Joers James M, Adanyeguh Isaac M, Deelchand Dinesh K, Hutter Diane H, Eberly Lynn E, Iltis Isabelle, Bushara Khalaf O, Lenglet Christophe, Henry Pierre-Gilles
Center for Magnetic Resonance Research and Department of Radiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, MN 55455, USA.
Brain Commun. 2022 Oct 3;4(5):fcac246. doi: 10.1093/braincomms/fcac246. eCollection 2022.
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 alterations in Friedreich ataxia using MRI and diffusion MRI. However, to our knowledge no 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 (H-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%, = 8 × 10), higher eccentricity (+10%, = 5 × 10), lower total N-acetyl-aspartate (tNAA) (-36%, = 6 × 10) and higher myo-inositol (mIns) (+37%, = 2 × 10) corresponding to a lower ratio tNAA/mIns (-52%, = 2 × 10), lower fractional anisotropy (-24%, = 10), as well as higher radial diffusivity (+56%, = 2 × 10), mean diffusivity (+35%, = 10) and axial diffusivity (+17%, = 4 × 10) relative to controls. Longitudinally, spinal cord cross-sectional area decreased by 2.4% per year relative to baseline ( = 4 × 10), the ratio tNAA/mIns decreased by 5.8% per year ( = 0.03), and fractional anisotropy showed a trend to decrease (-3.2% per year, = 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, = 7 × 10) and between cross-sectional area and Friedreich ataxia Rating Scale total neurological score (R = -0.60, = 4 × 10). 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.
弗里德赖希共济失调是最常见的遗传性共济失调。脊髓萎缩是该疾病的标志性特征之一。磁共振成像（MRI）和磁共振波谱（MRS）是研究脊髓病理变化的强大且非侵入性的工具。少数研究报告了使用MRI和扩散加权MRI对弗里德赖希共济失调患者的改变。然而，据我们所知，尚未有关于脊髓的MRI、扩散加权MRI或MRS结果的报道。在此，我们使用包括形态学（解剖学MRI）、微观结构（扩散加权MRI）和神经化学（氢质子磁共振波谱）评估的多模态磁共振成像方案，研究了弗里德赖希共济失调患者颈髓的早期横断面改变和纵向变化。我们招募了28例弗里德赖希共济失调早期患者和20例年龄及性别匹配的对照者（横断面研究）。基线时的病程为5.5±4.0年，基线时弗里德赖希共济失调评定量表的总神经学评分为42.7±13.6。21例弗里德赖希共济失调参与者返回进行1年随访，其中19例进行2年随访（队列研究）。每次访视包括临床评估和磁共振扫描。对照者仅在基线时进行扫描。在基线时，弗里德赖希共济失调患者的脊髓横截面积显著降低（-31%，P = 8×10⁻⁴），偏心率增加（+10%，P = 5×10⁻⁴），总N-乙酰天门冬氨酸（tNAA）降低（-36%，P = 6×10⁻⁴），肌醇（mIns）增加（+37%，P = 2×10⁻⁴），对应tNAA/mIns比值降低（-52%，P = 2×10⁻⁴），分数各向异性降低（-24%，P = 10⁻³），以及相对于对照者，径向扩散率增加（+56%，P = 2×10⁻⁴）、平均扩散率增加（+35%，P = 10⁻³）和轴向扩散率增加（+17%，P = 4×10⁻⁴）。纵向来看，相对于基线，脊髓横截面积每年降低2.4%（P = 4×10⁻⁴），tNAA/mIns比值每年降低5.8%（P = 0.03），分数各向异性呈降低趋势（每年-3.2%，P = 0.08）。脊髓横截面积与临床指标密切相关，在横截面积与共济失调评估和评分量表之间（R = -0.55，P = 7×10⁻⁴）以及横截面积与弗里德赖希共济失调评定量表总神经学评分之间（R = -0.60，P = 4×10⁻⁴）发现了最强的相关系数。分数各向异性和tNAA/mIns的相关性较弱但仍显著。我们在此报告了弗里德赖希共济失调患者脊髓的首个定量纵向磁共振成像结果。脊髓横截面积的纵向效应量最大，其次是tNAA/mIns和分数各向异性。我们的结果提供了直接证据，表明脊髓异常不仅源于发育不全，还源于神经退行性变，并表明可以在脊髓中对疾病进展进行非侵入性监测。
