IRCCS San Raffaele Scientific Institute
Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience

Author Of 1 Presentation

Comorbidities Oral Presentation

PS04.05 - Cardiovascular risk factors affect brain volume in young MS patients

Speakers
Presentation Number
PS04.05
Presentation Topic
Comorbidities
Lecture Time
11:12 - 11:24

Abstract

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.

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Author Of 6 Presentations

Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0247 - Comparison of the 2017 and 2010 revisions of the McDonald criteria in patients with cis suggestive of MS: a multicentre MAGNIMS study (ID 1121)

Abstract

Background

In 2017, a revision of the 2010 McDonald criteria for multiple sclerosis (MS) diagnosis in clinically isolated syndrome (CIS) patients has been proposed. However, its validation in a large multicenter cohort of CIS patients is still needed.

Objectives

To compare the performance of 2017 and 2010 revisions of the McDonald criteria with respect to MS development in a large multicentric cohort of CIS suggestive of MS.

Methods

Brain and spinal cord magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination obtained ≤5 months from CIS onset and a follow-up brain MRI acquired ≤15 months from CIS onset were assessed in 626 CIS patients from 9 European MS centres. The occurrence of a second clinical attack (clinically definite [CD] MS) was recorded. Performances of the 2017 and 2010 revisions of McDonald criteria for dissemination in space (DIS), time (DIT) and DIS plus DIT, also including OCB assessment, were evaluated with a time-dependent receiver operating characteristic curve analysis. Median time to MS diagnosis for the different sets of criteria was estimated through Kaplan-Meier curves.

Results

At the last evaluation (median=61.9 months [IQR=39.1-102.5]), 319 (51%) of 626 patients had CDMS. At 36 months, for DIS, the 2017 MRI criteria had higher sensitivity (0.84 [95% CI=0.79-0.88] vs 0.77 [0.72-0.82]), lower specificity (0.33 [0.28-0.39] vs 0.40 [0.35-0.46]), and similar area under the curve values (AUC, 0.59 [0.55-0.62] for both). The 2017 DIS plus DIT MRI criteria had higher sensitivity (0.68 [0.63-0.74] vs 0.62 [0.56-0.68]), lower specificity (0.55 [0.49-0.61] vs 0.62 [0.56-0.68]), and similar AUC values (0.62 [0.58-0.66] for both). CSF-specific OCB assessment as part of the 2017 criteria revision, increased the sensitivity (0.81 [0.75-0.85]), decreased specificity (0.40 [0.34-0.46]) and preserved AUC values (0.60 [0.56-0.64]). Median time to MS diagnosis was earlier with the 2017 revision compared to the 2010 or CDMS criteria, especially with OCB assessment (2017 revision with OCBs=3.6 months [3.1-4.0], 2017 revision without OCB=11.6 months [7.8-13.5], 2010 revision=13.9 months [12.4-15.3], CDMS=56.3 months [43.8-76.0]).

Conclusions

The 2017 revision of the McDonald criteria showed overall similar accuracy to the 2010 McDonald criteria in predicting CDMS development. The suggested modifications are expected to simplify the clinical use of MRI criteria without reducing accuracy and allow an earlier diagnosis of MS.

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Imaging Poster Presentation

P0608 - MRI-based clustering of MS patients in the perspective of personalized medicine (ID 1075)

Speakers
Presentation Number
P0608
Presentation Topic
Imaging

Abstract

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).

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Neuropsychology and Cognition Poster Presentation

P0813 - Impact of multiple sclerosis on cognitive aging: a multicenter study (ID 1137)

Speakers
Presentation Number
P0813
Presentation Topic
Neuropsychology and Cognition

Abstract

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.

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Neuropsychology and Cognition Poster Presentation

P0830 - Unraveling the substrates of cognitive impairment in multiple sclerosis: the contribution of a multiparametric structural and functional MRI approach (ID 1081)

Speakers
Presentation Number
P0830
Presentation Topic
Neuropsychology and Cognition

Abstract

Background

Cognitive impairment (CI) affects up to 70% of multiple sclerosis (MS) patients. Although several magnetic resonance imaging (MRI) correlates of CI have been suggested, their relative contribution to explain CI requires further investigation.

Objectives

To evaluate the combined contribution of white matter (WM) lesions, gray matter (GM) atrophy and resting state (RS) functional (f) MRI abnormalities in explaining CI in a large cohort of MS patients.

