Longitudinal Lesion Expansion in Chronic Traumatic Brain Injury.

Traumatic brain injury (TBI) is a risk factor for neurodegeneration and cognitive decline, yet the underlying pathophysiologic mechanisms are incompletely understood. This gap in knowledge is in part related to the lack of analytic methods to account for cortical lesions in prior neuroimaging studies. The objective of this study was to develop a lesion detection tool and apply it to an investigation of longitudinal changes in brain structure among individuals with chronic TBI. We identified 24 individuals with chronic moderate-to-severe TBI enrolled in the Late Effects of TBI (LETBI) study who had cortical lesions detected by T1-weighted MRI at two time points. Initial MRI scans were performed more than 1-year post-injury and follow-up scans were performed 3.1 (IQR=1.7) years later. We leveraged FreeSurfer parcellations of T1-weighted MRI volumes and a recently developed super-resolution technique, SynthSR, to identify cortical lesions in this longitudinal dataset. Trained raters received the data in a randomized order and manually corrected the automated lesion segmentation, yielding a final lesion mask for each scan at each timepoint. Lesion volume significantly increased between the two time points with a median volume change of 3.2 (IQR=5.9) mL (p<0.001), and the increases significantly exceeded the possible variance in lesion volume changes due to manual tracing errors (p < 0.001). Lesion volume significantly expanded longitudinally in 23 of 24 subjects, with all FDR corrected p-values ≤ 0.02. Inter-scan duration was not associated with the magnitude of lesion growth. We also demonstrated that the semi-automated tool showed a high level of accuracy compared to "ground truth" manual lesion segmentation. Semi-automated lesion segmentation is feasible in TBI studies and creates opportunities to elucidate mechanisms of post-traumatic neurodegeneration.

Spatial proteomics of hippocampal subfield-specific pathology in Alzheimer's disease and primary age-related tauopathy.

INTRODUCTION: Alzheimer's disease (AD) and primary age-related tauopathy (PART) both harbor 3R/4R hyperphosphorylated-tau (p-tau)-positive neurofibrillary tangles (NFTs) but differ in the spatial p-tau development in the hippocampus. METHODS: Using Nanostring GeoMx Digital Spatial Profiling, we compared protein expression within hippocampal subregions in NFT-bearing and non-NFT-bearing neurons in AD (n = 7) and PART (n = 7) subjects. RESULTS: Proteomic measures of synaptic health were inversely correlated with the subregional p-tau burden in AD and PART, and there were numerous differences in proteins involved in proteostasis, amyloid beta (Aß) processing, inflammation, microglia, oxidative stress, and neuronal/synaptic health between AD and PART and between definite PART and possible PART. DISCUSSION: These results suggest subfield-specific proteome differences that may explain some of the differences in Aß and p-tau distribution and apparent pathogenicity. In addition, hippocampal neurons in possible PART may have more in common with AD than with definite PART, highlighting the importance of Aß in the pathologic process. HIGHLIGHTS: Synaptic health is inversely correlated with local p-tau burden. The proteome of NFT- and non-NFT-bearing neurons is influenced by the presence of Aß in the hippocampus. Neurons in possible PART cases share more proteomic similarities with neurons in ADNC than they do with neurons in definite PART cases.

The neuropathology of intimate partner violence.

Lifelong brain health consequences of traumatic brain injury (TBI) include the risk of neurodegenerative disease. Up to one-third of women experience intimate partner violence (IPV) in their lifetime, often with TBI, yet remarkably little is known about the range of autopsy neuropathologies encountered in IPV. We report a prospectively accrued case series from a single institution, the New York City Office of Chief Medical Examiner, evaluated in partnership with the Brain Injury Research Center of Mount Sinai, using a multimodal protocol comprising clinical history review, ex vivo imaging in a small subset, and comprehensive neuropathological assessment by established consensus protocols. Fourteen brains were obtained over 2 years from women with documented IPV (aged 3rd-8th decade; median, 4th) and complex histories including prior TBI in 6, nonfatal strangulation in 4, cerebrovascular, neurological, and/or psychiatric conditions in 13, and epilepsy in 7. At autopsy, all had TBI stigmata (old and/or recent). In addition, white matter regions vulnerable to diffuse axonal injury showed perivascular and parenchymal iron deposition and microgliosis in some subjects. Six cases had evidence of cerebrovascular disease (lacunes and/or chronic infarcts). Regarding neurodegenerative disease pathologies, Alzheimer disease neuropathologic change was present in a single case (8th decade), with no chronic traumatic encephalopathy neuropathologic change (CTE-NC) identified in any. Findings from this initial series then prompted similar exploration in an expanded case series of 70 archival IPV cases (aged 2nd-9th decade; median, 4th) accrued from multiple international institutions. In this secondary case series, we again found evidence of vascular and white matter pathologies. However, only limited neurodegenerative proteinopathies were encountered in the oldest subjects, none meeting consensus criteria for CTE-NC. These observations from this descriptive exploratory study reinforce a need to consider broad co-morbid and neuropathological substrates contributing to brain health outcomes in the context of IPV, some of which may be potentially modifiable.

