Project III "Cognitive Difficulty in LB and AD Dementias"

项目三“LB和AD痴呆症的认知困难”

• 批准号: 10452564
• 负责人: MURRAY GROSSMAN
• 金额: $ 95.44万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10452564
• 关键词: Address; Algorithms; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Anatomy; Atrophic; Autopsy; Basic Science; Biological Models; Biometry; Case Study; Cerebrospinal Fluid; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Corpus striatum structure; Cross-Sectional Studies; Dementia; Dementia with Lewy Bodies; Differential Diagnosis; Diffuse; Disease; Etiology; Histology; Human; Impaired cognition; Language; Language Disorders; Lewy Bodies; Lewy Body Disease; Lewy neurites; Magnetic Resonance Imaging; Medial; Molecular; Monoclonal Antibodies; Names; Nerve Degeneration; Parkinson Disease; Parkinson' s Dementia; Pathologic; Pathology; Patients; Pattern; Phenotype; Subgroup; Temporal Lobe; Work; alpha synuclein; base; brain tissue; cerebral atrophy; clinical diagnostics; clinical heterogeneity; data management; design; diagnostic criteria; digital; entorhinal cortex; frontal lobe; imaging biomarker; improved; in vivo; insight; meetings; multimodality; neuropathology; novel; putamen; tau Proteins; tool

Abstract The presence of α-synuclein (aSyn) pathology defines Lewy Body Disorders (LBD), including Parkinson's dementia (PDD) and Dementia with Lewy Bodies (DLB). However, LBD has significant clinical heterogeneity, and current, purely clinical criteria do not identify the mixed pathology found in LBD. We hypothesize two forms of human aSyn pathology that are biologically meaningful: “pure” aSyn with minimal AD co-pathology (aSyn- AD), and aSyn modified by AD co-pathology (aSyn+AD). Moreover, these pathologies are related to pathologic maturity and distinct strains developed in model systems in Projects I/II: One aSyn strain (Strain A) is associated with less mature pathology and induces only aSyn, and we expect to find this in both aSyn-AD and aSyn+AD; a second strain (Strain B) is associated with more mature aSyn pathology and induces both aSyn and less mature tau pathology, and we expect much more Strain B in aSyn+AD than aSyn-AD. We assess mixed pathologies further using a 2X2 design and compare LBD with AD, where half of clinical AD have “pure” AD pathology (AD-aSyn) and half have aSyn co-pathology (AD+aSyn) at autopsy. We expect aSyn strains to be minimal in AD-aSyn, but we expect Strain A in AD+aSyn. Moreover, we expect mature tau pathology in AD. Aim 1 examines digital histology of the maturity and strain-related pathology in LBD and AD. We use a validated, parametric histology (DHist) approach to study the anatomy of aSyn, tau and Aβ pathology, relate these to antemortem clinical features and assess monoclonal antibodies (mAbs) raised against aSyn strains in Projects I/II. In aSyn+AD, we expect more mature aSyn and less mature tau pathology in frontal and temporal regions with executive and language deficits, respectively, and less striatal pathology, related to Strain B mAb; but aSyn-AD will have less aSyn cortical pathology and less impaired cognition, related to less mature aSyn and mAb to strain A. AD will show more mature tau in a different anatomic locus since the distribution of tau is guided in part by aSyn Strain B found in aSyn+AD but not AD-aSyn, and less mature aSyn pathology related to Strain A in AD+aSyn. Aim 2 studies in vivo MRI and cerebrospinal fluid (CSF) markers of strain-related disease in LBD and AD. Using validated CSF markers of pathology to define cases, we study cross-sectional and longitudinal cognition and MRI in living patients with likely LBD (aSyn-AD, aSyn+AD) vs. AD (AD-aSyn, AD+aSyn). In LBD with CSF consistent with aSyn+AD, we expect progressive MRI atrophy in frontal and temporal regions greater than in striatum, related to declining executive and language function, respectively. MRI in LBD with CSF consistent with aSyn-AD has less cortical and cognitive decline. Since tau is guided by the anatomic locus of aSyn induced by Strain B in aSyn+AD, cognitive deficits and MRI atrophy will differ from AD. Aim 3 studies atrophy in critical medial temporal lobe (MTL) subfields and amygdala in LBD and AD. Using DHist pathology and state-of-the-art in vivo MTL subfield segmentation, we expect distinct subfield and amygdala distributions of aSyn and tau in LBD and AD.

