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: 10454273
• 负责人: MURRAY GROSSMAN
• 金额: $ 27.9万
• 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/10454273
• 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; 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.

主要进行性失语症（PPA）的临床研究标准可靠地识别语义变异PPA（SVPPA） 和非氟/农业变体PPA（NAPPA）。虽然统计与潜在的病理相关，但 这些标准和区域MRI萎缩都不能可靠地支持额颞叶的体内诊断 具有零星FTLD-TDP或FTLD-TAU的个体中的变性（FTLD病理）。我们建议确定 宏观网络指标和超高分辨率7 Tesla（7T）MRI轮廓，对这两者都敏感 散发性PPA变体的区域解剖特征和皮质层流特征，我们验证了我们的发现 在尸检确认病例和家族性FTLD（FFTLD）突变携带者中的原始成像中 病理。我们以三个具体目标追求这些目标。 AIM 1检验了多模式3T的假设 结构性MRI（SMRI）和扩散加权MRI（DMRI）网络在不同的图中显示出独特的图理论指标 散发性SVPPA和NAPPA对区域解剖和层流特异性敏感 疾病，并评估偶发动体病例和FFTLD的原型MRI中的相同特征 具有FTLD-TDP和FTLD-TAU的突变载体。我们还将退化的网络功能与 可以筛查疾病的廉价目标语言措施。该假设基于 我们的临床病理学系列，表明FTLD-TDP具有前颞叶和轨道额叶病理 与同一地区的SMRI萎缩有关，通常在SVPPA中命名受损，该病理是 浅层薄片中的密集;相比之下，FTLD-TAU具有与 Smri萎缩通常在纳帕（Nappa）中带有非浮力语音，而病理学在更深的薄片中相对较密集。在 AIM 2，我们检验了以下假设：在纵向中可以看到进行性疾病的部分截然不同的指标， 散发性SVPPA和NAPPA的多模式3T MRI网络，这些网络与网络指标重叠 在载op型PPA和FFTLD病例的纵向成像中，与FTLD-TDP和FTLD相关 tau分别。 AIM 3检查层流和区域解剖功能的组合更直接 评估PPA和FFTLD病例中的超高分辨率7T MRI。 7T MRI预计将相对识别 零星的SVPPA与NAPPA中的独特皮质层层和白质（WM）特征，以及在FFTLD中 FTLD-TDP和FTLD-TAU病理学分别 在3T处发现的指标。这是基于初步发现，该发现表明尸体案件的体内7T MRI显示 相对不同的病理学确定的皮质层层和WM特征：FTLD-TDP病理学很密集 浅表皮质薄片，而ftld-tau病理学在更深的薄片中相对较密集，并且具有更大的状态 WM病理学。新颖的，病理引导的皮质层流特征，结合区域解剖标记， 将为将FTLD-TDP与ftld-tau区分开的创新方法奠定基础，并导致 疾病进展的纵向标志物急需进行疾病改良治疗试验。