Imaging Iron-Rich Pathology to Monitor and Diagnose FLTD Subtypes

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PROJECT SUMMARY Frontotemporal lobar degeneration (FTLD) is a debilitating neurodegenerative disease that in almost all cases has one of two underlying proteinopathies – FTLD-tau and FTLD-TDP. To date MRI-based measures have not been able to reliably distinguish clinical syndromes or their underlying proteinopathies. A key feature of FTLD is the localized pattern of degeneration associated with various disease subtypes. These spatial patterns have been associated with clinical syndromes, as well as the underlying proteinopathies that are most-relevant for treatment studies. However, to date these patterns alone are not sufficiently specific to fully predict syndromes or separate FTLD-tau from FTLD-TDP in a single patient. We have recently shown that, in addition to atrophy, FTLD is associated with iron-rich cortical pathology. Moreover, our findings indicate that the specific cortical layers impacted by this pathology are distinct in FTLD-tau and FTLD-TDP, offering a potential target for the development of imaging biomarkers. We propose to use iron-sensitive MRI as the basis for the development of novel imaging biomarkers, with the aim of both monitoring disease progression and diagnosing underlying pathologic subtypes, addressing a highest priority recommendation of the 2019 ADRD Summit. We propose a two-pronged approach to this goal: First, we will use joint ex vivo MRI and histopathology in 50 human hemispheres, donated by patients with FTLD and typical age-matched controls, to quantify the distributions of iron-rich pathology. In particular, we will quantify both the laminar distribution and its relation to the patients’ underlying proteinopathies. In addition, we will evaluate the distribution of disease across the cortex, and associate this with clinical information collected during the patients’ lifetimes, including clinical syndrome and more fine-grained measures of symptoms. Second, we will use in vivo MRI at 3T and 7T with 100 FTLD patients an typical volunteers to develop and validate imaging protocols sensitive to the pathologic iron. At 3T, we will focus on quantifying the distribution of iron across the cortex. We will correlate these cortical findings with MRI-based measures of atrophy, and clinical measures including both symptoms and blood and CSF-based measures of degeneration and pathology. At 7T, we will develop and validate focal laminar imaging methods, with the aim of recapitulating our ex vivo findings in living patients and age-matched controls. The overall goal of this study is to develop and validate novel, iron-sensitive imaging biomarkers for FTLD to both monitor and diagnose underlying syndromes and pathologies. The ability to disciminate underlying proteinopathies is a key need in treatment trials which focus on either FTLD-tau or FTLD-TDP. Moreover, measuring the quantity and distribution of iron in the brain will also be valuable for monitoring disease progression, both in treatment trials, and more generally for FTLD patients in clinical care.