Objective To investigate the coexistence of anterograde and retrograde trans-synaptic axonal degeneration, and to explore the relationship between selective visual pathway damage and global brain ...involvement in longstanding multiple sclerosis (MS). Methods In this single-centre, cross-sectional study, patients with longstanding MS (N=222) and healthy controls (HC, N=62) were included. We analysed thickness of retinal layers (optical coherence tomography), damage within optic radiations (OR) (lesion volume and fractional anisotropy and mean diffusivity by diffusion tensor imaging) and atrophy of the visual cortex and that of grey and white matter of the whole-brain (structural MRI). Linear regression analyses were used to assess associations between the different components and for comparing patients with and without optic neuritis and HC. Results In patients with MS, an episode of optic neuritis (MSON) was significantly associated with decreased integrity of the ORs and thinning of the peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell complex (GCC). Lesion volume in the OR was negatively associated with pRNFL and GCC thickness in patients without optic neuritis (MSNON). The pRNFL and GCC showed associations with integrity of the OR, thickness of the primary visual cortex (only in patients with MSON), and also with global white and grey matter atrophy. In HCs, no such relationships were demonstrated. Interpretation This study provides evidence for presence of bidirectional (both anterograde and retrograde) trans–synaptic axonal degeneration in the visual pathway of patients with MS. Additionally, thinning of the retinal pRNFL and GCC are related to global white and grey matter atrophy in addition to pathology of the visual pathway.
Objective:
To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS).
Methods:
We performed a multicenter study ...including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes.
Results:
The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2–138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5–22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85–0.90) was higher than OCB (0.82; 95%CI = 0.79–0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78–0.88) was lower (OCB = 0.92; 95% CI = 0.89–0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB.
Conclusion:
Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS.
Objective Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent ...trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS). Methods A single-centre study, including patients with long-standing MS and healthy controls. Structural imaging of the brain (MRI) and retina (spectral-domain optical coherence tomography) were used to quantify the extent of atrophy of individual retinal layers and the primary and secondary visual cortex. Generalised estimation equations and multivariable regression analyses were used for comparisons. Results Following rigorous quality control (OSCAR-IB), data from 549 eyes of 293 subjects (230 MS, 63 healthy controls) were included. Compared with control data, there was a significant amount of atrophy of the inner retinal layers in MS following optic neuritis (ON) and also in absence of ON. For both scenarios, atrophy stopped at the level of the inner nuclear layer. In contrast, there was significant localised atrophy of the primary visual cortex and secondary visual cortex in MS following ON, but not in MS in absence of ON. Interpretation These data suggest that retrograde (trans-synaptic) axonal degeneration stops at the inner nuclear layer, a neuronal network capable of plasticity. In contrast, there seems to be no neuroplasticity of the primary visual cortex, rendering the structure vulnerable to anterograde (trans-synaptic) degeneration.
Background and purpose
To predict disability and cognition in multiple sclerosis (MS) after 6 and 12 years, using early clinical and imaging measures.
Methods
A total of 115 patients with MS were ...selected and followed up after 2 and 6 years, with 79 patients also being followed up after 12 years. Disability was measured using the Expanded Disability Status Scale (EDSS); cognition was measured only at follow‐up using neuropsychological testing. Predictors of interest included EDSS score, baseline brain and lesion volumes and their changes over 2 years, baseline age, clinical phenotype, sex and educational level.
Results
Higher 6‐year EDSS score was predicted by early EDSS score and whole‐brain volume changes and baseline diagnosis of primary progressive MS (adjusted R2 = 0.56). Predictors for 12‐year EDSS score included larger EDSS score changes and higher T1‐hypointense lesion volumes (adjusted R2 = 0.38). Year 6 cognition was predicted by primary progressive MS phenotype, lower educational level, male sex and early whole‐brain atrophy (adjusted R2 = 0.26); year 12 predictors included male sex, lower educational level and higher baseline T1‐hypointense lesion volumes (adjusted R2 = 0.14).
Conclusions
Patients with early signs of neurodegeneration and a progressive disease onset were more prone to develop both disability progression and cognitive dysfunction. Male sex and lower educational level only affected cognitive dysfunction, which remains difficult to predict and probably needs more advanced imaging measures.
Background:
Clinical measures in multiple sclerosis (MS) face limitations that may be overcome by utilising smartphone keyboard interactions acquired continuously and remotely during regular typing.
...Objective:
The aim of this study was to determine the reliability and validity of keystroke dynamics to assess clinical aspects of MS.
Methods:
In total, 102 MS patients and 24 controls were included in this observational study. Keyboard interactions were obtained with the Neurokeys keyboard app. Eight timing-related keystroke features were assessed for reliability with intraclass correlation coefficients (ICCs); construct validity by analysing group differences (in fatigue, gadolinium-enhancing lesions on magnetic resonance imaging (MRI), and patients vs controls); and concurrent validity by correlating with disability measures.
Results:
Reliability was moderate in two (ICC = 0.601 and 0.742) and good to excellent in the remaining six features (ICC = 0.760–0.965). Patients had significantly higher keystroke latencies than controls. Latency between key presses correlated the highest with Expanded Disability Status Scale (r = 0.407) and latency between key releases with Nine-Hole Peg Test and Symbol Digit Modalities Test (ρ = 0.503 and r = −0.553, respectively), ps < 0.001.
