Amsterdam UMC, location VUmc
Anatomy and Neurosciences

Author Of 13 Presentations

Machine Learning/Network Science Poster Presentation

P0008 - Divergent patterns of ventral attention network centrality relate to cognitive conversion in MS (ID 473)

Speakers
Presentation Number
P0008
Presentation Topic
Machine Learning/Network Science

Abstract

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.

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Imaging Poster Presentation

P0539 - Artificial double inversion recovery images for cortical lesion visualization in multiple sclerosis (ID 817)

Speakers
Presentation Number
P0539
Presentation Topic
Imaging

Abstract

Background

Cortical lesions (CLs) in multiple sclerosis (MS) are clinically important, but highly inconspicuous on conventional clinical MRI. Double inversion recovery (DIR) is sensitive to CL detection, but difficult to implement in clinical practice and research settings, as it is difficult to set up and proper acquisition may take significant time due to the required inversion times (i.e.,~8 to 10 minutes). This work examines whether artificial intelligence can mitigate this dilemma through generation of artificial DIR images from –readily available– conventional clinical MR sequences.

Objectives

To determine whether artificially generated DIR (aDIR) images can be used for CL detection in MS and assess how this compares to conventionally acquired DIR (cDIR) images.

Methods

In this retrospective study, aDIR images were generated from conventional 1.5 Tesla 3D-T1 and 2D-proton density/T2 images in 73 patients with MS (49 RRMS, 20 SPMS, 4 PPMS) and 42 controls. A fully convolutional 3D conditional adversarial network following an adapted U-Net design with skip-connections was trained, using images of 58 patients and 34 controls. The remaining subjects were assigned to the test set for which artificial 3D-DIR images were generated. To determine detection reliability, precision and recall, the aDIR and cDIR images of subjects in the test set were blindly scored for CLs.

Results

A total of 626 CLs were detected on 15 aDIR images versus 696 on cDIR images (ICC=0.92, 95% confidence interval 0.68-0.98 (F(32.755)). Compared to cDIR images, CLs were detected on aDIR images with an average precision and recall of 0.84±0.06 and 0.76±0.09, respectively. The largest difference in CL discernibility was observed in frontal and temporal regions.

Conclusions

Artificially generated DIR images showed excellent reliability, precision and recall in detected cortical lesions when compared to conventionally acquired DIR images. The technique has the potential to broaden DIR availability and to enable retrospective implementation of cortical lesion detection with DIR. Histopathological and multi-center validation are necessary to formally compare sensitivity and specificity and cross-scanner robustness.

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Imaging Poster Presentation

P0570 - Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis (ID 1455)

Speakers
Presentation Number
P0570
Presentation Topic
Imaging

Abstract

Background

More than 80% of multiple sclerosis (MS) patients experience symptoms of fatigue. MS-related fatigue can only partly be explained by structural (lesions and atrophy) and functional (brain activation and conventional static functional connectivity) brain changes.

Objectives

To investigate the relationship of dynamic functional connectivity (dFC) with present and future fatigue in MS patients and compare this with commonly used clinical and MRI parameters.

Methods

In 35 relapsing-remitting MS patients (age: 42.8, female/male: 20/15, disease duration: 11 years) and 19 healthy controls (HC) (age: 41.4, female/male: 11/8), fatigue was measured using the CIS-20r questionnaire at baseline and at a 6-month follow-up. Furthermore, disability (EDSS) was assessed for patients. All subjects underwent structural MRI and resting-state functional MRI at baseline. We calculated global static functional connectivity (sFC) and assessed dynamic connectivity using a tapered sliding-window approach by calculating the summed difference (diff) and coefficient of variation (cov). Moreover, we calculated connectivity between basal ganglia and cortical regions previously associated with fatigue in MS (medial prefrontal cortex, posterior cingulate cortex, and precuneus). We performed hierarchical regression analyses with forward selection to identify the most important predictors of fatigue at baseline and follow-up.

Results

Patients were more fatigued than HCs at baseline (MS: 74.36 ± 29.33; HC: 46.72 ± 17.06; p=0.001) and follow-up (MS: 69.91 ± 27.01; HC: 45.11 ± 19.84; p=0.002). No difference in sFC was found between patients and controls. Patients had higher baseline global dFC than controls (p<0.05) but no difference in basal ganglia-cortical dFC. Basal ganglia-cortical dFC-cov added 12.5% extra explained variance (standardized β=-0.353, p=0.032) on top of EDSS (standardized β=0.380, p=0.022) to a regression model for baseline fatigue in patients (adjusted R2=0.211, p=0.011). Post-hoc analysis revealed lower basal ganglia-cortical dFC-cov in patients with severe fatigue at baseline (0.89 ± 0.06) compared to non-fatigued patients (0.93 ± 0.05; p=0.036).

Conclusions

Less dynamic connectivity between the basal ganglia and the cortex is associated with greater fatigue in MS patients, independent of disability status. These findings may reflect less efficient network reconfigurations of those connections as a potential additional neural correlate of fatigue in MS.

