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

Author Of 7 Presentations

Observational Studies Oral Presentation

PS01.04 - Comparison of disability trajectories in relapsing Multiple Sclerosis patients treated with early intensive or escalation treatment strategies

Abstract

Background

to date, no consensus exists on how aggressively and timely treat relapsing-remitting multiple sclerosis (RRMS) patients.

Objectives

To evaluate disability trajectories in a cohort of RRMS patients stratified according to two different disease modifying therapy (DMT) strategies, early intensive treatment (EIT) or moderate-efficacy treatment followed by escalation to higher-efficacy DMT (ESC).

Methods

RRMS patients with ≥5-year follow-up and ≥3 visits after start DMT, and a first visit within 3 years from disease onset were selected from the Italian MS Registry. EIT group included patients who received, as first DMT, fingolimod, natalizumab, mitoxantrone, alemtuzumab, ocrelizumab, cladribine. ESC group included those who received the high efficacy DMT after ≥1 year of glatiramer acetate, interferons, azathioprine, teriflunomide or dimethylfumarate treatment. Patients were 1:1 propensity score(PS)-matched for characteristics at the first DMT. The follow-up time from the first DMT start has been segmented into 12-month periods. The disability trajectories were evaluated by applying a longitudinal model for repeated measures with an autoregressive variance-covariance structure. The effect of early versus late start of high-efficacy DMT was assessed by the mean annual EDSS changes compared to baseline values (delta-EDSS) in EIT and ESC groups.

Results

The study cohort included 2,652 RRMS patients from 62 Italian MS centers. The PS matching procedure produced 365 pairs. The median (IQR) follow-up after the first DMT start was 8.5 (6.5–11.7) years. All of the ESC patients escalated to a higher-efficacy DMT after a median time of 5.1 (3.1–8.4) years. The estimated baseline EDSS with relative confidence interval (95% CI) value was 2.52 (2.33-2.71) in the ESC group and 2.45 (2.26-2.64) in the EIT group. Mean delta-EDSS at each 12 month period were all significantly (p<0.02) higher in the ESC group compared to the EIT group. In particular, the mean delta-EDSS differences between the two groups tend to increase from 0.1 (0.01-0.19, p=0.03) at 1 year to 0.30 (0.07-0.53, p=0.009) at 5 years and to 0.67 (0.31-1.03, p=0.0003) at 10 years.

Conclusions

Our results indicate that EIT strategy is more effective than ESC strategy in controlling disability progression and the effect tends to increase over time despite patients in the ESC group escalated to a higher-efficacy DMT.

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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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Observational Studies Oral Presentation

PS05.03 - Disease modifying treatment may delay time to wheelchair in primary progressive multiple sclerosis: a real-life cohort

Abstract

Background

Background: Except for ocrelizumab, treatment options in primary progressive multiple sclerosis (PPMS) are lacking, as randomized clinical trials failed to show efficacy in reducing disability progression in this patient population.

Objectives

Objective: To investigate the effectiveness of disease-modifying treatment (DMT) on hard disability outcomes (EDSS 6 and 7) in a real-life population of PPMS patients.

Methods

Methods: Using the Italian MS Registry, we selected PPMS patients with at least three EDSS evaluations and three years of follow-up. Study baseline was defined as the first EDSS evaluation for untreated patients and the date of the first DMT initiation for treated patients. The impact of DMT on the risk of reaching EDSS 6 and 7 was assessed as a dichotomous variable (yes versus no) and as a time-dependent covariate through multivariable Cox regression models (adjusted for age at baseline, sex, first EDSS score, symptoms at onset, annualized visit rate, annualized relapse rate). We compared outcomes with an as-treated analysis and used propensity-score matching (PSM) to select cohorts with comparable baseline characteristics. DMT-exposure was also evaluated in terms of quartiles of exposure.

Results

Results: Of the 1214 patients we included 671 females, mean ± Standard Deviation baseline age 48.7 ± 11.1 years, mean EDSS score 4.1 ± 1.8, 790 (65%) received a DMT during the follow-up (57% platform and 43% highly active treatments). In the whole sample, after a mean follow-up of 11.6 ± 6.3 years, 994 (82%) patients reached EDSS 6 and 539 (44%) EDSS 7. In the multivariable Cox regression models, the use of DMT analyzed as a dichotomous variable did not influence the risk of reaching EDSS 6 (aHR=1.1, 95% CI 0.95-1.28, p=0.181) and EDSS 7 (aHR = 0.93, 95% CI 0.77-1.12. p = 0.454). However, longer DMT exposure significantly reduced the risk of reaching EDSS 7 (aHR = 0.73, 95% CI 0.56-0.95, p =0.021). Of note, patients in the upper quartile of DMT exposure compared with those with shorter DMT exposure were younger at baseline (mean age 44.1 ± 10.6 years; p < 0.001) and received the first DMT closer to the disease onset (mean time to first DMT 6.8 years ± 6.1 ; p=0.002). All these findings were confirmed in the PSM analysis.

Conclusions

Conclusion: Our results suggest that longer exposure to DMT may delay time to wheelchair in PPMS patients. Moreover, treating younger patients and reducing the delay to treatment initiation may improve the patients’ long-term disability outcomes. To optimize treatment decision-making in PPMS further profiling of the best candidates to treatment is needed.

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Neuro-Ophthalmology Oral Presentation

PS15.05 - Retinal neuro-axonal loss reflects disability accrual in progressive multiple sclerosis independently from disease activity

Speakers
Presentation Number
PS15.05
Presentation Topic
Neuro-Ophthalmology
Lecture Time
13:39 - 13:51

Abstract

Background

The visual pathway has emerged as an elective platform to study the interaction between demyelination and neurodegeneration in multiple sclerosis (MS)

Objectives

We specifically assessed neural damage at this level in progressive MS (PMS), also exploring the evolution over time of functional (trough visual evoked potentials - VEPs) and structural (trough optical coherence tomography - OCT) parameters, as well as their relations with disease course and clinical disability.

Methods

We performed a prospective longitudinal study enrolling 350 PMS patients (228 secondary progressive MS - SPMS, 122 primary progressive MS - PPMS) who underwent a cross-sectional evaluation comprehensive of Expanded Disability Statur Scale (EDSS) assessment, high (HCVA)- and low-contrast (LCLA) visual acuity test, full-field (ff-VEPs) as well as multifocal (mf-VEPs) VEPs, and OCT. We performed a follow-up assessment (mean interval 2.0±0.9 years) in 147 patients (52 PPMS and 95 SPMS); a parallel collection of clinical records (including reports MRI scans, performed as per clinical practice) has been also obtained.

