Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)
Jeffrey Gelfand1, David Lynch2, Charles Wade3, Nicole Wolf4, Wolfgang Koehler5, Caroline Bergner5, Ludger Schols6, Stefanie Hayer6, Elizabeth Finger7, Jennifer Orthmann Murphy8, Spyros Papapetropoulos9, Benjamin Matys10, Donald McLaren10, Andreas Meier10, Rajasimhan Rajagovindan10, Zbigniew Wszolek11
1University of California, San Francisco, 2National Hospital for Neurology & Neurosurgery; UCL Institute of Neurology, 3University College London, 4Amsterdam University Medical Centers, 5University of Leipzig Medical Center, 6Tübingen University Hospital, 7Western University, 8Hospital of the University of Pennsylvania, 9Formerly Vigil Neuroscience, Inc., 10Vigil Neuroscience, Inc., 11Mayo Clinic, Jacksonville
Objective:
Report clinical, biomarker, and MRI findings from ILLUMINATE, the first NHS in individuals with ALSP (NCT05020743).
Background:
ALSP is a rare, autosomal-dominant, neurodegenerative disorder caused by a colony-stimulating factor-1 gene (CSF1R) mutation and characterized by brain white matter (WM) demyelination, swollen axons, and pigmented glial cells and clinical symptoms of cognitive, neuropsychiatric, and motor dysfunction, typically developing around 40 years of age. No approved therapies exist.
Design/Methods:
ILLUMINATE is a prospective, multicenter NHS of individuals with definitive or prodromal (satisfies genetic and radiologic but not full clinical symptom criteria) ALSP. Up to 50 enrollees will be followed for 24 months, with clinical assessments and MRI collected at screening and every 6 months. MRI ALSP severity score and WM lesion and regional brain volumes will be derived; blood and cerebrospinal fluid (CSF) disease biomarkers will be measured at specific visits.
Results:
As of September 2023, of 41 enrollees with a confirmed CSF1R mutation, 23 were symptomatic (mean±SD age, 45.2±9.5 years; 52.2% female) and 18 were prodromal (42.9±17.0 years; 47.8% female). Baseline WM lesion and ventricle volumes were higher in symptomatic vs prodromal participants, while total gray matter volume was lower. Longitudinally, greater expansion in WM lesion volume and ventricle volume and gray matter volume reduction were observed in symptomatic vs prodromal participants. Baseline soluble CSF1R was substantially reduced in prodromal and symptomatic participants vs healthy volunteers, indicating reduced microglial activity. CSF and serum levels of neurofilament light chain (NfL), a marker of neuroaxonal injury, were elevated multifold in symptomatic participants vs prodromal and healthy individuals. Longitudinal fluid biomarker and clinical data will be disclosed at the meeting.
Conclusions:
These ILLUMINATE findings demonstrate that MRI measures and NfL levels are sensitive markers of ALSP pathophysiology, with potential to inform optimal clinical endpoints and therapeutic intervention study design in ALSP and improve overall understanding of disease progression.