Methods

Brain 3T dual-echo, 3D T1-weighted and RS fMRI scans were acquired from 100 healthy controls (HC) and 276 MS patients. All MS patients underwent the Rao’s battery. CI was defined by ≥2 tests with a z-score<-1.5. Distribution of brain WM lesions, GM atrophy and RS functional connectivity (FC) abnormalities within the default mode (DMN) and salience (SN) networks were compared between HC and MS patients at a voxel level. Using sex-, age- and phenotype-adjusted stepwise logistic regression models, the role of WM lesions (model 1), GM atrophy (model 2), RS FC (model 3) and their combination (model 4) in explaining CI was investigated. Model performances were assessed by the area under the curve (AUC).

Results

Eighty-three MS patients had CI. In model 1, lesions in left (L) superior longitudinal fasciculus (SLF) (odds ratio [OR]=1.84), L medial lemniscus (OR=1.79) and L inferior longitudinal fasciculus (OR=1.57) predicted CI (p≤0.009). In model 2, L precuneus (OR=0.52) and L caudate (OR=0.56) volumes predicted CI (p≤0.007). In model 3, increased RS FC in L caudate (DMN) (OR=1.77) and decreased RS FC in right (R) thalamus (DMN) (OR=0.66) and L inferior frontal gyrus (IFG) (SN) (OR=0.68) predicted CI (p≤0.02). In model 4, R middle cerebellar peduncle (OR=2.05) and L SLF (OR=1.84) lesions, L precuneus atrophy (OR=0.46), increased RS FC in L caudate (DMN) (OR=1.64), and decreased RS FC in L IFG (SN) (OR=0.64) predicted CI (p≤0.02). Compared to demographic and clinical variables only (AUC=0.73), the separate models performed significantly better (AUC=0.82, 0.81 and 0.80, respectively, p≤0.003), with model 4 having the best performance (AUC=0.86, p<0.001).

Conclusions

The combination of multiparametric MRI techniques contributes to better understand the structural and functional substrates of cognitive dysfunction in MS patients. The accumulation of focal WM lesions and GM atrophy in strategic brain regions together with maladaptive functional mechanisms explains CI in MS.

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Pathogenesis – Neurodegeneration Poster Presentation

P0953 - Damage of the subventricular zone: relation with striatal atrophy and cognitive performance in MS (ID 1091)

Speakers
Presentation Number
P0953
Presentation Topic
Pathogenesis – Neurodegeneration

Abstract

Background

The subventricular zone (SVZ), a 2-mm layer alongside brain lateral ventricles, is the largest neural stem cells niche in adult humans. It is likely to exert a neuroprotective role on striatal neurons and its damage has been associated with cognitive decline after brain radiation. Multiple sclerosis (MS) can be considered as a disease-related model of SVZ injury, since periventricular lesions involve this region. In MS, cognitive dysfunction is common and information processing speed is affected from the earliest phases of the disease despite relatively low lesion volume (LV) and atrophy.

Objectives

In this study, we characterized SVZ damage in terms of focal lesions and microstructural alterations in MS and assessed its association with striatal atrophy and cognitive dysfunction, evaluated with the Symbol Digit Modalities Test (SDMT).

Methods

3.0 T brain MRI scans were acquired from 97 MS patients and 43 age- and sex-matched healthy controls (HC). After lesion refilling, normalized (N-) brain volumes and cortical thickness (CT) were obtained. According to anatomical references, SVZ mask was segmented on T1-weighted images in the Montreal Neurological Institute space and then registered on fractional anisotropy (FA) and mean diffusivity (MD) maps. Age- and sex-adjusted linear models, partial correlations, and stepwise multiple linear regressions were used to assess SVZ damage and to identify predictors of N-striatal volume and SDMT scores.

Results

In MS, mean SVZ percentage LV was 4.2%. Compared to HC, SVZ normal appearing (NA) tissue was characterized by increased MD (0.89 vs 0.86, p=0.04) and preserved FA values. N-striatal volume correlated with all measures of brain damage (p range: <0.0001-0.02, r absolute values range: 0.24-0.70), while SDMT correlated with SVZ damage (percentage LV, lesional FA , NA MD, p range:0.028-0.0028, r absolute values range: 0.33-0.36) and brain T2-weighted LV (p=0.0051, r=-0.37). N-brain volume (p<0.0001), white matter MD (p=0.0236), SVZ percentage LV (p=0.0052), and mean CT (p=0.0354) were independent predictors of N-striatal volume (R2=0.67). SVZ percentage LV was selected as the only predictor of SDMT performance (p=0.0018, R2=0.26).

Conclusions

SVZ damage is associated with striatal atrophy and cognitive dysfunction in MS. These results might provide a novel key lecture on cognitive impairment in this disease, suggesting a possible role of periventricular injury in MS cognition.

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Pediatric MS Poster Presentation

P1070 - Age at disease onset influences grey matter and white matter integrity in MS (ID 1070)

Speakers
Presentation Number
P1070
Presentation Topic
Pediatric MS

Abstract

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).

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