Methods of treating a cognitive impairment

Abstract

The invention pertains to treating a cognitive impairment, for example, an aging-associated cognitive impairment. In certain aspects, a sample obtained from a subject is assayed for the ratio between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RSP3, VAV3, SIRT3 and SERPINB8. A subject may be having or suspected of having a cognitive impairment. The cognitive impairment can be caused by a neurodegenerative disease, such as Alzheimer's disease. A subject may be identified as likely or not likely to respond positively to the plasma exchange therapy based on the ratio between the levels of measured proteins. In certain aspects, methods for treating a cognitive impairment in the subject comprise administering a plasma exchange therapy comprising a full and / or low volume plasma exchange. Also provided are kits suitable for performing such methods.

Description

I. INTRODUCTION Field This invention pertains to methods of treating subjects for cognitive impairment. Background The following is offered as background information only and is not admitted as prior art to the present invention. Aging is an important risk factor for multiple human diseases including cognitive impairment, cancer, arthritis, vision loss, osteoporosis, diabetes, cardiovascular disease, and stroke. Aging-associated neuronal neurodegeneration is a major factor causing cognitive impairment. As such, aging remains the single most dominant risk factor for dementia-related neurodegenerative diseases such as Alzheimer’s disease (AD) (Bishop, N.A. et al., Neural mechanisms of ageing and cognitive decline. Nature 464(7288), 529-535 (2010); Heeden, T. et al., Insights into the ageing mind: a view from cognitive neuroscience. Nat. Rev. Neurosci. 5(2), 87-96 (2004); Mattson, M.P., et al., Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 7(4), 278-294 (2006)). Aging affects all tissues and functions of the body including the central nervous system, and neurodegeneration and a decline in functions such as cognition or motor skills, can severely impact quality of life. Treatment for cognitive decline, motor impairment, and neurodegenerative disorders has had limited success in preventing and reversing impairment. Moreover, while certain treatments, such as blood plasma based therapies or plasma exchange therapies have shown promise (Boada et al., Alzheimers Dement:, 16:1412-25, 2020), these treatments are not always successful. In other words, while certain patients show positive results with such treatments for cognitive impairment, certain other patients do not. This causes loss of valuable time and resources as the disease progresses. Thus, it is desirable to identify patients that are likely or not likely to respond positively to treatments for cognitive impairment before such treatments are administered. II. SUMMARY In certain aspects, the invention provides methods of treating cognitive impairment. Such treatments can comprise plasma exchange therapies. In some cases, the subjects are identified as likely or not likely to respond positively to plasma exchange therapies. The determination of whether subjects are likely or not likely to respond positively to plasma exchange therapies may be based on the results of an assay of samples of the subjects for ratios between the levels of any two proteins selected from: Delta-like protein 1 (UniProtID: 000548, DLL1), SPARC-related modular calcium-binding protein 1 (UniProtID: Q9H4F8, SMOC1), CD59 glycoprotein (UniProtID: P13987, CD59), Thiosulfate:glutathione sulfurtransferase (UniProtID: Q8NFU3, TSTD1), Signal transducer and activator of transcription 3 (UniProtID: P40763, STAT3), DNA Polymerase Delta subunit 4 (UniProtID: Q9HCU8, POUD4), Protein mono-ADP-ribosyltransferase PARP11 (UniProtID: Q9NR21, PARP11), Deft-Right Determination Factor 2 (UniProtID: 000292, LEFTY2), Netnn receptor UNC5B (UniProtID: Q8IZJ1, UNC5B), Complement C5 (UniProtID: P01031, C5), Complement C5b-C6 complex (UniProtID: P01031 / P13671, C5.C6), Setl / Ash2 histone methyltransferase complex subunit ASH2 (UniProtID: Q9UBL3, ASH2D), Inhibin Beta B Chain (UniProtID: P09529, INHBB), Small ribosomal subunit protein uS3 (UniProtID: P23396, RPS3), Guanine nucleotide exchange factor VAV3 (UniProtID: Q9UKW4, VAV3), NAD-dependent protein deacetylase sirtuin-3, mitochondrial (UniProtID: Q9NTG7, SIRT3), and Serpin B 8 (UniProtID: P50452, SERPINB8). Any suitable assay could be used to determine the levels of the assayed protein and to determine the ratios between the levels of the assayed proteins. In certain embodiments, the levels of the assayed proteins are determined using an aptamer-based multiplex proteomic assay, such as SomaScan™ assay. Accordingly, in certain aspects, the invention provides methods of assaying samples for the ratios between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. The subjects may have or suspected of having a cognitive impairment. A cognitive impairment may be caused by a neurodegenerative disease, such as Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia. Further aspects of the invention provide kits comprising reagents for assaying in samples the levels of any two proteins selected from DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. The ratios between the levels of the protein pairs can be determined based on the assay results for the protein pairs. III. INCORPORATION BY REFERENCE All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. IV. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a schematic representation of an example of a plasma exchange therapy. In an example described in Figure 1, Alzheimer's Management By Albumin Replacement (AMBAR) treatment comprised an intensive period of 6 weeks of conventional therapeutic PE (TPE, also called FPE - full plasma exchange) processing 1 plasma volume [~ 2500- 3000 mL]) with albumin 5% replacement (1 TPE / week) followed by a maintenance period of 12 months of low volume PE (LVPE: removing approximately 1 / 3 plasma volume [~ 690-880 mL]) with albumin 20% replacement or IVIG (1 LVPE / month) for all 3 active arms: in one arm, 20 grams of Albutein 20% were used for replacement in LVPE, whereas in the other two arms, visits for Albutein 20% replacement (20 or 40 grams) were alternated with Flebogamma DIF 5% (10 or 20 grams). (1)-(8) point out the moments wherein biological samples were collected before the TPE or LVPE procedure and after the TPE or LVPE procedure: (1) serum sample pre-TPEl, (2) CSF sample pre-TPEl, (3) serum sample post-TPEl, (4) serum sample pre-LVPEl, (5) CSF sample pre-LVPEl, (6) serum sample post-LVPEl, (7) serum sample at the end-of-study (EOS), and (8) CSF sample at EOS. IVIG: Intravenous Immunoglobulin; Albutein and Flebogamma DIF are commercially available products. Figure 2. Proteomics analysis of samples. Brief description of statistical analysis to identify protein pairs and ratios between protein pairs. Figures 3A-3C show prediction power of baseline plasma protein ratio DLL1 / SMOC1. A. Relationship between baseline plasma protein ratio of DLL1 / SMOC1 and Clinical Dementia Rating-Sum of Boxes (CDR-sb) improvement at the end of study (EOS). Higher baseline plasma protein ratio of DLL1 / SMOC1 is associated with CDR-sb improvement (rho = -0.645***). B. ROC of DLL1 / SMOC1 ratio predict better than bl scores of CDR-sb at EOS (AUC_better= 80.8% (70.7%, 91.0%). C. ROC of DLL1 / SMOC1 to predict no worse than CMC (Clinically Meaningful Change, better or equal of bl scores of CDR-sb) at EOS (AUC_CMC = 83.3% (75.0%, 91.6%)). Figures 4A-4C show prediction power of baseline plasma protein ratio DLL1 / CD59. A. Relationship between baseline plasma protein ratio of DLL1 / CD59 and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / CD59 is associated with CDR-sb improvement (rho = -0.627***). B. ROC of DLL1 / CD59 to predict better than bl scores of CDR-sb at EOS (AUC better = 80.7% (70.6%, 90.8%)). C. ROC of DLL1 / CD59 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 82.0% (73.3%, 90.8%)). Figures 5A-5C show prediction power of baseline plasma protein ratio DLL1 / LEFTY2. A. Relationship between baseline plasma protein ratio of DLL1 / LEFTY2 and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / LEFTY2 is associated with CDR-sb improvement (rho = -0.597***). B. ROC of DLL1 / LEFTY2 to predict better than bl scores of CDR-sb at EOS (AUC_better = 84.6% (75.6%, 93.6%)). C. ROC of DLL1 / LEFTY2 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 77.3% (67.5%, 87.0%)). Figures 6A-6C show prediction power of baseline plasma protein ratio DLL1 / UNC5B. A. Relationship between baseline plasma protein ratio of DLL1 / UNC5B and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / UNC5B is associated with CDR-sb improvement (rho = -0.591***). B. ROC of DLL1 / UNC5B to predict better than bl scores of CDR-sb at EOS (AUC_better = 80.5% (69.4%, 91.6%)). C. ROC ofDLLl / UNC5B to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 79.2% (69.8%, 88.6%)). Figures 7A-7C show prediction power of baseline plasma protein ratio DLL1 / C5. A. Relationship between baseline plasma protein ratio of DLL1 / C5 and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / C5 is associated with CDR-sb improvement (rho = -0.584***). B. ROC of DLL1 / C5 to predict better than bl scores of CDR-sb at EOS (AUC better = 80.8% (70.8%, 90.9%)). C. ROC of DLL1 / C5 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 79.2% (70.0%, 88.5%)). Figures 8A-8C show prediction power of baseline plasma protein ratio DLL1 / C5.C6. A. Relationship between baseline plasma protein ratio of DLL1 / C5.C6 and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / C5.C6 is associated with CDR-sb improvement (rho = -0.578***). B. ROC of DLL1 / C5.C6 to predict better than bl scores of CDR-sb at EOS (AUC_better = 80.6% (70.9%, 90.3%)). C. ROC of DLL1 / C5.C6 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 81.4% (72.2%, 90.5%)). Figures 9A-9C show prediction power of baseline plasma protein ratio DLL1 / INHBB. A. Relationship between baseline plasma protein ratio of DLL1 / INHBB and CDR-sb improvement. Higher baseline plasma ratio of DLL1 / INHBB is associated with CDR-sb improvement (rho = -0.564***). B. ROC of DLL1 / INHBB to predict better than bl scores of CDR-sb at EOS (AUC_better = 80.3% (69.5%, 91.0%)). C. ROC of DLL1 / INHBB to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 81.0% (71.8%, 90.1%)). Figures 10A-10C show prediction power of baseline plasma protein ratio TSTD1 / STAT3. A. Relationship between baseline plasma protein ratio of TSTD1 / STAT3 and CDR-sb improvement. Higher baseline plasma ratio of TSTD1 / STAT3 is associated with CDR-sb improvement (rho = -0.627***). B. ROC of TSTD1 / STAT3 to predict better than bl scores of CDR-sb at EOS (AUC_better = 85.1% (75.9%, 94.2%)). C. ROC of TSTD1 / STAT3 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 79.9% (70.5%, 89.2%)). Figures 11A-11C show prediction power of baseline plasma protein ratio POLD4 / PARP11. A. Relationship between baseline plasma protein ratio of POLD4 / PARP 11 and CDR-sb improvement. Higher baseline plasma ratio of POLD4 / PARP11 is associated with CDR-sb improvement (rho = -0.606***). B. ROC of POLD4 / PARP11 to predict better than bl scores of CDR-sb at EOS (AUC_better = 86.9% (78.1%, 95.8%)). C. ROC of POLD4 / PARP11 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 80.2% (70.6%, 89.8%)). Figures 12A-12C show prediction power of baseline plasma protein ratio ASH2L / PARP11. A. Relationship between baseline plasma protein ratio of ASH2L / PARP11 and CDR-sb improvement. Higher baseline plasma ratio of ASH2L / PARP11 is associated with CDR-sb improvement (rho = -0.571***). B. ROC of ASH2L / PARP11 to predict better than bl scores of CDR-sb at EOS (AUC_better = 83.7% (73.0%, 94.3%)). C. ROC of ASH2L / PARP11 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 79.5% (70.0%, 89.0%)). Figures 13A-13C show prediction power of baseline plasma protein ratio RPS3 / PARP11. A. Relationship between baseline plasma protein ratio of RPS3 / PARP11 and CDR-sb improvement. Higher baseline plasma ratio of RPS3 / PARP11 is associated with CDR-sb improvement (rho = -0.564***). B. ROC of RPS3 / PARP11 to predict better than bl scores of CDR-sb at EOS (AUC_better = 86.5% (76.3%, 96.7%)). C. ROC of RPS3 / PARP11 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 78.4% (68.5%, 88.4%)). Figures 14A-14C show prediction power of baseline plasma protein ratio VAV3 / SIRT3. A. Relationship between baseline plasma protein ratio of VAV3 / SIRT3 and CDR-sb improvement. Higher baseline plasma ratio of VAV3 / SIRT3 is associated with CDR-sb improvement (rho = -0.559***). B. ROC of VAV3 / SIRT3 to predict better than bl scores at of CDR-sb EOS (AUC_better = 79.8% (68.9%, 90.7%)). C. ROC of VAV3 / SIRT3 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 80.1% (70.4%, 89.8%)). Figures 15A-15C show prediction power of baseline plasma protein ratio SERPINB8 / PARP11. A. Relationship between  baseline plasma protein  ratio  of SERPINB8 / PARP11  and  CDR-sb improvement.    Higher baseline plasma  ratio  of SERPINB8 / PARP11 is associated with CDR-sb improvement (rho = -0.554***). B. ROC of SERPINB8 / PARP11 to predict better than bl scores of CDR-sb at EOS (AUC better = 82.4% (72.0%, 92.8%)). C. ROC of SERPINB8 / PARP11 to predict no worse than CMC (better or equal of bl scores) at EOS (AUC_CMC = 78.0% (68.2%, 87.8%)). V. DETAILED DESCRIPTION A. Introduction The present invention relates to treating a cognitive impairment, for example, aging-associated cognitive impairment. In certain aspects, the invention provides methods of assaying a sample obtained from a subject for a ratio between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. In some cases, the subject has or is suspected of having a cognitive impairment. In certain embodiments, the cognitive impairment is caused by a neurodegenerative disease, such as AD. The methods further comprise identifying a subject as likely or not likely to respond positively to a plasma exchange therapy. In even further aspects, the invention describes methods for treating a cognitive impairment in the subject by a plasma exchange therapy, wherein based on the specific protein expression data, the subject is identified as likely or not likely to respond positively to the plasma exchange therapy. The plasma exchange therapy can be full and / or low volume plasma exchange. In some cases, plasma exchange comprises albumin replacement. Also provided are kits suitable for performing the methods of the invention. Before describing the present invention in detail, it is to be understood that this invention is not limited to particular methods or compositions described, as such may, of course, vary. It is also understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims. The publications discussed herein are provided solely for their invention prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed. Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both limits, ranges excluding either or both of those included limits are also included in the invention. As will be apparent to those of skill in the art upon reading this invention, each of the individual embodiments described and illustrated herein have discrete components and features which may be readily separated from or combined with the features of any of the other several embodiments without departing from the scope or the spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible. B. Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present invention supersedes any invention of an incorporated publication to the extent there is a contradiction. It must be noted that as used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a sample” includes a plurality of such samples. In describing methods of the present invention, the terms “subject”, “individual” and “patient” are used interchangeably and refer to any mammal in need of such treatment according to the disclosed methods. Such mammals include, e.g., humans, ovines, bovines, equines, porcines, canines, felines, non-human primate, mice, and rats. In certain embodiments, the subject is a nonhuman mammal. In some embodiments, the subject is a farm animal. In other embodiments, the subject is a pet. In some embodiments, the subject is a mammal. In certain instances, the subject is human. Other subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees, and monkeys). As such, subjects of the invention, include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees and other apes and monkey species; and the like, where in certain embodiments the subject are humans. The term subject is also meant to include a person or organism of any age, weight or other physical characteristic, where the subjects may be an adult, a child, an infant or a newborn. As used herein, “treatment” refers to the reduction or elimination of a cognitive impairment. Treatment may be administered therapeutically, i.e., following the onset of the disease. The effect may include improving cognitive performance in the subject having a cognitive impairment. Thus, the term “treatment” as used herein covers any treatment of a cognitive impairment in a mammal and includes: (a) inhibiting the disease, i.e., arresting its development; or (b) relieving the disease, i.e., causing regression of the disease. Treatment may result in a variety of different physical manifestations, e.g., modulation in gene expression, rejuvenation of tissue or organs, etc. The therapy may be administered during or after the onset of cognitive impairment. The treatment of ongoing cognitive impairment, where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of interest. Such treatment may be performed prior to complete loss of function in the affected tissues. The subject therapies may be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease. A “cognitive impairment” is an impairment in cognitive ability of an individual relative to a healthy individual, e.g., an age-matched healthy individual, or relative to the ability of the individual at an earlier time-point, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years or more previously. By “cognitive ability,” or “cognition,” it is meant the mental processes that include attention and concentration, learning complex tasks and concepts, memory (acquiring, retaining, and retrieving new information in the short and / or long term), information processing (dealing with information gathered by the five senses), visuospatial function (visual perception, depth perception, using mental imagery, copying drawings, constructing objects or shapes), producing and understanding language, verbal fluency (word-finding), solving problems, making decisions, and executive functions (planning and prioritizing). By “cognitive decline,” it is meant a progressive decrease in one or more of these abilities, e.g., a decline in memory, language, thinking, judgment, etc. In some embodiments, a cognitive impairment is “an aging-associated cognitive impairment.” By “aging-associated cognitive impairment,” it is meant an impairment in cognitive ability that is typically associated with aging, including, for example, cognitive impairment associated with the natural aging process, e.g., mild cognitive impairment (M.C.I.); and cognitive impairment associated with an aging-associated disorder, that is, a disorder that is seen with increasing frequency with increasing senescence, e.g., a neurodegenerative condition such as AD, Parkinson's disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia, and the like. In some embodiments, the cognitive impairment in a subject is caused by neuroinflammation, for example, aging-associated increase in neuroinflammation in an individual. “Neuroinflammation” refers to biochemical and cellular responses of the nervous system to injury, infection, or neurodegenerative diseases. Such responses are directed at decreasing the triggering factors by involving central nervous system immunity to defend against potential harm. Neurodegeneration occurs in the central nervous system and exhibits hallmarks of loss of neuronal structure and function. Neuroinflammatory diseases or neuroinflammatory-associated conditions or diseases, includes by way of example and not limitation, neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and the like. C. Assay methods Certain aspects of the invention provide methods of analyzing a sample obtained from a subject, the method comprising: assaying the sample for a ratio between the levels of any two markers, particularly protein markers, selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. In some cases, the subject has or is suspected of having a cognitive impairment. DLL1 protein is found in several organisms, including humans. In humans, an example of DLL1 protein is described in Uniprot database with ID NO.: 000548. The sequence of a human DLL1 protein is given below: MGSRCALALAVLSALLCQVWSSGVFELKLQEFVNKKGLLGNRNCCRGGAGPPP CACRTFFRVCLKHYQASVSPEPPCTYGSAVTPVLGVDSFSLPDGGGADSAFSNPIRFPFG FTWPGTFSLIIEALHTDSPDDLATENPERLISRLATQRHLTVGEEWSQDLHSSGRTDLKYS YRFVCDEHYYGEGCSVFCRPRDDAFGHFTCGERGEKVCNPGWKGPYCTEPICLPGCDE QHGFCDKPGECKCRVGWQGRYCDECIRYPGCLHGTCQQPWQCNCQEGWGGLFCNQD LNYCTHHKPCKNGATCTNTGQGSYTCSCRPGYTGATCELGIDECDPSPCKNGGSCTDLE NSYSCTCPPGFYGKICELSAMTCADGPCFNGGRCSDSPDGGYSCRCPVGYSGFNCEKKI DYCSSSPCSNGAKCVDLGDAYLCRCQAGFSGRHCDDNVDDCASSPCANGGTCRDGVN DFSCTCPPGYTGRNCSAPVSRCEHAPCHNGATCHERGHRYVCECARGYGGPNCQFLLP ELPPGPAWDLTEKLEGQGGPFPWVAVCAGVILVLMLLLGCAAVWCVRLRLQKHRPP ADPCRGETETMNNLANCQREKDISVSIIGATQIKNTNKKADFHGDHSADKNGFKARYPA VDYNLVQDLKGDDTAVRDAHSKRDTKCQPQGSSGEEKGTPTTLRGGEASERKRPDSGC STSKDTKYQSVYVISEEKDECVIATEV (SEQ ID NO: 1). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 1 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 1. For example, a person of ordinary skill in the art can readily identify a homolog of human DLL1 protein having a sequence of SEQ ID NO: 1 in an organism of interest and then assay such DLL1 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. SMOC1 protein is also found in several organisms, including humans. In humans, an example of SMOC1 protein is described in Uniprot database with ID NO.: Q9H4F8. The sequence of a human SMOC1 protein is given below: MLPARCARLLTPHLLLVLVQLSPARGHRTTGPRFLISDRDPQCNLHCSRTQPKPIC ASDGRSYESMCEYQRAKCRDPTLGWHRGRCKDAGQSKCRLERAQALEQAKKPQEAV FVPECGEDGSFTQVQCHTYTGYCWCVTPDGKPISGSSVQNKTPVCSGSVTDKPLSQGNS GRKDDGSKPTPTMETQPVFDGDEITAPTLWIKHLVIKDSKLNNTNIRNSEKVYSCDQERQ SALEEAQQNPREGIVIPECAPGGLYKPVQCHQSTGYCWCVLVDTGRPLPGTSTRYVMPS CESDARAKTTEADDPFKDRELPGCPEGKKMEFITSLLDALTTDMVQAINSAAPTGGGRF SEPDPSHTLEERWHWYFSQLDSNSSNDINKREMKPFKRYVKKKAKPKKCARRFTDYC DLNKDKVISLPELKGCLGVSKEGRLV (SEQ ID NO: 2). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 2 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 2. For example, a person of ordinary skill in the art can readily identify a homolog of human SMOC1 protein having a sequence of SEQ ID NO: 2 in an organism of interest and then assay such SMOC1 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. CD59 protein is also found in several organisms, including humans. In humans, an example of CD59 protein is described in Uniprot database with ID NO.: P13987. The sequence of a human CD59 protein is given below: MGIQGGS VLFGLLLVLAVFCHS GHSLQCYNCPNPTADCKTAVNC S SDFD ACLIT KAGLQVYNKCWKFEHCNFNDVTTRLRENELTYYCCKKDLCNFNEQLENGGTSLSEKTV LLLVTPFLAAAWSLHP (SEQ ID NO: 3). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 3 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 3. For example, a person of ordinary skill in the art can readily identify a homolog of human CD59 protein having a sequence of SEQ ID NO: 3 in an organism of interest and then assay such CD59 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. TSTD1 protein is also found in several organisms, including humans. In humans, an example of TSTD1 protein is described in Uniprot database with ID NO.: Q8NFU3. The sequence of a human TSTD1 protein is given below: MAGAPTVSLPELRSLLASGRARLFDVRSREEAAAGTIPGALNIPVSELESALQMEP AAFQALYSAEI<PI<LEDEHLVFFCQMGI<RGLQATQLARSLGYTGARNYAGAYREWLEI< ES (SEQ ID NO: 4). