2016 Awardees

Bertrand R. Huber, M.D., Ph.D.,
Director, PTSD Brain Bank, Veterans Affairs Boston Healthcare System
Assistant Professor of Neurology, Boston University School of Medicine
Neuropathologist, Neuropathology Core, Boston University Alzheimer’s Disease & Chronic Traumatic Encephalopathy Centers

This is a study of the breakdown of the Blood Brain Barrier (BBB) in Chronic Traumatic Encephalopathy (CTE) and the mechanism of associated perivascular phospho-tau aggregation. Feasibility of the study is demonstrated in preliminary results showing vascular leakage of fibrinogen/fibrin in CTE perivascular lesions preferentially at the depths of sulci and colocalization of fibrinogen/fibrin with tau. This pattern is distinct from Alzheimer’s Disease (AD) where perivascular fibrinogen/fibrin deposition can be observed in gyral and sulcal regions. The Perivascular lesions in CTE demonstrate a reduction of astrocytes that constitute the glial limitans and loss of astrocyte end-feet. The remaining perivascular astrocytes display dystrophic morphology and are filled with aggregated phospho-tau. The perivascular space, while lacking of astrocytes, still retains dendrites and these dendrites contain dot-like inclusions of phospho-tau. This finding suggests that disruption of the BBB in CTE may serve as a nidus for formation of tau aggregates in dendrites. These aggregates may then act as “seeds” for further tau pathology and may in part explain why the spread of CTE neuropathology begins in the sulci of the frontal cortices. The seeding of tau pathology in CTE may also enhance other neurodegenerative processes and support the hypothesis that CTE and trauma play a role in the development of AD, by providing a misfolded tau template that initiates further tau aggregation.

To determine whether perivascular fibrinogen/fibrin lesions are more concentrated within the cortical areas affected by CTE and the number of lesions correlates with disease stage.

To determine whether regions of astrocytic loss in CTE correlate with dendritic dysfunction and the formation of aggregated dot-like tau pathology.

This study will explore the role of glial limitans breakdown in the development of dendritc tau aggregates in chronic traumatic encephalopathy to provide important human data to guide future experimental and interventiaonal studies. The goal of the study is to lead to an improved understanding of tau aggregation in the setting of CTE and to provide pathophysiological mechanisms that could be targeted with theraputics.

Michael Alosco, PhD
NRSA Postdoctoral Fellow
Boston University Alzheimer’s Disease and Chronic Traumatic Encephalopathy Centers
Boston University School of Medicine
The Role of White Matter Signal Abnormalities in the Clinical Presentation of Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy that can currently only be diagnosed postmortem and is caused by repetitive head impacts (RHI). Investigators at the Boston University Alzheimer’s Disease & CTE Center (BU ADCTEC) published clinical research criteria for CTE, known as Traumatic Encephalopathy Syndrome (TES). CTE clinically presents with a combination of early  life behavioral/mood symptoms and/or later-ˇlife cognitive deficits. The reason for this clinical heterogeneity is unclear and may involve interindividual differences in disease and non-ˇdisease specific pathology.

This BU ADCTEC Pilot Grant will examine patterns of white matter signal abnormalities (WMSA) in individuals at risk for CTE, and whether WMSA differentiate the TES subtypes. WMSA are a MRI marker of pathology, often vascular and ischemic in nature. Concussion can disturb brain perfusion, and WMSA were common in a case series of former NFL players, and have pathological correlates frequent in CTE. WMSA contribute to the clinical phenotype of neurodegenerative illnesses, like Alzheimer’s disease (AD). This study will involve former NFL subjects (at high risk for CTE) who participated in the BU DETECT study, and similar aged and vascular risk-matched normal controls (NC), and subjects with probable AD (similar age and vascular risk matched) from the BU ADCTEC Registry. All subjects complete neuropsychological testing and MRI. TES (and other) diagnoses are made at diagnostic consensus conferences. We will test whether former NFL players exhibit a distinct pattern of WMSA relative to AD subjects and NC, and whether WMSA differentiate cognitive and behavioral/mood subtypes. This study will expand the limited knowledge on CTE and identify WMSA as a contributor to clinical outcomes in CTE. Given the millions of Americans exposed to RHI, identifying clinical features of CTE will have a major public health impact by facilitating research into the clinical diagnosis, prevention, and treatment of CTE.