Neurocognitive Changes in Spinocerebellar Ataxia Type 3: A Systematic Review with a Narrative Design

Abstract

Spinocerebellar ataxia type 3 (SCA3), the commonest dominantly inherited ataxia worldwide, is characterized by disruption in the cerebellar-cerebral and striatal-cortical networks. Findings on SCA3-associated cognitive impairments are mixed. The classification models, tests and scoring systems used, language, culture, ataxia severity, and depressive symptoms are all potential confounders in neuropsychological assessments and may have contributed to the heterogeneity of the neurocognitive profile of SCA3. We conducted a systematic review of studies evaluating neurocognitive function in SCA3 patients. Of 1304 articles identified, 15 articles met the eligibility criteria. All articles were of excellent quality according to the National Institutes of Health quality assessment tool for casecontrol studies. In line with the disrupted cerebellar-cerebral and striatal-cortical networks in SCA3, this systematic review found that the neurocognitive profile of SCA3 is characterized by a core impairment of executive function that affects processes such as nonverbal reasoning, executive aspects of language, and recall. Conversely, neurocognitive domains such as general intelligence, verbal reasoning, semantic aspect of language, attention/processing speed, recognition, and visuospatial perception and construction are relatively preserved. This review highlights the importance of evaluating neurocognitive function in SCA3 patients. Considering the negative impact of cognitive and affective impairment on quality of life, this review points to the profound impairments that existing or future treatments should prioritize.

Magnetic Resonance Imaging and Its Clinical Correlation in Spinocerebellar Ataxia Type 3: A Systematic Review

“…This finding is consistent with the cerebellum's role in EF processing due to its extensive reciprocal connections with areas of the cerebrum, including the prefrontal and posterior parietal cortex and the basal ganglia (Stoodley and Schmahmann, 2010;Bostan et al, 2013). Contradictorily, no correlation was found with the prefrontal-striatal circuit, which is impaired in SCA3 and plays a crucial role in higherorder cognitive functions (Alexander et al, 1986;Yap et al, 2022b). Instead, strong correlations were found between general intelligence and precentral gyrus and superior occipital gyrus (De Rezende et al, 2015).…”

“…The presence of clinical syndrome may compound each other; that is, ataxia and dystonia may exacerbate each other when measured with their respective clinical scales. Likewise, motor impairment is often a confounding factor for clinical scales from truly reflecting cognitive impairment (Yap et al, 2022b). This issue is often exacerbated as few tests assess only a single domain (i.e., true process-pure tests), thereby affecting the test utility in the cerebellar patient population.…”

“…Apart from the cerebellum, individual differences in the extracerebellar involvement further contribute to the varying degree of ataxia, non-ataxia, and cognitive impairment in SCA3 (Lindsay and Storey, 2017). In addition, the severity of ataxia may exacerbate the cognitive impairment on pen-and-paper tests (Yap et al, 2022b). Therefore, clinical measures alone might not reflect progressive disease changes, requiring correlations with objective measures such as magnetic resonance imaging (MRI) (Döhlinger et al, 2008).…”

A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET

“…This finding fits with the cognitive (and affective) functions of the cerebellum, through connections with cortical and limbic structures ( Schmahmann & Sherman, 1998 ). A recent systematic review concluded that the neurocognitive profile of SCA3 is mainly characterized by impairments of executive function ( Yap et al, 2021 ). Prefrontal-striatal circuitry is implied in such higher-order cognitive functions.…”

“…Neuropathological studies in SCA3 have revealed variable neuronal loss in cerebellum, brainstem, thalamus, subthalamic nucleus, pallidum, and motor cortex ( Rüb et al, 2008 , Rüb et al, 2013 , Seidel et al, 2012 ). The cerebellum is most severely affected, with ataxia as the presenting and most prominent feature, but patients may also develop pyramidal and extra-pyramidal signs, neuropathy, oculomotor dysfunction, and cognitive problems ( Pilotto and Saxena, 2018 , Ruano et al, 2014 , Yap et al, 2021 ). More than direct effects of local pathology, clinical manifestations are likely to be a consequence of more widespread functional changes in cerebellar-thalamo-cerebral and striatal-cortical networks.…”