COGNITIVE AND NEURAL IMPAIRMENT IN FTLD

FTLD 中的认知和神经损伤

• 批准号: 8645562
• 负责人: MURRAY GROSSMAN
• 金额: $ 28.87万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8645562
• 关键词: Accounting; Address; Adult; Age-Years; Agrammatism; Alzheimer' s Disease; Anatomy; Aphasia; Area; Atrophic; Auditory; Behavior; Behavioral; Biological Neural Networks; Categories; Clinical; Cognitive; Comparative Study; Comprehension; Consensus; Defect; Development; Diagnostic; Disease; Disinhibition; Dorsal; Executive Dysfunction; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional Magnetic Resonance Imaging; Genetic; Genotype; Haplotypes; Histopathology; Image; Impairment; Knowledge; Language Disorders; Left; Magnetic Resonance Imaging; Motivation; Names; Pathology; Patient Care; Patients; Phenotype; Pick Disease of the Brain; Population; Progressive Supranuclear Palsy; Psyche structure; Resources; Role; Semantic Dementias; Semantic memory; Semantics; Speech; Speech Sound; Stress; Syndrome; Tauopathies; Techniques; Temporal Lobe; Testing; Ubiquitin; Variant; Visual; Work; abstracting; association cortex; base; cognitive neuroscience; corticobasal degeneration; diagnostic accuracy; gray matter; improved; language processing; motor control; novel; protein TDP-43; relating to nervous system; social; social cognition; tau Proteins; treatment trial; white matter

PROJECT SUMMARY: Our prior work demonstrated hypothesis-driven characterizations of the phenotypes associated with frontotemporal lobar degeneration (FTLD), including progressive non-fluent aphasia (PNFA), semantic dementia (SD), and behavioral variant patients with a social and executive disorder (bvFTD). We also began to relate these syndromes to the major pathologies underlying FTLD. However, little work has determined the value of clinical features for predicting pathology. We propose novel studies that optimize features we can use to characterize PNFA, SD and bvFTD. We will obtain converging evidence for these observations from novel MRI techniques integrating grey matter (GM) atrophy and white matter (WM) tract defects, and from functional MRI (fMRI) studies of healthy adults using the same materials. Finally, we will relate FTLD phenotypes to pathology, and determine how these associations are modulated by genetic factors. Aim 1 addresses the basis for non-fluent speech in PNFA. We propose studies of conversational discourse in PNFA to highlight the combined role of grammatical and executive deficits in their language disorder. Integrated GM-WM imaging will relate this to left frontal disease, and converging evidence for an fMRI study of healthy adults will confirm this. Aim 2 will examine the role of degraded perceptual feature knowledge in the semantic deficit of SD patients. Imaging studies will, relate poor knowledge of visual object features to visual association cortex in the ventral temporal lobe and poor auditory feature knowledge to dorsal temporal regions. An fMRI study in healthy adults will provide converging evidence for the anatomic relationships of visual and auditory feature knowledge of object concepts. Aim 3 will demonstrate the role executive limitations in the most devastating social disorders of bvFTD patients. We will identify two forms of apathy - a vegetative form manifested as poor motivation, and an executive form that relates apathy to difficulty with multi-step tasks. Using integrated GM-WM imaging, we expect these two forms of apathy to be associated with disease in different frontal regions. Different forms of disinhibition also will be identified. One form will be related in part to impoverished social knowledge and right temporal disease, and a second form related to executive dysfunction (e.g. mental switching difficulty) involving right ventral prefrontal disease. Aim 4 will test the hypothesis that non-fluent speech due to grammatical difficulty in PNFA is associated with FTLD-Tau, and this association will be strengthened by tau haplotype. Degraded feature knowledge for object concepts in SD will be associated with FTLD-TDP, and this will be strengthened by TMEM106B. We will also test the hypothesis that the vegetative form of apathy in bvFTD is related to FTLD-Tau, while disinhibition due to impaired social knowledge is related to FTLD-TDP. This work will advance cognitive neuroscience in the areas of language processing, semantic memory, and social cognition. These findings will contribute crucially to diagnostic accuracy, clarify specific clinical features that are most likely to refiect underlying pathology, and provide meaningful endpoints for treatment trials.

项目摘要：我们之前的工作证明了与额颞叶变性 (FTLD) 相关的表型的假设驱动特征，包括进行性非流利性失语症 (PNFA)、语义痴呆 (SD) 以及患有社交和执行障碍的行为变异患者。 bvFTD）。我们还开始将这些综合征与 FTLD 的主要病理联系起来。然而，很少有工作确定临床特征对于预测病理学的价值。我们提出了新颖的研究来优化可用于表征 PNFA、SD 和 bvFTD 的特征。我们将从整合灰质（GM）萎缩和白质（WM）束缺陷的新型 MRI 技术以及使用相同材料对健康成年人进行的功能性 MRI（fMRI）研究中获得这些观察结果的聚合证据。最后，我们将 FTLD 表型与病理学联系起来，并确定遗传因素如何调节这些关联。目标 1 解决 PNFA 中不流利言语的基础。我们建议对 PNFA 中的会话话语进行研究，以强调语法和执行缺陷在语言障碍中的综合作用。综合 GM-WM 成像将把这一点与左额叶疾病联系起来，对健康成年人进行的功能磁共振成像研究的汇聚证据将证实这一点。目标 2 将研究感知特征知识退化在 SD 患者语义缺陷中的作用。影像学研究将对视觉物体特征的了解不足与腹侧颞叶的视觉关联皮层联系起来，而对听觉特征的了解则与背侧颞叶区域联系起来。对健康成年人的功能磁共振成像研究将为物体概念的视觉和听觉特征知识的解剖关系提供聚合证据。目标 3 将展示 bvFTD 患者最具破坏性的社交障碍中的角色执行限制。我们将识别两种形式的冷漠——一种表现为动力不足的植物性形式，以及一种将冷漠与多步骤任务的困难联系起来的执行型。使用综合 GM-WM 成像，我们预计这两种形式的冷漠与不同额叶区域的疾病相关。还将确定不同形式的去抑制。一种形式部分与缺乏社会知识和右颞叶疾病有关，第二种形式与涉及右腹前额叶疾病的执行功能障碍（例如精神转换困难）有关。目标 4 将检验以下假设：PNFA 中由于语法困难而导致的不流利言语与 FTLD-Tau 相关，并且这种关联将通过 tau 单倍型得到加强。 SD 中对象概念的退化特征知识将与 FTLD-TDP 相关联，并且这将通过 TMEM106B 得到加强。我们还将检验以下假设：bvFTD 中的植物性冷漠与 FTLD-Tau 相关，而由于社会知识受损而导致的去抑制与 FTLD-TDP 相关。这项工作将推进语言处理、语义记忆和社会认知领域的认知神经科学。这些发现将对诊断准确性做出至关重要的贡献，阐明最有可能反映潜在病理学的具体临床特征，并为治疗试验提供有意义的终点。