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 multiple sclerosis (MS), cortical damage is a relevant predictor of clinical disability, but MRI measures more specific to cortical pathology are needed. Neurite orientation dispersion and density imaging (NODDI) model is a multi-compartment diffusion model to better evaluate the complexity of brain microarchitecture.

Objectives

To characterize, using NODDI, the microstructural abnormalities of normal-appearing cortex (NA-cortex) and cortical lesions (CLs) and their relations with disease phenotypes and clinical disability in a relatively large cohort of MS patients.

Methods

Brain 3D T1-weighted, FLAIR, double inversion recovery (DIR) and diffusion-weighted (DW) sequences were acquired from 164 MS patients (94 relapsing-remitting [RR], 70 progressive [P] MS) and 51 healthy controls (HC). The cortex was segmented from 3D T1-weighted sequence, whereas CLs were quantified on DIR. CLs and NA-cortex masks were then transformed into DW space. Using NODDI, intracellular volume fraction (ICV_f), representing neurite density, extracellular volume fraction (ECV_f) and orientation dispersion index (ODI), reflecting neurite orientation variability, were assessed in NA-cortex and CLs. Between-group comparisons and correlations with clinical and structural MRI measures were investigated.

Results

One hundred and twelve (68.3%) MS patients had ≥1 CL. MS NA-cortex had a significant lower ICV_f vs HC NA-cortex (p=0.001). CLs showed a significant increased ECV_f (p<0.001) and decreased ICV_f and ODI compared to NA-cortex of HC (p<0.001) and MS (p=0.035 and <0.001). Compared to RRMS, PMS had a significant decreased NA-cortex ICV_f (p=0.024). Higher burden of CLs (p<0.001) were found in PMS vs RRMS, without microstructural differences. In MS patients, NA-cortex ICV_f, ECV_f and ODI were significantly correlated with disease duration, EDSS, white matter lesion volumes, CL volumes and whole brain and gray matter atrophy (r from -0.37 to 0.71, p from <0.001 to 0.048).

Conclusions

A significant neurite loss occurs in MS NA-cortex, being more severe with longer disease duration, higher disability and PMS. CLs show a further reduction of neurite density, together with an increased extracellular space, possibly due to inflammation and gliosis, and a reduced ODI suggestive of increased tissue coherence and simplification of neurite complexity. NODDI is reliable and clinically relevant to investigate in vivo the heterogeneous pathological processes affecting MS cortex.

Funding. This study is supported by a senior research fellowship FISM – Fondazione Italiana Sclerosi Multipla – cod. 2019/BS/009 and financed or co-financed with the ‘5 per mille’ public funding.

Background

The main clinical and MRI features driving therapeutic choices are not as clear for pediatric multiple sclerosis (MS) patients as for adults.

Objectives

We aimed at assessing early predictors of long-term clinically-relevant outcomes in a large cohort of pediatric MS patients.

Methods

Clinical and MRI assessment was obtained at disease onset and after 1, 2 and 3 years, in a cohort of 123 pediatric MS patients. The longest clinical follow-up (mean 9.33 +/- 3.45 years) was considered for long-term outcomes. Cox proportional hazards models were used to assess predictors of time to first relapse, while multivariable logistic and linear regression models identified clinical and MRI predictors of long-term outcomes.

Results

Across baseline features, optic nerve involvement predicted a shorter time to first relapse (hazard ratio=1.9, p=0.03). Predictors of annualized relapse rate (ARR) were: at baseline, presence of cerebellar (b=-0.16, p=0.00) and number of cervical cord lesions (b=0.14, p=0.01); considering short-term predictors, the same baseline variables together with time to first relapse (2-year: b=-0.12, p=0.01; 3-year: b=-0.08, p=0.00) and the number of relapses (1-year: b=0.14, p=0.00; 2-year: b=0.06, p=0.02). Baseline predictors of 10-year disability worsening were: at baseline, presence of optic nerve [odds ratio(OR)=6.45, p=0.01] and brainstem lesions (OR=6.17, p=0.04); considering short-term predictors, Expanded Disability Status Scale (EDSS) changes at 1 (OR=26.05, p=0.00) and 2 (OR= 16.38, p=0.02) years and the detection of at least two new T2-lesions in 2 years (2-year: OR=4.91, p=0.02; 3-year: OR=5.49, p=0.09). Predictors of higher 10-year EDSS score were: at baseline, EDSS score (b=0.58, p<0.001), presence of brainstem (b=0.31, p=0.04) and number of cervical cord lesions (b=0.22, p=0.05); considering short-term predictors, EDSS changes (1-year: b=0.82, p<0.001; 2-year: b=0.79, p<0.001, 3-year: b=0.27, p=0.04 ), together with the detection of at least two new T2-lesions at 1 (b=0.28, p=0.03) and 2 (b=0.35, p=0.01) years.

