Natural History of Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP): A Retrospective Patient Cohort Study

INTRODUCTION: Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, progressive, fatal neurodegenerative disorder caused by pathogenic CSF1R gene variants, resulting in microglial dysfunction and neurodegeneration. In patients with CSF1R-ALSP, brain magnetic resonance imaging (MRI) shows early white matter lesions followed by brain atrophy accompanied by progressive cognitive, neuropsychiatric, and motor dysfunction. However, the natural history (NH) of this disease is not yet fully understood. METHODS: This study examined clinical features, brain MRI findings, and fluid biomarkers in a cohort of 16 symptomatic adults from Germany with genetically confirmed CSF1R-ALSP using a retrospective chart review to evaluate changes in symptoms and imaging during disease progression. RESULTS: In this cohort, median age of symptom onset was 45 years and disease duration varied widely (2‒15 years). The most common presenting clinical symptoms were cognitive impairment (81% of patients) and aphasia (63% of patients), which progressed rapidly over 24 months of observation. Scores for the Montreal Cognitive Assessment and the Barthel Index of independence in performing activities of daily living declined sharply during the observational period. MRI data showed white matter degeneration and brain atrophy accompanied by increased ventricular volume with significant annual progression. Significant correlations were observed between key volumetric MRI measures and clinical outcome assessments of cognition and functional independence. CONCLUSION: This retrospective study provides qualitative and quantitative data from the clinical setting for further characterization of the NH of CSF1R-ALSP, a rare neurological disorder with significant unmet medical need. Data will inform the design of and endpoint selection for future NH studies and interventional clinical trials, which will be central to the development of safe and efficacious therapies for CSF1R-ALSP. Further, it will guide clinicians less familiar with the disease in providing patients and caregivers with appropriate support and information about CSF1R-ALSP.