Progressive Neurochemical Abnormalities in Cognitive and Motor Subgroups of Amyotrophic Lateral Sclerosis: A Prospective Multicenter Study.

OBJECTIVE: To evaluate progressive cerebral degeneration in amyotrophic lateral sclerosis (ALS) by assessing alterations in N-acetylaspartate (NAA) ratios in the motor and prefrontal cortex within clinical subgroups of ALS. METHODS: Seventy-six patients with ALS and 59 healthy controls were enrolled in a prospective, longitudinal, multicenter study in the Canadian ALS Neuroimaging Consortium. Participants underwent serial clinical evaluations and magnetic resonance spectroscopy at baseline and 4 and 8 months using a harmonized protocol across 5 centers. NAA ratios were quantified in the motor cortex and prefrontal cortex. Patients were stratified into subgroups based on disease progression rate, upper motor neuron (UMN) signs, and cognitive status. Linear mixed models were used for baseline and longitudinal comparisons of NAA metabolite ratios. RESULTS: Patients with ALS had reduced NAA ratios in the motor cortex at baseline (p < 0.001). Ratios were lower in those with more rapid disease progression and greater UMN signs (p < 0.05). A longitudinal decline in NAA ratios was observed in the motor cortex in the rapidly progressing (p < 0.01) and high UMN burden (p < 0.01) cohorts. The severity of UMN signs did not change significantly over time. NAA ratios were reduced in the prefrontal cortex only in cognitively impaired patients (p < 0.05); prefrontal cortex metabolites did not change over time. CONCLUSIONS: Progressive degeneration of the motor cortex in ALS is associated with more aggressive clinical presentations. These findings provide biological evidence of variable spatial and temporal cerebral degeneration linked to the disease heterogeneity of ALS. The use of standardized imaging protocols may have a role in clinical trials for patient selection or subgrouping. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that MRS NAA metabolite ratios of the motor cortex are associated with more rapid disease progression and greater UMN signs in patients with ALS. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT02405182.

Age effects on voxel-based relaxometry used for epileptic patients.

PURPOSE: T2 voxel-based relaxometry (VBR) is a technique that allows for a quantitative, unbiased analysis of T2 relaxation time across the whole brain. Previous studies have shown that this technique is effective for clinical analysis of single patients; however, the effects of age normal age-related changes on these data were unknown. Our study was therefore designed to assess the effect of normal aging on VBR data. METHODS: A linear regression with age as a predictor of T2 was run in both a (1) whole-brain voxel-based manner to determine regions which showed significant age-related change and subsequently (2) on a selection of regions-of-interest to allow for a more detailed analysis of the trends. RESULTS: T2 estimates showed a significant increase with age in the frontal lobe white matter and a significant decrease with age in the putamen with region-of-interest and voxel-based regressions (p<0.05). There was also a general trend for T2 to decrease in inferior temporal lobe grey matter in the voxel-based regression. CONCLUSIONS: Age causes changes in T2 relaxation time in healthy control subjects, with increases being observed in frontal lobe white matter and decreases in the putamen. These changes should be accounted for when interpreting single subject VBR data.

Single-subject voxel-based relaxometry for clinical assessment of temporal lobe epilepsy.

PURPOSE: T2 relaxometry, quantitative assessment of T2 relaxation time in magnetic resonance (MR) data, typically uses manually drawn regions of interest (ROIs). This approach is limited by its subjectivity and its restricted scope of investigation. A recently developed approach called voxel-based relaxometry (VBR) provides an unbiased statistical analysis of the whole brain. Our objective was to assess the clinical utility of single-subject VBR for patients with temporal lobe epilepsy (TLE). METHODS: Forty-five patients with TLE confirmed by history, EEG, and structural MRI and 25 control subjects were scanned at 3T using a modified Carr-Purcell-Meiboom-Gill MR sequence. ROIs were drawn for each patient and control subject, and measurements were made on unregistered T2 maps. VBR was performed on a single-subject basis at a significance level of alpha=0.05. Patients were grouped according to seizure focus (left mesial, right mesial, other), and whether structural MR imaging was normal or abnormal. RESULTS: Up to 85% of patients in the temporal lobe groups demonstrated T2 abnormalities. VBR detected abnormalities either in equal numbers or in more patients (up to 23% more) than ROI analysis for each group. The number of detected abnormalities per patient was higher using VBR (3.38 versus 2.04, p<0.05). VBR also identified abnormalities that were missed by ROI analysis. The rate of VBR detection of abnormalities was higher for patients than controls (76% versus 36%). CONCLUSIONS: VBR can be performed on single subjects with TLE and it detects considerably more abnormalities than ROI analysis. VBR may be a clinically useful tool for the detection of T2 abnormalities at the seizure focus and sites remote from it.