PROJECT SUMMARY The overarching goal of this proposal is to advance the clinical trial readiness of candidate magnetic resonance imaging (MRI) biomarkers of disease progression in Charcot-Marie-Tooth (CMT) disease type 1A (CMT1A), a dysmyelinating inherited neuropathy with secondary axonal loss. Although promising treatments for CMT1A are on the horizon, the evaluation of therapies in human trails is hindered by a lack of responsive biomarkers, which is critical due to the slowly progressive nature of CMT1A. The CMT neuropathy score (CMTNS) is a composite disability score proposed as a biomarker of CMT; however, the limited responsiveness of the CMTNS annually demands a formidably large sample size for use in CMT clinical studies. More recently, in- tramuscular fat percentage (via fat-water MRI) has been proposed as a more sensitive biomarker. Unfortunate- ly, fat replacement represents the chronic endpoint of CMT1A; therefore, it may be difficult to evaluate thera- pies that slow or halt (rather than reverse) progression in muscles that are already denervated using this measure. Based on our developed nerve MRI methods, we hypothesize that directly imaging the pathology of interest within nerves themselves may offer complementary information and improve our ability to monitor disease progression in patients with CMT1A. Published results from our labs indicate that sciatic nerve mag- netization transfer ratios (MTR), which are sensitive to myelin content changes from de/dysmyelination and axonal loss, relate to disability across CMT subtypes, and additional preliminary data indicate that nerve MTRs are responsive to disease progression. More recent preliminary and published data indicate that MRI- based nerve diameter estimates may be a specific biomarker of CMT1A. Together, these results indicate that nerve MRI may yield viable biomarkers of CMT; however, questions remain regarding: i) the relative respon- siveness of potential biomarkers based on nerve MRI (MTR and diameter) and muscle MRI (intramuscular fat); ii) the relationships between these candidate biomarkers and function (CMTNS, dynamometry), electrophysi- ology (nerve conduction studies, NCS), pathology (skin biopsy), and quality-of-life in the same cohort; and iii) whether imaging biomarkers of nerve/muscle yield reliable results across sites and vendors for use in future trials. We aim to address these gaps via the following aims: 1) determine the responsiveness of MRI-derived nerve MTR, nerve diameter, and intramuscular fat percentage values to disease progression in patients with CMT1A and 2) determine the inter-site and inter-vendor reproducibility and repeatability of nerve MTR, nerve diameter, and intramuscular fat percentage values. This proposal builds upon existing expertise of the teams at Wayne State and the Barrow Neurological Institute and is designed for each aim to be undertaken in parallel with coordinated effort across sites. If successful, these studies will provide responsive imaging biomarkers of CMT1A progression for future trials, which is critical due to the inverse relationship between responsiveness and the sample size needed to power clinical trials in this rare neurological disorder.

PROJECT NARRATIVE Significant progress has been made toward a treatment for Charcot-Marie-Tooth disease Type 1A (CMT1A) diseases, a dysmyelinating inherited neuropathy with secondary axonal loss; however, translation of these treatments into patients with CMT1A is hindered by a lack of sensitive and objective biomarkers of disease progression and treatment response. We propose to develop and evaluate innovative magnetic resonance im- aging methods of peripheral nerves and skeletal muscle to overcome this limitation. If successful, these new strategies could objectively evaluate new treatments for CMT1A in future clinical trials.