Blinded Comparison of Different Alpha-Synuclein Seeding Assays as Cutaneous Biomarkers of Lewy Body Dementias

不同 α-突触核蛋白接种测定作为路易体痴呆皮肤生物标志物的盲法比较

• 批准号: 10064563
• 负责人: CHARLES H ADLER
• 金额: $ 62.13万
• 依托单位: BANNER HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10064563
• 关键词: Affect; Aging; Arizona; Autopsy; Biological Assay; Biological Markers; Biopsy; Blinded; Brain; Clinic; Clinical; Clinical Trials; Clinical dementia rating scale; Cognition Disorders; Cognitive; Cutaneous; Data; Dementia; Dementia with Lewy Bodies; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic Sensitivity; Diagnostic Trial; Disease; Disease Progression; Enrollment; Gold; Health; Immunohistochemistry; Iowa; Laboratories; Lewy Body Dementia; Longevity; Measures; Methods; Molecular; Monitor; Motor; Movement Disorder Society Unified Parkinson' s Disease Rating Scale; Movement Disorders; Needle biopsy procedure; Nerve Degeneration; Neurodegenerative Disorders; Parkinson' s Dementia; Parkinsonian Disorders; Peripheral; Population; Positron-Emission Tomography; Process; Proteins; Public Health; Publishing; Punch Biopsy; Research Institute; Sensitivity and Specificity; Severities; Site; Skin; Specificity; Submandibular gland; Surveys; Testing; The Sun; Time; Tissues; Universities; Work; accurate diagnostics; alpha synuclein; cognitive testing; density; diagnostic assay; imaging modality; prognostic; prognostic value; protein aggregation; protein misfolding cyclic amplification; response; targeted treatment

Abstract With increasing longevity in our population, dementia is widely recognized as an impending public health crisis. Lewy body dementia (LBD), encompassing dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), is the second most common cause. LBD is characterized by abnormal aggregation and accumulation of a protein, α-synuclein (aSyn). PDD and DLB are clinically separated only by the relative timing of the onset of parkinsonism and dementia. At present, advances in the treatment of these conditions are critically hampered by the lack of non-invasive, inexpensive biomarkers that can provide accurate diagnostic and prognostic information. This situation may soon be resolved, as in recent years it has become apparent, through our own studies and those of others, that biopsies of peripheral tissue sites can detect diagnostically significant aSyn. Our project will assess aSyn in punch biopsies of the skin. Our preliminary data from new “seeding assay” methods including real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), from autopsy-confirmed LBD subjects, indicate high sensitivity and specificity for predicting the presence of aSyn in the skin of affected subjects. Further work is necessary to confirm these results in living subjects with these conditions, which is the objective of this proposed project. We will biopsy, twice during a four year period, 90 subjects with aSyn disease, 30 each with PD, PDD and DLB, as well as 30 normal control subjects. Two independent laboratories will blindly perform separately-developed seeding assays, rigorously testing the interlaboratory reliability and providing estimates of aSyn density change over time. The seeding assay results will be compared with those obtained by the current gold-standard biopsy method, immunohistochemistry (IHC). All subjects will receive cognitive and movement disorder assessments at two timepoints in this four year project, enabling comparisons of assay measures with cognitive and motor decline rates. Many of the subjects will be enrolled in the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND), a longitudinal clinicopathological study with an autopsy rate exceeding 90%. This will allow, in a substantial subset, eventual neuropathological confirmation of the molecular cause of parkinsonism and dementia in each subject.

摘要 随着我国人口寿命的增加，痴呆症被广泛认为是一种迫在眉睫的公共卫生危机。 路易体痴呆（LBD），包括路易体痴呆（DLB）和帕金森病痴呆 (PDD)是第二大常见原因。LBD的特征是异常聚集和积累的 α-突触核蛋白（aSyn）。PDD和DLB在临床上仅通过相对的发病时间来区分。 帕金森症和痴呆症。目前，这些疾病的治疗进展严重受阻， 由于缺乏非侵入性的，廉价的生物标志物，可以提供准确的诊断和预后 信息.这种情况可能很快就会得到解决，因为近年来， 研究和其他人的研究表明，外周组织部位的活检可以检测诊断上显著的aSyn。 我们的项目将评估aSyn在皮肤穿刺活检中的作用。我们来自新“接种试验”的初步数据 包括实时振荡诱导转换（RT-QuIC）和蛋白质错误折叠循环扩增的方法 （PMCA），从尸检证实的LBD受试者，表明高灵敏度和特异性预测 受影响受试者皮肤中aSyn的存在。进一步的工作是必要的，以确认这些结果在生活中 这些条件的主体，这是这个拟议项目的目标。我们将活检，两次， 在4年的时间里，90例aSyn病患者，30例PD、PDD和DLB患者，以及30例正常对照 科目两个独立的实验室将严格盲法进行单独开发的接种试验， 测试实验室间的可靠性并提供aSyn密度随时间变化的估计。播种 将测定结果与通过目前的金标准活组织检查方法获得的结果进行比较， 免疫组织化学（IHC）。所有受试者将在下午2点接受认知和运动障碍评估。 在这个为期四年的项目的时间点，使测定措施与认知和运动下降的比较 rates.许多受试者将参加亚利桑那州的衰老和神经退行性疾病研究 （ASANDAND），一项纵向临床病理学研究，尸检率超过90%。这将允许，在一个 实质性子集，最终神经病理学证实帕金森综合征的分子原因， 每个人的痴呆症。