Abstract Details

Title Findings from the ILLUMINATE Prospective Natural History Study (NHS) in Individuals with Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia (ALSP)

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P3 - Poster Session 3 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-001

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.

Objective Report clinical, biomarker, and MRI findings from ILLUMINATE, the first NHS in individuals with ALSP (NCT05020743).

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.

Authors/Disclosures
David S. Lynch, MBBS, PhD PRESENTER	Dr. Lynch has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vigil Neuroscience. Dr. Lynch has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Lynch has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Vigil Neuroscience.
Jeffrey M. Gelfand, MD, MAS, FAAN (University of California, San Francisco)	Dr. Gelfand has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arialys. Dr. Gelfand has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ventyx Bio. An immediate family member of Dr. Gelfand has received personal compensation in the range of $50,000-$99,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Headache: The Journal of Head and Face Pain. The institution of Dr. Gelfand has received research support from Genentech/Roche. The institution of Dr. Gelfand has received research support from Vigil Neurosciences. An immediate family member of Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has received publishing royalties from a publication relating to health care. Dr. Gelfand has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant and Expert, Vaccine Injury Compensation Program with United States Health and Human Services and Department of Justice. Dr. Gelfand has a non-compensated relationship as a Trial Steering Committee Chairperson and member with Roche / Genentech that is relevant to AAN interests or activities.
Charles L. Wade, MBBS	Dr. Wade has nothing to disclose.
Nicole Wolf	No disclosure on file
Wolfgang Koehler (University of Leipzig Medical Center)	Wolfgang Koehler has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Minoryx. Wolfgang Koehler has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vigil. Wolfgang Koehler has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for United Leukodystrophy Foundation. Wolfgang Koehler has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for European Leukodystrophy Association. The institution of Wolfgang Koehler has received research support from Minoryx. The institution of Wolfgang Koehler has received research support from Vigil. The institution of Wolfgang Koehler has received research support from SwanBio. The institution of Wolfgang Koehler has received research support from Alexion.
Caroline Bergner	No disclosure on file
Ludger Schols, MD (Eberhard-Karls-University)	Dr. Schols has received personal compensation in the range of $500-$4,999 for serving as a Consultant for VICO Therapeutics. Dr. Schols has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Schols has received research support from Vigil.
Stefanie Hayer (Charité - Universitätsmedizin Berlin)	No disclosure on file
Elizabeth Finger, MD, FAAN	Dr. Finger has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vigil Neuro. Dr. Finger has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Denali Therapeutics. The institution of Dr. Finger has received research support from CIHR. The institution of Dr. Finger has received research support from Physician Servcices Incorporated. The institution of Dr. Finger has received research support from Weston Foundation. Dr. Finger has received personal compensation in the range of $500-$4,999 for serving as a Annual Meeting Course Director with American Academy of Neurology.
Jennifer L. Orthmann Murphy, MD, PhD (Hospital of the University of Pennsylvania)	Dr. Orthmann Murphy has received personal compensation in the range of $0-$499 for serving as a Consultant for Vigil Neuroscience. Dr. Orthmann Murphy has received personal compensation in the range of $0-$499 for serving as a Consultant for NovoGlia. The institution of Dr. Orthmann Murphy has received research support from Vigil Neurosciences. The institution of Dr. Orthmann Murphy has received research support from National MS Society. The institution of Dr. Orthmann Murphy has received research support from Fishman Family Foundation. The institution of Dr. Orthmann Murphy has received research support from Global Leukodystrophy Initiative Clinical Trial Network. The institution of Dr. Orthmann Murphy has received research support from NINDS. The institution of Dr. Orthmann Murphy has received research support from Montague Investigator Award. Dr. Orthmann Murphy has received personal compensation in the range of $500-$4,999 for serving as a Developing CME content on Neurogenetics with American Neurological Association. Dr. Orthmann Murphy has received personal compensation in the range of $500-$4,999 for serving as a Faculty, Honoraria with CMSC.
Spyros Papapetropoulos	No disclosure on file
Benjamin Matys (Vigil Neuroscience)	No disclosure on file
Donald McLaren	No disclosure on file
Andreas Meier, MD	Dr. Meier has received personal compensation for serving as an employee of Vigil Neuroscience. Dr. Meier has received personal compensation for serving as an employee of Voyager Therapeutics. Dr. Meier has stock in Vigil Neuroscience. Dr. Meier has stock in Voyager Therapeutics.
Rajasimhan Rajagovindan, PhD (Vigil)	Dr. Rajagovindan has received personal compensation for serving as an employee of Biogen. Dr. Rajagovindan has received personal compensation for serving as an employee of Vigil. Dr. Rajagovindan has stock in Biogen. Dr. Rajagovindan has stock in Vigil .
Zbigniew K. Wszolek, MD, FAAN (Mayo Clinic- Jacksonville)	Dr. Wszolek has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Polish Neurological Society/Via Medica.