Transcranial Magnetic Stimulation Improves Executive Functioning through Modulation of Social Cognitive Networks in Patients with Mild Cognitive Impairment: Preliminary Results.

(1) Background: Patients with mild cognitive impairment (MCI) often present impairment in executive functions (EFs). This study aimed to investigate the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) on EFs in patients with MCI. (2) Methods: A prospective trial was conducted on 11 patients with MCI. Participants underwent 25 min of 20 Hz rTMS for ten days on the right temporo-parietal junction (RTPJ) and medial prefrontal cortex (MPFC). Before (T0) and after rTMS treatment (T1), global cognitive profile and EFs were investigated using the Montreal cognitive assessment (MoCA), trial making test (TMT) A and B, and frontal assessment battery (FAB). Depression symptoms were assessed using the geriatric depression scale (GDS). Statistical analysis included Wilcoxon signed-rank test. (3) Results: After treatment, patients showed a significant improvement in the MoCA EFs subtask (T0 vs. T1, p = 0.015) and TMT-B (T0 vs. T1, p = 0.028). Five MCI patients with EF impairment showed full recovery of these deficits. No significant changes in the GDS were observed. (4) Conclusions: rTMS stimulation over the TPJ and MPFC induced significant short-term improvements in EFs in MCI patients. These findings suggest that the TPJ and MPFC may be involved in the attention-executive skills to redirect attention toward behaviorally relevant stimuli.

Relationship between cognitive disturbances and sleep disorders in multiple sclerosis is modulated by psychiatric symptoms.

BACKGROUND: Multiple sclerosis (MS) patients with cognitive impairment (CI) frequently suffer from sleep disturbances and emotional symptoms. The aim of this study was to investigate the relationship between CI and sleep disturbances and the role of anxiety and depression on this relationship in MS patients. METHODS: Prospective cross-sectional study including 80 MS patients that underwent neurologic, cognitive, psychiatric assessment, and polysomnographic registration. Partial correlations analysis adjusted by demographic and clinical variables were used to investigate associations between cognitive and sleep measures. Moderator role effect of psychiatric symptoms was also explored with linear models. RESULTS: Thirty-six MS patients had CI. In all patients, worse performances at global, memory and attention cognitive domains were correlated with reduced sleep efficacy and longer periods of nocturnal wake (NW), while poor attention performances were associated with reduced REM-sleep (r = 0.26, p = 0.022). Memory performances were also negatively correlated with anxiety (r = -0.27, p = 0.015). The relationship between NW and memory performances was moderated by trait anxiety (p < 0.001). CONCLUSIONS: Our findings suggest that low sleep efficiency, NW, and reduced REM-sleep might affect cognitive abilities in MS. Higher trait anxiety appeared to impact on the relationship between increased NW and poor memory performances. Treatment of sleep and psychiatric disturbances may contribute to mitigating cognitive disorders in MS.

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.

Migraine in Multiple Sclerosis Patients Affects Functional Connectivity of the Brain Circuitry Involved in Pain Processing.

Migraine is particularly common in patients with multiple sclerosis (MS) and has been linked to the dysfunction of the brain circuitry modulating the peripheral nociceptive stimuli. Using MRI, we explored whether changes in the resting state-functional connectivity (RS-FC) may characterize the occurrence of migraine in patients with MS. The RS-FC characteristics in concerned brain regions were explored in 20 MS patients with migraine (MS+M) during the interictal phase, and compared with 19 MS patients without migraine (MS-M), which served as a control group. Functional differences were correlated to the frequency and severity of previous migraine attacks, and with the resulting impact on daily activities. In MS+M, the loss of periaqueductal gray matter (PAG) positive connectivity with the default mode network and the left posterior cranial pons was associated with an increase of migraine attacks frequency. In contrast, the loss of PAG negative connectivity with sensorimotor and visual network was linked to migraine symptom severity and related daily activities impact. Finally, a PAG negative connection was established with the prefrontal executive control network. Migraine in MS+M patients and its impact on daily activities, underlies RS-FC rearrangements between brain regions involved in pain perception and modulation.

Contribution of sleep disturbances to fatigue in multiple sclerosis: a prospective study using clinical and polysomnographic parameters.

