Abstract OBJECTIVE: To examine the longitudinal relationship between poor physical performance and risk of dementia in non-demented oldest-old. BACKGROUND: We have previously reported a strong, dose-dependent cross-sectional relationship between poor physical performance and odds of dementia, where poorer physical performance was associated with increased odds of prevalent dementia. DESIGN/METHODS: The 90+ Study is a population based investigation of dementia in people aged 90 and older. 594 participants from The 90+ Study were included in this study. Physical performance measures (5 chair-stands, 10-second balance, 4-m walk and handgrip) were scored from 0-4 (0= unable to perform, 4= best performance). The outcome was dementia, diagnosed by applying DSM-IV criteria. Hazard Ratios (HR) for dementia in relation to physical performance were estimated by Cox Regression after adjustment for age and gender. RESULTS: At baseline, all participants were non-demented (normal: 57%, cognitively impaired non-demented: 43%), mostly women (69%) with an average age of 93.3 (range 90.0-103.0) years. The average length of follow-up was 2.6 (range 0.1-9.0) years. Poor physical performance in all measures was significantly associated with increased risk of incident dementia. HR for every unit decrease in physical performance score were 1.18 for 5 chair-stands, 1.27 for balance, 1.35 for 4-m walk, 1.17 for handgrip (all p<0.05). In a subanalysis that only included participants with normal baseline cognitive status HRs remained unchanged for 5 chair-stand (HR=1.13, p=0.14) and balance (HR=1.27 p=0.004), but were lower for 4-m walk (HR 1.22 p=0.04), and slightly higher for handgrip (HR=1.27 p=0.004). CONCLUSIONS: In this cohort of people over age 90, participants with poor physical performance are at increased risk of developing dementia. Further evaluation is still required to determine if poor physical performance is a modifiable risk factor or merely a different manifestation of the same neurodegenerative process which is detected before cognitive impairment and dementia. Supported by: NIH T32-NS045540, NIH T32-AG000096, NIH R01-AG21055.

Traumatic brain injury (TBI) is associated with the development of a range of neurodegenerative pathologies, including chronic traumatic encephalopathy (CTE). Current consensus diagnostic criteria define the pathognomonic cortical lesion of CTE neuropathologic change (CTE-NC) as a patchy deposition of hyperphosphorylated tau in neurons, with or without glial tau in thorn-shaped astrocytes, typically towards the depths of sulci and clustered around small blood vessels. Nevertheless, although incorporated into consensus diagnostic criteria, the contribution of the individual cellular components to identification of CTE-NC has not been formally evaluated. To address this, from the Glasgow TBI Archive, cortical tissue blocks were selected from consecutive brain donations from contact sports athletes in which there was known to be either CTE-NC (n = 12) or Alzheimer's disease neuropathologic change  (n = 4). From these tissue blocks, adjacent tissue sections were stained for tau antibodies selected to reveal either solely neuronal pathology (3R tau; GT-38) or mixed neuronal and astroglial pathologies (4R tau; PHF-1). These stained sections were then randomised and independently assessed by a panel of expert neuropathologists, blind to patient clinical history and primary antibody applied to each section, who were asked to record whether CTE-NC was present. Results demonstrate that, in sections stained for either 4R tau or PHF-1, consensus recognition of CTE-NC was high. In contrast, recognition of CTE-NC in sections stained for 3R tau or GT-38 was poor; in the former no better than chance. Our observations demonstrate that the presence of both neuronal and astroglial tau pathologies facilitates detection of CTE-NC, with its detection less consistent when neuronal tau pathology alone is visible. The combination of both glial and neuronal pathologies, therefore, may be required for detection of CTE-NC.

Efforts to characterize the late effects of traumatic brain injury (TBI) have been in progress for some time. In recent years much of this activity has been directed towards reporting of chronic traumatic encephalopathy (CTE) in former contact sports athletes and others exposed to repetitive head impacts. However, the association between TBI and dementia risk has long been acknowledged outside of contact sports. Further, growing experience suggests a complex of neurodegenerative pathologies in those surviving TBI, which extends beyond CTE. Nevertheless, despite extensive research, we have scant knowledge of the mechanisms underlying TBI-related neurodegeneration (TReND) and its link to dementia. In part, this is due to the limited number of human brain samples linked to robust demographic and clinical information available for research. Here we detail a National Institutes for Neurological Disease and Stroke Center Without Walls project, the COllaborative Neuropathology NEtwork Characterizing ouTcomes of TBI (CONNECT-TBI), designed to address current limitations in tissue and research access and to advance understanding of the neuropathologies of TReND. As an international, multidisciplinary collaboration CONNECT-TBI brings together multiple experts across 13 institutions. In so doing, CONNECT-TBI unites the existing, comprehensive clinical and neuropathological datasets of multiple established research brain archives in TBI, with survivals ranging minutes to many decades and spanning diverse injury exposures. These existing tissue specimens will be supplemented by prospective brain banking and contribute to a centralized route of access to human tissue for research for investigators. Importantly, each new case will be subject to consensus neuropathology review by the CONNECT-TBI Expert Pathology Group. Herein we set out the CONNECT-TBI program structure and aims and, by way of an illustrative case, the approach to consensus evaluation of new case donations.

Diffusion tractography magnetic resonance imaging (MRI) can infer changes in network connectivity in patients with traumatic brain injury (TBI), but the pathological substrates of disconnected tracts have not been well defined because of a lack of high-resolution imaging with histopathological validation. We developed an ex vivo MRI protocol to analyze tract terminations at 750-μm isotropic resolution, followed by histopathological evaluation of white matter pathology, and applied these methods to a 60-year-old man who died 26 days after TBI. Analysis of 74 cerebral hemispheric white matter regions revealed a heterogeneous distribution of tract disruptions. Associated histopathology identified variable white matter injury with patchy deposition of amyloid precursor protein (APP), loss of neurofilament-positive axonal processes, myelin dissolution, astrogliosis, microgliosis, and perivascular hemosiderin-laden macrophages. Multiple linear regression revealed that tract disruption strongly correlated with the density of APP-positive axonal swellings and neurofilament loss. Ex vivo diffusion MRI can detect tract disruptions in the human brain that reflect axonal injury.