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”是针对RFA-NS-19-026号文件提交的，该文件要求研究创伤性脑损伤的慢性静态影响(如稳定性认知障碍)与进行性神经变性(如认知功能减退、阿尔茨海默病(AD))相关的临床和生物学特征。脑损伤是阿尔茨海默病(AD)和相关痴呆(ADRD)的公认危险因素，包括血管认知障碍(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这种相对常见和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、机制和病理生物学尚不清楚，临床和研究界将不同的生理过程混为一谈，未能区分慢性静止性脑损伤(csTBI；例如，稳定性认知障碍)和PT-ADRD(例如，认知功能下降)。这排除了描述脑损伤可能引发或加重AD/ADRD的机制途径。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，这些衰退与反映阿尔茨海默氏症/ADRD相关变化的纵向变化有关(例如，皮质厚度变化、tau和淀粉样β蛋白的积累)。为了验证这一假设，我们将丰富和扩展一个潜在的脑捐赠者计划，即脑损伤的后期影响(LETBI)项目。这个队列的特点是临床、生物学和神经成像AD/ADRD工具，因为它们与其他大规模AD/ADRD研究工作重叠而被选中。我们将应用先进的心理测量学和统计学方法、新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来增进对PT-ADRD的认识。在目标1中，我们将基于认知、行为和运动功能的AD/ADRD测量的纵向变化来检验PT-ADRD(例如，认知障碍)与csTBI(例如，认知衰退)不同的假设。在目标2中，我们将通过检验以下假设来识别PT-ADRD的成像生物标记物：皮质体积的网络特异性变化(AD生物标记物)与随着时间的推移领域特异性临床下降相关。在目标3中，我们将确定PT-ADRD的流体生物标志物，检验NFL、GFAP、tau(T-tau，PTau)和β淀粉样蛋白(aβ42/40)水平与临床下降相关的假设。对于AIMS 1-3，我们将检验这样的假设，即PT-ADRD患者的AD/ADRD病理负担(tau[T-tau，ptau]，β淀粉样蛋白[aβ42/40])比csTBI患者更大。在探索性目标4中，我们将评估损伤特征、AD/ADRD危险因素和候选生物标记物对AD/ADRD风险的贡献。我们将创建丰富的数据资源，以加快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

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

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