BACKGROUND AND PURPOSE: Fatigue is amongst the most frequent and disabling symptoms of multiple sclerosis and a close relation between fatigue and sleep quality has been hypothesized. In this study the contribution of sleep disturbances measured by clinical and polysomnographic parameters to fatigue in multiple sclerosis was investigated. METHODS: This was a prospective instrumental study performed at the Neurocenter of Southern Switzerland. Demographic data and clinical characteristics including fatigue (as measured by the modified fatigue impact scale [MFIS]), neurological disability, psychiatric symptoms, medications and sleep-related variables were collected at baseline visit and by a home full-night polysomnography. The associations between sleep-related variables and the MFIS were tested using partial correlations adjusted by demographic and sleep-unrelated clinical factors. RESULTS: Seventy-six patients were included in the study, of whom 53 (69.7%) had an MFIS ≥38 points (median 49.5, interquartile range 31.0-62.0). MFIS scores were positively associated with age, neurological disability, symptoms of depression and anxiety, and use of benzodiazepines and selective serotonin reuptake inhibitors. When adjusting for these variables, the presence of restless legs syndrome (RLS) (r = 0.37, p = 0.005) and periodic leg movements index (r = -0.33, p = 0.014) were associated with MFIS. Excessive daytime sleepiness, total sleep time, sleep efficiency, respiratory disturbances, and percentage of time spent in the different sleep stages (N1, N2, N3 and rapid eye movement) were not associated with fatigue. CONCLUSIONS: Multiple sclerosis patients with a diagnosis of RLS had significantly higher global fatigue scores compared to those without RLS. Future studies should investigate whether medical treatment of RLS can ameliorate fatigue.

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.

A randomized pilot trial of oral prednisone taper vs placebo following iv methylprednisolone for multiple sclerosis relapses: Effects on adrenal function and clinical efficacy.

We performed a pilot trial investigating the effect of a steroid taper on adrenal function and safety measures after acute MS relapses. Twenty-five patients were randomized to either prednisone taper (n=12) or placebo (n=13) after 3 days of intravenous methylprednisolone. No patient showed signs of adrenal insufficiency at any time by cortisol response to ACTH. This significantly increased between baseline and 6 months in both groups. Patients remained clinically and radiologically stable, but those under prednisone taper experienced more frequently mood disorders, hyperglycaemia and weight increase. If confirmed by sufficiently powered studies, these results would question the need of a steroid taper following short-term intravenous methylprednisolone.

Effect of cognitive reserve on structural and functional MRI measures in healthy subjects: a multiparametric assessment.

BACKGROUND: Cognitive reserve (CR) contributes to inter-individual variability of cognitive performance and to preserve cognitive functioning facing aging and brain damage. However, brain anatomical and functional substrates of CR still need to be fully explored in young healthy subjects (HS). By evaluating a relatively large cohort of young HS, we investigated the associations between CR and structural and functional magnetic resonance imaging (MRI) measures in early adulthood. METHODS: A global Cognitive Reserve Index (CRI), combining intelligence quotient, leisure activities and education, was measured from 77 HS and its brain anatomical and functional substrates were evaluated through a multiparametric MRI approach. Substrates of the three subdomains (cognitive/social/physical) of leisure activities were also explored. RESULTS: Higher global and subdomain CRIs were associated with higher gray matter volume of brain regions involved in motor and cognitive functions, such as the right (R) supplementary motor area, left (L) middle frontal gyrus and L cerebellum. No correlation with measures of white matter (WM) integrity was found. Higher global and subdomains CRIs were associated with lower resting-state functional connectivity (RS FC) of L postcentral gyrus and R insula in sensorimotor network, L postcentral gyrus in salience network and R cerebellum in the executive-control network. Moreover, several CRIs were also associated with higher RS FC of R cuneus in default-mode network. CONCLUSIONS: CR modulates structure and function of several brain motor and cognitive networks responsible for complex cognitive functioning already in young HS. CR could promote optimization of the recruitment of brain networks.

De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis.

BACKGROUND: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens. OBJECTIVE: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis. METHODS: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19+ B cell, and IgG concentrations were analyzed. RESULTS: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5-4.5) and 12 months (3.5 (2.5-5.5) p = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9-45.2) pg/mL) and 12 months (9.1 (5.9-21.3) pg/mL, p = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = -0.439, p = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71-22.9, p = 0.005). CONCLUSION: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

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.

