Cognitive Impairment Is Related to Glymphatic System Dysfunction in Pediatric Multiple Sclerosis.

OBJECTIVE: The aim of this study was to investigate whether, compared to pediatric healthy controls (HCs), the glymphatic system is impaired in pediatric multiple sclerosis (MS) patients according to their cognitive status, and to assess its association with clinical disability and MRI measures of brain structural damage. METHODS: Sixty-five pediatric MS patients (females = 62%; median age = 15.5 [interquartile range, IQR = 14.5;17.0] years) and 23 age- and sex-matched HCs (females = 44%; median age = 14.1 [IQR = 11.8;16.2] years) underwent neurological, neuropsychological and 3.0 Tesla MRI assessment, including conventional and diffusion tensor imaging (DTI). We calculated the diffusion along the perivascular space (DTI-ALPS) index, a proxy of glymphatic function. Cognitive impairment (Co-I) was defined as impairment in at least 2 cognitive domains. RESULTS: No significant differences in DTI-ALPS index were found between HCs and cognitively preserved (Co-P) pediatric MS patients (estimated mean difference [EMD] = -0.002 [95% confidence interval = -0.069; 0.065], FDR-p = 0.956). Compared to HCs and Co-P patients, Co-I pediatric MS patients (n = 20) showed significantly lower DTI-ALPS index (EMD = -0.136 [95% confidence interval = -0.214; -0.058], FDR-p ≤ 0.004). In HCs, no associations were observed between DTI-ALPS index and normalized brain, cortical and thalamic volumes, and normal-appearing white matter (NAWM) fractional anisotropy (FA) and mean diffusivity (MD) (FDR-p ≥ 0.348). In pediatric MS patients, higher brain WM lesion volume (LV), higher NAWM MD, lower normalized thalamic volume, and lower NAWM FA were associated with lower DTI-ALPS index (FDR-p ≤ 0.016). Random Forest selected lower DTI-ALPS index (relative importance [RI] = 100%), higher brain WM LV (RI = 59.5%) NAWM MD (RI = 57.1%) and intelligence quotient (RI = 51.3%) as informative predictors of cognitive impairment (out-of-bag area under the curve = 0.762). INTERPRETATION: Glymphatic system dysfunction occurs in pediatric MS, is associated with brain focal lesions, irreversible tissue loss accumulation and cognitive impairment. ANN NEUROL 2024;95:1080-1092.

Regional white matter and gray matter damage and cognitive performances in multiple sclerosis according to sex.

In this study, we investigated whether regional distribution of white matter (WM) lesions, normal-appearing [NA] WM microstructural abnormalities and gray matter (GM) atrophy may differently contribute to cognitive performance in multiple sclerosis (MS) patients according to sex. Using the same scanner, brain 3.0T MRI was acquired for 287 MS patients (females = 173; mean age = 42.1 [standard deviation, SD = 12.7] years; relapsing-remitting = 196, progressive = 91; median Expanded Disability Status Scale = 2.5 [interquartile range, IQR = 1.5-5.0]; median disease duration = 12.1 [IQR = 6.3-19.0] years; treatment: none = 70, first-line = 130, second-line = 87) and 172 healthy controls (HC) (females = 92; mean age = 39.3 [SD = 14.8] years). MS patients underwent also Rao's neuropsychological battery. Using voxel-wise analyses, we investigated in patients sex-related differences in the association of cognitive performances with WM lesions, NAWM fractional anisotropy (FA) and GM volumes (p < 0.01, family-wise error [FWE]). Sixty-six female (38%) and 48 male (42%) MS patients were cognitively impaired, with no significant between-group difference (p = 0.704). However, verbal memory performance was worse in males (p = 0.001), whereas verbal fluency performance was worse in females (p = 0.004). In both sexes, a higher T2-hyperintense lesion prevalence in cognitively-relevant WM tracts was significantly associated with worse cognitive performance (p ≤ 0.006), with stronger associations in females than males in global cognition (p ≤ 0.004). Compared to sex-matched HC, male and female MS patients had widespread lower NAWM FA and GM volume (p < 0.01). In both sexes, worse cognitive performance was associated with widespread reduced NAWM FA (p < 0.01), with stronger associations in females than males in global cognition and verbal memory (p ≤ 0.009). Worse cognitive performance was significantly associated with clusters of cortical GM atrophy in males (p ≤ 0.007) and mainly with deep GM atrophy in females (p ≤ 0.006). In this study, only limited differences in cognitive performances were found between male and female MS patients. A disconnection syndrome due to focal WM lesions and diffuse NAWM microstructural abnormalities seems to be more relevant in female MS patients to explain cognitive impairment.

