Author Of 1 Presentation
PS13.03 - MRI correlates of Cognitive Improvement after Home-Based EEG Neurofeedback Training in MS: A Pilot Study
Abstract
Background
Neurofeedback training shows promise to improve cognitive function in neurological patients. However, to date the underlying brain mechanisms of such improvements are poorly understood.
Objectives
To investigate MRI correlates of cognitive improvement after EEG-based neurofeedback training in patients with MS (pwMS).
Methods
Fourteen pwMS (7 female; mean age = 38.9, SD=2.2; disease duration = 9 years, SD= 1.9; median EDSS= 2.5 (3.5)) performed ten neurofeedback training sessions within 3-4 weeks at home using a tele-rehabilitation system. Half of the pwMS (N = 7 Responder) successfully learned to self-regulate sensorimotor rhythm (SMR, 12-15 Hz) in the EEG by receiving visual feedback and showed cognitive improvements (assessed by the overall T-score change of the BRB-N) after neurofeedback training. Non-responders (N=7) did neither improve in cognitive function nor were able to modulate their brain activity. Diffusion-tensor imaging and resting-state fMRI was performed before and after neurofeedback training. Whole brain fractional anisotropy (FA) and functional connectivity (FC) of the default-mode, sensorimotor and salience network were explored.
Results
At baseline, responders and non-responders were comparable regarding sex, age, education, disease duration, physical and cognitive function and T2-lesion-load. Responders showed increased FA and FC within the salience network (FCSal) and sensorimotor network after neurofeedback training compared to non-responders. Training-related increases in FCSal correlated with cognitive improvement (r=0.886, p<0.0001).
Conclusions
This exploratory study suggests that neurofeedback training could successfully lead to cognitive improvement and associated changes in brain microstructure and FC.
Author Of 8 Presentations
BD01.02 - Presentation 02 (ID 173)
P0127 - Oral therapies for treatment of relapsing-remitting multiple sclerosis in Austria (ID 252)
Abstract
Background
Studies matching the clinical efficacy between fingolimod (FTY), dimethylfumarate (DMF) and teriflunomide (TERI) provided conflicting results. These discrepancies ask for further investigations to confirm or rebut the published findings, especially by real-life experiences.
Objectives
To compare the efficacies, frequencies and reasons for treatment interruption of FTY, DMF or TERI in a nationwide observational cohort.
Methods
Twocohorts of patients with relapsing-remitting multiple sclerosis (RRMS) having started treatment with FTY, DMF or TERI documented in the Austrian MS Treatment Registry (AMSTR) since 2014 and either staying on therapy for at least 24 months (24m cohort) or with at least one follow-up visit after start of treatment (total cohort). The 24m cohort included 629 RRMS patients: 295 in the FTY, 227 in the DMF and 107 in the TERI group. We used multinomial propensity scores for inverse probability weighting in generalized linear and Cox proportional hazards models to correct for the bias of this non-randomised registry study.
Results
Estimated mean annualized relapse rates (ARR) over 24 months were 0.13 for FTY, 0.09 for DMF and 0.11 for TERI treatment. For TERI in comparison with DMF, we observed higher probability for treatment interruption (p=0.023) and reduced sustained EDSS regression for 12 (p=0.016) and 24 weeks (p=0.031) and, for the comparison of DMF versus FTY, a reduced sustained EDSS progression for 12 weeks (p=0.02).
Conclusions
Relapse rates with treatment with FTY, DMF and TERI were similar. Patients treated with DMF showed less sustained disability progression for 12 weeks than FTY treated patients. However, FTY and DMF treatment was associated with more likely EDSS regression for 12 and 24 weeks and a lowerprobability for treatment interruptionas compared to TERI treated patients.
P0156 - Serum neurofilament light levels correlate with reduced grey matter volume in advanced multiple sclerosis. (ID 770)
Abstract
Background
Grey matter (GM) pathology is associated with physical and cognitive impairment in patients with multiple sclerosis (pwMS). Increased levels of serum Neurofilament light (sNfL), indicating neuro-axonal damage, have been described in MS and were related to the development of global brain atrophy. However, the relation of sNFL to MRI-based measures of distinct brain volumes, in particular the grey matter, is still poorly investigated.
Objectives
To investigate the association of sNfL with compartmental brain volumes in pwMS in a cross-sectional and longitudinal manner.
