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MRI plays a central role in the diagnosis of multiple sclerosis (MS) and in the monitoring of disease course and treatment response. Advanced MRI techniques have shed light on MS biology and facilitated the search for neuroimaging markers that may be applicable in clinical practice. MRI has led to improvements in the accuracy of MS diagnosis and a deeper understanding of disease progression. This has also resulted in a plethora of potential MRI markers, the importance and validity of which remain to be proven. Here, five recent emerging perspectives arising from the use of MRI in MS, from pathophysiology to clinical application, will be discussed. These are the feasibility of noninvasive MRI-based approaches to measure glymphatic function and its impairment; T1-weighted to T2-weighted intensity ratio to quantify myelin content; classification of MS phenotypes based on their MRI features rather than on their clinical features; clinical relevance of gray matter atrophy versus white matter atrophy; and time-varying versus static resting-state functional connectivity in evaluating brain functional organization. These topics are critically discussed, which may guide future applications in the field., (© RSNA, 2023.)

Background Altered callosal integrity has been associated with motor deficits in patients with multiple sclerosis (MS), but its contribution to disability has, to the knowledge of the authors, not been investigated by using multiparametric MRI approaches. Purpose To investigate structural and functional interhemispheric MRI substrates of global disability at different milestones and upper limb motor impairment in MS. Materials and Methods In this cross-sectional study, healthy control patients and patients with MS (between January 1, 2008, and December 31, 2016) were retrospectively selected from our hospital database. Clinical assessment included Expanded Disability Status Scale (EDSS), nine-hole peg test, and digital finger tapping test. By using structural and resting-state functional MRI sequences, probabilistic tractography of hand corticospinal tract fibers, and transcallosal fibers between hand-motor cortices (hereafter, referred to as hand-M1), supplementary motor areas (SMAs), premotor cortices (PMCs), and voxel-mirror homotopic connectivity (VMHC) were analyzed. Random forest analyses identified the MRI predictors of clinical disability at different milestones (EDSS scores of 3.0, 4.0, 6.0) and upper limb motor impairment (nine-hole peg test and finger tapping test z scores < healthy control patients 5th percentile). Results One-hundred thirty healthy control patients (median age, 39 years; interquartile range, 31-50 years; 70 women) and 340 patients with MS (median age, 43 years; interquartile range, 33-51 years; 213 women) were studied. EDSS 3.0 predictors ( n = 159) were global measures of atrophy and lesions together with damage measures of corticospinal tracts and transcallosal fibers between PMCs and SMAs (accuracy, 86%; P = .001-.01). For EDSS 4.0 ( n = 131), similar predictors were found in addition to damage in transcallosal fibers between hand-M1 (accuracy, 89%; P = .001-.049). No MRI predictors were found for EDSS 6.0 ( n = 70). Nine-hole peg test (right, n = 161; left, n = 166) and finger tapping test (right, n = 117; left, n = 111) impairments were predicted by damage in transcallosal fibers between SMAs and PMCs (accuracy range, 69%-77%; P = .001-.049). VMHC abnormalities did not explain clinical outcomes. Conclusion Structural, not functional, abnormalities at MRI in transcallosal premotor and motor white matter fibers predicted severity of global disability and upper limb motor impairment in patients with multiple sclerosis. The informative role of such predictors appeared less evident at higher disability levels. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Barkhof and Pontillo in this issue.