Choroid plexus and perivascular space enlargement in neuropsychiatric systemic lupus erythematosus.

Choroid plexus (CP) enlargement is proposed as a marker of neuroinflammation in immune-mediated conditions. CP involvement has also been hypothesized in the immunopathology of systemic lupus erythematosus (SLE). We investigated whether CP enlargement occurs in SLE patients and its association with neuropsychiatric involvement. Additionally, we explored abnormalities along the glymphatic system in SLE patients through enlarged perivascular space (PVS) quantification. Clinical assessment and 3 Tesla brain dual-echo and T1-weighted MRI scans were obtained from 32 SLE patients and 32 sex and age-matched healthy controls (HC). CPs were manually segmented on 3D T1-weighted sequence and enlarged PVS (ePVS) were assessed through Potter's score. Compared to HC, SLE patients showed higher normalized CP volume (nCPV) (p = 0.023), with higher CP enlargement in neuropsychiatric SLE (NPSLE) (n = 12) vs. non-NPSLE (p = 0.027) patients. SLE patients with antiphospholipid antibodies (APA) positivity (n = 18) had higher nCPV compared to HC (p = 0.012), while APA negative ones did not. SLE patients also had higher Potter's score than HC (p < 0.001), with a tendency towards a higher number of basal ganglia ePVS in NPSLE vs. non-NPSLE patients. Using a random forest analysis, nCPV emerged as a significant predictor of NPSLE, together with T2-hyperintense white matter (WM) lesion volume (LV) and APA positivity (out-of-bag AUC 0.81). Our findings support the hypothesis of a role exerted by the CP in SLE physiopathology, especially in patients with neuropsychiatric involvement. The higher prevalence of ePVS in SLE patients, compared to HC, suggests the presence of glymphatic system impairment in this population.

2.5-Year changes of connectivity dynamism are relevant for physical and cognitive deterioration in multiple sclerosis.

BACKGROUND: In MS, functional connectivity (FC) dynamism may influence disease evolution. OBJECTIVES: The objective is to assess time-varying functional connectivity (TVFC) changes over time at 2.5-year follow-up in MS patients according to physical and cognitive worsening. METHODS: We collected 3T magnetic resonance imaging (MRI) for TVFC assessment (performed using sliding-window analysis of centrality) and clinical evaluations at baseline and 2.5-year follow-up from 28 healthy controls and 129 MS patients. Of these, 79 underwent baseline and follow-up neuropsychological assessment. At 2.5 years, physical/cognitive worsening was defined according to disability/neuropsychological score changes. RESULTS: At follow-up, 25/129 (19.3%) MS patients worsened physically and 14/79 (17.7%) worsened cognitively. At baseline, MS patients showed reduced TVFC versus controls. At 2.5-year follow-up, no TVFC changes were detected in controls. Conversely, TVFC decreased over time in parieto-temporal regions in stable MS patients and in default-mode network in worsened MS. In physically worsened MS, basal ganglia TVFC reductions were also found. Reduced TVFC over time in the putamen in physically worsened and reduced TVFC in the precuneus in cognitively worsened were significant versus stable MS. DISCUSSION: At 2.5-year follow-up, default-mode network TVFC reductions were found in worsening MS. Moreover, reduced deep gray matter TVFC characterized physically worsened patients, whereas precuneus involvement characterized cognitively worsened MS patients.

Brain and cervical spinal cord MRI correlates of sensorimotor impairment in patients with multiple sclerosis.

