Journal Article

DZNE-2026-00826

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The ILLUMINATE natural history study in colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia.

Lynch, D. S. ; Wade, C. ; Schöls, L.DZNE* ; Hayer, S. N.DZNE* ; Gelfand, J. M. ; Köhler, W. ; Bergner, C.-C. ; de Souza, P. V. S. ; Finger, E. C. ; Wolf, N. I. ; Beerepoot, S. ; Orthmann-Murphy, J. L. ; Chmiela, T. ; Rajagovindan, R. ; McLaren, D. G. ; Gaudreault, F. ; Mirescu, C. ; Raitcheva, D. ; Meier, A. ; Gray, D. ; Chavez, J. ; Kaufmann, P. ; Wszolek, Z. K.

2026
Oxford University Press [Oxford]

This record in other databases:    

Please use a persistent id in citations: doi:10.1093/braincomms/fcag271

Abstract: Colony-stimulating factor 1 receptor-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (CSF1R-ALSP) is a rare, fatal, autosomal-dominant neurodegenerative disorder caused by pathogenic CSF1R variants and characterized by progressive cognitive, neuropsychiatric, and motor dysfunction, white matter lesions on brain imaging, and white matter demyelination, swollen axons, and pigmented glial cells on pathology. Limited data regarding clinical, biofluid or radiological biomarkers of disease severity are available, and no clinical trial endpoints have yet been validated. The objectives of this first-of-its-kind, prospective, observational natural history study were to characterize the clinical trajectory of CSF1R-ALSP and to identify and evaluate key biomarkers and clinical endpoints indicative of disease severity and progression. ILLUMINATE (NCT05020743) was a multicentre, noninterventional natural history study of adults with CSF1R-ALSP and prodromal carriers of CSF1R variants. Participants were followed for up to 36 months, with clinical assessments, fluid biomarkers and volumetric MRI assessments of brain atrophy collected at screening and every 6 months. This study was terminated early (4 June 2025). The analyses reported here include data collected through 19 February 2025. Of 53 participants, 19 were prodromal and 34 were symptomatic (11 of whom had a history of haematopoietic stem cell transplant and 23 who did not). Mean participant age was 47.8 (standard deviation, 4.5) years, and 36.4% were female. Prodromal participants remained relatively stable over 36 months, with little change in neurological function, neurodegeneration biomarkers or radiological disease burden. Impaired neurological function, MRI characteristics of CSF1R-ALSP, and elevated NfL (neurofilament light chain; neurodegeneration biomarker) and GFAP (glial fibrillary acidic protein; astrogliosis biomarker) levels were more pronounced at baseline and often showed progression over time among symptomatic participants who had not previously received haematopoietic stem cell transplant compared with participants who had previously received haematopoietic stem cell transplant. Significant correlations were observed at baseline and longitudinally between MRI measures of brain atrophy and clinical outcome measures. Based on the fluid biomarkers, MRI measures, and clinical outcome assessments evaluated here, active neurodegeneration, widespread changes visualized on brain MRI, and impaired cognitive and motor function were observed in symptomatic patients with CSF1R-ALSP. The neurological impairment can be assessed using the Montreal Cognitive Assessment and Cortical Basal ganglia Functional Scale. Our data suggest that quantification of brain atrophy using MRI volumetry is a potential biomarker of disease severity and progression in CSF1R-ALSP. It is hoped that this report will contribute to the understanding of disease progression in CSF1R-ALSP and inform future drug development.

Keyword(s): CSF1R-related leukoencephalopathy ; hereditary diffuse leukoencephalopathy with spheroids ; leukodystrophy ; magnetic resonance imaging ; primary microgliopathy

---

Contributing Institute(s):

1. Clinical Neurogenetics (AG Schöls)
2. Cell Biology of Neurological Diseases (AG Jucker)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)
2. 352 - Disease Mechanisms (POF4-352) (POF4-352)

---

Database coverage:
; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Emerging Sources Citation Index ; Fees ; IF < 5 ; JCR ; SCOPUS ; Web of Science Core Collection

---