Cognitive Changes in the Spinocerebellar Ataxias Due to Expanded Polyglutamine Tracts: A Survey of the Literature

Abstract

The dominantly-inherited ataxias characterised by expanded polyglutamine tracts—spinocere bellar ataxias (SCAs) 1, 2, 3, 6, 7, 17, dentatorubral pallidoluysian atrophy (DRPLA) and, in part, SCA 8—have all been shown to result in various degrees of cognitive impairment. We survey the literature on the cognitive consequences of each disorder, attempting correlation with their published neuropathological, magnetic resonance imaging (MRI) and clinical features. We suggest several psychometric instruments for assessment of executive function, whose results are unlikely to be confounded by visual, articulatory or upper limb motor difficulties. Finally, and with acknowledgement of the inadequacies of the literature to date, we advance a tentative classification of these disorders into three groups, based on the reported severity of their cognitive impairments, and correlated with their neuropathological topography and MRI findings: group 1—SCAs 6 and 8—mild dysexecutive syndrome based on disruption of cerebello-cortical circuitry; group 2—SCAs 1, 2, 3, and 7—more extensive deficits based largely on disruption of striatocortical in addition to cerebello-cerebral circuitry; and group 3—SCA 17 and DRPLA—in which cognitive impairment severe enough to cause a dementia syndrome is a frequent feature.

Cognitive Dysfunction in Repeat Expansion Diseases: A Review

“…SCA6, SCA8, and SCA10 could be defined as mild dysexecutive syndromes and the impaired brain region was prominent in the cerebellum, while in the remaining SCA subtypes including SCA1, SCA2, SCA3, and SCA 7, more extensive deficits were noted. This conclusion was consistent with another review (Lindsay and Storey, 2017 ).…”

“…According to the literature published to date, cognitive dysfunction in polyglutamine ataxias is prominent in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17, and dentatorubral-pallidoluysian atrophy (DRPLA), which are caused by expanded CAG repeats in the coding exons (Schöls et al, 2004 ; Gatchel and Zoghbi, 2005 ; Lindsay and Storey, 2017 ; Giocondo and Curcio, 2018 ). As for mutation in the non-coding area, patients with SCA8, SCA10, and SCA12 present cognitive dysfunction or dementia (Gatchel and Zoghbi, 2005 ; Lindsay and Storey, 2017 ; Giocondo and Curcio, 2018 ), (CTG)n repeats in Ataxin8 3'UTR causes SCA8 (Koob et al, 1999 ), (ATTCT)n in Ataxin10 intron results in SCA10 (Matsuura et al, 2000 ), and (CAG)n in PPP2R2B 5'UTR leads to SCA12 (Holmes et al, 1999 ). The pathogenic mutations and repeat numbers of each SCA with cognitive impairment are listed in Table 1 .…”

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

“…As the disease progresses, the SCA3 neuropathology gradually affects the cerebrum, in which extensive atrophy is observed in the cerebral cortex and basal ganglia in the late stages of SCA3 (Rezende et al, 2018). This process results in widespread brain degeneration, contributing to and exacerbating non-ataxia and cognitive impairment in SCA3 (Lindsay and Storey, 2017).…”

“…Ataxia severity is commonly measured using the Scale for the Assessment and Rating of Ataxia (SARA; 0-40) and the International Cooperative Ataxia Rating Scale (ICARS; 0-100) (Zhou et al, 2011). 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).…”

KCND3-Related Neurological Disorders: From Old to Emerging Clinical Phenotypes

“…Cognitive decline and ID are non-motor symptoms described in several types of SCAs [55,56]. A recent work attempted to predict type and severity of cognitive issues in the expanded-polyglutamine tracts SCAs according to the underlying genetic diagnosis (i.e., SCA type 1, 2, 3, 6, 7, 8, and 17 and dentato pallidoluysian atrophy) [57]. A prominent executive dysfunction was found in SCA 1 subjects compared to SCA type 2 and 3 [58].…”