Background In multiple sclerosis (MS), knowledge about how spinal cord abnormalities translate into clinical manifestations is incomplete. Comprehensive, multiparametric MRI studies are useful in this perspective, but studies for the spinal cord are lacking. Purpose To identify MRI features of cervical spinal cord damage that could help predict disability and disease course in MS by using a comprehensive, multiparametric MRI approach. Materials and Methods In this retrospective hypothesis-driven analysis of longitudinally acquired data between June 2017 and April 2019, 120 patients with MS (58 with relapsing-remitting MS [RRMS] and 62 with progressive MS [PMS]) and 30 age- and sex-matched healthy control participants underwent 3.0-T MRI of the brain and cervical spinal cord. Cervical spinal cord MRI was performed with three-dimensional (3D) T1-weighted, T2-weighted, and diffusion-weighted imaging; sagittal two-dimensional (2D) short inversion time inversion-recovery imaging; and axial 2D phase-sensitive inversion-recovery imaging at the C2-C3 level. Brain MRI was performed with 3D T1-weighted, fluid-attenuated inversion-recovery and T2-weighted sequences. Associations between MRI variables and disability were explored with age-, sex- and phenotype-adjusted linear models. Results In patients with MS, multivariable analysis identified phenotype, cervical spinal cord gray matter (GM) cross-sectional area (CSA), lateral funiculi fractional anisotropy (FA), and brain GM volume as independent predictors of Expanded Disability Status Scale (EDSS) score ( R 2 = 0.86). The independent predictors of EDSS score in RRMS were lateral funiculi FA, normalized brain volume, and cervical spinal cord GM T2 lesion volume ( R 2 = 0.51). The independent predictors of EDSS score in PMS were cervical spinal cord GM CSA and brain GM volume ( R 2 = 0.44). Logistic regression analysis identified cervical spinal cord GM CSA and T2 lesion volume as independent predictors of phenotype (area under the receiver operating characteristic curve = 0.95). An optimal cervical spinal cord GM CSA cut-off value of 11.1 mm 2 was found to enable accurate differentiation of patients with PMS, having values below the threshold, from those with RRMS (sensitivity = 90% [56 of 62], specificity = 91% [53 of 58]). Conclusion Cervical spinal cord MRI involvement has a central role in explaining disability in multiple sclerosis (MS): Lesion-induced damage in the lateral funiculi and gray matter (GM) in relapsing-remitting MS and GM atrophy in patients with progressive MS are the most relevant variables. Cervical spinal cord GM atrophy is an accurate predictor of progressive phenotype. Cervical spinal cord GM lesions may subsequently cause GM atrophy, which may contribute to evolution to PMS. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Zivadinov and Bergsland in this issue.

Purpose: To assess brachial plexus magnetic resonance (MR) imaging features and limb-girdle muscle abnormalities as signs of muscle denervation in patients with amyotrophic lateral sclerosis (ALS)., Materials and Methods: This study was approved by the local ethical committees on human studies, and written informed consent was obtained from all subjects before enrollment. By using an optimized protocol of brachial plexus MR imaging, brachial plexus and limb-girdle muscle abnormalities were evaluated in 23 patients with ALS and clinical and neurophysiologically active involvement of the upper limbs and were compared with MR images in 12 age-matched healthy individuals. Nerve root and limb-girdle muscle abnormalities were visually evaluated by two experienced observers. A region of interest-based analysis was performed to measure nerve root volume and T2 signal intensity. Measures obtained at visual inspection were analyzed by using the Wald χ(2) test. Mean T2 signal intensity and volume values of the regions of interest were compared between groups by using a hierarchical linear model, accounting for the repeated measurement design., Results: The level of interrater agreement was very strong (κ = 0.77-1). T2 hyperintensity and volume alterations of C5, C6, and C7 nerve roots were observed in patients with ALS (P < .001 to .03). Increased T2 signal intensity of nerve roots was associated with faster disease progression (upper-limb Medical Research Council scale progression rate, r = 0.40; 95% confidence interval: 0.001, 0.73). Limb-girdle muscle alterations (ie, T2 signal intensity alteration, edema, atrophy) and fat infiltration also were found, in particular, in the supraspinatus muscle, showing more frequent T2 signal intensity alterations and edema (P = .01) relative to the subscapularis and infraspinatus muscles., Conclusion: Increased T2 signal intensity and volume of brachial nerve roots do not exclude a diagnosis of ALS and suggest involvement of the peripheral nervous system in the ALS pathogenetic cascade. MR imaging of the peripheral nervous system and the limb-girdle muscle may be useful for monitoring the evolution of ALS and distinguishing patients with ALS from those with inflammatory neuropathy, respectively., ((©) RSNA, 2015.)

Purpose: To investigate the patterns of regional gray matter (GM) and white matter (WM) atrophy, WM microstructural tissue damage, and changes in patients with a clinically isolated syndrome (CIS) suggestive of multiple sclerosis at 2 years from clinical onset., Materials and Methods: Institutional review board approval and written informed consent from all patients were obtained. Neurologic assessment and conventional, diffusion-tensor, and volumetric brain MR imaging sequences were performed in 37 patients with CIS within 2 months of clinical onset, and after 3, 12, and 24 months. Fourteen healthy control subjects also were studied. Longitudinal GM and WM volume changes and WM microstructural abnormalities were assessed by using voxel-based morphometry (P < .001, uncorrected) and tract-based spatial statistics (P < .05, corrected)., Results: At 24 months, 33 of 37 (89%) patients had developed multiple sclerosis. At month 3, patients with CIS showed a transient volume increase in frontal, parietal, temporal, and cerebellar GM regions. At 12 months, patients with CIS developed atrophy of the thalami, caudate nuclei, cerebellum, and frontal, parietal, and temporal lobes. At 24 months GM volume of the frontal, temporal, and parietal cortical areas further decreased from that at 12 months. WM atrophy involved only a few WM regions at 2 months from clinical onset, with progressive involvement of additional WM tracts with time. A diffuse pattern of WM microstructural abnormalities was detected within 2 months of onset and had worsened at 24 months., Conclusion: After an acute inflammatory event, dynamic modifications of regional GM and WM damage occur in patients with CIS, with a progressive evolution of WM damage from disease onset and a transient, early increase in GM volume, followed by GM atrophy. Neurodegenerative processes start early in patients with multiple sclerosis.

