Background

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.

Objectives

To characterize the functional network changes related to conversion to CI in a large sample of MS patients over a period of 5 years.

Methods

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.

Results

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.

Conclusions

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.

Background

The early detection and monitoring of cognitive and ambulatory dysfunction in multiple sclerosis (MS) may be enhanced with smartphone-adapted cognition and walking tests. Contrary to clinical measures, smartphone-based assessment allows more frequent measurements in the everyday environment, which potentially better reflects daily functioning.

Objectives

To determine the reliability, concurrent and ecological validity of self-administered smartphone-adapted Symbol Digit Modalities Test (SDMT) and Two-Minute Walking Test (2MWT).

Methods

Patients with MS were recruited. At baseline the SDMT and Timed 25-foot Walk Test (T25FW) were assessed clinically. During a 28-day follow-up, patients used the MS sherpa® app to perform the smartphone SDMT and 2MWT three times a week. The smartphone SDMT was assessed through tapping numbers corresponding to symbols on the smartphone during 90 seconds. The 2MWT measured walking distance utilizing the smartphone built-in sensors during two minutes of normal walking. Reliability of the smartphone tests were assessed by calculating intra-class correlation coefficients (ICC) between scores from week 2 and 3. Concurrent validity was addressed by calculation of correlation coefficients between the smartphone tests and their clinical counterparts. MS sherpa® also included one-item self-report scores for perceived fatigue and impact of MS on daily functioning. To assess ecological validity, the temporal association between the MS sherpa® tests and self-report scores from the everyday environment were analyzed using linear mixed models with the repeated measures as random effects.

Results

102 patients with MS were included. During the 28-day follow-up 102 patients completed a mean (± SD) of 12.1 (± 6.8) SDMTs and 74 patients completed a mean (± SD) of 8.8 (± 6.1) 2MWTs. Smartphone SDMT correlated significantly with the clinical SDMT (r = 0.607, p < 0.001) and demonstrated excellent reliability (ICC = 0.923). 2MWT was significantly correlated with T25FW (ρ = -0.352, p = 0.001) and demonstrated good reliability (ICC = 0.845). Over the 28-day period, higher 2MWT scores were related with lower perceived impact of MS on daily functioning (b = -0.005, 95% CI [-0.010, -0.001]) and higher SDMT scores were related with lower perceived fatigue (b = -0.014, 95% CI [-0.026, -0.003]).

Conclusions

Smartphone-adapted cognition and walking tests can be assessed frequently from the participants’ own environment and demonstrated validity and reliability in assessment of information processing speed and ambulatory function in MS. Support for ecological validity was found for perceived fatigue and impact on functioning in the everyday environment.

Background

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.

Objectives

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).

Methods

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.

Results

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).

Conclusions

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.

Background

Typing behavior on a smartphone may be used as a biomarker in patients with multiple sclerosis (MS) by analyzing their keystroke dynamics (KD). The continuous acquisition of high sample rate data may provide unprecedented insights in short-term changes in important health outcomes in MS.

Objectives

To investigate the sensitivity of KD to clinically relevant change (i.e. responsiveness) in disease activity, fatigue, and clinical disability outcomes in patients with MS.

Methods

Patients with MS were recruited in this cohort study. Clinical outcomes were assessed at baseline and 3 months follow-up, including: MRI gadolinium-enhancing lesions (Gd-EL), patient-perceived fatigue, and clinical disability measures (Expanded Disability Status Scale, EDSS; Timed 25-foot Walk Test, TWT; Nine-Hole Peg Test, NHPT; Arm function in MS Questionnaire, AMSQ). Throughout the study, patients used the Neurokeys App which replaces the native keyboard with a smart-keyboard and unobtrusively collects time-stamped key press and release events in the real-world setting. Keystroke data of 14 days surrounding the clinical visits were aggregated for the analyses. The area under the receiver operating characteristics curve (AUROC) was calculated to assess responsiveness of KD in classifying anchor-based change within clinical outcomes. The minimally important change (MIC) was calculated as the mean change in KD in the lower +2 SD portion (to approximate minimal change) of patients with clinically relevant change for each clinical outcome. The MIC was compared to the smallest detectable change (SDC) to assess the capability of KD to distinguish important change from measurement error.