Cognitive impairment in benign multiple sclerosis: a multiparametric structural and functional MRI study.

INTRODUCTION: The substrates of cognitive impairment in benign MS (BMS) still need to be identified. We investigated whether cognitive impairment in BMS patients is associated with specific patterns of brain structural and functional abnormalities. METHODS: Thirty-seven BMS patients (EDSS score ≤ 3.0 and disease duration ≥ 15 years) and 50 healthy controls (HC) were studied. In BMS patients, a cognitive impairment index (CII) was derived. Gray matter (GM) volumes, white matter (WM) fractional anisotropy (FA) and resting-state (RS) functional connectivity (FC) were investigated for whole-brain relevant regions (cortex, lobes, subcortical nuclei, fiber tracts) and functional networks. Univariate and multivariate analyses identified independent predictors of cognitive impairment. RESULTS: In BMS, median CII was 9 (IQR: 4-16). Compared to HC, BMS patients showed reduced WM FA, GM atrophy and increased RS FC in fronto-temporo-parietal regions. At multivariate analysis, percentage of T2-lesions of the corpus callosum, reduced posterior corona radiata (PCR) FA and caudate nucleus atrophy were independent predictors of worse CII. A multivariate model identified reduced PCR FA (R2 = 0.39; p = 0.001) as the only predictor of CII. CONCLUSIONS: Cognitive impairment in BMS is associated with structural damage of relevant brain areas. WM damage of parietal regions was the predominant predictor of worse cognitive performance in these patients.

Effects of Natalizumab and Fingolimod on Clinical, Cognitive, and Magnetic Resonance Imaging Measures in Multiple Sclerosis.

Studies comparing the effects of natalizumab and fingolimod in relapsing-remitting multiple sclerosis (RRMS) are limited. We aimed to compare natalizumab and fingolimod effects on clinical, neuropsychological, and MRI measures in RRMS patients after 2 years of treatment. RRMS patients starting natalizumab (n = 30) or fingolimod (n = 25) underwent neurologic, neuropsychological, and brain MRI assessments at baseline, month (M) 6, M12, and M24. Volumes of lesions, brain, gray matter (GM), white matter (WM), and deep GM were measured. Fifteen healthy controls (HC) were also scanned at baseline and M24. Treatment groups were matched for baseline variables. At M24 versus baseline, both drugs reduced the relapse rate (p value < 0.001), stabilized disability, and improved cognitive function (fingolimod: p value = 0.03; natalizumab: p value = 0.01), without between-group differences. The natalizumab group had a higher proportion of freedom from MRI activity (67% vs 36%, p value = 0.02) and no evidence of disease activity-3 (NEDA-3) (57% vs 28%, p value = 0.04). At M24 vs M6, brain (- 0.35%, p value = 0.002 [fingolimod]; - 0.42%, p value < 0.001 [natalizumab]), GM (- 0.62%, p value < 0.001 [fingolimod]; - 0.64%, p value < 0.001 [natalizumab]), and WM (- 0.98%, p value < 0.001 [fingolimod]; - 0.99%, p value < 0.001 [natalizumab]) atrophy progressed at higher rates than in HC, but similarly between treatment groups, whereas only the natalizumab group showed deep GM atrophy (- 0.79%, p value = 0.02) (p value vs fingolimod not significant). In both groups, atrophy progression was correlated with lesion accumulation (r from - 0.49 to - 0.36, p values from 0.013 to 0.05), whereas no correlation was found between clinical and MRI changes. Natalizumab and fingolimod reduce disease activity and improve cognition in RRMS. Natalizumab seems superior to limit lesion accumulation, whereas both drugs similarly modify atrophy progression.

Functional brain connectivity abnormalities and cognitive deficits in neuromyelitis optica spectrum disorder.

