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: 10020336
• 负责人: MURRAY GROSSMAN
• 金额: $ 52.54万
• 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/10020336
• 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; Biological Models; Biometry; Case Study; Cerebrospinal Fluid; Clinical; Clinical Research; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Corpus striatum structure; Cross-Sectional Studies; Dementia; Diagnostic; Differential Diagnosis; Diffuse; Disease; Etiology; Histology; Human; Impaired cognition; Language; Language Disorders; Lewy Bodies; Lewy Body Dementia; 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; 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