A recent review showed different fluid biomarkers were involved in neurodegeneration, oxidative stress, metabolism, microRNA and novel genes in spinocerebellar ataxia type 3.
Alexandra E. Soto-Piña, PhD
(Credit: Autonomous University of the State of Mexico)
A systematic review recently published in the International Journal of Molecular Sciences demonstrated that neurofilament light chain (Nfl) and ataxin 3 with a longer polyQ tract (polyQ-ATXN3) were the most prevalent biomarkers in body fluids and disease stages of spinocerebellar ataxia type 3 (SCA3). These findings suggest that biomarker profile assessment of NfL and polyQ-ATXN3 may be a more beneficial approach to tracking SCA3 progression and clinical trial efficacy compared to only relying on one alone.1
Among 2838 patients (ataxic, n = 1320; preataxic, n = 168; healthy controls, n = 1350), the most frequent biomarkers tested were NfL and polyQ-ATXN3 with the most widely analyzed marker being NfL (n = 8/21). In a heterogeneity analysis, I2 was 0% in NfL plasma concentrations in both patients with preataxic and ataxic. Notably, the serum values were higher than 90%; in the cerebrospinal fluid (CSF), they were 0%, and in controls and patients with ataxic, they were 53%. Investigators noted that these data indicate that I2 could potentially be a reliable approach to assessment heterogeneity in plasma and CSF, showing statistically significant in mean difference between preclinical/ataxic and control/ataxic (P <.0001).
“This study has shown the different fluid biomarkers that can be included in the assessment profile for SCA3 diagnosis and prognosis. This could be useful for thoroughly evaluating disease staging and therapeutic efficacy. NfL and polyQ-ATXN3 provide a closer view of disease progression, and they have been assessed as state biomarkers,” lead author Alexandra E. Soto-Piña, PhD, professor of pharmacology at the Autonomous University of the State of Mexico, and colleagues wrote.1 “This being said, more information about their patterns during the preclinical stages and ataxic onset is needed in order to clarify their use as trait biomarkers. These may be complemented by other biomarkers that have been successfully evaluated in the preclinical stage, such as the novel genes found in transcriptomics.”
In this review, investigators performed a search in PubMed using inclusion criteria that consisted of cross-sectional and longitudinal studies that involved measures of protein, DNA and RNA markers in body fluids. In a total of 24 publications, as of 4 July 2024, complied with the review criteria and the STROBE guidelines for cohorts and case–control studies. In these studies, patients with ataxia were defined as those who had a SARA score of at least 3, as well as alterations in balance, gait, coordination, lower limb spasticity, vision, cognition, dysarthria, dysphagia and structural brain abnormalities. Researchers then compared neurofilament light between controls and preclinical and patients with ataxia utilizing a random effect analysis for continuous outcome variables.2
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“Moreover, the subclassification of the asymptomatic and preataxic stages should also include clinical evaluations and imaging correlations. Assessing fluid biomarkers could be a good start in validating SCA3 diagnosis and prognosis, but they may not be completely conclusive when considered alone,” Soto-Piña et al noted.1 “Furthermore, increased preataxic and asymptomatic group sizes should be considered in future investigations, and diagnostic procedures must be improved in order to detect patients in these stages.”
Further findings showed that polyQ-ATXN3 was the second most frequently measured biomarker in SCA3 (n = 3/21); however, few studies evaluated their concentrations in plasma (n = 2), urine (n = 1) and CSF (n = 2). Additionally, only one study revealed differences between the preclinical and ataxic stages in plasma.3 Regardless, authors highlighted that polyQ-ATXN3 can be a valuable biomarker for assessing the efficacy of novel, targeted therapies against expanded ATXN3. Moreover, polyQ-ATXN3 was successfully measured in peripheral blood mononuclear cells and thus may be a potential trait and state marker for tracking disease progression and the efficacy of therapeutic strategies.4
“In future endeavors in developing clinical management guidelines and finding therapeutic targets, evaluating trait and state biomarkers could be a first step. Being armed with a battery of sensible and specific molecular biomarkers may open up more options for identifying correlations between clinical and neuroimaging variables. Such approaches could potentially help to understand SCA3 pathological pathways and find appropriate time windows for therapeutic interventions,” Soto-Piña et al noted.1
