Sensorimotor network dynamics predict decline in upper and lower limb function in people with multiple sclerosis.

BACKGROUND: Upper and lower limb disabilities are hypothesized to have partially independent underlying (network) disturbances in multiple sclerosis (MS). OBJECTIVE: This study investigated functional network predictors and longitudinal network changes related to upper and lower limb progression in MS. METHODS: Two-hundred fourteen MS patients and 58 controls underwent functional magnetic resonance imaging (fMRI), dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) measurements (baseline and 5 years). Patients were stratified into progressors (>20% decline) or non-progressors. Functional network efficiency was calculated using static (over entire scan) and dynamic (fluctuations during scan) approaches. Baseline measurements were used to predict progression; significant predictors were explored over time. RESULTS: In both limbs, progression was related to supplementary motor area and caudate efficiency (dynamic and static, respectively). Upper limb progression showed additional specific predictors; cortical grey matter volume, putamen static efficiency and posterior associative sensory (PAS) cortex, putamen, primary somatosensory cortex and thalamus dynamic efficiency. Additional lower limb predictors included motor network grey matter volume, caudate (dynamic) and PAS (static). Only the caudate showed a decline in efficiency over time in one group (non-progressors). CONCLUSION: Disability progression can be predicted using sensorimotor network measures. Upper and lower limb progression showed unique predictors, possibly indicating different network disturbances underlying these types of progression in MS.

Altered functional brain states predict cognitive decline 5 years after a clinically isolated syndrome.

BACKGROUND: Cognitive impairment occurs in the earliest stages of multiple sclerosis (MS) together with altered functional connectivity (FC). OBJECTIVE: The aim of this study was to investigate the evolution of dynamic FC states in early MS and their role in shaping cognitive decline. METHODS: Overall, 32 patients were enrolled after their first neurological episode suggestive of MS and underwent cognitive evaluation and resting-state functional MRI (fMRI) over 5 years. In addition, 28 healthy controls were included at baseline. RESULTS: Cognitive performance was stable during the first year and declined after 5 years.At baseline, the number of transitions between states was lower in MS compared to controls (p = 0.01). Over time, frequency of high FC states decreased in patients (p = 0.047) and increased in state with low FC (p = 0.035). Cognitive performance at Year 5 was best predicted by the mean connectivity of high FC state at Year 1. CONCLUSION: Patients with early MS showed reduced functional network dynamics at baseline. Longitudinal changes showed longer time spent in a state of low FC but less time spent and more connectivity disturbance in more integrative states with high within- and between-network FC. Disturbed FC within this more integrative state was predictive of future cognitive decline.

Artificial double inversion recovery images for (juxta)cortical lesion visualization in multiple sclerosis.

BACKGROUND: Cortical lesions are highly inconspicuous on magnetic resonance imaging (MRI). Double inversion recovery (DIR) has a higher sensitivity than conventional clinical sequences (i.e. T1, T2, FLAIR) but is difficult to acquire, leading to overseen cortical lesions in clinical care and clinical trials. OBJECTIVE: To evaluate the usability of artificially generated DIR (aDIR) images for cortical lesion detection compared to conventionally acquired DIR (cDIR). METHODS: The dataset consisted of 3D-T1 and 2D-proton density (PD) T2 images of 73 patients (49RR, 20SP, 4PP) at 1.5 T. Using a 4:1 train:test-ratio, a fully convolutional neural network was trained to predict 3D-aDIR from 3D-T1 and 2D-PD/T2 images. Randomized blind scoring of the test set was used to determine detection reliability, precision and recall. RESULTS: A total of 626 vs 696 cortical lesions were detected on 15 aDIR vs cDIR images (intraclass correlation coefficient (ICC) = 0.92). Compared to cDIR, precision and recall were 0.84 ± 0.06 and 0.76 ± 0.09, respectively. The frontal and temporal lobes showed the largest differences in discernibility. CONCLUSION: Cortical lesions can be detected with good reliability on artificial DIR. The technique has potential to broaden the availability of DIR in clinical care and provides the opportunity of ex post facto implementation of cortical lesions imaging in existing clinical trial data.

A randomized trial predicting response to cognitive rehabilitation in multiple sclerosis: Is there a window of opportunity?

