Tau and neurofilament light‐chain as fluid biomarkers in spinocerebellar ataxia type 3

Abstract

Background and purpose Clinical trials in spinocerebellar ataxia type 3 (SCA3) will require biomarkers for use as outcome measures. Methods To evaluate total tau (t‐tau), glial fibrillary acidic protein (GFAP), ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and neurofilament light‐chain (NfL) as fluid biomarkers in SCA3, ATXN3 mutation carriers (n = 143) and controls (n = 172) were clinically assessed, and the plasma concentrations of the four proteins were analysed on the Simoa HD‐1 platform. Eleven ATXN3 mutation carrier cerebrospinal fluid samples were analysed for t‐tau and phosphorylated tau (p‐tau181). A transgenic SCA3 mouse model (MJDTg) was used to measure cerebellar t‐tau levels. Results Plasma t‐tau levels were higher in mutation carriers below the age of 50 compared to controls, and the Inventory of Non‐Ataxia Signs was associated with t‐tau in ataxic patients (p = 0.004). Pre‐ataxic carriers showed higher cerebrospinal fluid t‐tau and p‐tau181 concentrations compared to ataxic patients (p = 0.025 and p = 0.014, respectively). Cerebellar t‐tau was elevated in MJDTg mice compared to wild‐type (p = 0.033) only in the early stages of the disease. GFAP and UCHL1 did not show higher levels in mutation carriers compared to controls. Plasma NfL concentrations were higher in mutation carriers compared to controls, and differences were greater for younger carriers. The Scale for the Assessment and Rating of Ataxia was the strongest predictor of NfL in ataxic patients (p < 0.001). Conclusion Our results suggest that tau might be a marker of early disease stages in SCA3. NfL can discriminate mutation carriers from controls and is associated with different clinical variables. Longitudinal studies are required to confirm their potential role as biomarkers in clinical trials.

The 2022 Lady Estelle Wolfson lectureship on neurofilaments

“…For SCA3, higher blood NfL levels were found in young mutation carriers (Garcia-Moreno et al, 2022).…”

“…The effect sizes were smaller for SCA1 ( n = 23) compared to healthy controls ( n = 25, 1.00; 95% CI 0.39–1.60); Friedreich ataxia ( n = 217) compared to healthy controls ( n = 62, 0.62; 95% CI 0.21–1.03) and SCA2 ( n = 16) compared to healthy controls ( n = 22, 0.59; 95% CI 0.27–0.91) (Peng et al, 2022). For SCA3, higher blood NfL levels were found in young mutation carriers (Garcia‐Moreno et al, 2022).…”

Blood neurofilament light chain levels are associated with disease progression in a transgenic SCA3 mouse model

“…Because clinical trials for SCA3 are routinely preceded by preclinical assays and interventions conducted in mouse models of this disease, it is essential that these models show biofluid biomarkers and biomarker changes like patients with SCA3. Hence, we sought to evaluate whether aged SCA3 YACQ84 transgenic mice expressing the full-length human ATXN3 disease gene (Cemal et al, 2002), frequently used in preclinical trials for SCA3 (Rodriguez-Lebron et al, 2013b, Ashraf et al, 2019, McLoughlin et al, 2018, Moore et al, 2017, Costa et al, 2013, replicate the increased blood NfL levels observed in patients with SCA3 (Wilke et al, 2020b, Li et al, 2019, Wilke et al, 2018, Peng et al, 2022, Garcia-Moreno et al, 2022, Coarelli et al, 2021.…”

“…In particular, NfL has been evidenced to hold notable value as a biomarker for SCA3. Patients with SCA3 exhibit significantly higher levels of NfL in serum, plasma, and CSF compared to healthy controls (Wilke et al, 2020b, Li et al, 2019, Peng et al, 2022, Garcia-Moreno et al, 2022, Coarelli et al, 2021, Prudencio et al, 2020, Wilke et al, 2018. Remarkably, SCA3 carriers in pre-ataxic stages also show increased abundance of NfL in biofluids with proximity to age of onset of clinical ataxia presentation (Wilke et al, 2020b).…”

Early Diagnosis of Alzheimer’s Disease: Moving Toward a Blood-Based Biomarkers Era

“…23 Furthermore, plasma t-tau elevation is not specific in AD, and is also found in several other neurodegenerative diseases. 24 CSF NfL is one of the most promising neurodegenerative biomarkers. Notably, plasma NfL corresponds well to CSF measures, making it a good blood-based biomarker.…”