Spinocerebellar ataxias are dominantly inherited disorders that are associated with progressive brain degeneration, mainly affecting the cerebellum and brainstem. As part of the multicentre European integrated project on spinocerebellar ataxias study, 37 patients with spinocerebellar ataxia-1, 19 with spinocerebellar ataxia-3 and seven with spinocerebellar ataxia-6 were clinically examined and underwent magnetic resonance imaging at baseline and after a 2-year follow-up. All patients were compared with age-matched and gender-matched healthy control subjects. Magnetic resonance imaging analysis included three-dimensional volumetry and observer-independent longitudinal voxel-based morphometry. Volumetry revealed loss of brainstem, cerebellar and basal ganglia volume in all genotypes. Most sensitive to change was the pontine volume in spinocerebellar ataxia-1, striatal volume in spinocerebellar ataxia-3 and caudate volume in spinocerebellar ataxia-6. Sensitivity to change, as measured by standard response mean, of the respective MRI measures was greater than that of the most sensitive clinical measure, the Scale for the Assessment and Rating of Ataxia. Longitudinal voxel-based morphometry revealed greatest grey matter loss in the cerebellum and brainstem in spinocerebellar ataxia-1, in the putamen and pallidum in spinocerebellar ataxia-3 and in the cerebellum, thalamus, putamen and pallidum in spinocerebellar ataxia-6. There was a mild correlation between CAG repeat length and volume loss of the bilateral cerebellum and the pons in spinocerebellar ataxia-1. Quantitative volumetry and voxel-based morphometry imaging demonstrated genotype-specific patterns of atrophy progression in spinocerebellar ataxias-1, 3 and 6, and they showed a high sensitivity to detect change that was superior to clinical scales. These structural magnetic resonance imaging findings have the potential to serve as surrogate markers, which might help to delineate quantifiable endpoints and non-invasive methods for rapid and reliable data acquisition, encouraging their use in clinical trials.

ObjectiveFriedreich's ataxia (FRDA) is a spinocerebellar degenerative disorder, in which cognitive deficits are sparsely explored. In this behavioral and multimodal magnetic resonance imaging (MRI) study, we investigated the neurocognitive profile and cortico‐cerebellar dysfunctions underlying executive functioning in individuals with FRDA.Methods22 FRDA patients and 22 controls were clinically and neuropsychologically examined. Fifteen of each underwent structural and functional MRI using a verbal‐fluency task with phonemic and semantic conditions. Gray (GM) and white matter (WM) alterations were assessed by means of voxel‐based morphometry and diffusion‐tensor imaging.ResultsThe neuropsychological profile demonstrated deficits in verbal fluency, working memory and social cognition. Functional MRI data showed most pronounced group‐differences in phonemic fluency with patients exhibiting enhanced activity in the cerebellum (VI, Crus I), fronto‐insular, premotor and temporo‐occipital regions. The semantic condition only revealed reduced activity in the anterior cerebellum; for overt speech, we found increased activity in the motor cortex. Functional connectivity‐analysis showed higher co‐activation within cerebellar and cortical regions, respectively, and impaired interregional coupling between the cerebellum and fronto‐insular cortex for phonemic processing, which was also related to poorer task performance. GM reduction in FRDA was mainly found in lobule VI, whereas WM degeneration was more pronounced including brainstem, cerebellum, and cortex. Decreased cerebellar GM was associated with enhanced activity in the fronto‐insular cortex, while loss of WM integrity may translate cortico‐cerebellar pathway disruptions.InterpretationThe pattern of increased neural response with both cerebellar and cortical involvement underlying executive functioning indicates functional reorganization driven by disease‐related structural damage in FRDA.

Current treatment in late-life cognitive impairment and dementia is still limited, and there is no cure for brain tissue degeneration or reversal of cognitive decline. Physical activity represents a promising non-pharmacological interventional approach in many diseases causing cognitive impairment, but its effect on brain integrity is still largely unknown. Especially research of cerebral alterations in disease state that goes beyond observations of clinical improvement is crucial to understand disease processes and possible effective treatments. In this systematic review, we address the question how physical activity and fitness in mild cognitive impairment (MCI) and Alzheimer's disease (AD) influences brain architecture compared to cognitively healthy elderly. We review both interventional studies comprising aerobic, coordinative and resistance exercises and observational studies on fitness and physical activity combined with Magnetic Resonance imaging (MRI). Different MRI approaches were included such as volumetric and structural analyses, Diffusion Tensor Imaging (DTI), functional MRI and Cerebral Blood Flow (CBF). We evaluate MRI results for different exercise modalities and performed a methodological evaluation of interventional studies in cognitive decline compared to normal aging. According to our results, among 12 interventions in AD/MCI, aerobic exercise is most frequently applied (9 studies). Interventions in AD/MCI altogether reveal a higher methodological quality compared to interventions in healthy elderly (8.33 ± 2.19 vs. 6.25 ± 2.36 out of 13 points), with most frequent missing aspects related to descriptions of complications, lack of intention-to-treat and statistical power analyses. Effects of aerobic exercise and fitness seem to mainly impact brain structures sensitive to neurodegeneration, which especially comprise frontal, temporal and parietal regions, such as the hippocampal/parahippocampal region, precuneus, anterior cingulate and prefrontal cortex, which are reported by several studies. General fitness measured via an objective fitness assessment and questionnaires seems to have a more global cerebral effect, probably due to its long-term application, whereas distinct intervention effects of durations between 3 and 6 months seem to concentrate on more local brain regions as the hippocampus, which can also be influenced by region of interest analyses. There is still a lack of evidence on other or combined types of intervention modalities, such as resistance, coordinative as well as multicomponent exercise during cognitive decline, and complex interventions as dancing. Future research should examine their beneficial effect on brain integrity, since several non-MRI studies already point to their advantageous impact. As a further future prospect, combination and application of newly developed imaging methods such as metabolic im...