Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

Abstract

ObjectiveSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominantly inherited neurodegenerative disease mainly affecting the cerebellum and brainstem. In this Cuban‐German research collaboration, we aimed to characterize atrophy patterns and associations with clinical measures in preclinical and manifest SCA2.MethodsIn this study, 16 nonmanifest SCA2 mutation carriers, 26 manifest patients with SCA2, and 18 healthy control subjects underwent magnetic resonance imaging, as well as genetic and clinical characterization including assessment of ataxia (Scale for the Assessment and Rating of Ataxia) and saccade velocity in Cuba were enrolled. Semiautomated quantitative volumetry of the cerebellum and brainstem, subdivided into the medulla oblongata, the pontine brainstem, and mesencephalon was performed. Additionally, the anteroposterior diameter of the pontine brainstem was measured.ResultsAnalysis of volumetric data revealed degeneration of the cerebellum and brainstem, in particular of pontine volumes and the anteroposterior diameter of the pons, in both manifest SCA2 patients and individuals at risk for SCA2 compared to controls. Comparing patients with nonataxic preclinical SCA2 mutation carriers, we found more pronounced reductions of the pontine brainstem and cerebellum in manifest SCA2. Volumetric data further showed associations with CAG repeat length and predicted age of onset in preclinical SCA2 individuals, and by trend with ataxia signs in patients. Although saccade velocity was associated with reduction in the pontine brainstem in preclinical and manifest SCA2, reduced ability to suppress interfering stimuli measured by the Stroop task was related to cerebellar volume loss in patients.InterpretationPreclinical SCA2 mutation carriers exhibit brain abnormalities, which could be targeted as surrogate parameters for disease progression and in future preventive trials.

Atxn2-CAG100-KnockIn mouse spinal cord shows progressive TDP43 pathology associated with cholesterol biosynthesis suppression

“…It is therefore important to state that the progressive expression reduction of Unc80 and Eif5a2 concerns factors within the ATXN2 interactome and might thus represent primary and specific effects of SCA2 pathology. At present, clinical trials in SCA2 depend on the quantification of clinical, neurophysiological and imaging features with documented progression, such as the clinical SARA score [39, 83], quantification of sensory neuropathy [213], saccade slowing [162, 217, 218], periodic leg movements during sleep [161, 221] and brain volumetry [1, 159]. Since any improvement in these disease features occurs over extended periods of time, there is an unmet need to characterize molecular biomarkers that mirror therapeutic benefits very rapidly.…”

Motor and cognitive impairments in spinocerebellar ataxia type 7 and its correlations with cortical volumes

“…The decrease of executive functions in pure cerebellar syndromes and SCAs with a more widespread damage (including the frontal lobe) has been related to the interruption of the fronto‐ponto‐cerebellar pathway, in which the cerebellum is the main hub impaired (Le Pira et al., ; Reetz et al., ; Schmahmann & Sherman, ; Suenaga et al., ). Either way, it is possible that we failed to find associations of verbal memory and verbal fluency impairments with the cerebellum GMV because, as the most structurally affected region in SCA7, we expected that a more homogenous and advanced changes across individuals would “wash out” correlations in group analysis.…”

Neuroimaging Biomarkers in SCA2 Gene Carriers

“…Volumes of the brainstem and cerebellum showed inverse correlations with severity of clinical deficit [17], age of onset and CAG repeat length [16].…”

“…Differently from multiple system atrophy, the T2 signal in the striata is normal [9,11] (Figure 1). Morphometry performed on T1-weighted images using volumetry of regions of interest or whole-brain analytical software, including voxel-based morphometry (VBM) or tensor-based morphometry, allows a quantitative assessment of the selective brainstem and cerebellar atrophy in SCA2 [12][13][14] (Figure 2) which is already present in pre-symptomatic gene carriers [15,16] ( Figure 3). Atrophy of the right temporo-occipital cortex (parahippocampal, fusiform and lingual gyri) was observed in a meta-analysis of the VBM studies [14] (Figure 2).…”