Animal Models of Ischemic Stroke. Part One: Modeling Risk Factors

Ischemic stroke is one of the leading causes of long-term disability and death in developed and developing countries. As emerging disease, stroke related mortality and morbidity is going to step up in the next decades. This is both due to the poor identification of risk factors and persistence of unhealthy habits, as well as to the aging of the population. To counteract the estimated increase in stroke incidence, it is of primary importance to identify risk factors, study their effects, to promote primary and secondary prevention, and to extend the therapeutic repertoire that is currently limited to the very first hours after stroke. While epidemiologic studies in the human population are essential to identify emerging risk factors, adequate animal models represent a fundamental tool to dissect stroke risk factors to their molecular mechanism and to find efficacious therapeutic strategies for this complex multi- factorial disorder. The present review is organized into two parts: the first part deals with the animal models that have been developed to study stroke and its related risk factors and the second part analyzes the specific stroke models. These models represent an indispensable tool to investigate the mechanisms of cerebral injury and to develop novel therapies

Drawing in Alzheimer-type dementia

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Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS

Brain volume; Multiple sclerosis; OzanimodVolumen cerebral; Esclerosis múltiple; OzanimodVolum cerebral; Esclerosi múltiple; OzanimodBackground Cognitive dysfunction, including slowed cognitive processing speed (CPS), is one of the most disabling symptoms of multiple sclerosis (MS). The Symbol Digit Modalities Test (SDMT) is a preferred measure of CPS for MS trials and routine screening. Based on encouraging SDMT results in the phase 3 SUNBEAM trial, these post hoc, exploratory analyses were conducted to further compare effects of the sphingosine 1-phosphate receptor modulator ozanimod versus intramuscular interferon β-1a on CPS in participants with relapsing multiple sclerosis (RMS). Methods In the phase 3, double-blind, double-dummy, SUNBEAM study, adults (aged 18‒55 years) with RMS (N=1,346) were randomized to once-daily oral ozanimod 0.92 or 0.46 mg, or weekly intramuscular interferon β-1a 30 µg. The study continued until the last participant was treated for 12 months. CPS was measured as part of a secondary endpoint using the SDMT. Exploratory, post hoc analyses evaluated SDMT change and percentages of participants with clinically meaningful (≥4-point) SDMT improvement or worsening at months 6 and 12, and relationship between SDMT and brain volume on magnetic resonance imaging. Results Ozanimod improved SDMT scores compared with interferon β-1a at months 6 and 12. At month 12, least squares mean difference in SDMT z-scores for ozanimod 0.92 mg versus interferon β-1a was 0.102 (95% CI, 0.031‒0.174, nominal p = 0.0051; standardized mean difference = 0.1376). A greater percentage of ozanimod 0.92 mg‒treated participants had clinically meaningful improvements in SDMT scores versus interferon β-1a at month 6 (30.0% versus 22.2%) and month 12 (35.6% versus 27.9%). Of those with SDMT improvement at month 6, 66.4% of those treated with ozanimod 0.92 mg and 55.9% of those treated with interferon β-1a had sustained improvement at month 12. Brain volume loss was similar for those with SDMT improvement versus worsening at month 12. Conclusions In these exploratory analyses, ozanimod had modestly beneficial effects on CPS in RMS participants. The effects of ozanimod on SDMT are being further evaluated in an ongoing 3-year clinical trial. SUNBEAM is registered on clinicaltrials.gov (NCT02294058) and the European Clinical Trials Database (EudraCT 2014‐002320‐27).SUNBEAM was sponsored by Celgene Corporation. The sponsor was involved in data analysis and interpretation, and manuscript preparation, review, and approval. All authors vouch for data accuracy, reviewed all drafts, and approved the final manuscript

Opinion & Special Articles: Professionalism in neurology

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Pharmacokinetics and pharmacodynamics of natalizumab in pediatric patients with RRMS

This phase I study investigated pharmacokinetic (PK) and pharmacodynamic (PD) profiles of natalizumab in pediatric patients with relapsing-remitting MS (RRMS)

Microbial Risk Factors of Cardiovascular and Cerebrovascular Diseases: Potential Therapeutical Options

Infection and inflammation may have a crucial role in the pathogenesis of atherosclerosis. This hypothesis is supported by an increasing number of reports on the interaction between chronic infection, inflammation, and atherogenesis. Assessment of serological and inflammatory markers of infection may be useful adjuncts in identifying those patients who are at a higher risk of developing vascular events, and in whom more aggressive treatments might be warranted

No evidence of disease activity status in patients treated with early vs. delayed subcutaneous interferon β-1a.