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 4 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 4. For example, a person of ordinary skill in the art can readily identify a homolog of human TSTD1 protein having a sequence of SEQ ID NO: 4 in an organism of interest and then assay such TSTD1 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. STAT3 protein is also found in several organisms, including humans. In humans, an example of STAT3 protein is described in Uniprot database with ID NO.: P40763. The sequence of a human STAT3 protein is given below: MAQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHA TLVFHNLLGEIDQQYSRFLQESNVLYQHNLRRIKQFLQSRYLEKPMEIARIVARCLWEES RLLQTAATAAQQGGQANHPTAAWTEKQQMLEQHLQDVRKRVQDLEQKMKVVENLQ DDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGLLS AMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEE LQQI<VSYI<GDPIVQHRPMLEERIVELFRNLMI<SAFVVERQPCMPMHPDRPLVII<TGVQF TTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESNNGSL SAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVIS NICQMPNAWASILWYNMLTNNPKNVNFFTKPPIGTWDQVAEVLSWQFSSTTKRGLSIEQ LTTLAEKLLGPGVNYSGCQITWAKFCKENMAGKGFSFWVWLDNIIDLVKKYILALWNE GYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQIQSVEPYTKQ QLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGSAA PYLKTKFICVTPTTCSNTIDLPMSPRTLDSLMQFGNNGEGAEPSAGGQFESLTFDMELTS ECATSPM (SEQ ID NO: 5). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 5 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 5. For example, a person of ordinary skill in the art can readily identify a homolog of human STAT3 protein having a sequence of SEQ ID NO: 5 in an organism of interest and then assay such STAT3 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. POLD4 protein is found in several organisms, including humans. In humans, an example of POLD4 protein is described in Uniprot database with ID NO.: Q9HCU8. The sequence of a human POLD4 protein is given below: MGRKRLnDSYPWKRREGPAGHSKGELAPELGEEPQPRDEEEAELELLRQFDLA WQYGPCTGITRLQRWCRAKQMGLEPPPEVWQVLKTHPGDPRFQCSLWHLYPL (SEQ ID NO: 6). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 6 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 6. For example, a person of ordinary skill in the art can readily identify a homolog of human POLD4 protein having a sequence of SEQ ID NO: 6 in an organism of interest and then assay such POLD4 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. PARP11 protein is found in several organisms, including humans. In humans, an example of PARP11 protein is described in Uniprot database with ID NO.: Q9NR21. The sequence of a human PARP11 protein is given below: MWEANPEMFHKAEELFSKTTNNEVDDMDTSDTQWGWFYLAECGKWHMFQPD TNSQCSVSSEDIEKSFKTNPCGSISFTTSKFSYKIDFAEMKQMNLTTGKQRLIKRAPFSISA FSYICENEAIPMPPHWENVNTQVPYQLIPLHNQTHEYNEVANLFGKTMDRNRIKRIQRIQ NLDLWEFFCRKKAQLKKKRGVPQINEQMLFHGTSSEFVEAICIHNFDWRINGIHGAVFG KGTYFARDAAYSSRFCKDDIKHGNTFQIHGVSLQQRHLFRTYKSMFLARVLIGDYINGD SI<YMRPPSI<DGSYVNLYDSCVDDTWNPI<IFVVFDANQIYPEYLIDFH (SEQ ID NO: 7). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 7 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 7. For example, a person of ordinary skill in the art can readily identify a homolog of human PARP11 protein having a sequence of SEQ ID NO: 7 in an organism of interest and then assay such PARP 11 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. LEFTY2 protein is found in several organisms, including humans. In humans, an example of LEFTY2 protein is described in Uniprot database with ID NO.: 000292. The sequence of a human LEFTY2 protein is given below: MWPLWLCWALWVLPLAGPGAALTEEQLLGSLLRQLQLSEVPVLDRADMEKLVI PAHVRAQYWLLRRSHGDRSRGKRFSQSFREVAGRFLASEASTHLLVFGMEQRLPPNSE LVQAVLRLFQEPVPKAALHRHGRLSPRSAQARVTVEWLRVRDDGSNRTSLIDSRLVSVH ESGWKAFDVTEAVNFWQQLSRPRQPLLLQVSVQREHLGPLASGAHKLVRFASQGAPAG LGEPQLELHTLDLRDYGAQGDCDPEAPMTEGTRCCRQEMYIDLQGMKWAKNWVLEPP GFLAYECVGTCQQPPEALAFNWPFLGPRQCIASETASLPMIVSIKEGGRTRPQVVSLPNM RVQKCSCASDGALVPRRLQP (SEQ ID NO: 8). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 8 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 8. For example, a person of ordinary skill in the art can readily identify a homolog of human LEFTY2 protein having a sequence of SEQ ID NO: 8 in an organism of interest and then assay such LEFTY2 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. UNC5B protein is found in several organisms, including humans. In humans, an example of UNC5B protein is described in Uniprot database with ID NO.: Q8IZJ1. The sequence of a human UNC5B protein is given below: MGARSGARGALLLALLLCWDPRLSQAGTDSGSEVLPDSFPSAPAEPLPYFLQEPQ DAYIVKNKPVELRCRAFPATQIYFKCNGEWVSQNDHVTQEGLDEATGLRVREVQIEVSR QQVEELFGLEDYWCQCVAWSSAGTTKSRRAYVRIAYLRKNFDQEPLGKEVPLDHEVLL QCRPPEGVPVAEVEWLKNEDVIDPTQDTNFLLTIDHNLIIRQARLSDTANYTCVAKNIVA KRRSTTATVIVYVNGGWSSWAEWSPCSNRCGRGWQKRTRTCTNPAPLNGGAFCEGQA FQKTACTTICPVDGAWTEWSKWSACSTECAHWRSRECMAPPPQNGGRDCSGTLLDSK NCTDGLCMQNKKTLSDPNSHLLEASGDAALYAGLWAIFVWAILMAVGVWYRRNC RDFDTDITDSSAALTGGFHPVNFKTARPSNPQLLHPSVPPDLTASAGIYRGPVYALQDST DKIPMTNSPLLDPLPSLKVKVYS S S TTGSGPGLADGADLLGVLPPGTYPSDFARDTHFLH LRSASLGSQQLLGLPRDPGSSVSGTFGCLGGRLSIPGTGVSLLVPNGAIPQGKFYEMYLLI NKAESTLPLSEGTQTVLSPSVTCGPTGLLLCRPVILTMPHCAEVSARDWIFQLKTQAHQG HWEEWTLDEETLNTPCYCQLEPRACHILLDQLGTYVFTGESYSRSAVKRLQLAVFAPA LCTSLEYSLRVYCLEDTPVALKEVLELERTLGGYLVEEPKPLMFKDSYHNLRLSLHDLP HAHWRSKLLAKYQEIPFYHIWSGSQKALHCTFTLERHSLASTELTCKICVRQVEGEGQIF QLHTTLAETPAGSLDTLCSAPGSTVTTQLGPYAFKIPLSIRQKICNSLDAPNSRGNDWRM LAQKLSMDRYLNYFATKASPTGVILDLWEALQQDDGDLNSLASALEEMGKSEMLVAV ATDGDC (SEQ ID NO: 9). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 9 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 9. For example, a person of ordinary skill in the art can readily identify a homolog of human UNC5B protein having a sequence of SEQ ID NO: 9 in an organism of interest and then assay such UNC5B protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. C5 protein is found in several organisms, including humans. In humans, an example of C5 protein is described in described in Uniprot database with ID NO.: P01031. The sequence of a human C5 protein is given below: MGLLGILCFLIFLGKTWGQEQTYVISAPKIFRVGASENIVIQVYGYTEAFDATISIK S YPDKKFS YS SGHVHLS SENKFQNS AILTIQPKQLPGGQNPVS YVYLEWSKHFSKSKRM PITYDNGFLFIHTDKPVYTPDQSVKVRVYSLNDDLKPAKRETVLTFIDPEGSEVDMVEEI DHIGIISFPDFKIPSNPRYGMWTIKAKYKEDFSTTGTAYFEVKEYVLPHFSVSIEPEYNFIG YKNFKNFEITIKARYFYNKWTEADVYITFGIREDLKDDQKEMMQTAMQNTMLINGIAQ VTFDSETAVKELSYYSLEDLNNKYLYIAVTVIESTGGFSEEAEIPGIKYVLSPYKLNLVAT PLFLKPGIPYPIKVQVKDSLDQLVGGVPVTLNAQTIDVNQETSDLDPSKSVTRVDDGVAS FVLNLPSGVTVLEFNVKTDAPDLPEENQAREGYRAIAYSSLSQSYLYIDWTDNHKALLV GEHLNIIVTPKSPYIDKITHYNYLILSKGKIIHFGTREKFSDASYQSINIPVTQNMVPSSRLL VYYIVTGEQTAELVSDSVWLNIEEKCGNQLQVHLSPDADAYSPGQTVSLNMATGMDS WVALAAVDSAVYGVQRGAKKPLERVFQFLEKSDLGCGAGGGLNNANVFHLAGLTFLT NANADDSQENDEPCKEILRPRRTLQKKIEEIAAKYKHSVVKKCCYDGACVNNDETCEQ RAARISLGPRCIKAFTECCWASQLRANISHKDMQLGRLHMKTLLPVSKPEIRSYFPESW LWEVHLVPRRKQLQFALPDSLTTWEIQGVGISNTGICVADTVKAKVFKDVFLEMNIPYS WRGEQIQLKGTVYNYRTSGMQFCVKMSAVEGICTSESPVIDHQGTKSSKCVRQKVEGS SSHLVTFTVLPLEIGLHNINFSLETWFGKEILVKTLRVVPEGVKRESYSGVTLDPRGIYGTI SRRKEFPYRIPLDLVPKTEIKRILSVKGLLVGEILSAVLSQEGINILTHLPKGSAEAELMSV VPVFYVFHYLETGNHWNIFHSDPLIEI<QI<LI<I<I<LI<EGMLSIMSYRNADYSYSVWI<GGS ASTWLTAFALRVLGQVNKYVEQNQNSICNSLLWLVENYQLDNGSFKENSQYQPIKLQG TLPVEARENSLYLTAFTVIGIRKAFDICPLVKIDTALIKADNFLLENTLPAQSTFTLAISAY ALSLGDI<THPQFRSIVSALI<REALVI<GNPPIYRFWI<DNLQHI<DSSVPNTGTARMVETTA YALLTSLNLKDINYVNPVIKWLSEEQRYGGGFYSTQDTINAIEGLTEYSLLVKQLRLSMD IDVSYI<HI<GALHNYI<MTDI<NFLGRPVEVLLNDDLIVSTGFGSGLATVHVTTVVHI<TST SEEVCSFYLKIDTQDIEASHYRGYGNSDYKRIVACASYKPSREESSSGSSHAVMDISLPTG ISANEEDLKALVEGVDQLFTDYQIKDGHVILQLNSIPSSDFLCVRFRIFELFEVGFLSPATF TVYEYHRPDKQCTMFYSTSNIKIQKVCEGAACKCVEADCGQMQEELDLTISAETRKQTA CKPEIAYAYKVSITSITVENVFVKYKATLLDIYKTGEAVAEKDSEITFIKKVTCTNAELVK GRQYLIMGKEALQIKYNFSFRYIYPLDSLTWIEYWPRDTTCSSCQAFLANLDEFAEDIFL NGC (SEQIDNO: 10). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 10 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 10. For example, a person of ordinary skill in the art can readily identify a homolog of human C5 protein having a sequence of SEQ ID NO: 10 in an organism of interest and then assay such C5 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. C6 protein is found in several organisms, including humans. In humans, an example of C6 protein is described in UniProt database with ID NO: P13671. The sequence of a human C6 protein is given below: MARRS VLYFILLNALINKGQACFCDHYAWTQWTSCSKTCNSGTQSRHRQIVVDK YYQENFCEQICSKQETRECNWQRCPINCLLGDFGPWSDCDPCIEKQSKVRSVLRPSQFG GQPCTAPLVAFQPCIPSKLCKIEEADCKNKFRCDSGRCIARKLECNGENDCGDNSDERDC GRTKAVCTRKYNPIPSVQLMGNGFHFLAGEPRGEVLDNSFTGGICKTVKSSRTSNPYRV PANLENVGFEVQTAEDDLKTDFYKDLTSLGHNENQQGSFSSQGGSSFSVPIFYSSKRSEN INHNSAFI<QAIQASHI<I<DSSFIRIHI<VMI<VLNFTTI<AI<DLHLSDVFLI<ALNHLPLEYNSA LYSRIFDDFGTHYFTSGSLGGVYDLLYQFSSEELKNSGLTEEEAKHCVRIETKKRVLFAK KTKVEHRCTTNKLSEKHEGSFIQGAEKSISLIRGGRSEYGAALAWEKGSSGLEEKTFSEW LESVKENPAVIDFELAPIVDLVRNIPCAVTKRNNLRKALQEYAAKFDPCQCAPCPNNGRP TLSGTECLCVCQSGTYGENCEKQSPDYKSNAVDGQWGCWSSWSTCDATYKRSRTREC NNPAPQRGGKRCEGEKRQEEDCTFSIMENNGQPCINDDEEMKEVDLPEIEADSGCPQPV PPENGFIRNEKQLYLVGEDVEISCLTGFETVGYQYFRCLPDGTWRQGDVECQRTECIKPV VQEVLTITPFQRLYRIGESIELTCPKGFWAGPSRYTCQGNSWTPPISNSLTCEKDTLTKL KGHCQLGQKQSGSECICMSPEEDCSHHSEDLCVFDTDSNDYFTSPACKFLAEKCLNNQQ LHFLHIGSCQDGRQLEWGLERTRLSSNSTKKESCGYDTCYDWEKCSASTSKCVCLLPPQ CFKGGNQLYCVKMGSSTSEKTLNICEVGTIRCANRKMEILHPGKCLA (SEQ ID NO: 11). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is a complex of proteins having the sequences of SEQ ID NOs: 10 and 11 or a complex of proteins, one of which has the sequences at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 10 and the other has the sequences at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 11. For example, a person of ordinary skill in the art can readily identify homologs of human C5 and C6 proteins having sequences of SEQ ID NOs: 10 and 11 in an organism of interest and then assay a complex of such proteins in a sample obtained from such organism. Such embodiments are within the purview of the invention. ASH2L protein is found in several organisms, including humans. In humans, an example of ASH2L protein is described in UniProt database with ID NO.: Q9UBL3. The sequence of a human ASH2L protein is given below: MAAAGAGPGQEAGAGPGPGAVANATGAEEGEMKPVAAGAAAPPGEGISAAPT VEPSSGEAEGGEANLVDVSGGLETESSNGKDTLEGAGDTSEVMDTQAGSVDEENGRQL GEVELQCGICTKWFT ADTFGIDTS S CLPFMTNYSFHCNVCHHS GNTYFLRKQ ANLKEMC LSALANLTWQSRTQDEHPKTMFSKDKDIIPFIDKYWECMTTRQRPGKMTWPNNIVKTM SKERDVFLVKEHPDPGSKDPEEDYPKFGLLDQDLSNIGPAYDNQKQSSAVSTSGNLNGG IAAGSSGKGRGAKRKQQDGGTTGTTKKARSDPLFSAQRLPPHGYPLEHPFNKDGYRYIL AEPDPHAPDPEKLELDCWAGKPIPGDLYRACLYERVLLALHDRAPQLKISDDRLTWGE KGYSMVRASHGVRKGAWYFEITVDEMPPDTAARLGWSQPLGNLQAPLGYDKFSYSWR SKKGTKFHQSIGKHYSSGYGQGDVLGFYINLPEDTETAKSLPDTYKDKALIKFKSYLYFE EKDFVDKAEKSLKQTPHSEIIFYKNGVNQGVAYKDIFEGVYFPAISLYKSCTVSINFGPCF KYPPKDLTYRPMSDMGWGAVVEHTLADVLYHVETEVDGRRSPPWEP (SEQ ID NO: 12). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 12 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 12. For example, a person of ordinary skill in the art can readily identify a homolog of human ASH2L protein having a sequence of SEQ ID NO: 12 in an organism of interest and then assay such ASH2L protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. INHBB protein is also found in several organisms, including humans. In humans, an example of INHBB protein is described in UniProt database with ID NO.: P09529. The sequence of a human INHBB protein is given below: MDGLPGRALGAACLLLLAAGWLGPEAWGSPTPPPTPAAPPPPPPPGSPGGSQDTC TSCGGFRRPEELGRVDGDFLEAVKRHILSRLQMRGRPNITHAVPKAAMVTALRKLHAG KVREDGRVEIPHLDGHASPGADGQERVSEIISFAETDGLASSRVRLYFFISNEGNQNLFV VQASLWLYLKLLPYVLEKGSRRKVRVKVYFQEQGHGDRWNMVEKRVDLKRSGWHTF PLTEAIQALFERGERRLNLDVQCDSCQELAWPVFVDPGEESHRPFVWQARLGDSRHRI RKRGLECDGRTNLCCRQQFFIDFRLIGWNDWIIAPTGYYGNYCEGSCPAYLAGVPGSAS SFHTAWNQYRMRGLNPGTVNSCCIPTKLSTMSMLYFDDEYNIVKRDVPNMIVEECGC A (SEQ ID NO: 13). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 13 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 13. For example, a person of ordinary skill in the art can readily identify a homolog of human INHBB protein having a sequence of SEQ ID NO: 13 in an organism of interest and then assay such INHBB protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. RPS3 protein is also found in several organisms, including humans. In humans, an example of RPS3 protein is described in UniProt database with ID NO.: P23396. The sequence of a human RPS3 protein is given below: MAVQISKKRKFVADGIFKAELNEFLTRELAEDGYSGVEVRVTPTRTEIIILATRTQ NVLGEKGRRIRELTAWQKRFGFPEGSVELYAEKVATRGLCAIAQAESLRYKLLGGLAV RRACYGVLRFIMESGAI<GCEVVVSGI<LRGQRAI<SMI<FVDGLMIHSGDPVNYYVDTAV RHVLLRQGVLGIKVKIMLPWDPTGKIGPKKPLPDHVSIVEPKDEILPTTPISEQKGGKPEP PAMPQPVPTA (SEQ ID NO: 14). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 14 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 14. For example, a person of ordinary skill in the art can readily identify a homolog of human RPS3 protein having a sequence of SEQ ID NO: 14 in an organism of interest and then assay such RPS3 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. VAV3 protein is also found in several organisms, including humans. In humans, an example of VAV3 protein is described in UniProt database with ID NO.: Q9UKW4. The sequence of a human VAV3 protein is given below: MEPWKQCAQWLIHCKVLPTNHRVTWDSAQVFDLAQTLRDGVLLCQLLNNLRA HSINLKEINLRPQMSQFLCLKNIRTFLTACCETFGMRKSELFEAFDLFDVRDFGKVIETLS RLSRTPIALATGIRPFPTEESINDEDIYKGLPDLIDETLVEDEEDLYDCVYGEDEGGEVYE DLMKAEEAHQPKCPENDIRSCCLAEIKQTEEKYTETLESIEKYFMAPLKRFLTAAEFDSV FINIPELVI<LHRNLMQEIHDSIVNI<NDQNLYQVFINYI<ERLVIYGQYCSGVESAISSLDYI SKTKEDVKLKLEECSKRANNGKFTLRDLLVVPMQRVLKYHLLLQELVKHTTDPTEKAN LKLALDAMKDLAQYVNEVKRDNETLREIKQFQLSIENLNQPVLLFGRPQGDGEIRITTLD KHTKQERHIFLFDLAVIVCKRKGDNYEMKEIIDLQQYKIANNPTTDKENKKWSYGFYLI HTQGQNGLEFYCKTKDLKKKWLEQFEMALSNIRPDYADSNFHDFKMHTFTRVTSCKVC QMLLRGTFYQGYLCFKCGARAHKECLGRVDNCGRVNSGEQGTLKLPEKRTNGLRRTP KQVDPGLPKMQVIRNYSGTPPPALHEGPPLQLQAGDTVELLKGDAHSLFWQGRNLASG EVGFFPSDAVKPCPCVPKPVDYSCQPWYAGAMERLQAETELINRVNSTYLVRHRTKES GEYAISIKYNNEAKHIKILTRDGFFHIAENRKFKSLMELVEYYKHHSLKEGFRTLDTTLQF PYKEPEHSAGQRGNRAGNSLLSPKVLGIAIARYDFCARDMRELSLLKGDWKIYTKMSA NGWWRGEVNGRVGWFPSTYVEEDE (SEQ ID NO: 15). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 15 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 15. For example, a person of ordinary skill in the art can readily identify a homolog of human VAV3 protein having a sequence of SEQ ID NO: 15 in an organism of interest and then assay such VAV3 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. SIRT3 protein is also found in several organisms, including humans. In humans, an example of SIRT3 protein is described in UniProt database with ID NO.: Q9NTG7. The sequence of a human SIRT3 protein is given below: MAFWGWRAAAALRLWGRWERVEAGGGVGPFQACGCRLVLGGRDDVSAGLR GSHGARGEPLDPARPLQRPPRPEVPRAFRRQPRAAAPSFFFSSIKGGRRSISFSVGASSW GSGGSSDKGKLSLQDVAELIRARACQRVWMVGAGISTPSGIPDFRSPGSGLYSNLQQY DLPYPEAIFELPFFFHNPKPFFTLAKELYPGNYKPNVTHYFLRLLHDKGLLLRLYTQNIDG LERVSGIPASKLVEAHGTFASATCTVCQRPFPGEDIRADVMADRVPRCPVCTGVVKPDI VFFGEPLPQRFLLHWDFPMADLLLILGTSLEVEPFASLTEAVRSSVPRLLINRDLVGPLA WHPRSRDVAQLGDVVHGVESLVELLGWTEEMRDLVQRETGKLDGPDK (SEQ ID NO: 16). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 16 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 16. For example, a person of ordinary skill in the art can readily identify a homolog of human SIRT3 protein having a sequence of SEQ ID NO: 16 in an organism of interest and then assay such SIRT3 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. SERPINB8 protein is also found in several organisms, including humans. In humans, an example of SERPINB8 protein is described in UniProt database with ID NO.: P50452. The sequence of a human SERPINB8 protein is given below: MDDLCEANGTFAISLFKILGEEDNSRNVFFSPMSISSALAMVFMGAKGSTAAQMS QALCLYKDGDIHRGFQSLLSEVNRTGTQYLLRTANRLFGEKTCDFLPDFKEYCQKFYQA ELEELSFAEDTEECRKHINDWVAEKTEGKISEVLDAGTVDPLTKLVLVNAIYFKGKWNE QFDRKYTRGMLFKTNEEKKTVQMMFKEAKFKMGYADEVHTQVLELPYVEEELSMVIL LPDDNTDLAWEKALTYEKFKAWTNSEKLTKSKVQVFLPRLKLEESYDLEPFLRRLGMI DAFDEAKADFSGMSTEKNVPLSKVAHKCFVEVNEEGTEAAAATAWRNSRCSRMEPRF CADHPFLFFIRHHKTNCILFCGRFSSP (SEQ ID NO: 17). Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject for a ratio between the levels of two proteins, one of which is the protein having the sequence of SEQ ID NO: 17 or a protein having at least 70%, such as at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% sequence identity to the sequence of SEQ ID NO: 17. For example, a person of ordinary skill in the art can readily identify a homolog of human SERPINB8 protein having a sequence of SEQ ID NO: 17 in an organism of interest and then assay such SERPINB8 protein in a sample obtained from such organism. Such embodiments are within the purview of the invention. The markers being assayed are also referenced herein as “target markers.” A pair of markers, the ratio of the levels of which is determined, is called a “target marker pair.” The proteins being assayed are also referenced herein as “target proteins.” A pair of proteins, the ratio of the levels of which is determined, is called a “target protein pair.” The sample may be obtained from a subject having or suspected of having a cognitive impairment. A sample may be any convenient biological sample. A “biological sample” refers to both the native organism or a subset of its tissues as well as to a homogenate, lysate or extract prepared from the organism or a subset of its tissues, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, sections of the skin, respiratory, gastrointestinal, cardiovascular, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. Biological samples may be any type of organismic tissue, including both healthy and diseased tissue (e.g., cancerous, malignant, necrotic, etc.). In certain embodiments, the biological sample is a liquid sample, such as blood or derivative thereof, e.g., plasma, tears, urine, semen, etc., where in some instances the sample is a blood sample, including whole blood, such as blood obtained from venipuncture or fingerstick (where the blood may or may not be combined with any reagents prior to assay, such as preservatives, anticoagulants, etc.). Additional examples of biological samples are well known to a person of ordinary skill in the art and such embodiments are within the purview of the invention. Methods of obtaining such samples from subjects are also well known in the art and such embodiments are within the purview of the invention. The term “expression” is used herein to mean the process by which a polypeptide is produced from DNA. The process involves the transcription of the gene into mRNA and the translation of this mRNA into a polypeptide. Depending on the context in which used, “expression” may refer to the production of RNA, protein or both. The term "expression level" or “level of expression”, are used interchangeably and refers to the measurable quantity of an expression product, produced by a gene, in a sample of the subject, wherein the expression product can be a transcriptional product or a translational product. As understood by the person skilled in the art, the expression level can be quantified by measuring the messenger RNA levels of said gene or by measuring the levels of the protein encoded by said gene (including all the physiologically relevant post-translational chemical modifications forms of the protein, for example, glycosylation, phosphorylation, acetylation, etc., provided that the functionality of the protein is maintained). In some cases, the methods disclosed herein comprise quantitatively assaying the sample for the one or more target markers. In some cases, the methods disclosed herein comprise quantitatively assaying the sample for the one or more target proteins. Certain non-limiting examples of quantitatively assaying one or more target proteins include immunoassays, mass-spectrometry analyses, and protein detecting array analyses. An immunoassay typically comprises contacting a sample with a binding agent that specifically binds to a target protein and then detecting the binding between the binding agent and the target protein. Such detecting can comprise detecting a label conjugated to the binding agent or a label conjugated to a second binding agent that specifically binds to the binding agent and / or the binding agent-target protein complex. The binding agent is typically an antibody or an antigen binding fragment of an antibody. The binding agent can also be an aptamer, or a peptide binding member. Non-limiting examples of immunoassays include westem-blot analysis, enzyme-linked immunosorbent assay (ELISA), radio-immune assay (RIA), lateral flow immunoassays, particle based immunoassays, quantum dots based immunoassays, etc. Details of the methods of performing certain exemplary immunoassays are described in a review article by Rizzo (2022), Chemosensors, 10(8), 326, the contents of which are incorporated herein by reference in its entirety. Mass-spectrometry for detecting target proteins typically involve digesting a sample containing proteins into peptides, ionizing the peptides, and analyzing the ionized peptides to determine the identity of the digested proteins. Because of unique sequences of the proteins, specific digestion of target proteins produces unique digested and ionized peptides, which are identified in a mass-spectrometer. Presence and amount of such unique ionized peptides facilitates target protein identification. Non-limiting examples of mass-spectrometry methods for assaying one or more target proteins include quadrupole mass spectrometry, time of flight mass spectrometry, magnetic sector mass spectrometry, electrostatic sector mass spectrometry, quadrupole ion trap mass spectrometry, and ion cyclotron resonance spectrometry. Details of the methods of performing certain exemplary mass spectrometry based assays are described in a review article by Ma (2022), Molecules, 27, 6466, the contents of which are incorporated herein by reference in its entirety. Protein detecting array analysis involves detecting binding of a target protein in a sample to binding agents, typically antibodies localized in defined locations on a support. A sample is contacted with such an array and binding of a target protein to corresponding binding agent, such as antibody in a localized spot on the solid support, is visualized, for example, using detectable labels. For example, captured target proteins can be detected and / or quantified by a labeled secondary antibody, for example, a fluorescent dye labeled secondary antibody. Alternatively to binding agents localized on a solid support, lysate microarrays comprise immobilizing a lysate of a sample onto a support, such as nitrocellulose-coated glass slides. The immobilized proteins are then detected using detectable label-conjugated solution-phase binding agents, such as fluorescent-labeled solution-phase specific antibodies. Differentially labeled binding agents, such as various fluorescent-labeled antibodies to different target proteins allows multiplexed detection of proteins thus allowing simultaneously assaying two or more proteins. Non-limiting examples of protein detecting array analyses include analytical protein microarrays, functional protein microarrays, and reverse-phase protein microarrays. A person of ordinary skill in the art can determine a suitable protein microarray for use in the methods disclosed herein. Details of the methods of performing certain exemplary protein detecting array analysis are described in a review article by Neagu et al. (2019), World Acad. Set. J., 1:113-124, the contents of which are incorporated herein by reference in its entirety. In some cases, the ratio of the levels of protein pairs described herein are analyzed in a subject’s sample using SomaScan™ assay. Certain details of SomaScan™ assays are described in the reference Gold et al. (2010), PLoS One; 5(12): el 5004, which is incorporated herein in its entirety. Briefly, SomaScan™ assay uses aptamers, called SOMAmers, that specifically bind to target proteins. The assay involves binding the SOMAmers to target proteins in a sample and isolating the SOMAmers such that a complex mixture of SOMAmers is produced containing SOMAmers proportional to the proteins present in the sample. The resulting mixture of SOMAmers is quantified using a DNA microarray technique to produce relative fluorescence units (RFU) readout. Thus, a SomaScan™ assay provides the levels of various proteins in a sample as “relative fluorescence units” (RFU) or a derivative of RFU, such as log2RFU. A ratio between the levels of proteins in a target protein pair can be determined based on the RFU values or derivative of RFU values, such as log2RFU. The ratio data provided below were obtain following this SomaScan™ technology. In some cases, the methods disclosed herein comprise quantitatively assaying the sample for the one or more target mRNA markers. Suitable methods to determine gene expression levels at the mRNA level include, without limitation, standard assays for determining mRNA expression levels such as qPCR, RT-PCR, RNA protection analysis, Northern blot, RNA dot blot, in situ hybridization, microarray technology, tag based methods such as serial analysis 15 of gene expression (SAGE) including variants such as LongSAGE and SuperSAGE, microarrays, fluorescence in situ hybridization (FISH), including variants such as Flow-FISH, qFiSH and double fusion FISH (D-FISH), and the like. In some cases, the ratio between markers is determined by (a) determining the level (i.e., amount or concentration) of each one of the markers (either in the form of protein or mRNA) expressed in the same units, and (b) determining the ratio of the level (i.e., amount or concentration) of one marker vs another marker. In some cases, the methods comprise assaying a sample for a ratio between the expression levels of any two markers selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. In some cases, the methods comprise assaying a sample for a ratio between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. In some cases, one of the two proteins in the assayed protein pair is DLL1. When one of the two proteins is DLL1, the other protein can be a protein selected from: SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8, particularly, from: SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB. In one embodiment, when one of the two markers is DLL1, the ratio is calculated as the level of expression of DLL1 with respect to the level of expression of a marker selected from: SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8, particularly, of a marker selected from: SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB. In certain embodiments, the methods comprise assaying a sample for a ratio between the levels of the following marker pair, particularly protein pairs: i. DLL1 and SMOC1 (particularly ratio DLLESMOCl), ii. DLL1 and CD59 (particularly ratio DLLECD59), iii. DLL1 and LEFTY2 (particularly ratio DLL1 :LEFTY2), iv. DLL1 and UNC5B (particularly ratio DLLEUNC5B), v. DLL1 and C5 (particularly ratio DLLEC5), vi. DLL1 and C5.C6 (particularly ratio DLL1 :C5.C6), vii. DLL1 and INHBB (particularly DLLEINHBB). In some cases, one of the two proteins in the assayed protein pair can be PARP11. When one of the two proteins is PARP11, the other protein can be selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8, particularly, from: POLD4, ASH2L, RPS3, and SERPINB8. When one of the two markers is PARP11, then the ratio is calculated as: the level of expression of one marker selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8, particularly, from POLD4, ASH2L, RPS3, and SERPINB8, divided by the level of expression of PARP11. In certain embodiments, the methods comprise assaying a sample for a ratio between the levels of the following protein pairs: i.     