Background

Cardiovascular (CV) risk factors have been associated with changes in clinical and MRI outcomes in patients with multiple sclerosis (MS). However, previous studies have not set an age-limit, while older patients may be affected by cerebral small vessel disease-related damage in addition to MS.

Objectives

To investigate the impact of cardiovascular risk factors on brain atrophy in patients with multiple sclerosis under the age of 50.

Methods

One-hundred and twenty-four (79 relapsing-remitting, 45 progressive) MS patients (74 females, age 36 ± 8, range 18 – 50), and 95 age- and sex-matched healthy controls (HC) (47 females, age 35 ± 8, range 18 – 50) underwent brain 3T MRI with pulse sequences for assessing lesions and atrophy, and complete neurological examination. Traditional CV risk factors were assessed: having smoked ≥5 pack-years (py), and presence of hypertension, dyslipidemia, diabetes/prediabetes. More stringent cut-offs were also assessed: having smoked ≥10py, and hypertension, dyslipidemia or diabetes under treatment. Linear models adjusted for age, sex, disease duration, phenotype and treatment were used to determine the impact of CV risk factors on MRI variables.

Results

Nineteen HC and 48 MS patients had one traditional CV risk factor, 4 HC and 15 MS patients had more than one. Ten HC and 30 MS patients had one stringent CV risk factor, 3 and 8 had more than one. Most of our subjects had a smoking history as a CV risk factor (16 HC and 42 MS patients among traditional, 8 HC and 23 MS patients among stringent). In MS patients, the presence of at least two traditional CV risk factors was associated with reduced normalized grey matter volume (NGMV) (p=0.01), white matter volume (NWMV) (p=0.03) and brain volume (NBV) (p=0.003), and not with T2-lesion volume (T2-LV) (p=0.27). Among traditional CV risk factors, only hypertension (n=8) was associated with MRI measures (NWMV and NBV). In MS patients, the presence of one stringent CV risk factor was associated with reduced NGMV (p=0.006), NWMV (p=0.003) and NBV (p<0.001), and higher T2-LV (p=0.03). In HC, no differences were observed according to either traditional or stringent risk factor presence.

Conclusions

The presence of CV risk factors is associated with brain atrophy in MS patients, even under age 50. CV risk factors seem to have synergistic effects, determining brain atrophy even for levels of exposure that may often be overlooked by clinicians, when present in combination.

Background

In neuromyelitis optica spectrum disorders (NMOSD), cognitive impairment (CI) is nowadays considered as a unique relapse-unrelated manifestation of the disease. As a proof-of-concept, anti-aquaporin4 (AQP4)-IgG seems to inhibit neuronal plasticity and long-term potentiation. Structural and functional MRI (fMRI) studies have disclosed an association with damage of the precuneus (PCUN) and cognitive impairment (CI) in several neurological conditions.

Objectives

To explore the role of dynamic functional connectivity (dFC) of the PCUN at resting state (RS) to explain cognitive alterations in NMOSD patients.

Methods

3.0 T RS fMRI were acquired from 27 AQP4-positive NMOSD patients and 30 age- and sex-matched healthy controls (HC). Patients underwent an extensive neuropsychological evaluation including the assessment of global and domain-specific cognitive impairment index (CII) and Beck Depression Inventory II (BDI-II) scores. DFC of the left (L) and right (R) PCUN was assessed by means of sliding-window seed-voxel correlation analysis. Standard deviation of dFC across windows was used as a measure of dynamicity (the higher the better). Age- and sex-adjusted between-group dFC comparisons and correlations with cognitive scores were assessed using SPM12 and full-factorial models. A p value <0.001 was considered statistically significant.

Results

Compared to HC, NMOSD patients had reduced L-PCUN dFC with caudate nucleus, rectus, olfactory bulb and occipital inferior gyrus and increased dFC between the L-PCUN and the middle temporal gyrus and between the R-PCUN the middle occipital gyrus. Global CII positively correlated with higher L-intra-PCUN dFC, as well as with higher dFC between the L-PCUN and the middle temporal and middle frontal gyrus and between the R-PCUN and the middle cingulate gyrus. Impairment of information processing speed (IPS, 59.2%) and depression (63.0%) were the most common cognitive alterations. The IPS index positively correlated with a higher L-intra-PCUN-dFC, and a higher dFC between the R-PCUN and the middle cingulate gyrus. The BDI-II score positively correlated with a higher dFC between the R-PCUN and the middle frontal gyrus.

Conclusions

The assessment of PCUN dFC supports the role of PCUN in NMOSD cognitive dysfunction. We observed a protective effect of higher dynamic connections with limbic regions for cognitive performance, while those with the frontal lobe were detrimental for depressive symptoms.