Results

Independently from previous optic neuritis (ON), we found visual conduction to be slower among SPMS compared to PPMS patients, particularly for mf-VEPs: mean latency 168.9 ms (95% CI 166.2-171.1) vs 163.8 ms (95% CI 160.7-166.9) respectively, p=0.019. Retinal Nerve Fiber Layer (RNFL) was also found to be thinner among SPMS in comparison to PPMS patients: mean 83.4 μm (95% CI 81.4-85.4) vs 87.0 μm (95% CI 84.4-89.6), p=0.040, with similar results for Ganglion Cell-Inner Plexiform Layer (GCIPL). Considering the evolution over time of functional and structural parameters, we found no significant differences comparing PPMS and SPMS patients. Reclassifying our cohort according to EDSS status (“stable” vs “worsened”) we found a significant between-groups difference in terms of RNFL evolution: mean annualized percent change -0.163 %/year (95% CI -0.467 - -0.141) vs -0.854 %/year (95% CI -1.188 - -0.521) respectively, p=0.003. Similar findings were obtained for GCIPL change. In both cases, these observations were independent from the evidence of MRI activity during follow-up.

Conclusions

our results suggest the presence of a greater functional and structural involvement of the visual system among SPMS compared to PPMS patients, independently from previous ON history; follow-up data suggest however neurodegeneration accrual over time to be similar between these two clinical subgroups. The longitudinal relation between RNFL - GCIPL thinning and EDSS worsening, even in the absence of overt MRI activity and/or clinical relapses, suggests OCT to represent a useful tool to monitor disease progression and to assess neuroprotection in PMS.

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Neuromyelitis Optica and Anti-MOG Disease Oral Presentation

PS16.05 - Application of deep-learning to NMOSD and unclassified seronegative patients

Speakers
Presentation Number
PS16.05
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease
Lecture Time
13:39 - 13:51

Abstract

Background

Current diagnostic criteria of neuromyelitis optica spectrum disorders (NMOSD) allow the diagnosis of aquaporin-4 (AQP4) seropositive patients with limited manifestations, whereas seronegative patients with limited phenotypes remain unclassified and are usually considered as prodromal phases of multiple sclerosis (MS) or different entities themselves. Nowadays, there is great effort to perform an automatic diagnosis of different neurological diseases using deep-learning-based imaging diagnostics, which is a form of artificial intelligence, allowing predicting or making decisions without a priori human intervention.

Objectives

To provide a deep-learning classification of NMOSD patients with different serological profiles and to compare these results with their clinical evolution.

Methods

228 T2- and T1-weighted brain MRIs were acquired from patients with AQP4-seropositive NMOSD (n=85), early MS (n=95), AQP4-seronegative NMOSD (n=11, 3 with anti-myelin oligodendrocyte glycoprotein antibodies) and unclassified double-seronegative limited phenotypes (n=17 idiopathic recurrent optic neuritis [IRON], n=20 idiopathic recurrent myelitis [IRM]). The latter had a clinical re-evaluation after 4-year follow-up. The neural network architecture was based on four 3D convolutional layers. It was trained and validated on MRI scans (n=180) from AQP4-seropositive NMOSD and MS patients. Then, it was applied to AQP4-seronegative NMOSD and double-seronegative patients with limited phenotypes to evaluate their classification as NMOSD or MS in comparison with their clinical follow-up.

Results

The final algorithm discriminated between AQP-4-seropositive NMOSD and MS with an accuracy of 0.95. Forty-seven/48 (97.9%) seronegative patients were classified as NMOSD (one patient with IRON was classified as MS). Clinical follow-up was available in 27/37 (73%) double-seronegative limited phenotypes: one patient evolved to MS, three developed NMOSD and the others did not change phenotype.

Conclusions

Deep-learning may help in the diagnostic work-up of NMOSD. Our findings support the inclusion of AQP4-seronegative patients to the spectrum of NMO and suggest its enlargement to double-seronegative limited phenotypes.

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Neuropsychology and Cognition Oral Presentation

YI02.03 - Identifying distinct cognitive phenotypes in multiple sclerosis 

Speakers
Presentation Number
YI02.03
Presentation Topic
Neuropsychology and Cognition
Lecture Time
11:39 - 11:51

Abstract

Background

Cognitive impairment is one of the most disabling symptoms of multiple sclerosis (MS), affecting about 50% of patients.

Objectives

We sought to define homogeneous cognitive phenotypes in a large cohort of MS patients by using a data-driven approach, and to assess their distinctive clinical and MRI features.

Methods

A cohort of 1212 MS patients and 196 healthy controls (HC) from 8 Italian MS centers underwent cognitive evaluation with Rao’s Brief Repeatable Battery and Stroop Color Word Test. A subgroup (172 MS patients and 50 HC) also underwent a 3T MRI examination, including 3D T1-weighted and dual-echo sequences. Latent-profile analysis was used on cognitive tests’ z-scores for identifying cognitive phenotypes. Linear regression and mixed effects models were used to define the clinical and MRI features of each phenotype.

Results

Five cognitive phenotypes were identified, characterized by “preserved-cognition” (19%), “mild verbal memory/semantic fluency” impairment (30%), “mild-multi-domain” impairment (19%), “severe-attention/executive” impairment with mild impairment of other domains (14%), and “severe-multi-domain” impairment (18%). “Preserved-cognition” patients had shorter disease duration and lower Expanded Disability Status Scale (EDSS) score than all other groups, and mildly impaired phenotypes included patients with shorter disease duration and less likely progressive disease compared to severely impaired groups. However, the “preserved-cognition” group also included patients with progressive disease and high EDSS scores, and severely impaired phenotypes were also represented in early MS stages. Comparing each phenotype to “preserved-cognition” group, distinctive MRI features emerged: “mild verbal memory/semantic fluency” patients had reduced hippocampal volume (p=0.02), “mild-multi-domain” reduced cortical gray matter volume (p=0.04), “severe-attention/executive” higher lesion volume (p=0.04) and severe-multi-domain” extensive brain damage (p<0.01 for lesion, brain, gray matter and thalamic volumes).

Conclusions

We identified five cognitive phenotypes of MS patients, with distinctive MRI substrates. By defining homogenous and clinically meaningful groups, this characterization may be useful for future research on cognitive impairment in MS, and for defining personalized management approaches and rehabilitative strategies in clinical practice.

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Pediatric MS Oral Presentation

YI02.05 - Cognition and socio-professional attainment in paediatric onset multiple sclerosis: a reappraisal after 10 years

Abstract

Background

Cognitive impairment (CI) affects nearly 30% of paediatric patients with Multiple Sclerosis (MS) and has a negative impact on school performance and participation in social activities. This study is a re-appraisal of cognitive functioning and socio-professional attainment in adulthood in an Italian cohort of paediatric MS patients after 10 years from baseline neuropsychological assessment.

Objectives

To re-assess cognitive performance and its impact on socio-professional attainment in our cohort of paediatric MS patients after 10 years from baseline evaluation and to determine predictors of the individual outcomes.

