Author Of 5 Presentations
P0008 - Divergent patterns of ventral attention network centrality relate to cognitive conversion in MS (ID 473)
Cognitive impairment (CI) is common in multiple sclerosis (MS), but due to a lack of longitudinal data it remains unclear which mechanisms relate to conversion to mild or even severe CI. Previous cross-sectional work has suggested the importance of cognition-related resting-state networks, such as the default-mode and attention networks.
To characterize the functional network changes related to conversion to CI in a large sample of MS patients over a period of 5 years.
A total of 233 MS patients and 59 healthy controls (HC), all part of the Amsterdam MS cohort, underwent extensive neuropsychological testing and resting-state fMRI at baseline and follow-up (mean time-interval 4.9±0.9 years). At baseline, MS patients were categorized as being cognitively impaired (scoring ≤-2 SD on ≥2 domains, N=74), mildly impaired (MCI, being impaired on 1 domain or scoring between -1.5 and -2SD on ≥2 domains, N=33) or preserved (CP, not fulfilling the CI or MCI criteria, N=126). In addition, these groups were categorized according to the group to which they converted at follow-up (e.g. CP to CI). Network function was quantified using eigenvector centrality, a measure of network importance, which was averaged over established resting-state networks at both time-points. Correlations with brain volumes were calculated.
Over time, 26.2% of CP patients deteriorated and developed MCI (66.7%) or CI (33.3%) and 73.8% remained CP. 23.5% of MCI patients, progressed to CI. Centrality analysis showed that patients who were CI at baseline demonstrated a higher cross-sectional DMN centrality compared to controls (P=.05). Longitudinally, patients who remained CP and CP-to-MCI converters showed increasing ventral attention network (VAN) centrality over time time (P=.017 and .008, respectively), , whereas in the MCI and CI converter groups this increase was absent. Patients with less severe deep gray matter atrophy at baseline showed stronger increases in VAN centrality over time.
We showed that conversion from intact cognition to impairment in MS is related to an increase in centrality of the VAN, which is absent when overt impairment has manifested, then shifting towards DMN dysfunction. As the ventral attention network is known to normally relay information to the DMN, our results suggest that developing cognitive impairment is related to a progressive loss of control over the DMN by means of VAN dysfunction.
P0151 - Serum contactin-1 levels as a biomarker of long-term disease progression in natalizumab-treated multiple sclerosis. (ID 1674)
Contactin-1 (CNTN1) is a protein that is expressed in paranodal axonal domains and involved in myelin formation in the central nervous system (CNS) by way of axo-glia interaction, which is affected in multiple sclerosis (MS). Studying patients under natalizumab treatment provides a model to investigate correlations of novel biomarkers with non-inflammation induced disease progression in MS.
To investigate longitudinal serum CNTN1 in relation to clinical and radiological disease activity and progression independent of inflammatory disease activity in relapsing-remitting MS (RRMS).
Eighty-nine natalizumab-treated RRMS patients with minimum follow-up of 3 years were selected from an ongoing observational cohort study. Serum CNTN1 was analyzed at baseline before natalizumab initiation, and at 3, 12, 24 months and last follow-up. Clinical and radiological characteristics and CNTN1 levels were compared between patients with either progressive, stable or improved disability according to ‘EDSS plus’ criteria: Expanded Disability Status Scale (EDSS), 9-hole peg test (9HPT) and timed 25-foot walk test (T25W) combined. A significant change in at least one assessment was defined as progression (increase) or improvement (decrease), and no significant changes in any assessment as stability.
Forty-three subjects (48%) showed disability progression on EDSS plus between reference and last follow-up visit, 34 (38%) remained stable and 12 (13%) improved (median [interquartile range (IQR)] follow-up 5.2 [4.3-6.7] years). No statistically significant differences were found in the proportion of patients with clinical and radiological evidence of disease activity 1 year prior to baseline or during follow-up. Baseline serum CNTN1 (median [IQR], pg/mL) was significantly lower in the group with progressive disability (920 [798-1283]) compared to patients with either stable (1169 [861-1367] p=0.043) or improved disability (1133 [1046-1378], p=0.031). A 100 pg/ml increase in baseline CNTN1 was consistent with an odds ratio [95% confidence interval] of 0.809 [0.684-0.958] (p=0.014) for disability progression. Longitudinal serum CNTN1 levels remained consistently lower in the group with progressive disability compared to the non-progressive group (stable and improved group together).
Long-term disability progression in MS patients treated with natalizumab was associated with lower serum CNTN1 concentrations compared to patients with either stable or improved disability.