POLD4 and PARP11 (particularly, ratio POLD4:PARP11), ii.     ASH2L and PARP11 (particularly, ratio ASH2L:PARP11), iii. RPS3 and PARP11 (particularly, ratio RPS3:PARP11), and iv. SERPINB8 and PARP11 (particularly, ratio SERPINB8:PARP11). In some cases, the methods comprise assaying a sample for a ratio between the levels of the following protein pairs: i. TSTD1 and STAT3 (particularly, ratio TSTD1:STAT3), and ii. VAV3 and SIRT3 (particularly, ratio VAV3:SIRT3). Thus, in certain embodiments, the methods comprise assaying the sample for the ratio between the levels of DLL1 and SMOC1. In certain embodiments, the methods comprise assaying the sample for the ratio between the levels of DLL1 and CD59. In some cases, the methods comprise assaying the sample for the ratio between the levels of DLL 1 andLEFTY2. In further embodiments, the methods comprise assaying the sample for the ratio between the levels of DLL1 and UNC5B. In even further embodiments, the methods comprise assaying the sample for the ratio between the levels of DLL1 and C5. In some cases, the methods comprise assaying the sample for the ratio between the levels of DLL 1 andC5.C6. In additional cases, the methods comprise assaying the sample for the ratio between the levels of DLL1 and INHBB. In certain cases, the methods comprise assaying the sample for the ratio between the levels ofTSTDl and STAT3. In further cases, the methods comprise assaying the sample for the ratio between the levels ofPOLD4and PARP11. In even further cases, the methods comprise assaying the sample for the ratio between the levels of ASH2L and PARP11. In some cases, the methods comprise assaying the sample for the ratio between the levels ofRPS3 andPARPll. In certain cases, the methods comprise assaying the sample for the ratio between the levels of VAV3 and SIRT3. In certain cases, the methods comprise assaying the sample for the ratio between the levels of SERPINB8 and PARPI1. The methods of assaying a sample for a ratio between the levels of any two proteins as disclosed herein may further comprise comparing the assay results to a reference ratio. A reference ratio refers to a ratio between the levels of proteins in a protein pair that could be used to distinguish between a subject that is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment and a subject that is not likely to respond positively to a plasma exchange therapy for treating a cognitive impairment. A reference ratio may be a predetermined ratio, for example, based on a ratio between the expression levels of a marker pair in individuals that are known to have responded to therapies for a cognitive impairment. Particularly, the reference ratio may be a predetermined ratio, for example, based on a ratio between the levels of a protein pair in individuals that are known to have responded to therapies for a cognitive impairment. For example, retrospective assays for certain protein pairs may be performed in a group of subjects that responded to a therapy for a cognitive impairment. These retrospective assays may be used to determine a reference ratio that indeed indicates the likelihood that a subject is responsive to a therapy for a cognitive impairment. In specific embodiments, the therapy is a plasma exchange therapy, e.g., as described in detail below. Alternatively, a reference ratio may be predetermined, for example, based on a ratio between the expression levels of a marker pair in individuals that are known not to have responded to therapies for a cognitive impairment. Particularly, the reference ratio may be predetermined, for example, based on a ratio between the levels of proteins in a protein pair in individuals that are known not to have responded to therapies for a cognitive impairment. For example, retrospective assays for certain protein pairs may be performed in a group of subjects that did not respond to a therapy for a cognitive impairment. These retrospective assays may be used to determine a reference ratio that indeed indicates the likelihood that a subject is not responsive to a therapy for a cognitive impairment. In specific embodiments, the therapy is a plasma exchange therapy, which is described in detail below. A reference sample may contain target marker pairs at relative levels that are known to indicate responsiveness of a subject to a plasma exchange therapy for treating a cognitive impairment. A reference sample may contain target protein pairs at relative levels that are known to indicate responsiveness of a subject to a plasma exchange therapy for treating a cognitive impairment. The samples for assaying one or more target protein pairs in the methods disclosed herein may be obtained from a subject that has a cognitive impairment. Alternatively, the samples for assaying one or more target protein pairs in the methods disclosed herein may be obtained from a subject that is suspected of having a cognitive impairment. The term “a subject that has a cognitive impairment” as used herein refers to a subject that exhibits symptoms of a cognitive impairment. The term “an individual that is suspected of having a cognitive impairment” as used herein refers to a subject that exhibits symptoms of other conditions that are associated with cognitive impairment. For example, and as discussed in detail later, subjects may show certain signs of neurodegenerative diseases, such as AD or Parkinson’s disease, but haven’t yet developed cognitive impairment. Such subjects are encompassed by the term “subjects are suspected of having a cognitive impairment.” In certain embodiments, a cognitive impairment is caused by a neurodegenerative disease. Non-limiting examples of neurodegenerative disease that may cause a cognitive impairment include Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, and vascular dementia. These diseases are described below and additional information about these diseases is well-known in the art. In specific embodiments, the neurodegenerative disease is AD, i.e., a subject has a cognitive impairment caused by AD. In certain embodiments, the sample is obtained from a subject that is a candidate for a plasma exchange therapy for treating the cognitive impairment. Any suitable sample from a subject may be assayed according to the methods disclosed herein. In specific embodiments, the sample is a blood sample, a serum sample, a plasma sample, or a cerebrospinal fluid sample. In some cases, a sample may be aqueous humor, vitreous humor, bile, chyle, endolymph, perilymph, lymph, mucus (including nasal drainage and phlegm), pericardial fluid, peritoneal fluid, pleural fluid, pus, rheum, saliva, sputum, or synovial fluid. Additional examples of biological samples are well known to a person of ordinary skill in the art and such embodiments are within the purview of the invention. Methods of obtaining such samples from subjects are also well known in the art and such embodiments are within the purview of the invention. D. Diagnostic methods Certain aspects of the invention provide, further to assaying the ratio of the levels of one or more marker pairs in a sample obtained from a subject, as provided in any of the previous embodiments, whether the subject is likely or not likely to respond positively to a therapy for treating a cognitive impairment in the subject. In some embodiments, the therapy is a plasma exchange therapy. Details of plasma exchange therapies that could be administered according to the invention are discussed in detail below and are applicable to the diagnostic methods described herein. All the embodiments provided under “Assay methods” section are also embodiments of any of the diagnostic methods provided hereinafter. The expression "respond positively to" or “likely to respond positively to” a therapy, as used herein, refers to an improvement in one or more symptoms of a cognitive disorder or condition a patient is affected with. Preferably, it refers to at least a statistically significant improvement of cognitive ability measured as described below. The terms "improvement" and "enhancement" may be used interchangeably. For example, according to the present invention, a favorable response of a patient affected by a neuro degenerative disease, such as AD, to treatment may be improvement in the cognitive function, such as improvement in learning, plasticity, and / or long term memory. The inventors have found that some inflammation-related markers (in particularly those listed in previous embodiments) were differentially expressed in responders and no-responders, and that a robust predictive information, in terms of predicting response to PE therapy, could be provided when the expression level ratio between marker pairs was calculated. Thus, in some embodiments, the subject is identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of an assay of a sample of the subject for a ratio between the expression levels of any two markers, particularly the ratio between the levels of any two proteins, selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. For example, a subject is identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio of one or more of the following combinations of markers, particularly proteins: i. DLL1 and SMOC1 (particularly ratio DLL1 / SMOC1), ii. DLL1 and CD59 (particularly ratio DLL1 / CD59), iii. DLL1 and LEFTY2 (particularly ratio DLL1 / LEFTY2), iv. DLL1 and UNC5B (particularly ratio DLL1 / UNC5B), v. DLL1 and C5 (particularly ratio DLL1 / C5), vi. DLL1 and C5.C6 (particularly ratio DLL1 / C5.C6), vii. DLL1 and INHBB (particularly ratio DLL1 / INHBB), viii. TSTD1 and STAT3 (particularly ratio TSTD1 / STAT3), ix.    POLD4 and PARP11 (particularly ratio POLD4 / PARP11), x.     ASH2L and PARP11 (particularly ratio ASH2L / PARP11), xi. RPS3 and PARP11 (particularly ratio RPS3 / PARP11), xii. VAV3 and SIRT3 (particularly ratio VAV3 / SIRT3), and xiii. SERPINB8 and PARP11 (particularly ratio SERPINB8 / PARP11). In certain embodiments of determining, based on the results of the assay, whether the subject is likely or not likely to respond positively to a therapy for treating a cognitive impairment in the subject comprises comparing the assay results to a reference ratio. As noted above, such reference ratio may be predetermined, for example, based on the relative expression level of one, two or more assayed marker pairs, particularly protein pairs, in individuals that are known to have responded to therapies for a cognitive impairment. For example, retrospective assays for the one or more ratios between protein pairs may be performed in a group of subjects that responded to a therapy for a cognitive impairment. These retrospective assays may be used to determine a reference ratio that indeed indicates the likelihood that a subject is responsive to a therapy for a cognitive impairment. In specific embodiments, the therapy is a plasma exchange therapy, which is described in detail below. Also, as noted above, such reference ratio may be predetermined, for example, based on the relative expression level of one or more assayed marker pairs, particularly protein pairs, in individuals that are known not to have responded to therapies for a cognitive impairment. For example, retrospective assays for the relative levels of one or more protein pairs may be performed in a group of subjects that did not respond to a therapy for a cognitive impairment. These retrospective assays may be used to determine a reference ratio that indeed indicates the likelihood that a subject is responsive to a therapy for a cognitive impairment. In specific embodiments, the therapy is a plasma exchange therapy, which is described in detail below. A reference sample may contain markers from a target marker pairs at concentrations that are known to indicate responsiveness of a subject to a plasma exchange therapy for treating a cognitive impairment. A reference sample may contain proteins from a target protein pairs at concentrations that are known to indicate responsiveness of a subject to a plasma exchange therapy for treating a cognitive impairment. In some embodiments, the subject is identified as likely or not likely to respond positively to a plasma exchange therapy for treating the cognitive impairment based on different ratios in the expression levels of markers, particularly level of protein markers, in the sample obtained from the subject compared to a reference ratio. As discussed above, in some cases, the levels of the proteins described herein are analyzed in a patient sample using SomaScan™ assay. Table 1 below shows the identified candidate plasma protein pairs based on Spearman correlation. Table 1. Various protein pairs and their correlation with CDR-sb change. Association with CDR-sb change at EOS Identified candidate protein pair rho p value DLL1 / SMOC1 -0.6452961 1.15E-11 DLL1 / CD59 -0.6272522 6.20E-11 TSTD1 / STAT3 -0.6266781 6.53E-11 POLD4 / PARP11 -0.6061878 3.88E-10 DLL1 / LEFTY2 -0.5966138 8.57E-10 DLL1 / UNC5B -0.5910143 1.34E-09 DLL1 / C5 -0.5835512 2.42E-09 DLL1 / C5.C6 -0.5778987 3.74E-09 ASH2L / PARP11 -0.5712394 6.17E-09 DLL1 / INHBB -0.5643062 1.03E-08 RPS3 / PARP11 -0.5637586 1.07E-08 VAV3 / SIRT3 -0.558742 1.54E-08 SERPINB8 / PARP11 -0.5536106 2.21E-08 • 13 protein pairs identified, involving 17 proteins. • 7 out of 13 (61.5%) protein pairs involved in DLL1, 4 (30.8%) of them with PARP11, 4 5 proteins involved in inflammation: CD59, STAT3, C5, C5.C6. Tables 2-3 below shows the evaluation of prediction powers of identified candidate serum protein pairs on treatment benefits: Table 2: Prediction power for treatment benefit (CDR-sb at EOS better than baseline). Prediction power for treatment benefit (CDR-sb at EOS better than baseline) Protein pairs AUCbetter (CI %) Thresholdbetter Sensitivity_ better Specificitybetter Accuracybetter DLL1 / SMOC1 80.8(70.7,91.0) 0.78265 17(63.0%) 56(91.8%) 73(83.0%) DLL1 / CD59 80.7(70.6,90.8) 0.89667 20(74.1%) 52(85.2%) 72(81.8%) TSTD1 / STAT3 85.1(75.9,94.2) 0.85863 23(85.2%) 53(86.9%) 76(86.4%) POLD4 / PARP11 86.9(78.1,95.8) 0.83544 25(92.6%) 46(75.4%) 71(80.7%) DLL1 / LEFTY2 84.6(75.6,93.6) 0.81600 21(77.8%) 52(85.2%) 73(83.0%) DLL1 / UNC5B 80.5(69.4,91.6) 0.83009 20(74.1%) 54(88.5%) 74(84.1%) DLL1 / C5 80.8(70.8,90.9) 0.84965 19(70.4%) 52(85.2%) 71(80.7%) DLL1 / C5.C6 80.6(70.9,90.3) 0.99646 24(88.9%) 42(68.9%) 66(75.0%) ASH2L / PARP11 83.7(73.0,94.3) 0.96355 22(81.5%) 52(85.2%) 74(84.1%) DLL1 / INHBB 80.3(69.5,91.0) 0.83381 22(81.5%) 49(80.3%) 71(80.7%) RPS3 / PARP11 86.5(76.3,96.7) 0.81703 22(81.5%) 55(90.2%) 77(87.5%) VAV3 / SIRT3 79.8(68.9,90.7) 1.04476 22(81.5%) 46(75.4%) 68(77.3%) SERPINB8 / PAR Pll 82.4(72.0,92.8) 0.9429 23(85.2%) 48(78.7%) 71(80.7%) Table 3: Prediction power for treatment benefit (CDR-sb change < 1 point increase to bl) Protein information Prediction power for treatment benefit (CDR-sb change < 1 point increase to bl) Protein ratio AUCCMC (CI %) Threshold CMC Sensitivity CMC Specificity CMC Accuracy CMC3 DLL1 / SMOC1 83.3(75.0,91.6) 0.76732 36(76.6%) 32(78.0%) 68(77.3%) DLL1 / CD59 82.0 (73.3,90.8) 0.87300 40(85.1%) 28(68.3%) 68(77.3%) TSTD1 / STAT3 79.9(70.5,89.2) 0.85835 29(61.7%) 38(92.7%) 67(76.1%) POLD4 / PARP11 80.2(70.6,89.8) 0.83544 35(74.5%) 36(87.8%) 71(80.7%) DLL 1 / LEFT Y2 77.3(67.5,87.0) 0.81671 26(55.3%) 39(95.1%) 65(73.9%) DLL1 / UNC5B 79.2(69.8,88.6) 0.82501 29(61.7%) 39(95.1%) 68(77.3%) DLL1 / C5 79.2(70.0,88.5) 0.83604 31(66.0%) 35(85.4%) 66(75.0%) DLL1 / C5.C6 81.4(72.2,90.5) 0.98761 39(83.0%) 32(78.0%) 71(80.7%) ASH2L / PARP11 79.5(70.0,89.0) 0.94690 33(70.2%) 36(87.8%) 69(78.4%) DLL1 / INHBB 81.0(71.8,90.1) 0.83381 31(66.0%) 38(92.7%) 69(78.4%) RPS3 / PARP11 78.4(68.5,88.4) 0.78255 35(74.5%) 34(82.9%) 69(78.4%) VAV3 / SIRT3 80.1(70.4,89.8) 1.04343 36(76.6%) 35(85.4%) 71(80.7%) SERPINB8 / PARP11 78.0(68.2,87.8) 0.92421 34(72.3%) 31(75.6%) 65(73.9%) CMC= Clinically Meaningful change; 2019 Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials] Generally, Tables 2 and 3 demonstrates the strong predictive power of the protein ratio 5 pairs for treatment benefit, as indicated by the CDR-sb scores at the end of the study being better than baseline. The high AUC values, along with sensitivity and accuracy metrics, highlight the effectiveness of these biomarkers in predicting cognitive improvement. Table 4 below shows in silico verification in other clinical outcome, AUC for predicting better than baseline or not at least worsening larger than CMC. 10 Table 4. Verification with another clinical outcome from AMBAR clinical trial. ADASCog change at EOS (n = 88, CMC: 3 points). ADAS Cog change at EOS (n = 88, CMC: 3 points) Protein ratio rho p. value AUC_better(CI %) AUC_CMC(CI %) DLL1 / SMOC1 -0.479 2.30E-06 76.0(65.9,86.2) 70.4(59.5,81.4) DLL1 / CD59 -0.415 5.89E-05 70.9(59.9,82.0) 64.6(52.9,76.2) TSTD1 / STAT3 -0.483 1.86E-06 70.8(58.9,82.7) 70.6(59.6,81.7) DLL1 / LEFTY2 -0.454 9.01E-06 72.7(61.8,83.5) 68.7(57.7,79.7) DLL1 / UNC5B -0.396 1.33E-04 70.3(58.9,81.6) 63.0(51.3,74.7) DLL1 / C5 -0.440 1.76E-05 74.0(63.1,84.9) 69.1(58.1,80.2) DLL1 / C5.C6 -0.488 1.46E-06 73.5(62.7,84.4) 71.3(60.4,82.2) ASH2L / PARP11 -0.448 1.18E-05 71.5(59.8,83.2) 68.6(57.1,80.1) DLL1 / INHBB -0.402 1.05E-04 70.2(58.1,82.2) 65.1(53.6,76.6) RPS3 / PARP11 -0.453 9.49E-06 72.8(60.9,84.7) 70.5(59.5,81.6) SERPINB8 / PARP11 -0.412 6.79E-05 70.5(58.7,82.3) 69.8(58.7,80.8) Table 4 presents the predictive power of various protein ratio pairs for treatment benefit, as indicated by the ADAS Cog scores at the end of the study compared to baseline. The AUC values, and the sensitivity and accuracy metrics, highlight the effectiveness of these biomarkers in predicting cognitive improvement. In some cases, the results of the assay for the ratio between the expression levels of a marker pair can be compared to a reference ratio for that corresponding marker pair. As a person skilled in the art would recognize, reference ratios for comparison would depend on the type of sample, for example, blood sample or cerebrospinal fluid sample. In some cases, the results of the assay for the ratio between the levels of a protein pair can be compared to a reference ratio for that corresponding protein pair. As a person skilled in the art would recognize, reference ratios for comparison would depend on the type of sample, for example, blood sample or cerebrospinal fluid sample. Statistical Analysis Certain terms used in statistical analyses of the data obtained by analyzing body fluid samples of the subject are described below. These statistical analyses can be used to identify a subject as likely or not likely to respond positively to a treatment of a cognitive impairment based on the ratios between one or more protein pairs in a sample from the subject. Firstly, treatment benefits were confirmed by comparing clinical outcome changes between treated and placebo groups. Candidate protein pairs were then identified by significant Spearman correlation coefficient between baseline ratios of the levels of proteins in protein pairs measured by certain assays (here by SomaScan assay) and changed cognitive outcomes at the end of study (Table 1). The predictive powers of these candidate protein pairs to indicate whether the subject will have better cognitive outcomes (with treatment benefit) or not (without treatment benefit) after treatment is evaluated by Receiving Operating Characteristics (ROC) and measured by Area Under the Curve (AUC) of ROC. ROC is a plot of sensitivity over specificity for a plurality of threshold values for a protein pair. ROC is used to show the predictive power of a continuous protein pair on binary outcome, e.g., has treatment benefit vs does not have treatment benefit. AUC represents the probability of correctly ordering patients with or without treatment benefits based on the continuous protein pair. Typically, AUC > 70% is considered acceptable and AUC > 80% is considered to have excellent prediction. High or low protein ratio is then defined by optimal decision threshold. For example, best cut off point or the reference value of baseline protein ratio can be defined based on Youden’s index, which maximizes the accuracy (overall rate of correct classification as shown in Table 5 below). The best binary protein pairs were finally identified based on their prediction powers measured by accuracy, specificity and sensitivity (their calculations are explained below and shown in Table 5). Al, Bl, AO, and BO used in the following paragraphs are as shown in the Table 5 below: Table 5 Truly have treatment benefit (1) Truly did not have treatment benefit (0) High protein ratio (will have treatment benefit) Al A0 Low protein ratio (will not have treatment benefit) Bl B0 Accuracy represents the percentage of right classification: i.e., (number of subjects that truly have treatment benefit + the number of subj ects that truly did not have treatment benefit) / total number of predictions. ((Al + B0) / N, N = total number of predictions.) Specificity represents true negative rate, i.e., percentage of subjects truly with no treatment benefit of the total number of subjects predicted not to have treatment benefit (B0 / (A0 + BO). Sensitivity represents true positive rate, i.e., percentage of subjects truly with treatment benefit of the total number of subjects predicted to have treatment benefit (Al / (Al + Bl)). These identified protein pairs were then in silico verified, such as testing in other clinical outcomes, in random reselected samples, in other visits or / and in similar clinical trials. According to the methods described herein, at least 60%, such as, at least 70%, at least 80%, or at least 90% of the subjects identified as likely to respond positively to a treatment for a cognitive impairment actually respond positively to a treatment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below. Conversely, according to the methods described herein, at least 60%, such as, at least 70%, at least 80%, or at least 90% of the patients identified as not likely to respond positively to a treatment for a cognitive impairment actually do not respond positively a treatment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below. In some cases, a subject identified as not likely to respond positively to a treatment, such as a plasma exchange therapy, for a cognitive impairment is not administered a treatment, such as a plasma exchange therapy. In some cases, the ratio of the levels of proteins for the protein pairs described herein that 5 indicate whether a subject is likely or not likely to respond positively to a plasma therapy for treating a cognitive impairment are as provided in Table 6 below: Table 6. The ratios of the levels of different protein pairs in blood that indicate whether a subject is likely or not likely to respond positively (better than baseline) to a plasma therapy (e.g., the plasma therapy described in the Experimental section below) for treating a cognitive 10 impairment. Protein pair Ratio DLL1 / SMOC1 0.78265 DLL1 / CD59 0.89667 TSTD1 / STAT3 0.85863 POLD4 / PARP11 0.83544 DLL1 / LEFTY2 0.81600 DLL1 / UNC5B 0.83009 DLL1 / C5 0.84965 DLL1 / C5.C6 0.99646 ASH2L / PARP11 0.96355 DLL1 / INHBB 0.83381 RPS3 / PARP11 0.81703 VAV3 / SIRT3 1.04476 SERPINB8 / PARP11 0.94290 Ratio for predicting better than baseline scores of CDR-sb after treatment: ratios higher than the ratio mentioned in the table indicates treatment benefit and ratios lower than the ratio mentioned in the table indicates lack of treatment benefit. 