Methods

Sixty-three paediatric patients were assessed at baseline and 48 followed-up after five years. To date, 31 out of these 48 patients (17 females, mean age 27.9±2.5 years, mean EDSS 1.7±1.6) were reassessed on an extensive neuropsychological battery and compared with a matched group of 31 healthy controls. CI was defined as the failure of > 2 tests. Socio-professional attainment was evaluated on the Work and Social Assessment Scale (WSAS). Predictors of CI and WSAS score were assessed through multivariable logistic and linear models.

Results

After a mean follow-up of 12.5±2.3 years, 15 (54%) subjects were classified as cognitively impaired. Patients with CI compared with those cognitively preserved at follow-up had higher Expanded Disability Status Scale (EDSS) score (1.9±1.4 vs 1.0±0.7; p = 0.046), lower baseline intelligence quotient (IQ) (86.2±23.8 vs 103.6±14.7; p = 0.025) and were less frequently treated with disease modifying therapy (DMT) at baseline [6 (35.3%) vs 11 (78.6%); p = 0.016]. In the regression model, CI after 10 years was related to lower IQ (OR 0.93, 95% CI 0.87-0.99, p = 0. 027) and absence of DMT at baseline assessment (OR 17.78 95%; 1.72-183.65, p = 0.017).

Baseline predictors of worse socio-professional attainment on the WSAS in adulthood were CI (B=6.3, p=0.016), higher EDSS (B=2.2, p=0.023) and higher age at onset (B=0.6, p=0.041). As for 10-year correlates, only CI was associated to poor functional outcome (B=5.2, p=0.006).

Conclusions

Complete data collection is ongoing; available findings to date show that in paediatric onset subjects CI remains significant in adulthood, is related to lower cognitive reserve, higher levels of neurological impairment and delay in DMT initiation. Moreover, CI plays a key role in predicting the subject social performance and professional outcome. Early treatment and promotion of strategies aimed at enhancing cognitive reserve are recommended in paediatric patients with MS.

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Author Of 25 Presentations

Disease Modifying Therapies – Risk Management Poster Presentation

LB1154 - COVID-19 in cladribine-treated patients with relapsing-remitting multiple sclerosis: a monocentric experience (ID 1085)

Speakers
Presentation Number
LB1154
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Cladribine significantly reduces disease activity and disability progression in relapsing-remitting multiple sclerosis (RRMS) through a selective but transient depletion of lymphocyte subsets. The SARS-COV-2 outbreak has raised several concerns regarding cladribine use for RRMS patients.

Objectives

To evaluate the prevalence and clinical features of COVID-19 disease among cladribine-treated relapsing-remitting MS patients.

Methods

Fifty-six RRMS patients treated with cladribine in our centre (female=39; mean age=33.8 years [y]; median Expanded Disability Status Scale [EDSS]=1.5, disease duration [DD]=5.2 y, treatment duration=1.15 y) were asked if they had developed manifestations suggestive of SARS-COV-2 infection up to June 30th 2020. Their detailed characteristics were collected.

Results

At June 30th 2020, nasal/pharyngeal swabs have been found positive in 0.94% of the Lombardy population. Since the pandemic start, 2/56 (3.6%) cladribine-treated RRMS complained a symptomatology suggestive of COVID-19 disease, with a prevalence similar to that of the whole MS population of our centre (84/2950, 2.8%). The first patient was a 30-year-old male with RRMS (DD=1.2 y, EDSS=1.5) and no comorbidities. He started cladribine on January 10th 2020. One week later, he developed fever (<37.5°), ageusia, cough, fatigue, sputum production, sore throat, nasal congestion, shortness of breath without desaturation and conjunctivitis.

The second patient is a 39-year-old female with RRMS (DD=13.2 y, EDSS=3.5), and no comorbidities. She started cladribine on February 13th 2020 and underwent the second week of the first treatment course from March 5th 2020. On March 30th, she developed fever (<37.8°), anosmia, ageusia, cough, fatigue, and bone/joint pain. Serology for SARS-COV-2 was positive in May 2020. For both patients, blood examinations performed before and after COVID-19 disease were within normal limits. Both patients were telephone-monitored at home and completely recovered within 15 days.

Conclusions

Only a minority of cladribine-treated RRMS patients developed a mild and self-limiting COVID-19 disease. In our cohort, this occurred in two RRMS patients within a few weeks from treatment course and the possible nadir of selective immunosuppression. Both patients recovered completely. Cladribine administration seems to be safe also in the setting of the COVID-19 pandemic.

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Neuropsychology and Cognition Poster Presentation

LB1158 - COVID-19 pandemic and mental distress in Multiple Sclerosis: implications for clinical management (ID 1300)

Abstract

Background

in multiple sclerosis (MS), disease-related factors and dysfunctional coping might favour the development of mental distress induced by COVID-19 containment measures.

Objectives

to explore the relationship between mental distress, disability and coping strategies in the Italian MS population under lockdown.

Methods

Structural equation modeling (SEM) was applied to information collected via web-survey to identify modifiable factors that could account for mental distress. Information about the following domains was collected: (1) socio-demographic features; (2) general and MS related health status; (3) changes in lifestyle; (4) COVID-19 infection and risk perception; (5) physical disability assessed via the Patient-Determined Disease Steps (PDDS) scale and the Upper Extremity Function – Short Form (UEF) from the Quality of Life in Neurological Disorders (Neuro-QoL) measurement system; (6) cognitive function investigated using the Cognition Function– Short Form from the Neuro-QoL. Abstract reasoning, logical thinking and, in part, sustained attention, were measured using six Raven-like matrices; (7) mental distress: four domains from the Neuro-QoL were explored. Specifically, sleep disturbances, anxiety feelings, depressive symptoms, emotional dyscontrol; (8) coping strategies: individual response to lockdown was assessed using 18 items from the COPE-NVI-25, evaluating five independent coping strategies: avoidance (AV), social support (SS), positive attitude (PA), problem solving (PS) and turning to religion (TR).

Results

845 subjects (497 MS and 348 controls) were included in the study. MS patients showed higher scores than controls for depression (p=0.005), but not for anxiety, emotional dyscontrol or sleep disturbances. The SEM explained 74% of the variance observed in depression score. Within the model, three latent factors were characterized from measured variables: motor disability and cognitive dysfunction contributed to disability (β=0.509 and β=0.836, p<0.001); positive attitude and exercise contributed to active attitude (β=0.386 and β=0.297, p<0.001); avoidance, social support and watching TV contributed to passive attitude (β=0.301, β=0.243 and β=0.212, p<0.001). As per the relationship between latent factors and their influence on depression, disability contributed to passive attitude (β=0.855, p<0.001) while both passive and active attitude significantly influenced depression (β=0.729 and β=-0.456, p<0.001).

