Background and Purpose
Modulation of the sphingosine 1‐phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti‐inflammatory effect of retaining lymphocytes ...within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection.
Experimental Approach
In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin‐induced experimental demyelination. We used histological, immunohistochemical and gene expression methods.
Key Results
The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone‐induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein‐positive spheroids in axons was less distinct in FTY720‐treated animals, indicating that this compound alleviated ongoing axonal damage.
Conclusions and Implications
We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined.
Neuroinflammation is a devastating pathophysiological process that results in brain damage and neuronal death. Pathogens, cell fragments and cellular dysfunction trigger inflammatory responses. ...Irrespective of the cause, inflammasomes are key intracellular multiprotein signalling platforms that sense neuropathological conditions. The activation of inflammasomes leads to the auto‐proteolytic cleavage of caspase‐1, resulting in the proteolysis of the pro‐inflammatory cytokines interleukin (IL)1β and IL18 into their bioactive forms. It also initiates pyroptosis, a type of cell death. The two cytokines contribute to the pathogenesis in acute and chronic brain diseases and also play a central role in human aging and psychiatric disorders. Sex steroids, in particular oestrogens, are well‐described neuroprotective agents in the central nervous system. Oestrogens improve the functional outcome after ischaemia and traumatic brain injury, reduce neuronal death in Parkinson′s and Alzheimer′s disease, as well as in amyotrophic lateral sclerosis, attenuate glutamate excitotoxicity and the formation of radical oxygen species, and lessen the spread of oedema after damage. Moreover, oestrogens alleviate menopause‐related depressive symptoms and have a positive influence on depressive disorders probably by influencing growth factor production and serotonergic brain circuits. Recent evidence also suggests that inflammasome signalling affects anxiety‐ and depressive‐like behaviour and that oestrogen ameliorates depression‐like behaviour through the suppression of inflammasomes. In the present review, we highlight the most recent findings demonstrating that oestrogens selectively suppress the activation of the neuroinflammatory cascade in the brain in acute and chronic brain disease models. Furthermore, we aim to describe putative regulatory signalling pathways involved in the control of inflammasomes. Finally, we consider that psychiatric disorders such as depression also contain an inflammatory component that could be modulated by oestrogen.
Background and purpose
Subsyndromal delirium (SSD) refers to patients with delirious symptoms who do not meet the criteria for delirium. The aim was to determine the prognostic significance of SSD in ...stroke patients.
Methods
In all, 564 patients with ischaemic stroke (median age 71 years, 50.5% female) were included. The Confusion Assessment Method was used to assess symptoms of delirium and the Diagnostic and Statistical Manual of Mental Disorders, 5th edn, criteria were used to diagnose delirium. SSD was defined as one or more core features of delirium without fulfilling diagnostic criteria. Functional outcome was assessed using the modified Rankin Scale at 3 and 12 months after stroke.
Results
Delirium was diagnosed in 23.4% of patients and SSD in 10.3% of patients. SSD was associated with increased risk of poor functional outcome. The adjusted odds ratios (ORs) for unfavourable outcome at 3 and 12 months were 2.88 95% confidence interval (CI) 1.43–5.79, P < 0.01 and 2.93 (95% CI 1.39–6.22, P < 0.01), respectively. In multivariate analysis, delirium was an independent predictor of poor functional outcome at 3 months (OR 6.41, 95% CI 3.36–12.21, P < 0.01) and 12 months (OR 6.11, 95% CI 3.05–12.27, P < 0.01) after stroke. Delirium was also independently associated with increased risk of death within 3 months (hazard ratio 3.68, 95% CI 1.69–8.02, P < 0.01) and 12 months (hazard ratio 3.76, 95% CI 2.05–6.90, P < 0.01). SSD was not associated with increased risk of death.
Conclusions
In SSD patients the risk of poor functional outcome after stroke is increased and intermediate between patients with and patients without delirium.
Systemic thrombolysis with rt-PA is contraindicated in patients with acute ischemic stroke anticoagulated with dabigatran. This expert opinion provides guidance on the use of the specific reversal ...agent idarucizumab followed by rt-PA and/or thrombectomy in patients with ischemic stroke pre-treated with dabigatran. The use of idarucizumab followed by rt-PA is covered by the label of both drugs.
The cuprizone model is a suitable animal model of de- and remyelination secondary to toxin-induced oligodendrogliopathy. From a pharmaceutical point of view, the cuprizone model is a valuable tool to ...study the potency of compounds which interfere with toxin-induced oligodendrocyte cell death or boost/inhibit remyelinating pathways and processes. The aim of this study was to analyze the vulnerability of neighboring white mater tracts (i.e., the fornix and cingulum) next to the midline of the corpus callosum which is the region of interest of most studies using this model. Male mice were fed cuprizone for various time periods. Different white matter areas were analyzed for myelin (anti-PLP), microglia (anti-IBA1), and astrocyte (anti-GFAP) responses by means of immunohistochemistry. Furthermore, Luxol fast blue–periodic acid Schiff stains were performed to validate loss of myelin-reactive fibers in the different regions. Cuprizone induced profound demyelination of the midline of the corpus callosum and medial parts of the cingulum that was paralleled by a significant astrocyte and microglia response. In contrast, lateral parts of the corpus callosum and the cingulum, as well as the fornix region which is just beneath the midline of the corpus callosum appeared to be resistant to cuprizone exposure. Furthermore, resistant areas displayed reduced astrogliosis and microgliosis. This study clearly demonstrates that neighboring white matter tracts display distinct vulnerability to toxin-induced demyelination. This important finding has direct relevance for evaluation strategies in this frequently used animal model for multiple sclerosis.
