Alterations of Microstructure and Sodium Homeostasis in Fast Amyotrophic Lateral Sclerosis Progressors: A Brain DTI and Sodium MRI Study.

BACKGROUND AND PURPOSE: While conventional MR imaging has limited value in amyotrophic lateral sclerosis, nonconventional MR imaging has shown alterations of microstructure using diffusion MR imaging and recently sodium homeostasis with sodium MR imaging. We aimed to investigate the topography of brain regions showing combined microstructural and sodium homeostasis alterations in amyotrophic lateral sclerosis subgroups according to their disease-progression rates. MATERIALS AND METHODS: Twenty-nine patients with amyotrophic lateral sclerosis and 24 age-matched healthy controls were recruited. Clinical assessments included disease duration and the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale. Patients were clinically differentiated into fast (n = 13) and slow (n = 16) progressors according to the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale progression rate. 3T MR imaging brain protocol included 1H T1-weighted and diffusion sequences and a 23Na density-adapted radial sequence. Quantitative maps of diffusion with fractional anisotropy, mean diffusivity, and total sodium concentration were measured. The topography of diffusion and sodium abnormalities was assessed by voxelwise analyses. RESULTS: Patients with amyotrophic lateral sclerosis showed significantly higher sodium concentrations and lower fractional anisotropy, along with higher sodium concentrations and higher mean diffusivity compared with healthy controls, primarily within the corticospinal tracts, corona radiata, and body and genu of the corpus callosum. Fast progressors showed wider-spread abnormalities mainly in the frontal areas. In slow progressors, only fractional anisotropy measures showed abnormalities compared with healthy controls, localized in focal regions of the corticospinal tracts, the body of corpus callosum, corona radiata, and thalamic radiation. CONCLUSIONS: The present study evidenced widespread combined microstructural and sodium homeostasis brain alterations in fast amyotrophic lateral sclerosis progressors.

Streamline density and lesion volume reveal a postero-anterior gradient of corpus callosum damage in multiple sclerosis.

BACKGROUND AND PURPOSE: Although interhemispheric disconnection significantly contributes to disability in multiple sclerosis (MS), the topography, timeline and relationship of callosal damage accrual with hemispheric damage are still unclear. METHODS: Streamline density and the presence of focal lesions in five callosal subregions were computed in 55 people with MS [13 relapsing-remitting (RRMS), 20 secondary progressive (SPMS), 22 primary progressive (PPMS)] and 24 healthy controls. RESULTS: Streamline density decrease was identified in SPMS in all corpus callosum (CC) subregions, in PPMS in the posterior CC and mid-posterior CC and in RRMS in the posterior CC. CC density was independently predicted by CC lesion volume and hemispheric lesion volume and independently predicted visuospatial memory, Expanded Disability Status Scale, manual dexterity and ambulation. CONCLUSIONS: The reduction in CC density across phenotypes suggests an earlier involvement of the posterior regions, followed only at a later stage by involvement of the anterior portions of the CC. Such interhemispheric disconnection seems to develop as a consequence of white matter macroscopic damage and exerts a relevant impact on motor and, to a lesser extent, cognitive disability.

Spinal Cord Gray Matter Atrophy in Amyotrophic Lateral Sclerosis.

BACKGROUND AND PURPOSE: There is an emerging need for biomarkers to better categorize clinical phenotypes and predict progression in amyotrophic lateral sclerosis. This study aimed to quantify cervical spinal gray matter atrophy in amyotrophic lateral sclerosis and investigate its association with clinical disability at baseline and after 1 year. MATERIALS AND METHODS: Twenty-nine patients with amyotrophic lateral sclerosis and 22 healthy controls were scanned with 3T MR imaging. Standard functional scale was recorded at the time of MR imaging and after 1 year. MR imaging data were processed automatically to measure the spinal cord, gray matter, and white matter cross-sectional areas. A statistical analysis assessed the difference in cross-sectional areas between patients with amyotrophic lateral sclerosis and controls, correlations between spinal cord and gray matter atrophy to clinical disability at baseline and at 1 year, and prediction of clinical disability at 1 year. RESULTS: Gray matter atrophy was more sensitive to discriminate patients with amyotrophic lateral sclerosis from controls (P = .004) compared with spinal cord atrophy (P = .02). Gray matter and spinal cord cross-sectional areas showed good correlations with clinical scores at baseline (R = 0.56 for gray matter and R = 0.55 for spinal cord; P < .01). Prediction at 1 year with clinical scores (R2 = 0.54) was improved when including a combination of gray matter and white matter cross-sectional areas (R2 = 0.74). CONCLUSIONS: Although improvements over spinal cord cross-sectional areas were modest, this study suggests the potential use of gray matter cross-sectional areas as an MR imaging structural biomarker to monitor the evolution of amyotrophic lateral sclerosis.

