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Combined microstuctural and sodium homeostasis alterations in ALS are widespread in fast progressors: a brain DTI and sodium MRI study1Aix Marseille Univ, CNRS, CRMBM, Marseille, France, 2APHM, Hopital de la Timone, CEMEREM, Marseille, France, 3APHM, Hôpital de la Timone, Referral Centre for Neuromuscular Diseases and ALS, Marseille, France
Synopsis
Amyotrophic lateral sclerosis (ALS) is a heterogeneous condition showing variable progression rates. Conventional MRI lacks sensitivity and specificity to detect abnormalities in ALS and is mainly used to exclude ALS-mimics. Non-conventional MRI has gradually characterized specific neurodegeneration features in ALS.The present brain DTI and sodium MRI study evidenced combined microstructural and sodium homeostasis alterations in ALS and widespread damage in fast progressors. Our results confirm previous reports showing that non-conventional MRI technics might contribute to the diagnostic work-up of patients with different clinical profiles, especially when combined with mathematical modeling enabling predicting disease progression trajectory of a single patient.
INTRODUCTION
Amyotrophic lateral sclerosis (ALS) is a relentlessly progressive neurodegenerative disorder leading to paralysis and ultimately death within 3 years. ALS is a heterogeneous condition showing variable progression rates. Conventional MRI lacks sensitivity and specificity to detect abnormalities in ALS and is mainly used to exclude ALS-mimics. Non-conventional MRI has gradually characterized specific neurodegeneration features in ALS1. Notably, diffusion MRI showed variable microstructural alterations according to disease progression rate2-3. More recently, a sodium MRI study in ALS showed increase of total sodium concentration (TSC) reflecting brain ionic homeostasis disturbance4.We aimed at investigating the topography of brain regions showing a combined microstructural and sodium homeostasis alterations in ALS subgroups according to their disease progression rates.METHODS
SubjectsPatients with ALS (n=29, mean age 54±10 years, mean disease duration (DD) 1.6±1.2 years) and age and gender-matched healthy controls (HC) (n=24, mean age 51±11 years) were recruited. Patients were clinically scored on the revised ALS Functional Rating Scale (ALSFRS-R)5,6. Patients were clinically differentiated in fast and slow progressors according to their ALFSRS-R rate of progression (i.e. [48-ALSFRS-R]/DD in months; threshold = -0.5 per month).
MRI acquisition
MRI acquisition was performed on a 3T Verio system (Siemens, Erlangen, Germany) using a 23Na-1H head coil (Rapid Biomedical, Rimpar, Germany) and a 32-channel phased-array 1H head coil.
1H-MRI protocol included a T1-weighted (T1w) 3D-Magnetization-Prepared Rapid Acquisition Gradient-Echo (MPRAGE) sequence (TE/TR/TI=3/2300/0.9 ms, 160 slices, resolution=1 mm isotropic, TA=6 min), and a diffusion EPI sequence (64 encoding directions, b=1000 s/mm2 and a b0, TE/TR=95/10700 ms, 60 contiguous slices, resolution=2 mm isotropic, TA=12 min).
23Na MRI protocol included a 3D density-adapted radial sequence (TE/TR=0.2/120 ms, 17000 projections; resolution=3.6 mm isotropic, TA=34 min) and two reference tubes of 50 mmol/L of sodium placed within the FOV for quantification4,7,8.
Data processing
Anatomical. T1w images were normalized to the Montreal National Institute 152 template standard space (MNI152)9.
Diffusion tensor imaging. Diffusion images were denoised and corrected for eddy currents and head motion10,11. Fractional anisotropy (FA), mean diffusivity (MD) maps were computed by fitting a tensor model12. Normalized and skeletonized FA and MD images were generated using TBSS-FSL tools, prior to voxel-wise analysis12,13.
Sodium imaging. Sodium images were reconstructed offline, denoised, and then normalized relative to reference tubes signal to compute quantitative TSC4,8. Spatially normalized TSC maps (MNI152) were smoothed with a Gaussian kernel (8 × 8 × 8 mm), prior to voxel-wise analysis12.
Statistical analysis
Groups comparisons. Differences for age, disease duration, gender and the ALSFRS-R score between groups were assessed using Student t-test, Kruskal-Wallis test and Chi-square test, when applies.
Voxel-wise analysis. Differences in TSC and DTI maps between groups were assessed using permutation inference statistics (5000 permutations), combined with t-testing. Threshold-free cluster enhancement (TFCE) with a significance interval of p-value < 0.05 was used to correct for multiple comparisons12.
RESULTS
There were no significant differences in demographical nor in clinical data between groups (all p-values > 0.05), except for disease progression rate between fast and slow progressors (p < 0.001) (Table 1).Both ALS patients and fast progressors showed significantly higher TSC and lower FA, higher TSC and higher MD, compared to HC mainly at the level of the body and the genu of corpus callosum, the corticospinal tracts and the corona radiata (Figure 1). Fast progressors showed wider spread abnormalities than in the whole ALS group, including additional tracts such as the forceps minor, the longitudinal fasciculus and the thalamic radiation as well as the frontal pole as demonstrated by TSC (Figure 2). In slow progressors, only FA showed abnormalities, located in focal regions of the corticospinal tracts, the body of corpus callosum, the corona radiata and the thalamic radiation, when compared to HC (Figure 3). There were no significant differences in TSC, neither in DTI between fast and slow progressors.
DISCUSSION
This study highlighted brain regions with common microstructural and sodium homeostasis disturbances corresponding to relevant regions involved in ALS. Interestingly, fast progressors showed widespread combined alterations while slow progressors only showed restricted microstructure damage. Recently, increasing evidences emphasized that heterogeneous disease progression rates influence diagnosis, prognosis and might affect the responsiveness to treatment. Therefore, there is an urgent need of patient stratification. Our results confirm previous reports showing that non-conventional and multiparametric MRI technics might contribute to the diagnostic work-up of patients with different clinical profiles1, especially when combined with mathematical modeling and artificial intelligence to predict disease progression trajectory of a single patient14.CONCLUSION
The present brain DTI and sodium MRI study evidenced combined microstuctural and sodium homeostasis alterations in ALS and widespread damage in fast progressors patients.Acknowledgements
We are grateful to all subjects and their relatives. This research was funded by APHM (AORC Junior 2014 program), ARSLA (Association pour la Recherche sur la Sclérose Latérale Amyotrophique et autres maladies du motoneurone) and FRC (Fédération pour la Recherche sur le Cerveau).References
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