Purpose: To investigate whether specific patterns of brain gray matter (GM) regional volumes and white matter (WM) microstructural abnormalities and spinal cord atrophy occur in patients with pure and complicated hereditary spastic paraplegias (HSPs). Relationships between clinical and cognitive features of patients with HSP who had brain and cervical cord damage were also investigated., Materials and Methods: This study was approved by the local ethical committees on human studies, and written informed consent from all subjects was obtained prior to enrollment. Forty-four patients with HSP (20 genetically defined cases and 24 without genetic diagnosis) and 19 healthy control subjects underwent clinical, neuropsychological, and advanced magnetic resonance (MR) imaging evaluations. Patterns of GM atrophy and WM microstructural damage obtained by using structural and diffusion-tensor MR imaging were compared between groups. Cervical cord atrophy was also assessed by using an active surface method. Correlations between clinical, cognitive, and diffusion-tensor MR imaging measures were evaluated., Results: Clinical data showed that spastic paraplegia is accompanied by a number of other features, including sensory disturbances, and verbal and spatial memory deficits, not only in complicated HSP but also in pure HSP. MR imaging demonstrated a similar involvement of motor, association, and cerebellar WM pathways (P < .05, family-wise error corrected for multiple comparisons) and cervical cord (P < .001) in patients with HSP relative to healthy control subjects, regardless of their clinical picture. The severity of WM damage correlated with the degree of spasticity (P < .05, family-wise error corrected) and cognitive impairment (r values, -0.39 to 0.51; P values, .001-.05) in both pure and complicated HSP., Conclusion: The detection of a distributed pattern of central nervous system damage in patients with pure and complicated HSP suggests that the "primary" corticospinal tract involvement known to occur in these patients may be associated with a neurodegenerative process, which spreads out to extramotor regions, likely via anatomic connections. This observation is in line with emerging pieces of evidence that, independent of the clinical phenotype, there is a common neurodegenerative cascade shared by different neurologic disorders.

Purpose: To use magnetic resonance (MR) imaging and advanced analysis to assess the role of lesions in normal-appearing white matter ( NAWM normal-appearing white matter ) and gray matter ( GM gray matter ) damage, global versus regional damage, and atrophy versus microstructural abnormalities in the pathogenesis of fatigue in multiple sclerosis ( MS multiple sclerosis )., Materials and Methods: Local ethics committee approval and written informed consent were obtained. Dual-echo, double inversion-recovery, high-resolution T1-weighted and diffusion-tensor ( DT diffusion tensor ) MR was performed in 31 fatigued patients, 32 nonfatigued patients, and 35 control subjects. Global and regional atrophy and DT diffusion tensor MR measures of damage to lesions, NAWM normal-appearing white matter , and GM gray matter were compared (analysis of variance)., Results: Lesional, atrophy, and DT diffusion tensor MR measures of global damage to brain, white matter ( WM white matter ), and GM gray matter did not differ between fatigued and nonfatigued patients. Compared with nonfatigued patients and control subjects, fatigued patients experienced atrophy of the right side of the accumbens (mean volume ± standard deviation, 0.37 mL ± 0.09 in control subjects; 0.39 mL ± 0.1 in nonfatigued patients; and 0.33 mL ± 0.09 in fatigued patients), right inferior temporal gyrus ( ITG inferior temporal gyrus ) (Montreal Neurological Institute [ MNI Montreal Neurological Institute ] coordinates: 51, -51, -11; t value, 4.83), left superior frontal gyrus ( MNI Montreal Neurological Institute coordinates: -10, 49, 24; t value, 3.40), and forceps major ( MNI Montreal Neurological Institute coordinates: 11, -91, 18; t value, 3.37). They also had lower fractional anisotropy ( FA fractional anisotropy ) of forceps major ( MNI Montreal Neurological Institute coordinates: -17, -78, 6), left inferior fronto-occipital fasciculus ( MNI Montreal Neurological Institute coordinates: -25, 2, -11), and right anterior thalamic radiation ( ATR anterior thalamic radiation ) ( MNI Montreal Neurological Institute coordinates: 11, 2, -6) (P < .05, corrected). More lesions were found at T2-weighted imaging in fatigued patients. Multivariable model was used to identify right ITG inferior temporal gyrus atrophy (odds ratio, 0.83; 95% confidence interval [ CI confidence interval ]: 0.82, 0.97; P = .009) and right ATR anterior thalamic radiation FA fractional anisotropy (odds ratio, 0.74; 95% CI confidence interval : 0.61, 0.90; P = .003) as covariates independently associated with fatigue (C statistic, 0.85)., Conclusion: Damage to strategic brain WM white matter and GM gray matter regions, in terms of microstructural abnormalities and atrophy, contributes to pathogenesis of fatigue in MS multiple sclerosis , whereas global lesional, WM white matter , and GM gray matter damage does not seem to have a role.