BACKGROUND: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness. OBJECTIVE: To identify patient characteristics associated with response and non-response to cognitive training. METHODS: Eighty-two PwMS were randomized into a 7-week attention training (n = 58, age = 48.4 ± 10.2 years) or a waiting-list control group (n = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied. RESULTS: Responders (n = 36) and non-responders (n = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders (p = 0.018) and HCs (p = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC (p = 0.004) and DMN-frontoparietal FC (p = 0.029) (Nagelkerke R2 = 0.25). CONCLUSION: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions.

Disability in multiple sclerosis is related to thalamic connectivity and cortical network atrophy.

BACKGROUND: Thalamic atrophy is proposed to be a major predictor of disability progression in multiple sclerosis (MS), while thalamic function remains understudied. OBJECTIVES: To study how thalamic functional connectivity (FC) is related to disability and thalamic or cortical network atrophy in two large MS cohorts. METHODS: Structural and resting-state functional magnetic resonance imaging (fMRI) was obtained in 673 subjects from Amsterdam (MS: N = 332, healthy controls (HC): N = 96) and Graz (MS: N = 180, HC: N = 65) with comparable protocols, including disability measurements in MS (Expanded Disability Status Scale, EDSS). Atrophy was measured for the thalamus and seven well-recognized resting-state networks. Static and dynamic thalamic FC with these networks was correlated with disability. Significant correlates were included in a backward multivariate regression model. RESULTS: Disability was most strongly related (adjusted R2 = 0.57, p < 0.001) to higher age, a progressive phenotype, thalamic atrophy and increased static thalamic FC with the sensorimotor network (SMN). Static thalamus-SMN FC was significantly higher in patients with high disability (EDSS ⩾ 4) and related to network atrophy but not thalamic atrophy or lesion volumes. CONCLUSION: The severity of disability in MS was related to increased static thalamic FC with the SMN. Thalamic FC changes were only related to cortical network atrophy, but not to thalamic atrophy.

Inhibitory synaptic loss drives network changes in multiple sclerosis: An ex vivo to in silico translational study.

BACKGROUND: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning. OBJECTIVE: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling. METHODS: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning. RESULTS: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity. CONCLUSION: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

The cerebellum and its network: Disrupted static and dynamic functional connectivity patterns and cognitive impairment in multiple sclerosis.

BACKGROUND: The impact of cerebellar damage and (dys)function on cognition remains understudied in multiple sclerosis. OBJECTIVE: To assess the cognitive relevance of cerebellar structural damage and functional connectivity (FC) in relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS). METHODS: This study included 149 patients with early RRMS, 81 late RRMS, 48 SPMS and 82 controls. Cerebellar cortical imaging included fractional anisotropy, grey matter volume and resting-state functional magnetic resonance imaging (MRI). Cerebellar FC was assessed with literature-based resting-state networks, using static connectivity (that is, conventional correlations), and dynamic connectivity (that is, fluctuations in FC strength). Measures were compared between groups and related to disability and cognition. RESULTS: Cognitive impairment (CI) and cerebellar damage were worst in SPMS. Only SPMS showed cerebellar connectivity changes, compared to early RRMS and controls. Lower static FC was seen in fronto-parietal and default-mode networks. Higher dynamic FC was seen in dorsal and ventral attention, default-mode and deep grey matter networks. Cerebellar atrophy and higher dynamic FC together explained 32% of disability and 24% of cognitive variance. Higher dynamic FC was related to working and verbal memory and to information processing speed. CONCLUSION: Cerebellar damage and cerebellar connectivity changes were most prominent in SPMS and related to worse CI.

Cortical axonal loss is associated with both gray matter demyelination and white matter tract pathology in progressive multiple sclerosis: Evidence from a combined MRI-histopathology study.

