Lewy Body Dementia Biomarkers

认知障碍和痴呆是神经退行性变患者常见的致残问题 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氏症 痴呆症(PDD)或路易体痴呆症(DLB)。此标签区别基于以下顺序 帕金森症与痴呆症的表现--在PDD患者中，运动障碍首先发生，而在DLB患者中，认知障碍首先发生 损害发生在帕金森症发病后第一年或一年内。PDD和DLB表现出几乎相同的病理改变 尸检结果。发现的异常包括α-Syn，A-β淀粉样蛋白和tau蛋白的病理沉积， 后者为神经元内成对螺旋细丝或“神经原纤维缠结”(NFT)。在个体大脑中，仅α-syn可能 存在于细胞体(路易小体)或突触终末(路易突触)。在其他大脑中，α-syn存款是 伴有β-淀粉样斑块。在其他大脑中，α-syn、β-淀粉样蛋白和tau NFT病理都是 目前，常被诊断为阿尔茨海默病(AD)合并帕金森病(PD)。神经病理学的发现并没有， 然而，这与受试者的临床分类如PDD和DLB有很大的相关性。 α-突触核苷酸病痴呆的有效治疗的未来发展可能需要靶向 涉及的病理途径，这反过来又要求有能力确定存在的病理类型(S) 个别患者和对哪些病理因素的评估最强烈地推动认知障碍的进展。成为 这种疗法在改善疾病方面是有效的，需要对只有轻微症状的患者进行测试和应用。在……里面 在目前的建议中，我们将确定α-突触核苷酸病患者的轻度痴呆的内表型。 正电子发射断层扫描(PET)多示踪分子脑成像我们将确定α的存在- SYN神经病理学的基础是[11C]二氢替他苯肼(DTBZ)黑质纹状体投射完整性的PET成像。 我们将通过[11C]匹兹堡化合物-B(PIB)正电子发射计算机断层扫描确定β-淀粉样斑块沉积的存在，以及 在[18F]AV1451(以前命名为T807)PET成像中存在tau NFT病理。总而言之，这些成像 结果将允许将每个受试者归类为：“纯”联核症，或伴β-淀粉样蛋白的联核病，或AS 同时伴有β-淀粉样蛋白和tau蛋白的突触核病。我们将检验这一假设，即认知衰退的进展将 在同时具有β-淀粉样蛋白和tau内表型的联核症中速度更快，认知进展 具有这种内表型的受试者的损害将与NFT病理的进展相关，如在 随访[18F]AV1451-PET。 PDD和DLB神经退行性病变的可靠特征生物标志物的开发将使在 开发和评估这些综合征迫切需要的新的治疗干预措施。

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.