Chmiela, Tomasz

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.

Abstract Background Spinocerebellar ataxia type 3 (SCA3), the most common autosomal dominant ataxia, is driven by the accumulation of polyglutamine‐expanded (polyQ) ATXN3 proteins. While promising as biomarkers, their longitudinal trajectories across multiple biofluids remain poorly defined. Objectives To quantify polyQ ATXN3 levels in cerebrospinal fluid (CSF), plasma, and urine within a comprehensive cohort, utilizing serial measurements to map protein dynamics. Methods We employed a validated immunoassay to quantify polyQ ATXN3 in 97 symptomatic and 13 presymptomatic SCA3 patients, correlating levels with clinical features, ancestry, disease status, and longitudinal progression. Results Asian participants exhibited lower plasma but elevated urinary polyQ ATXN3 levels relative to other ancestries. While CSF levels were higher in symptomatic patients at baseline, they showed a significant longitudinal decline. Conclusions PolyQ ATXN3 is a viable multi‐biofluid biomarker. Declining CSF levels likely reflect neurodegeneration, supporting its role in tracking progression and emphasizing the need for ancestry‐based adjustment in trials. © 2026 International Parkinson and Movement Disorder Society.

Introduction Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) are progressive neurodegenerative disorders characterized by alpha-synuclein pathology. As current therapies largely target symptoms, there is a clear need for disease-modifying treatments. Emerging evidence links these disorders to glucose metabolism dysregulation, suggesting antidiabetic agents may hold therapeutic potential. Methods This was a prospective, randomized, double-blind pilot study involving 12 subjects with PD or DLB to evaluate the tolerability and preliminary effects of a dipeptidyl peptidase 4 (DPP4) inhibitor (sitagliptin 100 mg) vs. sodium glucose like transporter 2 (SGLT2) inhibitor (dapagliflozin 10 mg) over a 4-week period, compared to a placebo. We assessed changes in Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores, cognitive function, and autonomic biomarkers. Both sitagliptin and dapagliflozin were well-tolerated, with no adverse events. While no significant changes were observed in cognitive scores, a significant difference was found in the change from baseline for MDS-UPDRS part 1 ( P = 0.008), part 2 ( P = 0.020), and total scores ( P = 0.047) when comparing the three groups. Discussion The dapagliflozin group showed more favorable trends in MDS-UPDRS scores. Limitations include small study size and duration as well as all participants had PD except one subject in the DPP4 inhibitor group with DLB. This pilot study suggests that these inhibitors are safe in PD and DLB patients. The preliminary findings, particularly the trends in the dapagliflozin group, provide a basis for larger-scale, long-term studies to confirm these potential symptomatic benefits and explore disease-modifying effects. Clinical trial registration https://clinicaltrials.gov/study/NCT06263673 , identifier: NCT06263673.

Sleep disturbances are common in multiple sclerosis (MS) and contribute to increased symptom burden. Behavioral sleep hygiene practices are potentially modifiable factors influencing sleep and related symptoms, yet their role in MS remains insufficiently explored. This cross-sectional study comprised 175 MS patients. Sleep hygiene was assessed using a behavioral checklist covering a regular sleep schedule, avoidance of daytime naps, limitation of evening caffeine intake, reduced evening screen exposure, and optimization of the sleep environment. The instruments included the Fatigue Severity Scale (FSS), the Modified Fatigue Impact Scale (MFIS), the Athens Insomnia Scale (AIS), the Epworth Sleepiness Scale (ESS), and the Hospital Anxiety and Depression Scale (HADS). Higher sleep hygiene adherence was associated with lower daytime sleepiness (ESS: r = −0.18, p = 0.020), anxiety (HADS-A: r = −0.16, p = 0.034), and depression (HADS-D: r = −0.15, p = 0.047). Patients with higher adherence (score ≥ 3) demonstrated significantly lower MFIS, AIS, ESS, and HADS-D scores compared with those with lower adherence (all p < 0.05). Multivariate regression showed that sleep hygiene adherence was independently associated with lower MFIS (β = −3.24, 95% CI: −6.06 to −0.41, p = 0.025), ESS (β = −0.85, 95% CI: −6.06 to −0.41, p = 0.016), HADS-A (β = −0.67, 95% CI: −1.23 to −0.11, p = 0.019), and HADS-D scores (β = −0.62, 95% CI: −1.17; −0.08, p = 0.026). Better adherence to sleep hygiene practices may be associated with a lower symptom burden in MS.

Abstract Alzheimer's disease (AD) is neuropathologically defined by amyloid‐beta (Aβ) plaques and tau neurofibrillary tangles. However, co‐pathologies and other pathobiological processes are involved in the pathogenesis of AD, contributing to neurodegeneration and clinical symptoms. The most common co‐pathologies in people with AD are alpha‐synucleinopathy, vascular brain injury and transactive response DNA‐binding protein of 43 kDa‐related pathology. Neuroinflammation, iron accumulation, cholinergic dysfunction and cellular senescence are recognized pathobiological processes beyond Aβ‐ and tau‐related pathology. However, the exact mechanisms by which these co‐pathologies and pathobiological processes contribute to the neurodegeneration and clinical symptoms in people with AD remain unclear. The individual combination of these co‐pathologies and pathobiological processes increases phenotypical heterogeneity in people with AD. This highlights the unmet need to advance their current understanding, and the field strives to develop accurate biomarkers for personalized assessment and investigation. Elucidating this biologic‐clinical complexity and heterogeneity is crucial for increasing our current understanding of AD, with implications for diagnosis, prognosis and therapeutics.

Objective This longitudinal study evaluated the long-term efficacy and safety of hematopoietic stem cell transplantation (HSCT) in slowing the progression of CSF1R-related disorder (CSF1R-RD).Methods Six symptomatic patients (mean follow-up, 6.6 years) were compared with six matched, untreated controls. The CSF1R Clinical Severity Score (CCSS), Montreal Cognitive Assessment, and Sundal radiological score were used for evaluation.Results Post-HSCT clinical progression slowed significantly from 14.1 to 3.7 CCSS/year, compared with 15.2 CCSS/year in the control group (p<0.01). Cognitive decline was substantially reduced (-1.5 points/year vs. -7.6 points/year), and radiological deterioration slowed (0.4 per year vs. 3.9 per year). Notably, during the observation period, all HSCT patients survived, whereas 50% of the patients in the control group died. No serious transplant-related complications were observed.Conclusion HSCT is a potent disease-modifying therapy for CSF1R-RD that drastically improves survival and slows deterioration. These findings underscore the necessity of early intervention during the symptomatic phase to maximize the preservation of quality of life for affected individuals.