BACKGROUND: Neuroaxonal degeneration is one of the hallmarks of clinical deterioration in progressive multiple sclerosis (PMS). OBJECTIVE: To elucidate the association between neuroaxonal degeneration and both local cortical and connected white matter (WM) tract pathology in PMS. METHODS: Post-mortem in situ 3T magnetic resonance imaging (MRI) and cortical tissue blocks were collected from 16 PMS donors and 10 controls. Cortical neuroaxonal, myelin, and microglia densities were quantified histopathologically. From diffusion tensor MRI, fractional anisotropy, axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD) were quantified in normal-appearing white matter (NAWM) and white matter lesions (WML) of WM tracts connected to dissected cortical regions. Between-group differences and within-group associations were investigated through linear mixed models. RESULTS: The PMS donors displayed significant axonal loss in both demyelinated and normal-appearing (NA) cortices (p < 0.001 and p = 0.02) compared with controls. In PMS, cortical axonal density was associated with WML MD and AD (p = 0.003; p = 0.02, respectively), and NAWM MD and AD (p = 0.04; p = 0.049, respectively). NAWM AD and WML AD explained 12.6% and 22.6%, respectively, of axonal density variance in NA cortex. Additional axonal loss in demyelinated cortex was associated with cortical demyelination severity (p = 0.002), explaining 34.4% of axonal loss variance. CONCLUSION: Reduced integrity of connected WM tracts and cortical demyelination both contribute to cortical axonal loss in PMS.

Increased functional sensorimotor network efficiency relates to disability in multiple sclerosis.

BACKGROUND: Network abnormalities could help explain physical disability in multiple sclerosis (MS), which remains poorly understood. OBJECTIVE: This study investigates functional network efficiency changes in the sensorimotor system. METHODS: We included 222 MS patients, divided into low disability (LD, Expanded Disability Status Scale (EDSS) ⩽3.5, n = 185) and high disability (HD, EDSS ⩾6, n = 37), and 82 healthy controls (HC). Functional connectivity was assessed between 23 sensorimotor regions. Measures of efficiency were computed and compared between groups using general linear models corrected for age and sex. Binary logistic regression models related disability status to local functional network efficiency (LE), brain volumes and demographics. Functional connectivity patterns of regions important for disability were explored. RESULTS: HD patients demonstrated significantly higher LE of the left primary somatosensory cortex (S1) and right pallidum compared to LD and HC, and left premotor cortex compared to HC only. The logistic regression model for disability (R2 = 0.38) included age, deep grey matter volume and left S1 LE. S1 functional connectivity was increased with prefrontal and secondary sensory areas in HD patients, compared to LD and HC. CONCLUSION: Clinical disability in MS associates with functional sensorimotor increases in efficiency and connectivity, centred around S1, independent of structural damage.

Functional brain network organization measured with magnetoencephalography predicts cognitive decline in multiple sclerosis.

BACKGROUND: Cognitive decline remains difficult to predict as structural brain damage cannot fully explain the extensive heterogeneity found between MS patients. OBJECTIVE: To investigate whether functional brain network organization measured with magnetoencephalography (MEG) predicts cognitive decline in MS patients after 5 years and to explore its value beyond structural pathology. METHODS: Resting-state MEG recordings, structural MRI, and neuropsychological assessments were analyzed of 146 MS patients, and 100 patients had a 5-year follow-up neuropsychological assessment. Network properties of the minimum spanning tree (i.e. backbone of the functional brain network) indicating network integration and overload were related to baseline and longitudinal cognition, correcting for structural damage. RESULTS: A more integrated beta band network (i.e. smaller diameter) and a less integrated delta band network (i.e. lower leaf fraction) predicted cognitive decline after 5 years (Radj2=15%), independent of structural damage. Cross-sectional analyses showed that a less integrated network (e.g. lower tree hierarchy) related to worse cognition, independent of frequency band. CONCLUSIONS: The level of functional brain network integration was an independent predictive marker of cognitive decline, in addition to the severity of structural damage. This work thereby indicates the promise of MEG-derived network measures in predicting disease progression in MS.

Infratentorial and spinal cord lesions: Cumulative predictors of long-term disability?