BACKGROUND: Functional magnetic resonance imaging (fMRI) correlates of cognitive deficits have not been thoroughly studied in patients with neuromyelitis optica spectrum disorders (NMOSDs). OBJECTIVE: To investigate resting state (RS) functional connectivity (FC) abnormalities within the main cognitive networks in NMOSD patients and their correlation with cognitive performance. METHODS: We acquired RS fMRI from 25 NMOSD patients and 30 healthy controls (HC). Patients underwent an extensive neuropsychological evaluation. Between-group RS FC comparisons and correlations with cognitive performance were assessed on the main cognitive RS networks identified by independent component analysis. RESULTS: NMOSD patients showed higher RS FC versus HC in the precuneus of the default mode network (DMN) and right working memory network (WMN), as well as in several frontoparietal regions of the salience network (SN) and bilateral WMNs. Reduced frontal RS FC in NMOSD versus HC was detected in the left WMN. Increased RS FC in the DMN and right WMN was correlated with better cognitive performance, while decreased RS FC in the left WMN was associated with worse cognitive performance. CONCLUSION: Cognitive-network reorganization occurs in NMOSD. Clinico-imaging correlations suggest an adaptive role of increased RS FC. Conversely, reduced RS FC seems to be a maladaptive mechanism associated with a worse cognitive performance.

Influence of CNS T2-focal lesions on cervical cord atrophy and disability in multiple sclerosis.

BACKGROUND: Mechanisms associated with cervical spinal cord (CSC) and upper thoracic spinal cord (TSC) atrophy in multiple sclerosis (MS) are poorly understood. OBJECTIVE: To assess the influence of brain, CSC and TSC T2-hyperintense lesions on cord atrophy and disability in MS. METHODS: Thirty-four MS patients underwent 3T brain, cervical and thoracic cord magnetic resonance imaging (MRI) and Expanded Disability Status Scale (EDSS) score assessment. CSC/TSC lesion number and volume (LV), whole-brain and cortico-spinal tract (CST) LVs were obtained. Normalized whole CSC and upper TSC cross-sectional areas (CSAn) were also derived. Age- and sex-adjusted regression models assessed associations of brain/cord lesions with CSAn and EDSS and identified variables independently associated with CSAn and EDSS with a stepwise variable selection. RESULTS: CSC CSAn (ß = -0.36, p = 0.03) and TSC CSAn (ß = -0.60, p < 0.001) were associated with CSC T2 LV. EDSS (median = 3.0) was correlated with CSC T2 LV (ß = 0.42, p = 0.01), brain (ß = 0.34, p = 0.04) and CST LV (ß = 0.35, p = 0.03). The multivariate analysis retained CSC LV as significant predictor of CSC CSAn (R2 = 0.20, p = 0.023) and TSC CSAn (R2 = 0.51, p < 0.001) and retained CSC and CST LVs as significant predictors of EDSS (R2 = 0.55, p = 0.001). CONCLUSIONS: CSC LV is an independent predictor of cord atrophy. When neurological impairment is relatively mild, central nervous system (CNS) lesion burden is a better correlate of disability than atrophy.

Use of glatiramer acetate between 2010-2015: effectiveness, safety and reasons to start GA as first or second line treatment in Swiss multiple sclerosis patients.

BACKGROUND: Glatiramer acetate (GA) is one of the first therapies approved for multiple sclerosis (MS). We prospectively included and monitored drug-naïve and pre-treated MS patients who had been prescribed GA for 1 year, to investigate reasons for GA prescription, its effectiveness and safety in real life clinical practice. METHODS: One year, prospective, multicentre, observational study performed between 2010 and 2015 in consecutive MS and clinically isolated syndrome patients starting GA as a first ("naïve") or second ("switcher") line therapy. Primary endpoint was the annualized relapse rate (ARR) over 1 year of GA treatment (from baseline, V1, to 12 months, V2) in naïve and switchers compared to previous 24 months. Secondary endpoints were: EDSS changes between V1 and V2, frequency of adverse events, and reasons for prescribing and discontinuing GA. Baseline demographics and clinical characteristics were retrieved from medical records, and outcome measures were documented at V1 and V2, and in case of clinical worsening. RESULTS: One hundred ninety-four consecutive patients were monitored over 12 months (N = 64 naïve, N = 130 switchers). Side effect profile (naïve = 36%, switchers = 28%) and comorbidities (naïve = 31%, switchers = 15%) were the most frequent reasons to start GA. The ARR was reduced in both naïve and switchers during V1-2 as compared to the 24 months preceding V1 [naïve: 0.0 (0.0-0.0) vs 0.5 (0.5-1.0, p = 2.9e-10); switchers: 0.0 (0.0-0.0) vs 0.5 (0.0-0.5, p = 0.022)]. EDSS at V2 was significantly reduced only in naïve [(1.5 (1.0-2.5) vs 2.0 (1.5-2.5), p = 0.003)]. Naïve status and EDSS at V1 were negatively associated with EDSS change between V1-V2 in multivariable analysis (regression coefficient = - 0.436, p = 0.008, and regression coefficient = - 0.263, p = 6.18e-05, respectively). No new unexpected AE was reported. CONCLUSION: In our Swiss cohort, GA was prescribed mainly to naïve or switcher MS patients fearing interferon related side effects, with various comorbidities or considering pregnancy, and showed effectiveness and safety comparable with data of previous GA studies.

