Methods of treating a cognitive impairment

Abstract

The disclosure pertains to treating a cognitive impairment, for example, an aging-associated cognitive impairment. In certain aspects, the disclosure describes methods of assaying a sample obtained from a subject having or suspected of having a cognitive impairment for one or more proteins selected from: DLL1, VNN2, VAV3, and SUMF1. In certain embodiments, the cognitive impairment is caused by a neurodegenerative disease, such as Alzheimer's disease. The methods further comprise identifying a subject as likely or not likely to respond positively to the plasma exchange therapy. In even further aspects, the disclosure 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. Also provided are kits suitable for performing the methods disclosed herein.

Description

[0001] Methods of Treating a Cognitive Impairment

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] Pursuant to 35 U.S.C. § 119(e), this application claims priority to the filing date of United States Provisional Patent Application No. 63 / 539,280 filed September 19, 2023; the disclosure of which application is herein incorporated by reference.

[0004] REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0005] The contents of the electronic sequence listing (ALKA-034WO_SEQ_LIST.xml; Size: 6,935 bytes; and Date of Creation: September 5, 2024) is herein incorporated by reference in its entirety.

[0006] I. INTRODUCTION

[0007] Field

[0008] This disclosure pertains to methods of treating subjects for cognitive impairment.

[0009] Background

[0010] The following is offered as background information only and is not admitted as prior art to the present invention.

[0011] 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)).

[0012] 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.

[0013] 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.

[0014] II. SUMMARY

[0015] In certain aspects, the disclosure 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 one or more proteins indicative of the subject's responsiveness to the treatments. Certain such proteins can be one or more of: delta like canonical notch ligandl (DLL1), vascular non-inflammatory molecule 2 (VNN2), Guanine nucleotide exchange factor (VAV3), and Sulfatase-modifying factor 1 (SUMF1). In certain embodiments, the proteins are assayed using an aptamer-based multiplex proteomic assay, such as SomaScan™ assay.

[0016] Accordingly, in certain aspects, the disclosure provides methods of assaying samples for one or more proteins selected from: DLL1, VNN2, VAV3, and SUMF1; wherein the subjects have or are suspected of having a cognitive impairment.

[0017] 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.

[0018] Further aspects of the disclosure provide kits comprising reagents for assaying in samples one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0019] III. INCORPORATION BY REFERENCE

[0020] 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.

[0021] IV. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 shows schematic representation of an example of a plasma exchange therapy. In an example described in Figure 1 , Alzheimer's Management By Albumin Replacement (AMB AR) 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). IVIG: Intravenous Immunoglobulin; Albutein and Flebogamma DIF are commercially available products.

[0023] Figures 2A-2B. Proteomics analysis of samples. A. Brief description of statistical analysis to identify protein biomarkers. B. A flow-chart of a process to identify one or more proteins that can indicate a subject’s responsiveness to a treatment of a cognitive impairment.

[0024] Figures 3A-3C show certain examples of predicted clinical changes in stratified subjects based on the protein DLL1. A. Relationship between baseline plasma DLL1 levels and Clinical Dementia Rating- Sum of Boxes (CDR.Sb) improvement. Higher baseline level of DLL1 is associated with CDR.Sb improvement (measured as change from baseline) (Spearman correlation coefficient (rho) = -0.552, Area Under the Curve (AUC) = 0.770 for better than baseline and AUC=0.791 for not worse than baseline). B. Receiving Operating Characteristics (ROC) of DLL1 to predict better than bl scores of CDR.Sb at end of study (EOS). C. Estimated changes in stratified DLL1 groups after plasma exchange treatment.

[0025] Figures 4A-4C show certain examples of predicted clinical changes in stratified subjects based on the protein VNN2. A. Relationship between baseline plasma VNN2 levels and CDR.Sb improvement. Higher baseline level of VNN2 is associated with CDR.Sb improvement (rho = -0.476, AUC = 0.761 for better than baseline and AUC=0.726 for not worse than baseline ). B. ROC of VNN2 to predict better than bl scores of CDR.Sb at EOS. C. Estimated changes in CDR.Sb in stratified VNN2 groups after plasma exchange treatment.

[0026] Figures 5A-5C show certain examples of predicted clinical changes in stratified subjects based on the protein VAV3. A. Relationship between baseline plasma VAV3 levels and CDR.Sb improvement. Higher baseline level of VAV3 is associated with CDR.Sb improvement (rho = -0.494, AUC = 0.788 for better than baseline and AUC=0.724 for not worse than baseline). B. ROC of VAV3 to predict better than bl scores of CDR.Sb at EOS. C. Estimated changes in CDR.Sb in stratified VAV3 groups after plasma exchange treatment.

[0027] Figures 6A-6C show certain examples of predicted clinical changes in stratified subjects based on the protein SUMF1. A. Relationship between baseline plasma SUMF1 levels and CDR.Sb improvement. Higher baseline level of SUMF1 is associated with CDR.Sb improvement (rho = -0.489, AUC = 0.696 for better than baseline and AUC=0.756 for not worse than baseline). B. ROC of SUMF1 to predict equal or better than bl scores of CDR.Sb at EOS. C. Estimated changes in CDR.Sb in stratified SUNF1 groups after plasma exchange treatment. V. DETAILED DESCRIPTION

[0028] A. Introduction

[0029] The present invention relates to treating a cognitive impairment, for example, aging-associated cognitive impairment. In certain aspects, the disclosure provides methods of assaying a sample obtained from a subject having or suspected of having a cognitive impairment for one or more proteins selected from: DLL1, VNN2, VAV3, and SUMF1. 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 disclosure 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 disclosure.

[0030] Before describing the present invention in detail, it is to be understood that this disclosure 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 disclosure will be limited only by the appended claims.

[0031] The publications discussed herein are provided solely for their disclosure 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.

[0032] 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 of the limits, ranges excluding either or both of those included limits are also included in the invention. It is noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements or use of a “negative” limitation.

[0033] As will be apparent to those of skill in the art upon reading this disclosure, 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.

[0034] B. Definitions

[0035] 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 disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0036] 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.

[0037] In describing methods of the present invention, the terms “host”, “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 non-human 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.