BACKGROUND: Cervical spinal cord (cSC) lesions and atrophy contribute to disability in multiple sclerosis (MS), but associations with specific sensorimotor dysfunction require further exploration. OBJECTIVE: To investigate the associations of brain and cSC magnetic resonance imaging (MRI) measures with sensorimotor impairment in MS. METHODS: One hundred fifty-one MS patients and 69 healthy controls underwent 3T MRI and clinical assessments including Expanded Disability Status Scale (EDSS), 9-hole peg test (9-HPT), finger tapping test (FTT), timed 25-foot walk test (T25FWT), and vibration detection threshold (VDT). Random forest ranked brain (T2-hyperintense lesion volume (T2-LV) and normalized deep gray matter (GM), cortical and white matter (WM) volumes) and cSC (T2-LV and total, GM, and WM cross-sectional areas (CSAs) at C2/C3 level) MRI measures relevance in explaining EDSS milestones (EDSS ⩾3.0, ⩾4.0, and ⩾6.0), VDT, pyramidal and sensory functional systems (P-FS and S-FS ⩾2), and motor tests impairment. RESULTS: Various combinations of brain and cSC MRI measures explained EDSS milestones (area under the curve (AUC) =0.879-0.900), VDT (R2 = 0.194), and impaired P-FS (AUC = 0.820), S-FS (AUC = 0.795), 9-HPT (AUC = 0.793), FTT (AUC = 0.740), and T25FWT (AUC = 0.825). cSC GM CSA was the most informative feature for all outcomes, except 9-HPT. CONCLUSION: cSC MRI measures, especially GM CSA, explain EDSS and sensorimotor dysfunction better than brain measures in MS.

Influence of cardiorespiratory fitness and MRI measures of neuroinflammation on hippocampal volume in multiple sclerosis.

BACKGROUND: The hippocampus is a clinically relevant region where neurogenesis and neuroplasticity occur throughout the whole lifespan. Neuroinflammation and cardiorespiratory fitness (CRF) may influence hippocampal integrity by modulating the processes promoting neurogenesis and neuroprotection that contribute to the preservation of functions. This study aimed to investigate the effects of neuroinflammation and CRF on hippocampal volume in multiple sclerosis (MS) patients with relapsing-remitting (RR) and progressive (P) clinical phenotypes. The influence of neuroinflammation and CRF on brain, grey matter (GM) and thalamic volumes was also assessed to determine whether the effects were specific for the hippocampus. METHOD: Brain 3T structural MRI scans and maximum oxygen consumption (VO2max), a proxy of CRF, were acquired from 81 MS patients (27 RR and 54 P) and 45 age-matched and sex-matched healthy controls. T2-hyperintense white matter lesion volume (T2-LV) and choroid plexuses volume (CPV) were quantified as neuroinflammatory measures. Associations of demographic, clinical, neuroinflammatory and CRF measures with normalised brain, GM, hippocampal and thalamic volumes in relapsing-remitting MS (RRMS) and progressive MS patients were assessed using Shapley and best subset selection regression. RESULTS: For most volumetric measures, the largest portions of variance were explained by T2-LV (variable importance (VI)=9.4-39.4) and CPV (VI=4.5-26.2). VO2max explained the largest portion of variance of normalised hippocampal volume only in RRMS patients (VI=16.9) and was retained as relevant predictor (standardised ß=0.374, p=0.023) with T2-LV (standardised ß=-0.330, p=0.016). CONCLUSIONS: A higher CRF may play a specific neuroprotective role on MS patients' hippocampal integrity, but only in the RR phase of the disease.

Choroid plexus enlargement in paediatric multiple sclerosis: clinical relevance and effect of sex.

BACKGROUND: Choroid plexus (CP) enlargement has been suggested as a reliable marker of neuroinflammation in adult multiple sclerosis (MS). We investigated CP volume in patients with paediatric MS compared with matched healthy controls (HC), possible sex-related effect, and the associations with clinical and structural MRI variables. METHODS: Brain 3.0 T dual-echo and three-dimensional (3D) T1-weighted sequences were selected retrospectively from 69 patients with paediatric MS and 23 age-matched and sex-matched HC. CP volume was manually obtained from 3D T1-weighted scans by two expert raters. RESULTS: CP segmentation was highly reproducible (intraobserver agreement: rater I=0.963, rater II=0.958; interobserver agreement=0.968). Compared with HC, patients with paediatric MS showed higher normalised CP volume (p<0.001). Both female and male patients with paediatric MS showed higher normalised CP volume compared with sex-matched HC (women: p<0.001 and men: p=0.021), with a significant disease×sex interaction (p=0.040). In patients with MS, a higher normalised CP volume was significantly associated with higher brain lesional volume (ß=0.252, p=0.017), larger lateral ventricle volume (ß=0.470, false discovery rate (FDR)-p<0.001), lower normalised brain volume (ß=-0.413, FDR-p=0.002) and lower normalised thalamic volume (ß=0.291, FDR-p=0.046). No associations with disease duration, Expanded Disability Status Scale score, normalised cortical and white matter volumes were found (FDR-p≥0.172). A significant effect of the disease in the negative association between normalised volumes of CP and thalami was observed (FDR-p=0.046). CONCLUSIONS: CP enlargement occurs in paediatric MS, suggesting its early involvement in the pathophysiology of the disease. The higher CP volume, which is found especially in female patients, supports the hypothesis of sex-related differences occurring already in paediatric MS.

