In preataxia individuals, serum neurofilament levels increased with proximity to predicted ataxia onset, with significant elevations already present 5 years before onset.
Among patients with spinocerebellar ataxia type 1 (SCA1), new data show increased blood levels of neurofilament light (NfL) not only at the ataxic, but in the preataxic stage, paralleled by increased NfL levels in the cerebrospinal fluid (CSF).1
Taken together, the findings indicate that serum NfL (sNfL) levels might serve as a biomarker for stratification of the preataxic stage, early neuronal decay at the preataxic stage, and potentially treatment response at the preataxic and ataxic stages in SCA1. Additionally, the study also provides preliminary sample size estimates for future trials of disease-modifying therapies in SCA1, with the reduction of increased sNfL levels used as a treatment response indicator.
Led by Carlo Wilke, MD, assistant doctor, University of Tubingen, the trial evaluated both sNfL and CSF NfL (cNfL) levels in 23 individuals with preataxic and 17 individuals with ataxic SCA1, with 89 additional healthy controls. Investigators observed, rather than only predicted, 11 individuals convert from the preataxic to ataxic stages. Levels of sNfL and cNfL were assessed by single-molecule array and ELISA technique, respectively.
At the conclusion of the study, sNfL levels were significantly increased in the ataxia group (median, 31.6 pg/mL; IQR, 26.2-37.7; U = 1666; z = 6.51; P <.001) and preataxic groups (median, 15.5 pg/mL; IQR, 10.5-21.1 pg/mL; U = 2091; z = 5.70; P <.001) compared with controls (median, 6.0 pg/mL; IQR, 4.7-8.6), yielding high age-corrected effect sizes (preataxic: r = 0.62; ataxic: r = 0.63).
cNfL levels at the preataxic (1030 pg/mL) and ataxic (median, 2971 pg/mL) stages were clearly above the age-specific normal range of controls. When compared to levels of controls of similar age (range, ±5 years), the cNfL increases were significant in both preataxic (V = 0; P = .002) and ataxic (U = 150; z = 3.51; P <.001) individuals with SCA1, yielding high effect sizes (preataxic: r = 0.48; ataxic: r = 0.62).
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SCA1 is caused by a translated CAG repeat expansion in the ATXN1 gene. After modeling the baseline sNfL levels with the predictor age and ATXN1 CAG repeat length, investigators found that for a given age, each increase in the CAG repeat count was associated with higher sNfL levels. For a given CAG repeat count, in turn, the sNfL level increased with age. Overall, both age (P <.001) and repeat length (P <.001) were highly significant predictors of sNfL level (F2,34 = 28.95; P <.001; adjusted R2 = 0.61).
The sNfL levels observed in individuals with SCA1 did not correlate with disease duration (p = 0.38; P = 0.169) despite the presence of clinical progression, supporting the notion that sNfL levels are biomarkers reflecting the rate of ongoing neuronal decay, whereby stable increases of sNfL levels might reflect stable progression at the ataxia stage of SCA1. Additionally, sNfL levels of ataxia individuals with SCA1 also did not correlate with clinical disease severity, as assessed by SARA (p = 0.08; P = .747), suggesting that sNfL levels do not reflect clinical disease severity.
When stratifying preataxic individuals by sNfL levels, the median time to predicted ataxia onset was 5.3 years in those with high sNfL levels (>15.5 pg/mL) compared with 12.7 years for those with low sNfL levels (<15.5 pg/mL; X2 = 8.0; log-rank test, P = .005). For preataxic individuals with high sNfL levels, the hazard for developing ataxia at any given time was almost 3 times as high for individuals with low sNfL levels (HR, 3.58; 95% CI, 1.40-9.11; P = .008).
"Our longitudinal assessment of sNfL levels shows that intraindividual biological variation of sNfL levels is likely only a minimal source of noise in observation and intervention trials of SCA1," Wilke et al wrote. "The use of sNfL levels as an outcome variable might thus help to reduce trial sample sizes compared to clinical and other surrogate outcome measures.For instance, our estimates suggest that a total sample size of 14 individuals would suffice to detect therapeutic effect sizes of 50% at the ataxic stage of SCA1."