OBJECTIVE: The objective of the study was to determine whether early infratentorial and/or spinal cord lesions are long-term cumulative predictors of disability progression in multiple sclerosis (MS). METHODS: We selected 153 MS patients from the longitudinal Amsterdam MS cohort. Lesion analysis was performed at baseline and year 2. Disability progression after 6 and 11 years was measured using the Expanded Disability Status Scale (EDSS) and EDSS-plus (including 25-foot walk and 9-hole peg test). Patients with spinal cord or infratentorial lesions were compared for the risk of 6- and 11-year disability progression to patients without spinal cord or infratentorial lesions, respectively. Subsequently, patients with lesions on both locations were compared to patients with only spinal cord or only infratentorial lesions. RESULTS: Baseline spinal cord lesions show a higher risk of 6-year EDSS progression (odds ratio (OR): 3.6, p = 0.007) and EDSS-plus progression (OR: 2.5, p = 0.028) and 11-year EDSS progression (OR: 2.8, p = 0.047). Patients with both infratentorial and spinal cord lesions did not have a higher risk of 6-year disability progression than patients with only infratentorial or only spinal cord lesions. CONCLUSION: The presence of early spinal cord lesions seems to be a dominant risk factor of disability progression. Simultaneous presence of early infratentorial and spinal cord lesions did not undisputedly predict disability progression.

A pilot study of the effects of running training on visuospatial memory in MS: A stronger functional embedding of the hippocampus in the default-mode network?

BACKGROUND/OBJECTIVE: Endurance exercise can improve memory function in persons with multiple sclerosis (pwMS), but the effects on hippocampal functioning are currently unknown. We investigated the effects of a running intervention on memory and hippocampal functional connectivity in pwMS. METHODS/RESULTS: Memory and resting-state functional magnetic resonance imaging (fMRI) data were collected in a running intervention (n = 15) and waitlist group (n = 14). Visuospatial memory improvement was correlated to increased connectivity between the hippocampus and the default-mode network (DMN) in the intervention group only. CONCLUSION: As a result of endurance exercise, improvements in visuospatial memory may be mediated by a stronger functional embedding of the hippocampus in the DMN.

Resting-state MEG measurement of functional activation as a biomarker for cognitive decline in MS.

BACKGROUND: Neurophysiological measures of brain function, such as magnetoencephalography (MEG), are widely used in clinical neurology and have strong relations with cognitive impairment and dementia but are still underdeveloped in multiple sclerosis (MS). OBJECTIVES: To demonstrate the value of clinically applicable MEG-measures in evaluating cognitive impairment in MS. METHODS: In eyes-closed resting-state, MEG data of 83 MS patients and 34 healthy controls (HCs) peak frequencies and relative power of six canonical frequency bands for 78 cortical and 10 deep gray matter (DGM) areas were calculated. Linear regression models, correcting for age, gender, and education, assessed the relation between cognitive performance and MEG biomarkers. RESULTS: Increased alpha1 and theta power was strongly associated with impaired cognition in patients, which differed between cognitively impaired (CI) patients and HCs in bilateral parietotemporal cortices. CI patients had a lower peak frequency than HCs. Oscillatory slowing was also widespread in the DGM, most pronounced in the thalamus. CONCLUSION: There is a clinically relevant slowing of neuronal activity in MS patients in parietotemporal cortical areas and the thalamus, strongly related to cognitive impairment. These measures hold promise for the application of resting-state MEG as a biomarker for cognitive disturbances in MS in a clinical setting.

Fronto-limbic disconnection in patients with multiple sclerosis and depression.

BACKGROUND: The biological mechanism of depression in multiple sclerosis (MS) is not well understood. Based on work in major depressive disorder, fronto-limbic disconnection might be important. OBJECTIVE: To investigate structural and functional fronto-limbic changes in depressed MS (DMS) and non-depressed MS (nDMS) patients. METHODS: In this retrospective study, 22 moderate-to-severe DMS patients (disease duration 8.2 ± 7.7 years), 21 nDMS patients (disease duration 15.3 ± 8.3 years), and 12 healthy controls underwent neuropsychological testing and magnetic resonance imaging (MRI; 1.5 T). Brain volumes (white matter (WM), gray matter, amygdala, hippocampus, thalamus), lesion load, fractional anisotropy (FA) of fronto-limbic tracts, and resting-state functional connectivity (FC) between limbic and frontal areas were measured and compared between groups. Regression analysis was performed to relate MRI measures to the severity of depression. RESULTS: Compared to nDMS patients, DMS patients (shorter disease duration) had lower WM volume ( p < 0.01), decreased FA of the uncinate fasciculus ( p < 0.05), and lower FC between the amygdala and frontal regions ( p < 0.05). Disease duration, FA of the uncinate fasciculus, and FC of the amygdala could explain 48% of variance in the severity of depression. No differences in cognition were found. CONCLUSION: DMS patients showed more pronounced (MS) damage, that is, structural and functional changes in temporo-frontal regions, compared to nDMS patients, suggestive of fronto-limbic disconnection.