[0038] 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.

[0039] 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.

[0040] 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 (wordfinding), 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.

[0041] 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 (MCI); 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.

[0042] 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.

[0043] C. Assay methods

[0044] Certain aspects of the disclosure provide methods of analyzing a sample obtained from a subject, the method comprising: assaying the sample for one or more proteins selected from: DLL1, VNN2, VAV3, and SUMF1; wherein the subject has or is suspected of having a cognitive impairment.

[0045] 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:

[0046] MGSRCALALAVLSALLCQVWSSGVFELKLQEFVNKKGLLGNRNCCRGGAGPPPCACRT FFRVCLKHYQASVSPEPPCTYGSAVTPVLGVDSFSLPDGGGADSAFSNPIRFPFGFTWPGTFSLIIE ALHTDSPDDLATENPERLISRLATQRHLTVGEEWSQDLHSSGRTDLKYSYRFVCDEHYYGEGCS VFCRPRDDAFGHFTCGERGEKVCNPGWKGPYCTEPICLPGCDEQHGFCDKPGECKCRVGWQGR YCDECIRYPGCLHGTCQQPWQCNCQEGWGGLFCNQDLNYCTHHKPCKNGATCTNTGQGSYTC SCRPGYTGATCELGIDECDPSPCKNGGSCTDLENSYSCTCPPGFYGKICELSAMTCADGPCFNGG RCSDSPDGGYSCRCPVGYSGFNCEKKIDYCSSSPCSNGAKCVDLGDAYLCRCQAGFSGRHCDDN VDDCASSPCANGGTCRDGVNDFSCTCPPGYTGRNCSAPVSRCEHAPCHNGATCHERGHRYVCE CARGYGGPNCQFLLPELPPGPAVVDLTEKLEGQGGPFPWVAVCAGVILVLMLLLGCAAVVVCV RLRLQKHRPPADPCRGETETMNNLANCQREKDISVSIIGATQIKNTNKKADFHGDHSADKNGFK ARYPAVDYNLVQDLKGDDTAVRDAHSKRDTKCQPQGSSGEEKGTPTTLRGGEASERKRPDSGC STSKDTKYQSVYVISEEKDECVIATEV (SEQ ID NO: 1).

[0047] Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject that has or is suspected of having a cognitive impairment for 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 if 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 disclosure. VNN2 protein is also found in several organisms, including humans. In humans, an example of VNN2 protein is described in Uniprot database with ID NO.: 095498. The sequence of a human VNN2 protein is given below:

[0048] MVTSSFPISVAVFALITLQVGTQDSFIAAVYEHAVILPNKTETPVSQEDALNLMNENIDILE TAIKQAAEQGARIIVTPEDALYGWKFTRETVFPYLEDIPDPQVNWIPCQDPHRFGHTPVQARLSC LAKDNSIYVLANLGDKKPCNSRDSTCPPNGYFQYNTNVVYNTEGKLVARYHKYHLYSEPQFNV PEKPELVTFNTAFGRFGIFTCFDIFFYDPGVTLVKDFHVDTILFPTAWMNVLPLLTAIEFHSAWAM GMGVNLLVANTHHVSLNMTGSGIYAPNGPKVYHYDMKTELGKLLLSEVDSHPLSSLAYPTAVN WNAYATTIKPFPVQKNTFRGFISRDGFNFTELFENAGNLTVCQKELCCHLSYRMLQKEENEVYV LGAFTGLHGRRRREYWQVCTLLKCKTTNLTTCGRPVETASTRFEMFSLSGTFGTEYVFPEVLLTE IHLSPGKFEVLKDGRLVNKNGSSGPILTVSLFGRWYTKDSLYSSCGTSNSAITYLLIFILLMIIALQN IVML (SEQ ID NO: 2).

[0049] Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject that has or is suspected of having a cognitive impairment for 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 if SEQ ID NO: 2. For example, a person of ordinary skill in the art can readily identify a homolog of human VNN2 protein having a sequence of SEQ ID NO: 2 in an organism of interest and then assay such VNN2 protein in a sample obtained from such organism. Such embodiments are within the purview of the disclosure.

[0050] Similarly, 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:

[0051] MEPWKQCAQWLIHCKVLPTNHRVTWDSAQVFDLAQTLRDGVLLCQLLNNLRAHSINLK EINLRPQMSQFLCLKNIRTFLTACCETFGMRKSELFEAFDLFDVRDFGKVIETLSRLSRTPIALATG IRPFPTEESINDEDIYKGLPDLIDETLVEDEEDLYDCVYGEDEGGEVYEDLMKAEEAHQPKCPEN DIRSCCLAEIKQTEEKYTETLESIEKYFMAPLKRFLTAAEFDSVFINIPELVKLHRNLMQEIHDSIV NKNDQNLYQVFINYKERLVIYGQYCSGVESAISSLDYISKTKEDVKLKLEECSKRANNGKFTLRD LLVVPMQRVLKYHLLLQELVKHTTDPTEKANLKLALDAMKDLAQYVNEVKRDNETLREIKQFQ LSIENLNQPVLLFGRPQGDGEIRITTLDKHTKQERHIFLFDLAVIVCKRKGDNYEMKEIIDLQQYKI ANNPTTDKENKKWSYGFYLIHTQGQNGLEFYCKTKDLKKKWLEQFEMALSNIRPDYADSNFHD FKMHTFTRVTSCKVCQMLLRGTFYQGYLCFKCGARAHKECLGRVDNCGRVNSGEQGTLKLPEK RTNGLRRTPKQVDPGLPKMQVIRNYSGTPPPALHEGPPLQLQAGDTVELLKGDAHSLFWQGRNL ASGEVGFFPSDAVKPCPCVPKPVDYSCQPWYAGAMERLQAETELINRVNSTYLVRHRTKESGEY AISIKYNNEAKHIKILTRDGFFHIAENRKFKSLMELVEYYKHHSLKEGFRTLDTTLQFPYKEPEHS AGQRGNRAGNSLLSPKVLGIAIARYDFCARDMRELSLLKGDVVKIYTKMSANGWWRGEVNGR VGWFPSTYVEEDE (SEQ ID NO: 3).