Methods
We included 109 pwMS (mean age = 38.1 years, standard deviation (SD) ±11.7 years, 63.3% female) and 17 sex- and age-matched non-inflammatory neurological controls (NC) (mean age = 39.2 years, SD± 9.8 years). The MS cohort consisted of 16 clinically isolated syndrome (CIS), 72 relapsing-remitting MS (RRMS) and 21 progressive MS (PMS) patients. sNfL levels were measured by an ultrasensitive Single Molecule Array (Simoa®). In MS, we assessed whole and compartmental normalized and lesion-filled brain volumes and T2-lesion loads based on 3T MRI data, using T2-FLAIR and T1-weighted 1mm isotropic structural scans, processed with SienaX (part of FSL, fsl.fmrib.ox.ac.uk).
Results
In the entire cohort sNfL levels correlated with age (r = 0.329, p < 0.001). sNfL was significantly elevated in RRMS (p = 0.019) and PMS (p < 0.010) compared to NC, as well as in PMS compared to CIS (p = 0.035). Similarly, we found decreased brain volumes in PMS vs. CIS and RRMS. This was evident for whole brain, white matter (WM), total GM and cortical GM (p ≤ 0.001). Likewise, WM lesion volume was elevated in PMS vs. CIS (p = 0.001) and RRMS (p = 0.022). In deep GM areas, including basal ganglia and thalamus, volumes were decreased in PMS vs. CIS (p = 0.001 and 0.012 respectively) and PMS vs. RRMS (p = 0.038 and 0.015 respectively).
Only in patients with PMS we found sNfL to be negatively correlated with volumes of the whole brain after correcting for age (r = –0.571, p = 0.008). This was mainly driven by the correlation with total GM (r = –0.615, p = 0.004) and cortical GM (r = –0.664, p = 0.001). Regarding deep grey matter, only in PMS we observed a negative correlation of sNfL with basal ganglia volume (r = –0.571, p = 0.011). There was no correlation of sNfL with thalamus volume in any subgroup.
Conclusions
Although sNfL is already increased in earlier phases of MS, our data indicates that its relation to brain tissue damage, in particular GM pathology, might only become apparent in more advanced progressive forms of the disease. Further analysis of longitudinal MRI and clinical data is currently ongoing to confirm and extend our results.
P0247 - Comparison of the 2017 and 2010 revisions of the McDonald criteria in patients with cis suggestive of MS: a multicentre MAGNIMS study (ID 1121)
- P. Preziosa
- A. Meani
- A. Rovira
- S. Mesaros
- O. Ciccarelli
- J. Frederiksen
- C. Enzinger
- F. Barkhof
- C. Gasperini
- E. Fainardi
- W. Brownlee
- J. Drulovic
- X. Montalban
- S. Cramer
- M. Kalil
- M. Hagens
- S. Ruggieri
- G. Dalla Costa
- V. Martinelli
- K. Miszkiel
- M. Tintore
- G. Comi
- I. Dekker
- B. Uitdehaag
- J. Ivanović
- M. Amato
- M. Rocca
Abstract
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.
P0609 - Multimodal MRI of the Brain to Improve Prediction of Disease Progression in Multiple Sclerosis (ID 1428)
Abstract
Background
One of the challenges in multiple sclerosis (MS) research is to improve prediction of disease progression. While information from conventional MRI of the brain is essential in the diagnosis of MS, it only allows prognosis to some extent. Given the complexity of the disease, a combined analysis of structural and functional MRI changes appears more promising to identify markers associated with disease progression.
Objectives
We thus investigated how multimodal MRI can contribute to predicting disease progression in a single-centre cohort of patients with MS (PwMS).
Methods
We analyzed multimodal MRI-data from 123 PwMS (71 women; age (years): M=37.2, SD=10.4; nCIS=16; nRRMS=98; nPMS=9). All patients had undergone clinical and 3T MRI evaluations between 2015 and 2016 (baseline, BL) and clinical re-evaluations 2 years later (SD=1.0; follow-up, FU). Brain-volume, T2 lesion load, fractional anisotropy (FA) and resting-state functional connectivity (rsFC) of the default-mode (DMN) and sensorimotor network (SMN) at BL were correlated with the patients’ disease severity score progression (absolute Expanded Disability Status Scale (EDSS) score change from BL to FU).
