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Background and Objectives: To investigate whether age at onset influences brain gray matter volume (GMV) and white matter (WM) microstructural abnormalities in adult patients with multiple sclerosis (MS), given its influence on clinical phenotype and disease course., Methods: In this hypothesis-driven cross-sectional study, we enrolled 67 patients with pediatric-onset MS (POMS) and 143 sex- and disease duration (DD)-matched randomly selected patients with adult-onset MS (AOMS), together with 208 healthy controls. All participants underwent neurologic evaluation and 3T MRI acquisition. MRI variables were standardized based on healthy controls, to remove effects of age and sex. Associations with DD in patients with POMS and patients with AOMS were studied with linear models. Time to reach clinical and MRI milestones was assessed with product-limit approach., Results: At DD 1 year, GMV and WM fractional anisotropy (FA) were abnormal in AOMS but not in POMS. Significant interaction of age at onset (POMS vs AOMS) into the association with DD was found for GMV and WM FA. The crossing point of regression lines in POMS and AOMS was at 20 years of DD for GMV and 14 for WM FA. For POMS and AOMS, median DD was 29 and 19 years to reach Expanded Disability Status Scale score 3 ( p < 0.001), 31 and 26 years to reach abnormal Paced Auditory Serial Addition Task, 3-second version ( p = 0.01), 24 and 18 years to reach abnormal GMV ( p = 0.04), and 19 and 17 years to reach abnormal WM FA ( p = 0.36)., Discussion: Younger patients are initially resilient to MS-related damage. Then, compensatory mechanisms start failing with loss of WM integrity, followed by GM atrophy and finally disability., (© 2021 American Academy of Neurology.)

Objective: To explore cross-sectional and longitudinal gray matter (GM) volume changes in patients with migraine and their association with patients' clinical characteristics and disease activity., Methods: Brain T2-weighted and 3-dimensional T1-weighted scans were acquired from 73 episodic migraineurs and 46 age- and sex-matched nonmigraine controls at baseline. Twenty-four migraineurs and 25 controls agreed to be reexamined after a mean follow-up of 4 years. Using a general linear model and SPM12, a whole-brain analysis was performed to assess GM volume modifications., Results: At baseline, compared to controls, patients with migraine showed lower cerebellar GM volume and higher volume of regions of the frontotemporal lobes. At follow-up, migraineurs were significantly older than controls. Over the follow-up, migraineurs developed an increased volume of frontotemporoparietal regions, which was more prominent in patients with a higher baseline disease activity: long disease duration and high attack frequency. Migraineurs also developed decreased GM volume of visual areas, which was related to higher pain severity. Patients with an increased attack frequency at follow-up experienced both increased and decreased volume of nociceptive regions. In migraineurs, reduced GM volume of extrastriate visual areas during the follow-up was significantly correlated to baseline disease activity: shorter disease duration and lower attack frequency., Conclusion: In this cohort, the migraine brain changes dynamically over time, and different pathophysiologic mechanisms can occur in response to patients' disease severity. The interaction between predisposing brain traits and experience-dependent responses might vary across different nociceptive and visual areas, thus leading to distinct patterns of longitudinal GM volume changes., (© 2018 American Academy of Neurology.)

Objective: To explore structural and functional changes of the brain and cervical cord in patients with amyotrophic lateral sclerosis (ALS) due to mutation in the superoxide dismutase ( SOD1 ) gene compared with sporadic ALS., Methods: Twenty patients with SOD1 ALS, 11 with sporadic ALS, and 33 healthy controls underwent clinical evaluation and brain MRI. Cortical thickness analysis, diffusion tensor MRI of the corticospinal tracts (CST) and corpus callosum, and resting-state functional connectivity were performed. Patients with ALS also underwent cervical cord MRI to evaluate cord cross-sectional area and magnetization transfer ratio (MTR)., Results: Patients with SOD1 ALS showed longer disease duration and slower rate of functional decline relative to those with sporadic ALS. No cortical thickness abnormalities were found in patients with ALS compared with controls. Fractional anisotropy showed that sporadic ALS patients had significant CST damage relative to both healthy controls ( p = 0.001-0.02) and SOD1-related ALS ( p = 0.05), although the latter showed alterations that were intermediate between controls and sporadic ALS. Functional hyperconnectivity of the motor cortex in the sensorimotor network was observed in patients with sporadic ALS relative to controls. Conversely, patients with SOD1 ALS showed lower cord cross-sectional area along the whole cervical cord relative to those with sporadic ALS ( p < 0.001). No cord MTR differences were found between patient groups., Conclusions: Patients with SOD1 ALS showed cervical cord atrophy relative to those with sporadic ALS and a relative preservation of brain motor structural and functional networks. Neurodegeneration in SOD1 ALS is likely to occur primarily in the spinal cord. An objective and accurate estimate of spinal cord damage has potential in the future assessment of preventive SOD1 ALS therapies., (© 2018 American Academy of Neurology.)

Objective: To explore the structural and functional integrity of the sustained attention system in patients with pediatric multiple sclerosis (MS) and its effect on cognitive impairment., Methods: We enrolled 57 patients with pediatric MS and 14 age- and sex-matched healthy controls (HCs). Patients with >3 abnormal tests at neuropsychological evaluation were classified as cognitively impaired (CI). Sustained attention system activity was studied with fMRI during the Conners Continuous Performance Test (CCPT). Structural integrity of attention network connections was quantified with diffusion tensor (DT) MRI., Results: Within-group analysis showed similar patterns of recruitment of the attention network in HCs and patients with pediatric MS. Diffuse network DT MRI structural abnormalities were found in patients with MS. During CCPT, with increasing task demand, patients with pediatric MS showed increased activation of the left thalamus, anterior insula, and anterior cingulate cortex (ACC) and decreased recruitment of the right precuneus compared to HCs. Thirteen patients (23%) were classified as CI. Compared to cognitively preserved patients, CI patients with pediatric MS had decreased recruitment of several areas located mainly in parietal and occipital lobes and cerebellum and increased deactivation of the ACC, combined with more severe structural damage of white matter tracts connecting these regions., Conclusions: Our results suggest that the age-expected level of sustained attention system functional competence is achieved in patients with pediatric MS. Inefficient regulation of the functional interaction between different areas of this system, due to abnormal white matter integrity, may result in global cognitive impairment in these patients., (© 2017 American Academy of Neurology.)

Patients with the main clinical phenotypes of multiple sclerosis (MS) manifest varying degrees of brain atrophy beyond that of normal aging. Assessment of atrophy helps to distinguish clinically and cognitively deteriorating patients and predicts those who will have a less-favorable clinical outcome over the long term. Atrophy can be measured from brain MRI scans, and many technological improvements have been made over the last few years. Several software tools, with differing requirements on technical ability and levels of operator intervention, are currently available and have already been applied in research or clinical trial settings. Despite this, the measurement of atrophy in routine clinical practice remains an unmet need. After a short summary of the pathologic substrates of brain atrophy in MS, this review attempts to guide the clinician towards a better understanding of the methods currently used for quantifying brain atrophy in this condition. Important physiologic factors that affect brain volume measures are also considered. Finally, the most recent research on brain atrophy in MS is summarized, including whole brain and various compartments thereof (i.e., white matter, gray matter, selected CNS structures). Current methods provide sufficient precision for cohort studies, but are not adequate for confidently assessing changes in individual patients over the scale of months or a few years., (© 2016 American Academy of Neurology.)