15 As shown in Table 6, in some cases, the invention provides ratios of the levels of different protein pairs in blood for indicating treatment benefit better than baseline of CDR-sb. For example, if a blood sample from a subject shows the ratio of DLL1 / SMOC1 higher than Ratio mentioned in Table 6, the subject is likely to experience treatment benefit better than baseline of CDR-sb. If a blood sample from a subject shows the ratio of DLL1 / SMOC1 lower than Ratio mentioned in Table 6, the subject is not likely to experience treatment benefit better than baseline of CDR-sb. Similar indications of treatment benefits or lack thereof can be made for each of the protein pairs listed in Table 6 based on the corresponding values of Ratio. In some embodiments, the method may comprise providing a report indicating whether the subject is likely or not likely to be responsive to a plasma therapy for treating a cognitive impairment. In some embodiments, this step may involve calculating a score based on the results of the assays for the ratios of one or more protein pairs, where the scores correlate with the responsiveness and can be a number such as a probability, likelihood or score out of 10. In these embodiments, the method may comprise inputting the amounts of each of the ratios of the protein pairs into one or more algorithms or calculations, executing the algorithms or calculation, and receiving a score based on the calculations. In these embodiments, other measurements from the subject, e.g., whether the subject is male or female, the age of the subject, current extent of cognitive impairment, etc. may be considered in the algorithm or calculations. In some embodiments, the method may involve creating the report e.g., in an electronic form, and forwarding the report to a doctor or other medical professional to help identify a suitable course of action, e.g., to identify a subject as suitable for plasma exchange therapy for treating a cognitive impairment. The report may be used along with other metrics to determine a proper course of action. In some cases, a report can be forwarded to a “remote location”, where “remote location,” means a location other than the location at which the report is generated. For example, a remote location could be another location (e.g., office, lab, etc.) in the same city, another location in a different city, another location in a different state, another location in a different country, etc. As such, when one item is indicated as being “remote” from another, the two items can be in the same room but separated, or at least in different rooms or different buildings, and can be at least one mile, ten miles, or at least one hundred miles apart. “Communicating” information references transmitting the data representing that information as electrical signals over a suitable communication channel (e.g., a private or public network). “Forwarding” an item refers to any means of getting that item from one location to the next, whether by physically transporting that item or otherwise (where that is possible) and includes, at least in the case of data, physically transporting a medium carrying the data or communicating the data. Examples of communicating media include radio or infra-red transmission channels as well as a network connection to another computer or networked device, and the internet or including email transmissions and information recorded on websites and the like. In certain embodiments, the report may be analyzed by an MD or other qualified medical professional, and a report based on the results of the analysis of the image may be forwarded to the subject from which the sample was obtained. In computer-related embodiments, a system may include a computer containing a processor, a storage component (i.e., memory), a display component, and other components typically present in general purpose computers. The storage component stores information accessible by the processor, including instructions that may be executed by the processor and data that may be retrieved, manipulated or stored by the processor. The storage component includes instructions for determining whether the subject is likely to be responsive to a plasma exchange therapy for treating a cognitive impairment using the results of the assay for one or more proteins as discussed above. The computer processor is coupled to the storage component and configured to execute the instructions stored in the storage component in to receive patient data and analyze patient data according to one or more algorithms or calculations. The display component may display information regarding the responsiveness of the patient to a plasma therapy for treating a cognitive impairment. The storage component may be of any type capable of storing information accessible by the processor, such as a hard-drive, memory card, ROM, RAM, DVD, CD-ROM, USB Flash drive, write-capable, and read-only memories. The processor may be any well-known processor, such as processors from Intel Corporation. Alternatively, the processor may be a dedicated controller such as an ASIC. The instructions may be any set of instructions to be executed directly (such as machine code) or indirectly (such as scripts) by the processor. In that regard, the terms “instructions,” “steps” and “programs” may be used interchangeably herein. The instructions may be stored in object code form for direct processing by the processor, or in any other computer language including scripts or collections of independent source code modules that are interpreted on demand or compiled in advance. Data may be retrieved, stored or modified by the processor in accordance with the instructions. For instance, although the system disclosed herein is not limited by any particular data structure, the data may be stored in computer registers, in a relational database as a table having a plurality of different fields and records, XML documents, or flat files. The data may also be formatted in any computer-readable format such as, but not limited to, binary values, ASCII or Unicode. Moreover, the data may comprise any information sufficient to identify the relevant information, such as numbers, descriptive text, proprietary codes, pointers, references to data stored in other memories (including other network locations) or information which is used by a function to calculate the relevant data. E. Treatment methods Certain aspects of the invention provide, further to determining a subject as likely or not likely to respond positively to a therapy for a cognitive impairment, treating the subject for the cognitive impairment by administering the therapy to the subject. All the embodiments provided under the section “Diagnostic methods” are also embodiments encompassed by the section of “Treatment methods”. Thus, certain aspects of the invention provides methods for treating a subject for cognitive impairment, the method comprising administering to the subject a plasma exchange therapy, wherein the subject is identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment. In some cases, the subject is identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on results of an assay of a sample of the subject for a ratio between the expression levels of any two markers, particularly levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. Details of identifying a subject as likely or not likely to respond positively to the plasma exchange therapy for treating a cognitive impairment based on results of an assay of a sample of the subject for a ratio between the expression levels of any two markers, particularly levels of any two proteins, selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8 are described above under “Diagnostic methods.” Briefly, a subject may be identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the ratio between the expression levels of any two markers, particularly between the levels of any two proteins, selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. In some embodiments, one or more protein pairs are selected from the following: i. DLL1 and SMOC1, particularly DLL1 / SMOC1; ii. DLL1 and CD59, particularly DLL1 / CD59; hi. DLL1 and LEFTY2, particularly DLL1 / LEFTY2; iv. DLL1 and UNC5B, particularly DLL1 / UNC5B; v. DLL1 and C5, particularly DLL1 / C5; vi. DLL1 and C5.C6, particularly DLL1 / C5.C6; vii. DLL1 and INHBB, particularly DLL1 / INHBB; viii. TSTD1 and STAT3, particularly TSTD1 / STAT3; ix. POLD4 and PARP11, particularly POLD4 / PARP11; x. ASH2L and PARP 11, particularly ASH2L / PARP11; xi. RPS3 and PARP11, particularly RPS3 / PARP11; xii. VAV3 and SIRT3, particularly VAV3 / SIRT3; and xiii. SERPINB8 and PARP11; particularly SERPINB8 / PARP11. A subject may be identified as likely or not likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the ratio or ratios of the levels of one or more marker (such as protein) pairs in a sample from a subject compared to a reference ratio. A “plasma exchange therapy” refers to replacing a subject’s plasma, either in its entirety or a fraction, by a plasma replacement solution. Typically, during a plasma exchange therapy, blood is gradually removed from a subject, blood components, such as blood cells and platelets are separated from plasma, a plasma replacement solution is mixed with the separated blood components, and the resultant mixture is returned to the subject. Plasma exchange therapy may comprise replacing substantially all of a subject’s plasma with a plasma replacement solution, which is referenced herein as “full plasma exchange.” In full plasma exchange, substantially all of a subject’s plasma, such as at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of a subject’s plasma is replaced with a plasma exchange solution. In some cases of full plasma exchange, the plasma replacement solution is an albumin solution having between 3% to 10% w / v albumin, such as 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% w / v albumin solution. In one embodiment, the plasma replacement solution for a full plasma exchange is a 5% w / v albumin solution. Plasma exchange therapy may also comprise replacing a portion of a subject plasma with a plasma replacement solution, which is referenced herein as “low volume plasma exchange.” In low volume plasma exchange, between 10% and 50%, such as between 15% and 45%, between 20% and 40%, between 25% and 35%, or about 30% of a subject plasma is replaced with a plasma exchange solution. In some cases of low volume plasma exchange, the plasma replacement solution is an albumin solution having between 15% to 25% w / v albumin, such as 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25% w / v albumin. In certain embodiments, the plasma exchange therapy comprises a course of a full plasma exchange. In some cases, the course of the full plasma exchange comprises the full plasma exchange once a week for 1 week to 8 weeks, such as once a week for, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks. In certain such embodiments, the plasma replacement solution comprises 5% w / v albumin. In further embodiments, a plasma exchange therapy comprises, after a course of full plasma exchange, a course of a low volume plasma exchange with a second albumin solution. The course of low volume plasma exchange may be administered once a month for at least 1 month to at least 10 months, for example, once a month for 12 to 16 months, such as 12, 13, 14, 15, or 16 months. In certain such embodiments, the plasma replacement solution comprises 20% w / v albumin. In a specific embodiment, a plasma therapy comprises the therapy as depicted in Figure 1. Such therapy comprises a full plasma exchange once a week for 6 weeks with a plasma replacement solution comprising 5% w / v albumin. Following such a course of full plasma exchange, the plasma exchange therapy comprises low volume plasma exchange therapy once a month for 10 to 16 months, such as 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, or 16 months. The low volume plasma exchange therapy comprises replacing between 15% and 25%, such as 20% of a subject’s plasma with a plasma replacement solution comprising 20 gm to 40 gm albumin, such as 20 g, 30 g, or 40 g albumin. In some cases, the low volume plasma exchange therapy comprises replacing between 15% and 25%, such as 20% of a subject’s plasma with a plasma replacement solution comprising 20 gm to 40 gm albumin, such as 20 g, 30 g, or 40 g albumin and 10 g to 20 g immunoglobulins, such as 10 g, 15 g, or 20 g immunoglobulins. In some cases, a plasma exchange therapy comprises a full plasma exchange once a week for 6 weeks with a plasma replacement solution comprising 5% w / v albumin. For example, during full plasma exchange, 2500 to 3000 mL of the patient’s plasma is replaced with the same volume of 5% albumin solution (e.g., 5% albutein). Following the full plasma exchange, the plasma exchange therapy comprises low volume plasma exchange once a month for 10 to 16 months, such as 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, or 16 months. During low volume plasma exchange, between 600 mL to 900 mL (e.g. 650 mL to 880 mL) of the patient’s plasma is replaced with 100 mL or 200 mL of 20% albumin (e.g., 20% albutein). In some cases, the low volume plasma exchange therapy comprises: between 20 g and 40 g, such as 20 g, 30 g, and 40 g of albumin in 20% albumin solution (e.g., Albutein 20%) is used as replacement. In some cases, albumin replacement is alternated with immunoglobulin replacement, e.g., replacement with between 10 g and 30 g, such as 10 g, 20 g, or 30 g immunoglobin as 5% immunoglobulin solution (e.g., Flebogamma DIF 5%). Plasma replacement solutions In certain cases, any plasma replacements solutions described below is used for plasma exchange therapies. Two general categories of Albumin Plasma Products (“APP”): plasma protein fraction (“PPF”) and human albumin solution (“HAS”). PPF is derived from a process with a higher yield than HAS but has a lower minimum albumin purity than HAS (>83% for PPF and > 95% for HAS) (Production of human albumin solution: a continually developing colloid, P. Matejtschuk et al., British J. of Anaesthesia 85(6): 887-95, at 888 (2000)). In some instances, PPF has albumin purity of between 83% and 95% or alternatively 83% and 96%. The albumin purity can be determined by electrophoresis or other quantifying assays such as, for example, by mass spectrometry. Those of skill in the art will recognize that there are, or have been, several commercial sources of PPF (the “Commercial PPF Preparations.”). These include Plasma-Plex™ PPF (Armour Pharmaceutical Co., Tarrytown, NY), Plasmanate™ PPF (Grifols, Clayton, NC), Plasmatein™ (Alpha Therapeutics, Los Angeles, CA), and Protenate™ PPF (Baxter Labs, Inc. Deerfield, IL). Those of skill in the art will also recognize that there are, or have been, several commercial sources of HAS (the “Commercial HAS Preparations.”). These include Albuminar™ (CSL Behring), AlbuRx™ (CSL Behring), Albutein™ (Grifols, Clayton, NC), Buminate™ (Baxatla, Inc., Bannockburn, IL), Flexbumin™ (Baxatla, Inc., Bannockburn, IL), and Plasbumin™ (Grifols, Clayton, NC). Plasma Protein Fraction (Human) (PPF) According to the United States Food and Drug Administration (“FDA”), “Plasma Protein Fraction (Human),” or PPF, is the proper name of the product defined as “a sterile solution of protein composed of albumin and globulin, derived from human plasma.” (Code of Federal Regulations “CFR” 21 CFR 640.90 which is herein incorporated by reference). PPF’s source material is plasma recovered from Whole Blood prepared as prescribed in 21 CFR 640.1 - 640.5 (incorporated by reference herein), or Source Plasma prepared as prescribed in 21 CFR 640.60 -640.76 (incorporated by reference herein). PPF is tested to determine if it meets the following standards as per 21 CFR 640.92 (incorporated by reference herein): (a)    The final product shall be a 5.0 +1- 0.30 percent solution of protein; and (b)    The total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin. The protein composition is determined by a method that has been approved for each manufacturer by the Director, Center for Biologies Evaluation and Research, Food and Drug Administration. As used herein, “Plasma Protein Fraction” or “PPF” refers to a sterile solution of protein composed of albumin and globulin, derived from human plasma, with an albumin content of at least 83% with no more than 17% globulins (including al, a2, 0, and y globulins) and other plasma proteins, and no more than 1% gamma globulin as determined by electrophoresis. (Hink, J.H., Jr., et al., Preparation and Properties of a Heat-Treated Human Plasma Protein Fraction, VOX SANGUINIS 2(174) (1957)). PPF can also refer to a solid form, which when suspended in solvent, has similar composition. The total globulin fraction can be determined through subtracting the albumin from the total protein. (Busher, J., Serum Albumin and Globulin, CLINICAL METHODS: THE HISTORY, PHYSICAL, AND LABORATORY EXAMINATIONS, Chapter 10, Walker HK, Hall WD, Hurst JD, eds. (1990)). Albumin (Human) (HAS) According to the FDA, “Albumin (Human)” (also referred to herein as “HAS”) is the proper name of the product defined as “sterile solution of the albumin derived from human plasma.” (Code of Federal Regulations “CFR” 21 CFR 640.80 which is herein incorporated by reference.) The source material for Albumin (Human) is plasma recovered from Whole Blood prepared as prescribed in 21 CFR 640.1-640.5 (incorporated by reference herein), or Source Plasma prepared as prescribed in 21 CFR 640.60-640.76 (incorporated by reference herein). Other requirements for Albumin (Human) are listed in 21 CFR 640.80 - 640.84 (incorporated by reference herein). Albumin (Human) is tested to determine if it meets the following standards as per 21 CFR 640.82: (a) Protein concentration. Final product shall conform to one of the following concentrations: 4.0 + / -0.25 percent; 5.0 + / -0.30 percent; 20.0 + / -1.2 percent; and 25.0 + / -1.5 percent solution of protein. (b) Protein composition. At least 96 percent of the total protein in the final product shall be albumin, as determined by a method that has been approved for each manufacturer by the Director, Center for Biologies Evaluation and Research, Food and Drug Administration. As used herein, “Albumin (Human)” or “HAS” refers to a to a sterile solution of protein composed of albumin and globulin, derived from human plasma, with an albumin content of at least 95%, with no more than 5% globulins (including al, a2, 0, and y globulins) and other plasma proteins. HAS can also refer to a solid form, which when suspended in solvent, has similar composition. The total globulin fraction can be determined through subtracting the albumin from the total protein. As can be recognized by one having ordinary skill in the art, PPF and HAS fractions can also be freeze-dried or in other solid form. Such preparations, with appropriate additives, can be used to make tablets, powders, granules, or capsules, for example. The solid form can be formulated into preparations for injection by dissolving, suspending or emulsifying them in an aqueous solution; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. F. Indications The subject methods and compounds find use in treating a cognitive impairment, such as cognitive impairment caused by neuroinflammation. In some cases, cognitive impairment is an aging-associated cognitive impairment, such as impairments in the cognitive ability of individuals caused by age. Non-limiting examples of such cognitive impairment includes aging-associated dementia, immunological conditions, and physical or functional decline. Individuals having or suspected of having a cognitive impairment that will benefit from treatments disclosed herein include individuals that are about 50 years old or older, e.g., 60 years old or older, 70 years old or older, 80 years old or older, 90 years old or older, and 100 years old or older, i.e., between the age of about 50 and 100, e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 years old, and are having cognitive impairment associated with natural aging process, e.g., mild cognitive impairment (MCI); and individuals that are about 50 years old or older, e.g., 60 years old or older, 70 years old or older, 80 years old or older, 90 years old or older, and usually no older than 100 years old, i.e., between the ages of about 50 and 90, e.g., 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or about 100 years old, that have not yet begun to show symptoms of cognitive impairment. Examples of cognitive impairments / indications that may be due to natural aging include the following: 1. Mild cognitive impairment (MCI) Mild cognitive impairment is a modest disruption of cognition that manifests as problems with memory or other mental functions such as planning, following instructions, or making decisions that have worsened over time while overall mental function and daily activities are not impaired. Thus, although significant neuronal death does not typically occur, neurons in the aging brain are vulnerable to sub-lethal age-related alterations in structure, synaptic integrity, and molecular processing at the synapse, all of which impair cognitive function. Individuals having or suspected of having an aging-associated cognitive impairment that will benefit from treatment the methods disclosed herein. The subjects envisioned herein also include individuals of any age that have a cognitive impairment due to an aging-associated disorder; and individuals of any age that have been diagnosed with an aging-associated disorder that is typically accompanied by cognitive impairment. Examples of such aging-associated disorders include the following: 2. Alzheimer's disease Alzheimer's disease is a progressive, inexorable loss of cognitive function associated with an excessive number of senile plaques in the cerebral cortex and subcortical gray matter, which also contains b-amyloid and neurofibrillary tangles consisting of tau protein. The common form affects persons > 60 yrs. old, and its incidence increases as age advances. It accounts for more than 65% of the dementias in the elderly. The cause of AD is not known. The disease runs in families in about 15 to 20% of cases. The remaining, so-called sporadic cases have some genetic determinants. The disease has an autosomal dominant genetic pattern in most early-onset and some late-onset cases but a variable late-life penetrance. Environmental factors are the focus of active investigation. In the course of the disease, synapses, and ultimately neurons are lost within the cerebral cortex, hippocampus, and subcortical structures (including selective cell loss in the nucleus basalis of Meynert), locus coeruleus, and nucleus raphe dorsalis. Cerebral glucose use and perfusion is reduced in some areas of the brain (parietal lobe and temporal cortices in early-stage disease, prefrontal cortex in late-stage disease). Neuritic or senile plaques (composed of neurites, astrocytes, and glial cells around an amyloid core) and neurofibrillary tangles (composed of paired helical filaments) play a role in the pathogenesis of AD. Senile plaques and neurofibrillary tangles occur with normal aging, but they are much more prevalent in persons with AD. 3. Parkinson's Disease Parkinson's Disease (PD) is an idiopathic, slowly progressive, degenerative CNS disorder characterized by slow and decreased movement (bradykinesia), muscular rigidity, resting tremor (dystonia), muscle freezing, and postural instability. Originally considered primarily a motor disorder, PD is now recognized to also cause depression and emotional changes. PD also can affect cognition, behavior, sleep, autonomic function, and sensory function. The most common cognitive impairments include an impairment in attention and concentration, working memory, executive function, producing language, and visuospatial function. A characteristic of PD is symptoms related to reduced motor function usually precede those related to cognitive impairment, which aids in diagnosis of the disease. In primary Parkinson's disease, the pigmented neurons of the substantia nigra, locus coeruleus, and other brain stem dopaminergic cell groups degenerate. The cause is not known. The loss of substantia nigra neurons, which project to the caudate nucleus and putamen, results in depletion of the neurotransmitter dopamine in these areas. Onset is generally after age 40, with increasing incidence in older age groups. Parkinson’s disease is newly diagnosed in about 60,000 Americans each year and currently affects approximately one million Americans. Even though PD is not fatal in itself, its complications are the fourteenth leading cause of death in the United States. At present, PD cannot be cured, and treatment is generally prescribed to control symptoms, with surgery prescribed in later, severe cases. Treatment options for PD include administration of pharmaceuticals to help manage motor deficits. These options increase or substitute for the neurotransmitter, dopamine, of which PD patients have low brain concentrations. Such medications include: carbidopa / levodopa (which create more dopamine in the brain); apomorphine, pramipexolole, ropinirole, and rotingotine (dopamine agonists); selegiline and rasagiline (MAO-B inhibitors which prevent breakdown of dopamine); entacapone and tolcapone (Catechol-O-methyltransferase [COMT] inhibitors which make more levodopa available in the brain); benztropine and trihexyphenidyl (anticholinergics); and amantadine (controls tremor and stiffness). Exercise / physical therapy is also commonly prescribed to help maintain physical and mental function. Current treatment options, however, treat the symptoms of PD, are not curative, and fail to prevent disease progression. Additionally, current medications tend to lose efficacy in late-stage PD. The most prescribed drug, levodopa, commonly results in adverse effects within 5 to 10 years after commencing the medication. These adverse effects can be severe and can result in motor fluctuations and unpredictable swings in motor control between doses as well as jerking / twitching (dyskinesia) which are difficult to manage and are even as disabling as PD’s own symptoms. Thus, there remains a need for new therapies with new mechanisms of action which can either be administrated along or in combination with current PD medications. 