Conclusions

As practical implication of our model, favoring exercise would enhance active attitude and its positive impact on mental well-being while, at the same time, reducing the negative impact of disability on depression, representing a valuable tool for the long term management of COVID-19 related mental distress in MS.

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COVID-19 Late Breaking Abstracts

LB1190 - The Emotional Impact of the COVID-19 Pandemic on Individuals with Progressive Multiple Sclerosis. (ID 1989)

Abstract

Background

Pre-existing chronic illness is associated with increased psychiatric distress due to the spread of COVID-19, specifically increased stress, anxiety and depression. This potentially placed individuals with MS in a uniquely vulnerable position to experience greater psychiatric symptomatology.

Objectives

To examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS).

Methods

Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe (The CogEx Trial, ClinicalTrials.gov Identifier: NCT03679468). Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with patient report outcome (PRO) measures of depressive and anxiety symptoms, quality of life and MS symptomatology that were previously administered pre-pandemic.

Results

The time between baseline PRO completion and lockdown survey completion varied (M=9.5 months, SD=4.1 months). 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS depression scores increased significantly at follow up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS and changes in symptoms of depression or anxiety.

Most participants reported impact of the virus on their psychological well-being, with little impact on financial well-being. Perceived impact of the pandemic on physical and psychological well-being correlated significantly with the impact of MS symptomatology on daily life, as well as changes in depression.

Conclusions

Overall, in a sample confined exclusively to people with chronic progressive MS, little clinically significant change was noted in symptoms of depression or anxiety or quality of life during the pandemic lockdown.

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Clinical Outcome Measures Poster Presentation

P0100 - Italian prospective multicentric observational real-life study of aggressive Relapsing Remitting Multiple Sclerosis treated with alemtuzumab (ID 1730)

Abstract

Background

Alemtuzumab(ALEM) is an anti-CD52 monoclonal antibody approved for the treatment of active Multiple Sclerosis(MS) which showed an overall high efficacy in clinical trials, also in the highly active subgroup of patients.

Objectives

The aim of this multicenter obervational study is to evaluate efficacy and safety of ALEM-treatment in a population of aggressive MS naïve-patients at year 2 and 3 after a complete cycle of treatment.

Methods

We conducted a multicenter prospective observational study in a cohort of ALEM-naïve MS patients. Clinical and neuroradiological parameters were collected from patients’ clinical records in 26 Italian MS Centers from October 2015 to May 2020.

Results

133 naïve patients were treated with ALEM: 60,2% females, mean age 31,4(± 8,9) years, mean disease duration 18,5(± 22,7) months, mean follow-up(FU) 34,2(± 12,1) months, median EDSS 3(0-6,5), ARR in the year preceding treatment 1,8 (± 0,9), mean number of brain T2/FLAIR-hyperintense lesions 29,8 (± 20,8) and mean number of Gd-enhancing lesions 3,4(± 5,1). Regarding ALEM efficacy, we report data obtained after the first complete cycle of treatment (2 ALEM-courses) because the occurrence of disease activity between the first and second course is not indicative of a therapeutic failure. 99 and 61 over 133 patients have at least 24 and 36 months FU respectively: 97% and 82% were relapse-free, ARR was 0,02 and 0,1, 92.9% and 82% were MRI activity-free and 97,7% and 91,8% progression-free with median EDSS of 2,0 and 1,5 (IQR 1 – 2,5) at year 2 and 3. The mean time to first relapse was 27,6(± 6,4) months 89,2% and 69,4% of patients reached NEDA-3 at year 2 and year 3 respectively. 5,3% of patients needed a third cycle of therapy. Overall 74,4% of patients had adverse events. Infusion-reaction and infections occurred respectively in 70,1% and 9,8% of patients; regarding secondary autoimmune disease the most frequent was thyroid dysfunction (15,8%).

Conclusions

In our very active MS-population after ALEM-treatment a strong reduction of both relapse rate and MRI activity was achieved. These results strengthen the assumption that aggressive naïve patient is an ideal candidate for immune system resetting, likely due to young age, short disease duration and low disability. Furthermore, absence of previous immunomodulating/immunosuppressant drugs altering the immune system could play a key role in determining effectiveness of this powerful drug. However, longer FU is needed to confirm our data and evaluate whether an early induction therapy could be worthy in this specific population, balancing benefit-risk ratio.

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Diagnostic Criteria and Differential Diagnosis Poster Presentation

P0261 - Paramagnetic rim lesions are specific to multiple sclerosis: an international multicenter 3T MRI study (ID 1025)

Abstract

Background

In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on MRI by their paramagnetic rims, and increasing evidence supports their association with clinical disease severity.

Objectives

To assess the prevalence and MS-specificity of paramagnetic rim lesions (PRL) on 3-tesla susceptibility-based MR brain images in MS vs non-MS cases in a multicenter sample drawn from 5 academic research hospitals at sites in Europe (Brussels, Lausanne, Milan) and the United States (NIH and JHU).

Methods

On submillimetric 3D T2*-segmented EPI brain MRI, the presence of PRL and central vein sign (CVS) were evaluated in the supratentorial brain of adults with MS (n=329) and non-MS neurological conditions (n=83). Non-MS cases were grouped as follows: (1) other-inflammatory neurological diseases (n=41); (2) HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=10); (3) HIV-infected (n=10); (4) non-inflammatory neurological diseases (n=22).

ROC curve analysis, with diagnosis as dependent variable (MS vs non-MS), was applied to examine the diagnostic accuracy for each biomarker (PRL and CVS). Youden’s index method was used to obtain the optimal cutoff value for each biomarker.

Results

PRL were detected in 172/329 (52%) of MS cases vs. 6/83 non-MS cases (7%).

In MS, 58% of progressive cases had at least one PRL, compared to 50% of relapsing cases. MS cases with more than 4 PRL were more likely to have higher disability scores (EDSS, MSSS and ARMSS), but not significantly longer disease duration or older age.

In non-MS cases, PRL were seen exclusively in only a few inflammatory/infectious neurological conditions, including Susac syndrome (3 cases), neuromyelitis optica spectrum disorder (1 case), Sjögren disease (1 case) and HAM/TSP (1 case). Unlike in MS, PRL in non-MS cases were not associated with a high frequency of CVS+ lesions.

The identification of at least one PRL (optimal cutoff) was associated with high diagnostic specificity (93%), but relatively low sensitivity (52%) and accuracy (area under ROC curve=0.77), whereas CVS detection alone (optimal cutoff 35.5-38%) could better discriminate MS from non-MS cases with high specificity (96%), sensitivity (99%), and accuracy (area under ROC curve=0.99). The combination of the two biomarkers further improved the specificity (99%), but sensitivity remained low (59%).