[0052] Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject that has or is suspected of having a cognitive impairment for 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 if SEQ ID NO: 3. 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: 3 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 disclosure.

[0053] Similarly, SUMF1 protein is also found in several organisms, including humans. In humans, an example of SUMF 1 protein is described in Uniprot database with ID NO.: P01042. The sequence of a human SUMF 1 protein is given below:

[0054] MAAPALGLVCGRCPELGLVLLLLLLSLLCGAAGSQEAGTGAGAGSLAGSCGCGTPQRPG AHGSSAAAHRYSREANAPGPVPGERQLAHSKMVPIPAGVFTMGTDDPQIKQDGEAPARRVTIDA FYMDAYEVSNTEFEKFVNSTGYLTEAEKFGDSFVFEGMLSEQVKTNIQQAVAAAPWWLPVKGA NWRHPEGPDSTILHRPDHPVLHVSWNDAVAYCTWAGKRLPTEAEWEYSCRGGLHNRLFPWGN KLQPKGQHYANIWQGEFPVTNTGEDGFQGTAPVDAFPPNGYGLYNIVGNAWEWTSDWWTVHH SVEETLNPKGPPSGKDRVKKGGSYMCHRSYCYRYRCAARSQNTPDSSASNLGFRCAADRLPTM D (SEQ ID NO: 4).

[0055] Accordingly, in certain embodiments, the methods disclosed herein comprise assaying a sample from a subject that has or is suspected of having a cognitive impairment for 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 if SEQ ID NO: 4. For example, a person of ordinary skill in the ait can readily identify a homolog of human SUMF1 protein having a sequence of SEQ ID NO: 4 in an organism of interest and then assay such SUMF1 protein in a sample obtained from such organism. Such embodiments are within the purview of the disclosure.

[0056] The protein or proteins being assayed are also referenced herein as “target protein” or “target proteins.”

[0057] In some cases, the methods disclosed herein comprise qualitatively assaying the sample for the one or more target proteins.

[0058] Certain non-limiting examples of a qualitative assay for a target protein includes determining the sequence of the ta get protein or proteins and / or post-translational modification of the target protein or proteins. Any suitable methods may be used for such qualitative assaying of one or more target proteins in a sample. 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 ar e well known to a person of ordinary skill in the art and such embodiments ar e within the purview of the invention. Methods of obtaining such samples from subjects are also well known in the ai t and such embodiments are within the purview of the disclosure.

[0059] In some cases, the levels of proteins described herein are analyzed in a subject’s sample using SomaScanI VIassay. Certain details of SomaScan™ assays are described in the reference Gold et al. (2010), PLoS One 5(12): el5004, 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 SomaScan1 Massay provides the levels of various proteins in a sample as “relative fluorescence units” (RFU) or a derivative of RFU, such as logjRFU.

[0060] Further non-limiting examples of methods that may be used for determining a sequence of a target protein include mass spectrometry or Edman degradation using a protein sequencer.

[0061] Non-limiting examples of methods that may be used for determining post-translation modification of a target protein includes mass spectrometry and post-translational modification based antibody binding assays, such as western blotting or immunoassays.

[0062] 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.

[0063] 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.

[0064] 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. 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.

[0065] 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.

[0066] 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.

[0067] 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.

[0068] 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.

[0069] 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. Sci. J., 1:113-124, the contents of which are incorporated herein by reference in its entirety.

[0070] In some cases, the methods comprise assaying a sample for the one of: DLL1, VNN2, VAV3, and SUMF1.

[0071] In some cases, the methods comprise assaying a sample for any two of: DLL1, VNN2, VAV3, and SUMF1, for example, the following combinations: DLL1 and VNN2; DLL1 and VAV3; DLL1 and SUMF1; VNN2 and VAV3; VNN2 and SUMF1; and VAV3 and SUMF1.

[0072] In further embodiments, the methods comprise assaying a sample for any three of: DLL1, VNN2, VAV3, and SUMF1, for example, the following combinations: DLL1, VNN2 and VAV3; DLL1, VAV3, and SUMF1; DLL1, VNN2, and SUMF1; and VNN2, VAV3, and SUMF1.

[0073] In certain embodiments, the methods comprise assaying a sample for all four of: DLL1, VNN2, VAV3, and SUMF1.

[0074] In some cases, the methods comprise assaying a sample for only one of: DLL1, VNN2, VAV3, and SUMF1 and no additional proteins, except in some instances certain control proteins.

[0075] In some cases, the methods comprise assaying a sample for only two of: DLL1, VNN2, VAV3, and SUMF1 and no additional proteins, except certain control proteins. For example, only the following combinations of proteins are assayed: DLL1 and VNN2; DLL1 and VAV3; DLL1 and SUMF1; VNN2 and VAV3; VNN2 and SUMF1; and VAV3 and SUMF1 and, in addition, one or more control proteins may be assayed.

[0076] In further embodiments, the methods comprise assaying a sample for only three of: DLL1, VNN2, VAV3, and SUMF1 and no other proteins, except certain control proteins. For example, the following combinations of proteins are assayed: DLL1, VNN2 and VAV3; DLL1, VAV3, and SUMF1; DLL1, VNN2, and SUMF1; and VNN2, VAV3, and SUMF1 and, in addition, one or more control proteins may be assayed.

[0077] In certain embodiments, the methods comprise assaying a sample for only the following four proteins: DLL1, VNN2, VAV3, and SUMF1 and no additional proteins, except in some instances certain control proteins.

[0078] A “control protein” as used herein refers to a protein that does not distinguish between a subject that is likely to respond positively to a plasma exchange therapy for beating a cognitive impairment and a subject that is not likely to respond positively to a plasma exchange therapy for beating a cognitive impairment. In other words, the level of control protein is same in subjects regardless of their responsiveness to a plasma exchange therapy for treating a cognitive impairment. A person of ordinary skill in the art knows or can readily determine such proteins.

[0079] The methods of assaying one or more proteins as disclosed herein may further comprise comparing the assay results to a threshold, a reference value, or a reference sample.

