Abstract
Friedreich's ataxia (FRDA) is an inherited neurodegenerative movement disorder with early onset, widespread cerebral and cerebellar pathology, and no cure still available. Functional MRI (fMRI) studies, although currently limited in number, have provided a better understanding of brain changes in people with FRDA. This systematic review aimed to provide a critical overview of the findings and methodologies of all fMRI studies conducted in genetically confirmed FRDA so far, and to offer recommendations for future study designs. About 12 cross-sectional and longitudinal fMRI studies, included 198 FRDA children and young adult patients and, 205 healthy controls (HCs), according to the inclusion criteria. Details regarding GAA triplet expansion and demographic and clinical severity measures were widely reported. fMRI designs included motor and cognitive task paradigms, and resting-state studies, with widespread changes in functionally activated areas and extensive variability in study methodologies. These studies highlight a mixed picture of both hypoactivation and hyperactivation in different cerebral and cerebellar brain regions depending on fMRI design and cohort characteristics. Functional changes often correlate with clinical variables. In aggregate, the findings provide support for cerebro-cerebellar loop damage and the compensatory mechanism hypothesis. Current literature indicates that fMRI is a valuable tool for gaining in vivo insights into FRDA pathology, but addressing that its limitations would be a key to improving the design, interpretation, and generalizability of studies in the future.
Highlights
Friedreich’s ataxia (FRDA) is an inherited neurodegenerative movement disorder that affects the cerebellum and cerebellar pathways to various degrees
About 181 records were excluded because they were not relevant to the systematic review as they consisted of the studies focusing on susceptibility-weighted imaging (SWI), iron imaging, diffusion tensor imaging (DTI), volumetric MRI, magnetic resonance spectroscopy (MRS), positron emission tomography (PET), single-photon emission CT (SPECT), diagnoses other than FRDA, video neuroimaging, cardiac function, did not genetically confirm FRDA diagnoses, were written in languages other than English, and review articles
We choose to describe the results for single studies assembled into two main categories: studies with motor and non-motor tasks (Supplementary Material S1)
Summary
Friedreich’s ataxia (FRDA) is an inherited neurodegenerative movement disorder that affects the cerebellum and cerebellar pathways to various degrees. Patients with FRDA present with equilibrium impairment, gait ataxia, dysmetria, nystagmus, oculomotor disturbances, tremor, dysarthria, and nonneurological impairments, including cardiomyopathy [1]. This condition is transmitted in a recessive autosomal mode, most commonly due to biallelic triplet repeat expansions in the FXN gene [2], which leads to impaired expression of the protein frataxin [3]. The principal sites of neuropathology in FRDA are the dorsal root ganglia in the spinal cord, cerebellum, and cerebellar tracts there is increasing evidence of more widespread cerebral pathology and dysfunction, and extensive white matter damage [4]. There is an ever-growing body of research investigating the disease at multiple levels of biology (i.e., from genes to systems), alongside an increasing range of therapeutic trials
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