抽象的 α-突触核蛋白（ASYN）病理的存在定义了Lewy身体疾病（LBD），包括帕金森氏症 痴呆症（PDD）和痴呆症具有Lewy身体（DLB）。但是，LBD具有明显的临床异质性， 当前的纯临床标准无法确定LBD中发现的混合病理。我们假设两种形式 在生物学上有意义的人类ASYN病理学：“纯” Asyn具有最小的AD辅助病理学（Asyn- AD），ASYN通过AD Co-Phatology（ASYN+AD）进行了修改。此外，这些病理与病理有关 在项目I/II的模型系统中发展的成熟度和不同的菌株：一个ASYN菌株（A菌株A）是 与较不成熟的病理相关，仅诱导Asyn，我们希望在Asyn-AD和 asyn+ad;第二株（菌株B）与更成熟的ASYN病理学有关，并诱导两者ASYN 和不太成熟的tau病理学，我们预计ASYN+AD中的应变B要比Asyn-AD多得多。我们评估 混合病理使用2x2设计并将LBD与AD进行比较，其中一半的临床广告具有“纯” AD病理学（AD-ASYN）和一半在尸检时具有ASYN的共同病理学（AD+ASYN）。我们希望Asyn菌株能够 在AD-Asyn中保持最小，但我们期望AD+Asyn中的a a+a a a+asyn。此外，我们预计AD中成熟的Tau病理学。 AIM 1考试LBD和AD中的成熟度和与应变有关的病理学的数字组织学。我们使用一个 经过验证的参数组织学（DHIST）研究ASYN，TAU和Aβ病理学的解剖学，相关的解剖学方法 这些是触及临床特征并评估针对ASYN菌株的单克隆抗体（mAb） 项目I/II。在Asyn+AD中，我们期望额叶和临时性的成熟的Asyn和不太成熟的Tau病理 具有执行和语言的区域分别定义了与菌株MAB有关的纹状体病理学和更少的纹状体病理； 但是Asyn-AD的Asyn皮质病理学将较少，认知受损，与不太成熟的Asyn有关 和mab菌株A。AD将在不同的解剖基因座中显示出更加成熟的tau，因为Tau的分布为 部分由Asyn+AD中的Asyn菌株B引导，但不是AD-Asyn，而与成熟的Asyn病理学相关 将A中的A纳入AD+ASYN。 AIM 2研究与应变相关的体内MRI和脑脊液（CSF）标记 LBD和AD中的疾病。我们使用经过验证的CSF病理标记来定义病例，我们研究横截面 与可能LBD（Asyn-AD，Asyn+AD）的活着患者的纵向认知和MRI相对于AD（AD-ASYN， AD+Asyn）。在与Asyn+AD一致的CSF的LBD中，我们预计在额叶和 临时区域大于纹状体，分别与执行和语言功能下降有关。 与ASYN-AD一致的CSF的LBD中的MRI具有较少的皮质和认知能力下降。因为tau被指导 ASYN+AD中菌株B诱导的ASYN的解剖基因座，认知定义和MRI萎缩将与 广告。 AIM 3研究在关键内侧临时叶（MTL）子场和LBD中的杏仁核的萎缩和 广告。使用DHIST病理学和最新的体内MTL子场分段，我们期望独特的子场 LBD和AD中Asyn和Tau的杏仁核分布。