Purpose: To assess whether a structural disconnection between the cerebellum and the cerebral hemispheres contributes to cerebellar and brainstem symptoms in multiple sclerosis (MS)., Materials and Methods: This study was approved by the local ethics committee, and written informed consent was obtained from each participant. Brain T2 lesion load, cerebellar white matter and gray matter volumes, and tract-specific measures of the middle and superior cerebellar peduncles were derived from 172 patients with MS and 46 control subjects. Predictors of clinical impairment, which was determined at ambulation and with cerebellar and brainstem functional system scores, were identified by using random forest analysis., Results: Of the 172 patients, 112 (65%) had middle cerebellar peduncle T2 lesions and 74 (43%) had superior cerebellar peduncle T2 lesions. T2 lesions in the middle and superior cerebellar peduncles were more common in clinically impaired patients than in unimpaired patients (P = .05 to <.0001). Most conventional magnetic resonance imaging metrics were more abnormal in impaired patients than in unimpaired patients (P = .03 to <.0001). Except for axial diffusivity, diffusivity abnormalities of the middle and superior cerebellar peduncles were more severe in clinically impaired patients than in unimpaired patients (P = .04 to <.0001). A minimal overlap was found between diffusivity abnormalities and T2 lesions. Compared with volumetric measures of T2 lesions or cerebellar atrophy, diffusivity measures of middle or superior cerebellar peduncle damage enabled better differentiation between clinically impaired and unimpaired patients (C statistics: 61%-70%)., Conclusion: The assessment of middle and superior cerebellar peduncle damage contributes to the explanation of cerebellar and/or brainstem symptoms and ambulatory impairment in MS.

Purpose: To evaluate brain changes after cognitive rehabilitation in patients with clinically stable relapsing-remitting (RR) multiple sclerosis (MS) by using neuropsychologic assessment and structural and functional magnetic resonance (MR) imaging techniques., Materials and Methods: The study was conducted with approval of the involved institutional review boards. Written informed consent was obtained from each participant. Twenty patients with RR MS and cognitive deficits at baseline were randomly assigned to undergo treatment (n = 10), which entailed computer-assisted cognitive rehabilitation of attention and information processing and executive functions, or to serve as a control subjects (n = 10) without cognitive rehabilitation. All patients underwent a standardized neuropsychologic assessment and MR imaging at baseline and after 12 weeks. Changes in gray matter (GM) volumes on three-dimensional T1-weighted images and changes in normal-appearing white matter (NAWM) architecture on diffusion-weighted images were assessed. Changes in functional activity at functional MR imaging during the Stroop task and at rest were also investigated by using linear models., Results: As compared with their performance at baseline, the patients in the treatment group improved at tests of attention and information processing and executive functions. Neither structural modifications to GM volume nor modifications to NAWM architecture were detected at follow-up in both groups. Functional MR imaging demonstrated modifications of the activity of the posterior cingulate cortex (PCC)/precuneus and dorsolateral prefrontal cortex (PFC) during the Stroop task, as well as modifications of the activity of the anterior cingulum, PCC and/or precuneus, left dorsolateral PFC, and right inferior parietal lobule at rest in the treatment group compared with the control group. In the treatment group, functional MR imaging changes were correlated with cognitive improvement (P < .0001 to .01)., Conclusion: Rehabilitation of attention and information processing and executive functions in RR MS may be effected through enhanced recruitment of brain networks subserving the trained functions., (© RSNA, 2012.)

