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We demonstrate high sensitivity for detecting longitudinal change as well as diagnostic sensitivity in ALS by applying recent advances in MRI data acquisition and analysis to multimodal brain and cervical spinal cord data. We acquired high quality diffusion MRI data from the brain and cervical cord, and high quality T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten participants with ALS and 14 healthy control participants, and 11 participants with ALS and 13 healthy control participants were re-scanned at 6-month and 12-month follow-up visits respectively. We analyzed cross-sectional differences and longitudinal changes in brain diffusion metrics and cortical thickness to identify white and gray matter areas affected by the disease. We also used fixel-based microstructure measures, i.e. fiber density and fiber cross-section, that are found more sensitive to longitudinal changes. Combining the brain metrics with our previously reported diffusion and cross-sectional area measures of the spinal cord, we demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of cross-sectional data, including high sensitivity for diagnosis of lower motor neuron-predominant ALS. Fiber density and cross-section provided the greatest sensitivity for change in our longitudinal dataset. We demonstrate evidence of progression in a cohort of 11 participants with slowly progressive ALS, including in participants with very slow change in ALSFRS-R (less than 0.5 points per month). More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. Our findings suggest that fixel-based measures may serve as potential biomarkers of disease progression in clinical trials. We also provide a comprehensive list of affected areas both in the white matter and cortical gray matter, and report correlations between ALSFRS-R and the fiber density and cross-section.

Movement disorders 38(1), 45-56 (2023). doi:10.1002/mds.29261, Published by Wiley, New York, NY

A high degree of structural order by white matter (WM) fibre tracts creates a physicochemical environment where water relaxations are rendered anisotropic. Recently, angularly dependent longitudinal relaxation has been reported in human WM. We have characterised interrelationships between T1 relaxation and diffusion MRI microstructural indices at 3 and 7 T. Eleven volunteers consented to participate in the study. Multishell diffusion MR images were acquired with b-values of 0/1500/3000 and 0/1000/2000 s/mm

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.

Friedreich ataxia is the most common hereditary ataxia. Atrophy of the spinal cord is one of the hallmarks of the disease. MRI and magnetic resonance spectroscopy are powerful and non-invasive tools to investigate pathological changes in the spinal cord. A handful of studies have reported cross-sectional alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no longitudinal MRI, diffusion MRI or MRS results have been reported in the spinal cord. Here, we investigated early-stage cross-sectional alterations and longitudinal changes in the cervical spinal cord in Friedreich ataxia, using a multimodal magnetic resonance protocol comprising morphometric (anatomical MRI), microstructural (diffusion MRI), and neurochemical (1H-MRS) assessments.We enrolled 28 early-stage individuals with Friedreich ataxia 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 total neurological score at baseline was 42.7 ± 13.6. Twenty-one Friedreich ataxia 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 magnetic resonance scans. Controls were scanned at baseline only. At baseline, individuals with Friedreich ataxia had significantly lower spinal cord cross-sectional area (−31%, P = 8 × 10−17), higher eccentricity (+10%, P = 5 × 10−7), lower total N-acetyl-aspartate (tNAA) (−36%, P = 6 × 10−9) and higher myo-inositol (mIns) (+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 (R = −0.55, P = 7 × 10−6) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = −0.60, P = 4 × 10−7). Less strong but still significant correlations were found for fractional anisotropy and tNAA/mIns. We report here the first quantitative longitudinal magnetic resonance results in the spinal cord in Friedreich ataxia. 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.

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.

Neurology : official journal of the American Academy of Neurology / Genetics 8(6), e200034 (2022). doi:10.1212/NXG.0000000000200034, Published by [Verlag nicht ermittelbar], Minneapolis, Minn.