Cognition in Friedreich's ataxia: a behavioral and multimodal imaging study

Abstract

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.

Structural characteristics of the central nervous system in Friedreich ataxia: an in vivo spinal cord and brain MRI study

“…As the thalamus is an important relay station connecting the cerebellum and cerebrum, the latter may indicate disruptions of the cerebello-thalamic-cortical projections and network alterations 4. Brainstem and cerebellar volumes in addition to spinal cord data contributed to the prediction of clinical decline.…”

Cerebral compensation during motor function in Friedreich ataxia: The IMAGE‐FRDA study

“…1 Moreover, previous functional MRI studies of cognition in FRDA have generally found a relative sparing of top-down control/attention networks. 4,8,26 As such, individuals with FRDA may use these relatively intact executive resources to compensate for impairments in other systems, perhaps by employing different cognitive strategies relative to healthy individuals. 18,24,35 This shift to alternate strategies is supported by the observation of increased engagement of the dorsal attention network in individuals with FRDA who successfully completed the fMRI task, but who demonstrated worse offline motor precision.…”

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

“…Within the central nervous system, the most prominent pathology includes atrophy of the dorsal spinal tracts and cerebellar dentate nuclei (Pandolfo, ). Neuroimaging studies of cerebral gray and white matter demonstrate compelling evidence of abnormalities in cerebral structure (Della Nave, Ginestroni, Giannelli, et al, ; Rezende et al, ; Selvadurai et al, ), function (Dogan et al, ; Georgiou‐Karistianis et al, ; Harding et al, ; Harding et al, ), and both intra‐cerebral and cerebello‐cerebral connectivity (Akhlaghi et al, ; Akhlaghi et al, ; Cocozza et al, ; Dogan et al, ; Harding et al, ; Rizzo et al, ; Zalesky et al, ). This body of evidence represents significant advances in the characterization of brain changes in individuals with FRDA.…”

“…Interestingly in individuals with FRDA, widespread white matter deficits in cerebellar and cerebral tracts have been observed across a range of in vivo neuroimaging techniques. Firstly, diffusion tensor imaging studies have demonstrated widespread microstructural abnormalities across multiple measurements, including consistently reduced fractional anisotropy (FA), increased mean diffusivity (MD), and increased radial diffusivity (RD) (Akhlaghi et al, ; Akhlaghi et al, ; Della Nave, Ginestroni, Giannelli, et al, ; Della Nave et al, ; Dogan et al, ; Rezende et al, ; Rezende et al, ; Rizzo et al, ; Vavla et al, ; Vieira Karuta et al, ). The direction of changes in axial diffusivity has differed between studies (Akhlaghi et al, ; Della Nave et al, ; Rezende et al, ; Rezende et al, ; Vavla et al, ; Vieira Karuta et al, ).…”