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

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.

Optimizing the Accuracy of Cortical Volumetric Analysis in Traumatic Brain Injury

“…For example, lesion-induced cortical volume changes within the limbic, default mode, and frontoparietal networks (the three most frequently lesioned networks) can be tested for correlations with symptoms that are putatively attributable to their dysfunction, such as behavioral dysregulation, altered self-awareness, and executive dysfunction, respectively. From a phenomenological standpoint, the application of the new lesion correction tool to large clinical-radiological-pathological databases being acquired by the LETBI, 12 Transforming Research and Clinical Knowledge in TBI (TRACK-TBI), 21 Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI), 22 and other studies, has potential to elucidate pathological signatures of TBI phenotypic classification, with implications for clinical trial selection 23 and prognostication. 10…”

“…Between May, 2014 and January, 2019, we prospectively enrolled 141 patients with a history of TBI at two academic medical centers as part of the Late Effects of TBI (LETBI) study. 12 Patients were included if they had sustained a moderate-to-severe TBI at least one year prior to enrollment. We characterized TBI severity based on the United States Department of Defense classification system, 13 as detailed in the Supplementary Material.…”

7 Tesla MRI of the ex vivo human brain at 100 micron resolution

“…1), without evidence of mass lesions or cerebrovascular disease. To ensure adequate fixation and prevent specimen flattening (which can prevent specimens from fitting into custom ex vivo MRI coils), we followed a series of standard specimen processing procedures, as previously described 15 .…”

The Ansa Subthalamica: A Neglected Fiber Tract

“…We scanned the fixed whole‐brain specimen 3 months after the patient's death on a 7T Siemens Magnetom MRI scanner (Siemens Medical Solutions), using a custom‐built head coil. Details regarding the ex vivo scanning protocol have been previously published . Briefly, we acquired a multiecho fast low angle shot sequence at 200‐μm spatial resolution, with total scan time of 18 hours 31 minutes.…”