Multimodal MRI improves diagnostic accuracy and sensitivity to longitudinal change in amyotrophic lateral sclerosis.

BACKGROUND: Recent advances in MRI acquisitions and image analysis have increased the utility of neuroimaging in understanding disease-related changes. In this work, we aim to demonstrate increased sensitivity to disease progression as well as improved diagnostic accuracy in Amyotrophic lateral sclerosis (ALS) with multimodal MRI of the brain and cervical spinal cord. METHODS: We acquired diffusion MRI data from the brain and cervical cord, and T1 data from the brain, of 20 participants with ALS and 20 healthy control participants. Ten ALS and 14 control participants, and 11 ALS and 13 control participants were re-scanned at 6-month and 12-month follow-ups respectively. We estimated cross-sectional differences and longitudinal changes in diffusion metrics, cortical thickness, and fixel-based microstructure measures, i.e. fiber density and fiber cross-section. RESULTS: We demonstrate improved disease diagnostic accuracy and sensitivity through multimodal analysis of brain and spinal cord metrics. The brain metrics also distinguished lower motor neuron-predominant ALS participants from control participants. Fiber density and cross-section provided the greatest sensitivity to longitudinal change. 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. More importantly, we demonstrate that longitudinal change is detectable at a six-month follow-up visit. We also report correlations between ALSFRS-R and the fiber density and cross-section metrics. CONCLUSIONS: Our findings suggest that multimodal MRI is useful in improving disease diagnosis, and fixel-based measures may serve as potential biomarkers of disease progression in ALS clinical trials.

ALS is a disease affecting the brain and spinal cord which leads to weakness and muscle wasting. It is important to be able to measure disease-related changes whilst clinical trials are ongoing to assess whether the treatments being tested are working. We imaged the brain and spinal cord of people with and without ALS at 3 time points over a year. We found changes in the brain and spine over time. This study demonstrates that brain imaging could be potentially used to assess changes in disease progression during clinical trials, giving an indication of whether the treatments being tested are having an effect.

Tract-specific analysis improves sensitivity of spinal cord diffusion MRI to cross-sectional and longitudinal changes in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a late-onset fatal neurodegenerative disease that causes progressive degeneration of motor neurons in the brain and the spinal cord. Corticospinal tract degeneration is a defining feature of ALS. However, there have been very few longitudinal, controlled studies assessing diffusion MRI (dMRI) metrics in different fiber tracts along the spinal cord in general or the corticospinal tract in particular. Here we demonstrate that a tract-specific analysis, with segmentation of ascending and descending tracts in the spinal cord white matter, substantially increases the sensitivity of dMRI to disease-related changes in ALS. Our work also identifies the tracts and spinal levels affected in ALS, supporting electrophysiologic and pathologic evidence of involvement of sensory pathways in ALS. We note changes in diffusion metrics and cord cross-sectional area, with enhanced sensitivity to disease effects through a multimodal analysis, and with strong correlations between these metrics and spinal components of ALSFRS-R.

Neurochemical correlates of functional decline in amyotrophic lateral sclerosis.

OBJECTIVE: To determine whether proton magnetic resonance spectroscopy (1H-MRS) can detect neurochemical changes in amyotrophic lateral sclerosis (ALS) associated with heterogeneous functional decline. METHODS: Nineteen participants with early-stage ALS and 18 age-matched and sex ratio-matched controls underwent ultra-high field 1H-MRS scans of the upper limb motor cortex and pons, ALS Functional Rating Scale-Revised (ALSFRS-R total, upper limb and bulbar) and upper motor neuron burden assessments in a longitudinal observational study design with follow-up assessments at 6 and 12 months. Slopes of neurochemical levels over time were compared between patient subgroups classified by the rate of upper limb or bulbar functional decline. 1H-MRS and clinical ratings at baseline were assessed for ability to predict study withdrawal due to disease progression. RESULTS: Motor cortex total N-acetylaspartate to myo-inositol ratio (tNAA:mIns) significantly declined in patients who worsened in upper limb function over the follow-up period (n=9, p=0.002). Pons glutamate + glutamine significantly increased in patients who worsened in bulbar function (n=6, p<0.0001). Neurochemical levels did not change in patients with stable function (n=5-6) or in healthy controls (n=14-16) over time. Motor cortex tNAA:mIns and ALSFRS-R at baseline were significantly lower in patients who withdrew from follow-up due to disease progression (n=6) compared with patients who completed the 12-month scan (n=10) (p<0.001 for tNAA:mIns; p<0.01 for ALSFRS-R), with a substantially larger overlap in ALSFRS-R between groups. CONCLUSION: Neurochemical changes in motor areas of the brain are associated with functional decline in corresponding body regions. 1H-MRS was a better predictor of study withdrawal due to ALS progression than ALSFRS-R.

Occurrence of post-acute recanalization and collateral formation in patients with cerebral venous and sinus thrombosis. A serial venographic study.

BACKGROUND: The underlying mechanism for symptomatic recovery in patients with cerebral venous and sinus thrombosis (CVST) is not clear, although post-acute recanalization and collateral formation have been proposed as possible mechanisms. To identify the occurrence of recanalization and collateral formation among survivors of CVST and explore its association with symptomatic recovery. METHODS: We identified all the patients admitted with CVST over a 5-year period and who underwent initial magnetic resonance (MR) or computed tomographic (CT) venography and a follow-up CT or MR venography between 3 and 12 months after onset. All the images were reviewed by a single observer using the classification for recanalization proposed by Qureshi grade I--partial recanalization of one or more occluded dural sinus with improved flow or visualization of branches; grade II--complete recanalization of one sinus but persistent occlusion of the other sinuses [A--no residual flow, B--non occlusive flow]; grade III--complete recanalization and for collateral formation (grade I--collaterals bypass occluded segment of dural venous sinus but connect within the same sinus; grade II--collaterals bypass occluded segment but connect with a different sinus; grade III--collaterals bypass the occluded segment and connect with different circulation). RESULTS: A total of 39 patients with CVST (mean age 34.82 [± 17.1 SD]; 19 were men) had an initial and follow-up venographic study performed. Of these, 21 patients underwent serial venographic imaging using the same modality allowing a direct comparison. Of the 17 patients who had recanalization during follow-up, 10 patients had grade I recanalization, 7 had grade III recanalization, and 4 had no recanalization. Collateral formation was seen in 8 patients: grade I in 3 patients, grade II in 1 patient, and grade III in 4 patients. The proportion of patients with persistent headaches appeared higher in those with no or partial recanalization than with complete recanalization (5 of 14 patients vs. 0 of 7 patients) and in patients with no collaterals than patients with collaterals (4 out of 13 vs. 1 out of 8). None of the patients experienced any recurrence or new symptoms. CONCLUSIONS: Complete or partial recanalization and collateral formation are seen in a prominent proportion of patients with CVST in the months following initial diagnosis. Further studies need to identify the temporal course and clinical significance of venographic recanalization and collateral formation, and factors influencing venographic changes.