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

Brian L. Edlow, C. Dirk Keene, Daniel P. Perl, Diego Iacono, Rebecca D. Folkerth, William Stewart, Christine L. Mac Donald, Jean Augustinack, Ramon Diaz-Arrastia, Camilo Estrada, Elissa Flannery, Wayne A. Gordon, Thomas J. Grabowski, Kelly Hansen, Jeanne Hoffman, Christopher Kroenke, Eric B. Larson, Patricia Lee, Azma Mareyam, Jennifer A. McNabJeanne McPhee, Allison L. Moreau, Anne Renz, Katierose Richmire, Allison Stevens, Cheuk Y. Tang, Lee S. Tirrell, Emily H. Trittschuh, Andre Van Der Kouwe, Ani Varjabedian, Lawrence L. Wald, Ona Wu, Anastasia Yendiki, Liza Young, Lilla Zöllei, Bruce Fischl, Paul K. Crane, Kristen Dams-O'Connor

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1604-1619
Number of pages16
JournalJournal of neurotrauma
Issue number14
StatePublished - Jul 15 2018


  • dementia; MRI; neurodegeneration; neuropathology; traumatic brain injury

ASJC Scopus subject areas

  • Clinical Neurology


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