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dc.contributor.authorBarnes, Douglasen_US
dc.date.accessioned2016-07-05T17:22:27Z
dc.date.available2016-07-05T17:22:27Z
dc.date.issued2016
dc.identifier.urihttps://hdl.handle.net/2144/16788
dc.description.abstractTransactive response DNA-binding protein of 43 kDa (TDP-43) is the major protein found within pathological inclusions in Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) (Neumann et al., 2006). TDP-43 is a ubiquitously expressed protein mainly involved in RNA metabolism. It is a member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family and in its normal state is predominantly found in the nucleus. In its pathological state TDP-43 is cleaved, phosphorylated, ubiquitinated, and located in cytoplasmic or nuclear inclusions. Along with ALS and FTLD, TDP-43 is also observed in many other neurodegenerative diseases. Pathological TDP-43 inclusions have been previously reported in cases of Chronic Traumatic Encephalopathy (CTE) (King et al., 2010)(McKee et al., 2010)(Saing et al., 2012)(Hazrati et al., 2013), however no previous study has reported on the incidence and extent of TDP-43 cellular inclusions in a large cohort of autopsy cases diagnosed with CTE. This study finds that TDP-43 inclusions are a frequent feature of CTE, as TDP-43 inclusions are identified in 43% (20/47) of subjects in a CTE+, FTLD-, low-likelihood-of-AD cohort. Furthermore, this study finds that in CTE there is no consistent initial focus of TDP-43 pathology which spreads to neighboring regions as the disease progresses. Despite the lack of a clear progression of TDP-43 pathology, a TDP Staging Scheme for CTE which accurately reflects the extent and severity of TDP-43 pathology in not only the study cohort, but likely in all subjects without FTLD, was established. Four stages were identified: TDP Stage 0 showed no TDP-43 inclusions in the substantia nigra, dorsolateral frontal cortex, or dentate gyrus; TDP Stage 1 showed inclusions in either the substantia nigra or the dorsolateral frontal cortex; TDP Stage 2 showed inclusions either in the dentate gyrus or in both the substantia nigra and the dorsolateral frontal cortex; and TDP Stage 3 showed inclusions in the substantia nigra, dorsolateral frontal cortex, and dentate gyrus. Finally, a correlation was found between the presence of TDP-43 inclusions and the levels of activated microglia in the dorsolateral frontal cortex of CTE+ subjects. This finding aligns with the theory that the pathological changes of TDP-43 found in CTE are driven by the pro-inflammatory cytokines released by chronically activated microglia.en_US
dc.language.isoen_US
dc.subjectPathologyen_US
dc.subjectTDP-43en_US
dc.subjectChronic traumatic encephalopathyen_US
dc.titleTDP-43 pathology in chronic traumatic encephalopathyen_US
dc.typeThesis/Dissertationen_US
dc.date.updated2016-06-17T19:41:35Z
etd.degree.nameMaster of Scienceen_US
etd.degree.levelmastersen_US
etd.degree.disciplineMedical Sciencesen_US
etd.degree.grantorBoston Universityen_US


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