COGNITIVE AND NEURAL IMPAIRMENT IN FTLD

FTLD 中的认知和神经损伤

• 批准号: 8444448
• 负责人: MURRAY GROSSMAN
• 金额: $ 27.82万
• 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/8444448
• 关键词: Accounting; Address; Adult; Age-Years; Agrammatism; Alzheimer' s Disease; Anatomy; Aphasia; Area; Atrophic; Auditory; Behavioral; Categories; Clinical; Cognitive; Consensus; Defect; Development; Diagnostic; Disease; Disinhibition; Dorsal; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional Magnetic Resonance Imaging; Functional disorder; Genetic; Genotype; Haplotypes; 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; Role; Semantic Dementias; Semantic memory; Semantics; Speech; Speech Sound; Syndrome; Tauopathies; Techniques; Temporal Lobe; Testing; Ubiquitin; Variant; Visual; Work; 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：我们先前的工作证明了与额颞叶变性（FTLD）相关的表型的假设驱动的特征，包括渐进性非浮力失气（PNFA），语义痴呆症（SD），以及具有社交和执行障碍（BVFTD）的行为变异患者（BVFTD）。我们还开始将这些综合征与FTLD基础的主要病理联系起来。但是，很少的工作决定了预测病理学的临床特征的价值。我们提出了新的研究，以优化可以用来表征PNFA，SD和BVFTD的功能。我们将从整合灰质（GM）萎缩和白质（WM）缺陷的新型MRI技术以及功能性MRI（fMRI）研究中对健康成年人使用相同材料的功能性MRI（fMRI）研究中获得这些观察结果的融合证据。最后，我们将将FTLD表型与病理学联系起来，并确定如何通过遗传因素调节这些关联。 AIM 1解决了PNFA中非流利语音的基础。我们建议对PNFA中的对话性话语进行研究，以强调语法和执行缺陷在其语言障碍中的综合作用。 GM-WM综合成像将与左额叶疾病有关，对健康成年人进行fMRI研究的融合证据将证实这一点。 AIM 2将研究降解感知特征知识在SD患者语义不足中的作用。成像研究将使对视觉对象特征的知识与腹侧颞叶中的视觉缔合皮质相关，而听觉知识则与背侧颞区域相关。在健康成年人中进行的fMRI研究将为视觉和听觉特征对象概念的解剖学关系提供融合的证据。 AIM 3将证明在BVFTD患者最具破坏性的社会障碍中，执行局限性。我们将确定两种形式的冷漠形式 - 一种营养形式，表现为不良动机，而执行形式将冷漠与与多步骤任务的困难有关。使用集成的GM-WM成像，我们希望这两种形式的冷漠与不同额叶区域的疾病有关。还将确定不同形式的抑制作用。一种形式将部分与贫困的社会知识和正确的颞疾病有关，第二种形式与涉及右腹前额外疾病的执行功能障碍（例如心理转换难度）有关。 AIM 4将检验以下假设：PNFA中由于语法难度引起的非浮力语音与FTLD-TAU有关，并且这种关联将通过Tau单倍型加强。 SD中对象概念的降级特征知识将与FTLD-TDP相关联，TMEM106B将加强这一点。我们还将检验以下假设：BVFTD中冷漠的营养形式与FTLD-TAU有关，而由于社会知识受损而引起的抑制作用与FTLD-TDP有关。这项工作将在语言处理，语义记忆和社会认知领域中提高认知神经科学。这些发现将对诊断准确性至关重要，阐明最有可能改善潜在病理的特定临床特征，并为治疗试验提供有意义的终点。