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.

摘要 α-突触核蛋白(ASyn)病理的存在定义了路易体疾病，包括帕金森氏症 痴呆(PDD)和路易体痴呆(DLB)。然而，LBD具有显著的临床异质性， 目前的纯临床标准并不能确定LBD中发现的混合病理。我们假设有两种形式 具有生物学意义的人类aSyn病理：具有最小AD共同病理的纯aSyn(aSyn- AD共病理改变的aSyn(aSyn+AD)。此外，这些病理与病理有关。 在项目I/II的模型系统中开发的成熟度和不同的菌株：一个aSyn菌株(菌株A)是 与不太成熟的病理相关，仅诱导aSyn，我们预计在aSyn-AD和 ASyn+AD；第二个菌株(菌株B)与更成熟的aSyn病理有关，并诱导两种aSyn 和不太成熟的tau病理，我们预计aSyn+AD比aSyn-AD更多的菌株B。我们评估 混合病理进一步使用2X2设计，并将LBD与AD进行比较，后者有一半的临床AD是“纯”的 AD病理(AD-aSyn)，半数尸检发现AD-aSyn共同病理(AD+aSyn)。我们预计aSyn菌株将 在AD-aSyn中最小，但我们预计AD+aSyn中有A株。此外，我们预计在AD时会出现成熟的tau病理。 目的1研究LBD和AD的成熟度和应变相关病理的数字组织学。我们使用一种 验证参数组织学(DHIST)方法研究aSyn、tau和Aβ病理的解剖学，相关 这些都是为了评估死前临床特征和针对aSyn株的单抗(MAbs) 项目I/II。在aSyn+AD中，我们预计额叶和颞叶的aSyn更成熟，tau病理更不成熟 与B株mAb相关的执行和语言缺陷以及纹状体病变较少的区域； 但aSyn-AD的皮质病变较少，认知损伤较少，与不太成熟的aSyn有关 而抗A.AD株的mAb将在不同的解剖位点显示更成熟的tau，因为tau的分布是 部分是由aSyn+AD中发现的aSyn菌株B而不是AD-aSyn中发现的，以及与以下方面相关的不太成熟的aSyn病理 菌株A在AD+aSyn。目的2体内研究应变相关的MRI和脑脊液标记物 LBD和AD的疾病。使用经过验证的脑脊液病理标志物来定义病例，我们进行横断面研究 LBD(aSyn-AD，aSyn+AD)与AD(AD-aSyn， Ad+aSyn)。在脑脊液符合aSyn+AD的LBD中，我们预计额叶和 颞区大于纹状体，分别与执行功能和语言功能下降有关。 脑脊液符合a Syn-AD的LBD患者的MRI表现皮质和认知功能减退较少。因为tau是由 B株诱导的aSyn在aSyn+AD中的解剖位点、认知障碍和MRI萎缩将不同于 广告。目的3研究LBD患者关键内侧颞叶(MTL)亚区和杏仁核的萎缩。 广告。使用DHist病理和最先进的体内MTL子场分割，我们预计会有不同的子场 杏仁核中aSyn和tau在LBD和AD中的分布。