Judith A. Dunmore

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.

Colony-stimulating factor 1 receptor-related disorder (CSF1R-RD) is a neurodegenerative condition characterized by rapid progression, leading to profound functional decline and ultimately resulting in a persistent vegetative state. Although an effective treatment option exists, there remains a lack of identified biomarkers capable of monitoring disease progression and detecting the earliest symptom onset in CSF1R pathogenic variant carriers, limiting the ability of clinicians to make informed decisions regarding patient care. 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. 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. 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. Overall, our study provides evidence for plasma NfL and GFAP as valuable biomarkers of earliest symptom onset and disease progression for CSF1R-RD One Sentence Summary: This study identifies plasma biomarkers NfL and GFAP as promising tools to detect CSF1R-RD onset and progression, with potential to improve patient outcomes.

Spinocerebellar ataxia type 7 (SCA7), a rare form of ataxia, possesses a wide phenotypic spectrum ranging from classic ataxic symptoms to blindness, multiorgan failure, cardiomyopathy, and early death among younger age groups. Biomarkers associated with disease progression and severity could aid in disease prognostication. We evaluated the utility of glial fibrillary acidic protein (GFAP) and neurofilament light (NfL) in distinguishing patients with SCA7 from healthy controls and estimating patient prognosis. GFAP and NfL levels were measured in 23 plasma and 20 cerebrospinal fluid (CSF) samples from asymptomatic (N = 3) and symptomatic SCA7 participants (N = 10) and from healthy controls (N = 8). GFAP concentrations were elevated in the plasma (82.7 pg/mL) and CSF (9318 pg/mL) of patients with SCA7 compared to controls (plasma: 48.0 pg/mL; CSF: 89,056 pg/mL). Similarly, NfL plasma (21.6 pg/mL) and CSF (2615.0 pg/mL) levels were also significantly upregulated in SCA7 compared to controls (plasma: 8.2 pg/mL; CSF: 414.6 pg/mL). Higher levels of NfL, but not of GFAP, significantly discriminated symptomatic SCA7 patients from controls (area under de curve, AUC: 0.898, p = 0.0059, in plasma, and AUC: 1.0, p = 0.0012, in CSF). The levels of both biomarkers increased overtime, with plasma NfL levels strongly associated with a worse score in the scale for the assessment and rating of ataxia (SARA) (Spearman r: 0.8354, p = 0.0007; regression analysis: β: 0.021, 95% CI: 0.008–0.035, p = 0.0048). These findings suggest that NfL could serve as a valuable biomarker for monitoring disease progression and prognosis in SCA7 patients.

Frontotemporal dementia and amyotrophic lateral sclerosis (FTD-ALS) are associated with both a repeat expansion in the C9orf72 gene and mutations in the TANK-binding kinase 1 ( TBK1 ) gene. We found that TBK1 is phosphorylated in response to C9orf72 poly(Gly-Ala) [poly(GA)] aggregation and sequestered into inclusions, which leads to a loss of TBK1 activity and contributes to neurodegeneration. When we reduced TBK1 activity using a TBK1-R228H (Arg ²²⁸ →His) mutation in mice, poly(GA)-induced phenotypes were exacerbated. These phenotypes included an increase in TAR DNA binding protein 43 (TDP-43) pathology and the accumulation of defective endosomes in poly(GA)-positive neurons. Inhibiting the endosomal pathway induced TDP-43 aggregation, which highlights the importance of this pathway and TBK1 activity in pathogenesis. This interplay between C9orf72 , TBK1 , and TDP-43 connects three different facets of FTD-ALS into one coherent pathway.

Hospitalized patients with COVID-19 show increased serum concentrations of neurofilament light chain that correlate with worse clinical outcomes.

PolyQ ATXN3 is a pharmacodynamic marker for SCA3, and a SNP associated with the expanded allele may serve to specifically target mutant ATXN3 .