Background

The functional substrates of deficits of executive function (EF), a relevant disabling symptom in MS patients, have been scarcely investigated.

Objectives

To investigate changes of resting state (RS) functional connectivity (FC) in patients with MS and their correlation with neuropsychological measures related to EF.

Methods

High-resolution T1-weighted and RS functional MRI (fMRI) scans were acquired from 116 MS patients and 65 matched healthy controls (HC). All subjects underwent a neuropsychological evaluation, including the computerized version of the Wisconsin Card Sorting Test (WCST), a multidimensional EF assessment. MS patients also underwent a clinical evaluation, including the expanded disability status scale (EDSS). RS FC was assessed using a seed-voxel correlation analysis. Seed regions relevant for EF were derived from the literature: left (L) inferior parietal sulcus (IPS), L frontal pole (FP) and right (R) cerebellum (Crus I and II). We used SPM and voxel-wise models to compare RS FC between MS patients and HC within the identified networks. Then, associations between RS FC and age- and education-corrected WCST scores and EDSS were evaluated.

Results

Twenty-five (21.5%) MS patients failed the WCST. Compared to HC, MS patients showed significantly decreased RS FC of the L IPS with bilateral middle frontal, L middle temporal and L cerebellar regions, as well as increased RS FC of the L IPS with bilateral thalami. MS patients also exhibited decreased RS FC between the L FP and superior parietal regions. A widespread RS FC decrease was found in MS vs HC between the R Crus I/II and bilateral cerebellar regions and fronto-parietal cortices. Significantly increased RS FC was finally detected between the R Crus I/II and the bilateral orbitofrontal cortex. In MS patients, significantly increased RS FC between the R Crus I/II regions and the orbitofrontal cortex was associated with better performance at the WCST (r=range 0.19-0.27, p=range 0.03-0.003). Conversely, decreased fronto-cerebellar and parieto-cerebellar RS FC was correlated with higher EDSS score (r=range -0.19 to -0.35, p=range 0.03-<0.001).

Conclusions

In an MS group relatively spared by relevant EF deficits, increased RS FC strength in EF-related functional networks was detected. The association between increased RS FC and better WCST scores suggests a compensatory role of detected RS FC abnormalities in these patients.

Background

Cognitive deterioration affects a large proportion of multiple sclerosis (MS) patients, but it occurs also with healthy aging. The effects of aging on cognitive performance in MS have not been fully investigated yet.

Objectives

By evaluating a large multicentric cohort of healthy controls (HC) and MS patients, we compared the age-related decline of cognitive functions occurring in HC and MS patients.

Methods

Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was evaluated in 301 healthy controls (HC) (150 females, age 18-76 years, mean education=14.9 years) and 664 MS patients (421 females; age 18-77 years; mean education=13.3 years; 536 relapsing-remitting and 128 progressive MS) recruited from 3 centers of the Italian Neuroimaging Network Initiative (INNI, www.inni-ms.org). BRB-N allowed to assess verbal memory (Selective Reminding Test [SRT]), visuospatial memory (10/36 Spatial Recall Test [SPART] and delayed-recall), information processing speed (Symbol Digit Modalities Test [SDMT], Paced Auditory Serial Addition Test [PASAT] 3” and 2”) and verbal fluency (Word List Generation [WLG]). Raw scores of each test were converted to Z-scores, based on HC’s cohort by running linear models to regress out the effects of sex, age, education and center. The residuals for both HC and MS patients were then divided by the HC’s error term. Linear models were built for investigating the association of standardized scores with age in MS patients.

Results

In HC, scores of all the BRB-N tests except PASAT 3” and WLG declined significantly with aging (p from <0.0001 to 0.003). Compared to HC, MS patients showed significant worse estimated mean performances already from the age of 20 years in all BRB-N tests (p from <0.0001 to 0.003), except for SPART, SPART delayed-recall and PASAT 3”, whose estimated mean scores significantly worsened later in age (p from 0.03 to 0.04). MS patients showed also a steeper age-related decline of SPART, SPART delayed-recall, SDMT, PASAT 3”, PASAT 2” performances compared to HC (p from <0.0001 to 0.008). No differential effect of age compared to HC was detected in MS patients for WLG and SRT.

Conclusions

Cognitive deficits already affect young adult MS patients and progress faster during patients’ lifespan compared to healthy aging. A different susceptibility to age-effect exists in the cognitive tests currently used to assess cognition in MS patients. The accumulation of MS-related damage combined with brain aging may have synergic detrimental effects on cognitive performances of MS patients.

Funding. This project has been supported by a research grant from the Fondazione Italiana Sclerosi Multipla (FISM2018/S/3), and financed or co-financed with the ‘5 per mille’ public funding.