Association Between Serum Neurofilament Light Chain and Neurochemistry Deficits in Patients with Spinocerebellar Ataxia Type 3

Abstract

Extensive evidence supports the claim that serum neuro lament light chain (sNfL) can be used as a biomarker for monitoring disease severity in patients with spinocerebellar ataxia type 3 (SCA3). However, little is known about the associations between sNfL levels and neurochemical alterations in SCA3 patients. Serum samples were collected from ATXN3 mutation carriers (n = 20) and normal controls (n = 14). sNfL levels, measured by a single-molecule array, were compared between SCA3 patients and controls. We explored the relationship between sNfL levels and metabolic changes via magnetic resonance spectroscopy (MRS) scans. sNfL levels in SCA3 patients were higher than those in healthy controls, and these levels were correlated with disease severity. Associations emerged between the elevation of sNfL levels and lower brain metabolite changes, re ected as N-acetyl aspartate/creatine (NAA/Cr). These associations remained signi cant after multiple comparison corrections. Our results con rmed that serum sNfL levels are increased in SCA3 and are correlated with cerebellar hemisphere metabolic changes. Brain metabolic changes and sNfL levels show promise as potential complementary biomarkers for clinical trials for patients with SCA3.

Antisense Oligonucleotide Silencing Reverses Abnormal Neurochemistry in Spinocerebellar Ataxia 3 Mice

“…Altered tCho levels have been previously linked to oligodendrocyte disturbances, due to the role of choline in cell membrane synthesis and energy metabolism. 32,37 Patients with SCA3 exhibit decreased cerebellar vermis NAA/Cr ratios, 49 and patients with SCA1 exhibit decreased pons Cho/Cr ratios 35 that are paralleled by mouse models, with rescue of cerebellar tCho levels under ASO treatment. 22 We found a pronounced correlation between brainstem tCho levels and reduction in aggregated high-molecular weight and mutant monomeric ATXN3, suggesting a noteworthy correlation between oligodendrocyte function and mutant protein levels.…”

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

“…Thus, the observed correlation between serum NfL and cerebellar neurochemicals in aged homozygous Q84/Q84 mice suggests an association between the magnitude of cellular disturbances and blood NfL. Studies in patients with SCA3 have revealed notable correlations between increased serum NfL levels and neurometabolite abnormalities, specifically decreased cerebellar NAA/Cho and NAA/Cr ratios (Chen et al, 2023). Interestingly, we observed no correlation between NfL and tNAA or myo-Ins, markers of neuronal health and glial contributions, respectively.…”

Blood levels of neurofilament light are associated with disease progression in a mouse model of spinocerebellar ataxia type 3

“…Additionally, decreased tNAA has been demonstrated in multiple neurodegenerative diseases ( Adanyeguh et al, 2015 ), including SCA3 ( Miranda et al, 2022 ; Chandrasekaran et al, 2022 ), and is classified as a marker of neuronal and axonal degeneration. A recent study in patients with SCA3 revealed notable correlations between increased serum NfL levels and neurometabolite abnormalities, specifically decreased cerebellar NAA/choline and NAA/creatine ratios, reflective of neuronal degeneration in the cerebellum ( Chen et al, 2023 ). Intriguingly, our study found no correlation between serum NfL and cerebellar tNAA.…”