Results
Across the entire cohort, median EDSS scores were significantly higher at FU (Med=1; IQR=2.5) than at BL (Med=1; IQR=2; p=0.04), with a low rate of disease severity score progression (assessed by EDSS BL – EDSS FU/ FU duration; Med = 0; IQR = 0.5). Neither normalized brain volume (NBV) nor T2 lesion load, extracted mean scores of whole brain FA or rsFC within DMN or SMN significantly correlated with disease severity score progression. Whole brain voxel-based analyses (controlled for age and disease duration) indicated trends for decreased FA within the corpus callosum (CC) and the corticospinal tract (CST) and decreased rsFC within the anterior cingulate cortex (ACC) and the hand motor area to be associated with disease progression. Subsequent ROI analyses revealed a significant decrease in mean FA in the CC genu (p=0.024), the CC forceps minor (p=0.020) and right CST (p=0.020) related to disease progression. Moreover, ROI analyses showed a decrease in mean rsFC in the left hand motor area (p=0.012) and the ACC (p=0.005) with increased disease progression.
Conclusions
Our results show that even within a relatively low rate of clinical disease progression over short term FU, subtle microstructural and functional changes may represent more sensitive predictors compared to gross morphological measures obtained from conventional MRI.
P0822 - Processing speed improves prediction of physical impairment in patients with multiple sclerosis (ID 743)
Abstract
Background
In recent years, a few studies found correlations between processing speed and physical disability in patients with multiple sclerosis (pwMS). However, it remains unclear if this specific cognitive subdomain improves prediction of physical impairment in pwMS.
Objectives
The aim of this study was to investigate, if cognitive performance at baseline improves prediction of physical impairment at follow-up, controlling for demographics, clinical and MRI data.
Methods
We investigated pwMS who had undergone clinical, cognitive and MRI assessment at two timepoints (baseline and follow-up). Physical impairment was measured using the Expanded Disability Status Scale (EDSS) and was defined by an EDSS-Score above 3.0. Cognitive performance was assessed by the Z-score of the Symbol Digit Modality Test (SDMT), measuring processing speed.
Results
109 pwMS took part at baseline (70 female; 34 clinically isolated syndrome (CIS), 64 relapsing-remitting MS (RRMS), 8 secondary-progressive MS (SPMS), 1 SPMS with relapses, 2 primary-progressive MS (PPMS)) and follow-up assessment (20 CIS, 70 RRMS, 14 SPMS, 3 SPMS with relapses, 2 PPMS). Their mean age at baseline was 36 years (10 SD) and the mean follow-up duration was seven years (3.8 SD). At baseline, MS patients had a mean SDMT Z-score of -1.16 (1.19 SD). The median EDSS at baseline and follow-up was 2.0 (range 0 - 8). A binary-logistic regression (Nagelkerke R2= .560, p < 0.001) that included age, disease duration, clinical phenotype, baseline physical impairment, cognitive performance, lesion load and normalized gray matter volume at baseline showed that processing speed (OR: 0.392, p = .007) and age (OR: 1.094, p = .035) at baseline were the only significant independent predictors of physical impairment at follow-up. MRI data at baseline correlated with EDSS at FU, but did not add to this prediction.
Conclusions
Processing speed at baseline independently improved prediction of physical impairment in pwMS after seven years. This highlights the importance of cognitive assessment in addition to the rating of physical impairment. In future, neuropsychological examination could further support determination of the degree of disability in pwMS.
P0940 - Anti-CD20 therapy prevents cortical demyelination in a new rat model (ID 342)
Abstract
Background
Cortical demyelination is thought to be a substrate for diffuse cognitive impairment often seen in the progressive stage of multiple sclerosis (MS). Unlike white matter plaques in brain or spinal cord, cortical MS lesions lack inflammatory T-cell infiltrates. B-cell depleting anti-CD20 therapy is effective in the relapsing-remitting course of MS, however not much is known about a possible effect of anti-CD20 directed therapy in prevention of cortical grey matter demyelination.
Objectives
We recently developed a new rat model (Ücal et al., 2017), suitable for research of cortical demyelination and associated cellular hallmarks seen in progressive MS. The aim of our study was to investigate the effect of anti-CD20 therapy on the development of cortical grey matter pathology in this model.
