Lewy Body Dementia Biomarkers

路易体痴呆生物标志物

基本信息

批准号：
9514273
负责人：
KIRK A. FREY
金额：
$ 41.07万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-25 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9514273
关键词：
Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid deposition Attentional deficit Autopsy Binding Biological Markers Brain Brain Injuries Brain Pathology Brain imaging Cells Characteristics Classification Clinical Cognitive Cognitive deficits Corpus striatum structure Cross-Sectional Studies Dementia Deposition Deterioration Development Diagnosis Disease Exhibits Failure Frequencies Future Goals Image Impaired cognition Individual Intervention Label Lead Lewy Bodies Lewy Body Dementia Memory Memory impairment Methods Modification Molecular Movement Disorders Natural History Nerve Degeneration Neurites Neurofibrillary Tangles Neurons Parkinson Disease Parkinson&apos s Dementia Parkinsonian Disorders Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Pittsburgh Compound-B Positron-Emission Tomography Presynaptic Terminals Proteins Research Proposals Senile Plaques Severities Source Stratification Symptoms Syndrome Testing Therapeutic Trials Tracer alpha synuclein amyloid peptide base brain research clinical Diagnosis cognitive change design dihydrotetrabenazine disability dopaminergic neuron effective therapy endophenotype extracellular follow-up imaging approach imaging biomarker imaging modality individual patient longitudinal analysis mental function molecular imaging neocortical neuropathology novel therapeutic intervention paired helical filament patient subsets prevent protein aggregate recruit synucleinopathy tau Proteins tau aggregation trait virtual

项目摘要

Cognitive impairment and dementia are common and disabling problems in patients with neurodegenerations characterized by intraneuronal α-synuclein (α-Syn) aggregates. These patients are classified clinically as either Parkinson disease with dementia (PDD) or as dementia with Lewy bodies (DLB). This labeling distinction is based on the order of presentation of parkinsonism versus dementia – in PDD, the movement disorder occurs first, while in DLB, the cognitive impairment occurs first or within 1-year of parkinsonism onset. PDD and DLB exhibit virtually identical pathological findings at autopsy. Abnormalities found include pathological depositions of α-Syn, Aβ-amyloid, and tau proteins, the latter as intraneuronal paired helical filaments or “neurofibrillary tangles” (NFT). In individual brains, α-Syn alone may be present in cell bodies (Lewy bodies) or in synaptic terminals (Lewy neurites). In other brains, α-Syn deposits are present together with Aβ-amyloid plaques. In still other brains, α-Syn, Aβ-amyloid and tau NFT pathologies are all present, often diagnosed neuropathologically as Alzheimer disease (AD) with PD. The neuropathologic findings do not, however, correlate substantially with subject clinical classification as PDD versus DLB. The future development of effective therapy for dementia in α-synucleinopathy will likely require targeting of the pathologic pathways involved, and this in turn, necessitates ability to determine the type(s) of pathology present in individual patients and assessment of which pathologies most strongly drive progression of cognitive impairments. To be effective in disease modification, therapies will require testing and application in patients with only mild symptoms. In the present proposal, we will determine endophenotypes of mild dementia in patients with α-synucleinopathy, employing multi-tracer molecular brain imaging with positron emission tomography (PET). We will determine the presence of α- Syn neuropathology on the basis of [11C]dihydroteterabenazine (DTBZ) PET imaging of nigrostriatal projection integrity. We will identify the presence of Aβ-amyloid plaque deposition with [11C]Pittsburgh compound-B (PiB) PET imaging, and the presence of tau NFT pathology with [18F]AV1451 (formerly designated T807) PET imaging. Together, these imaging results will permit classification of each subject as: “pure” synucleinopathy, or synucleinopathy with Aβ-amyloid, or as synucleinopathy with both Aβ-amyloid and tau. We will test the hypothesis that the progression of cognitive decline will be more rapid in the synucleinopathy with both Aβ-amyloid and tau endophenotype, and that the progression of cognitive impairment in subjects with this endophenotype will correlate with the progression of NFT pathology as determined in follow-up [18F]AV1451-PET. The development of reliable trait biomarkers of neurodegenerative pathologies in PDD and DLB will enable progress in the development and assessment of new therapeutic interventions desperately needed in these syndromes.

认知障碍和痴呆是神经退行性疾病患者常见的致残问题以神经元内 α-突触核蛋白 (α-Syn) 聚集为特征的患者在临床上被分类为帕金森病。痴呆症 (PDD) 或路易体痴呆 (DLB) 此标记区别基于以下顺序。帕金森症与痴呆的表现——在 PDD 中，首先出现运动障碍，而在 DLB 中，首先出现认知障碍 PDD 和 DLB 表现出几乎相同的病理特征。尸检发现的异常包括 α-Syn、Aβ-淀粉样蛋白和 tau 蛋白的病理沉积。后者作为神经元内成对的螺旋丝或“神经原纤维缠结”（NFT），在个体大脑中，α-Syn 可能单独存在。 α-Syn 沉积物存在于细胞体（路易体）或突触末梢（路易神经突）中。在其他大脑中，α-Syn、Aβ-淀粉样蛋白和 tau NFT 病变均与 Aβ-淀粉样蛋白斑块一起存在。目前，通常在神经病理学上诊断为阿尔茨海默病 (AD) 并伴有 PD，但神经病理学结果并不如此。然而，与 PDD 与 DLB 的受试者临床分类显着相关。未来开发针对 α-突触核蛋白病痴呆的有效疗法可能需要靶向所涉及的病理途径，而这反过来又需要能够确定存在于其中的病理类型个体患者并评估哪些病理最强烈地驱动认知障碍的进展。为了有效改变疾病，治疗方法需要在症状轻微的患者中进行测试和应用。在目前的建议中，我们将确定 α-突触核蛋白病患者轻度痴呆的内表型，采用使用正电子发射断层扫描 (PET) 进行多示踪剂分子脑成像我们将确定 α- 的存在。基于 [11C]二氢丁苯那嗪 (DTBZ) PET 成像的黑质纹状体投射完整性的同步神经病理学。我们将通过 [11C]匹兹堡化合物-B (PiB) PET 成像来识别 Aβ-淀粉样蛋白斑沉积的存在，并且 tau NFT 病理学的存在与 [18F]AV1451（以前称为 T807）PET 成像一起进行。结果将允许将每个受试者分类为：“纯”突触核蛋白病，或伴有 Aβ-淀粉样蛋白的突触核蛋白病，或 Aβ-淀粉样蛋白和 tau 蛋白共核蛋白病我们将检验认知能力下降的假设。在同时具有 Aβ 淀粉样蛋白和 tau 内表型的突触核蛋白病中，认知功能的进展更快具有这种内表型的受试者的损伤将与 NFT 病理学的进展相关，如后续[18F]AV1451-PET。 PDD 和 DLB 神经退行性疾病的可靠特征生物标志物的开发将有助于在这些综合征迫切需要开发和评估新的治疗干预措施。