[0080] A threshold or reference value may be predetermined, for example, based on the concentrations of one or more assayed proteins in individuals that are known to have responded to therapies for a cognitive impairment. For example, retrospective assays for the one or more proteins 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 threshold or reference value 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.

[0081] Alternatively, such threshold or reference value may be predetermined, for example, based on the concentrations of one or more assayed proteins in individuals that are known not to have responded to therapies for a cognitive impairment. For example, retrospective assays for the one or more proteins 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 threshold or reference value 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.

[0082] A reference sample may contain one or more target proteins at concentrations that are known to indicate responsiveness of a subject to a plasma exchange therapy for treating a cognitive impairment.

[0083] The samples for assaying the one or more target proteins in the methods disclosed herein may be obtained from a subject that has a cognitive impairment. Alternatively, the samples for assaying the one or more target proteins in the methods disclosed herein may be obtained from a subject that is suspected of having the cognitive impairment.

[0084] The term “a subject that has a cognitive impairment” as used herein refers to a subject that exhibits symptoms of cognitive impairment.

[0085] 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.”

[0086] In certain embodiments, a cognitive impairment is caused by a neurodegenerative disease. Nonlimiting 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, vascular dementia. These diseases are described below and additional information about these diseases is well-known in the art.

[0087] In specific embodiments, the neurodegenerative disease is AD, i.e., a subject has a cognitive impairment caused by AD.

[0088] In certain embodiments, the sample is obtained from a subject that is a candidate for a plasma exchange therapy for treating the cognitive impairment.

[0089] 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.

[0090] 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 ordinar y 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 disclosure.

[0091] D. Diagnostic methods

[0092] Certain aspects of the disclosure provide, further to assaying one or more protein in a sample obtained from a subject having or suspected of having a cognitive impairment, 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. In some embodiments, the therapy is a plasma exchange therapy. Details of plasma exchange therapies that could be administered according to the disclosure are discussed in detail below and are applicable to the diagnostic methods described herein.

[0093] 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 results of an assay of a sample of the subject for one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1. 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 DLL1. Also, 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 results of the assay of the sample of the subject for VNN2. Further, 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 results of the assay of the sample of the subject for VAV3. Furthermore, 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 results of the assay of the sample of the subject for SUMF1.

[0094] In further embodiments, a subject can be 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 two or more proteins selected from DLL1, VNN2, VAV3, and SUMF1. Such combinations include: DLL1 and VNN2; DLL1 and VAV3; DLL1 and SUMF1; VNN2 and VAV3; VNN2 and SUMF1; and VAV3 and SUMF1.

[0095] Also, a subject can be 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 three or more proteins selected from DLL1, VNN2, VAV3, and SUMF1. Such combinations include: DLL1, VNN2 and VAV3; DLL1, VAV3, and SUMF1; DLL1, VNN2, and SUMF1; and VNN2, VAV3, and SUMF1.

[0096] Moreover, a subject can be 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 all of the proteins DLL1, VNN2, VAV3, and SUMF1.

[0097] 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 threshold, a reference value.

[0098] As noted above, such threshold or reference value may be predetermined, for example, based on the concentrations of one or more assayed proteins in individuals that are known to have responded to therapies for a cognitive impairment. For example, retrospective assays for the one or more proteins 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 threshold or reference value 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.

[0099] Also, as noted above, such threshold or reference value may be predetermined, for example, based on the concentrations of one or more assayed proteins in individuals that are known not to have responded to therapies for a cognitive impairment. For example, retrospective assays for the one or more proteins 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 threshold or reference value 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.

[0100] A reference sample may contain one or more target proteins 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 an increased level of the assayed one or more proteins in the sample obtained from the subject compared to a threshold or a reference value or a reference sample.

[0101] As discussed above, in some cases, the levels of the proteins described herein are analyzed in a patient sample using SomaScan™ assay. Tables 2 and 3 below provide certain threshold values for proteins quantified using SomaScan™ assay and that are indicative of subjects’ responsiveness to a therapy for a cognitive impairment.

[0102] Accordingly, logzRFU value as determined by SomaScan™ assay for DLL protein in a sample from a subject of at least 9 to 13, for example, at least 9, at least 10, at least 11, at least 12, at least 13, or at least 11.2 indicates that the subject is likely to respond positively to a therapy, such as plasma exchange therapy for treating a cognitive impairment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below.

[0103] Similarly, logiRFU value as determined by SomaScan™ assay for VNN2 protein in a sample from a subject of at least 8 to 12, for example, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 10.6 indicates that the subject is likely to respond positively to a therapy, such as plasma exchange therapy for treating a cognitive impairment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below.

[0104] Further, logiRFU value as determined by SomaScan™ assay for VAV3 protein in a sample from a subject of at least 8 to 12, for example, at least 8, at least 9, at least 10, at least 11, at least 12, or at least 10.4 indicates that the subject is likely to respond positively to a therapy, such as plasma exchange therapy for treating a cognitive impairment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below.

[0105] Furthermore, log2RFU value as determined by SomaScan™ assay for SUMF1 protein in a sample from a subject of at least 10 to 14, for example, at least 10, at least 11, at least 12, at least 13, at least 14, or at least 12.1 indicates that the subject is likely to respond positively to a therapy, such as plasma exchange therapy for treating a cognitive impairment. In some cases, the plasma exchange therapy is as described in FIG. 1 or the Experimental section below.

[0106] As also discussed above, protein levels of the proteins described herein can be determined using techniques other than the SomaScan™ assay. Based on the SomaScan™ assay results and associated logiRFU values of the proteins described herein, a skilled artisan can determine the actual protein concentrations that indicate whether a patient is likely to respond or not likely to respond positively to a therapy, such as plasma exchange therapy for treating a cognitive impairment. Certain such techniques are described above in the discussion of suitable methods that may be used for such qualitative assaying of one or more target proteins in a sample and such embodiments are within the purview of the disclosure.

[0107] When certain such methods other than the SomaScan™ assay are used, a person of ordinary skill in the art can determine an appropriate threshold or a reference value or a reference sample that could be used to compare the results of an assay to determine an increased level of the one or more proteins. For example, such threshold or reference value may indicate the highest level of the one or more proteins that may indicate responsiveness or non-responsiveness to a plasma exchange therapy for a cognitive impairment. Hence, a level of one or more proteins above such threshold or reference value indicates that a subject is responsive to a plasma therapy for treating a cognitive impairment.