Spinal cord lesions and brain grey matter atrophy independently predict clinical worsening in definite multiple sclerosis: a 5-year, multicentre study.

OBJECTIVES: To evaluate the combined contribution of brain and cervical cord damage in predicting 5-year clinical worsening in a multicentre cohort of definite multiple sclerosis (MS) patients. METHODS: Baseline 3.0T brain and cervical cord T2-weighted and three-dimensional T1-weighted MRI was acquired in 367 patients with MS (326 relapse-onset and 41 progressive-onset) and 179 healthy controls. Expanded Disability Status Scale (EDSS) score was obtained at baseline and after a median follow-up of 5.1 years (IQR=4.8-5.2). At follow-up, patients were classified as clinically stable/worsened according to EDSS changes. Generalised linear mixed models identified predictors of clinical worsening, evolution to secondary progressive (SP) MS and reaching EDSS=3.0, 4.0 and 6.0 milestones at 5 years. RESULTS: At follow-up, 120/367 (33%) patients with MS worsened clinically; 36/256 (14%) patients with relapsing-remitting evolved to SPMS. Baseline predictors of EDSS worsening were progressive-onset versus relapse-onset MS (standardised beta (ß)=0.97), higher EDSS (ß=0.41), higher cord lesion number (ß=0.41), lower normalised cortical volume (ß=-0.15) and lower cord area (ß=-0.28) (C-index=0.81). Older age (ß=0.86), higher EDSS (ß=1.40) and cord lesion number (ß=0.87) independently predicted SPMS conversion (C-index=0.91). Predictors of reaching EDSS=3.0 after 5 years were higher baseline EDSS (ß=1.49), cord lesion number (ß=1.02) and lower normalised cortical volume (ß=-0.56) (C-index=0.88). Baseline age (ß=0.30), higher EDSS (ß=2.03), higher cord lesion number (ß=0.66) and lower cord area (ß=-0.41) predicted EDSS=4.0 (C-index=0.92). Finally, higher baseline EDSS (ß=1.87) and cord lesion number (ß=0.54) predicted EDSS=6.0 (C-index=0.91). CONCLUSIONS: Spinal cord damage and, to a lesser extent, cortical volume loss helped predicting worse 5-year clinical outcomes in MS.

MRI of Transcallosal White Matter Helps to Predict Motor Impairment in Multiple Sclerosis.

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.

Exploring in vivo multiple sclerosis brain microstructural damage through T1w/T2w ratio: a multicentre study.

OBJECTIVES: To evaluate white matter and grey matter T1-weighted (w)/T2w ratio (T1w/T2w ratio) in healthy controls and patients with multiple sclerosis, and its association with clinical disability. METHODS: In this cross-sectional study, 270 healthy controls and 434 patients with multiple sclerosis were retrospectively selected from 7 European sites. T1w/T2w ratio was obtained from brain T2w and T1w scans after intensity calibration using eyes and temporal muscle. RESULTS: In healthy controls, T1w/T2w ratio increased until 50-60 years both in white and grey matter. Compared with healthy controls, T1w/T2w ratio was significantly lower in white matter lesions of all multiple sclerosis phenotypes, and in normal-appearing white matter and cortex of patients with relapsing-remitting and secondary progressive multiple sclerosis (p≤0.026), but it was significantly higher in the striatum and pallidum of patients with relapsing-remitting, secondary progressive and primary progressive multiple sclerosis (p≤0.042). In relapse-onset multiple sclerosis, T1w/T2w ratio was significantly lower in white matter lesions and normal-appearing white matter already at Expanded Disability Status Scale (EDSS) <3.0 and in the cortex only for EDSS ≥3.0 (p≤0.023). Conversely, T1w/T2w ratio was significantly higher in the striatum and pallidum for EDSS ≥4.0 (p≤0.005). In primary progressive multiple sclerosis, striatum and pallidum showed significantly higher T1w/T2w ratio beyond EDSS=6.0 (p≤0.001). In multiple sclerosis, longer disease duration, higher EDSS, higher brain lesional volume and lower normalised brain volume were associated with lower lesional and cortical T1w/T2w ratio and a higher T1w/T2w ratio in the striatum and pallidum (ß from -1.168 to 0.286, p≤0.040). CONCLUSIONS: T1w/T2w ratio may represent a clinically relevant marker sensitive to demyelination, neurodegeneration and iron accumulation occurring at the different multiple sclerosis phases.