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)
- P. Preziosa
- A. Meani
- A. Rovira
- S. Mesaros
- O. Ciccarelli
- J. Frederiksen
- C. Enzinger
- F. Barkhof
- C. Gasperini
- E. Fainardi
- W. Brownlee
- J. Drulovic
- X. Montalban
- S. Cramer
- M. Kalil
- M. Hagens
- S. Ruggieri
- G. Dalla Costa
- V. Martinelli
- K. Miszkiel
- M. Tintore
- G. Comi
- I. Dekker
- B. Uitdehaag
- J. Ivanović
- M. Amato
- M. Rocca
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.
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.
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.
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]).
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.
P0605 - More dynamic functional network switching in cognitively declining multiple sclerosis patients (ID 777)
Cognitive impairment in multiple sclerosis (MS) is strongly related to functional network dysfunction. In the absence of MS, optimal cognitive functioning of an individual is ensured by dynamically adapting the configuration of the functional network as needed. How these dynamic patterns are altered in MS remains unclear.
Our aim was to investigate the dynamic reconfiguration of cognitively relevant brain networks in MS, to identify specific brain network patterns related to progression of cognitive impairment.
Resting-state functional MRI (rs-fMRI) and cognitive scores were acquired from 230 patients with MS and 59 matched healthy controls, at baseline and at 5 year follow-up. Seven cognitive domains were examined with the expanded Brief Repeatable Battery of Neuropsychological tests. A sliding-window approach was used on the rs-fMRI data, for which brain regions were assigned to one of seven classic literature-based resting-state networks based on connectivity patterns at that point in time. How regions switched between networks was described using measures of promiscuity (number of networks switched to), flexibility (number of switches), cohesion (switches with another region), and disjointedness (independent switches). Linear mixed models were used for baseline and longitudinal analyses, controlling for age, sex, and education.
At baseline, 42% of patients showed cognitive impairment (CI) (18% Mild CI, ≥2 tests Z<-1.5; 23% severe CI, ≥2 tests Z<-2) and 28% of patients declined over time (≥2 tests yearly reliable decline>0.25). At baseline, CI patients showed increased promiscuity, flexibility and cohesion (i.e. more switching between networks) compared to preserved patients. Patients displaying cognitive deterioration showed increases in cohesion over time. Higher baseline cohesion was related to less gray matter volume, and more white matter integrity loss and lesion volume. Within cognitive domains, cohesion was inversely related to verbal memory, information processing speed, and working memory.
In patients with MS, increased switching between brain networks was related to cognitive impairment and structural damage. Cohesion particularly increased over time in patients showing cognitive decline, indicating that switching together with other regions might be particularly more common. These results provide support for the hypothesis of a progressive destabilization of the functional brain network in MS.
P0640 - Sensorimotor network dynamics predicts loss of upper and lower limb function in people with multiple sclerosis (ID 1048)
Both upper and lower limb disability is common in multiple sclerosis (MS), but do not always occur together, suggesting partially independent underlying mechanisms. Physical disability strongly relates to brain network disturbances in MS, yet network mechanisms underlying upper and lower disability progression remain unclear.
To investigate the relationship between upper and lower limb progression and functional sensorimotor network changes in MS.
Longitudinal data was included from a prospectively acquired cohort, with baseline data collected between 2008 and 2012 and follow-up assessments between 2014 and 2017. Participants underwent MRI and dexterity (9-Hole Peg Test) and mobility (Timed 25-Foot Walk) tests at baseline and after 5 years. Patients were stratified into progressors (>20% decline) or non-progressors for both tests. Measures of network efficiency were calculated from resting-state functional MRI data using both static (i.e. calculated on the entire scan) and dynamic (i.e. fluctuations during the scan) approaches and compared between patient groups. Multiple logistic regression was used to identify independent predictors of upper and lower limb progression and baseline connectivity patterns.
This study included 214 people with MS (age 47±11; 149 women) and 58 healthy controls (age 46±10; 31 women). Compared to respective non-progressors, upper limb progression (n=24) was related to higher dynamic efficiency of the right premotor cortex, somatosensory cortex and thalamus, while lower limb progression (n=37) was related to higher dynamic efficiency of the right supplementary motor area at baseline (p<0.05). Logistic regression showed that dynamic efficiency of the thalamus and supplementary motor area best predicted upper and lower limb progression respectively, independent of the severity of structural damage (p<0.01). Both areas displayed widespread higher dynamic connectivity in progressing compared to non-progressing patients at baseline (p<0.05).
Disability progression can be predicted by the severity of fluctuations (i.e. higher dynamics) in the efficiency of the sensorimotor network. The dynamic behavior of the thalamus and supplementary motor area were respectively related to upper and lower limb progression, possibly indicating different mechanisms underlying these types of progression in MS.