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Imaging Poster Presentation

P0582 - High resolution functional mapping of upper and lower limb sensorimotor function in minimally disabled people with multiple sclerosis using 7T MRI (ID 1050)

Speakers
Presentation Number
P0582
Presentation Topic
Imaging

Abstract

Background

In multiple sclerosis (MS) upper and lower limbs can be affected, but impairments only moderately relate to each other. Previous motor task studies have focussed predominantly on imaging hand function at clinical field strengths, preventing the detection of subtle changes and differentiation of mechanisms underlying subtle motor impairment.

Objectives

To investigate functional brain changes related to upper and/or lower limb motor task performance in minimally disabled MS patients using ultra-high field MRI.

Methods

Twenty-eight MS patients and seventeen healthy controls underwent visually-guided force-matching fMRI tasks using either hand or foot. Task performance (force error and lag) and activation level during upper and lower limb movements were compared between groups. Correlations were assessed between task activation and behavioural performance.

Results

During lower limb force tracking, MS patients showed significantly (p<0.01) longer lag, higher force error, higher primary motor and premotor cortex activation and lower cerebellar Crus I/II activation, compared to controls. No differences were seen in upper limb performance or activation. Upper and lower limb task performance was related to the level of activation in cerebellar, visual and motor areas in MS patients.

Conclusions

Altered lower limb movements and brain activation with preserved upper limb function and activation in minimally disabled patients suggests partially divergent functional mechanisms underlying upper and lower limb disability.

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Imaging Poster Presentation

P0605 - More dynamic functional network switching in cognitively declining multiple sclerosis patients (ID 777)

Speakers
Presentation Number
P0605
Presentation Topic
Imaging

Abstract

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.

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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

P0615 - Physical disability is related to resting-state network atrophy and altered MEG-based functional network topology in multiple sclerosis. (ID 1350)

Speakers
Presentation Number
P0615
Presentation Topic
Imaging

Abstract

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.

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Imaging Poster Presentation

P0640 - Sensorimotor network dynamics predicts loss of upper and lower limb function in people with multiple sclerosis (ID 1048)

Speakers
Presentation Number
P0640
Presentation Topic
Imaging

Abstract

Background

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.

Objectives

To investigate the relationship between upper and lower limb progression and functional sensorimotor network changes in MS.

Methods

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.

Results

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).

Conclusions

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.

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Imaging Poster Presentation

P0642 - Spatial distribution of cortical lesions in multiple sclerosis correlates to clinical and cognitive decline (ID 818)

Speakers
Presentation Number
P0642
Presentation Topic
Imaging

Abstract

Background

Cortical lesions are of eminent clinical relevance in patients with multiple sclerosis (MS), since they have been associated with clinical decline and disease progression. Heretofore, cortical lesions were commonly assessed at a whole-brain level, and were found to correlate with EDSS. However, there is no evidence on correlations between the spatial distribution of cortical lesions and cognition. We hypothesize that the distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline.

Objectives

To further elucidate the spatial distribution of cortical lesions and assess their association with clinical and cognitive decline.

Methods

One-hundred-fourteen patients (59 RRMS, 37 SPMS, 16 PPMS, mean age 54.49 ±8.99, 76 female) underwent MRI (double inversion recovery (DIR) and 3D-T1), and neuropsychological assessment (BRB-N, Stroop, Memory comparison task). Raw cognition data were converted to Z-scores based on the control scores, and averaged over the domains. For each patient, cortical lesions were identified and delineated on DIR. The extent of lesioned cortex was measured and cortical lesion maps were generated to enable vertex-wise cortical lesion probability maps and correlations using FreeSurfer.

Results

Cortical lesions were preponderantly situated in frontal and temporal lobes, as well as in the motor and anterior cingulate cortex. Significant clusters of vertex-wise correlations between cortical lesions and EDSS were primarily found for the motor cortex. Significant clusters of vertex-wise correlations between cortical lesions and cognition were primarily found for the frontal and temporal lobe.

Conclusions

The presence of frontal and temporal cortical lesions specifically predicted cognitive decline, while cortical lesions in the motor cortex were related to physical functioning. This confirms the hypothesis that the spatial distribution of cortical lesions contributes to explaining the variance of both clinical and cognitive decline. Further studies should investigate whether the location of cortical lesions is relevant to specific cognitive functions (e.g., memory or executive functioning).

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Neuro-Ophthalmology Poster Presentation

P0769 - Saccadic eye movements reflect functional connectivity of the oculomotor brain network in MS patients (ID 1108)

Speakers
Presentation Number
P0769
Presentation Topic
Neuro-Ophthalmology

Abstract

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.

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Neuropsychology and Cognition Poster Presentation

P0792 - Cerebrospinal fluid amyloid-β as potential biomarker for cognitive functioning in multiple sclerosis. (ID 1698)

Speakers
Presentation Number
P0792
Presentation Topic
Neuropsychology and Cognition

Abstract

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.