[0108] In some cases, the results of the assay for one protein can be compared to a threshold or a reference value for that corresponding protein. As a person skilled in the art would recognize, control samples or reference values for comparison would depend on the type of sample, for example, blood sample or cerebrospinal fluid sample.

[0109] In certain other cases, the results of the assay for two, three, or four proteins can be compared to a threshold or a reference value for that corresponding combination of two, three, or four proteins. When comparing results of two or more proteins, certain statistical analysis could be performed on the results of individual proteins to arrive at a combined result for two or more proteins, which can then be compared to the threshold or a reference value.

[0110] For example, results for a combination of two proteins may show statistically increased level of the two proteins when considered as a combination when one of the proteins may show no change or even decreased level. Similarly, results for a combination of three proteins may show statistically increased level of the three proteins when considered as a combination when one or two proteins may show no change or even decreased level. Also, results for a combination of four proteins may show statistically increased level of the four proteins when considered as a combination when one, two, or three proteins may show no change or even decreased level. Statistical analyses to produce a combined value for the level of two or more proteins are well known in the art. For example, in some cases, protein ratios and multivariate linear and non-linear modeling can be used to compare protein expression data.

[0111] Statistical Analysis

[0112] 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 subject’ biomarker levels.

[0113] Firstly, treatment benefits were confirmed by comparing clinical outcome changes between treated and placebo groups. Candidate proteomic biomarkers were then identified by significant Spearman correlation coefficient between baseline protein levels measured by certain assays (here by SomaScan assay and expressed as log2 (RFU) and changed cognitive outcomes at the end of study. The predictive powers of these candidate proteomic biomarkers 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 biomarker. ROC is used to show the predictive power of a continuous biomarker on binary outcome, e.g., has treatment benefit vs does not have treatment benefit.

[0114] AUC represents the probability of correctly ordering patients with or without treatment benefits based on the continuous biomarker. Typically, AUC > 70% is considered acceptable and AUC > 80% is considered to have excellent prediction.

[0115] High biomarker (here baseline protein level) and low biomarker level is then defined by optimal decision threshold (here best cut off point or the reference value of baseline protein levels) based on Youden's index, which maximizes the accuracy (overall rate of correct classification as shown in Table 1 below). The best binary biomarkers were finally identified based on their prediction powers measured by accuracy, specificity and sensitivity (their calculations are explained below and shown in Table 1).

[0116] Al, Bl, AO, and BO used in the following paragraphs are as shown in the Table 1 below:

[0117] Accuracy represents the percentage of right classification: i.e., (number of subjects that truly have treatment benefit + the number of subjects that truly did not have treatment benefit) / total number of predictions. ((Al + B0) / N, N = total number of predictions.)

[0118] 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 (BO / (B1 + BO).

[0119] 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 (A1 / (A1 + AO)).

[0120] These identified biomarkers 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.

[0121] 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.

[0122] In some cases, the baseline biomarker level that indicates 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 2 below:

[0123] Table 2. Baseline biomarker levels 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 impairment.

[0124] Table 3. Baseline biomarker levels in blood that indicate whether a subject is likely or not likely to respond positively (less than 1 point worsening — clinically meaningful changes for CDR sum of box) to a plasma therapy (e.g., the plasma therapy described in the Experimental section below) for treating a cognitive impairment.

[0125] 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 assay for one or more proteins, where the scores correlates 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 proteins 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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

[0133] Certain aspects of the disclosure 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.

[0134] Thus, certain aspects of the disclosure 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 heating the cognitive impairment.

[0135] 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 one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0136] Details of identifying a subject as likely or not likely to respond positively to the plasma exchange therapy for heating a cognitive impairment based on results of an assay of a sample of the subject for one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1 are described above under “Diagnostic methods.”

[0137] 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 results of the assay of the sample of the subject for one, two, three, or four proteins from: DLL1, VNN2, VAV3, and SUMF1.

[0138] 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 an increased level of the assayed one, two, three, or four proteins in the sample obtained from the subject compared to a reference value or a reference sample.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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 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.

[0144] 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%).

[0145] Plasma replacement solutions

[0146] In certain cases, any plasma replacements solutions described below is used for plasma exchange therapies.

[0147] 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.

[0148] 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).

[0149] 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).

[0150] Plasma Protein Fraction (Human) (PPF)

[0151] 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).

[0152] PPF is tested to determine if it meets the following standards as per 21 CFR 640.92 (incorporated by reference herein):

[0153] (a) The final product shall be a 5.0 + / - 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.

[0154] 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, |3, 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)).

[0155] Albumin (Human) (HAS)

[0156] 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).

[0157] Albumin (Human) is tested to determine if it meets the following standards as per 21 CFR 640.82:

[0158] (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.

[0159] (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.

[0160] 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, , 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.

[0161] F. Indications

[0162] The subject methods and compounds find use in treating a cognitive impairment, such as cognitive impairment caused by neuroinflarmnation. In some cases, cognitive impairment is an aging-associated cognitive impairment, such as impairments in the cognitive ability of individuals caused by age.

[0163] 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:

[0164] 1. Mild cognitive impairment (MCI)

[0165] 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.

[0166] 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:

[0167] 2. Alzheimer's disease

[0168] 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.

[0169] 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.

[0170] 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 raphae 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.

[0171] 3. Parkinson's Disease

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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-methyl transferase [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.

[0176] 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 / t witching (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.

[0177] 4. Parkinsonism

[0178] 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

[0179] 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:

[0180] 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.

[0181] 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 non-verbal 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.

[0182] 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 self-monitoring, 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 hypeiphagia. While some of the symptoms can initially be alleviated, the disease progresses, and patients often die within two to ten years.

[0183] 6. Huntington's disease

[0184] 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).

[0185] 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 (4pl 6.3). 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.

[0186] 7. Amyotrophic lateral sclerosis

[0187] 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.

[0188] 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.

[0189] 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

[0190] 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.

