Clinical & biological signatures of post-traumatic neurodegeneration: Toward in vivo diagnosis of the late effects of TBI.

RFA-NS-19-026要求对创伤性脑损伤（如稳定性认知障碍）和进行性神经退行性损伤（如认知能力下降、阿尔茨海默病（AD））相关慢性静态影响的临床和生物学特征进行调查，提交R01提案“创伤后认知障碍、认知能力下降、阿尔茨海默病和相关痴呆的临床和生物学机制”。脑损伤是阿尔茨海默病（AD）和相关痴呆（ADRD）的已知危险因素，包括血管性认知障碍（VCID）、额颞叶变性（FTLD/FTD）、帕金森病（PD）、路易体痴呆（DLB）和轻度认知障碍（MCI）。目前迫切需要确定头部创伤（一种相对常见且日益普遍的暴露）是否以及如何影响AD和adrd的发病机制。创伤后adrd （PT-ADRD）的临床特征、机制和病理生物学仍不清楚，临床和研究界由于未能区分慢性静态TBI （csTBI，如稳定性认知障碍）和PT-ADRD（如认知能力下降），将生理上不同的过程混为一谈。这就排除了对创伤性脑损伤可能引发或加剧AD/ADRD的机制途径的描述。我们的中心假设是，PT-ADRD与csTBI的区别是基于认知能力下降、神经行为和运动能力下降，这与反映阿尔茨海默病/ adrd相关变化的纵向变化有关（例如，皮质厚度变化、tau和β淀粉样蛋白的积累）。为了验证这一假设，我们将丰富和扩大一个前瞻性的脑捐赠计划，即TBI的晚期效应（LETBI）项目。该队列的特点是临床、生物学和神经影像学的AD/ADRD工具选择与其他大规模AD/ADRD研究工作重叠。我们将应用先进的心理测量和统计方法，新型神经成像处理工具，超灵敏单分子阵列（Simoa）技术和最先进的神经病理学方法来推进PT-ADRD的知识。在目标1中，我们将基于AD/ADRD认知、行为和运动功能测量的纵向变化来检验PT-ADRD（例如，认知障碍）与csTBI（例如，认知能力下降）不同的假设。在Aim 2中，我们将通过验证皮层体积（AD生物标志物）的网络特异性变化与区域特异性临床衰退相关的假设来识别PT-ADRD的成像生物标志物。在Aim 3中，我们将确定PT-ADRD的液体生物标志物，验证NfL、GFAP、tau （T-tau、pTau）和β淀粉样蛋白（a - β42/40）水平与临床衰退相关的假设。在Aims 1-3中，我们将检验PT-ADRD患者比csTBI患者有更大的AD/ADRD病理负担（tau [T-tau, pTau]， β淀粉样蛋白[a - β42/40]）的假设。在探索性目标4中，我们将评估损伤特征、AD/ADRD风险因素和候选生物标志物对AD/ADRD风险的贡献。我们将创造丰富的数据资源，以加快ADRD的诊断和新的治疗目标。

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 (aβ42/40) 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 [aβ42/40]) 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.