Cognitive impairment and the regional distribution of cerebellar lesions in multiple sclerosis.

BACKGROUND: Cerebellar lesions are often reported in relapsing-remitting multiple sclerosis (RRMS) and have been associated with impaired motor function and cognitive status. However, prior research has primarily focused on summary measures of cerebellar involvement (e.g. total lesion load, gray/white matter volume) and not on the effect of lesion load within specific regions of cerebellar white matter. OBJECTIVE: Spatially map the probability of cerebellar white matter lesion (CWML) occurrence in RRMS and explore the relationship between cognitive impairment and lesion (CWML) location within the cerebellum. METHODS: High-resolution structural magnetic resonance imaging (MRI) was acquired on 16 cognitively impaired (CI) and 15 cognitively preserved (CP) RRMS subjects at 3T and used for lesion identification and voxel-based lesion-symptom mapping (VLSM). RESULTS: CI RRMS demonstrated a predilection for the middle cerebellar peduncle (MCP). VLSM results indicate that lesions of the MCP are significantly associated with CI in RRMS. Measures of cerebellar lesion load were correlated with age at disease onset but not disease duration. CONCLUSION: A specific pattern of cerebellar lesions involving the MCP, rather than the total CWML load, contributes to cognitive dysfunction in RRMS. Cerebellar lesion profiles may provide a biomarker of current or evolving risk for cognitive status change in RRMS.

Asymptomatic spinal cord lesions do not predict the time to disability in patients with early multiple sclerosis.

BACKGROUND: The presence of asymptomatic spinal cord (SC) lesions in patients with clinically isolated syndrome (CIS) or relapsing-remitting multiple sclerosis (RRMS) predicts conversion to clinically definite multiple sclerosis (CDMS). The relation between asymptomatic SC abnormalities and disability progression warrants further investigation. OBJECTIVE: To determine the prognostic value of asymptomatic SC lesions in CIS and early RRMS with respect to the time to disability development. METHODS: Clinical and demographic data, brain and SC magnetic resonance imaging (MRI) were collected of CIS or early RRMS patients. Two main analyses were performed. For the first analysis, patients were divided into two groups: (1) patients with asymptomatic SC lesions and (2) patients without SC lesions and patients with symptomatic SC lesions. The second analysis excluded patients with symptomatic SC lesions. Incidence curves were used to analyse differences between these groups in time to the development of disability and time to a second relapse. RESULTS: A total of 178 patients were included, and 42 patients (23.6%) had asymptomatic SC lesions. No significant differences were found on the time to disability development or the time to a second event. CONCLUSION: Asymptomatic SC lesions early in the disease course do not predict the time to disability development in patients diagnosed with CIS or early RRMS.

Metabolites predict lesion formation and severity in relapsing-remitting multiple sclerosis.

BACKGROUND: Multiple sclerosis is characterized by white matter lesions, which are visualized with conventional T2-weighted magnetic resonance imaging (MRI). Little is known about local metabolic processes preceding the appearance and during the pathological development of new lesions. OBJECTIVE: To identify metabolite changes preceding white matter (WM) lesions and pathological severity of lesions over time. METHODS: A total of 59 relapsing-remitting multiple sclerosis (MS) patients were scanned four times, with 6-month intervals. Imaging included short-TE magnetic resonance spectroscopic imaging (MRSI) and diffusion tensor imaging (DTI). RESULTS: A total of 16 new lesions appeared within the MRSI slab in 12 patients. Glutamate increased (+1.0 mM (+19%), p = 0.039) 12 and 6 months before new lesions appeared. In these areas, the increase in creatine and choline 6 months before until lesion appearance was negatively correlated with radial diffusivity (ρ = -0.73, p = 0.002 and ρ = -0.72, p = 0.002). Increase in creatine also correlated with the increase of axial diffusivity in the same period (ρ = -0.53, p = 0.034). When splitting the lesions into "mild" and "severe" based on radial diffusivity, only mild lesions showed an increase in creatine and choline during lesion formation ( p = 0.039 and p = 0.008, respectively). CONCLUSION: Increased glutamate heralded the appearance of new T2-visible WM lesions. In pathologically "mild" lesions, an increase in creatine and choline was found during lesion formation.

