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.

这项R01提案：“创伤后认知障碍，认知下降，阿尔茨海默氏病和相关痴呆症的临床和生物学机制”是针对RFA-NS-NS-19-026的响应而提交的”神经变性（例如，认知能力下降，阿尔茨海默氏病（AD））。脑损伤是阿尔茨海默氏病（AD）和相关痴呆症（ADRD）的确定危险因素，包括血管认知障碍（VCID）（VCID），额叶Lobar变性（FTLD/FTD），帕金森氏病（PD），痴呆症，具有Lewy Bodies（DLB）的痴呆症（DLB）和轻度Coind Impimbimt（Mciaim Impim）。迫切需要确定头部创伤（相对普遍且越来越普遍）是否会影响AD和ADRD的发病机理。创伤后ADRDS（PT-ADRD）的临床特征，机制和病理生物学仍然未知，并且临床和研究社区通过将慢性静态TBI（CSTBI; e. e.g.，稳定的认知障碍）与PT-ADRD（E.G.G. G.G. G. G. G.，Scocnsssockssopssock）区分开来使身体上不同的过程与身体上不同的过程混为一谈。这已被排除在TBI可能启动或加剧AD/ADRD的机械途径的描述。我们的中心假设是，PT-ADRD与基于认知能力下降，神经行为和运动衰落的CSTBI有区别，这与纵向变化有关，反映了阿尔茨海默氏症/ADRD相关的变化（例如，皮质厚度，Tau和amyyboid beta的累积，是皮质厚度变化，肿块）。为了检验这一假设，我们将丰富和扩展一个预期的脑供体计划，即TBI（LETBI）项目的后期影响。该队列的特征是临床，生物学和神经影像学广告/ADRD工具，以与其他大型AD/ADRD研究工作重叠。我们将采用先进的心理测量和统计方法，新颖的神经影像学处理工具，超敏感的单分子阵列（SIMOA）技术以及最新的神经病理学方法来提高对PT-ADRD的了解。 AIM 1我们将检验以下假设：基于AD/ADRD测量的认知，行为和运动功能的AD/ADRD测量，PT-ADRD（例如认知障碍）与CSTBI（例如认知下降）不同。在AIM 2中，我们将通过测试以下假设，即皮质体积特异性变化（AD BioMarker）与域特异性临床下降有关，从而确定了PT-ADRD的生物标志物。在AIM 3中，我们将确定PT-ADRD的流体生物标志物，检验了NFL，GFAP，TAU（T-TAU，PTAU）和β-淀粉样蛋白（Aβ42/40）水平与临床下降有关的假设。对于目标1-3，我们将检验以下假设：PT-ADRD患者的AD/ADRD病理学伯恩（Tau [T-Tau，ptau]，β42/40]）比患有CSTBI的淀粉样蛋白[Aβ42/40]）。在探索性目标4中，我们将评估伤害特征，AD/ADRD风险因素以及候选生物标志物对AD/ADRD风险的贡献。我们将创建丰富的数据资源来加速ADRD诊断和新颖的治疗目标。

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