Lewy Body Dementia Biomarkers

路易体痴呆生物标志物

基本信息

批准号：
9272242
负责人：
KIRK A. FREY
金额：
$ 96.34万
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 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9272242
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 Dementia Deposition Deterioration Development Diagnosis Disease Exhibits Failure Figs - dietary 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 Recruitment Activity Research Research Proposals Senile Plaques Severities Source Stratification Symptoms Syndrome Testing Therapeutic Trials Tracer alpha synuclein amyloid peptide base clinical Diagnosis cognitive change design dihydrotetrabenazine disability dopaminergic neuron effective therapy endophenotype extracellular follow-up imaging biomarker imaging modality individual patient mental function molecular imaging neocortical neuropathology novel therapeutic intervention paired helical filament patient subsets prevent protein aggregate synucleinopathy tau Proteins tau aggregation trait

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.

认知障碍和痴呆症是常见的，并且在神经退行性患者中残疾问题以神经元α-突触核蛋白（α-SYN）聚集体为特征。这些患者在临床上被分类为帕金森患有痴呆症（PDD）的疾病或有Lewy身体（DLB）的痴呆症。此标签拆分基于帕金森氏症与痴呆症的介绍 - 在PDD中，运动障碍首先发生，而在DLB中，认知障碍损伤首先或在帕金森主义发作1年之内发生。 PDD和DLB暴露于实际上相同的病理尸检的发现。发现的异常包括α-Syn，Aβ-淀粉样蛋白和Tau蛋白的病理沉积，后者作为神经内膜成对的螺旋丝或“神经纤维缠结”（NFT）。在单个大脑中，仅α-syn可能存在于细胞体（Lewy体）或突触末端（Lewy Neurotes）中。在其他大脑中，α-syn沉积物是与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病理都是存在，通常在神经病理学上诊断为患有PD的阿尔茨海默氏病（AD）。神经病理学发现没有，但是，与受试者与DLB相比，与受试者的临床分类基本相关。未来在α-突触核病中痴呆症的有效疗法的发展可能需要针对涉及的病理途径，反过来，确定存在的病理类型的必要能力个体患者和哪些病理学最强烈推动认知障碍的进展。是在疾病修饰方面有效，疗法将需要仅在轻度症状的患者中进行测试和应用。在本提案，我们将确定使用α-突触核病患者中轻度痴呆的内型型具有极性发射断层扫描（PET）的多跟踪分子脑成像。我们将确定存在α- 基于[11C]二氢苯甲酰嗪（DTBZ）的Syn神经病理学的宠物成像。我们将在[11C]匹兹堡化合物B（PIB）PET成像中确定Aβ-淀粉样菌斑沉积的存在，并且具有[18F] AV1451（以前指定的T807）PET成像的Tau NFT病理学的存在。在一起，这些成像结果将允许将每个受试者分类为：“纯”突触核苷，或与Aβ-淀粉样蛋白或AS 与Aβ-淀粉样蛋白和tau的肌醇病。我们将检验以下假设，即认知能力下降的进展将会与Aβ-淀粉样蛋白和tau内表型的突触核蛋白病更快，并且认知的进展具有这种内表型受试者的受试者的损害将与NFT病理的进展相关。后续[18F] AV1451-PET。 PDD和DLB中神经退行性病理的可靠特征生物标志物的发展将使这些综合症迫切需要的新治疗干预措施的开发和评估。