Hippocampal-related memory network in multiple sclerosis: A structural connectivity analysis.

BACKGROUND: We used graph theoretical analysis to quantify structural connectivity of the hippocampal-related episodic memory network and its association with memory performance in multiple sclerosis (MS) patients. METHODS: Brain diffusion and T1-weighted sequences were obtained from 71 MS patients and 50 healthy controls (HCs). A total of 30 gray matter regions (selected a priori) were used as seeds to perform probabilistic tractography and create connectivity matrices. Global, nodal, and edge graph theoretical properties were calculated. In patients, verbal and visuospatial memory was assessed. RESULTS: MS patients showed decreased network strength, assortativity, transitivity, global efficiency, and increased average path length. Several nodes had decreased strength and communicability in patients, whereas insula and left temporo-occipital cortex increased communicability. Patients had widespread decreased streamline count (SC) and communicability of edges, although a few ones increased their connectivity. Worse memory performance was associated with reduced network efficiency, decreased right hippocampus strength, and reduced SC and communicability of edges related to medial temporal lobe, thalamus, insula, and occipital cortex. CONCLUSION: Impaired structural connectivity occurs in the hippocampal-related memory network, decreasing the efficiency of information transmission. Network connectivity measures correlate with episodic memory, supporting the relevance of structural integrity in preserving memory processes in MS.

Cognitive reserve, cognition, and regional brain damage in MS: A 2 -year longitudinal study.

BACKGROUND: According to the cognitive reserve (CR) theory, enriching experiences protect against cognitive decline. OBJECTIVES: To investigate the dynamic interaction between CR and global/regional measures of brain white matter (WM) and gray matter (GM) damage and their effect on cognitive performance in multiple sclerosis (MS). METHODS: Baseline and 2 -year three-dimensional (3D) T1-weighted scans were obtained from 54 MS patients and 20 healthy controls. Patients' cognitive functions were tested and a cognitive reserve index (CRI) was calculated. Baseline regional atrophy and longitudinal volume changes were investigated using voxel-wise methods. Structural damage and CRI effects on cognitive performance were explored with linear models. RESULTS: At baseline, MS patients showed atrophy of the deep GM nuclei, GM/WM frontal-temporal-parietal-occipital regions, and left cerebellum. Controlling for atrophy, higher CRI explained significant portions of variance in verbal memory and verbal fluency (∆ R2 = 0.07-0.16; p < 0.03). The interaction between thalamic volume and CRI was significant (∆ R2 = 0.05; p = 0.03). Longitudinal changes in memory and attention performance were associated with local/global variations of GM/WM and T2 lesions. CRI had no effect on longitudinal cognitive changes. CONCLUSION: In MS, CR may have a protective role in preserving cognitive functions, moderating the effect of structural damage on cognitive performance. This protective role may diminish with disease progression.

Imaging patterns of gray and white matter abnormalities associated with PASAT and SDMT performance in relapsing-remitting multiple sclerosis.

