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

临床

• 批准号: 9914761
• 负责人: Kristen Dams-O'Connor
• 金额: $ 690.79万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914761
• 关键词: Address; Age; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Autopsy; Behavior; Behavioral; Biological; Biological Assay; Biological Markers; Blood; Brain; Brain Injuries; Characteristics; Chronic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Common Data Element; Communities; Craniocerebral Trauma; Data; Data Element; Dementia; Diagnosis; Diagnostic; Disease; Family; Frontotemporal Lobar Degenerations; Glial Fibrillary Acidic Protein; Goals; Image; Impaired cognition; Impairment; Injury; Investigation; Knowledge; Late Effects; Lewy Body Dementia; Light; Link; Liquid substance; Measures; Methods; Modernization; Molecular; Motor; Nerve Degeneration; Network-based; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Plasma; Population; Positioning Attribute; Process; Protocols documentation; Psychometrics; Recording of previous events; Recovery; Research; Resources; Risk; Risk Factors; Sampling; Serological; Statistical Methods; Survivors; Technology; Testing; Thick; Time; Tissues; Traumatic Brain Injury; Unconscious State; Validation; Vascular Cognitive Impairment; Vascular Diseases; Visit; Work; abeta deposition; base; brain tissue; candidate marker; clinically significant; cohort; data resource; dementia risk; demographics; design; experience; image guided; imaging biomarker; improved; in vivo; mild cognitive impairment; multimodal data; neurobehavioral; neurofilament; neuroimaging; neuropathology; novel; prevent; programs; progressive neurodegeneration; prospective; response; single molecule; targeted treatment; tau Proteins; tau aggregation; tool

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.

本 R01 提案“创伤后认知障碍、认知衰退、阿尔茨海默病和相关痴呆的临床和生物学机制”是为了响应 RFA-NS-19-026 而提交的，该提案要求调查区分慢性认知障碍的临床和生物学特征与进行性神经变性（例如认知能力下降、阿尔茨海默氏病 (AD)）相关的创伤性脑损伤（例如稳定认知障碍）的静态影响 脑损伤是阿尔茨海默氏病的既定危险因素。疾病（AD）和相关痴呆（ADRD），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）。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、临床特征、机制和病理学。创伤后 ADRD（PT-ADRD）仍然未知，临床和研究界未能区分慢性静态 TBI（csTBI；例如，稳定认知障碍）与 PT-ADRD（例如，认知能力下降），从而将生理上不同的过程混为一谈。这妨碍了对 TBI 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 的区别在于。认知衰退、神经行为和运动衰退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蛋白和β淀粉样蛋白的积累）。为了检验这一假设，我们将丰富和扩展前瞻性大脑捐赠计划。 ，TBI 的晚期效应 (LETBI) 项目的特点是选择与其他大规模 AD/ADRD 研究工作重叠的临床、生物学和神经影像学 AD/ADRD 工具。心理测量和统计方法、新颖的神经影像处理工具、超灵敏单分子阵列 (Simoa) 技术和最先进的神经病理学方法，以增进对 PT-ADRD 的了解。在目标 1 中，我们将检验 PT-ADRD 的假设。 ADRD（例如认知障碍）与 csTBI（例如认知衰退）不同，基于 AD/ADRD 认知、行为和运动功能测量的纵向变化，我们将在目标 2 中确定。通过检验皮质体积（AD 生物标志物）的网络特异性变化与特定领域的临床随时间下降相关的假设，对 PT-ADRD 的生物标志物进行成像。在目标 3 中，我们将识别 PT-ADRD 的液体生物标志物，并检验该假设。 NfL、GFAP、tau（T-tau、pTau）和 β 淀粉样蛋白 (aβ42/40) 水平与临床衰退相关 对于目标 1-3，我们将检验以下假设： PT-ADRD 患者比 csTBI 患者具有更大的 AD/ADRD 病理负担（tau [T-tau、pTau]、β 淀粉样蛋白 [aβ42/40]）。在探索性目标 4 中，我们将评估损伤特征、AD/ADRD 的贡献。我们将创建丰富的数据资源来加速 ADRD 诊断和新的治疗目标。

项目成果

Convergent Validity of In-Person Assessment of Inpatients With Traumatic Brain Injury Using the Brief Test of Adult Cognition by Telephone (BTACT).

• DOI: 10.1097/htr.0000000000000677
• 发表时间: 2021-07-01
• 期刊: The Journal of head trauma rehabilitation
• 作者: DiBlasio CA;Novack TA;Cook EW 3rd;Dams-O'Connor K;Kennedy RE
• 通讯作者: Kennedy RE

Research Letter: Impact of Obstructive Sleep Apnea Disease Duration on Neuropsychological Functioning After Traumatic Brain Injury: A Veterans Affairs TBI Model Systems Study.

• DOI: 10.1097/htr.0000000000000797
• 发表时间: 2022-11-01
• 期刊: JOURNAL OF HEAD TRAUMA REHABILITATION
• 影响因子: 2.4
• 作者: Silva, Marc A.;Lee, Jaylene M.;Garcia, Amanda;Dams-O'Connor, Kristen;Nakase-Richardson, Risa
• 通讯作者: Nakase-Richardson, Risa

Scoping Review of Opioid Use After Traumatic Brain Injury.

• DOI: 10.1097/htr.0000000000000721
• 发表时间: 2021-09-01
• 期刊: The Journal of head trauma rehabilitation
• 作者: Starosta AJ;Adams RS;Marwitz JH;Kreutzer J;Monden KR;Dams O'Connor K;Hoffman J
• 通讯作者: Hoffman J

International Survey of Antiseizure Medication Use in Patients with Complicated Mild Traumatic Brain Injury: A New York Neurotrauma Consortium Study.

复杂性轻度创伤性脑损伤患者抗癫痫药物使用的国际调查：纽约神经创伤联盟研究。

• DOI: 10.1016/j.wneu.2022.09.110
• 发表时间: 2022
• 期刊: World neurosurgery
• 影响因子: 2
• 作者: Hickman,ZacharyL;Spielman,LisaA;Barthélemy,ErnestJ;Choudhri,TanvirF;Engelman,Brittany;Giwa,AlO;Greisman,JacobD;Margetis,Konstantinos;Race,Meaghan;Rahman,Jueria;Todor,DRoxanne;Tsetsou,Spyridoula;Ullman,JamieS;Unadkat,Pras
• 通讯作者: Unadkat,Pras