[0191] 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 arc rapidly incapacitated; for a few the course can be rapidly progressive.

[0192] 9. Glaucoma

[0193] 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).

[0194] 10. Myotonic dystrophy

[0195] 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.

[0196] 11. Dementia

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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

[0201] 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, et al., Future Neurology, 3(6) (2008)).

[0202] 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 35-50 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):175-80 (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.)

[0203] 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).

[0204] 13. Progressive supranuclear palsy

[0205] 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 fust 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.

[0206] 14. Ataxia

[0207] 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.

[0208] 15. Multiple-system atrophy

[0209] 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.

[0210] 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.

[0211] 16. Frailty

[0212] 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.)

[0213] 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)).

[0214] 17. Neuromyelitis Optica Spectrum Disorder

[0215] 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.

[0216] 18. Post-operative cognitive dysfunction

[0217] 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.

[0218] 19. Chronic traumatic encephalopathy

[0219] 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.

[0220] 20. Traumatic brain injury

[0221] 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.

[0222] 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.

[0223] 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- associatcd cognitive impairment, and progression of cognitive impairment observed prior to treatment with the disclosed methods will be halted following treatment by the disclosed methods.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] G. Methods of Monitoring for Improvement

[0228] 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

[0229] 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 mini-mental 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).

[0230] 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.c. Babinski sign); muscle strength often on the MRC scale 1 to 5; muscle tone and signs of rigidity.

[0231] Certain embodiments of methods of the disclosure 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 disclosur e include employment of the rating scales discussed below.

[0232] 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.

[0233] 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).

[0234] General motor function can be evaluated using widely-used scales including the General Motor Function Scale (GMF). This 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).

[0235] Certain embodiments of methods of the disclosure 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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)).

[0240] The disclosure 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.

[0241] An embodiment of the invention also contemplates determining the level of neurogenesis before, during, and / or after therapies according to the disclosure, 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.

[0242] H. Exercise

[0243] Exercise can be characterized by aerobic or anaerobic activity and can involve high calorie-burning 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.

[0244] 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 disclosure. 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.

[0245] I. Kits, Reagents, and Devices

[0246] Certain aspects of the disclosure provide kits comprising reagents for measuring in a sample an amount of one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0247] As discussed above, assaying one or more target proteins can be performed by any suitable methods, such as qualitative or quantitative methods. Accordingly, kits disclosed herein could be designed for qualitative or quantitative assays of one or more target proteins.

[0248] Thus, in certain cases, the kits disclosed herein provide reagents and / or devices for determining a sequence of a target protein. Certain such reagents and / or devices can be used in conducting qualitative target protein analysis using mass spectrometry. Such reagents and / or devices comprise reagents for lysing proteins in a sample, such as enzymes for digesting protein, e.g., trypsin; various solvents, such as water, methanol, acetonitrile, chloroform, tetrahydrofuran, and dichloromethane; various buffer reagents for preparing the buffers used in the analysis.

[0249] Certain other reagents and / or devices can be used in conducting qualitative target protein analysis using Edman degradation using a protein sequencer. Such reagents include phenyl isothiocyanate. Other reagents used in Edman degradation sequencing are well-known in the art and kits containing such reagents are within the purview of the disclosure.

[0250] In some cases, the kits disclosed herein are designed for quantitatively assaying the sample for the one or more proteins. Certain non-limiting examples include kits for quantitatively assaying one or more target proteins via immunoassays, mass-spectrometry analyses, and protein detecting array analyses.

[0251] 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 disclosure provide kits for performing one or more of these assays for one or more target proteins disclosed herein.

[0252] In one embodiment, the kits comprise lateral flow immunoassay devices. Such devices allow detection and / or quantification of one or more of the target proteins from: DLL1, VNN2, VAV3, and SUMF1. Lateral flow immunoassay devices may also include an internal control that shows a reference value or threshold.

[0253] In some cases, the lateral flow immunoassay devices allow detection and / or quantification of only one, only two, only three, or only four of proteins from: DLL1, VNN2, VAV3, and SUMF1. In addition to the one or more target proteins, the lateral flow immunoassay devices may allow detection and / or quantification of one or more control proteins.

[0254] Certain kits may allow detection of one or more target proteins via protein detecting array. Certain such protein detecting arrays may comprise specific binding agents, such as antibodies that specifically bind to one or more proteins from: DLL1, VNN2, VAV3, and SUMF1. 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 proteins in a sample and the binding agents on the array. Such reagents include labeled secondary antibodies, for example, a fluorescent dye labeled secondary antibody.

[0255] In certain embodiments, the kits allow detection of one or more target proteins 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 proteins are then detected using labeled solution-phase specific binding agents to the one or more target proteins, such as fluorescent-labeled antibodies that specifically bind to one or more target proteins. As such, the kits comprise labeled binding agents to one or more target proteins, particularly, fluorescent-labeled antibodies that specifically bind to one or more target proteins. In some cases, the antibodies against different target proteins are differentially labelled thereby allowing multiplexed detection and / or quantitation of two or more target proteins.

[0256] In some cases, the kits are designed to allow assaying a sample for the one of: DLL1, VNN2, VAV3, and SUMF1. For example, certain kits allow assaying samples for DLL1. Certain other kits allow assaying samples for VNN2. Further embodiments describe kits that allow assaying samples for VAV3. Even further kits allow assaying samples for SUMF1.

[0257] In some cases, the kits are designed to allow assaying a sample for any two of: DLL1, VNN2, VAV3, and SUMF1, for example, the following combinations: DLL1 and VNN2; DLL1 and VAV3; DLL1 and SUMF1; VNN2 and VAV3; VNN2 and SUMF1; and VAV3 and SUMF1.

[0258] In further embodiments, the kits are designed to allow assaying a sample for any three of: DLL1, VNN2, VAV3, and SUMF1, for example, the following combinations: DLL1, VNN2 and VAV3; DLL1, VAV3, and SUMF1; DLL1, VNN2, and SUMF1; and VNN2, VAV3, and SUMF1. In certain embodiments, the kits are designed to allow assaying a sample for all four of: DLL1, VNN2, VAV3, and SUMF1.

