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Lewy Body Dementia Biomarkers

路易体痴呆生物标志物

基本信息

批准号：
9838296
负责人：
KIRK A. FREY
金额：
$ 76.82万
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/9838296
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 Dementia with Lewy Bodies Deposition Deterioration Development Diagnosis Disease Exhibits Failure Frequencies Future Goals Image Impaired cognition Individual Intervention Label Lead Lewy Bodies Lewy Body Dementia Lewy neurites 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 aggregation 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性问题以神经元内α-突触核蛋白（α-Syn）聚集体为特征。这些患者在临床上被归类为帕金森病或帕金森病。痴呆（PDD）或路易体痴呆（DLB）。这种标签区分是基于以下顺序帕金森病与痴呆的表现-在PDD中，运动障碍首先发生，而在DLB中，认知障碍首先发生。损伤首先发生或在帕金森病发作的1年内发生。PDD和DLB表现出几乎相同的病理尸检发现发现的异常包括α-Syn、Aβ-淀粉样蛋白和tau蛋白的病理性沉积，后者为神经元内成对螺旋丝或“神经纤维缠结”（NFT）。在个体大脑中，单独的α-Syn可能存在于细胞体（路易体）或突触末梢（路易神经突）中。在其他大脑中，α-Syn沉积物与Aβ-淀粉样斑块一起存在。在其他大脑中，α-Syn，Aβ-淀粉样蛋白和tau NFT病理都是目前，经常在神经病理学上被诊断为阿尔茨海默病（AD）伴PD。神经病理学检查结果没有，然而，与PDD与DLB受试者临床分类基本相关。 α-突触核蛋白病痴呆症的有效治疗的未来发展可能需要靶向α-突触核蛋白病。涉及的病理途径，这反过来又需要能够确定存在于个体患者和评估哪些病理最强烈地驱动认知障碍的进展。是治疗方法在改善疾病方面是有效的，但需要在只有轻微症状的患者中进行测试和应用。在目前的建议，我们将确定轻度痴呆症患者的α-突触核蛋白病，采用多示踪剂分子脑成像与正电子发射断层扫描（PET）。我们将确定α- 基于黑质纹状体投射完整性的[11 C]二氢丁苯那嗪（DTBZ）PET成像的Syn神经病理学。我们将通过[11 C]匹兹堡化合物-B（PiB）PET成像确定Aβ-淀粉样蛋白斑块沉积的存在，用[18F] AV 1451（以前称为T807）PET成像观察tau NFT病理的存在。总之，这些图像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，或同时伴有Aβ-淀粉样蛋白和tau蛋白的突触核蛋白病。我们将检验这样一个假设，即认知能力下降的进程将在具有Aβ-淀粉样蛋白和tau内表型的突触核蛋白病中更快，并且认知障碍的进展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，随访[18 F] AV 1451-PET。 PDD和DLB中神经退行性病理学的可靠性状生物标志物的开发将使得在以下方面取得进展：开发和评估这些综合征迫切需要的新的治疗干预措施。