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

原发性进行性失语(PPA)临床研究标准可靠识别语义变异型PPA(SvPPA) 和非流利/无语法变体PPA(Nappa)。虽然从统计学上讲与潜在的病理有关， 无论是这些标准还是区域性MRI萎缩都不能可靠地支持额颞叶的活体诊断 散发性FTLD-TDP或FTLD-Tau患者的退行性变(FTLD病理)。我们建议确定 对两者都敏感的宏观网络指标和超高分辨率7特斯拉(7T)MRI配置文件 散发性PPA变异的局部解剖特征和皮质层特征，我们验证了我们的发现 在尸检确诊病例和已知的家族性FTLD(FFTLD)突变携带者的死前成像中 病理学。我们在三个具体目标中追求这些目标。Aim 1检验多模式3T的假设 结构磁共振成像(SMRI)和扩散加权磁共振成像(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均敏感 疾病，并在散发性尸检病例的生前MRI和fFTLD中评估相同的特征 突变载体分别为FTLD-TDP和FTLD-Tau。我们还将降级的网络功能与 可以筛查疾病的廉价的有针对性的语言措施。这一假说是基于 我们的临床病理系列，显示FTLD-TDP具有前颞部和眼眶额部病变 与相同区域的sMRI萎缩有关，通常在svPPA伴命名受损，病理是 浅层密度较高；相比之下，FTLD-Tau的额下部和中额部病变与 SMRI萎缩，常见于说话不流利的枕骨，病理表现为椎板较深处密度较大。在……里面 目的2，我们检验这样的假设，即进展性疾病的部分不同的指标在纵向上可见， 零星的svPPA和nappa的多模式3T MRI网络，这些与网络指标部分重叠 在与FTLD-TDP和FTLD相关的尸检PPA和FFTLD病例的生前纵向成像中， 分别为Tau和Tau。Aim 3通过以下方式更直接地检查组合的层流和局部解剖特征 超高分辨率7T磁共振在PPA和FFTLD中的应用7T核磁共振有望识别出相对 散发性svPPA与Nappa患者及伴有FFTLD的FFTLD患者的皮质板层和白质(WM)特征明显 FTLD-TDP与FTLD-Tau病理分别比较，这些将与区分网络部分重叠 在3T找到的指标。这是基于尸检病例的体外7T核磁共振显示的初步结果 相对明显的病理决定的皮质板层和WM特征：FTLD-TDP病理在 皮质浅层，而FTLD-Tau病理较深层密度高，有较大的 WM病理学。新颖的、以病理为导向的皮质层特征，结合局部解剖标记， 将为体内区分FTLD-TDP和FTLD-Tau的创新方法奠定基础，并导致 疾病改良治疗试验迫切需要疾病进展的纵向标志。

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.