Spinal cord multi-parametric magnetic resonance imaging for survival prediction in amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Assessing survival is a critical issue in patients with amyotrophic lateral sclerosis (ALS). Neuroimaging seems to be promising in the assessment of disease severity and several studies also suggest a strong relationship between spinal cord (SC) atrophy described by magnetic resonance imaging (MRI) and disease progression. The aim of the study was to determine the predictive added value of multimodal SC MRI on survival. METHODS: Forty-nine ALS patients were recruited and clinical data were collected. Patients were scored on the Revised ALS Functional Rating Scale and manual muscle testing. They were followed longitudinally to assess survival. The cervical SC was imaged using the 3 T MRI system. Cord volume and cross-sectional area (CSA) at each vertebral level were computed. Diffusion tensor imaging metrics were measured. Imaging metrics and clinical variables were used as inputs for a multivariate Cox regression survival model. RESULTS: On building a multivariate Cox regression model with clinical and MRI parameters, fractional anisotropy, magnetization transfer ratio and CSA at C2-C3, C4-C5, C5-C6 and C6-C7 vertebral levels were significant. Moreover, the hazard ratio calculated for CSA at the C3-C4 and C5-C6 levels indicated an increased risk for patients with SC atrophy (respectively 0.66 and 0.68). In our cohort, MRI parameters seem to be more predictive than clinical variables, which had a hazard ratio very close to 1. CONCLUSIONS: It is suggested that multimodal SC MRI could be a useful tool in survival prediction especially if used at the beginning of the disease and when combined with clinical variables. To validate it as a biomarker, confirmation of the results in bigger independent cohorts of patients is warranted.

The value of magnetic resonance imaging as a biomarker for amyotrophic lateral sclerosis: a systematic review.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal, rapidly progressive neurodegenerative disease that mainly affects the motor system. A number of potentially neuroprotective and neurorestorative disease-modifying drugs are currently in clinical development. At present, the evaluation of a drug's clinical efficacy in ALS is based on the ALS Functional Rating Scale Revised, motor tests and survival. However, these endpoints are general, variable and late-stage measures of the ALS disease process and thus require the long-term assessment of large cohorts. Hence, there is a need for more sensitive radiological biomarkers. Various sequences for magnetic resonance imaging (MRI) of the brain and spinal cord have may have value as surrogate biomarkers for use in future clinical trials. Here, we review the MRI findings in ALS, their clinical correlations, and their limitations and potential role as biomarkers. METHODS: The PubMed database was screened to identify studies using MRI in ALS. We included general MRI studies with a control group and an ALS group and longitudinal studies even if a control group was lacking. RESULTS: A total of 116 studies were analysed with MRI data and clinical correlations. The most disease-sensitive MRI patterns are in motor regions but the brain is more broadly affected. CONCLUSION: Despite the existing MRI biomarkers, there is a need for large cohorts with long term MRI and clinical follow-up. MRI assessment could be improved by standardized MRI protocols with multicentre studies.

Demyelination and degeneration in the injured human spinal cord detected with diffusion and magnetization transfer MRI.

Characterizing demyelination/degeneration of spinal pathways in traumatic spinal cord injured (SCI) patients is crucial for assessing the prognosis of functional rehabilitation. Novel techniques based on diffusion-weighted (DW) magnetic resonance imaging (MRI) and magnetization transfer (MT) imaging provide sensitive and specific markers of white matter pathology. In this paper we combined for the first time high angular resolution diffusion-weighted imaging (HARDI), MT imaging and atrophy measurements to evaluate the cervical spinal cord of fourteen SCI patients and age-matched controls. We used high in-plane resolution to delineate dorsal and ventrolateral pathways. Significant differences were detected between patients and controls in the normal-appearing white matter for fractional anisotropy (FA, p<0.0001), axial diffusivity (p<0.05), radial diffusivity (p<0.05), generalized fractional anisotropy (GFA, p<0.0001), magnetization transfer ratio (MTR, p<0.0001) and cord area (p<0.05). No significant difference was detected in mean diffusivity (p=0.41), T1-weighted (p=0.76) and T2-weighted (p=0.09) signals. MRI metrics were remarkably well correlated with clinical disability (Pearson's correlations, FA: p<0.01, GFA: p<0.01, radial diffusivity: p=0.01, MTR: p=0.04 and atrophy: p<0.01). Stepwise linear regressions showed that measures of MTR in the dorsal spinal cord predicted the sensory disability whereas measures of MTR in the ventro-lateral spinal cord predicted the motor disability (ASIA score). However, diffusion metrics were not specific to the sensorimotor scores. Due to the specificity of axial and radial diffusivity and MT measurements, results suggest the detection of demyelination and degeneration in SCI patients. Combining HARDI with MT imaging is a promising approach to gain specificity in characterizing spinal cord pathways in traumatic injury.