Abstract Background Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the effect of early CIS treatment with once weekly (qw) or three times weekly (tiw) subcutaneous interferon (scIFN) β-1a vs. delayed treatment (DT) on the composite endpoint of no evidence of disease activity (NEDA)-3. Methods In REFLEX, patients with CIS were randomized to double-blind scIFN β-1a 44 µg tiw, qw, or placebo for 24 months. Upon clinically-definite MS, patients switched to open-label scIFN β-1a tiw. Patients who completed REFLEX entered an extension (REFLEXION). Patients initially randomized to placebo switched to tiw (DT); scIFN β-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n = =171; qw, n = =175; DT, n = =171). All p values are nominal. CIS was defined using the McDonald 2010 criteria. Results Patients receiving early treatment (ET) with scIFN β-1a tiw and qw were more likely to achieve NEDA-3 than DT at year 2 (tiw vs. DT: OR 4.26, 95% CI 2.02–8.98, p = =0.0001; qw vs. DT: OR 2.99, 95% CI 1.39–6.43, p = =0.005). Compared with DT, ET with scIFN β-1a tiw was more likely to achieve NEDA-3 at year 3 (OR 3.73, 95% CI 1.63–8.55, p = =0.002) and year 5 (OR 12.96, 95% CI 1.66–101.04, p = =0.015). Between ET regimens, the odds of achieving NEDA-3 were not significantly improved by scIFN β-1a 44 µg tiw at year 2 (OR 1.42, 95% CI 0.81–2.50, p = =0.22) but were at year 3 (OR 2.26, 95% CI 1.11–4.60, p = =0.024) and year 5 (OR 3.22, 95% CI 1.01–10.22, p = =0.048), indicating that the beneficial effects of more frequent scIFN β-1a dosing become more apparent over time in patients with CIS. In the subgroup of patients with Gd+ lesions at baseline the odds for achieving NEDA-3 were higher for ET up to year 2 compared with DT (tiw: OR 10.21, 95% CI 1.23–84.82, p = =0.03; qw: OR 8.97, 95% CI 1.08–74.28, p = =0.04). In patients without Gd+ lesions at baseline, those receiving ET were more likely to achieve NEDA-3 at year 2 (OR 3.56, 95% CI 1.56–8.10, p = =0.003), year 3 (OR 2.54, 95% CI 1.05–6.18, p = =0.04) and year 5 (OR 9.63, 95% CI 1.19–77.79, p = =0.034) than patients who received DT. Conclusions ET with scIFN β-1a tiw was associated with a higher likelihood of achieving NEDA-3 not only at 2 but also at 3 and 5 years

Involvement of cortico-subcortical circuits in normoacousic chronic tinnitus: A source localization EEG study

To better characterize brain circuits dysfunctions in normoacousic tinnitus sufferers. Methods: 17 normoacousic chronic, unilateral high-pitched tinnitus sufferers (6 females, 43.6 ± 9.8 y.o, disease duration 22 ± 35 months) underwent a 29-channel resting-state electroencephalography (EEG – 5 min opened-eyes, 5 min closed-eyes) and auditory oddball paradigm for event-related potentials analyses (ERPs – N1, P2 and P300). Cortical 3D distribution of current source density was computed with sLORETA. Results were compared with 17 controls (9 females, 45.7 ± 15.1 y.o). Results: Eyes opened, tinnitus sufferers had lower alpha and beta sources in the left inferior parietal lobule. Eyes closed, tinnitus sufferers had decreased alpha sources in the left inferior temporal and post-central gyri, and low gamma sources in the left middle temporal gyrus. EEG data did not correlate with tinnitus sufferers’ clinical features. Subjects with tinnitus had shorter N1 and P2 latencies. P300 did not differ between groups. sLORETA solutions showed decreased sources of these ERPs in the left inferior temporal gyrus in the tinnitus group. Conclusions: We showed cortico-thalamo-cortical involvements in normoacousic tinnitus with hyperexcitability of the left auditory cortex and inferior temporal gyrus. Significance: This might reflect processes of maladaptive cortical plasticity and memory consolidation. Further validation is needed to establish the value of this tool in customizing therapeutic approach

Evidence for Cortical Functional Changes in Patients With Migraine and White Matter Abnormalities on Conventional and Diffusion Tensor Magnetic Resonance Imaging

Background— In this study, we used functional MRI (fMRI) to investigate the pattern of cortical activations after a simple motor task in patients with migraine and white matter (WM) abnormalities on conventional MRI scans of the brain. We also investigated whether the extent of brain activations was correlated with WM structural pathology measured using diffusion tensor (DT) MRI. Methods— From 15 right-handed patients with migraine and 15 sex- and age-matched, right-handed healthy volunteers, we obtained the following: (1) fMRI (repetitive flexion-extension of the last 4 fingers of the right hand), (2) dual-echo turbo spin echo scans, and (3) pulsed-gradient spin-echo echo-planar sequence to calculate DT-MRI maps. fMRI analysis was performed using SPM99 and cluster detection. We measured the volume, the average mean diffusivity ( ), and the average fractional anisotropy of all lesions seen on the dual-echo scans. histograms of the normal-appearing WM were also produced. Results— Compared with healthy volunteers, migraine patients had a larger relative activation of the contralateral primary sensorimotor cortex ( P =0.01) and a rostral displacement of the supplementary motor area ( P =0.03). The shapes of the curves reflecting the time course for fMRI signal intensity changes were similar between migraine patients and controls for all of the cortical areas we studied. Compared with healthy subjects, migraine patients had significantly lower histogram peak height of the normal-appearing WM histogram ( P =0.02), which was found to be correlated with the extent of displacement of the supplementary motor area ( r =−0.80, P <0.001). Conclusions— This study suggests that functional cortical changes occur in patients with migraine and brain MRI abnormalities and that they might be secondary to the extent of subcortical structural damage