Conclusions

PRL yielded high specificity for MS lesions. Future prospective multicenter studies should further validate its role as a diagnostic biomarker.

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Disease Modifying Therapies – Mechanism of Action Poster Presentation

P0344 - Injectable versus oral first-line disease-modifying therapies: results from Italian MS register (ID 1384)

Abstract

Background

The advent of oral first-line disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) has expanded considerably the therapeutic landscape. However, here is an important need to gather real-world evidence data regarding long-term treatment effectiveness and safety in comparison to the old first-line injectables DMTs.

Objectives

To compare old injectable and oral first line DMTs for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation in a cohort of RRMS patients extracted from the Italian MS Registry.

Methods

Multicentre, observational, retrospectively acquired and propensity-adjusted cohort study of RRMS-naïve patients in the Italian MS Register starting injective or oral first line DMTs between 1 January 2010 and 31 December 2017 to evaluate their impact on disability outcomes in patients. Enrolled patients were divided into two groups: injectable group (IG) and oral group (OG).

Results

From a cohort of 11,416 patients, 4,602 were enrolled (3,919 on IG and 683 on OG). IG had higher rate of women (67.3% vs 63.4%, p<.05) and a lower mean age (36.1±10.9 vs 38.9±11.8, p<.001). For the event time to first relapse, Cox models after PS adjustment revealed a lower risk for OG patients (HR 0.58 CI95% 0.47-0.70, p<0.001). About the risk of CDP, no differences were found in the two groups (HR 1.14 CI95% 0.88-1.48, p=0.306). About the risk of DMT discontinuation, OG patients showed lower risk (HR 0.70 CI95% 0.57-0.86 p=0.001) than IG patients.

Conclusions

Real-world data from the Italian MS registry suggest that first line oral DMTs are associated to lower risks of experiencing a new relapse and of therapy discontinuation in comparison to injectable DMTs.

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Epidemiology Poster Presentation

P0506 - Towards a validated Secondary Progressive Multiple Sclerosis definition: A study from the Italian MS Register (ID 1432)

Abstract

Background

No clear metrics for sensitive and reliable identification of the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive (SP)MS are available.

Objectives

To compare diagnostic performances of two different data-driven Secondary Progressive Multiple Sclerosis definitions.

Methods

patient with RRMS with a follow-up ≥5 years, with a current age ≥18 years, and with ≥3 EDSS scores recorded were selected from the Italian MS Registry. Annual incidence of SPMS conversion was reported as number of patients converting to SP every 100 patients/year. Three different SPMS definitions have been used. Data-driven definitions based on the Lorscheider’s algorithm (LA) and on the EXPAND trial inclusion criteria were validated, using the neurologist’s definition as gold standard, in terms of calibration, discrimination and goodness of fit by calculating: sensitivity, specificity, Positive Predictive Value (PPV), Negative Predictive Value (NPV), the Akaike information criterion (AIC), the Area Under the Curve (AUC). The overall calibration of the data-driven definitions was evaluated by the Calibration Slope test.

Results

a cohort of 10,240 RRMS patients was extracted from the Italian MS Registry. According to the neurologist judgment, 880 (8.59%) patients were classified as SPMS in the dataset. By applying the LA and the EXPAND definition, 1,806 (17.64%) and 1,134 (11.07%) patients, respectively, were classified as SPMS. The annual rate of SP conversion during the follow-up was 0.74 every 100 patients/year based on the neurologist’s definition, 1.57 every 100 patients/year using the LA and 0.94 every 100 patients/year applying the EXPAND definition. Both the data-driven definitions were well calibrated, with a p-value of the Calibration Slope test higher than 0.05 (LA=0.55; EXPAND definition=0.57). The AIC (LA=4301; EXPAND definition=5510) and the R-Square (LA=0.15 vs EXPAND definition=0.05), were in favor of the LA. The LA showed a greater discrimination power (AUC: 0.83 vs 0.65) and a higher sensitivity (77.1% vs 38.0%) in comparison to the EXPAND definition. Both definitions showed similar specificity (88.0% vs 91.5%). The PPV and the NPV were both higher using the LA than those obtained by the EXPAND definition (37.5% vs 29.5%; 97.6% vs 94.0%, respectively).

Conclusions

An accurate definition of SP transition is needed for a timely and efficacious treatment of SPMS patients. Real-world data from the Italian MS Registry suggests that data-driven definitions had a greater ability to capture SP transition than neurologist’s definition and that the global accuracy of LA seems to be higher than a definition based on the EXPAND trial inclusion criteria.

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Genetics and Epigenetics Poster Presentation

P0516 - BDNF Val66Met polymorphism effect on hippocampal subfields in multiple sclerosis patients (ID 1688)

Abstract

Background

Brain-derived neurotrophic factor (BDNF) can promote neuronal growth and repair, playing a key role in synaptic plasticity, especially in the hippocampus. The BDNF Val66Met polymorphism was shown to strongly affect BDNF function, but its role in modulating gray matter damage in multiple sclerosis (MS) patients is still not clear.

Objectives

Considering BDNF relevance on hippocampal function, we aimed to explore the effect of BDNF Val66Met polymorphism on the atrophy of hippocampal subfields and its role in cognitive functioning in MS patients.

Methods

Using a 3T scanner, we obtained dual-echo and 3DT1-weighted sequences from 50 MS patients and 15 healthy controls (HC). MS patients also underwent genotype analysis of BDNF and an extensive neuropsychological evaluation. Hippocampal subfields were segmented by using Freesurfer 7.0.1 software. Multiple linear regression models adjusted for age, sex and disease duration were used for between-group comparisons and analysis of associations.

Results

The BDNF Val66Met polymorphism was found in 22 MS patients (44%). Compared to HC, MS patients had reduced volumes of: bilateral hippocampus-amygdala transition area (HATA); left cornus ammonis (CA)1, CA3 and granule cell layer of dentate gyrus (GCL-DG); and right fimbria and presubiculum. BDNF Val66Met polymorphism carriers compared to wild-type (Val66Val) MS patients had higher volume of left hippocampal CA1, CA3, CA4, GCL-DG, molecular layer of subiculum and HATA; and of right hippocampal tail, fissure and presubiculum. In MS patients, higher volume in left CA3 and in right presubiculum correlated with better performance in semantic fluency, while higher volume in left GCL-DG correlated with better visuo-spatial memory performance.

Conclusions

The BNDF Val66Met polymorphism has a protective role in MS patients against both hippocampal atrophy and cognitive deterioration. BDNF genotype may be a potential biomarker for predicting cognitive prognosis, and an interesting target to study for neuroprotective strategies.

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Imaging Poster Presentation

P0544 - Atrophy of different cortical and subcortical compartments contributes to explain clinical disability in patients with MS: a multicenter study (ID 1082)

Presentation Number
P0544
Presentation Topic
Imaging

Abstract

Background

In MS, neurodegenerative processes involve several cortical and subcortical structures of the central nervous system.

