Frontotemporal dementia

We hypothesize that each protienopathy associated with clinical FTD syndromes (i.e. FTLD-Tau, FTLD-TDP and AD – Figure 2) have distinct neuropathological patterns of neurodegeneration, both at a microscopic level and macroscopic regional distribution in the brain. We propose that these features can be used to develop tissue-specific imaging and biofluid biomarkers that can eventually be used in living patients to diagnose underlying neuropathologic diagnosis which is urgently needed for clinical trials. Indeed, using our digital histopathological measures we find divergent postmortem patterns of tau and TDP-43 pathology in grey and white matter across hemispheres in patients with bvFTD and PPA (Figure 3). We can use these digital metrics of microscopic disease burden to model disease propagation in the human brain using complementary approaches of network science (Figure 4) and mediation analyses (Figure 5). These data suggest a unique contribution of white matter disease in the spread of FTLD-Tau compared to FTLD-TDP. These human brain models of progressive disease will inform novel imaging biomarkers to detect and track FTLD proteinopathy in living patients.

We also perform ultra-high resolution ex vivo 7T MRI imaging of the intact hemispheres. Using this approach we recently discovered distinct patterns of iron-rich gliosis in FTLD-Tau compared to FTLD-TDP (Figure 6) We can eventually adapt these sequences to perform a “virtual biopsy” using 7T MRI in living patients. 

We hypothesize that each protienopathy associated with clinical FTD syndromes (i.e. FTLD-Tau, FTLD-TDP and AD – Figure 2) have distinct neuropathological patterns of neurodegeneration, both at a microscopic level and macroscopic regional distribution in the brain. We propose that these features can be used to develop tissue-specific imaging and biofluid biomarkers that can eventually be used in living patients to diagnose underlying neuropathologic diagnosis which is urgently needed for clinical trials. Indeed, we find divergent postmortem patterns of tau and TDP-43 pathology in grey and white matter across hemispheres in patients with bvFTD (Figure 3) and PPA (Figure 4), and our microscopic digital measures of pathology relate to antemortem structural imaging, suggesting an integrative approach to relate antemortem imaging to postmortem pathology will reveal novel insights into the patterns of spread of these distinct proteinopathies to cause clinical FTD. Please see our publications below which highlight our recent findings to support this overarching hypothesis.