Conclusions

In conclusion, baseline spinal cord, brainstem and optic nerve lesions have a major role in predicting long-term outcomes, both in term of disease activity and of disability worsening. In addition, an accurate clinical and MRI monitoring during the first 2 years of disease has proven to represent a powerful tool for counseling patients about long-term prognosis and personalizing treatment strategies.

Background

Multiple sclerosis (MS) patients have heterogeneous clinical manifestations, natural history, and treatment response, due to heterogeneous underlying pathophysiological differences.

Objectives

To find clusters of MS patients with homogeneous underlying pathophysiology, as determined by advanced MRI techniques.

Methods

One-hundred-and-fifteen MS (57 relapsing-remitting, 12 primary- and 46 secondary-progressive) patients, and 44 age- and sex-matched healthy controls (HC) underwent brain and cervical cord 3T MRI with pulse sequences for assessing lesions, atrophy, and microstructural damage (with diffusion-tensor metrics). A complete neurological assessment, with rating of Expanded Disability Status Scale (EDSS) was also performed. Clusters of MS patients were identified with hierarchical clustering on age- and sex-adjusted MRI variables.

Results

Five clusters of MS patients were identified: “early”; “intermediate-cord”, “intermediate-cortical”, “intermediate-late-lesion”; and “late”. “Early” patients showed similar MRI metrics vs HC (except lesions), low EDSS and short disease duration (DD). “Intermediate” groups had altered MRI metrics, higher EDSS and longer DD, compared to “early” (p<0.01). “Intermediate-cord” patients were characterized by high cord T2-lesion volume (LV) (p<0.001 vs all but “late” groups), and “intermediate-cortical” by low cortical thickness (p<0.001 vs all but “intermediate-late-lesion” and “late” groups). “Intermediate-late-lesion” patients showed higher brain T2-LV and deep grey matter (GM) atrophy, but also a longer DD, compared to all but “late” groups (p<0.01). “Late” patients had higher EDSS and DD, compared to “intermediate-cord” and “intermediate-cortical” (p<0.01); and worst corticospinal-tract diffusion-tensor metrics and cord/brain atrophy (p<0.01 vs all). “Intermediate-cord” patients could be divided into 2 groups with similar DD characterized by different cord GM atrophy and cortical thickness (p<0.01), the more impaired one including mostly progressive phenotypes and higher EDSS.

Conclusions

MRI-based clustering of MS patients is feasible. It contributes to demonstrate disease heterogeneity and in the future it may be useful for personalized medicine. “Intermediate-cord” patients may be the best target to study neuroprotective and regenerative strategies.

Funding: Partially supported by grants from Fondazione Italiana Sclerosi Multipla (FISM/2018/R/16).

Background

Natural history studies demonstrated clinical phenotype and course of multiple sclerosis (MS) are age-dependent. The comparison of pediatric (POMS) vs adult onset (AOMS) MS patients is a useful model for studying the effects of age on MS pathophysiology.

Objectives

To determine whether age of disease onset influences the extent, distribution and trajectories of development of brain grey matter volume (GMV) and white matter (WM) microstructural abnormalities in adult MS patients.

Methods

Sixty-seven POMS (40 females; age 30±9, range 18–53) and 143 sex- and disease duration-matched AOMS (85 females; age 46±11, range 20 – 70) patients, together with 208 age- and sex-matched healthy controls (HC) (120 females; age 37±14, range 18–70), underwent neurological examination (with Expanded Disability Status Scale [EDSS] scoring) and MRI acquisition on a 3T scanner, including dual echo, 3D T1-weighted, and diffusion-weighted sequences. T2-lesion volumes, GMV and WM fractional anisotropy (FA) were derived and standardized based on distribution in HC, to remove the effects of age and sex. Linear models were used to study associations with disease duration in POMS and AOMS patients. Time to reach clinical and radiological milestones was assessed with the product-limit approach.

Results

At disease duration=1year, GMV and WM FA were not abnormal in POMS, while they were already compromised in AOMS patients (p ranging from 0.04 to <0.001) compared to HC. Significant interaction of age at onset (POMS vs AOMS) into the association with disease duration was found for GMV (p=0.01) and WM FA (p=0.04). The crossing point of regression lines in POMS and AOMS was at 19 and 15 years of disease duration for GMV and WM FA, respectively. Median disease duration to reach EDSS=3 was 29 years for POMS and 19 years for AOMS patients (p<0.001), to reach brain GM volume z-score=-1.645 was 24 years for POMS and 19 years for AOMS (p=0.04), and to reach brain WM FA z-score=-1.645 was 19 years for POMS and 17 years for AOMS (p=0.31).

Conclusions

In POMS patients, disruption of WM integrity precedes GM damage and is initially less severe than in AOMS. The rate of WM damage accumulation is higher in POMS compared to AOMS, resulting in more severe WM damage with longer disease duration. Except for WM damage, POMS patients reach clinical and MRI milestones at younger age than AOMS, but take longer time.

Funding. Partially supported by grants from Italian Ministry of Health (GR-2009-1529671) and Fondazione Italiana Sclerosi Multipla (FISM2016/R/23).