Methods
Adult male Dark Agouti rats were implanted with a catheter into the cerebral cortex, immunized with a low dose of a recombinant myelin oligodendrocyte glycoprotein (MOG) in incomplete Freund’s Adjuvant and injected with pro-inflammatory cytokines through the catheter to induce cortical demyelination. Anti-CD20 antibody therapy was administered either after (Group 1) or before (Group 2) MOG immunization by intravenous injection into the tail base vein. Rats were sacrificed at peak disease (day 15 post-cytokine injection). Cortical demyelination, microglial activation, neuronal cell loss, astrocytic reactivity and apoptotic cells were assessed by immunohistochemistry using specific markers (PLP, Iba1, NeuN, GFAP, Caspase3, respectively).
Results
Histological analysis demonstrates a significant reduction of demyelination, microglial activation, neuronal loss, astrocyte activation as well as apoptotic cells in anti-CD20 treated animals, compared to animals treated with an isotype-matched control antibody. Both therapeutic approaches (Group 1 and Group 2) showed equal efficacy. There was no significant difference in cortical demyelination between the healthy control animals (0.0 PLP loss) and the anti-CD20 treated animals (Group 1 = 0.1 PLP loss/mm2; Q1 = 0.03, Q3 = 0.27; Group 2 = 0.1 PLP loss/mm2; Q1 = 0.02, Q3 = 0.07).
Conclusions
Anti-CD20 therapy preserves the investigated cortical structures in our animal model, indicating a role of B-cells in the formation of cortical pathology, presumably through various pathways. These findings pave the way for further research on the mode of action of B-cells and might improve our understanding of cellular mechanisms behind progressive MS. This may expand our therapeutic strategies for MS patients in the progressive disease stage.
P1144 - Comparison of deep grey matter iron deposition assessed by 3T MRI R2* relaxometry in Multiple Sclerosis, Alzheimer´s disease and in normal controls (ID 1479)
Abstract
Background
Increased brain iron deposition has been described in different nosologic entities such as Multiple Sclerosis (MS) and Alzheimer’s disease (AD). However, it is still unclear whether abnormal brain iron accumulation contributes to the pathology of these diseases or merely reflects an epiphenomenon.
Objectives
To investigate deep grey matter iron deposition and its association with morphological brain changes and clinical data in patients with MS, AD and in normal controls (NC).
Methods
Participants with MS (n=196, mean age: 39±11 years), AD (n=116, mean age: 73±9 years) and NC (n=164, mean age: 66±11 years), underwent comprehensive clinical examination and brain MRI at 3T. Iron concentrations in deep grey areas (basal ganglia (BG), thalamus, hippocampus) were quantified by R2* relaxometry. Normalized brain volumes, T2 lesion load (LL) in MS and White Matter Hyperintensity (WMH) volumes in AD and NC were determined on T2-FLAIR and T1-weighted sequences, respectively.
Results
R2* relaxation rates increased with age in the BG. This relationship was strongest in MS (r=0.63, p<0.001), followed by AD (r=0.25, p=0.005) and NC (r=0.25, p=0.001). Higher BG R2* relaxation rates were associated with lower brain volumes, particularly concerning grey matter in MS (r= -0.51, p<0.001) and NC (r= -0.23, p=0.002) but not in AD. BG R2* relaxation rates correlated to T2 LL (r=0.45, p<0.001) in MS, but were unrelated to WMH volume in AD and NC. In MS, BG R2* relaxation rates further correlated with higher EDSS scores (r=0.28, p<0.001) and increased disease duration (r=0.35, p<0.001). Multivariate linear regression analysis revealed, that in MS age (beta=0.53, p<0.001) and T2 LL (beta=0.33, p<0.001) independently predicted BG R2* relaxation rates. In contrast, age was the only variable independently predicting BG R2* relaxation rates in AD (beta=0.26, p=0.011) and NC (beta= 0.32, p=0.026).
Conclusions
This comparative study confirms that age is a main driving factor for deep grey matter iron accumulation in MS, AD and NC. However, only in MS we found evidence for increased BG iron deposition to be associated with morphologic brain changes, supporting the notion that a dysbalanced iron homeostasis is involved in MS pathology. Further analyses on longitudinal MRI and clinical data are currently ongoing to confirm and extent our findings.