Brain Volume Loss Correlation with Clinical Severity and Progression in Individuals with CSF1R-ALSP: Findings from the ILLUMINATE Prospective Natural History Study
David Lynch1, Jeffrey Gelfand2, Nicole Wolf3, Wolfgang Koehler4, Caroline Bergner4, Ludger Schols5, Stefanie Hayer5, Elizabeth Finger6, Jennifer Orthmann Murphy7, Andreas Meier8, Charles Wade1, Gheorghe Doros9, Donald McLaren10, Rajasimhan Rajagovindan10, Petra Kaufmann10, Zbigniew Wszolek11
1University College London, 2University of California, San Francisco, 3Amsterdam University Medical Centers, 4University of Leipzig Medical Center, 5Tübingen University Hospital, 6Western University, 7Hospital of the University of Pennsylvania, 8Formerly Vigil Neuroscience, Inc., 9Boston University, 10Vigil Neuroscience, Inc., 11Mayo Clinic- Jacksonville
Objective:
To examine whether brain volume loss measured by MRI is associated with clinical severity and progression over time in individuals with CSF1R-ALSP.
Background:
CSF1R-ALSP is a rare, autosomal-dominant, neurodegenerative disorder caused by colony-stimulating factor-1 gene (CSF1R) loss-of-function mutations and characterized by brain white matter demyelination, swollen axons, pigmented glial cells, and brain atrophy. Clinical symptoms include cognitive, neuropsychiatric, and motor dysfunction. Average age at onset is in the 4th decade. No approved therapies available.
Design/Methods:
ILLUMINATE (NCT05020743) is the first prospective, multi-center natural history study (NHS) in individuals with CSF1R-ALSP (symptomatic or prodromal). Participants are followed for up to 36 months with Clinical and MRI evaluations at baseline and every 6 months thereafter. Clinical assessments include Montreal Cognitive Assessment (MoCA) and Cortical Basal Ganglia Functional Scale (CBFS). Brain atrophy is measured via regional brain volume measures of ventricle, gray matter, and corpus callosum quantified from MRI. Correlation between MRI measures and clinical scales are examined.
Results:
Data from 42 participants (24 symptomatic and 18 prodromal) with confirmed CSF1R mutations was analyzed. Participants were sub-grouped by quartiles of baseline MoCA/CBFS, the most impaired quartile of participants had the least brain volume (e.g., larger ventricles, less gray matter, and smaller corpus callosum) at study baseline. When participants who showed clinical decline over time were compared to those stable or improved, participants with clinical decline had greater brain volume loss on all MRI measures. Statistically significant correlations between 12-month change from baseline in MoCA and MRI evaluations were observed (ventricles, r=-0.65; gray matter volume, r=0.58; and corpus callosum, r=0.62). Directionally consistent findings were observed between CBFS and MRI measures.
Conclusions:
Brain volume loss measured by MRI is associated with disease severity and progression in CSF1R-ALSP. This biomarker may be a sensitive tool to measure treatment response on underlying neurodegeneration in interventional trials.
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