Results

102 patients with MS were included, of whom 94 completed follow-up. Responsiveness of KD were acceptable for change in number of MRI Gd-EL (highest AUROC = 0.73) and arm function based on the AMSQ score (highest AUROCs = 0.75). KD had excellent responsiveness to change in ambulatory function measured with TWT (highest AUROC = 0.84). EDSS and NHPT had lower AUC values than KD in classifying change in Gd-EL and AMSQ, respectively. For all keystroke features the MIC exceeded the SDC with differences ranging from 3.6 to 92.4%.

Conclusions

KD collected in patients with MS using the Neurokeys App demonstrated responsiveness to clinically relevant changes in gadolinium-enhancing lesions on MRI and clinical disability measures for arm and ambulatory function. Responsiveness of KD was higher than commonly used clinical measures in MS and sensitive enough to discriminate important change from measurement error.

Background

The Guy’s Neurological Disability scale (GNDS) and the Multiple Sclerosis Impact Scale (MSIS-29) are patient reported outcome measures (PROMs) which can serve as a proxy for measuring disability and impact in patients with diagnosed multiple sclerosis (pwMS). In times of increased interest for telemedicine such measures are important.

Objectives

The aim of this study was to investigate correlations between two multi-domain PROMs and often used clinical outcome measures.

Methods

248 MS patients were assessed using the GNDS, the physical part of the MSIS-29 (MSIS-phys), the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9-HPT) and the Timed 25-foot walk test (T25WT) at baseline (BSL) and follow-up (FU) with a mean of 6.4 years. Cross-sectional and longitudinal correlations were studied between the overall scores and specific subcategories of the PROMs and clinical outcome measures. Additionally, the relationship between clinically significant changes in the PROMs and clinical outcomes were studied. We defined a clinically significant change of three or more points on the GDNS, eight or more points on the MSIS-phys and one point or more on an EDSS score <5.5 and one-half point or more on an EDSS score ≥5.

Results

Strong cross-sectional correlations were found between the “legs” domain of the GNDS and the pyramidal functional system (p-FS) of the EDSS (Rbsl(247)=.55, p<0.001; RFU(238)=.77, p<0.001) and the T25WT (RBSL(247)=.56, p=0.000; RFU(233)=.77, p<0.001) especially in progressive patients (PPMSbsl R(34)=.76, p<0.001; PPMSFU R(26)=.86, p<0.001, SPMSBSL R(21)=.61, P=0.003; SPMSFUR(34)=.82, p<0.001). The MSIS-phys also showed strong correlations compared to the p-FS of the EDSS RBSL(162)=.59, p<0.001; RFU(236)=.70, p<0.001) and T25WT RBSL(162)=.61, p<0.001; RFU(231)=.61, p<0.001). Only good correlations were found between the MSIS-phys and T25WT in RRMS patients (RBSL(114)=.45, p<0.001; RFU(172)=.54, p<0.001).

Longitudinal correlations for the global GNDS/MSIS-phys and EDSS/MSFC were relatively poor except for changes on the leg domain of the GNDS in relation to changes on the T25WT (R(231)=.58, p<0.001), especially in PPMS patients (R(25)=.68, p<0.001). In the majority of cases a clinically significant deterioration on the EDSS also resulted in a clinically significant worsening of the GDNS and MSIS-phys.

Conclusions

The GNDS and MSIS-phys correlate well with clinical outcome measures for physical disability. The GNDS in particular, for the lower limb function in progressive patients. PROMs are easy to apply, less-time consuming and are a more cost-effective way of capturing patients’ disability.

Background

Natalizumab is an effective disease-modifying therapy for relapsing remitting multiple sclerosis (RRMS). However, natalizumab trough concentrations remain high in a treatment regimen of 4-weekly infusions in 85% of patients. Previous studies showed that patients on extended interval dosing (EID) of natalizumab had comparable disease activity to standard interval dosing (SID) and a decreased risk of progressive multifocal leukoencephalopathy.