4. Parkinsonism Secondary parkinsonism (also referred to as atypical Parkinson’s disease or Parkinson’s plus) results from loss of or interference with the action of dopamine in the basal ganglia due to other idiopathic degenerative diseases, drugs, or exogenous toxins. The most common cause of secondary parkinsonism is ingestion of antipsychotic drugs or reserpine, which produce parkinsonism by blocking dopamine receptors. Less common causes include carbon monoxide or manganese poisoning, hydrocephalus, structural lesions (tumors, infarcts affecting the midbrain or basal ganglia), subdural hematoma, and degenerative disorders, including nigrostriatal degeneration. Certain disorders like Progressive Supranuclear Palsy (PSP), Multiple System Atrophy (MSA), Corticobasal degeneration (CBD) and Dementia with Lewy Bodies (DLB) can exhibit Parkinsonism symptoms before the cardinal symptoms necessary to the specific diagnosis can be made, and thus may be labeled as “Parkinsonism.” 5. Frontotemporal dementia Frontotemporal dementia (FTD) is a condition resulting from the progressive deterioration of the frontal lobe of the brain. Over time, the degeneration may advance to the temporal lobe. Second only to AD in prevalence, FTD accounts for 20% of pre-senile dementia cases. Symptoms are classified into three groups based on the functions of the frontal and temporal lobes affected: Behavioral variant FTD (bvFTD), with symptoms include lethargy and aspontaneity on the one hand, and disinhibition on the other; progressive nonfluent aphasia (PNFA), in which a breakdown in speech fluency due to articulation difficulty, phonological and / or syntactic errors is observed but word comprehension is preserved; and semantic dementia (SD), in which patients remain fluent with normal phonology and syntax but have increasing difficulty with naming and word comprehension. Other cognitive symptoms common to all FTD patients include an impairment in executive function and ability to focus. Other cognitive abilities, including perception, spatial skills, memory and praxis typically remain intact. FTD can be diagnosed by observation of reveal frontal lobe and / or anterior temporal lobe atrophy in structural MRI scans. A number of forms of FTD exist, any of which may be treated or prevented using the subject methods and compositions. For example, one form of frontotemporal dementia is Semantic Dementia (SD). SD is characterized by a loss of semantic memory in both the verbal and nonverbal domains. SD patients often present with the complaint of word-finding difficulties. Clinical signs include fluent aphasia, anomia, impaired comprehension of word meaning, and associative visual agnosia (the inability to match semantically related pictures or objects). As the disease progresses, behavioral and personality changes are often seen like those seen in frontotemporal dementia although cases have been described of ‘pure’ semantic dementia with few late behavioral symptoms. Structural MRI imaging shows a characteristic pattern of atrophy in the temporal lobes (predominantly on the left), with inferior greater than superior involvement and anterior temporal lobe atrophy greater than posterior. As another example, another form of frontotemporal dementia is Pick’s disease (PiD, also PcD). A defining characteristic of the disease is build-up of tau proteins in neurons, accumulating into silver-staining, spherical aggregations known as “Pick bodies.” Symptoms include loss of speech (aphasia) and dementia. Patients with orbitofrontal dysfunction can become aggressive and socially inappropriate. They may steal or demonstrate obsessive or repetitive stereotyped behaviors. Patients with dorsomedial or dorsolateral frontal dysfunction may demonstrate a lack of concern, apathy, or decreased spontaneity. Patients can demonstrate an absence of selfmonitoring, abnormal self-awareness, and an inability to appreciate meaning. Patients with gray matter loss in the bilateral posterolateral orbitofrontal cortex and right anterior insula may demonstrate changes in eating behaviors, such as a pathologic sweet tooth. Patients with more focal gray matter loss in the anterolateral orbitofrontal cortex may develop hyperphagia. While some of the symptoms can initially be alleviated, the disease progresses, and patients often die within two to ten years. 6. Huntington's disease Huntington’s disease (HD) is a hereditary progressive neurodegenerative disorder characterized by the development of emotional, behavioral, and psychiatric abnormalities; loss of intellectual or cognitive functioning; and movement abnormalities (motor disturbances). The classic signs of HD include the development of chorea - involuntary, rapid, irregular, jerky movements that may affect the face, arms, legs, or trunk - as well as cognitive decline including the gradual loss of thought processing and acquired intellectual abilities. There may be impairment of memory, abstract thinking, and judgment; improper perceptions of time, place, or identity (disorientation); increased agitation; and personality changes (personality disintegration). Although symptoms typically become evident during the fourth or fifth decades of life, the age at onset is variable and ranges from early childhood to late adulthood (e.g., 70s or 80s). HD is transmitted within families as an autosomal dominant trait. The disorder occurs as the result of abnormally long sequences or "repeats" of coded instructions within a gene on chromosome 4 (4pl6.3). The progressive loss of nervous system function associated with HD results from loss of neurons in certain areas of the brain, including the basal ganglia and cerebral cortex. 7. Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, invariably fatal, neurological disease that attacks motor neurons. Muscular weakness and atrophy and signs of anterior horn cell dysfunction are initially noted most often in the hands and less often in the feet. The site of onset is random, and progression is asymmetric. Cramps are common and may precede weakness. Rarely, a patient survives 30 years; 50% die within 3 years of onset, 20% live 5 years, and 10% live 10 years. Diagnostic features include onset during middle or late adult life and progressive, generalized motor involvement without sensory abnormalities. Nerve conduction velocities are normal until late in the disease. Recent studies have documented the presentation of cognitive impairments as well, particularly a reduction in immediate verbal memory, visual memory, language, and executive function. A decrease in cell body area, number of synapses and total synaptic length has been reported in even normal-appearing neurons of the ALS patients. It has been suggested that when the plasticity of the active zone reaches its limit, a continuing loss of synapses can lead to functional impairment. Promoting the formation or new synapses or preventing synapse loss may maintain neuron function in these patients. 8. Multiple Sclerosis Multiple Sclerosis (MS) is characterized by various symptoms and signs of CNS dysfunction, with remissions and recurring exacerbations. The most common presenting symptoms are paresthesias in one or more extremities, in the trunk, or on one side of the face; weakness or clumsiness of a leg or hand; or visual disturbances, e.g., partial blindness and pain in one eye (retrobulbar optic neuritis), dimness of vision, or scotomas. Common cognitive impairments include impairments in memory (acquiring, retaining, and retrieving new information), attention and concentration (particularly divided attention), information processing, executive functions, visuospatial functions, and verbal fluency. Common early symptoms are ocular palsy resulting in double vision (diplopia), transient weakness of one or more extremities, slight stiffness or unusual fatigability of a limb, minor gait disturbances, difficulty with bladder control, vertigo, and mild emotional disturbances; all indicate scattered CNS involvement and often occur months or years before the disease is recognized. Excess heat may accentuate symptoms and signs. The course is highly varied, unpredictable, and, in most patients, remittent. At first, months or years of remission may separate episodes, especially when the disease begins with retrobulbar optic neuritis. However, some patients have frequent attacks and are rapidly incapacitated; for a few the course can be rapidly progressive. 9. Glaucoma Glaucoma is a common neurodegenerative disease that affects retinal ganglion cells (RGCs). Evidence supports the existence of compartmentalized degeneration programs in synapses and dendrites, including in RGCs. Recent evidence also indicates a correlation between cognitive impairment in older adults and glaucoma (Yochim BP, et al. Prevalence of cognitive impairment, depression, and anxiety symptoms among older adults with glaucoma. J Glaucoma. 2012;21(4):250-254). 10. Myotonic dystrophy Myotonic dystrophy (DM) is an autosomal dominant multisystem disorder characterized by dystrophic muscle weakness and myotonia. The molecular defect is an expanded trinucleotide (CTG) repeat in the 3' untranslated region of the myotonin protein kinase gene on chromosome 19q. Symptoms can occur at any age, and the range of clinical severity is broad. Myotonia is prominent in the hand muscles, and ptosis is common even in mild cases. In severe cases, marked peripheral muscular weakness occurs, often with cataracts, premature balding, hatchet facies, cardiac arrhythmias, testicular atrophy, and endocrine abnormalities (e.g., diabetes mellitus). Mental retardation is common in severe congenital forms, while an aging-related decline of frontal and temporal cognitive functions, particularly language and executive functions, is observed in milder adult forms of the disorder. Severely affected persons die by their early 50s. 11. Dementia Dementia describes a class of disorders having symptoms affecting thinking and social abilities severely enough to interfere with daily functioning. Other instances of dementia in addition to the dementia observed in later stages of the aging-associated disorders discussed above include vascular dementia, and dementia with Lewy bodies, described below. In vascular dementia, or “multi-infarct dementia,” cognitive impairment is caused by problems in supply of blood to the brain, typically by a series of minor strokes, or sometimes, one large stroke preceded or followed by other smaller strokes. Vascular lesions can be the result of diffuse cerebrovascular disease, such as small vessel disease, or focal lesions, or both. Patients suffering from vascular dementia present with cognitive impairment, acutely or subacutely, after an acute cerebrovascular event, after which progressive cognitive decline is observed. Cognitive impairments are similar to those observed in Alzheimer's disease, including impairments in language, memory, complex visual processing, or executive function, although the related changes in the brain are not due to AD pathology but to chronic reduced blood flow in the brain, eventually resulting in dementia. Single photon emission computed tomography (SPECT) and positron emission tomography (PET) neuroimaging may be used to confirm a diagnosis of multi-infarct dementia in conjunction with evaluations involving mental status examination. Dementia with Lewy bodies (DLB, also known under a variety of other names including Lewy body dementia, diffuse Lewy body disease, cortical Lewy body disease, and senile dementia of Lewy type) is a type of dementia characterized anatomically by the presence of Lewy bodies (clumps of alpha-synuclein and ubiquitin protein) in neurons, detectable in postmortem brain histology. Its primary feature is cognitive decline, particularly of executive functioning. Alertness and short-term memory will rise and fall. Persistent or recurring visual hallucinations with vivid and detailed pictures are often an early diagnostic symptom. DLB it is often confused in its early stages with Alzheimer's disease and / or vascular dementia, although, where Alzheimer's disease usually begins quite gradually, DLB often has a rapid or acute onset. DLB symptoms also include motor symptoms similar to those of Parkinson's. DLB is distinguished from the dementia that sometimes occurs in Parkinson's disease by the time frame in which dementia symptoms appear relative to Parkinson symptoms. Parkinson's disease with dementia (POD) would be the diagnosis when dementia onset is more than a year after the onset of Parkinson's. DLB is diagnosed when cognitive symptoms begin at the same time or within a year of Parkinson symptoms. 12. CADASIL Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), is a hereditary disorder associated with mutations in the NOTCH 3 gene. (Locatelli M, et al., Front. Pharmacol. 11:321 (2020)). It usually occurs in middle-aged adults, with manifestations including cognitive impairment leading to dementia and disability. (Id.) Other manifestations are mood disorders, migraine with aura, and recurring stroke. Effective treatment has been elusive because the manner in which the disease develops (pathogenesis) is still uncertain. (Id.) CADASIL is the most common hereditary subcortical type of vascular dementia. (Kalimo H, etal., Future Neurology, 3(6) (2008)). CADASIL is characterized by four primary common symptoms: migraine with aura, recurrent ischemic stroke, psychiatric disturbances, and cognitive decline. The first is usually the presenting symptom, occurring in 20-40% of the affected. The second symptom occur in 60-85% of symptomatic individuals. The third, psychiatric disturbances occur in 25-30% of patients in the form of moderate / major depression, bipolar disease, panic disorders, schizophrenia, and apathy. Cognitive impairment occurs in 60% of patients, becoming clinically detectable between ages 3550 and worsens progressively with aging. (Id.) In younger patients, attention, memory, and executive disturbances predominate. (Buffon F, et al., J Neurol Neurosurg Psychiatry 77(2): 17580 (2006)). Visuospatial abilities and reasoning deteriorate with age, mainly after 60 years of age. Dementia presents in 25% of patients, 75% of which are over the age of 60. But the number of ischemic attacks has not been associated with dementia. (Id.) CADASIL is a progressive and fatal disease. There has been no disease modifying treatment made to date. (Locatelli et al., supra). Symptomatic treatment is the only recourse for clinicians, based on regular clinical practice such as: acetazolamide or sodium valproate for migraines; daily aspirin to reduce chance of heart attack or stroke; and supportive care for loss of cognitive function. Notably, there are still no drugs that have clearly shown benefit on the loss of cognitive function associated with CADASIL. (Id.) Interventions that have been studied but have failed include donepezil (used to improve Alzheimer’s cognitive dysfunction), galantamine (acetylcholinesterase inhibitor used to treat cognitive dysfunction in Alzheimer’s), and L-dopa (used in Alzheimer’s and Parkinson’s diseases). 13. Progressive supranuclear palsy Progressive supranuclear palsy (PSP) is a brain disorder that causes serious and progressive problems with control of gait and balance, along with complex eye movement and thinking problems. One of the classic signs of the disease is an inability to aim the eyes properly, which occurs because of lesions in the area of the brain that coordinates eye movements. Some individuals describe this effect as a blurring. Affected individuals often show alterations of mood and behavior, including depression and apathy as well as progressive mild dementia. The disorder's long name indicates that the disease begins slowly and continues to get worse (progressive), and causes weakness (palsy) by damaging certain parts of the brain above pea-sized structures called nuclei that control eye movements (supranuclear). PSP was first described as a distinct disorder in 1964, when three scientists published a paper that distinguished the condition from Parkinson's disease. It is sometimes referred to as Steele-Richardson-Olszewski syndrome, reflecting the combined names of the scientists who defined the disorder. Although PSP gets progressively worse, no one dies from PSP itself. 14. Ataxia People with ataxia have problems with coordination because parts of the nervous system that control movement and balance are affected. Ataxia may affect the fingers, hands, arms, legs, body, speech, and eye movements. The word ataxia is often used to describe a symptom of incoordination which can be associated with infections, injuries, other diseases, or degenerative changes in the central nervous system. Ataxia is also used to denote a group of specific degenerative diseases of the nervous system called the hereditary and sporadic ataxias which are the National Ataxia Foundation's primary emphases. 15. Multiple-system atrophy Multiple-system atrophy (MSA) is a degenerative neurological disorder. MSA is associated with the degeneration of nerve cells in specific areas of the brain. This cell degeneration causes problems with movement, balance, and other autonomic functions of the body such as bladder control or blood-pressure regulation. The cause of MSA is unknown and no specific risk factors have been identified. Around 55% of cases occur in men, with typical age of onset in the late 50s to early 60s. MSA often presents with some of the same symptoms as Parkinson's disease. However, MSA patients generally show minimal if any response to the dopamine medications used for Parkinson's. 16. Frailty Frailty Syndrome (“Frailty”) is a geriatric syndrome characterized by functional and physical decline including decreased mobility, muscle weakness, physical slowness, poor endurance, low physical activity, malnourishment, and involuntary weight loss. Such decline is often accompanied and a consequence of diseases such as cognitive dysfunction and cancer. However, Frailty can occur even without disease. Individuals suffering from Frailty have an increased risk of negative prognosis from fractures, accidental falls, disability, comorbidity, and premature mortality. (C. Buigues, et al. Effect of a Prebiotic Formulation on Frailty Syndrome: A Randomized, Double-Blind Clinical Trial, Int. J. Mol. Sci. 2016, 17, 932). Additionally, individuals suffering from Frailty have an increased incidence of higher health care expenditure. (Id.) Common symptoms of Frailty can be determined by certain types of tests. For example, unintentional weight loss involves a loss of at least 10 lbs. or greater than 5% of body weight in the preceding year; muscle weakness can be determined by reduced grip strength in the lowest 20% at baseline (adjusted for gender and BMI); physical slowness can be based on the time needed to walk a distance of 15 feet; poor endurance can be determined by the individual’s self-reporting of exhaustion; and low physical activity can be measured using a standardized questionnaire. (Z. Palace et al., The Frailty Syndrome, Today’s Geriatric Medicine 7(1), at 18 (2014)). 17. Neuromyelitis Optica Spectrum Disorder Neuromyelitis Optica Spectrum Disorder (NMOSD), also known as Devic disease, is a rare, inflammatory disease of the central nervous system. It is characterized by optic neuritis (optic nerve inflammation) and myelitis (spinal cord inflammation). Typically, patients experience reoccurring bouts of inflammation separated by periods of remission. The disease is thought to be caused by auto-antibodies that often target myelin oligodendrocyte glycoprotein (MOG-IgG) or aquaporin 4 (AQP4-IgG), which leads to demyelination and axonal damage in the optic nerve and spinal cord. 18. Post-operative cognitive dysfunction Post-operative cognitive decline occurs following anesthesia and a surgical procedure. It is common in patients older than 60 and is diagnosed by pre- and post-surgery cognitive testing. Patients typically present with memory impairment, delirium, and impairment in performance on intellectual tasks. 19. Chronic traumatic encephalopathy Chronic traumatic encephalopathy (CTE) is a neurodegenerative brain disorder most commonly found in athletes, veterans, or others with a history of repeated head trauma. It is one of many tauopathies that is characterized by the overabundance of Tau protein in the brain of patients that leads to neuron loss. Symptoms include memory loss, changes in mood or personality, confusion, impaired judgement, impulse control, aggression, and depression. 