[0259] In some cases, the kits are designed to allow assaying a sample for only one of: DLL1, VNN2, VAV3, and SUMF1 and no additional proteins, except certain control proteins.

[0260] In some cases, the kits are designed to allow assaying a sample for only two of: DLL1, VNN2, VAV3, and SUMF1 and no additional proteins, except certain control proteins. For example, only the following combinations of proteins are assayed: DLL1 and VNN2; DLL1 and VAV3; DLL1 and SUMF1; VNN2 and VAV3; VNN2 and SUMF1; and VAV3 and SUMF1 and, in addition, one or more control proteins may be assayed.

[0261] In further embodiments, the kits are designed to allow assaying a sample for only three of: DLL1, VNN2, VAV3, and SUMF1 and no other proteins, except certain control proteins. For example, the following combinations of proteins are assayed: DLL1, VNN2 and VAV3; DLL1, VAV3, and SUMF1 ; DLL1, VNN2, and SUMF1; and VNN2, VAV3, and SUMF1 and, in addition, one or more control proteins may be assayed.

[0262] In certain embodiments, the kits are designed to allow assaying a sample for only the following four proteins: DLL1 , VNN2, VAV3, and SUMF1 and no additional proteins, except certain control proteins.

[0263] 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 one or more specific binding members are labeled with a detectable moiety, such as optically detectable moiety.

[0264] 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.

[0265] 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. VI. EXPERIMENTAL EXAMPLES

[0266] A. Example 1 - Identifying proteins predictive of responsiveness to a plasma exchange therapy for treating cognitive impairment

[0267] Example 1 describes an exemplary method of identifying protein biomarkers 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. Such analyses were also performed in subgroups if enough samples were available.

[0268] 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 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.

[0269] 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. In mild AD PE-treated group showed improvement while placebo group showed worsening of cognitive function. (Boada et al. (2020), Alzheimer’s & Dementia, 16:10, pp. 1412-1425.)

[0270] In a subset of the patients, baseline predictive biomarkers 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 associated with CDR.sb change at EOS. Such analysis indicated the strength of the proteomic biomarkers associated with continuous clinical changes.

[0271] Spearman correlation coefficient or Spearman’s rho and associated p value were reported. Positive rho indicated positive relationship and negative rho indicated negative relationship.

[0272] 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), Malawi Med J., 24(3): 69-71.)

[0273] 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 diagnostic / predictive power. High or low baseline protein level is then defined by optimal decision threshold (reference value) based on Youden’s index. The binary biomarker (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.

[0274] These identified candidate biomarkers were verified by in silico verification including tests in other clinical outcomes (ADAS_COg, ADCS_ADL from AMBAR study), in random reselected samples (1001 resampling datasets (80% of original sample size)).

[0275] The final list of candidate biomarkers based on the above results was prepared based on the flow- chart shown in Figure 2B.

[0276] Selected single plasma protein biomarkers are provided in Table 4 with additional predictive information provided in Tables 5 and 6.

[0277] Table 4. Identification of candidate plasma biomarkers based on spearman correlation:

[0278] Table 5. Prediction power for treatment benefit (CDR.Sb at EOS better than baseline (> 0)).

[0279] Table 6. Prediction power for treatment benefit (CDR.Sb change < 1 point increase to baseline, 2019 Disease severity and minimal clinically important differences in clinical outcome assessments for Alzheimer’s disease clinical trials.) CMC: Clinical meaningful changes.

[0280] The data in Tables 5 and 6 show that DLL1 levels could be used as exclusion criteria if looking for outcomes better than baseline after treatment since it has 92.5% specificity. DLL1 levels could be used as0 predictive biomarkers if looking for less than 1 point worsening after treatment, since it has balanced sensitivity and specificity and 78.4% accuracy.

[0281] Table 7 shows in silica verification in random samplings and other clinical outcomes, AUC for predicting better than baseline or at least not worsening larger than CMC. 1. What is the clinically relevant change on the ADAS-Cog? (2012) J. Neurol Neurosurg

[0282] Psychiatry ; 83 (2 ) : 171 -3.

[0283] Figures 3A-3C describe predicted clinical changes in stratified subjects example from candidate predictive biomarker baseline DLL1.

[0284] Figures 4A-4C describe predicted clinical changes in stratified subjects example from candidate predictive biomarker baseline VNN2.

[0285] Figures 5A-5C describe predicted clinical changes in stratified subjects example from candidate predictive biomarker baseline VAV3.

[0286] Figures 6A-6C describe predicted clinical changes in stratified subjects example from candidate predictive biomarker baseline SUMF1.

[0287] Notwithstanding the appended claims, the disclosure is also defined by the following clauses:

[0288] 1. A method of analyzing a sample obtained from a subject, the method comprising: assaying the sample for one or more proteins selected from: delta like canonical notch ligandl (DLL1 ), vascular non-inflammatory molecule 2 (VNN2), Guanine nucleotide exchange factor (VAV3), and Sulfatase-modifying factor 1 (SUMF1); wherein the subject has or is suspected of having a cognitive impairment.

[0289] 2. The method of clause 1, comprising assaying the sample for DLL1.

[0290] 3. The method of clause 1, comprising assaying the sample for VNN2.

[0291] 4. The method of clause 1, comprising assaying the sample for VAV3.

[0292] 5. The method of clause 1, comprising assaying the sample for SUMF1.

[0293] 6. The method of any one of clauses 1 to 5, comprising qualitatively assaying the sample for the one or more proteins.

[0294] 7. The method of any one of clauses 1 to 5, comprising quantitatively assaying the sample for the one or more proteins.

[0295] 8. The method of any one of clauses 1 to 7, wherein the subject has the cognitive impairment.

[0296] 9. The method of any one of clauses 1 to 7, wherein the subject is suspected of having the cognitive impairment.

[0297] 10. The method of any one of the preceding clauses, wherein the cognitive impairment is caused by a neurodegenerative disease.

[0298] 11. The method of clause 10, 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. 12. The method of clause 11, wherein the neurodegenerative disease is AD.

[0299] 13. 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.

[0300] 14. The method of any one of the preceding clauses, comprising assaying the one or more proteins in an immunoassay, mass-spectrometry analysis, or protein detecting array analysis.

