Author Of 6 Presentations
P0570 - Dynamic functional connectivity as a neural correlate of fatigue in multiple sclerosis (ID 1455)
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.
P0578 - Five years functional connectivity reorganization without clinical or cognitive decline in MS (ID 755)
Abstract
Background
Multiple sclerosis (MS) is a disease characterized radiologically by the accumulation of lesions in grey and white matter over time throughout the CNS. Accumulating evidence has demonstrated abnormal patterns of brain functional connectivity (FC) in MS patients as compared to healthy controls (HCs). A longitudinal approach that accounts for all alterations in FC following structural damage in MS is warranted to better understand the complex interplay between disease progression and FC reorganization.
Objectives
1) To assess fMRI-based FC anomalies in early MS 2) To determine the relation between FC changes and structural brain damage due to disease progression 3) To study the association between FC changes and cognitive and physical disability.
Methods
Structural MRI and resting-state fMRI were acquired from 76 early relapsing-remitting MS patients at baseline (average disease duration 71.7 months ± 63) and after five years. Ninety-four HCs matched for age and sex were included at baseline. Independent component analysis (ICA) and network modelling were used to measure FC. FC variation was related to expanded disability status scale, timed 25-foot walk test, 9 hole peg test and neuropsychological outcomes. Brain and lesion volumes were quantified using standard methods. We used the 25 independent components obtained from ICA to estimate the longitudinal stability of the brain functional connectome as a proxy for functional reorganization over time. We computed the stability of the brain functional connectome for each MS patient by vectorizing each participant’s whole-brain connectivity matrix. Then, we calculated the within subjects Spearman correlation coefficient between fMRI at baseline and follow-up, obtaining a measure of whole-brain connectome stability that is sensitive to all changes in FC in the follow-up period.
Results
The MS subjects (71% females, mean age 35.3 ± 7.3) were clinically and cognitively stable. Compared to HCs, FC abnormalities were detected within networks and in single connections, mainly in the default mode network and frontoparietal areas, in patients with early MS at baseline. Over time, FC was relatively invariable, but changes in FC were associated with progression of brain atrophy (ρ = 0.39, p = .06). No significant relationship with clinical and cognitive measures or lesion load was detected.
Conclusions
We used the stability of the brain functional connectome as a proxy for FC reorganization. Patients with MS showed altered FC in the early stages of the disease, with FC abnormalities being bidirectional (i.e. increased and decreased FC). Over time, changes in FC, independent of direction, could be related to progression of brain atrophy, which is associated with changes in clinical and cognitive functioning. Connectome stability enables fMRI data to be condensed into a proxy as a cross-sectional and longitudnal individual imaging marker.
P0605 - More dynamic functional network switching in cognitively declining multiple sclerosis patients (ID 777)
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.
P0642 - Spatial distribution of cortical lesions in multiple sclerosis correlates to clinical and cognitive decline (ID 818)
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).
P0792 - Cerebrospinal fluid amyloid-β as potential biomarker for cognitive functioning in multiple sclerosis. (ID 1698)
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.
P0961 - Excitation-inhibition balance in multiple sclerosis: a quantification of glutamatergic and GABA-ergic synapse loss (ID 903)
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).