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: 10654807
• 负责人: MURRAY GROSSMAN
• 金额: $ 52.7万
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654807
• 关键词: Address; Algorithms; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amygdaloid structure; Amyloid beta-Protein; Anatomy; Atrophic; Autopsy; Basic Science; Biological Models; Biometry; Cerebrospinal Fluid; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Corpus striatum structure; Cross-Sectional Studies; Dementia; Dementia with Lewy Bodies; Diagnostic; 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; brain tissue; cerebral atrophy; clinical heterogeneity; clinical translation; 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.

摘要 α-突触核蛋白（aSyn）病理学的存在定义了路易体障碍（LBD），包括帕金森氏病 痴呆（PDD）和路易体痴呆（DLB）。然而，LBD具有显著的临床异质性， 目前，纯临床标准不能识别LBD中发现的混合病理学。我们假设有两种形式 具有生物学意义的人aSyn病理学特征：具有最小AD共病理学的“纯”aSyn（aSyn-1）。 AD）和由AD共病理学修饰的aSyn（aSyn+AD）。此外，这些病理学与病理学有关。 在项目I/II的模型系统中开发的成熟和不同菌株： 与不太成熟的病理学相关，并且仅诱导aSyn，我们期望在aSyn-AD和 aSyn+AD;第二种菌株（菌株B）与更成熟的aSyn病理学相关，并诱导aSyn + AD 和较不成熟的tau病理，并且我们预期aSyn+AD中的菌株B比aSyn-AD中的菌株多得多。我们评估 混合病理进一步使用2X2设计，并比较LBD与AD，其中一半的临床AD具有“纯” AD病理（AD-aSyn）和一半有aSyn共同病理（AD+aSyn）在尸检。我们预计aSyn菌株 在AD-aSyn中最小，但我们预期AD+aSyn中的菌株A。此外，我们预计AD中的tau病理会成熟。 目的1研究LBD和AD的成熟和应变相关病理的数字组织学。我们使用一个 一种经验证的参数组织学（DHist）方法，用于研究aSyn、tau和Aβ病理学的解剖结构， 这些研究用于死前临床特征，并评估针对aSyn菌株产生的单克隆抗体（mAb）， 项目一/二.在aSyn+AD中，我们预期在额叶和颞叶中更成熟的aSyn和更不成熟的tau病理学。 与菌株B mAb相关的执行和语言缺陷区域，以及较少的纹状体病理; 但aSyn-AD具有较少的aSyn皮质病理和较少的认知受损，与较不成熟的aSyn相关。 和抗菌株A的mAb。AD将在不同的解剖学位点显示更成熟的tau，因为tau的分布是 部分由aSyn+AD中发现的aSyn菌株B而不是AD-aSyn引导，并且与以下相关的较不成熟的aSyn病理学 AD+aSyn中的菌株A。目的2研究在体MRI和脑脊液（CSF）中与应变相关的标志物 LBD和AD疾病。使用经验证的CSF病理学标记物来定义病例，我们研究了 以及可能患有LBD的存活患者（aSyn-AD，aSyn+AD）与AD（AD-aSyn， AD+aSyn）。在CSF与aSyn+AD一致的LBD中，我们预期额叶和海马进行性MRI萎缩， 颞区大于纹状体，分别与执行和语言功能下降有关。 与aSyn-AD一致的CSF的LBD的MRI具有较少的皮质和认知下降。由于τ是由 在aSyn+AD中由菌株B诱导的aSyn的解剖学位点、认知缺陷和MRI萎缩将不同于 AD.目的3研究LBD患者的关键内侧颞叶（MTL）亚区和杏仁核萎缩， AD.使用DHist病理学和最先进的体内MTL子场分割，我们预期不同的子场 aSyn和tau在LBD和AD中的杏仁核分布。