Predictive value of synaptic plasticity for functional decline in patients with multiple sclerosis.

Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs). Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: ß = -0.25, p = 0.02; BVMT-R: ß = -0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests.

SARS-CoV-2 Vaccination and Neuroimmunological Disease: A Review.

Importance: The temporal association between the occurrence of neurological diseases, many autoimmune diseases, and vaccination against SARS-CoV-2 has been topically interesting and remains hotly debated both in the medical literature and the clinic. Given the very low incidences of these events both naturally occurring and in relation to vaccination, it is challenging to determine with certainty whether there is any causative association and most certainly what the pathophysiology of that causation could be. Observations: Data from international cohorts including millions of vaccinated individuals suggest that there is a probable association between the adenovirus-vectored vaccines and Guillain-Barré syndrome (GBS). Further associations between other SARS-CoV-2 vaccines and GBS or Bell palsy have not been clearly demonstrated in large cohort studies, but the possible rare occurrence of Bell palsy following messenger RNA vaccination is a topic of interest. It is also yet to be clearly demonstrated that any other neurological diseases, such as central nervous system demyelinating disease or myasthenia gravis, have any causative association with vaccination against SARS-CoV-2 using any vaccine type, although it is possible that vaccination may rarely trigger a relapse or worsen symptoms or first presentation in already-diagnosed or susceptible individuals. Conclusions and Relevance: The associated risk between SARS-CoV-2 vaccination and GBS, and possibly Bell palsy, is slight, and this should not change the recommendation for individuals to be vaccinated. The same advice should be given to those with preexisting neurological autoimmune disease.

Diagnostic Value of Perfusion Parameters for Differentiation of Underlying Etiology in Internal Carotid Artery Occlusions.

PURPOSE: Occlusions of the internal carotid artery (ICA) may be caused by dissection, embolic or macroangiopathic pathogenesis, which partially influences the treatment; however, inferring the underlying etiology in computed tomography angiography can be challenging. In this study, we investigated whether computed tomography perfusion (CT-P) parameters could be used to distinguish between etiologies. METHODS: Patients who received CT­P in acute ischemic stroke due to ICA occlusion between 2012 and 2019 were retrospectively analyzed. Group comparisons between etiologies regarding the ratios of CT­P parameters between both hemispheres for relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), time to maximum (Tmax), and mean transit time (MTT) were calculated by one-factorial analysis of variance (ANOVA) and compared by pairwise Bonferroni post hoc tests. An receiver operating characteristics (ROC) analysis was performed if differences in group comparisons were found. Multinomial logistic regression (MLR) including pretherapeutic parameters was calculated for etiologies. RESULTS: In this study 69 patients (age = 70 ± 14 years, dissection = 10, 14.5%, embolic = 19, 27.5% and macroangiopathic = 40, 58.0%) were included. Group differences in ANOVA were only found for MTT ratio (p = 0.003, η2 = 0.164). In the post hoc test, MTT ratio showed a differentiability between embolic and macroangiopathic occlusions (p = 0.002). ROC analysis for differentiating embolic and macroangiopathic ICA occlusions based on MTT ratio showed an AUC of 0.77 (p < 0.001, CI = 0.65-0.89) and a cut-off was yielded at a value of 1.15 for the MTT ratio (sensitivity 73%, specificity 68%). The MLR showed an overall good model performance. CONCLUSION: It was possible to differentiate between patients with embolic and macroangiopathic ICA occlusions based on MTT ratios and to define a corresponding cut-off. Differentiation from patients with dissection versus the other etiologies was not possible by CT­P parameters in our sample.

[Cerebral Small Vessel Disease: Advances in Understanding its Pathophysiology]. / Zerebrale Mikroangiopathie: Fortschritte im Verständnis der Pathophysiologie.

