This R01 Proposal, ?Clinical & biological mechanisms of post-traumatic cognitive impairment, cognitive decline, Alzheimer?s disease and related dementias? is submitted in response to RFA-NS-19-026, which requests investigation into the clinical and biological features that distinguish chronic static effects of traumatic brain injury (e.g., stable cognitive impairment) from those associated with progressive neurodegeneration (e.g., cognitive decline, Alzheimer?s disease (AD)). Brain injury is an established risk factor for Alzheimer?s disease (AD) and related dementias (ADRD), including vascular cognitive impairment (VCID), frontotemporal lobar degeneration (FTLD/FTD), Parkinson?s disease (PD), Dementia with Lewy Bodies (DLB), and mild cognitive impairment (MCI). There is an urgent need to determine whether and how head trauma, a relatively common and increasingly prevalent exposure, may impact the pathogenesis of AD and ADRDs. The clinical signatures, mechanisms, and pathobiology of post-traumatic ADRDs (PT-ADRD) remain unknown, and the clinical and research communities have conflated physiologically distinct processes by failing to distinguish chronic-static TBI (csTBI; e.g., stable cognitive impairment) from PT-ADRD (e.g., cognitive decline). This has precluded delineation of the mechanistic pathways through which a TBI may initiate or exacerbate AD/ADRD. Our central hypothesis is that PT-ADRD is distinguishable from csTBI based on cognitive decline, neurobehavioral and motor decline that relates to longitudinal changes reflective of Alzheimer?s/ADRD-related change (e.g., cortical thickness changes, accumulation of tau and amyloid beta). To test this hypothesis, we will enrich and expand a prospective brain donor program, the Late Effects of TBI (LETBI) project. This cohort is characterized by clinical, biological and neuroimaging AD/ADRD tools selected for their overlap with other large-scale AD/ADRD research efforts. We will apply advanced psychometric and statistical methods, novel neuroimaging processing tools, ultra-sensitive single molecule array (Simoa) technology, and state-of-the-art neuropathology methods to advance knowledge of PT-ADRD.
In Aim 1 we will test the hypothesis that PT-ADRD (e.g., cognitive impairment) is distinct from csTBI (e.g., cognitive decline) based on longitudinal change in AD/ADRD measures of cognition, behavior, and motor function.
In Aim 2 we will identify imaging biomarkers of PT-ADRD by testing the hypothesis that network-specific changes in cortical volume (an AD biomarker) are associated with domain-specific clinical decline over time.
In Aim 3 we will identify fluid biomarkers of PT-ADRD, testing the hypothesis that NfL, GFAP, tau (T-tau, pTau), and beta amyloid (a?42/40) levels are associated with clinical decline.
For Aims 1 -3, we will test the hypothesis that patients with PT-ADRD have greater AD/ADRD pathology burden (tau [T-tau, pTau], beta amyloid [a?42/40]) than those with csTBI. In Exploratory Aim 4 we will evaluate contributions of injury characteristics, AD/ADRD risk factors, and candidate biomarkers to AD/ADRD risk. We will create rich data resources to accelerate ADRD diagnostics and novel treatment targets.
Traumatic brain injury (TBI) is widely recognized as a risk factor for Alzheimer?s disease and related dementias (AD/ADRDs), but the mechanisms through which it initiates or exacerbates clinical and/or pathological Alzheimer?s or ADRD features (e.g., cortical volumetric changes, tau [T-tau, pTau], beta amyloid [a?42/40]) are unknown. This project will elucidate the clinical signatures, mechanisms, and pathobiology of post-traumatic ADRDs (PT-ADRD) by distinguishing clinically significant cognitive decline from static cognitive impairment following head trauma in an enriched longitudinal sample of patients characterized with clinical and biological metrics of high relevance for Alzheimer?s and related dementia phenotyping. By applying advanced statistical methods, novel neuroimaging processing, ultra-sensitive single molecule array technology, and state-of-the-art neuropathology methods, we will identify clinical features and mechanistic biomarkers of PT-ADRD that can be used to improve ADRD diagnosis and inform new targets for disease-modifying therapies.
