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ObjectiveSpinal cord damage is a hallmark of Friedreich ataxia (FRDA), but its progression and clinical correlates remain unclear. Here we performed a characterization of cervical spinal cord structural abnormalities in a large multisite FRDA cohort.MethodsWe performed a cross-sectional analysis of cervical spinal cord (C1 to C4) cross-sectional area (CSA) and eccentricity using MRI data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched controls. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age.ResultsIndividuals with FRDA, relative to controls, had significantly reduced CSA at all examined levels, with large effect sizes (d>2.1) and significant correlations with disease severity (rd>1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, while CSA appears to decrease progressively, eccentricity remains stable over time.InterpretationPrevious research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage or both. Hence, our data support the hypothesis that damage to DC and CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, whereas CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression.

BackgroundFriedreich Ataxia (FRDA) is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. Magnetic resonance imaging (MRI) and spectroscopy (MRS) are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in FRDA using MRI and diffusion MRI (dMRI) in FRDA. However, to our knowledge no longitudinal MRI, dMRI or MRS results have been reported in the spinal cord in FRDA.ObjectiveTo investigate early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in FRDA, using a multimodal magnetic resonance (MR) protocol comprising morphometric (anatomical MRI), microstructural (dMRI), and neurochemical (1H MRS) assessments.DesignWe enrolled 28 early-stage individuals with FRDA and 20 age- and gender-matched controls (cross-sectional study). Disease duration at baseline was 5.5±4.0 years and Friedreich Ataxia Rating Scale (FARS) total neurological score at baseline was 42.7±13.6. Twenty-one FRDA participants returned for 1-year follow-up, and 19 of those for 2-year follow-up (cohort study). Each visit consisted in clinical assessments and MR scans. Controls were scanned at baseline only.ResultsAt baseline, individuals with FRDA had significantly lower spinal cord cross-sectional area (−31%, p=4.10−17), higher eccentricity (+10%, p=5.10−7), lower total N-acetyl-aspartate (−36%, p=6.10−9) and higher myo-inositol (+37%, p=2.10−6) corresponding to a lower ratio tNAA/mIns (−52%, p=2.10−13), lower fractional anisotropy (−24%, p=10−9) as well as higher radial diffusivity (+56%, p=2.10−9), mean diffusivity (+35%, p=10−8) and axial diffusivity (+17%, p=4.10−5) relative to controls.Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline (p=4.10−4), the ratio tNAA/mIns decreased by 5.8% per year (p=0.03), and fractional anisotropy showed a trend to decrease (−3.2% per year, p=0.08).Spinal cord cross-sectional area correlated strongly with clinical measures, with the strongest correlation coefficients found between cross-sectional area and Scale for the Assessment and Rating of Ataxia (SARA) (R=-0.55, p=7.10−6) and between cross-sectional area and FARS total neurological score (R=-0.60, p=4.10−7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns.ConclusionWe report here the first quantitative longitudinal MR results in the spinal cord in FRDA. The largest longitudinal effect size was found for spinal cord cross-sectional area, followed by tNAA/mIns and fractional anisotropy. Our results provide direct evidence that abnormalities in the spinal cord result not solely from hypoplasia, but also from neurodegeneration, and show that disease progression can be monitored non-invasively in the spinal cord.

The mechanisms contributing to increased expression of motor and cognitive impairment in people with Parkinson9s disease who lack muscle atonia during rapid eye movement (REM) sleep compared to those with muscle atonia are poorly understood. This study used tract-based spatial statistics to compare diffusion measures of white matter microstructure between people with Parkinson9s disease with and without REM sleep without atonia as well as the relationships of these measures to motor and cognitive function. Thirty-eight individuals with mild-to-moderate Parkinson9s disease and twenty-one matched control subjects underwent ultra-high-field MRI (7Tesla), quantitative motor assessments of gait and bradykinesia, and neuropsychological testing. The Parkinson9s disease cohort was separated post-hoc into those with and without elevated chin or leg muscle activity during REM sleep based on polysomnography findings. Fractional anisotropy was significantly higher, and radial and mean diffusivity significantly lower, in diffuse regions of the corpus callosum, projection, and association white matter pathways in the Parkinson9s group with normal REM sleep compared to controls. In contrast, there was no significant difference in fractional anisotropy between the Parkinson9s group with elevated muscle tone and controls. Fractional anisotropy was also significantly higher in a subset of pathways in the Parkinson9s disease group with normal REM sleep muscle tone compared to those with elevated REM sleep muscle tone. The group with elevated REM sleep muscle tone had significant impairments in gait and upper arm speed compared to controls and significantly worse scores in specific cognitive domains (executive function, visuospatial memory) compared to the Parkinson9s disease group with normal REM sleep muscle tone. Regression analyses showed that gait speed and step length in the Parkinson9s disease cohort were predicted by measures of mean fractional anisotropy of the anterior corona radiata, whereas elbow flexion velocity was predicted by fractional anisotropy of the superior corona radiata. Visuospatial memory task performance was predicted by the radial diffusivity of the posterior corona radiata. These findings demonstrate that people with mild-to-moderate severity of Parkinson9s disease who have normal muscle tone during REM sleep show alterations in white matter microstructure that are associated with preserved motor and cognitive function, but these adaptations are reduced or absent in those with increased REM sleep motor tone.

Although brain functionality is often remarkably robust to lesions and other insults, it may be fragile when these take place in specific locations. Previous attempts to quantify robustness and fragility sought to understand how the functional connectivity of brain networks is affected by structural changes, using either model-based predictions or empirical studies of the effects of lesions. We advance a geometric viewpoint relying on a notion of network curvature, the so-called Ollivier-Ricci curvature. This approach has been proposed to assess financial market robustness and to differentiate biological networks of cancer cells from healthy ones. Here, we apply curvature-based measures to brain structural networks to identify robust and fragile brain regions in healthy subjects. We show that curvature can also be used to track changes in brain connectivity related to age and autism spectrum disorder (ASD), and we obtain results that are in agreement with previous MRI studies., The brain can often continue to function despite lesions in many areas, but damage to particular locations may have serious effects. Here, the authors use the concept of Ollivier-Ricci curvature to investigate the robustness of brain networks.