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Pathogenesis – Immunology Poster Presentation

P0944 - B-cells uptake citrullinated myelin basic protein in MS meningeal tissue: cause or consequence? (ID 1076)

Speakers
Presentation Number
P0944
Presentation Topic
Pathogenesis – Immunology

Abstract

Background

Studies from our lab have reported extensive presence of myelin particles in the leptomeninges of multiple sclerosis (MS) cases, hinting at a potential role of this debris in instigating MS-related immunological responses.

Objectives

Here, to gain further insight into this possibility we closely looked at meningeal myelin fragments for the presence of posttranslational modifications (citrullination) which render myelin debris more immunogenic. We also tested whether citrullinated myelin is associated with antigen presenting cells relevant to induction of autoimmunity in MS, i.e B cells.

Methods

We performed immunohistochemistry experiments on post-mortem meningeal material coming from 8 SPMS patients (age: 61.29±4.66, disease duration: 30±4.40 years) and 7 non-neurological controls (age: 55.88±5.32 years). In addition, using confocal colocalization analysis tools, we investigated the presence of citrullinated myelin basic protein (MBP) in CD19+ B lymphocytes in MS meninges.

Results

Compared with tissue from non-neurological controls, meninges of MS patients presented with a larger surface proportion of citrullinated proteins (p=0.03). In MS material, this effect was accompanied by the presence of meningeal CD19+ B-cells. Almost all the analyzed CD19+ B-cells showed high citrulline content (n=144, 99% citrulline positive cells; mean % citrulline inside B-cells= 50.81±3.86 %) and 95.13% of these cells were also positive for myelin basic protein (MBP; median percent MBP which colocalizes with CD19= 42.05%). Interestingly, Mander´s coefficient analysis to colocalize MBP and citrulline inside B-cells underlined that almost half of the lymphocytic cellular surface was occupied by citrullinated MBP (40.06±3.23 %).

Conclusions

Our results are indicative of a B cell-mediated uptake mechanism that operates in MS meninges to clear up highly immunogenic myelin fragments. Although the question remains on whether myelin citrullination happens in the absence of a primary immunological response, studies in cuprizone mouse models of MS have highlighted that MBP citrullination already occurs before demyelination via intramyelinic Ca2+-dependent activation of protein arginine deiminases. This evidence combined with previous studies showing abundant citrulline content in both MS normal appearing white matter and white matter lesion support the concept that a primary cytodegenerative process instigates demyelination, which elicits secondary immune reactions in MS.

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Pathogenesis – Neurodegeneration Poster Presentation

P0961 - Excitation-inhibition balance in multiple sclerosis: a quantification of glutamatergic and GABA-ergic synapse loss (ID 903)

Speakers
Presentation Number
P0961
Presentation Topic
Pathogenesis – Neurodegeneration

Abstract

Background

Synaptic loss is a key feature of the secondary progressive phase of multiple sclerosis (MS) and is related to clinical and cognitive functioning. However, whether the excitatory or inhibitory synapses are more susceptible to MS pathology is insufficiently clarified to date.

Objectives

To quantify GABAergic and glutamatergic synaptic densities in a sample of post-mortem MS brains and, hence, to investigate whether there is reason to suspect an imbalance in excitatory versus inhibitory neurotransmission.

Methods

Brains of 33 neuro-pathologically verified MS cases (21 women, mean age=63±12y) and 9 non-neurological controls (NC, 5 women, mean age=72±6y) were dissected shortly after death (mean post-mortem delay in MS: 5:37±1:29h; in NC: 9:19±2:85h). Sections of the superior frontal cortices were stained for myelin, parvalbumin- and calretinin-expressing interneurons and glutamatergic and GABAergic synapses. Subsequently, synaptic densities were quantified through confocal microscopy in sections of pre-determined regions of interest (ROIs) and image analyses. Data were analyzed using linear mixed-effects models.

Results

Of the 71 defined ROIs in MS tissue, 24% were demyelinated, the remaining were normal-appearing grey matter (NAGM). No differences in densities of calretinin- and parvalbumin-expressing interneurons were observed between groups. For both excitatory and inhibitory synapse densities, there was a significant interaction between tissue type (NC NAGM, MS NAGM and MS demyelinated cortex) and cortical layer (P=.003; P=.001, respectively). Post-hoc testing revealed that the densities of both synapse types were reduced in cortical layer 6 (excitatory: P=.004; inhibitory: P=.002). NAGM in MS cortical layer 6 showed reductions of 12.5% (excitatory) and 14.9% (inhibitory) synaptic density as compared to NC values (P<.05). In demyelinated MS cortex a loss of 18.5% in excitatory synapses and 29.3% in inhibitory synapses was noted respective to NC values (P<.05).

Conclusions

In post-mortem MS tissue, we found a significant loss of excitatory and inhibitory synapses in layer 6 of superior frontal cortex. Interestingly, in NAGM the proportion of synaptic loss was similar for both synapse types, while in demyelinated cortex inhibitory synapses were affected more. The differential effects of fairly subtle differences in excitatory versus inhibitory synapse loss on functional measures may nonetheless have a substantial effect on cellular and network functioning. This effect is now being investigated in a corticothalamic mean-field model (results pending).

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