Improved Assessment of Longitudinal Spinal Cord Atrophy in Multiple Sclerosis Using a Registration-Based Approach: Relevance for Clinical Studies.

BACKGROUND: Reliable measurements of cervical cord atrophy progression may be useful for monitoring neurodegeneration in multiple sclerosis (MS). PURPOSE: To compare a new, registration-based (Reg) method with two existing methods (active surface [AS] and propagation segmentation [PropSeg]) to measure cord atrophy changes over time in MS. STUDY TYPE: Retrospective. SUBJECTS: Cohort I: Eight healthy controls (HC) and 28 MS patients enrolled at a single institution, and cohort II: 25 HC and 63 MS patients enrolled at three European sites. FIELD STRENGTH/SEQUENCE: 3D T1-weighted gradient echo sequence, acquired at 1.5 T (cohort I) and 3.0 T (cohort II). ASSESSMENT: Percentage cord area changes (PCACs) between baseline and follow-up (cohort I: 2.34 years [interquartile range = 2.00-2.55 years], cohort II: 1.05 years [interquartile range = 1.01-1.18 years]) were evaluated for all subjects using Reg, AS, and PropSeg. Reg included an accurate registration of baseline and follow-up straightened cord images, followed by AS-based optimized cord segmentation. A subset of studies was analyzed twice by two observers. STATISTICAL TESTS: Linear regression models were used to estimate annualized PCAC, and effect sizes expressed as the ratio between the estimated differences and HC error term (P < 0.05). Reproducibility was assessed by linear mixed-effect models. Annualized PCACs were used for sample size calculations (significance: α = 0.05, power: 1 - ß = 0.80). RESULTS: Annualized PCACs and related standard errors (SEs) were lower with Reg than with other methods: PCAC in MS patients at 1.5 T was -1.12% (SE = 0.22) with Reg, -1.32% (SE = 0.30) with AS, and -1.40% (SE = 0.33) with PropSeg, while at 3.0 T PCAC was -0.83% (SE = 0.25) with Reg, -0.92% (SE = 0.32) with AS, and -1.18 (SE = 0.53) with PropSeg. This was reflected in larger effect sizes and lower sample sizes. Intra- and inter-observer agreement range was 0.72-0.91 with AS, and it was >0.96 with Reg. DATA CONCLUSION: The results support the use of the registration method to measure cervical cord atrophy progression in future MS clinical studies. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

Neural correlates of visuospatial processing in migraine: does the pain network help?

Migraine patients frequently report cognitive symptoms during the different phases of migraine. The most affected cognitive domains are visuospatial abilities, processing speed, attention and executive functions. We explored migraine patients' performance during a visuospatial task and investigated the activity of brain areas involved in visuospatial processing. A functional magnetic resonance imaging (MRI) visuospatial task, including an angle and a colour discrimination paradigm, was administrated to 17 headache-free migraine patients and 16 controls. Correlations between functional MRI abnormalities and subjects' performance, clinical and neuropsychological variables were also investigated. Deficits at visuospatial cognitive tests were present in around 20% of patients. Migraine patients maintained a preserved behavioural performance (reaction time and number of correct responses) during the angle discrimination task, while they performed less correctly in the colour task compared to controls (p = 0.05).The comparison of angle vs. colour task revealed an increased activity of the right insula, bilateral orbitofrontal cortex and medial frontal gyrus, and decreased activity of the bilateral posterior cingulate cortex in migraine patients compared to controls. In migraine patients, a better performance in the angle task was associated with higher activation of the right insula and orbitofrontal cortex, as well as with decreased activation of the right posterior cingulate cortex. Our results suggest an adaptive functional plasticity that might help migraine patients to overcome impaired visuospatial skills and preserve an adequate performance during a visuospatial task. These compensatory mechanisms seem to take advantage of recruiting brain areas that are commonly involved also in nociception.

Clinical predictivity of thalamic sub-regional connectivity in clinically isolated syndrome: a 7-year study.

