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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：
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.

认知障碍和痴呆是神经退行性疾病患者常见的致残问题