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Original Investigation |

Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings

Paul K. Crane, MD, MPH1; Laura E. Gibbons, PhD1; Kristen Dams-O’Connor, PhD2; Emily Trittschuh, PhD3; James B. Leverenz, MD4; C. Dirk Keene, MD, PhD5; Joshua Sonnen, MD6; Thomas J. Montine, MD, PhD5,10; David A. Bennett, MD7; Sue Leurgans, PhD7; Julie A. Schneider, MD, MS8; Eric B. Larson, MD, MPH9
[+] Author Affiliations
1Department of Medicine, University of Washington, Seattle
2Department of Rehabilitation Medicine, Mt Sinai School of Medicine, New York, New York
3Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle
4Department of Neurology, Cleveland Clinic Foundation, Cleveland, Ohio
5Department of Pathology, University of Washington, Seattle
6Department of Pathology, University of Utah, Salt Lake City
7Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
8Department of Pathology, Rush University Medical Center, Chicago, Illinois
9Center for Health Studies, Group Health Research Institute, Seattle, Washington
10now with the Department of Pathology, Stanford University School of Medicine, Stanford, California
JAMA Neurol. 2016;73(9):1062-1069. doi:10.1001/jamaneurol.2016.1948.
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Importance  The late effects of traumatic brain injury (TBI) are of great interest, but studies characterizing these effects are limited.

Objective  To determine whether TBI with loss of consciousness (LOC) is associated with an increased risk for clinical and neuropathologic findings of Alzheimer disease (AD), Parkinson disease (PD), and other dementias.

Design, Setting, and Participants  This study analyzed data from the Religious Orders Study (ROS), Memory and Aging Project (MAP), and Adult Changes in Thought study (ACT). All ROS and MAP participants and a subset of ACT participants consent to autopsy. Studies performed annual (ROS and MAP) or biennial (ACT) cognitive and clinical testing to identify incident cases of dementia and AD. The 7130 participants included members of a Seattle-area health care delivery system (ACT), priests and nuns living in orders across the United States (ROS), and Chicago-area adults in retirement communities (MAP). Of these, 1589 underwent autopsy. Primary hypothesis was that TBI with LOC would be associated with increased risk for AD and neurofibrillary tangles. Data were accrued from 1994 to April 1, 2014.

Exposures  Self-reported TBI when the participant was free of dementia, categorized as no more than 1 vs more than 1 hour of LOC.

Main Outcomes and Measures  Clinical outcomes included incident all-cause dementia, AD, and PD in all studies and incident mild cognitive impairment and progression of parkinsonian signs in ROS and MAP. Neuropathologic outcomes included neurofibrillary tangles, neuritic plaques, microinfarcts, cystic infarcts, Lewy bodies, and hippocampal sclerosis in all studies.

Results  Of 7130 participants (2879 [40.4%] men; overall mean [SD] age, 79.9 [6.9] years), 865 reported a history of TBI with LOC. In 45 190 person-years of follow-up, 1537 incident cases of dementia and 117 of PD were identified. No association was found between TBI with LOC and incident dementia (ACT: HR for TBI with LOC ≤1 hour, 1.03; 95% CI, 0.83-1.27; HR for TBI with LOC >1 hour, 1.18; 95% CI, 0.77-1.78; ROS and MAP: HR for TBI with LOC ≤1 hour, 0.87; 95% CI, 0.58-1.29; HR for TBI with LOC >1 hour, 0.84; 95% CI, 0.44-1.57) or AD (findings similar to those for dementia). Associations were found for TBI with LOC and incident PD in ACT (HR for TBI with LOC >1 hour, 3.56; 95% CI, 1.52-8.28) and progression of parkinsonian signs in ROS and MAP (odds ratio [OR] for TBI with LOC ≤1 hour, 1.65; 95% CI, 1.23-2.21; OR for TBI with LOC >1 hour, 2.23; 95% CI, 1.16-4.29). Traumatic brain injury with LOC was associated with Lewy bodies (any Lewy body in ACT: RR for TBI with LOC >1 hour, 2.64; 95% CI, 1.40-4.99; Lewy bodies in substantia nigra and/or locus ceruleus in ACT: RR for TBI with LOC >1 hour, 3.30; 95% CI, 1.71-6.38; Lewy bodies in frontal or temporal cortex in ACT: RR for TBI with LOC >1 hour, 5.73; 95% CI, 2.18-15.0; ROS and MAP: RR for TBI with LOC ≤1 hour, 1.64; 95% CI, 1.00-2.70; pooled RR for TBI with LOC ≤1 hour, 1.59; 95% CI, 1.06-2.39) and microinfarcts (any cortical microinfarct in ROS and MAP: RR for TBI with LOC >1 hour, 2.12; 95% CI, 1.12-4.01; pooled RR for TBI with LOC >1 hour, 1.58; 95% CI, 1.06-2.35).

Conclusions and Relevance  Pooled clinical and neuropathologic data from 3 prospective cohort studies indicate that TBI with LOC is associated with risk for Lewy body accumulation, progression of parkinsonism, and PD, but not dementia, AD, neuritic plaques, or neurofibrillary tangles.

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