[0301] 15. The method of any one of clauses 1 to 13, comprising assaying the one or more proteins in an aptamer-based multiplexed proteomic assay.

[0302] 16. The method of any one of the preceding clauses, comprising comparing the assay result to a threshold or a reference value.

[0303] 17. 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.

[0304] 18. The method of any one of the preceding clauses, further comprising: based on the protein expression data, determining whether the subject is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment in the subject.

[0305] 19. The method of clause 18, 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.

[0306] 20. 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.

[0307] 21. The method of clause 20, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for heating the cognitive impairment based on results of an assay of a sample of the subject for one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0308] 22. The method of clause 20 or 21, 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 two or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0309] 23. The method of any one of clauses 20 to 22, 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 three or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0310] 24. The method any one of clauses 20 to 23, 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 all of the proteins DLL1, VNN2, VAV3, and SUMF1. 25. The method of clause 20 or 24, 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 DLL1.

[0311] 26. The method of clause 20 or 21, 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 VNN2.

[0312] 27. The method of clause 20 or 21, 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 VAV3.

[0313] 28. The method of clause 20 or 21, 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 SUMF1.

[0314] 29. The method of any one of clauses 20 to 28, wherein the subject is identified as likely to respond positively to the plasma exchange therapy for treating the cognitive impairment based on an increased level of the assayed one or more proteins in the sample obtained from the subject compared to a threshold, a reference value, or a reference sample.

[0315] 30. The method of any one of clauses 20 to 29, wherein the plasma exchange therapy comprises a course of a full plasma exchange.

[0316] 31. The method of clause 30, wherein the full plasma exchange comprises replacing substantially all of the subject's plasma with a first albumin solution.

[0317] 32. The method of clause 30 or 31 , wherein the course of the full plasma exchange comprises the full plasma exchange once a week for 5 to 8 weeks.

[0318] 33. The method of any one of clauses 30 to 32, wherein the course of the full plasma exchange comprises the full plasma exchange once a week for 6 weeks.

[0319] 34. The method of any one of clauses 31 to 33, wherein the first albumin solution comprises 5% albumin.

[0320] 35. The method of any one of clauses 30 to 34, 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.

[0321] 36. The method of clause 35, wherein the low volume plasma exchange comprises exchanging between 20% and 40% of the subject’s plasma with the second albumin solution.

[0322] 37. The method of clause 35 or 36, wherein the course of low volume plasma exchange comprises the low volume plasma exchange once a month for at least 10 months. 38. The method of any one of clauses 35 to 37, wherein the course of low volume plasma exchange comprises the low volume plasma exchange once a month for 12 to 16 months.

[0323] 39. The method of any one of clauses 35 to 38, wherein the second albumin solution comprises 20% albumin.

[0324] 40. A kit comprising reagents for measuring in a sample an amount of one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

[0325] 41. The kit of clause 40, comprising reagents for measuring in the sample the amount of DLL1.

[0326] 42. The kit of clause 40, comprising reagents for measuring in the sample the amount of VNN2.

[0327] 43. The kit of clause 40, comprising reagents for measuring in the sample the amount of VAV3.

[0328] 44. The kit of clause 40, comprising reagents for measuring in the sample the amount of SUMF 1.

[0329] 45. The kit of any one of clauses 40 to 44, wherein the reagents comprise, one or more specific binding members that specifically bind to the corresponding one or more proteins.

[0330] 46. The kit of clause 45, wherein each of the one or more specific binding members is, independently, an antibody or an antigen binding fragment thereof, an aptamer, or a peptide binding member.

[0331] 47. The kit of clause 45 or 46, wherein the one or more specific binding members are labeled with a detectable moiety.

[0332] 48. The kit of clause 47, wherein the detectable moiety is optically detectable moiety.

[0333] 49. The kit of any one of clauses 40 to 48, wherein the kit is suitable for performing an immunoassay, western-blot analysis, mass-spectrometry analysis, or protein detecting array analysis.

[0334] 50. The kit of any one of clauses 40 to 48, wherein the kit is suitable for performing an aptamerbased multiplexed proteomic assay.

[0335] 51. The kit of any one of clauses 40 to 50, 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.

[0336] 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.

[0337] 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 inteipreted 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.”

[0338] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group.

[0339] 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 subranges 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.

[0340] 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.

[0341] 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 disclosure is explicitly recited in the claims.

[0342] 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.

Claims

CLAIMSWe Claim:

1. A method of analyzing a sample obtained from a subject, the method comprising: assaying the sample for one or more proteins selected from: delta like canonical notch ligandl(DLL1), vascular non-inflammatory molecule 2 (VNN2), Guanine nucleotide exchange factor (VAV3), and Sulfatase-modifying factor 1 (SUMF1); wherein the subject has or is suspected of having a cognitive impairment.

2. The method of claim 2, comprising qualitatively assaying the sample for the one or more proteins.

3. The method of claim 1 or 2, comprising quantitatively assaying the sample for the one or more proteins.

4. The method of any one of claims 1 to 3, wherein the subject has the cognitive impairment or is suspected of having the cognitive impairment.

5. The method of any one of the preceding claims, wherein the cognitive impairment is caused by a neurodegenerative disease.

6. The method of any one of the preceding claims, wherein the subject is a candidate for a plasma exchange therapy for heating the cognitive impairment.

7. The method of any one of the preceding claims, comprising assaying the one or more proteins in an immunoassay, mass-spectrometry analysis, protein detecting array analysis or in an aptamer-based multiplexed proteomic assay.

8. The method of any one of the preceding claims, comprising comparing the assay result to a threshold or a reference value.

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 sample.

10. The method of any one of the preceding claims, further comprising: based on the protein expression data, determining whether the subject is likely to respond positively to a plasma exchange therapy for treating a cognitive impairment in the subject.

11. The method of claim 10, 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.

12. 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.

13. The method of claim 12, 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 of the subject for one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

14. The method of claim 12 or 13, 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 two or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

15. A kit comprising reagents for measuring in a sample an amount of one or more proteins selected from DLL1, VNN2, VAV3, and SUMF1.

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