Objective
Posterior circulation ischemic stroke (PCiS) constitutes 20–30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) ...remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS.
Methods
Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression.
Results
PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%,
p
< 0
.05
; male sex 68% vs. 58%,
p
< 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04–1.61; male sex, OR = 1.46; 95% CI 1.21–1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%,
p
< 0.01) and cardioembolic mechanisms (17% vs. 11%,
p
< 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%,
p
< 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions.
Conclusion
Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.
Background. Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders affecting predominantly the motor cortex and pyramidal tract, which results in slowly progressing gait ...disorders, as well as spasticity and weakness of lower extremities. Repetitive transcranial magnetic stimulation (rTMS) has been previously investigated as a therapeutic tool for similar motor deficits in a number of neurologic conditions. The aim of this randomized, controlled trial was to investigate the therapeutic potential of rTMS in various forms of HSP, including pure and complicated forms, as well as adrenomyeloneuropathy. Methods. We recruited 15 patients (five women and 10 men; mean age 43.7±10.6 years) with the mentioned forms of HSP. The intervention included five sessions of bilateral 10 Hz rTMS over primary motor areas of the muscles of lower extremities and five sessions of similar sham stimulation. Results. One patient dropped out due to seizure, and 14 patients completed the study protocol. After real stimulation, the strength of the proximal and distal muscles of lower extremities increased, and the spasticity of the proximal muscles decreased. Change in spasticity was still present during follow-up assessment. No effect was observed regarding gait velocity. No changes were seen after sham stimulation. A post hoc analysis revealed an inverse relation between motor threshold and the change of the strength after active rTMS. Conclusions. rTMS may have potential in improving weakness and spasticity of lower extremities in HSP, especially of proximal muscles whose motor areas are located more superficially. This trial is registered with Clinicaltrials.gov NCT03627416.
In this paper an application of evolutionary algorithm to design minimal phase digital filters with non-standard amplitude characteristics and with finite bit word length is presented. Four digital ...filters with infinite impulse response were designed using the proposed method. These digital filters possess: linearly falling characteristics, linearly growing characteristics, nonlinearly falling characteristics, and nonlinearly growing characteristics, and they are designed using bit words with an assumed length. This bit word length is connected with a processing register size. This register size depends on hardware possibilities where digital filter is to be implemented. In this paper, a modification of the mutation operator is introduced too. Due to this modification, better results were obtained in relation to the results obtained using the evolutionary algorithm with other mutation operators. The digital filters designed using the proposed method can be directly implemented in the hardware (DSP system) without any additional modifications.
Accumulated evidence suggests that a variant within the CR1 gene (single nucleotide polymorphism rs6656401), known to increase risk for Alzheimer disease (AD), influences β-amyloid (Aβ) deposition in ...brain tissue. Given the biologic overlap between AD and cerebral amyloid angiopathy (CAA), a leading cause of intracerebral hemorrhage (ICH) in elderly individuals, we investigated whether rs6656401 increases the risk of CAA-related ICH and influences vascular Aβ deposition.
We performed a case-control genetic association study of 89 individuals with CAA-related ICH and 280 individuals with ICH unrelated to CAA and compared them with 324 ICH-free control subjects. We also investigated the effect of rs6656401 on risk of recurrent CAA-ICH in a prospective longitudinal cohort of ICH survivors. Finally, association with severity of histopathologic CAA was investigated in 544 autopsy specimens from 2 longitudinal studies of aging.
rs6656401 was associated with CAA-ICH (odds ratio OR = 1.61, 95% confidence interval CI 1.19-2.17, p = 8.0 × 10(-4)) as well as with risk of recurrent CAA-ICH (hazard ratio = 1.35, 95% CI 1.04-1.76, p = 0.024). Genotype at rs6656401 was also associated with severity of CAA pathology at autopsy (OR = 1.34, 95% CI 1.05-1.71, p = 0.009). Adjustment for parenchymal amyloid burden did not cancel this effect, suggesting that, despite the correlation between parenchymal and vascular amyloid pathology, CR1 acts independently on both processes, thus increasing risk of both AD and CAA.
The CR1 variant rs6656401 influences risk and recurrence of CAA-ICH, as well as the severity of vascular amyloid deposition.
In this paper the multi-objective optimization of a surface grinding process making use of an evolutionary algorithm is presented. Such factors as wheel speed, workpiece speed, depth of dressing and ...lead of dressing are optimized in order to minimize production cost and surface roughness or to minimize production cost and maximize production rate. In the algorithm, the optimization is introduced in Pareto’s sense, all acceptable and non-dominated solutions are remembered, and therefore the final result is not a single solution, but a whole set. The proposed method based on an example chosen from literature is tested, and the results obtained are compared with the results obtained by the use of other methods.
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