Traumatic brain injury history and baseline symptoms outweigh sex differences for risk of concussion in a sample of collegiate athletes.

OBJECTIVE: To test the hypothesis that a history of traumatic brain injury (TBI) prior to the collegiate pre-season is associated with risk for re-injury. We also investigate sex differences, cognitive functioning, and self-reported concussion symptoms and their associations with concussion risk. METHODS: A longitudinal cohort study consisting of collegiate athletes (n = 212) who completed consecutive preseason evaluations (P1 and P2) between 2012 and 2015, averaging 12.9 (SD = 4.2) months apart. RESULTS: There were 40 new concussions recorded between P1 and P2, 21 (53%) of which were among athletes who reported a lifetime history of mild TBI/concussion at P1. New P1-P2 concussions occurred in 24% of female athletes (n = 23) and 15% of male athletes (n = 17). History of TBI and female sex were significant predictors of new concussion between P1 and P2; however, in adjusted models, the inclusion of Impulse Control and PCSS Total symptom scores attenuated the effect of sex on the risk for new injury. CONCLUSION: Collegiate athletes with a lifetime history of TBI had a significantly higher risk of sustaining a subsequent concussion. Pre-season emotional and somatic symptomology may contribute to incident concussion risk. The findings highlight the importance of considering lifetime head injury exposure and baseline symptomatology when interpreting sex differences and evaluating concussion risk.

Multimodal Assessment of Bottlenose Dolphin Auditory Nuclei Using 7-Tesla MRI, Immunohistochemistry and Stereology.

The importance of assessing neurochemical processes in the cetacean brain as a tool for monitoring their cognitive health and to indirectly model human neurodegenerative conditions is increasingly evident, although available data are largely semiquantitative. High-resolution MRI for post-mortem brains and stereology allow for quantitative assessments of the cetacean brain. In this study, we scanned two brains of bottlenose dolphins in a 7-Tesla (7T) MR scanner and assessed the connectivity of the inferior colliculi and ventral cochlear nuclei using diffusion tensor imaging (DTI). Serial thick sections were investigated stereologically in one of the dolphins to generate rigorous quantitative estimates of identifiable cell types according to their morphology and expression of molecular markers, yielding reliable cell counts with most coefficients of error <10%. Fibronectin immunoreactivity in the dolphin resembled the pattern in a human chronic traumatic encephalopathy brain, suggesting that neurochemical compensation for insults such as hypoxia may constitute a noxious response in humans, while being physiological in dolphins. These data contribute to a growing body of knowledge on the morphological and neurochemical properties of the dolphin brain and highlight a stereological and neuroimaging workflow that may enable quantitative and translational assessment of pathological processes in the dolphin brain in the future.

Evidence of traumatic brain injury in headbutting bovids.

Traumatic brain injury (TBI) is a leading cause of neurologic impairment and death that remains poorly understood. Rodent models have yet to produce clinical therapies, and the exploration of larger and more diverse models remains relatively scarce. We investigated the potential for brain injury after headbutting in two combative bovid species by assessing neuromorphology and neuropathology through immunohistochemistry and stereological quantification. Postmortem brains of muskoxen (Ovibos moschatus, n = 3) and bighorn sheep (Ovis canadensis, n = 4) were analyzed by high-resolution MRI and processed histologically for evidence of TBI. Exploratory histological protocols investigated potential abnormalities in neurons, microglia, and astrocytes in the prefrontal and parietal cortex. Phosphorylated tau protein, a TBI biomarker found in the cerebrospinal fluid and in neurodegenerative lesions, was used to detect possible cellular consequences of chronic or acute TBI. MRI revealed no abnormal neuropathological changes; however, high amounts of tau-immunoreactive neuritic thread clusters, neurites, and neurons were concentrated in the superficial layers of the neocortex, preferentially at the bottom of the sulci in the muskoxen and occasionally around blood vessels. Tau-immunoreactive lesions were rare in the bighorn sheep. Additionally, microglia and astrocytes showed no grouping around tau-immunoreactive cells in either species. Our preliminary findings indicate that muskoxen and possibly other headbutting bovids suffer from chronic or acute brain trauma and that the males' thicker skulls may protect them to a certain extent.