Objectives

To validate the maintenance of efficacy, measured by radiological disease activity, of personalized EID of natalizumab based on natalizumab trough concentrations. Feasibility of further extending intervals up to trough concentration of 5 μg/ml will be studied in a subgroup.

Methods

In this national multicenter prospective study (ClinicalTrials.gov Identifier: NCT04225312), 300 patients diagnosed with RRMS that received ≥ 6 consecutive natalizumab infusions will be included. Patients will be included in the main personalized EID group (aimed trough concentration 10 μg/ml), the low EID group (trough 5 μg/ml) or the SID group. Follow-up is two years with an extension phase of two years with annual MRI brain scans and 6 monthly scans for patients in the low EID group. Questionnaires will be filled in yearly by all participants.

Results

Inclusion of patients started in February 2020. Participants will be included in 22 centers in The Netherlands. So far, 69 patients were included, of whom 19 in the main EID group, showing natalizumab trough concentrations at baseline of 18.5 μg/ml (IQR 9.2 to 30.0). Current treatment intervals are 4 weeks (n=5), 5 weeks (n=5), 6 weeks (n=8) or 7 weeks (n=1). In the low EID group (n=37), natalizumab trough concentrations at baseline were 15.0 μg/ml (IQR 10.3 to 21.8). Current treatment intervals are 4 weeks (n=2), 5 weeks (n=8), 6 weeks (n=17) or 7 weeks (n=10). In the SID group (n=13), natalizumab trough concentrations at baseline were 18.0 μg/ml (IQR 14.5 to 26.0). Wearing-off symptoms were present in 33.9% of participants at baseline. No signs of radiological or clinical disease activity were present during follow-up so far.

Conclusions

Personalized extended interval dosing of natalizumab based on trough concentrations has the potential to become a safe, standardized treatment for RRMS patients using natalizumab. Final results of this study are expected in January 2024.

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.

Background

Detecting factors that influence disease variability in MS patients is crucial to provide novel insights into the etiology of the disease and guide the search for effective therapies. To study the phenotypic variability, well-defined unbiased cohort studies are necessary. The most common and arguably most important variable to be considered as a confounding factor when studying variability of disease course in MS, is age.

Objectives

To identify determinants that explain phenotypic variability in MS, while eliminating the undesirable effect of age variation between MS patients.

Methods

Project Y is an ongoing population-based cross-sectional study of all people with MS born in the Netherlands in 1966. Participants are subjected to extensive examinations of a wide array of potential determinants and outcome measures: functional and static imaging, biomarkers in body fluid, physical and cognitive measurements, and lifestyle factors early and later in life. Age and sex matched controls are included.

Results

As for July 2020, a total of 386 eligible MS patients were identified, of which 31 refused to participate and 86 patients awaiting inclusion. Thirteen patients had passed away prior to study inclusion. Between December 2017 and July 2020, 269 MS patients participated with either a full or partial data collection, together with 125 healthy controls. The total number of identified cases (386) results in a prevalence of at least 1.7/1000 in the birth year 1966.

Conclusions

The first preliminary data of our unique cohort indicate that the previously presumed prevalence of MS in the Netherlands (1/1000) is a serious underestimation of the actual prevalence.

Background

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.

Objectives

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.

Methods

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.

Results

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.

Conclusions

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.

Background

Clinical disability in multiple sclerosis (MS) is insufficiently explained by structural damage as measured with standard magnetic resonance imaging (MRI) measures. More advanced measures of brain network atrophy and functional network changes might better explain symptoms and clinical deterioration.

Objectives

To investigate the relevance of functional network alterations in addition to network atrophy for explaining physical disability in MS.

Methods

In this cross-sectional study 143 MS patients and 36 healthy control participants underwent resting-state magnetoencephalography (MEG) and structural MRI. Functional connectivity between regions was estimated using the phase lag index, from which the minimum spanning tree (MST) was constructed, representing the backbone of the functional network. The topology of the MST was described using the so-called tree hierarchy (MST-Th). Gray matter (GM) volume was calculated within literature-based resting-state network maps (i.e. visual, sensorimotor, dorsal attention, ventral attention, limbic, fronto-parietal, default mode, deep gray matter, and cerebellar networks). Physical disability was quantified with the Expanded Disability Status Scale (EDSS), Nine Hole Peg Test (9HPT) and Timed 25-Foot Walk Test (TWT). Network atrophy and topology were compared between groups and related to disability.