Sporadic cerebral small vessel disease determines age- and vascular-risk-factor-related processes of the small brain vasculature. The underlying pathology develops in a stage-dependent manner - probably over decades - often already starting in midlife. Endothelial and pericyte activation precedes blood-brain barrier leaks, extracellular matrix remodeling and neuroinflammation, which ultimately result in bleeds, synaptic and neural dysfunction. Hemodynamic compromise of the small vessel walls promotes perivascular drainage failure and accumulation of neurotoxic waste products in the brain. Clinical diagnosis is mainly based on magnetic resonance imaging according to the Standards for Reporting Vascular Changes on Neuroimaging 2. Cerebral amyloid angiopathy is particularly stratified according to the Boston v2.0 criteria. Small vessel disease of the brain could be clinically silent, or manifested through a heterogeneous spectrum of diseases, where cognitive decline and stroke-related symptoms are the most common ones. Prevention and therapy are centered around vascular risk factor control, physically and cognitively enriched life style and, presumably, maintenance of a good sleep quality, which promotes sufficient perivascular drainage. Prevention of ischemic stroke through anticoagulation that carries at the same time an increased risk for large brain hemorrhages - particularly in the presence of disseminated cortical superficial siderosis - remains one of the main challenges. The cerebral small vessel disease field is rapidly evolving, focusing on the establishment of early disease stage imaging and biofluid biomarkers of neurovascular unit remodeling and the compromise of perivascular drainage. New prevention and therapy strategies will correspondingly center around the dedicated targeting of, e. g., cellular small vessel wall and perivascular tissue structures. Growing knowledge about brain microvasculature bridging neuroimmunological, neurovascular and neurodegenerative fields might lead to a rethink about apparently separate disease entities and the development of overarching concepts for a common line of prevention and treatment for several diseases.

The importance of pyramidal tract integrity for cortical plasticity and related functionality in patients with multiple sclerosis.

Background: Cortical plasticity induced by quadripulse stimulation (QPS) has been shown to correlate with cognitive functions in patients with relapsing-remitting multiple sclerosis (RRMS) and to not be reduced compared to healthy controls (HCs). Objective: This study aimed to compare the degree of QPS-induced plasticity between different subtypes of multiple sclerosis (MS) and HCs and to investigate the association of the degree of plasticity with motor and cognitive functions. We expected lower levels of plasticity in patients with progressive MS (PMS) but not RRMS compared to HCs. Furthermore, we expected to find positive correlations with cognitive and motor performance in patients with MS. Methods: QPS-induced plasticity was compared between 34 patients with PMS, 30 patients with RRMS, and 30 HCs using linear mixed-effects models. The degree of QPS-induced cortical plasticity was correlated with various motor and cognitive outcomes. Results: There were no differences regarding the degree of QPS-induced cortical plasticity between HCs and patients with RRMS (p = 0.86) and PMS (p = 0.18). However, we only found correlations between the level of induced plasticity and both motor and cognitive functions in patients with intact corticospinal tract integrity. Exploratory analysis revealed significantly reduced QPS-induced plasticity in patients with damage compared to intact corticospinal tract integrity (p < 0.001). Conclusion: Our study supports the notion of pyramidal tract integrity being of more relevance for QPS-induced cortical plasticity in MS and related functional significance than the type of disease.

Blend Sign and Haemorrhage Location and Volume Predict Late Recurrence and Mortality in Intracerebral Haemorrhage Patients.

BACKGROUND: Studies on risk factors for primary intracerebral haemorrhage (ICH) focus on short-term predictive values of distinct clinical parameters or computed tomography (CT) markers and disregard the others. We, therefore, studied independent predictive values of demographic, clinical, and CT markers regarding ICH expansion, late ICH recurrence, and late mortality. METHODS: In a retrospective study of 288 patients with primary ICH, ICH localization (158 lobar, 81 deep, and 49 cerebellar), volume, blend sign, spot sign, finger-like projections, and subarachnoid haemorrhages were evaluated. ICH localization-specific differences for demographic (age, sex), clinical parameters (vascular risk factors, antiplatelet, and anticoagulation therapy), and CT markers were evaluated using logistic regression. We applied Cox proportional hazards modelling using these parameters to predict risk factors for ICH expansion, late ICH recurrence, and late mortality. RESULTS: The blend sign in lobar ICH relates to increased risk of ICH expansion (HR2.3), late ICH recurrence (HR2.3), and mortality (HR1.6). Age, conditions requiring antiplatelet medication, deep ICH localization, volume, and blend sign represented the most important independent factors impacting overall mortality. CONCLUSIONS: Blend sign at baseline ICH is a manifestation of underlying detrimental vascular processes that signal increased ICH expansion risk, although is also indicative of long-term risks for late recurrent ICH and late mortality.

Long-term potentiation-like plasticity is retained during relapse in patients with Multiple Sclerosis.