20. Traumatic brain injury Traumatic brain injury (TBI) is caused by a violent hit to the head or body. It can also be caused by an object penetrating brain tissue during an injury. It results in bleeding, torn tissue, and physical damage to brain cells and cell death. The physical symptoms are varied, but include loss of consciousness, headaches, nausea, extreme fatigue, impaired speech, trouble sleeping, dizziness, blurred vision, sensitivity to light or sound, memory loss, and concentration problems. In some embodiments, the subject methods and compositions find use in slowing the progression of aging-associated cognitive impairment. In other words, cognitive impairment in the individual will decline more slowly following treatment by the disclosed methods than prior to or in the absence of treatment by the disclosed methods. In some such instances, the subject methods of treatment include measuring the progression of cognitive impairment after treatment and determining that the progression of decline is reduced. In some such instances, the determination is made by comparing to a reference, e.g., the rate of decline in the individual prior to treatment, e.g., as determined by measuring cognitive abilities at two or more time points prior to administration of the subject blood product. The subject methods and compositions also find use in stabilizing the cognitive abilities of an individual, e.g., an individual having an aging-associated cognitive impairment, or an individual suspected of having an aging-associated cognitive decline. For example, the individual may demonstrate some aging-associated cognitive impairment, and progression of cognitive impairment observed prior to treatment with the disclosed methods will be halted following treatment by the disclosed methods. As another example, the individual may be at risk for developing an aging-associated cognitive decline (e.g., the individual may be aged 50 years old or older or may have been diagnosed with an aging- associated disorder), and the cognitive abilities of the individual are substantially unchanged, i.e., no cognitive decline can be detected, following treatment by the disclosed methods as compared to prior to treatment with the disclosed methods. The subject methods and compositions also find use in reducing cognitive impairment in an individual having an aging-associated impairment. In other words, the affected cognitive ability is improved in the individual following treatment by the subject methods. For example, the cognitive ability in the individual is increased, e.g., by 2-fold or more, 5-fold or more, 10-fold or more, 15-fold or more, 20-fold or more, 30-fold or more, or 40-fold or more, including 50-fold or more, 60-fold or more, 70-fold or more, 80-fold or more, 90-fold or more, or 100-fold or more, following treatment by the subject methods relative to the cognitive ability that is observed in the individual prior to treatment by the subject methods. In some instances, treatment by the subject methods and compositions restores the cognitive ability in the individual having an aging-associated cognitive impairment, e.g., to their level when the individual was about 40 years old or less. In other words, cognitive or motor impairment is abrogated. G. Methods of Monitoring for Improvement In some instances, among the variety of methods to monitor disease progression and improvement in cognitive impairment the following types of assessments are used alone or in combination with subjects having a cognitive impairment. The following types of methods are presented as examples and are not limited to the recited methods. Any convenient methods to monitor disease may be used in practicing the invention, as desired. Those methods are also contemplated by the methods of the invention. i. General Cognition Certain embodiments of the methods of the invention further comprise methods of monitoring the effect of a medication or treatment on a subject for treating a cognitive impairment, such as an aging-associated cognitive impairment. Certain such methods comprise comparing cognitive function before and after treatment. Methods of evaluating cognitive function are well-known in the art. For example, and not by way of limitation, the method may comprise evaluation of cognitive function based on medical history, family history, physical and neurological examinations by clinicians who specialize in cognitive function, laboratory tests, and neuropsychological assessment. Additional embodiments which are contemplated by the invention include: the assessment of consciousness, such as using the Glasgow Coma Scale (EMV); mental status examination, including the abbreviated mental test score (AMTS) or minimental state examination (MMSE) (Folstein et al., J. Psychiatr. Res 1975; 12:1289-198); global assessment of higher functions; estimation of intracranial pressure such as by fundoscopy. In one embodiment, monitoring the effect on cognitive impairment, such as an aging-associate cognitive impairment, includes examining a 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12-point improvement using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-COG). In one embodiment, examinations of the peripheral nervous system may be used to evaluate cognitive function, including any one of the followings: sense of smell, visual fields and acuity, eye movements and pupils (sympathetic and parasympathetic), sensory function of face, strength of facial and shoulder girdle muscles, hearing, taste, pharyngeal movement and reflex, tongue movements, which can be tested individually (e.g. the visual acuity can be tested by a Snellen chart; a reflex hammer used testing reflexes including masseter, biceps and triceps tendon, knee tendon, ankle jerk and plantar (i.e. Babinski sign); muscle strength often on the MRC scale 1 to 5; muscle tone and signs of rigidity. Certain embodiments of methods of the invention further comprise monitoring the effects of a treatment for cognitive impairment on motor function before and after treatment. Certain such methods comprise evaluating motor function in a subject having PD and treated for a cognitive impairment according to methods disclosed herein. Methods of evaluating motor function are well-known in the art. For example, and not by way of limitation, the method may comprise evaluation of motor function based on medical history, family history, physical and neurological examinations by clinicians who specialize neurodegeneration and motor impairment, laboratory tests, and neurodegenerative assessment. Additional embodiments which are contemplated by the invention include employment of the rating scales discussed below. Several rating scales have been utilized for evaluating the progression of PD. The most widely-used scales include the Unified Parkinson’s Disease Rating Scale (UPDRS, which was introduced in 1987) (J. Rehabil Res. Dev., 2012 49(8): 1269-76), and the Hoehn and Yahr scale (Neruology, 1967 17(5): 427-42). Additional scales include the Movement Disorder Society (MDS)’s updated UPDRS scale (MDS-UPDRS) as well as the Schwab and England Activities of Daily Living (ADL) Scale. The UPDRS scale evaluates 31 items that contributed to three subscales: (1) mentation, behavior, and mood; (2) activities of daily living; and (3) motor examination. The Hoehn and Yahr scale classifies PD into five stages with discreet substages: 0 - no signs of disease; 1 -symptoms on one side only; 1.5 - symptoms on one side but also involving neck and spine; 2 -symptoms on both sides with no balance impairment; 2.5 - mild symptoms on both sides, with recovery when the ‘pull’ test is given; 3 - balance impairment with mild to moderate disease; 4 -severe disability, but ability to walk or stand unassisted; and 5 - need a wheelchair or bedridden without assistance. The Schwab and England scale classifies PD into several percentages (from 100% - complete independent to 10% - total dependent). General motor function can be evaluated using widely-used scales including the General Motor Function Scale (GMF). These tests comprises three components: dependence, pain, and insecurity. (Aberg A.C., et al. (2003) Disabil. Rehabil. 2003 May 6;25(9):462-72.). Motor function can also be assessed using home-monitoring or wearable sensors. For example: gait (speed of locomotion, variability, leg rigidity) can be sensed with an accelerometer; posture (trunk inclination) by a gyroscope; leg movement by an accelerometer; hand movement by an accelerometer and gyroscope; tremor (amplitude, frequency, duration, asymmetry) by an accelerometer; falling by an accelerometer; gait freezing by an accelerometer; dyskinesia by an accelerometer, gyroscope, and inertial sensors; bradykinesia (duration and frequency) by an accelerometer plus gyroscope, and aphasia (pitch) using a microphone. (Pastorino M, et al., Journal of Physics: Conference Series 450 (2013) 012055). Certain embodiments of methods of the invention further comprise monitoring the effects of a treatment for cognitive impairment on the progression or improvement of neurodegeneration. Certain such methods comprise evaluating the progression or improvement of neurodegeneration in a subject having a neurodegenerative disease, such as MS, HD, ALS, glaucoma, PSP, and treated for a cognitive impairment according to methods disclosed herein. Methods of monitoring the progression or improvement of neurodegeneration are well-known to those having ordinary skill in the art. By way of example, and not limitation, monitoring can be performed through techniques such as: cerebrospinal fluid (CSF) monitoring; magnetic resonance imaging (MRI) to detect lesions and development of demyelinating plaques; evoked potential studies; and gait monitoring. CSF analysis may be performed, for example, through lumbar puncture to obtain pressure, appearance, and CSF content. Normal values typically range as follows: pressure (70-180 mm H20); appearance is clear and colorless; total protein (15 - 60 mg / lOOmL); IgG is 3-12% of the total protein; glucose is 50 - 80 mg / 100 mL; cell count is 0-5 white blood cells and no red blood cells; chloride (110 - 125 mEq / L). Abnormal results may indicate the presence or progression of MS. MRI is another technique that may be performed to monitor disease progression and improvement. Typical criteria for monitoring MS with MRI include the appearance of patchy areas of abnormal white matter in cerebral hemisphere and in paraventricular areas, lesions present in the cerebellum and / or brain stem as well as in the cervical or thoracic regions of the spinal cord. Evoked potentials may be used to monitor the progression and improvement of MS in subjects. Evoked potentials measure slowing of electrical impulses such as in Visual Evoked Response (VER), Brain Stem Auditory Evoked Responses (BAER), and Somatosensory Evoked Responses (SSER). Abnormal responses help to indicate that there is a decrease in the speed of conduction in central sensory pathways. Gait monitoring can also be used to monitor disease progression and improvement in MS subjects. MS is often accompanied by an impairment in mobility and an abnormal gait due in part to fatigue. Monitoring may be performed, for example, with the use of mobile monitoring devices worn by subjects. (Moon, Y., et al., Monitoring gait in multiple sclerosis with novel wearable motion sensors, PLOS One, 12(2):e0171346 (2017)). The invention also contemplates treating or improving neurogenesis in a subject with declining or impaired neurogenesis, which may manifest itself, for example, through reduced cognitive or motor function, or through association with neuroinflammation. An embodiment of the invention also contemplates determining the level of neurogenesis before, during, and / or after therapies according to the invention, for example, plasma exchange therapies. Noninvasive techniques for evaluating neurogenesis have been reported. (Tamura Y. et al., J. Neurosci. (2016) 36(31):8123-31). Positron emission tomography (PET) used with the tracer, [18F] FLT, in combinations with the BBB transporter inhibitor probenecid, allows for accumulation of the tracer in neurogenic regions of the brain. Such imaging allows for an evaluation of neurogenesis in patients being treated for neurodegenerative disease. H. Exercise Exercise can be characterized by aerobic or anaerobic activity and can involve high calorieburning activity and moderate calorie-burning activity. Exercise may involve strength training (e.g., weight training or isometric exercise). Exercise may also involve, for example, running, bicycling, walking, dancing, marching, swimming, yoga, Tai Chi, balance exercises, leg bends, jumping rope, surfing, rowing, rotating or flexing the arms or legs, gardening, cleaning, active games such as bowling, aerobics, Pilates, and martial arts. An exercise regimen may include performing a single exercise at a certain frequency, or a combination of exercises at a certain frequency. The frequency may be one, two, three, four, five, six, or seven times per week. The frequency may vary from week-to-week. The exercise regimen may be at the same level of intensity and / or frequency as the subject practiced before administration of the compositions of the invention. The exercise regimen may also be at a higher level of intensity and / or frequency compared to the levels the subject practiced before administration of the therapies of the invention. The exercise regimen may have been suggested or prescribed by a health or fitness professional, or the exercise regimen may have been initiated by the subject himself or herself. I. Kits, Reagents, and Devices Certain aspects of the invention provide kits comprising reagents for measuring in a sample a ratio between the expression levels of any two markers, either in the form of proteins or mRNA, selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. As discussed above, assaying the ratio between the levels of protein or mRNA pairs can be performed by any suitable methods, such as qualitative or quantitative methods. Accordingly, kits disclosed herein could be designed for assaying the ratios of the levels of one or more target protein pairs. Thus, in certain cases, the kits disclosed herein provide reagents and / or devices for assaying the sample for the ratios in the levels of one or more protein or mRNA pairs. Certain non-limiting examples include kits for quantitatively assaying the ratios in the levels of one or more target protein pairs via immunoassays, mass-spectrometry analyses, and protein detecting array analyses. As discussed above, non-limiting examples of immunoassays include western-blot analysis, enzyme-linked immunosorbent assay (ELISA), radio-immune assay (RIA), lateral flow immunoassays, particle-based immunoassays, quantum dots based immunoassays, etc. Accordingly, certain embodiments of the invention provide kits for performing one or more of these assays for one or more target protein pairs disclosed herein. In one embodiment, the kits comprise lateral flow immunoassay devices. Such devices allow quantification of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. Lateral flow immunoassay devices may also include an internal control that shows a reference ratio. In some cases, the lateral flow immunoassay devices allow quantification of the ratio between the levels of one or more of the following protein pairs: i. DLL1 and SMOC1, particularly the ratio DLL1 / SMOC1; ii. DLL1 and CD59, particularly the ratio DLL1 / CD59; iii. DLL1 and LEFTY2, particularly the ratio DLL1 / LEFTY2; iv. DLL1 and UNC5B, particularly the ratio DLL1 / UNC5B; v. DLL1 and C5, particularly the ratio DLL1 / C5; vi. DLL1 and C5.C6, particularly the ratio DLL1 / C5.C6; vii. DLL1 and INHBB, particularly the ratio DLL1 / INHBB; viii. TSTD1 and STAT3, particularly the ratio TSTD1 / STAT3; ix.    POLD4 and PARP11, particularly the ratio POLD4 / PARP11; x.     ASH2L and PARP11, particularly the ratio ASH2L / PARP11; xi. RPS3 and PARP11, particularly the ratio RPS3 / PARP11; xii. VAV3 and SIRT3, particularly the ratio VAV3 / SIRT3; and xiii. SERPINB8 and PARP11, particularly the ratio SERPINB8 / PARP11. optionally following the instructions for calculating the ratio. In addition to the ratios in the levels of one or more target protein pairs, the lateral flow immunoassay devices may allow quantification of the levels of one or more control protein pairs. Certain kits may allow detection of the ratios between the levels of one or more target protein pairs via protein detecting array. Certain such protein detecting arrays may comprise specific binding agents, such as antibodies that specifically bind to any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. The antibodies are localized to specific spots on a solid support. The kit may further comprise reagents that facilitate visualization of specific binding between the target protein pairs in a sample and the binding agents on the array. Such reagents include labeled secondary antibodies, for example, a fluorescent dye labeled secondary antibody. In certain embodiments, the kits allow detection of one or more target protein pairs via lysate microarray analysis. Such kits allow preparing a lysate of a sample and immobilizing the lysate onto a support, such as nitrocellulose-coated glass slides. The target protein pairs are then detected using labeled solution-phase specific binding agents to the one or more target protein pairs, such as fluorescent-labeled antibodies that specifically bind to the proteins in the target protein pairs. As such, the kits comprise labeled binding agents to one or more target protein pairs, particularly, fluorescent-labeled antibodies that specifically bind to proteins in one or more target protein pairs. In some cases, the antibodies against different proteins in the target protein pairs are differentially labelled thereby allowing multiplexed detection and / or quantitation of two or more target protein pairs. In some cases, the kits are designed to allow assaying a sample for the ratio between the expression levels of only one of the following marker pairs, particularly protein pairs: i. DLL1 and SMOC1, particularly the ratio DLL1 / SMOC1; ii. DLL1 and CD59, particularly the ratio DLL1 / CD59; iii. DLL1 and LEFTY2, particularly the ratio DLL1 / LEFTY2; iv.    DLL1 and UNC5B, particularly the ratio DLL1 / UNCB5; v.     DLL1 and C5, particularly the ratio DLL1 / C5; vi. DLL1 and C5.C6, particularly the ratio DLL1 / C5.C6; vii. DLL1 and INHBB, particularly the ratio DLL1 / INHBB; viii. TSTD1 and STAT3, particularly the ratio TSTD1 / STAT3; ix.    POLD4 and PARP11, particularly the ratio POLD4 / PARP11; x.     ASH2L and PARP11, particularly the ratio ASH2L / PARP11; xi. RPS3 and PARP11, particularly the ratio RPS3 / PARP11; xii. VAV3 and SIRT3, particularly the ratio VAV3 / SIRT3; and xiii. SERPINB8 and PARP11; particularly the ratio SERPINB8 / PARP11. In some cases, the kits are designed to allow assaying a sample for the ratios between the levels of any two, any three, any four, any five, any six, any seven, any eight, any nine, any ten, any eleven, any twelve, or all thirteen of the protein pairs listed in the preceding paragraph. In some cases, each of the one or more specific binding members in the kits described herein comprise, independently, an antibody or an antigen binding fragment thereof, an aptamer, or a peptide binding member. The specific binding members are labeled with a detectable moiety, such as optically detectable moiety. In some cases, the kits disclosed herein are for use in the methods disclosed herein, i.e., for use in identifying whether a subject is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment in the subject. In addition to the above components, the subject kits may further include instructions for practicing the subject methods. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, etc. Yet another means would be a computer readable medium, e.g., diskette, CD, portable flash drive, etc., on which the information has been recorded. Yet another means that may be present is a website address which may be used via the internet to access the information at a remote site. In certain cases, the kit may provide information about a smartphone app, which will then provide the relevant information. Any other convenient means of communicating information may be present in the kits. In at least some of the previously described embodiments, one or more elements used in an embodiment can interchangeably be used in another embodiment unless such a replacement is not technically feasible. It will be appreciated by those skilled in the art that various other omissions, additions and modifications may be made to the methods and structures described above without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter, as defined by the appended claims. It will be understood by those within the art that, in general, terms used herein, and especially in the appended claims (e.g., bodies of the appended claims) are generally intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (e.g., “a” and / or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (e.g., the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In those instances where a convention analogous to “at least one of A, B, or C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (e.g., “ a system having at least one of A, B, or C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and / or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” “greater than,” “less than,” and the like include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. Thus, for example, a group having 1-3 articles refers to groups having 1, 2, or 3 articles. Similarly, a group having 1-5 articles refers to groups having 1, 2, 3, 4, or 5 articles, and so forth. VI. EXAMPLES This Example describes an exemplary method of identifying protein pairs to predict subjects’ responses to a plasma exchange (PE) therapy for treating cognitive impairment. Firstly, treatment benefits were confirmed by group comparison of changed clinical outcomes between treated group and placebo group based on appropriate statistical tests, such as t-test, ANOVA, MMRM, linear mixed models, chisq test, Fisher’s exact test, logistic regression, etc. In this example, Clinical Dementia Rating sum of boxes (CDR-sb) was used for the clinical outcomes. It was a global assessment for AD patients and a key secondary endpoint in AMBAR clinical trial. Six categories were evaluated: memory, orientation judgment and problem solving, community affairs, home and hobbies, and personal care. Higher CDR-sb means more severe dementia. Significant improvement by 1.1 points decrease at EOS at treated group (p = 0.002) was observed after PE treatment. Similar improvement (1.5 points) at moderate AD (p = 0.01) was observed, where both the PE and control groups got worse, but PE treatment reduced the worsening (Boadaeta / . (2020), Alzheimer’s & Dementia, 16:10, pp. 1412-1425.) Predictive protein pairs were identified for responsiveness to PE-Alb treatment on clinical improvement based on CDR-sb. Spearman correlation analysis was used to identify ratios of the plasma levels of protein pairs associated with CDR-sb change at EOS. Such analysis indicated the strength of the ratios of the levels of proteins associated with continuous clinical changes. Spearman correlation coefficient or Spearman’s rho and associatedp value were reported. Positive rho indicated positive relationship and negative rho indicated negative relationship. Absolute value of rho (abs(rho)) of > 0.3 was considered a true relationship, rho of 0.3-0.5 was considered low correlation, rho of 0.5-0.7 was considered moderate correlation, rho of 0.7-0.9 was considered high correlation, and rho of > 0.9 was considered for very high correlation. (See Mukaka (2012),MalawiMed J., 24(3): 69-71.) Based on concepts from diagnostic tests; changed CDR-sb at EOS was converted to two binary variable comparing to baseline: better or not better than baseline (including equal to baseline and worse than baseline), and not worse than clinically meaningful changes (1 point increase of CDR.sb). ROC was generated and AUC was calculated and compared for candidate protein pair’s diagnostic / predictive power. High or low baseline ratio of the levels of different protein pairs is then defined by optimal decision threshold (reference value) based on Youden’s index. The binary ratios (higher or lower than the reference ratios) were then evaluated based on their prediction powers measured by accuracy, sensitivity, and specificity. Estimated mean change of CDR-sb at each new group (high biomarker group and low biomarker group) was then calculated based on linear mixed model adjusted with age, sex and baseline CDR-sb score. These identified candidate biomarkers were verified by in silica verification including tests in other clinical outcomes (ADAS COg from AMBAR study), in random reselected samples (1001 resampling datasets (80% of original sample size)). The final list of candidate protein pairs based on the above results was prepared based on the flow-chart shown in Figure 2. Material and