Results

Atrophy was apparent in all resting-state networks. All volumes correlated positively (p<.001) with EDSS and 9HPT: Spearman’s ρ between .289 and .567, highest correlations for sensorimotor, default mode, fronto-parietal and dorsal attention networks. EDSS correlated negatively with MST-Th in the lower alpha band (α1) (p < 0.008), while 9HPT correlated negatively with MST-Th in the upper and lower alpha, gamma, delta and theta bands (p <0.05), indicating a less efficient network relating to worse disability. TWT was related to atrophy in all networks, but not network topology. Together, MST-Th-α1, age, cerebellar and fronto-parietal atrophy explained 36% of EDSS variance, while 19% of 9HPT variance was explained by deep GM atrophy and MST-Th-α1. Lesion volume had no added significant effect on variance.

Conclusions

These results suggest that more advanced measures of network atrophy and functional network topology can explain a significant degree of disability variance in MS. In addition, mobility scores were not related to network changes, which could imply different underlying pathological substrates compared to those that underlie upper limb dexterity.

Background

Dissemination in space is one of two conceptional columns on which consensus diagnostic criteria of multiple sclerosis (MS) rests. Consistently cross-sectional data has demonstrated that optical coherence tomography (OCT) can be used to reveal the inter-eye difference of retinal layers as an additional para-clinical test in this context.

Objectives

To test the validity of the inter-eye difference of retinal layers as a diagnostic test in multiple sclerosis longitudinally.

Methods

Patients with multiple sclerosis and healthy controls who were longitudinally followed up at the Multiple Sclerosis Centre Amsterdam underwent OCT assessment at baseline and two year follow-up. We calculated the inter-eye percentage difference (IEPD) for the macular ganglion-cell inner plexiform layer (mGCIPL). Previously published cut-off levels (IMSVISUAL) were used to calculate diagnostic sensitivity and specificity levels.

Results

We included 199 participants of which 39 were healthy controls (HC). Patients with multiple sclerosis either had never experienced a clinical attack of optic neuritis (Non-MSON, n=81), suffered from unilateral MSON (n=48) or bilateral MSON (n=31). Longitudinal progression on the EDSS was less marked in these groups compared to longitudinal progression of mGCIPL atrophy. At baseline the diagnostic sensitivity and specificity values for the IEPD of the mGCIPL for comparing HC with unilateral MSON were 70%/97%, and with bilateral MSON 86%/97%. At two year follow-up the respective diagnostic sensitivity and specificity levels were 71%/97% and 83%/97%.

Conclusions

The inter-eye difference of the mGCIPL could be validated as a robust para-clinical test for multiple sclerosis longitudinally. These data were based on presence of a clinical episode of either unilateral or bilateral MSON. Extension of this approach to consider asymptomatic optic nerve pathology is warranted to further increase diagnostic sensitivity levels.

Background

Eye movement is controlled by a widespread network of cortical and subcortical areas, the oculomotor brain network, thus accurate measurement of these movements could represent a non-invasive method to reflect (dys)functioning of these interconnected areas. This is especially relevant for diseases in which network disruption is known to represent a key pathological feature, as in multiple sclerosis (MS).

Objectives

To investigate the association between saccadic eye movements and functional connectivity of the oculomotor brain network in patients with MS.

Methods

Subjects were included from the prospective Amsterdam MS cohort. A validated standardized infrared oculography protocol (DEMoNS) was used for quantifying pro-saccades and anti-saccades (reflexive and voluntary saccadic eye movements, respectively). After resting-state magnetoencephalography (MEG) measurement, data pre-processing and beamforming of the MEG data to source space, 73 oculomotor regions of the Brainnetome atlas were included based on previous literature (i.e. the FOcuS atlas). The phase lag index (PLI) was used as a measure of functional connectivity (FC) between all regions within the oculomotor network (and it’s subnetworks) for the six conventional frequency bands. The relationship between saccadic parameters and mean FC was analyzed using multivariate linear regression models adjusted for sex, age and disease type. Effect size modification by sex was additionally investigated.