Objectives

To perform a multiparametric assessment of cortical, deep grey matter (DGM), cerebellar and cervical cord atrophy to characterize MS phenotypes and to explain patients’ disability.

Methods

3T brain and cervical cord T2- and 3D T1-weigthed images were acquired from 198 MS patients (139 relapsing-remitting [RR] MS, 59 progressive [P] MS) and 67 healthy controls (HC) at three European sites. Cortical thickness (CTh), DGM volumes, cerebellar volumes and cervical cord cross-sectional area (CSA) were compared between MS patients and HC and across clinical phenotypes. In patients, sex-, age-, and site-corrected stepwise linear regression models investigated the association of brain and cord lesion burden and cortical, DGM, cerebellar and cervical cord atrophy with clinical disability.

Results

Compared to HC, MS patients had widespread atrophy in all cortical lobes, DGM nuclei and cerebellar lobules, as well as reduced cord CSA. Similar results were observed in RRMS patients vs HC, except for the left superior parietal lobule and left frontal pole (p=range from <0.001 to 0.04). In PMS patients, additional cortical atrophy vs RRMS was identified in all investigated lobes (p=range from <0.001 to 0.03), except for selected cingulate, parietal and occipital regions. At the univariate analysis, in MS patients higher disability was associated with more severe cortical, DGM, cerebellar and cervical cord atrophy (p=range<0.00-0.047). The multivariate model retained cerebellar and cervical cord atrophy as significant predictors of higher EDSS score (R2=0.45, p<0.001) as well as of pyramidal (R2=0.42, p<0.001), sensory (R2=0.28, p<0.001) and cerebellar (R2=0.50, p<0.001) functional system scores.

Conclusions

Abnormalities of regional CTh, DGM volume, volume of the cerebellar lobules and cervical cord CSA characterized the main MS clinical phenotypes. Atrophy within the cerebellum and cervical cord was crucial for explaining clinical disability, mainly within sensorimotor domains.

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Imaging Poster Presentation

P0557 - Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: a voxel-wise, multicenter analysis (ID 1115)

Abstract

Background

In multiple sclerosis (MS) the cervical spinal cord is often affected by demyelination and neuro-axonal injury, leading to irreversible tissue loss.

Objectives

To use voxel-wise analysis to evaluate the distribution and changes over time of cervical cord atrophy in MS patients from a multicentre dataset acquired at 7 European sites.

Methods

Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluation were obtained from 54 healthy controls (HC) and 110 MS patients (13 clinically isolated syndromes [CIS], 75 relapsing-remitting [RR] and 22 progressive [P]MS). A pipeline optimized for longitudinal analysis was used to co-register baseline and 1-year follow-up cervical cord scans to a cord template, obtained by averaging straightened HC images from all centers. Voxel-wise differences of cervical cord atrophy, their longitudinal changes and correlations with clinical variables were assessed using SPM12 and full factorial models (sex-, age-, center- and total cord volume-corrected).

Results

Compared to HC, MS patients exhibited significant (p<0.05, family-wise error [FWE] corrected) baseline cervical cord atrophy, mainly located in anterior, posterior and lateral cord regions at C1/C2, as well as in posterior regions between C4 and C6. While CIS patients showed a slight cord tissue expansion vs HC at posterior C4, RRMS presented significant clusters of cord atrophy vs CIS, mostly in lateral and posterior C2-C4 regions, and PMS showed widespread cord atrophy vs RRMS patients at C4-C5 and C7 levels. During the follow-up, a significant progression (p<0.05, FWE) of cord atrophy was detected in MS patients, predominantly in the posterior and lateral cord at C2, and between C4 and C6. Such pattern of cord atrophy progression was mainly driven by RRMS patients, while CIS patients did not show cord tissue loss at follow-up vs baseline, and PMS patients showed circumscribed tissue loss in posterior regions at C2 and C6. A strong relationship (p<0.05, FWE) was found between baseline clinical disability and baseline cord atrophy in the posterior and lateral cord at C2-C4. Also, baseline atrophy in the lateral cord at C3-C4 correlated with clinical disability at 1-year follow-up.

Conclusions

Voxel-wise analysis of cervical atrophy allowed to detect a differential involvement of cord levels and to characterize 1-year evolution of tissue loss across phenotypes. Cord atrophy was clinically relevant and contributed to explain follow-up clinical disability.

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Imaging Poster Presentation

P0567 - Diffusion-based Structural connectivity abnormalities in MS phenotypes. (ID 1271)

Abstract

Background

People with MS present disruption of structural brain networks, but the differential characteristics of such changes among MS phenotypes and their clinical impact are not well elucidated.

Objectives

To characterize diffusion-based brain connectivity abnormalities in different MS phenotypes and their relation with disability in a large cohort of patients.

Methods

In this multicenter, retrospective, cross-sectional study, we collected clinical and brain MRI data from 344 patients with MS [median Expanded Disability Status Scale, EDSS 2.0 (range 0-7.0)] and 91 healthy volunteers (HV) from four MAGNIMS centers. Cognition was assessed with the Paced Auditory Serial Addition Test (PASAT) and Symbol Digits Modalities Test (SDMT) in 298 patients. We collected 3D-T1, FLAIR, diffusion-weighted images (DWI) and T2 or field maps acquisitions. FSL and ANTs packages were used to carry out DWI preprocessing and MRtrix software to generate connectivity matrices based on fractional anisotropy values. We computed six network measures (strength, global and local efficiency, clustering coefficient, assortativity and transitivity), and applied the ComBat tool to reduce inter-site variability. We calculated age-adjusted differences in graphs between groups using Mann-Whitney with FDR correction or Kruskal-Wallis with Dunn’s Test when necessary. Associations with clinical features were explored with Spearman’s rank correlation.

Results

Thirty-eight (11%) patients presented a clinically isolated syndrome (CIS), 262 (76%) had relapsing-remitting (RR) and 44 (13%) secondary progressive (SP) MS. CIS patients showed reduced global and local efficiency, clustering coefficient and transitivity compared to HV (corrected p<0.001), whilst RRMS did not differ from CIS patients. Compared with CIS and RRMS, patients with SPMS showed larger changes for the same previous graphs measures (corrected p<0.05), and lower strength than RRMS (corrected p=0.019).

In patients, reduced measures of strength, global and local efficiency, clustering and transitivity correlated with higher EDSS (rho:-0.12–-0.16, corrected p<0.034), lower PASAT (rho:0.26–0.30, corrected p<0.001) and worse SDMT scores (rho:0.28–0.32, corrected p<0.001).

