Consequences of Exposure to Repetitive Head Impacts Across the Lifespan

Boston University Medical Campus, Boston MA

Investigators

Abstract

Each year, millions of people are exposed to repetitive head impacts (RHI) from contact sports, military service, and interpersonal violence. Although RHI typically occurs early in life, the health consequences of RHI evolve over the lifespan and include neurobehavioral symptoms, cognitive impairment, and increased risk for Alzheimer's disease (AD) and AD-related dementias (ADRD), including chronic traumatic encephalopathy (CTE). In 2014, our team secured a U01 grant to establish the UNITE brain bank to investigate the long-term clinical and neuropathological outcomes of RHI exposure. Subsequent funding as a U54 grant expanded UNITE into the world's largest RHI and CTE brain tissue repository, totaling 1520 brains. Through UNITE, we have pioneered research delineating the neuropathological consequences of RHI, particularly in later life, including the development of diagnostic criteria for CTE, demonstrating the dose-dependent relationship between RHI exposure and risk for CTE and AD/ADRD, and elucidating how RHI contributes to clinical symptoms such as dementia through multiple pathological mechanisms. With rising numbers of young brain donors in UNITE, our latest studies have focused on young athletes. We recently showed that RHI experienced early in life initiates structural brain changes, perivascular hemosiderin-laden macrophages, gene expression changes, inflammation, microvascular alterations, neuronal and white matter (WM) loss, and perivascular ptau as CTE stage I-II in young athletes (<30 yrs) before the development of AD/ADRDs, and severe CTE. This proposal addresses a critical knowledge gap by examining how early-life RHI-induced brain alterations progress into latent neurodegeneration with aging, independent of further RHI exposure. The overarching goal of this proposal is to identify the early-life RHI-induced alterations that promote late-life CTE, AD, and ADRD neurodegeneration. Accordingly, this proposal has three aims spanning the adult lifecycle. The first aim will determine the clinical and pathological consequences of RHI in young adults aged 18-39 years, a period close to RHI exposure. The second aim will determine the consequences of RHI at mid-life, age 40-59 years, and the third aim will determine the consequences of RHI in late life, age 60-79 years. At all three time periods, we will examine how these early RHI-induced pathological, imaging, and clinical outcomes are modified by cardiovascular and metabolic disease, socioeconomic, sex, race, and lifestyle factors, and genetic variations (APOE ε4, TMEM106b, MAPT). To achieve these aims, we will employ cutting-edge neuropathological and imaging technologies, including multiplex immunofluorescence with advanced digital quantitation, single nucleus RNA sequencing (snRNA seq), spatial transcriptomics, optically cleared sections of postmortem human brain with 3D imaging (Clarity), novel AI machine learning, and ex vivo MRI with Connectome 2 analysis to precisely quantitate the changes that occur over the lifespan after early life RHI exposure. This proposal will spotlight biomarkers for early detection and potential therapeutic targets to interrupt AD, ADRD, and CTE in young to mid-life.