Methods Study design The study was performed on serum samples from patients participating in the AMBAR study (EudraCT#:2011-001598-25; ChmcalTrials.gov ID: NCT01561053), in which 322 individuals diagnosed with mild to moderate Alzheimer’s disease (Mini-Mental State Examination [MMSE] score from 18 to 26) were enrolled [Boada M, et al (2019. Alzheimers Dement 26, 5: 6169], Patients underwent a 14-month treatment program of plasma exchange with albumin replacement (PE-Alb) for AD treatment. Treatment groups In the AMBAR trial, patients were randomized to one of three PE-Alb treatment groups or to a control group (sham PE) in a 1:1:1:1 fashion (Fig. 1). The control (placebo) group underwent a simulated PE treatment through a noninvasive procedure (sham) that mimicked PE but without any actual fluid replacement. The intervention regime lasted 14 months, which included a first baseline visit, a first 6-week stage of intensive treatment with one session of conventional therapeutic plasma exchange (TPE) with replacement albumin (5% Albutein®, Grifols) per week for all the active groups, followed by an intermediate visit and a 25 second 12-month stage of maintenance treatment with one session of low-volume plasma exchange (LVPE) per month with replacement albumin (20% Albutein®, Grifols) and with or without IVIG (Flebogamma® 5% DIF, Grifols) according to three PE-Alb treatment modalities: - (LA) low dose albumin (20 g Albumin per PE procedure), - (LAF) low dose albumin (20 g Albumin per PE procedure) alternated with infusions of IVIG (F) (infusion of IVIG 10 g per PE procedure); and - (HAF) high dose albumin (40g Albumin per PE procedure) alternated with infusions of IVIG (F) (IVIG 20 g per PE procedure). A final follow-up visit at month 14 closed the study. Treatment periods and treatment groups are summarized in Figure 1. The removed and replaced plasma volume of each TPE was approximately that of 1 plasma volume and it depended on the patient’s sex, height, weight, and hematocrit (approximately 35 to 45 mL / kg, corresponding to a volume of approximately 2500 mL to 3000 mL). This volume was calculated automatically by the device or manually by the operator depending on the device used. The removed plasma volume was replaced with the same volume of albumin 5% during the procedure (50 g / L, approximately 125 g to 150 g albumin). This procedure is a conventional plasma exchange and each site performed the TPE using its standard plasmapheresis device. Therapeutic plasma exchange was performed using a commercial continuous flow cell separator with either centrifugation- or filtration-based technology. Either a peripheral (e.g., radial / cubital vein) or central access (e.g., subclavian / jugular vein) was used based on the individual characteristics of the patient. The plasma volume removed on each plasmapheresis during the LVPE period was between 650 mL and 880 mL (depending on the patient body weight). After the LVPE, albumin 20% was infused depending on treatment arm randomization (LA or HA) approximately 20 g to 40 g albumin. Further, the HAF treatment arm and one LAF arm received infusions of IVIG (F) as indicated above. For the purpose of the analysis, two comparison groups were considered: control / placebo patients and the pooled PE-Alb-treated patients (the three treated groups). Sampling The AMBAR study recruited patients (and, therefore, collected serum samples) from 2012 to 2017. In order to perform the biomarker analysis, the serum samples at 3 time points were considered: PRE-TPE 1 (week 1); PRE-LVPE 1 (month 3) and final visit (month 14). Biomarker assays 7K SomaScan™ Panel (SomaLogic, Boulder, Colorado, US) aptamer-based proteomic technology, was used for protein levels determination in serum. This technology uses modified DNA aptamers, called SOMAmers, to bind specifically to proteins in a sample. This binding is then quantified using a DNA microarray, allowing for the simultaneous measurement of thousands of proteins with high precision and sensitivity. Thus, the SomaScan™ assay provided the levels of various proteins in a sample as “relative fluorescence units (RFU) or a derivative of RFU, such as log2RFU. Clinical assessments The following clinical and neuropsychological measurements were performed: Clinical Dementia Rating Sum of Boxes (CDR-sb) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) as a cognitive scale. CDR (also known as “Clinical Dementia Rating”) is a numeric scale used to quantify the severity of symptoms of dementia that yields global and Sum of Boxes (SOB) scores. The CDR is obtained through semistructured interviews of patients and informants, and cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Each domain is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal care is scored on a 4-point scale without a 0.5 rating available). The CDR demonstrates good reliability and has been validated against neuropathologic finding. Scoring was performed as established in Hughes CP et al., “A new clinical scale for the staging of dementia”, Br J Psychiatry, 1982, 140:566-572. The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog; Rosen WG et al., “A new rating scale for Alzheimer’s disease”, Am. J. Psychiatry, 1984; 141:1356-1364) is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia and it is considered to be the “gold standard” for assessing antidementia treatments. Importantly, the evaluators / raters of the tests in the trial have no access to any information allowing them to identify patient assignment to treatment. Blinding of the evaluators to patient treatment is confirmed when evaluators sign a document to that effect. Data analysis and statistics Firstly, treatment benefits were confirmed by group comparison of changed clinical outcomes between treated group and placebo group based on appropriate statistical tests, such as t-test, ANOVA, MMRM, linear mixed models, chisq test, Fisher’s exact test, logistic regression, etc. Significant improvement by 1.1 points decrease at EOS at treated group (p = 0.002) was observed after PE treatment (Boada et al., “A randomized, controlled clinical trial of plasma exchange with albumin replacement for Alzheimer's disease: Primary results of the AMBAR Study”, Alzheimer’s & Dementia, 2020, 16:10, pp. 1412-1425). Baseline predictive biomarkers ratio were identified for responsiveness to PE-Alb treatment on clinical improvement based on CDR.sb. Spearman correlation analysis was used to identify baseline plasma proteins ratio associated with CDR.sb change at EOS. Such analysis indicated the strength of the proteomic biomarkers ratio associated with continuous clinical changes. Spearman correlation coefficient or Spearman’s rho and associatedp value were reported. Positive rho indicated positive relationship and negative rho indicated negative relationship. Absolute value of rho (abs(rho)) of > 0.3 was considered a true relationship, rho of 0.3-0.5 was considered low correlation, rho of 0.5-0.7 was considered moderate correlation, rho of 0.7-0.9 was considered high correlation, and rho of > 0.9 was considered for very high correlation. (See Mukaka (2012),MalawiMed J., 24(3): 69-71.) Based on concepts from diagnostic tests; changed CDR.sb at EOS was converted to two binary variable comparing to baseline: better or worse than baseline, and not worse than clinically meaningful changes (1 point increase of CDR.sb). ROC was generated and AUC was calculated and compared for candidate proteomic biomarker’s ratio diagnostic / predictive power. High or low baseline protein level ratio is then defined by optimal decision threshold (reference value) based on Youden’s index. The binary biomarker ratio (higher or lower than the reference value) were then evaluated based on their prediction powers measured by accuracy, sensitivity, and specificity. Estimated mean change of CDR.sb at each new group (high biomarker group and low biomarker group) was then calculated based on linear mixed model adjusted with age, sex and baseline CDR.sb score. These identified candidate biomarkers were verified by in silico verification including tests in other clinical outcomes (ADAS Cog from AMBAR study), in random reselected samples (1001 resampling datasets (80% of original sample size). All statistical analyses were performed with R version 4.1 (https: / / cran.r-project.org / ). Results The final list of identified candidate protein pairs is shown in Table 1. This table shows the Spearman correlation index and the p.value associated to each protein pair. It can be observed that Spearman correlation index ranged from -0.6452961 for the DLL1 / SMOC1 protein pair to -0.5536106 for the SERPINB8 / PARP11 protein pair. Graphically these correlations can be observed at Figure 3A and Figure 15A, respectively. All the protein pairs assessed showed very high statistical significance. When evaluating the predictive power parameters for treatment benefit (CDR-sb at EOS better than baseline) of identified candidate protein pairs, all of them demonstrated very good performance, with AUC values ranging from 86.9% for the POLD4 / PARP11 protein pair to 79.8% for the VAV3 / SIRT3 protein pair (Table 2). Graphically these ROC curves can be observed at Figure 1 IB and Figure 14B, respectively. Another way of assessing the efficacy of treatment, which is especially important in neurodegenerative diseases, is not only to assess whether patients show improvement at EOS, but also whether these patients do not worsen at the end of treatment. This has been assessed by calculating whether the increase in CDR-sb is less than one point at the end of treatment compared to the baseline (Table 3). In that table, again the predictive power values of identified candidate protein pairs are shown, and best AUC values are obtained for the DLL1 / SMOC1 protein pair (83.3%) Graphically this ROC curve can be observed at Figure 3C. In silico validation of candidate protein pairs was assessed in another clinical outcome: ADASCog. Table 4 shows the Spearman correlation index and the p.value associated to each protein pair as well as the predictive power parameters. Rho values ranges from -0.488 for the DLL1 / C5.C6 protein pair, to -0.343 for the POLD4 / PARP11 protein pair. Again, all the protein pairs assessed showed very high statistical significance. Regarding predictive power for treatment benefit, the best AUC value for ADAS Cog improvement at EOS, was obtained for DLL1 / SMOC1 protein pair (AUC = 76.0%), meanwhile, the best AUC-CMC (value for not worsening of patients at EOS) was obtained for DLL1 / C5.C6 protein pair (AUC = 71.3%). Table 6 shows the ratios of the levels of different protein pairs in serum, that indicate whether a subject is likely or not likely respond positively (better than baseline) to a plasma therapy (for example the plasma therapy described before) for treating a cognitive impairment. The results provided by Tables 1-6 above are also graphically supported by Figures 3-15. Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and embodiments of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. Moreover, nothing disclosed herein is intended to be dedicated to the public regardless of whether such invention is explicitly recited in the claims. The scope of the present invention, therefore, is not intended to be limited to the exemplary embodiments shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims. In the claims, 35 U.S.C. §112(f) or 35 U.S.C. §112(6) is expressly defined as being invoked for a limitation in the claim only when the exact phrase "means for" or the exact phrase "step for" is recited at the beginning of such limitation in the claim; if such exact phrase is not used in a limitation in the claim, then 35 U.S.C. § 112 (f) or 35 U.S.C. §112(6) is not invoked. Clauses For reasons of completeness, various aspects of the invention are set out in the following numbered clauses: Clause 1. A method of analyzing a sample obtained from a subject, the method comprising: assaying the isolated sample for a ratio between the levels of any two proteins selected from: Deltalike protein 1 (DLL1), SPARC-related modular calcium-binding protein 1 (SMOC1), CD59 glycoprotein (CD59), Thiosulfate:glutathione sulfurtransferase (TSTD1), Signal transducer and activator of transcription 3 (STAT3), DNA Polymerase Delta subunit 4 (POLD4), Protein mono-ADP-ribosyltransferase PARP11 (PARP11), Left-Right Determination Factor 2 (LEFTY2), Netrin receptor UNC5B (UNC5B), Complement C5 (C5), Complement C5b-C6 complex (C5.C6), Setl / Ash2 histone methyltransferase complex subunit ASH2 (ASH2L), Inhibin Beta B Chain (INHBB), Small ribosomal subunit protein uS3 (RPS3), Guanine nucleotide exchange factor VAV3 (VAV3), NAD-dependent protein deacetylase sirtuin-3, mitochondrial (USIRT3), and Serpin B 8 (SERPINB8). Clause 2. A method for predicting whether a subject is going to respond positively to a therapy for a cognitive impairment, the method comprising determining, in an isolated test sample, a ratio between the levels of any two proteins selected from: Delta-like protein 1 (DLL1), SPARC-related modular calcium-binding protein 1 (SMOC1), CD59 glycoprotein (CD59), Thiosulfate: glutathione sulfurtransferase (TSTD1), Signal transducer and activator of transcription 3 (STAT3), DNA Polymerase Delta subunit 4 (POLD4), Protein mono-ADP-ribosyltransferase PARP11 (PARP11), Left-Right Determination Factor 2 (LEFTY2), Netrin receptor UNC5B (UNC5B), Complement C5 (C5), Complement C5b-C6 complex (C5.C6), Setl / Ash2 histone methyltransferase complex subunit ASH2 (ASH2L), Inhibin Beta B Chain (INHBB), Small ribosomal subunit protein uS3 (RPS3), Guanine nucleotide exchange factor VAV3 (VAV3), NAD-dependent protein deacetylase sirtuin-3, mitochondrial (USIRT3), and Serpin B 8 (SERPINB8). Clause 3.     The method of clause 1 or 2, wherein one of the two proteins is DLL1 or PARP11. Clause 4.     The method of clause 3, wherein the other protein of the two proteins is selected from SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB. Clause 5. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of one or more of the following combinations of proteins: i.     DLL1 and SMOC1, h.    DLL1 and CD59, hi.    DLL1 and LEFTY2, iv.   DLL1 and UNC5B, v.    DLL1 and C5, vi.    DLL1 and C5.C6, vii.   DLL1 and INHBB, viii.   TSTD1 and STAT3, ix.   P0LD4 and PARP11, x.    ASH2L and PARP11, xi.    RPS3 andPARPll, xii.   VAV3 and SIRT3, and xiii.   SERPINB8 and PARP11. Clause 6. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and SMOC1. Clause 7. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and CD59. Clause 8. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and LEFTY2. Clause 9. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and UNC5B. Clause 10. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and C5. Clause 11. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of DLL1 and C5.C6. Clause 12. The method of clause 1, comprising assaying the sample for the ratio between the levels of DLL1 and INHBB. Clause 13. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of TSTD1 and STAT3. Clause 14. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of POLD4 and PARP11. Clause 15. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of ASH2L and PARP11. Clause 16. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of RPS3 and PARP11. Clause 17. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of VAV3 and SIRT3. Clause 18. The method of clause 1 or 2, comprising assaying the sample for the ratio between the levels of SERPINB8 and PARP11. Clause 19. The method of any one of clauses 2 to 18, wherein the subject has the cognitive impairment. Clause 20.   The method of any one of clauses 2 to 18, wherein the subject is suspected of having the cognitive impairment. Clause 21.   The method of any one of the preceding clauses, wherein the cognitive impairment is caused by a neurodegenerative disease. Clause 22. The method of clause 21, wherein the neurodegenerative disease is Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia. Clause 23.   The method of clause 22, wherein the neurodegenerative disease is AD. Clause 24.   The method of any one of the preceding clauses, wherein the subject is a candidate for a plasma exchange therapy for treating the cognitive impairment. Clause 25. The method of any one of the preceding clauses, comprising assaying the proteins in an immunoassay, mass-spectrometry analysis, or protein detecting array analysis. Clause 26. The method of any one of clauses 1 to 25, comprising assaying the proteins in an aptamer-based multiplexed proteomic assay. Clause 27. The method of any one of the preceding clauses, comprising comparing the ratio between the levels of the measured proteins to a reference ratio that is obtained from a reference sample. Clause 28. The method of any one of the preceding clauses, wherein the sample is a blood sample, a serum sample, a plasma sample, or a cerebrospinal fluid sample. Clause 29. The method of any one of the preceding clauses, further comprising: based on the ratio between the levels of the measured proteins, determining whether the subject is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment in the subject. Clause 30. The method of clause 29, further comprising, if the subject is determined as likely to respond positively to the plasma exchange therapy, treating the subject for the cognitive impairment by administering the plasma exchange therapy to the subject. Clause 31. A method for treating a subject for cognitive impairment, the method comprising: administering to the subject a plasma exchange therapy, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on results of an assay of a sample from the subject for a ratio between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. Clause 32.   The method of clause 31, wherein one of the two proteins is DLL1. Clause 33.    The method of clause 32, wherein the other protein in the two proteins is selected from SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB. Clause 34. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of one or more of the following combinations of proteins: xiv. DLL1 and SMOC1, xv. DLL1 and CD59, xvi. DLL1 and LEFTY2, xvii. DLL1 and UNC5B, xviii. DLL1 and C5, xix. DLL1 and C5.C6, xx. DLL1 and INHBB, xxi. TSTD1 and STAT3, xxii. POLD4 and PARP11, xxiii. ASH2L and PARP 11, xxiv. RPS3 and PARP11, xxv. VAV3 and SIRT3, and xxvi. S ERPINB 8 and PARP 11. Clause 35. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and SMOC1. Clause 36. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and CD59. Clause 37. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and LEFTY2. Clause 38. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and UNC5B. Clause 39. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and C5. Clause 40. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels ofDLLl and C5.C6. Clause 41. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of DLL1 and INHBB. Clause 42. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of TSTD1 and STAT3. Clause 43. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of POLD4 and PARP11. Clause 44. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of ASH2L and PARP11. Clause 45. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of RPS3 and PARP11. Clause 46. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of VAV3 and SIRT3. Clause 47. The method of clause 31, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the results of the assay of the sample of the subject for the ratio between the levels of SERPINB8 and PARP11. Clause 48. The method of any one of clauses 31 to 47, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on the ratio between the levels of the measured proteins in the sample obtained from the subject being different from a reference ratio that is obtained from a reference sample. Clause 49. The method of any one of clauses 28 to 48, wherein the plasma exchange therapy comprises a course of a full plasma exchange. Clause 50. The method of clause 49, wherein the full plasma exchange comprises replacing substantially all of the subject’s plasma with a first albumin solution. Clause 51. The method of clause 49 or 50, wherein the course of the full plasma exchange comprises the full plasma exchange once a week for 5 to 8 weeks. Clause 52. The method of any one of clauses 49 to 51, wherein the course of the full plasma exchange comprises the full plasma exchange once a week for 6 weeks. Clause 53. The method of any one of clauses 50 to 52, wherein the first albumin solution comprises 5% albumin. Clause 54. The method of any one of clauses 49 to 53, wherein the plasma exchange therapy comprises, after the course of full plasma exchange, a course of a low volume plasma exchange with a second albumin solution. Clause 55. The method of clause 54, wherein the low volume plasma exchange comprises exchanging between 20% and 40% of the subject’s plasma with the second albumin solution. Clause 56.   The method of clause 54 or 56, wherein the course of low volume plasma exchange comprises the low volume plasma exchange once a month for at least 10 months. Clause 57. The method of any one of clauses 54 to 55, wherein the course of low volume plasma exchange comprises the low volume plasma exchange once a month for 12 to 16 months. Clause 58. The method of any one of clauses 54 to 57, wherein the second albumin solution comprises 20% albumin. Clause 59. A kit comprising reagents for measuring in a sample a ratio between the levels of any two proteins selected from: DLL1, SMOC1, CD59, TSTD1, STAT3, POLD4, PARP11, LEFTY2, UNC5B, C5, C5.C6, ASH2L, INHBB, RPS3, VAV3, SIRT3, and SERPINB8. Clause 60.   The kit of clause 59, wherein one of the two proteins is DLL1. Clause 61.    The kit of clause 60, wherein the other protein in the two proteins is selected from SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB. Clause 62.   The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of one or more of the following combinations of proteins: i.     DLL1 and SMOC1, h.    DLL1 and CD59, hi.    DLL1 and LEFTY2, iv.   DLL1 and UNC5B, v.    DLL1 and C5, vi.    DLL1 and C5.C6, vii.   DLL1 and INHBB, viii.   TSTD1 and STAT3, ix.   POLD4 and PARP11, x.    ASH2L and PARP11, xi.    RPS3 andPARPll, xii.   VAV3 and SIRT3, and xiii.   SERPINB8 and PARP11. Clause 63.   The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and SMOC1. Clause 64. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and CD59. Clause 65. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of TSTD1 and STAT3. Clause 66. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of POLD4 and PARP11. Clause 67. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and LEFTY2. Clause 68. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and UNC5B. Clause 69. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and C5. Clause 70. The kit of clause 56, wherein the kit comprises reagents for measuring in the sample the ratio between the level of DLL1 and C5.C6. Clause 71. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of ASH2L and PARP11. Clause 72. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of DLL1 and INHBB. Clause 73. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the level of RPS3 and PARP11. Clause 74. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of VAV3 and SIRT3. Clause 75. The kit of clause 59, wherein the kit comprises reagents for measuring in the sample the ratio between the levels of SERPINB8 and PARP11. Clause 76. The kit of any one of clauses 59 to 75, wherein the reagents comprise two or more specific binding members that specifically bind to the measured proteins. Clause 77. The kit of clause 76, wherein each of the two or more specific binding members is, independently, an antibody or an antigen binding fragment thereof, an aptamer, or a peptide binding member. Clause 78. The kit of clause 76 or 77, wherein the two or more specific binding members are labeled with a detectable moiety. Clause 79. The kit of clause 78, wherein the detectable moiety is optically detectable moiety. Clause 80. The kit of any one of clauses 59 to 79, wherein the kit is suitable for performing an immunoassay, western-blot analysis, mass-spectrometry analysis, or protein detecting array analysis. 5 Clause 81. The kit of any one of clauses 59 to 80, wherein the kit is suitable for performing an aptamer-based multiplexed proteomic assay. Clause 82. The kit of any one of clauses 59 to 81, wherein the kit is for use in identifying whether a subject is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment in the subject.

