Amsterdam UMC, location VUmc
Anatomy & Neurosciences

Author Of 3 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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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 – 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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Presenter Of 2 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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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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