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.