The substrate of increased cortical FA in MS: A 7T post-mortem MRI and histopathology study.

BACKGROUND: Using diffusion tensor imaging (DTI), it was previously found that demyelinated gray matter (GM) lesions have increased fractional anisotropy (FA) when compared to normal-appearing gray matter (NAGM) in multiple sclerosis (MS). The biological substrate underlying this FA change is so far unclear; both neurodegenerative changes and microglial activation have been proposed as causal contributors. OBJECTIVE: To test the proposed hypothesis that microglia activation is responsible for increased FA in cortical GM lesions. METHODS: We investigated post-mortem cortical DTI changes in hemispheric, coronally cut sections and investigated the underlying histopathology using immunohistochemistry. RESULTS: Overall, there were few activated microglia/macrophages, and no difference between GM lesions and NAGM was observed. However, cell density was increased in GM lesions compared to NAGM (309.67 ± standard deviation (SD) 124.44 vs 249.95 ± SD 56.75, p = 0.002). CONCLUSION: FA increase was not due to lesional and non-lesional differences in microglia activation and/or proliferation. We found an increase in general cellular density without a notable difference in cellular size, that is, tissue compaction, as a possible alternative explanation.

High-resolution T1-relaxation time mapping displays subtle, clinically relevant, gray matter damage in long-standing multiple sclerosis.

BACKGROUND: Gray matter (GM) pathology has high clinical relevance in multiple sclerosis (MS), but conventional magnetic resonance imaging (MRI) is insufficiently sensitive to visualize the rather subtle damage. OBJECTIVE: To investigate whether high spatial resolution T1-relaxation time (T1-RT) measurements can detect changes in the normal-appearing GM of patients with long-standing MS and whether these changes are associated with physical and cognitive impairment. METHODS: High spatial resolution (1.05 × 1.05 × 1.2 mm(3)) T1-RT measurements were performed at 3 T in 156 long-standing MS patients and 54 healthy controls. T1-RT histogram parameters in several regions were analyzed to investigate group differences. Stepwise linear regression analyses were used to assess the relation of T1-RT with physical and cognitive impairment. RESULTS: In both thalamus and cortex, T1-RT histogram skewness was higher in patients than controls. In the cortex, this was driven by the frontal and temporal lobes. No differences were found in other GM histogram parameters. Cortical skewness, thalamus volume, and average white matter (WM) lesion T1-RT emerged as the strongest predictors for cognitive performance (adjusted R(2) = 0.39). CONCLUSION: Subtle GM damage was present in the cortex and thalamus of MS patients, as indicated by increased T1-RT skewness. Increased cortical skewness emerged as an independent predictor of cognitive dysfunction.

Multi-scale MRI spectrum detects differences in myelin integrity between MS lesion types.

BACKGROUND: Lesions with different extents of myelin pathology are found at autopsy in multiple sclerosis (MS), but the differences are not discernible in magnetic resonance imaging (MRI). OBJECTIVE: To determine whether analysis of the local spectrum in MRI is sensitive to lesion differences in myelin integrity. METHODS: We imaged fresh brain slices from 21 MS patients using 1.5T scanners. White matter lesions were identified in T2-weighted MRI, matched to corresponding specimens, and then classified into five categories in histology: pre-active (intact myelin); active, chronic active, chronic inactive (complete demyelination); and remyelinated lesions. Voxel-based frequency spectrum was calculated using T2-weighted MRI to characterize lesion structure (image texture). RESULTS: MRI texture heterogeneity resulting from all spectral scales was greater in completely demyelinated lesions than in myelin-preserved lesions (p = 0.02) and normal-appearing white matter (p < 0.01). Moreover, the spectral distribution pattern over low-frequency scales differentiated demyelinated lesions from remyelinated and pre-active lesions (p < 0.01), where different lesion types also showed distinct texture scales. CONCLUSION: Using multi-scale spectral analysis, it may be possible for standard MRI to evaluate myelin integrity in MS lesions. This can be critical for monitoring disease activity and assessing remyelination therapies for MS patients.