Conclusions

Structural network integrity at the whole brain level is already widely reduced in people with MS from the earliest phases of the disease and becomes more abnormal in SPMS. Network modifications may contribute to the clinical manifestations of the disease.

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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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Imaging Poster Presentation

P0611 - Neurite density explains cortical T1-/T2-weighted ratio in multiple sclerosis (ID 1090)

Speakers
Presentation Number
P0611
Presentation Topic
Imaging

Abstract

Background

Cortical damage is clinically relevant in multiple sclerosis (MS), however reliable MRI markers for its monitoring are still an unmet need. Ratio of T1-weighted (T1w) and T2-weighted (T2w) sequences (i.e., T1w/T2w-ratio) has been suggested as a feasible MRI measure to assess cortical abnormalities in patients with MS (PwMS), but its histopathological substrate has yet to be definitively elucidated.

Objectives

To define the histopathological substrate of T1w/T2w-ratio in normal-appearing and demyelinated cortices of PwMS by performing a combined post-mortem MRI/histopathology study.

Methods

Fifteen PwMS and ten age- and sex-matched non-neurological controls (nNC) underwent post-mortem in situ 3T MRI with 3D T1w and T2w sequences, followed by brain dissection.

One hundred and five paraffin embedded tissue blocks (49 from PwMS, 56 from nNC) were collected. Tissue regions were matched to T1w/T2w-ratio maps to obtain regional cortical T1w/T2w-ratio. Using immunohistochemistry and silver staining, cortical density of myelin, microglia, neurons, glial cells and neurites were evaluated. Correlates of T1w/T2w-ratio alterations with histological markers were assessed through linear mixed-effects models.

Results

Twenty-six cortical lesions (85% subpial) were found in 24/49 (51%) cortical regions from PwMS. Compared to nNC’s cortex, both PwMS’ normal-appearing and demyelinated cortices had a significantly lower T1w/T2w-ratio (p=0.045 and 0.001). In PwMS, demyelinated cortex showed a significant lower T1w/T2w-ratio compared to normal-appearing cortex (p=0.007). In PwMS, neurite density was significantly lower in both normal-appearing and demyelinated cortices compared to nNC (p=0.041 and 0.001), and in demyelinated vs. normal-appearing cortex (p=0.048). Demyelinated cortex showed also significant lower myelin density compared to normal-appearing cortex in both nNC and PwMS (p<0.001). Regarding the pathological substrate, T1w/T2w-ratio was positively associated with neurite density (β=3.464×10-2, p=0.004), whereas only a trend for myelin density was found (p=0.082).

Conclusions

Both demyelination and neurite loss were found in the cortex of PwMS. By evaluating several histopathological markers in nNC and PwMS (in normal-appearing and demyelinated cortices), T1w/T2w-ratio was found to be sensitive to MS cortical damage and more specific to neurite than myelin density. T1w/T2w-ratio could be useful to investigate cortical damage in MS.

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Imaging Poster Presentation

P0637 - Relevance of NODDI to characterise in vivo the microstructural abnormalities of multiple sclerosis cortex and cortical lesions: a 3T study (ID 1087)

Speakers
Presentation Number
P0637
Presentation Topic
Imaging

Abstract

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.

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Imaging Poster Presentation

P0639 - Sensorimotor cerebellar functional connectivity changes as compensatory  mechanisms of structural damage in patients with MS and no disability (ID 1777)

Speakers
Presentation Number
P0639
Presentation Topic
Imaging

Abstract

Background

The cerebellum plays a relevant role in both motor and cognitive function due to the high number of cerebellar connections with the brain and spinal cord. Alterations in cerebellar functional connectivity may modulate the relationship between brain structural damage and clinical impairment in multiple sclerosis.

Objectives

To investigate whether resting-state functional connectivity changes of the sensorimotor cerebellum represent adaptive neuroplastic mechanisms to reduce the effects of structural damage on physical disability in patients with multiple sclerosis and no disability.

Methods

A total of 144 multiple sclerosis patients with a score of ≤1.5 on the Expanded Disability Status Scale and 98 healthy subjects were selected from the Italian Neuroimaging Network Initiative database and included in this study. Both patients and healthy subjects underwent multimodal 3T-MRI including functional MRI at rest. After parcellation of the cerebellum, the sensorimotor cerebellum (lobules I-V + VIII) was identified and used as a seed for resting-state functional connectivity analysis.

Results

In patients, brain areas with decreased and increased sensorimotor cerebellar functional connectivity were found to coexist with respect to healthy subjects. Areas of decreased cerebellar functional connectivity, i.e. the lingual gyrus, insula, and precentral and postcentral gyri, negatively correlated with T2 lesion load and white matter atrophy. Areas of increased cerebellar functional connectivity, i.e. the posterior cerebellum, nucleus accumbens, prefrontal cortex, cingulate/paracingulate gyri, and precuneus, positively correlated with T2 lesion load and cerebellar and thalamic atrophy. Areas of increased cerebellar functional connectivity with the cingulate gyrus and precuneus negatively correlated with global grey and white matter atrophy.

Conclusions

In patients with multiple sclerosis, the sensorimotor cerebellum extensively reorganizes its functional links with other brain regions. Areas of decreased cerebellar functional connectivity related to white matter damage are present even in the absence of clinical manifestations and may represent a preclinical condition. Areas of increased cerebellar functional connectivity related to both lesion burden and thalamic or cerebellar atrophy likely represent a compensative reorganization of brain circuits. Lastly, global atrophy may influence functional connectivity changes in posterior cortical areas.

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Neuromyelitis Optica and Anti-MOG Disease Poster Presentation

P0683 - Altered resting state dynamic functional connectivity of precuneus contributes to cognition and depression in neuromyelitis optica spectrum disorders (ID 887)

Speakers
Presentation Number
P0683
Presentation Topic
Neuromyelitis Optica and Anti-MOG Disease

Abstract

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.

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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

P0823 - Resting state functional connectivity correlates of executive function in patients with multiple sclerosis (ID 1084)

Speakers
Presentation Number
P0823
Presentation Topic
Neuropsychology and Cognition

Abstract

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.

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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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Observational Studies Poster Presentation

P0852 - Clinical activity after fingolimod treatment in naïve RRMS patients compared to patients previously treated with other drugs (ID 1304)

Speakers
Presentation Number
P0852
Presentation Topic
Observational Studies

Abstract

Background

Fingolimod is a highly effective drug, with a significant proportion of subjects showing no evidence of disease activity (NEDA) at 2-years follow-up. However, it is not known whether the previous treatment history may influence clinical outcomes under fingolimod.

Objectives

To assess NEDA status in a Italian cohort of relapsing remitting (RR) MS patients treated with fingolimod (FTY), comparing naïve patients with patients previously treated with first-line and second-line drugs.