Claims

1. A method for predicting whether a subject, having or suspecting of having a cognitive impartment, is going to positively respond to a therapy, particularly to a plasma exchange therapy, the method comprising determining, in an isolated test sample, the ratio between the expression level of two markers involved in inflammation, whereinone of the markers is selected from Delta-like protein 1 (DLL 1), and Protein mono-ADP-ribosyltransferasePARPll (PARP11), andthe other marker is selected from SPARC-related modular calcium-binding protein 1 (SMOC1), CD59 glycoprotein (CD59), Thiosulfate: glutathione sulfurtransferase (TSTD1), Signal transducer and activator of transcription 3 (STAT3), DNA Polymerase Delta subunit 4 (POLD4), Left-Right Determination Factor 2 (LEFTY2), Netrin receptor UNC5B (UNC5B), Complement C5 (C5), Complement C5b-C6 complex (C5.C6), Setl / Ash2 histone methyltransferase complex subunit ASH2 (ASH2L), Inhibin Beta B Chain (INHBB), Small ribosomal subunit protein uS3 (RPS3), Guanine nucleotide exchange factor VAV3 (VAV3), NAD-dependent protein deacetylase sirtuin-3, mitochondrial (USIRT3), and Serpin B 8 (SERPINB8).

2. The method of claim 1, wherein one of the markers is DLL1 or PARP11 and the other marker is selected from SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB.

3. The method of claim 1, wherein one of the markers is DLL1 or PARP11 and the other marker is selected from ASH2L, RPS3 and SERPINB8.

4. The method of any of the preceding claims, comprising determining the ratio between the expression levels of one or more of the following combinations of markers:i. DLL1 and SMOC1,ii. DLL1 and C5.C6,in. DLL1 and CD59,iv. DLL1 and LEFTY2,v. DLL1 and UNC5B,vi. DLL1 and C5,vh. DLL1 and INHBB,viii. POLD4 and PARP11,ix. ASH2L and PARP11,x. RPS3 andPARPll, andxi. SERPINB8 and PARP11; particularly, the method comprises determining one or more of the following ratios:DLL1 / SMOC1, DLL1 / CD59, DLL1 / LEFTY2, DLL1 / UNC5B, DLL1 / C5, DLL1 / C5.C6, DLL1 / INHBB, POLD4 / PARP11, ASH2L / PARP11, RPS3 / PARP11, and SERPINB8 / PARP11.

5. The method of any one of the preceding claims, wherein the cognitive impairment is caused by a neurodegenerative disease; particularly by a neurodegenerative disease selected from Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, Huntington disease, amyotrophic lateral sclerosis, multiple sclerosis, glaucoma, myotonic dystrophy, vascular dementia; more particularly the neurodegenerative disease is AD.

6. The method of any one of the preceding claims, wherein the level of expression corresponds to the level of protein or the level of mRNA; particularly to the level of protein.

7. The method of any one of the preceding claims, wherein the level of expression corresponds to the level of protein, and the determination of the level of expression of each one of the markers is determined by an immunoassay, mass-spectrometry analysis, or protein detecting array analysis, such as by performing an aptamer-based multiplexed proteomic assay; particularly by performing an aptamer-based multiplexed proteomic assay.

8. The method of any one of the preceding claims, comprising the further step of comparing the ratio determined in the test sample with a reference ratio that is obtained from a reference sample.

9. The method of any one of the preceding claims, wherein the sample is a blood sample, a serum sample, a plasma sample, or a cerebrospinal fluid (CSF) sample; particularly serum or CSF.

10. A kit comprising reagents for measuring the level of expression of two markers involved in inflammation, whereinone of the markers is selected from Delta-like protein 1 (DLL 1), and Protein mono-ADP-ribosyltransferase PARP11 (PARP11), andthe other marker is selected from SPARC-related modular calcium-binding protein 1 (SMOC1), CD59 glycoprotein (CD59), Thiosulfate: glutathione sulfurtransferase (TSTD1), Signal transducer and activator of transcription 3 (STAT3), DNA PolymeraseDelta subunit 4 (P0LD4), Left-Right Determination Factor 2 (LEFTY2), Netrin receptor UNC5B (UNC5B), Complement C5 (C5), Complement C5b-C6 complex (C5.C6), Setl / Ash2 histone methyltransferase complex subunit ASH2 (ASH2L), Inhibin Beta B Chain (INHBB), Small ribosomal subunit protein uS3 (RPS3), Guanine nucleotide exchange factor VAV3 (VAV3), NAD-dependent protein deacetylase sirtuin-3, mitochondrial (USIRT3), and Serpin B 8 (SERPINB8); and optionally, instructions for determining the ratio between the two markers.

11. The kit of claim 10, wherein one of the two markers is DLL1 or PARP11 and the other marker is selected from SMOC1, CD59, LEFTY2, UNC5B, C5, C5.C6, and INHBB.

12. The kit of claim 10, wherein one of the markers is DLL1 or PARP11 and the other marker is selected from ASH2L, RPS3 and SERPINB8.

13. The kit of any of the claims 10-12, wherein the kit comprises reagents and instructions for determining the ratio between the level of expression of one or more of the following combinations of markers:xiv. DLL1 and SMOC1, xv. DLL1 and CD59, xvi. DLL1 and LEFTY2, xvn. DLL1 and UNC5B, xviii. DLL1 and C5, xix. DLL1 and C5.C6, xx. DLL1 and INHBB, xxi.   POLD4 and PARP 11,xxii. ASH2L and PARP11, xxiii. RPS3 and PARP11, andVII. SERPINB8 and PARP11; particularly, the method comprises determining one or more of the following ratios:DLLESMOCl, DLL1:CD59, DLL1:LEFTY2, DLL1:UNC5B, DLL1:C5, DLL1:C5.C6, DLL1 INHBB, POLD4:PARP11, ASH2L:PARP11, RPS3:PARP11, and SERPINB8PARPI1.

14. The kit of any of claims 10 to 13, wherein the reagents comprise two or more specific binding members that specifically bind to the markers; particularly wherein each of the two or more specific binding members is, independently, an antibody or an antigen binding 5 fragment thereof, an aptamer, or a peptide binding member; particularly wherein the two or more specific binding members are labeled with a detectable moiety, such as an optically detectable moiety.

15. Use of the kit of any of claims 10-14 in a method as defined in any of the claims 19.

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