Chmiela, Tomasz

ABSTRACT Objective This study aims to identify both fluid and neuroimaging biomarkers for CSF1R‐RD that can inform the optimal timing of treatment administration to maximize therapeutic benefit, while also providing sensitive quantitative measurements to monitor disease progression. Methods Our study compared neuroimaging and fluid (plasma and cerebrospinal fluid (CSF)) biomarkers across three distinct populations: asymptomatic CSF1R pathogenic variant carriers ( N = 14), symptomatic CSF1R pathogenic variant carriers ( N = 17), and healthy controls ( N = 30). We evaluated biomarker correlations with both an established (Montreal Cognitive Assessment (MoCA)) and a novel (CSF1R Clinical Severity Score (CCSS)) clinical diagnostic scale to investigate potential clinical utility. Additionally, we tested the relationship between select biomarkers and cortical thickness using 3D T1‐weighted MPRAGE scans, providing a highly valuable physiological component to our analyses. Results Our results demonstrate that while plasma glial fibrillary acidic protein (GFAP) displays a high sensitivity for distinguishing early‐stage CSF1R‐RD patients from healthy controls, plasma neurofilament light chain (NfL) is more effective for tracking disease progression following the onset of symptoms. Interpretation Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R‐RD.

Abstract Background Colony stimulating factor 1 receptor–related disorder (CSF1R‐RD) is a rare, rapidly progressive neurodegenerative disease with significant clinical heterogeneity. Apolipoprotein E (ApoE) polymorphism, known to modulate microglial function and influence neurodegeneration, may act as a genetic modifier in CSF1R‐RD. Objectives The objectives were to evaluate the distribution of ApoE alleles in CSF1R‐RD and assess their association with clinical and neuropathological features. Methods ApoE genotyping was performed in 55 individuals with CSF1R‐RD. Clinical data from 25 deceased patients were analyzed based on ApoE genotype. Neuropathological evaluation was conducted on brain tissue from 14 patients, with semiquantitative scoring of white matter pathology and microglial burden. Statistical comparisons were made between carriers and noncarriers of the ApoE4 allele. Results ApoE allele frequencies in CSF1R‐RD mirrored those of the general population (ε2: 7.3%, ε3: 79.1%, ε4: 13.6%). However, ApoE4 carriers exhibited significantly earlier symptom onset (median: 37.9 vs. 50.3 years, p = 0.0123) and death (median: 41.1 vs. 55.2 years, p = 0.0072). Neuropathological analysis revealed more severe white matter involvement and reduced microglial preservation in ApoE4 carriers ( p = 0.034). Conclusions Although ApoE allele distribution does not differ from the general population, the presence of the ApoE4 allele may influence the clinical trajectory and white matter pathology in CSF1R‐RD. These findings suggest that ApoE polymorphism is a potential modifier of disease course and should be considered in therapeutic planning and future research. © 2026 International Parkinson and Movement Disorder Society.

Objective Colony-stimulating factor-1 receptor (<i>CSF1R</i>)-related disorder (CSF1R-RD) is a rapidly progressive neurodegenerative disease with a median onset of 43 years. More than 200 <i>CSF1R</i> pathogenic variants have been identified. Patients develop rapidly progressive dementia and motor symptoms, with a median disease duration of 6.8 years. The p.R777Q variant causes CSF1R-RD; it is deleterious to protein function. We describe the clinical and pathological features of CSF1R-RD associated with p.R777Q and report a new family carrying this variant. We compare the neuropathological findings of an index patient (with short-duration disease) with those of a patient with long-duration CSF1R-RD.Methods We present clinical and imaging data from a new family with p.R777Q. We also describe the neuropathology of an index patient and contrast these findings with features of a patient with CSF1R-RD with an 11-year disease course caused by the c.2656_2657insC variant.Results We reviewed the literature on 13 individuals from 8 families with the p.R777Q variant from Asia, Europe, and North America. The mean age at onset was 41±14 years, ranging from 22 to 63 years, and the mean survival was 3.3±2.5 years. Neuropathologic studies of our index patient (10-month disease duration) revealed features consistent with CSF1R-RD. Axonal and myelin pathology was severe in the periventricular white matter. Compared with the patient with an 11-year disease duration, the index patient had less severe white matter lesions.Conclusion Compared with CSF1R-RD associated with other variants, the p.R777Q variant has an aggressive course. Compared with the patient with a long disease duration, the index patient had milder neuropathological findings. These differences may be specific to p.R777Q or associated with rapid clinical progression.