Methods

543 RRMS patients, who started fingolimod treatment at San Raffaele Hospital (Milan) between 2011 and 2018 were enrolled in the study. Patients were divided in three categories, according to the previous treatment: naïve patients (group 1, n=74), patients previously treated with first-line drugs (group 2, n=315) and patients previously treated with second-line and immunosuppressive drugs (group 3, n=146). NEDA status was assessed at two-year follow-up. Baseline characteristics were investigated in association with NEDA status, using logistic regression in univariable and multivariable models.

Results

Overall, 45.6% patients were NEDA (n=227) at 2-year follow-up; specifically 62.1% patients belonging to group 1, 47.4% to group 2 and 33.6% to group 3 respectively. In the multivariable analysis we observed that patients treated with a first-line and second-line therapy had an increased risk of being EDA (OR=2.2, p=0.036 and OR=3.9, p<0.001 respectively) compared to naïve patients. Moreover, a higher number of new/active MRI lesions (OR, 1.2, p=0.004), a higher annualized relapse rate in the 2 years before (OR=1.3, p=0.03) and a younger age (OR=0.97, p=0.01) at onset were independently associated with increased risk of being EDA.

Conclusions

We confirmed FTY effectiveness in a large monocentric cohort of Italian RRMS patients. Moreover, patients treated with FTY as first drug had a higher probability of being NEDA after 2 years compared to patients previously treated with second-line but also first-line drugs. These data suggest an early use of FTY in naïve patients with high inflammatory activity, considering the better clinical outcomes observed at short-term follow-up.

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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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Pathogenesis – the Blood-Brain Barrier Poster Presentation

P0982 - MR T2-relaxation time as an indirect measure of brain water accumulation in Neuromyelitis Optica Spectrum Disorders (ID 1077)

Speakers
Presentation Number
P0982
Presentation Topic
Pathogenesis – the Blood-Brain Barrier

Abstract

Background

One of the main unsolved issues in the clinical management of neuromyelitis optica spectrum disorders (NMOSD) is the lack of biomarkers predicting short-term relapses. In physiological conditions, the blood brain barrier (BBB) protects the CNS from water unbalance, with aquaporin-4 (AQP4) water channels on astrocytes podocytes being the main regulator of water influx and efflux. In NMOSD, BBB integrity might be threatened by the presence of antibodies targeting AQP4 water channels and triggering complement-mediated astrocytes damage. In line with this, increased T2-signal in acute lesions (“bright spotty lesions”) is considered specific for NMOSD. However, it remains unexplored whether these patients present a chronic water unbalance.

Objectives

To provide an indirect estimation of brain water content in NMOSD by measuring T2-relaxation time (T2rt) and to assess whether it differs in patients having a short-term relapse.

Methods

In this multicenter MR study, T2rt was calculated from brain dual echo turbo spin echo images assuming a mono exponential decay. T2rt maps of normal appearing white matter (NAWM), gray matter (GM) and basal ganglia were obtained from 77 AQP4-positive NMOSD and 84 HC. Short-term relapses were defined as those occurring within one month before or after MRI scan. Differences between NMOSD and HC were assessed with age-, sex- and site-adjusted linear models. ROC analyses were run to identify discriminators between stable and short-term relapsing patients.

Results

NMOSD patients and HC had similar ages. Compared to HC, T2rt was increased in the GM (103 vs 97 ms), NAWM (88 vs 84 ms) and putamen (75 vs 72 ms) of NMOSD patients (p<0.001 for all). Short-term relapses occurred in 20/77 (26%) of patients. According to ROC analysis, T2rt cut-offs of 87 ms in the NAWM, 87 ms in the thalamus and 88 ms in the caudatus were able to discriminate between short-term relapsing and stable patients with good accuracy (AUC=0.70, 0.76 and 0.79 respectively, p≤ 0.027).

Conclusions

NMOSD patients had increased T2rt values, in line with the hypothesis of subclinical water accumulation in this disorder. The burden of T2rt alterations might be useful for identifying those patients with incipient or recent relapses.

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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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Pediatric MS Poster Presentation

P1075 - Early clinical and MRI predictors of long-term disability in pediatric multiple sclerosis patients   (ID 1187)

Speakers
Presentation Number
P1075
Presentation Topic
Pediatric MS

Abstract

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.

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Rehabilitation and Comprehensive Care Poster Presentation

P1091 - Effect of BDNF Val66Met polymorphism on motor recovery after rehabilitation in progressive MS (ID 1676)

Speakers
Presentation Number
P1091
Presentation Topic
Rehabilitation and Comprehensive Care

Abstract

Background

It is known that a single-nucleotide polymorphism mapping to the Brain-Derived Neurotrophic Factor (BDNF) gene and resulting in the valine to methionine change (Val66Met or V66M), impacts memory, cognition and motor learning. Previous studies have shown that V66M polymorphism may exert a protective effect on grey matter atrophy in multiple sclerosis (MS) patients; however, its influence on motor recovery after rehabilitation is not known.

Objectives

To explore the possible influence of BDNF V66M polymorphism on motor recovery after rehabilitation in progressive MS subjects and to investigate the effect of two SNPs (rs2289656 and rs1212171) in NTRK2 gene, which encodes for BDNF receptor.

Methods

We retrospectively included in the study patients with primary progressive (PP) and secondary progressive (SP) MS, who were admitted to the Neurorehabilitation Unit and who had already available genetic data. The results of tests for gait (Six-minutes Walking Test, 6MWT; 10-Meters Test, 10MT) and hand dexterity (Nine-Hole Peg Test, 9HPT) were collected at baseline and after a 4-week inpatient rehabilitation program. We used ANCOVA models to explore the effects of the selected SNPs on the change of such clinical outcomes after rehabilitation, expressed as ratio values.

Results

100 patients (79 SP, 21 PP) with available clinical and genetic data were included in the study. Female:Male ratio was 1.27, mean age was 51±10 years and median EDSS score was 6.0 (range: 5.5-6.5). Sixty-eight patients were carriers of the more common genotype (GG), while the remaining were heterozygote (n=28) or homozygote (n=4) carriers of the V66M polymorphism (Met-carriers). Among 89 subjects with available data on 6MWT, Met-carriers showed greater improvement after rehabilitation if compared to GG patients (p=0.024; mean variation=0.16 [CI: 0.02-0.29]). SNPs in NTRK2 did not show any association with 6MWT change after rehabilitation neither alone, nor in interaction with V66M. As regards data on 10MT (n=42) and 9HPT (n=45), no associations were found for V66M or SNPs in NTRK2.

Conclusions

In the present pilot study, progressive MS patients carrying V66M polymorphism seem to have a greater improvement in walking performance at 6MWT after rehabilitation. These data need to be confirmed in larger and independent datasets, in order to better explore the effect of this polymorphism in MS patients undergoing intense rehabilitation program.

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Presenter Of 1 Presentation

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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