Purpose: To apply voxelwise analysis of diffusion-tensor (DT) magnetic resonance (MR) tractography and T2-weighted MR lesion measurements to characterize intrinsic damage to the brain white matter (WM) tracts and the relation of this damage to the presence and location of focal lesions among the main clinical phenotypes of multiple sclerosis (MS)., Materials and Methods: The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Brain dual-echo and DT MR images were obtained in 172 patients with MS (22 [13%] with clinically isolated syndromes [CIS] suggestive of MS, 51 [30%] with relapsing-remitting [RR] MS, 44 [26%] with secondary progressive MS, 20 [12%] with benign MS, 35 [20%] with primary progressive MS) and 46 healthy control subjects. Probability maps of the major brain WM tracts were produced. Between-group comparisons were assessed by using analysis of covariance., Results: Compared with the healthy control subjects, the patients with CIS had significantly increased (P < .001) mean diffusivity, axial diffusivity, and radial diffusivity in the majority of WM tracts. The primary progressive MS group showed diffuse increases in mean, axial, and radial diffusivity, with fractional anisotropy (FA) damage involving the majority of WM tracts. No relevant difference in diffusivity measures was found between the CIS and RR-MS groups. Compared with the benign MS group, the RR-MS group had reduced FA values in all WM tracts and decreased axial diffusivity in the majority of tracts. The secondary progressive MS group had pronounced damage to the majority of tracts and, compared with the benign MS group, pronounced FA alteration of the tracts relevant for motor impairment., Conclusion: Voxelwise assessment of DT MR index abnormalities is a rewarding strategy for understanding the heterogeneity of clinical MS phenotypes., (© RSNA, 2011.)

Purpose: To estimate the relative contributions of baseline thalamic atrophy and abnormalities shown at magnetization transfer (MT) magnetic resonance (MR) imaging, as well as their 12-month changes, in predicting accumulation of disability in a relatively large sample of patients with relapse-onset multiple sclerosis (MS) during an 8-year period., Materials and Methods: The study was conducted with approval of the institutional review board. Written informed consent was obtained from each participant. Conventional and MT MR imaging of the brain was performed at baseline and at 12-month follow-up in 13 healthy control subjects and 73 patients with relapse-onset MS; participants were monitored with clinical visits for 8 years. The following parameters were evaluated at baseline and at 12-month follow-up: volume of lesions with high signal intensity at T2-weighted imaging, volume of lesions with low signal intensity at T1-weighted imaging, mean lesion MT ratio, thalamic fraction, and thalamic MT ratio. A multivariate analysis was used to evaluate the predictors of long-term neurologic deterioration., Results: At 8-year follow-up, 44 patients showed worsening disability. During follow-up, reduction in thalamic fraction was more pronounced in patients with relapsing-remitting MS than in those with secondary progressive MS (P = .001); thalamic MT ratio decreased only in patients with secondary progressive MS (P = .007). In the multivariable model, baseline thalamic fraction (odds ratio = 0.62, P = .01) and mean percentage change in lesion MT ratio after 12 months (odds ratio = 0.90, P = .04) were independent predictors of worsening disability at 8 years. At baseline, thalamic fraction was correlated with lesion volumes at T2-weighted imaging (r = -0.75, P < .001) and T1-weighted imaging (r = -0.60, P < .001)., Conclusion: Thalamic atrophy is correlated with long-term accumulation of disability in patients with MS. White matter lesions are likely to contribute to the loss of tissue seen in the thalamus of patients with MS., (© RSNA, 2010.)

Purpose: To investigate in vivo severity and topographic distribution of brain white matter (WM) fiber bundle atrophy in patients with Friedreich ataxia, a condition characterized by an uneven involvement of brain WM, and to correlate such findings with the clinical status of the patients., Materials and Methods: The study was conducted with institutional review board approval. Written informed consent was obtained from each participant. Sixteen patients with Friedreich ataxia and 15 healthy control subjects were studied by using a 1.5-T magnetic resonance (MR) imager and 3-mm-thick diffusion-tensor images with 15 noncollinear directions. The size of WM fiber bundles was examined at a voxel level by using a recently developed method, which relies on production of anisotropy maps and nonlinear registration. Data were analyzed by using statistical parametric mapping software and an analysis of covariance model adjusted for age and sex., Results: Compared with control subjects, patients with Friedreich ataxia had WM atrophy in (a) the central portion of the medulla oblongata, (b) the dorsal upper pons, (c) the superior cerebellar peduncles, (d) the central portion of the midbrain, (e) the medial portion of the right cerebral peduncle, (f) the peridentate region, bilaterally, and (g) the optic chiasm. The severity of the neurologic deficits correlated significantly with atrophy of the peridentate WM, bilaterally, and that of the superior cerebellar peduncle decussation., Conclusion: Findings of this study show that it is feasible to obtain in vivo atrophy estimates of specific brain WM fiber bundles in patients with Friedreich ataxia and that such estimates correlate with patients' clinical status. This approach has the potential to provide new information that is likely to improve the understanding of the pathophysiology of inherited ataxias., (Copyright RSNA, 2010)