OBJECTIVES: To map the regional patterns of white matter (WM) microstructural abnormalities and gray matter (GM) atrophy exclusively associated with reduced performance in the Symbol Digit Modalities Test (SDMT) and Paced Auditory Serial Addition Test (PASAT) in relapsing-remitting (RR) multiple sclerosis (MS) patients. METHODS: In all, 177 RRMS patients and 80 healthy controls (HC) were studied. WM microstructural abnormalities were investigated on diffusion tensor images using tract-based spatial statistics analysis, and regional GM atrophy was estimated on three-dimensional (3D) T1-weighted images using voxel-based morphometry. RESULTS: Compared to HC, RRMS patients showed the expected pattern of cortical-subcortical GM atrophy and WM microstructural abnormalities. In patients, diffusivity abnormalities of supratentorial WM tracts correlated with both SDMT and PASAT scores. Lower SDMT performance was also associated with WM damage in several infratentorial WM tracts. Lower SDMT scores correlated with atrophy of the right anterior cingulate cortex, left postcentral gyrus, and right middle temporal gyrus, whereas lower PASAT scores correlated with atrophy of the deep GM nuclei, bilaterally, and several fronto-temporo-occipital regions. CONCLUSION: In RRMS patients, regional damage of different neural systems helps explaining reduced performance in SDMT and PASAT. WM microstructural damage typified reduced SDMT performance, whereas atrophy of several GM regions distinguished reduced PASAT performance.

Functional network connectivity abnormalities in multiple sclerosis: Correlations with disability and cognitive impairment.

OBJECTIVE: To investigate resting state (RS) functional connectivity (FC) abnormalities within the principal brain networks in a large cohort of multiple sclerosis (MS) patients, to define the trajectory of FC changes over disease stages and their relation with clinical and structural magnetic resonance imaging (MRI) measures. METHODS: RS functional magnetic resonance imaging (fMRI), clinical, and neuropsychological evaluation were obtained from 215 MS patients and 98 healthy controls. Connectivity abnormalities and correlations with clinical/neuropsychological/imaging measures were evaluated. We analyzed seed-voxel FC with seven major hubs, producing one visual/sensory, one motor, two cognitive, one cerebellar, and two subcortical networks. RESULTS: MS patients showed reduced network average RS FC versus controls in the default-mode network. At regional level, a complex pattern of decreased and increased RS FC was found. Reduced RS FC mainly involved sensorimotor, cognitive, thalamic, and cerebellar networks, whereas increased RS FC involved visual/sensory and subcortical networks. Reduced RS FC correlated with T2 lesions. Reduced thalamic RS FC correlated with better neuropsychological performance, whereas for all remaining networks reduced FC correlated with more severe clinical/cognitive impairment. CONCLUSION: Increased and decreased RS FC occurs in MS and contributes to a wide spectrum of clinical manifestations. RS FC reduction is related to T2 lesions. Such a paradigm is inverted for the thalamic network.

Progression of regional atrophy in the left hemisphere contributes to clinical and cognitive deterioration in multiple sclerosis: A 5-year study.

In this longitudinal study, we investigated the regional patterns of focal lesions accumulation, and gray (GM) and white matter (WM) atrophy progression over a five-year follow-up (FU) in multiple sclerosis (MS) patients and their association with clinical and cognitive deterioration. Neurological, neuropsychological and brain MRI (dual-echo and 3D T1-weighted sequences) assessments were prospectively performed at baseline (T0) and after a median FU of 4.9 years from 66 MS patients (including relapse-onset and primary progressive MS) and 16 matched controls. Lesion probability maps were obtained. Longitudinal changes of GM and WM volumes and their association with clinical and cognitive deterioration were assessed using tensor-based morphometry and SPM12. At FU, 36/66 (54.5%) MS patients showed a significant disability worsening, 14/66 (21.2%) evolved to a worse clinical phenotype, and 18/63 (28.6%) developed cognitive deterioration. At T0, compared to controls, MS patients showed a widespread pattern of GM atrophy, involving cortex, deep GM and cerebellum, and atrophy of the majority of WM tracts, which further progressed at FU (P < 0.001, uncorrected). Compared to stable patients, those with clinical and cognitive worsening showed a left-lateralized pattern of GM and WM atrophy, involving deep GM, fronto-temporo-parieto-occipital regions, cerebellum, and several WM tracts (P < 0.001, uncorrected).GM and WM atrophy of relevant brain regions occur in MS after 5 years. A different vulnerability of the two brain hemispheres to irreversible structural damage may be among the factors contributing to clinical and cognitive worsening in these patients. Hum Brain Mapp 38:5648-5665, 2017. © 2017 Wiley Periodicals, Inc.