Anatomic mechanisms of resilience and genetic susceptibility in TDP-related disorders

TDP 相关疾病的恢复力和遗传易感性的解剖学机制

基本信息

批准号：
10454274
负责人：
Lauren M Massimo
金额：
$ 27.83万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10454274
关键词：
Aging Anatomy Atrophic Behavioral Biological Brain Brain region Cells Cerebrovascular Circulation Cerebrum Clinical Clinical Management Clinical Trials Cognitive Complex Data Disease Disease Progression Education Emotional disorder Family Functional Magnetic Resonance Imaging Gene Frequency Genes Genetic Genetic Determinism Genetic Predisposition to Disease Genetic Variation Goals Graph Heterogeneity Histopathology Image Impaired cognition Impairment Individual Knowledge Leisure Activities Life Expectancy Life Style Link Magnetic Resonance Imaging Measures Modeling Moderate Activity Neurodegenerative Disorders Neurons Occupational Occupations Pathologic Pathology Patients Performance Personality Phase Play Property Psyche structure Resources Risk Role Single Nucleotide Polymorphism Source Specificity Syndrome Variant Work arterial spin labeling behavioral variant frontotemporal dementia burden of illness clinical diagnosis clinical predictors cognitive reserve cohort density emotion regulation executive function flexibility frontotemporal degeneration gray matter lifestyle factors network models neural network novel predictive modeling prognostic protein TDP-43 relating to nervous system resilience risk variant support network tau Proteins white matter

项目摘要

Project Summary Behavioral variant frontotemporal degeneration (bvFTD) is a common cause of young-onset neurodegenerative disease and life expectancy is approximately 7 years, but this is highly variable. Recent work associates change in cognitive and MRI imaging with pathologic phases of accumulating FTLD-TDP and FTLD-Tau pathology. However, major gaps in knowledge concern the tremendous variability in the rate of clinical progression in bvFTD, and the factors contributing to this variability. Studies have demonstrated that lifestyle factors moderate the rate of clinical progression in neurodegenerative disease. This is attributed to cognitive reserve, a form of resilience where cognitive strategies help support brain functioning in the face of relentlessly accumulating pathology and thus modulate the rate of longitudinal decline. For example, neuroanatomic factors may also play a role in neural implementation of compensatory function, such as supporting alternate brain networks for optimal performance. Genetic factors associated with single nucleotide polymorphisms (SNPs) also may impact the variable rate of decline in bvFTD by selectively increasing anatomic network vulnerability to disease burden. The overall aim of this proposal is to better understand how lifestyle and genetic factors impact neural networks to influence the rate of longitudinal decline. In Aim 1, we will examine education, occupation and leisure activities that moderate the rate of longitudinal decline on cognitive and functional measures. We will relate this to MRI of gray matter (GM) and white matter (WM) using powerful graph theoretic analyses that examine key metrics of network connectivity and elucidate the neuroanatomic basis of resilience. Aim 2 will use arterial spin labeling to enhance models of network connectivity that predict the rate of longitudinal clinical decline, and expect to find key connectomic properties of frontal networks related to cerebral blood flow that contribute to resilience in bvFTD. In Aim 3, we will examine hypothesis-driven SNPs that may moderate the rate of clinical decline and relate SNP variation to anatomic regions in connectomic networks. This unique combination of lifestyle, genetic and imaging factors will lead to novel predictive models of clinical disease progression that are critical for clinical management and clinical trial endpoints, while providing important prognostic data for patients and families. !

项目概要行为变异性额颞叶变性（bvFTD）是年轻发病的常见原因神经退行性疾病的预期寿命约为 7 年，但这存在很大差异。最近的工作将认知和 MRI 成像的变化与累积 FTLD-TDP 的病理阶段联系起来 FTLD-Tau 病理学。然而，知识上的主要差距涉及到发生率的巨大变化。 bvFTD 的临床进展以及导致这种变异的因素。研究表明生活方式因素可调节神经退行性疾病的临床进展速度。这归因于认知储备，一种弹性形式，认知策略有助于支持大脑在面对困难时的功能不断积累病理，从而调节纵向下降的速度。例如，神经解剖学因素也可能在代偿功能的神经实现中发挥作用，例如支持替代大脑网络以获得最佳性能。与单核苷酸相关的遗传因素多态性 (SNP) 也可能通过选择性增加 bvFTD 的可变下降率来影响解剖网络对疾病负担的脆弱性。该提案的总体目标是更好地了解如何生活方式和遗传因素影响神经网络，从而影响纵向下降的速度。在目标 1 中，我们将审查减缓纵向下降速度的教育、职业和休闲活动认知和功能测量。我们将使用以下方法将其与灰质 (GM) 和白质 (WM) 的 MRI 联系起来强大的图论分析，可检查网络连接的关键指标并阐明弹性的神经解剖学基础。目标 2 将使用动脉自旋标记来增强网络模型连接性可预测纵向临床衰退率，并期望找到关键的连接组特性与脑血流相关的额叶网络有助于 bvFTD 的恢复能力。在目标 3 中，我们将检查可能减缓临床衰退速度的假设驱动的 SNP，并将 SNP 变异与连接体网络中的解剖区域。这种生活方式、遗传和影像因素的独特组合将产生新的临床疾病进展预测模型，这对于临床管理和临床试验终点，同时为患者和家庭提供重要的预后数据。！