With molecular treatments coming into reach for spinocerebellar ataxia type 3 ( SCA 3), easily accessible, cross‐species validated biomarkers for human and preclinical trials are warranted, particularly for the preataxic disease stage. We assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy ( pNfH ) in ataxic and preataxic subjects of two independent multicentric SCA 3 cohorts and in a SCA 3 knock‐in mouse model. Ataxic SCA 3 subjects showed increased levels of both NfL and pNfH . In preataxic subjects, NfL levels increased with proximity to the individual expected onset of ataxia, with significant NfL elevations already 7.5 years before onset. Cross‐sectional NfL levels correlated with both disease severity and longitudinal disease progression. Blood NfL and pNfH increases in human SCA 3 were each paralleled by similar changes in SCA 3 knock‐in mice, here also starting already at the presymptomatic stage, closely following ataxin‐3 aggregation and preceding Purkinje cell loss in the brain. Blood neurofilaments, particularly NfL, might thus provide easily accessible, cross‐species validated biomarkers in both ataxic and preataxic SCA 3, associated with earliest neuropathological changes, and serve as progression, proximity‐to‐onset and, potentially, treatment‐response markers in both human and preclinical SCA3 trials.
Autosomal dominant spinocerebellar ataxias (SCAs) can present with a large variety of noncerebellar symptoms, including movement disorders. In fact, movement disorders are frequent in many of the various SCA subtypes, and they can be the presenting, dominant, or even isolated disease feature. When combined with cerebellar ataxia, the occurrence of a specific movement disorder can provide a clue toward the underlying genotype. There are reasons to believe that for some coexisting movement disorders, the cerebellar pathology itself is the culprit, for example, in the case of cortical myoclonus and perhaps dystonia. However, movement disorders in SCAs are more likely related to extracerebellar pathology, and imaging and neuropathological data indeed show involvement of other parts of the motor system (substantia nigra, striatum, pallidum, motor cortex) in some SCA subtypes. When confronted with a patient with an isolated movement disorder, that is, without ataxia, there is currently no reason to routinely screen for SCA gene mutations, the only exceptions being SCA2 in autosomal dominant parkinsonism (particularly in Asian patients) and SCA17 in the case of a Huntington's disease-like presentation without an HTT mutation.
The autosomal dominant spinocerebellar ataxias (SCAs) are a heterogeneous group of degenerative diseases of the cerebellum and connected regions. The discovery of various SCA genes and the subsequent possibility of predictive testing currently allow a genetic diagnosis to be established years or even decades before the actual appearance of ataxia symptoms. A growing body of evidence, however, indicates that this preclinical stage is subject to the earliest pathophysiologic changes. This review article comprehensively summarizes the studies conducted in preclinical carriers of a mutation in one of the SCA genes. From these data, it can indeed be concluded that the preclinical phase in SCA is already characterized by detectable central and peripheral nervous system changes, which are reflected by subtle abnormalities during a careful clinical examination, changes in structural and functional brain imaging, abnormal neurophysiologic measurements, and/or altered motor learning paradigms. As these may be compensated for a long time, ataxia symptoms probably only appear after a certain threshold of dysfunction or degeneration has been exceeded. Detailed knowledge of this disease stage is of particular relevance for a better understanding of the pathogenesis of SCAs, will allow us to determine the optimal point in time for interventions in future therapeutic trials, and points to objective, valid biomarkers to assess disease progression. Further studies will benefit from a consensus-based definition of the preclinical stage, from using one and the same validated ataxia rating scale with one fixed cutoff value, and from applying similar mathematical models to calculate time to predicted disease onset.
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