetes, diabetic nephropathy or diabetic kidney disease (DKD), insulin resistance, atherosclerosis, lipid storage disorders, glycogen storage diseases, medium-chain acyl-coenzyme A dehydrogenase deficiency, nonalcoholic fatty liver disease (e.g., nonalcoholic steatohepatitis (NASH)), and gout. The autoinflammatory disease may be cryopyrin-associated periodic syndromes (CAPS). CAPS can encompass familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID).

[0202] The success of or response to treatment (e.g., antibody treatment, standard of care treatment, and / or neuroprotective treatment) in the methods provided herein for treating inflammation or a disease, disorder, or condition caused by or associated with inflammation can also be monitored by measuring the level of at least one inflammasome protein. Thus, in some embodiments, a method of treating, evaluating, or diagnosing a patient with inflammation or a disease, disorder, or condition caused by or associated with inflammation further comprises measuring the level of at least one inflammasome protein, alone or in combination with at least one control biomarker protein, in a biological sample obtained from the patient after treatment, and providing a treatment protein signature associated with a positive response to the treatment, wherein the treatment protein signature comprises identifying patients who exhibit a decreased level of at least one inflammasome protein and / or a decreased level of at least one control biomarker protein and the presence of the treatment protein signature as responding positively to the treatment. A decrease in the level, abundance, or concentration of one or more inflammasome proteins (e.g., ASC, IL-18, caspase-8, caspase-11, or caspase-1) can indicate the effectiveness of treatment in a patient. A decrease in the level, abundance, or concentration of one or more control biomarker proteins (e.g., Gal-3, CRP (hs-CRP), AB (1-42) , A.B. (1-40)A decrease in the level, abundance, or concentration of sAPPα, sAPPβ, or NFL, or a combination thereof, may indicate the effectiveness of treatment in the patient. One or more inflammasome proteins measured in a sample obtained after treatment may be the same as or different from the inflammasome proteins measured in a sample obtained before treatment. One or more control biomarker proteins measured in a sample obtained after treatment may be the same as or different from the control biomarker proteins measured in a sample obtained before treatment. Inflammasome protein levels may also be used to adjust the dosage or frequency of treatment. Control biomarker protein levels may also be used to adjust the dosage or frequency of treatment. Inflammasome protein levels may be confirmed using the methods and techniques provided herein. Control biomarker protein levels may be confirmed using the methods and techniques provided herein.

[0203] In another embodiment, the composition for treating or alleviating inflammation comprises an antibody or an active fragment thereof as provided herein that specifically binds to NLRP1 or a domain or portion thereof. Any suitable anti-NLRP1 antibody can be used, and some are commercially available. Examples of anti-NLRP1 antibodies for use in the methods herein can be found in U.S. Patent No. 8,685,400, the contents of which are incorporated herein by reference in their entirety. Examples of commercially available anti-NLRP1 antibodies for use in the methods provided herein include human NLRP1 polyclonal antibody AF6788 from R&D Systems, EMD Millipore rabbit polyclonal anti-NLRP1 ABF22, Novus Biologicals rabbit polyclonal anti-NLRP1 NB100-56148, Sigma-Aldrich mouse polyclonal anti-NLRP1 SAB1407151, Abcam rabbit polyclonal anti-NLRP1 ab3683, Biobyt rabbit polyclonal anti-NLRP1 orb325922, BioSource rabbit polyclonal anti-NLRP1 MBS7001225, R&D systems sheep polyclonal AF6788, Aviva Systems mouse monoclonal anti-NLRP1 oaed00344, Aviva Systems rabbit polyclonal anti-NLRP1 ARO54478_P050, and Origene rabbit polyclonal anti-NLRP1 APO7775PU-N, Antibody Online rabbit polyclonal anti-NLRP1 ABIN768983, Prosci rabbit polyclonal anti-NLRP1 3037, Proteintech rabbit polyclonal anti-NLRP1 12256-1-AP, Enzo mouse monoclonal anti-NLRP1 ALX-804-803-C100, Invitrogen mouse monoclonal anti-NLRP1 MA1-25842, GeneTex mouse monoclonal anti-NLRP1 GTX16091, Rockland rabbit polyclonal anti-NLRP1 200-401-CX5, or Cell Signaling Technology rabbit polyclonal anti-NLRP1 4990.The human NLRP1 protein may have accession numbers AAH51787, NP_001028225, NP_055737, NP_127497, NP_127499, or NP_127500. In one embodiment, the antibody binds to the Pyrin, NACHT, LRR1-6, FIIND, or CARD domain of a mammalian NLRP1 protein (e.g., human NLRP1), or a portion or fragment thereof. In this embodiment, the antibody as described herein specifically binds to an amino acid sequence having at least 65% (e.g., 65%, 70%, 75%, 80%, 85%) sequence identity with a specific domain of human NLRP1 (e.g., Pyrin, NACHT, LRR1-6, FIIND, or CARD) or a fragment thereof. In one embodiment, a chicken anti-NLRP1 polyclonal antibody custom-designed and produced by Ayes Laboratories is used to reduce inflammation. The antibody can be directed against the following amino acid sequence in human NLRP1: CEYYTEIREREREKSEKGR (SEQ ID NO: 3) or the following amino acid sequence in rat NALP1: MEE SQS KEE SNT EG-cys (SEQ ID NO: 4). In one embodiment, an antibody that binds to an NLRP1 domain or fragment thereof as...

Claims

1. 1. A method for assisting in determining whether a patient is suffering from a condition selected from the group consisting of mild cognitive impairment (MCI), Alzheimer's disease (AD), and age-related macular degeneration (AMD), comprising: measuring the expression level of at least one inflammasome protein selected from apoptosis-associated speck-like protein (ASC) containing a caspase recruitment domain and interleukin-18 (IL-18) in a serum sample obtained from the patient; comparing the expression level of the at least one inflammasome protein in the serum sample to a predetermined reference value or range of reference values ​​for the at least one inflammasome protein; Including, A method in which a result in which the expression level of the at least one inflammasome protein is within the range of the predetermined reference value or exceeds the predetermined reference value indicates that the patient has AD, a result in which the expression level of ASC is greater than 264.9 pg / ml indicates that the patient has MCI, or a result in which the expression level of the at least one inflammasome protein is greater than the predetermined reference value indicates that the patient has AMD.

2. 2. The method of claim 1, wherein a result in which the expression level of ASC is greater than 258.7 pg / ml indicates that the patient has AD.

3. The method of claim 1, wherein the level of the at least one inflammasome protein in the protein signature is measured by an immunoassay utilizing one or more antibodies directed against the at least one inflammasome protein in the protein signature.

4. 2. The method of claim 1, wherein the at least one inflammasome protein comprises ASC, and the AUC of ASC as a biomarker for AMD is 0.9823.

5. 2. The method of claim 1, wherein the at least one inflammasome protein comprises IL-18, and the AUC of IL-18 as a biomarker for AMD is 0.7286.

6. 2. The method of claim 1, wherein the results indicate that the patient has MCI, AD or AMD with a sensitivity of at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% and a specificity of at least 55%.

7. The method of claim 1, wherein the at least one inflammasome protein is ASC, and the parameter representing the expression level of ASC indicating that the patient has AMD is a cutoff value of greater than 365.6 pg / mL.

8. 2. The method of claim 1, wherein the at least one inflammasome protein is IL-18, and the parameter representing the expression level of IL-18 indicating that the patient has AMD has a cutoff value of greater than 242.4 pg / mL.

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