Connectome and 7T MRI reflect pathologic networks in sporadic primary progressive aphasia and familial FTLD

连接组和 7T MRI 反映散发性原发性进行性失语症和家族性 FTLD 的病理网络

• 批准号: 10261340
• 负责人: MURRAY GROSSMAN
• 金额: $ 27.89万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 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/10261340
• 关键词: Aging; Anatomy; Anterior; Area; Atrophic; Autopsy; Cells; Characteristics; Clinical; Clinical Research; Communities; Complex; Diagnosis; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Disease Marker; Disease Progression; Frontotemporal Lobar Degenerations; Goals; Graph; Heterogeneity; Image; Impairment; Individual; Inferior; Lead; Linguistics; Link; Magnetic Resonance Imaging; Measures; Methods; Names; Network-based; Pathologic; Pathology; Pathway Analysis; Pattern; Primary Progressive Aphasia; Progressive Disease; Publishing; Regional Anatomy; Resolution; Semantics; Series; Spectrum Analysis; Speech Pathology; Structure; Syndrome; Testing; Variant; Work; base; connectome; density; frontotemporal degeneration; in vivo; innovation; longitudinal analysis; multimodality; mutation carrier; novel; screening; serial imaging; tau Proteins; treatment trial; ultra high resolution; white matter

Clinical research criteria for primary progressive aphasia (PPA) reliably identify semantic variant PPA (svPPA) and non-fluent/agrammatic variant PPA (naPPA). While statistically associated with underlying pathology, neither these criteria nor regional MRI atrophy reliably support in vivo diagnosis of frontotemporal lobar degeneration (FTLD pathology) in an individual with sporadic FTLD-TDP or FTLD-Tau. We propose to identify macroscale network metrics and ultra-high resolution 7 tesla (7T) MRI profiles that are sensitive to both regional anatomic features and cortical laminar features in sporadic PPA variants, and we validate our findings in antemortem imaging of autopsy-confirmed cases and in familial FTLD (fFTLD) mutation carriers with known pathology. We pursue these goals in three Specific Aims. Aim 1 tests the hypothesis that multimodal 3T structural MRI (sMRI) and diffusion-weighted MRI (dMRI) networks show distinct graph theoretic metrics in sporadic svPPA and naPPA that are sensitive to both regional anatomic and laminar-specific features of disease, and assesses the same features in antemortem MRI of sporadic autopsied cases and in fFTLD mutation carriers with FTLD-TDP and FTLD-Tau, respectively. We also relate degraded network features to inexpensive targeted linguistic measures that can screen for disease. This hypothesis is based on findings in our clinical-pathological series, showing that FTLD-TDP has anterior temporal and orbital frontal pathology related to sMRI atrophy in the same regions, often in svPPA with impaired naming, and that pathology is denser in superficial laminae; by comparison, FTLD-Tau has inferior frontal and midfrontal pathology related to sMRI atrophy, often in naPPA with non-fluent speech, and pathology is relatively denser in deeper laminae. In Aim 2, we test the hypothesis that partially distinct metrics of progressive disease are seen in longitudinal, multimodal 3T MRI network of sporadic svPPA and naPPA, and that these overlap in part with network metrics in antemortem longitudinal imaging of autopsied PPA and fFTLD cases associated with FTLD-TDP and FTLD- Tau, respectively. Aim 3 examines combined laminar and regional anatomic features more directly by assessing ultrahigh resolution 7T MRI in PPA and fFTLD cases. 7T MRI is expected to identify relatively distinct cortical laminar and white matter (WM) features in sporadic svPPA vs. naPPA, and in fFTLD with FTLD-TDP vs. FTLD-Tau pathology, respectively, and these will overlap in part with distinguishing network metrics found at 3T. This is based on preliminary findings that ex vivo 7T MRI of autopsied cases shows relatively distinct, pathology-determined cortical laminar and WM features: FTLD-TDP pathology is denser in superficial cortical laminae, while FTLD-Tau pathology is relatively denser in deeper laminae and has greater WM pathology. Novel, pathology-guided, cortical laminar features, combined with regional anatomic markers, will lay the groundwork for innovative methods to distinguish FTLD-TDP from FTLD-Tau in vivo, and lead to longitudinal markers for disease progression urgently needed for disease-modifying treatment trials.

原发性进行性失语（PPA）的临床研究标准可靠地识别语义变体PPA（svPPA） 和非流利/语法变体PPA（naPPA）。虽然与潜在病理学有统计学关联， 这些标准和局部MRI萎缩都不能可靠地支持额颞叶的活体诊断 在一些实施方案中，本发明提供了在患有散发性FTLD-TDP或FTLD-Tau的个体中的变性（FTLD病理学）的方法。我们建议确定 宏观网络指标和超高分辨率7特斯拉（7 T）MRI配置文件，对两者都敏感 区域解剖特征和皮质层状特征，我们证实了我们的研究结果 在尸检证实病例的死前成像中，以及在已知的家族性FTLD（fFTLD）突变携带者中， 病理我们在三个具体目标中追求这些目标。目的1检验多模式3 T 结构MRI（sMRI）和弥散加权MRI（dMRI）网络显示了不同的图论度量， 散发性svPPA和naPPA对局部解剖和椎板特异性特征敏感， 疾病，并评估了相同的功能，在生前MRI的零星尸检案件和fFTLD 分别用FTLD-TDP和FTLD-Tau突变携带者。我们还将降级的网络特征与 廉价的有针对性的语言措施，可以筛查疾病。这一假设是基于 我们的临床病理系列，显示FTLD-TDP具有前颞和眶额病变 与相同区域的sMRI萎缩相关，通常在命名受损的svPPA中，并且病理学是 在浅层中密度更大;相比之下，FTLD-Tau具有与以下相关的下额叶和中额叶病理学： sMRI萎缩，常发生在言语不流利的naPPA中，并且病理学在更深的椎板中相对更密集。在 目的2，我们检验了这样的假设，即在纵向上观察到进展性疾病的部分不同指标， 多模态3 T MRI网络的零星svPPA和naPPA，这些重叠部分与网络指标 在与FTLD-TDP和FTLD相关的尸检PPA和fFTLD病例的死前纵向成像中， Tau，分别。目的3通过以下方法更直接地检查椎板和局部解剖特征 评估PPA和fFTLD病例的高分辨率7 T MRI。7 T MRI有望识别相对 在散发性svPPA与naPPA中，以及在fFTLD中，具有不同的皮质层状和白色物质（WM）特征， FTLD-TDP vs. FTLD-Tau病理学，这些将与区分网络部分重叠， 在3 T上发现的指标。这是基于尸检病例的体外7 T MRI显示的初步发现， 相对明显的、病理学确定的皮质层状和WM特征：FTLD-TDP病理学在 FTLD-Tau病理学在更深层中相对更致密，并且具有更大的 WM病理学。新的、病理学引导的皮质层状特征，结合局部解剖标记， 将为在体内区分FTLD-TDP与FTLD-Tau的创新方法奠定基础，并导致 疾病进展的纵向标志物是疾病改善治疗试验迫切需要的。