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J Neurotrauma. 2018 Jul 15;35(14):1604-1619. doi: 10.1089/neu.2017.5457. Epub 2018 May 3.

Multimodal Characterization of the Late Effects of Traumatic Brain Injury: A Methodological Overview of the Late Effects of Traumatic Brain Injury Project.

Author information

1
1 Department of Neurology, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
2
2 Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital and Harvard Medical School , Charlestown, Massachusetts.
3
3 Department of Pathology, University of Washington , Seattle, Washington.
4
4 Brain Tissue Repository and Neuropathology Core, Uniformed Services University of the Health Sciences , Bethesda, Maryland.
5
5 Department of Pathology, Uniformed Services University of the Health Sciences , Bethesda, Maryland.
6
6 Department of Neurology, Uniformed Services University of the Health Sciences , Bethesda, Maryland.
7
7 The Henry M. Jackson Foundation for the Advancement of Military Medicine , Bethesda, Maryland.
8
8 Department of Pathology, Brigham and Women's Hospital , Harvard Medical School, Boston, Massachusetts.
9
9 City of New York Office of the Chief Medical Examiner and New York University School of Medicine , New York, New York.
10
10 Department of Neuropathology, Queen Elizabeth University Hospital and Institute of Neuroscience and Psychology, University of Glasgow , United Kingdom .
11
11 Department of Neurological Surgery, University of Washington , Seattle, Washington.
12
12 Department of Neurology and Center for Brain Injury and Repair, Hospital of the University of Pennsylvania , Philadelphia.
13
13 Kaiser Permanente Washington Health Research Institute , Seattle, Washington.
14
14 Department of Rehabilitation Medicine, Icahn School of Medicine at Mount Sinai , New York, New York.
15
15 Department of Neurology, University of Washington , Seattle, Washington.
16
16 Department of Radiology, University of Washington , Seattle, Washington.
17
17 Department of Rehabilitation Medicine, University of Washington , Seattle, Washington.
18
18 Advanced Imaging Research Center, Oregon Health and Science University , Portland, Oregon.
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19 Department of Radiology, Stanford University , Stanford, California.
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20 Department of Radiology, Icahn School of Medicine at Mount Sinai , New York, New York.
21
21 Department of Psychiatry and Behavioral Sciences, University of Washington , Seattle, Washington.
22
22 Geriatric Research Education and Clinical Center , VA Puget Sound Health Care System, Seattle, Washington.
23
23 Department of Medicine, University of Washington , Seattle, Washington.
24
24 Department of Neurology, Icahn School of Medicine at Mount Sinai , New York, New York.

Abstract

Epidemiological studies suggest that a single moderate-to-severe traumatic brain injury (TBI) is associated with an increased risk of neurodegenerative disease, including Alzheimer's disease (AD) and Parkinson's disease (PD). Histopathological studies describe complex neurodegenerative pathologies in individuals exposed to single moderate-to-severe TBI or repetitive mild TBI, including chronic traumatic encephalopathy (CTE). However, the clinicopathological links between TBI and post-traumatic neurodegenerative diseases such as AD, PD, and CTE remain poorly understood. Here, we describe the methodology of the Late Effects of TBI (LETBI) study, whose goals are to characterize chronic post-traumatic neuropathology and to identify in vivo biomarkers of post-traumatic neurodegeneration. LETBI participants undergo extensive clinical evaluation using National Institutes of Health TBI Common Data Elements, proteomic and genomic analysis, structural and functional magnetic resonance imaging (MRI), and prospective consent for brain donation. Selected brain specimens undergo ultra-high resolution ex vivo MRI and histopathological evaluation including whole-mount analysis. Co-registration of ex vivo and in vivo MRI data enables identification of ex vivo lesions that were present during life. In vivo signatures of postmortem pathology are then correlated with cognitive and behavioral data to characterize the clinical phenotype(s) associated with pathological brain lesions. We illustrate the study methods and demonstrate proof of concept for this approach by reporting results from the first LETBI participant, who despite the presence of multiple in vivo and ex vivo pathoanatomic lesions had normal cognition and was functionally independent until her mid-80s. The LETBI project represents a multidisciplinary effort to characterize post-traumatic neuropathology and identify in vivo signatures of postmortem pathology in a prospective study.

KEYWORDS:

MRI; dementia; neurodegeneration; neuropathology; traumatic brain injury

PMID:
29421973
PMCID:
PMC6016096
DOI:
10.1089/neu.2017.5457

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