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      Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy

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          Abstract

          Background:

          Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers.

          Objective:

          The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker.

          Methods:

          Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau.

          Results:

          The NFL group had higher exosomal tau than the control group ( p <  0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory ( p = 0.0126) and psychomotor speed ( p = 0.0093).

          Conclusion:

          These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.

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          Most cited references39

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          Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury.

          Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed dementia pugilistica, and more recently, chronic traumatic encephalopathy (CTE). We review 48 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 profession althletes, 1 football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular, and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta-amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. Chronic traumatic encephalopathy is a neuropathologically distinct slowly progressive tauopathy with a clear environmental etiology.
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            The measurement of pessimism: the hopelessness scale.

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              Methods of isolating extracellular vesicles impact down-stream analyses of their cargoes.

              Viable tumor cells actively release vesicles into the peripheral circulation and other biologic fluids, which exhibit proteins and RNAs characteristic of that cell. Our group demonstrated the presence of these extracellular vesicles of tumor origin within the peripheral circulation of cancer patients and proposed their utility for diagnosing the presence of tumors and monitoring their response to therapy in the 1970s. However, it has only been in the past 10 years that these vesicles have garnered interest based on the recognition that they serve as essential vehicles for intercellular communication, are key determinants of the immunosuppressive microenvironment observed in cancer and provide stability to tumor-derived components that can serve as diagnostic biomarkers. To date, the clinical utility of extracellular vesicles has been hampered by issues with nomenclature and methods of isolation. The term "exosomes" was introduced in 1981 to denote any nanometer-sized vesicles released outside the cell and to differentiate them from intracellular vesicles. Based on this original definition, we use "exosomes" as synonymous with "extracellular vesicles." While our original studies used ultracentrifugation to isolate these vesicles, we immediately became aware of the significant impact of the isolation method on the number, type, content and integrity of the vesicles isolated. In this review, we discuss and compare the most commonly utilized methods for purifying exosomes for post-isolation analyses. The exosomes derived from these approaches have been assessed for quantity and quality of specific RNA populations and specific marker proteins. These results suggest that, while each method purifies exosomal material, there are pros and cons of each and there are critical issues linked with centrifugation-based methods, including co-isolation of non-exosomal materials, damage to the vesicle's membrane structure and non-standardized parameters leading to qualitative and quantitative variability. The down-stream analyses of these resulting varying exosomes can yield misleading results and conclusions.
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                Author and article information

                Contributors
                Role: Handling Associate Editor
                Journal
                J Alzheimers Dis
                J. Alzheimers Dis
                JAD
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                1387-2877
                1875-8908
                10 February 2016
                12 April 2016
                2016
                : 51
                : 4
                : 1099-1109
                Affiliations
                [a ]Boston University Alzheimer’s Disease and CTE Center , Boston, MA, USA
                [b ] Department of Neurology, Boston University School of Medicine , Boston, MA, USA
                [c ] Department of Neurosurgery, Boston University School of Medicine , Boston, MA, USA
                [d ] Department of Anatomy and Neurobiology, Boston University School of Medicine , Boston, MA, USA
                [e ] Department of Biostatistics, Boston University School of Public Health , Boston, MA, USA
                [f ] Data Coordinating Center, Boston University School of Public Health , Boston, MA, USA
                [g ] Department of Neurosurgery, Emerson Hospital , Concord, MA, USA
                [h ]Aethlon Medical, San Diego, CA, USA
                [i ]Exosome Sciences, San Diego, USA
                [j ] Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine , Boston, MA, USA
                [k ] Department of Pathology, University of Washington , Seattle, WA, USA
                Author notes
                [1]

                Present address: Interfaculty Initiative in Health Policy, Harvard University, Cambridge, MA, USA.

                [2]

                Present address: OHSU Collaborative Life Sciences Building, Portland, OR, USA.

                [3]

                Present address: Theragnostex, Inc., Monmouth Junction, NJ, USA.

                [* ]Correspondence to: Robert A. Stern, PhD, Departments of Neurology, Neurosurgery, and Anatomy & Neurobiology, Boston University Alzheimer’s Disease and CTE Center, Boston University School of Medicine, 71 East Concord Street, Boston, MA 02118, USA. Tel.: +1 617 638 5678; Fax: +1 617 638 5679; E-mail: bobstern@ 123456bu.edu
                Article
                JAD151028
                10.3233/JAD-151028
                4833534
                26890775
                a8409d2d-c15b-4fb4-9e61-8c95b4432710
                IOS Press and the authors. All rights reserved

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 6 January 2016
                Categories
                Research Article

                biomarker,chronic traumatic encephalopathy,diagnosis,exosome,football,neurodegeneration,plasma,tau

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