Conclusion:
Keystroke dynamics were reliable, distinguished patients and controls, and were associated with clinical disability measures. Consequently, keystroke dynamics are a promising valid surrogate marker for clinical disability in MS.
To explore the added value of dynamic functional connectivity (dFC) of the default mode network (DMN) during resting-state (RS), during an information processing speed (IPS) task, and the ...within-subject difference between these conditions, on top of conventional brain measures in explaining IPS in people with multiple sclerosis (pwMS).
In 29 pwMS and 18 healthy controls, IPS was assessed with the Letter Digit Substitution Test and Stroop Card I and combined into an IPS-composite score. White matter (WM), grey matter (GM) and lesion volume were measured using 3 T MRI. WM integrity was assessed with diffusion tensor imaging. During RS and task-state fMRI (i.e. symbol digit modalities task, IPS), stationary functional connectivity (sFC; average connectivity over the entire time series) and dFC (variation in connectivity using a sliding window approach) of the DMN was calculated, as well as the difference between both conditions (i.e. task-state minus RS; ΔsFC-DMN and ΔdFC-DMN). Regression analysis was performed to determine the most important predictors for IPS.
Compared to controls, pwMS performed worse on IPS-composite (p = 0.022), had lower GM volume (p < 0.05) and WM integrity (p < 0.001), but no alterations in sFC and dFC at the group level. In pwMS, 52% of variance in IPS-composite could be predicted by cortical volume (β = 0.49, p = 0.01) and ΔdFC-DMN (β = 0.52, p < 0.01). After adding dFC of the DMN to the model, the explained variance in IPS increased with 26% (p < 0.01).
On top of conventional brain measures, dFC from RS to task-state explains additional variance in IPS. This highlights the potential importance of the DMN to adapt upon cognitive demands to maintain intact IPS in pwMS.
•Problems with information processing speed occur often in multiple sclerosis (MS)•Dynamics in brain communication can reflect information transfer within the brain•With fMRI, dynamic communication can be measured, which increases upon task demands•This increase in dynamics explains information processing speed in MS
Background
Multiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence ...clinical progression.
Objective
To study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing–remitting (RR) MS in relation to clinical progression.
Methods
Healthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM
z
-scores and changes in connected GM
z
-scores, and between baseline GM
z
-scores and changes in connected WM
z
-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners.
Results
We included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM
z
-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups.
Discussion
Lower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely.
Background:
Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday ...environment.
Objectives:
The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT).
Methods:
During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test–retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed.
Results:
Patients with MS and HC completed an average of 23.2 (SD = 10.0) and 18.3 (SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test–retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all ps < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599).
Conclusion:
Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed.
Introduction
Multiple sclerosis (MS) is a chronic inflammatory disease with an as yet not fully understood etiological background. The geographical distribution of MS is striking with a prevalence ...that increases with latitude. For this reason, vitamin D deficiency is considered a possible pathogenic co-factor in MS.
Materials and methods
To study the role of the vitamin D metabolism in MS, blood samples were taken twice (summer and winter) from 103 patients with MS and 110 healthy controls. Serum concentrations of 25-hydroxyvitamin D (25(OH) D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) were measured, and detailed information on disease characteristics and environmental factors that might influence the vitamin D metabolite levels was collected.
Results
Mean serum 25(OH)D and 1,25(OH)2D concentrations were significantly higher in summer compared to winter in both patients and controls. Using logistic regression methods, we found that in women for every 10 nmol/L increase of serum 25(OH)D level the odds of MS was reduced by 19% (odds ratio 0.81; 95% confidence interval: 0.69–0.95), suggesting a “protective” effect of higher 25(OH)D serum levels. In addition, also restricted to women, a negative correlation was found between Expanded Disability Status Scale and 25(OH)D levels (r = −0.29, P = 0.020).
Conclusions
Our data suggest that higher circulating levels of 25(OH)D are associated with a lower incidence of MS and MS-related disability in women. This may imply clues to the pathogenesis of the sex difference in risk and to the nature of the environmental factors involved in MS.
Wearing-off symptoms during natalizumab treatment in multiple sclerosis are characterized by an increase of MS-related symptoms prior to natalizumab administration. The influence of extended interval ...dosing (EID) on wearing-off symptoms are important to consider, as this might cause hesitancy in initiating or continuing EID.
Participants of the NEXT-MS trial, in which treatment intervals are adjusted based on drug concentrations, were divided into two groups: an extended group containing participants with at least one week of additional interval extension, and a group with a fixed interval during the trial (range 4–7 weeks). Changes in the occurrence, frequency, onset, and severity of wearing-off symptoms were evaluated.
255 participants were included (extended group n = 171, fixed group n = 84). The odds on occurrence of wearing-off symptoms in the extended group did not increase after extending the treatment interval. Additional analyses for frequency, onset, and severity of wearing-off symptoms showed no changes over time. Mean decrease in natalizumab drug concentration did not influence the frequency of wearing-off symptoms.
Wearing-off symptoms were not reinforced by further extending the natalizumab interval. Wearing-off symptoms might increase in a minority of patients after EID, although our data support the view that wearing-off symptoms appear to be unrelated to the decrease in natalizumab trough drug concentrations.
•Many natalizumab treated MS patients experience wearing-off symptoms.•Extension of natalizumab treatment intervals does not increase wearing-off symptoms.•Wearing-off symptoms are not related to natalizumab drug concentrations.
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