Here, we explored trajectories of sub-regional thalamic resting state (RS) functional connectivity (FC) modifications occurring in clinically isolated syndrome (CIS) patients early after their first clinical episode, and assessed their relationship with disability over 7 years. RS fMRI and clinical data were prospectively acquired from 59 CIS patients and 13 healthy controls (HC) over 2 years. A clinical re-assessment was performed in 53 (89%) patients after 7 years. Using a structural connectivity-based atlas, five thalamic sub-regions (frontal, motor, postcentral, occipital, and temporal) were used for seed-based RS FC. Thalamic RS FC abnormalities and their longitudinal changes were correlated with disability. Thirty-nine (66.1%) patients suffered a second clinical relapse, but the median EDSS remained stable over time. At baseline, CIS patients vs HC showed reduced RS FC (p < 0.001, uncorrected) with: (1) frontal cortices, for the whole thalamus, occipital, postcentral, and temporal thalamic sub-regions, (2) occipital cortices, for the occipital thalamic sub-region. In CIS, the longitudinal analysis revealed at year 2 vs baseline: (1) no significant whole-thalamic RS FC changes; (2) reduction of motor, postcentral, and temporal sub-regional RS FC with occipital cortices (p < 0.05, corrected); (3) an increase (p < 0.001, uncorrected) of postcentral and occipital sub-regional thalamic RS FC with frontal cortices, left putamen, and ipsi- and contralateral thalamus, this latter correlating with less severe clinical disability at year 7. Thalamo-cortical disconnections were present in CIS mainly in thalamic sub-regions closer to the third ventricle early after the demyelinating event, evolved in the subsequent 2 years, and were associated with long-term clinical disability.

Resting state network functional connectivity abnormalities in systemic lupus erythematosus: correlations with neuropsychiatric impairment.

Neuropsychiatric manifestations are highly prevalent in systemic lupus erythematosus (SLE)-patients. We aimed to unravel the substrates of these manifestations by investigating abnormalities of resting state (RS) functional connectivity (FC) and their correlations with neuropsychiatric variables in SLE-patients. Thirty-two SLE-patients and 32 age- and sex-matched healthy controls (HC) underwent brain 3T RS fMRI. Neuropsychological assessment was performed for all SLE-patients. The main large-scale cognitive and psychiatric functional networks were derived and between-group comparisons and correlations with neuropsychological measures were performed. Compared to HC, SLE-patients exhibited increased RS FC in the right middle cingulate cortex and decreased RS FC in the left precuneus within default-mode network (DMN). They also showed increased RS FC in the left cerebellar crus I and left posterior cingulate cortex, and decreased RS FC in the left angular gyrus within working-memory networks (WMN). Compared to HC, SLE-patients exhibited increased RS FC in the left insular cortex and decreased RS FC in the right anterior cingulate cortex within salience network (SN), as well as decreased RS FC in the right middle frontal gyrus within executive-control network (ECN). Correlation analysis indicated a maladaptive role for left angular gyrus and cerebellar RS FC abnormalities in WMN, affecting memory and executive functions; and for precuneus and insular abnormalities in DMN and SN for psychiatric symptoms. Cingulate cortex modifications within DMN and SN correlated with better memory and global cognitive performance. Significant RS FC alterations in relevant cognitive and psychiatric networks occur in SLE-patients and participate in the pathophysiology of neuropsychiatric symptoms.

Functional and structural MRI correlates of executive functions in multiple sclerosis.

BACKGROUND: Executive dysfunctions, including difficulties in attention, working memory, planning, and inhibition affect 15%-28% of multiple sclerosis (MS) patients. OBJECTIVES: To investigate structural and functional magnetic resonance imaging (MRI) abnormalities underlying executive function (EF) in MS patients. METHODS: A total 116 MS patients and 65 controls underwent resting-state (RS) and diffusion-weighted sequences and neuropsychological examination, including Wisconsin Card Sorting Test (WCST) to test EF. Brain RS cognitive networks and fractional anisotropy (FA) from a priori selected white matter tracts were derived. Associations of WCST scores with RS functional connectivity (FC) and FA abnormalities were investigated. RESULTS: In MS patients, predictors of working memory/updating were: lower corpus callosum (CC) FA, lower left working-memory network (WMN), right WMN RS FC for worse performance; lower executive control network (ECN), higher default-mode network (DMN), and salience network (SN) RS FC for better performance (R2 = 0.35). Predictors of attention were lower CC genu FA, lower left WMN, and DMN RS FC for worse performance; higher left WMN and ECN RS FC for better performance (R2 = 0.24). Predictors of worse shifting/inhibition were lower CC genu and superior cerebellar peduncle (SCP) FA, lower left WMN RS FC for worse performance; and higher ECN RS FC for better performance (R2 = 0.24). CONCLUSIONS: CC and SCP microstructural damage and RS FC abnormalities in cognitive networks underlie EF frailty in MS.