OBJECTIVE: To investigate the degree of synaptic plasticity in Multiple Sclerosis (MS) patients during acute relapses compared to stable MS patients and healthy controls (HCs) and to analyze its functional relevance. METHODS: Facilitatory quadripulse stimulation (QPS) was applied to the primary motor cortex in 18 acute relapsing and 18 stable MS patients, as well as 18 HCs. The degree of synaptic plasticity was measured by the change in motor evoked potential amplitude following QPS. Symptom recovery was assessed three months after relapse. RESULTS: Synaptic plasticity was induced in all groups. The degree of induced plasticity did not differ between acute relapsing patients, HCs, and stable MS patients. Plasticity was significantly higher in relapsing patients with motor disability compared to relapsing patients without motor disability. In most patients (n = 9, 50%) symptoms had at least partially recovered three months after the relapse, impeding meaningful analysis of the functional relevance of baseline synaptic plasticity. CONCLUSIONS: QPS-induced synaptic plasticity is retained during acute MS relapses. Subgroup analyses suggest that stabilizing metaplastic mechanisms may be more important to prevent motor disability but its functional relevance needs to be verified in larger, longitudinal studies. SIGNIFICANCE: New insights into synaptic plasticity during MS relapses are provided.

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity.

Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood-brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

Increased Remyelination and Proregenerative Microglia Under Siponimod Therapy in Mechanistic Models.

BACKGROUND AND OBJECTIVES: Siponimod is an oral, selective sphingosine-1-phosphate receptor-1/5 modulator approved for treatment of multiple sclerosis. METHODS: Mouse MRI was used to investigate remyelination in the cuprizone model. We then used a conditional demyelination Xenopus laevis model to assess the dose-response of siponimod on remyelination. In experimental autoimmune encephalomyelitis-optic neuritis (EAEON) in C57Bl/6J mice, we monitored the retinal thickness and the visual acuity using optical coherence tomography and optomotor response. Optic nerve inflammatory infiltrates, demyelination, and microglial and oligodendroglial differentiation were assessed by immunohistochemistry, quantitative real-time PCR, and bulk RNA sequencing. RESULTS: An increased remyelination was observed in the cuprizone model. Siponimod treatment of demyelinated tadpoles improved remyelination in comparison to control in a bell-shaped dose-response curve. Siponimod in the EAEON model attenuated the clinical score, reduced the retinal degeneration, and improved the visual function after prophylactic and therapeutic treatment, also in a bell-shaped manner. Inflammatory infiltrates and demyelination of the optic nerve were reduced, the latter even after therapeutic treatment, which also shifted microglial differentiation to a promyelinating phenotype. DISCUSSION: These results confirm the immunomodulatory effects of siponimod and suggest additional regenerative and promyelinating effects, which follow the dynamics of a bell-shaped curve with high being less efficient than low concentrations.

The degree of cortical plasticity correlates with cognitive performance in patients with Multiple Sclerosis.

BACKGROUND: Cortical reorganization and plasticity may compensate for structural damage in Multiple Sclerosis (MS). It is important to establish sensitive methods to measure these compensatory mechanisms, as they may be of prognostic value. OBJECTIVE: To investigate the association between the degree of cortical plasticity and cognitive performance and to compare plasticity between MS patients and healthy controls (HCs). METHODS: The amplitudes of the motor evoked potential (MEP) pre and post quadripulse stimulation (QPS) applied over the contralateral motor cortex served as measure of the degree of cortical plasticity in 63 patients with relapsing-remitting MS (RRMS) and 55 matched HCs. The main outcomes were the correlation coefficients between the difference of MEP amplitudes post and pre QPS and the Symbol Digit Modalities Test (SDMT) and Brief Visuospatial Memory Test-Revised (BVMT-R), and the QPSxgroup interaction in a mixed model predicting the MEP amplitude. RESULTS: SDMT and BVMT-R correlated significantly with QPS-induced cortical plasticity in RRMS patients. Plasticity was significantly reduced in patients with cognitive impairment compared to patients with preserved cognitive function and the degree of plasticity differentiated between both patient groups. Interestingly, the overall RRMS patient cohort did not show reduced plasticity compared to HCs. CONCLUSIONS: We provide first evidence that QPS-induced plasticity may inform about the global synaptic plasticity in RRMS which correlates with cognitive performance as well as clinical disability. Larger longitudinal studies on patients with MS are needed to investigate the relevance and prognostic value of this measure for disease progression and recovery.