Results

The 183 included patients with MS showed altered saccadic eye movements compared to the 58 included healthy controls. Regarding pro-saccades, worse saccadic eye movement performance was mainly related to a higher FC in theta and gamma bands and a lower connectivity in alpha and beta bands. Strongest relations with FC were found for peak velocity and the parietal eye field (theta band, β -2.1 E-4, p=0.006), gain and the precuneus (gamma band, β -1.3 E-4, p=0.003) and gain and the inferior frontal eye field (theta band, β -21.0 E-4, p<0.001). For anti-saccades, the strongest associations were found between the proportion of errors and the thalamus (beta band, β 8.0 E-4, p=0.006) and error of the final eye position and the precuneus (theta band, β -6.2 E-4, p=0.004). For female MS patients the proportion of errors was also strongly related to the supplementary eye field (gamma band, β 6.4 E-4, p=0.003) and for male patients the latency of a correct response to the cingulate eye field (delta band, β 5.3 E-4, p=0.006).

Conclusions

Saccadic eye movements were related to altered functional connectivity of fronto-parietal brain regions and the thalamus in patients with MS. Furthermore, there was evidence for a relevant sex difference in patterns of functional damage of the oculomotor brain network. This network approach provides an additional backing for the future use of eye movement measurement as an easy applicable tool for monitoring or predicting the disease MS.

Background

Cognitive dysfunction occurs in 40-65% of the people with MS (PwMS), which has been related to grey matter (GM) and thalamic atrophy. Whether biomarkers specific to Alzheimer’s disease (AD, i.e. amyloid beta (Aβ42), total Tau, phosphorylated Tau (ptau-181)) are also involved in cognitive dysfunction in MS is not fully elucidated yet.

Objectives

To identify biomarkers in the cerebrospinal fluid (CSF) that are associated with cognition in MS and determine its relation with brain volume.

Methods

In total 62 PwMS visiting the Second Opinion MS and Cognition Outpatient Clinic (41 females; mean age: 47.10±9.30; mean disease duration: 12.65±9.07) underwent lumbar puncture, brain MRI, neurological (EDSS) and neuropsychological examination (MACFIMS). PwMS were classified as cognitively impaired (CI) with 20% of the cognitive test scores of ≤-1.5 SD compared to normative scores. Aβ42 (pg/ml), total tau (pg/ml), ptau-181 (pg/ml), the ratio of ptau-181:Aβ42 and total proteins (mg/l) were measured using Elecsys immunoassays on the Cobas System. FSL’s SIENAX and FIRST were used to calculate brain volumes (white matter volume, GM volume (GMV), thalamus volume and lesion load). Differences between cognitively preserved (CP) and CI patients were calculated as were correlations between CSF biomarkers and brain volumes.

Results

Demographic and MS-specific characteristics were not different between CP and CI patients. Aβ42 was below the clinical cut-off (<1000pg/ml) in 13/35 CI patients compared to 2/25 CP patients (37% and 8% respectively, P=.013). The chance of being CI was 6.5 times higher if Aβ42 was below this cut-off (odds-ratio; 95% CI [1.3 – 32.3]). On a group level, a trend towards lowered Aβ42 was found in CI compared to CP patients (1264.20±478.63 versus 1490.79±384.37 pg/ml; P=.059), albeit within the normal range. No differences were found for the other CSF markers. CI patients had lower GMV (P=.002) and thalamic volume (P=.011), compared to CP patients. Only in CP patients, thalamus volume correlated with Aβ42 (r=.475, P=.019). No other correlations were found between Aβ42 and brain volumes.

Conclusions

Aβ42 levels below the clinical cut-off was seen more often in CI patients, as were a lower GMV and lower thalamic volume compared to CP patients. Only in CP patients Aβ42 and thalamic volume were correlated, which disappeared in the more advanced disease stage (CI), comparable to findings in mild cognitive impairment and AD. The specificity of Aβ42 pathology in relation to cognition in MS needs further investigation.