Differential association of cortical, subcortical and spinal cord damage with multiple sclerosis disability milestones: A multiparametric MRI study.

BACKGROUND: In multiple sclerosis (MS), cortical, subcortical and infratentorial structural damage may have a differential contribution to clinical disability according to disease phases. PURPOSE: To determine the relative contributions of cortical, deep (D) grey matter (GM), cerebellar and cervical cord damage to MS disability milestones. METHODS: Multi-centre 3T brain and cervical cord T2- and three-dimensional (3D) T1-weighted images were acquired from 198 MS patients (139 relapsing-remitting (RR) MS, 59 progressive (P) MS) and 67 healthy controls. Brain/cord lesion burden, cortical thickness (CTh), DGM and cerebellar volumetry and cord cross-sectional area (CSA) were quantified. Random forest analyses identified predictors of expanded disability status scale (EDSS) disability milestones (EDSS = 3.0, 4.0 and 6.0). RESULTS: MS patients had widespread atrophy in all investigated compartments versus controls (p-range: ⩽0.001-0.05). Informative determinants of EDSS = 3.0 were cord CSA, brain lesion volume, frontal CTh and thalamic and cerebellar atrophy (out-of-bag (OOB) accuracy = 0.84, p-range: ⩽0.001-0.05). EDSS = 4.0 was mainly predicted by cerebellar and cord atrophy, frontal and sensorimotor CTh and cord lesion number (OOB accuracy = 0.84, p-range: ⩽0.001-0.04). Cervical cord CSA (p = 0.001) and cord lesion number (p = 0.003) predicted EDSS = 6.0 (OOB accuracy = 0.77). CONCLUSION: Brain lesion burden, cortical and thalamic atrophy were the main determinants of EDSS = 3.0 and 4.0, while cord damage played a major contribution to EDSS = 6.0.

Action observation training promotes motor improvement and modulates functional network dynamic connectivity in multiple sclerosis.

We investigated modifications of resting state dynamic functional network connectivity (dFNC) following a 2-week action observation training (AOT) in 46 right-handed healthy controls (HC) and 41 patients with multiple sclerosis (pwMS) and dominant-hand motor impairment, who were randomized to AOT or control (C) training. PwMS had decreased baseline dFNC versus HC. After training, MS groups improved in right upper limb functions, mainly in AOT, and showed dFNC increase (larger in MS-AOT vs MS-C) in sensorimotor and cognitive networks (p range, ⩽0.001-0.01). Both HC groups showed decreased dFNC over time (p range, ⩽0.001-0.01). Clinical improvements following interventions correlated with sensorimotor and cognitive dFNC changes, suggesting their possible role in motor recovery.

MRI correlates of clinical disability and hand-motor performance in multiple sclerosis phenotypes.

BACKGROUND: Hand-motor impairment affects a large proportion of multiple sclerosis (MS) patients; however, its substrates are still poorly understood. OBJECTIVES: To investigate the association between global disability, hand-motor impairment, and alterations in motor-relevant structural and functional magnetic resonance imaging (MRI) networks in MS patients with different clinical phenotypes. METHODS: One hundred thirty-four healthy controls (HC) and 364 MS patients (250 relapsing-remitting MS (RRMS) and 114 progressive MS (PMS)) underwent Expanded Disability Status Scale (EDSS) rating, nine-hole peg test (9HPT), and electronic finger tapping rate (EFTR). Structural and resting state (RS) functional MRI scans were used to perform a source-based morphometry on gray matter (GM) components, to analyze white matter (WM) tract diffusivity indices and to perform a RS seed-based approach from the primary motor cortex involved in hand movement (hand-motor cortex). Random forest analyses identified the predictors of clinical impairment. RESULT: In RRMS, global measures of atrophy and lesions together with measures of structural damage of motor-related regions predicted EDSS (out-of-bag (OOB)-R2 = 0.19, p-range = <0.001-0.04), z9HPT (right: OOB-R2 = 0.14; left: OOB-R2 = 0.24, p-range = <0.001-0.03). No RS functional connectivity (FC) abnormalities were identified in RRMS models. In PMS, cerebellar and sensorimotor regions atrophy, cerebellar peduncles integrity and increased RS FC between left hand-motor cortex and right inferior frontal gyrus predicted EDSS (OBB-R2 = 0.16, p-range = 0.02-0.04). CONCLUSION: In RRMS, only measures of structural damage contribute to explain motor impairment, whereas both structural and functional MRI measures predict clinical disability in PMS. A multiparametric MRI approach could be relevant to investigate hand-motor impairment in different MS phenotypes.

Volume of hippocampal subfields and cognitive deficits in neuromyelitis optica spectrum disorders.

BACKGROUND: Aquaporin-4 (AQP4) water channel is involved in hippocampal plasticity and is the target of neuromyelitis optica spectrum disorders (NMOSD) autoimmunity. We measured volumes of hippocampal subfields and their association with cognitive performance in AQP4-seropositive NMOSD patients. METHODS: Global and regional hippocampal volumes were derived from 28 AQP4-seropositive NMOSD patients and 101 healthy controls (HC) from 3D-T1-weighted images. Normalized brain volumes were also calculated. A neuropsychological evaluation, including the Brief Repeatable Battery of Neuropsychological Tests, was performed in patients. Based on HC data, we estimated mean z-scores of volumes in the whole NMOSD group and compared them according to the status of global and domain-selective cognitive impairment. RESULTS: Global cognitive impairment was detected in 46.4% of NMOSD patients, with attentive (60.7%) and executive (21.4%) domains being the most affected. NMOSD patients had left hippocampal atrophy at global (p = 0.012) and regional level (fimbria, Cornu Ammonis [CA] 3, molecular layer, dentate gyrus [DG], and subicular complex, p values ranging between 0.033 and <0.001). On the right side the fimbria and hippocampal tail were atrophic (p = 0.024 for both). Cognitively impaired patients showed atrophy in the left CA3 and CA4 (p = 0.025-0.028), while patients presenting verbal and visual memory impairment had significant CA3 and DG atrophy. Those patients with attentive or executive impairment had preserved brain and hippocampal volumes. CONCLUSIONS: NMOSD patients showed hippocampal atrophy associated with verbal and visual memory impairment. Such damage did not explain attention and executive function alterations, which were the most common cognitive deficits in this population.

Unraveling the substrates of cognitive impairment in multiple sclerosis: A multiparametric structural and functional magnetic resonance imaging study.

BACKGROUND: Cognitive impairment frequently affects multiple sclerosis (MS) patients. However, its neuroanatomical correlates still need to be fully explored. We investigated the contribution of structural and functional magnetic resonance imaging (MRI) abnormalities in explaining cognitive impairment in MS. METHODS: Brain dual-echo, diffusion tensor, 3D T1-weighted and resting-state (RS) MRI sequences were acquired from 276 MS patients and 102 healthy controls. Using random forest analysis, the contribution of regional white matter (WM) lesions, WM fractional anisotropy (FA) abnormalities, gray matter (GM) atrophy and RS functional connectivity (FC) alterations to cognitive impairment in MS patients was investigated. RESULTS: Eighty-four MS patients (30.4%) were cognitively impaired. The best MRI predictors of cognitive impairment (relative importance [%]) (out-of-bag area under the curve [AUC] = 0.795) were (a) WM lesions in the right superior longitudinal fasciculus (100%), left anterior thalamic radiation (93.4%), left posterior corona radiata (78.5%), left medial lemniscus (74.2%), left inferior longitudinal fasciculus (70.4%), left optic radiation (68.7%), right middle cerebellar peduncle (60.6%) and right optic radiation (53.5%); (b) decreased FA in the splenium of the corpus callosum (64.3%), left optic radiation (61.0%), body of the corpus callosum (51.9%) and fornix (50.9%); and (c) atrophy of the left precuneus (91.4%), right cerebellum crus I (84.4%), right caudate nucleus (78.6%), left thalamus (76.2%) and left supplementary motor area (59.8%). The relevance of these MRI measures in explaining cognitive impairment was confirmed in a cross-validation analysis (AUC =0.765). CONCLUSION: Structural damage in strategic WM and GM regions explains cognitive impairment in MS patients more than RS FC abnormalities.