Risk factors for cognitive impairment and dementia after stroke: a systematic review and meta-analysis.

BACKGROUND: Cognitive impairment and dementia are highly prevalent among stroke survivors and represent a major burden for patients, carers, and health-care systems. We studied the risk factors for post-stroke cognitive impairment (PSCI) and dementia (PSD) beyond the well established risk factors of age and stroke severity. METHODS: In this systematic review and meta-analysis we conducted a systematic literature search from database inception until Sept 15, 2023. We selected prospective and retrospective cohort studies, post-hoc analyses from randomised controlled trials, and nested case-control studies of patients with acute stroke (ischaemic, haemorrhagic, and transient ischaemic attack), exploring associations between risk factors at baseline and PSCI or PSD over a follow-up period of at least 3 months. Study quality was assessed using the Newcastle-Ottawa quality assessment scale. We calculated pooled relative risks (RRs) with random-effects meta-analyses and performed subgroup, meta-regression, and sensitivity analyses. This study was preregistered with PROSPERO, CRD42020164959. FINDINGS: We identified 162 eligible articles for our systematic review, of which 113 articles (89 studies, 160 783 patients) were eligible for meta-analysis. Baseline cognitive impairment was the strongest risk factor for PSCI (RR 2·00, 95% CI 1·66-2·40) and PSD (3·10, 2·77-3·47). We identified diabetes (1·29, 1·14-1·45), presence or history of atrial fibrillation (1·29, 1·04-1·60), presence of moderate or severe white matter hyperintensities (WMH; 1·51, 1·20-1·91), and WMH severity (1·30, 1·10-1·55, per SD increase) as treatable risk factors for PSCI, independent of age and stroke severity. For PSD, we identified diabetes (1·38, 1·10-1·72), presence of moderate or severe WMH (1·55, 1·01-2·38), and WMH severity (1·61, 1·20-2·14, per SD increase) as treatable risk factors. Additional risk factors included lower educational attainment, previous stroke, left hemisphere stroke, presence of three or more lacunes, brain atrophy, and low baseline functional status. Associations of risk factors with PSD were weaker in studies conducted and published more recently. We found substantial interstudy heterogeneity and evidence of reporting bias. INTERPRETATION: Our results highlight the importance of cognitive impairment in the acute phase after stroke for long-term prediction of PSCI and PSD. Treatable risk factors include diabetes, atrial fibrillation, and markers of cerebral small vessel disease (ie, white matter hyperintensities and lacunes). Future trials should explore these risk factors as potential targets for prevention of PSCI and PSD. FUNDING: German Research Foundation.

[Clinico-psychological profile and life quality of patients with post-COVID syndrome]. / Kliniko-psikhologicheskii profil' i kachestvo zhizni patsientov s postkovidnym sindromom.

OBJECTIVE: To study clinico-psychological profile and life quality of patients with post-COVID syndrome. MATERIAL AND METHODS: We examined 162 patients aged 24-60 years with confirmed SARS-CoV-2 infection which having symptoms that served as the basis for the diagnosis of post-COVID syndrome. Patients underwent general neurological and somatic examination with allocation of the corresponding neurological syndromes. The intensity and quality of pain were assessed using the McGill Pain questionnaire. The level of psychosocial stress was determined by the Holmes-Ray questionnaire, the identification and severity of asthenia - by the MFI-20 asthenia scale. The level of reactive and personal anxiety was studied according to the Spielberger-Khanin questionnaire, depression - according to the Beck scale. The assessment of life quality was carried out using the Russian version of SF-36 questionnaire. To correct the identified disorders, Mexidol was used according to the scheme: 500 mg once daily intravenously for 14 days, followed by Mexidol FORTE 250 750 mg per day orally (250 mg 3 times a day) for 2 months. RESULTS: The course of treatment with Mexidol in patients with post-COVID syndrome led to decrease in the severity of subjective and objective symptoms, asthenic, anxiety and depressive disorders, and improved the life quality of patients. CONCLUSION: The high efficacy and safety of sequential therapy with Mexidol (injections followed by tablets of Mexidol FORTE 250) has been shown.

A neuropsychological profile and its correlation with neuroimaging markers in patients with subcortical ischaemic vascular dementia.

OBJECTIVES: Cognitive and neuroimaging assessments are still the main clinical practice methods for screening and diagnosing vascular dementia (VaD) patients. This study aimed to establish the neuropsychological characteristics of mild-to-moderate subcortical ischaemic vascular dementia (SIVD) patients, find an optimal cognitive marker for differentiating them from Alzheimer's disease (AD) patients, and explore the correlation between cognitive function and total small vessel disease (SVD) burden. METHODS: SIVD (n = 60) and AD (n = 30) patients and cognitively unimpaired healthy controls (HCs; n = 30) were recruited from our longitudinal MRI AD and SIVD study (ChiCTR1900027943) and received a comprehensive neuropsychological assessment and a multimodal MRI scan. Cognitive performance and MRI SVD markers were compared between groups. Combined cognitive scores were established for differentiating between SIVD and AD patients. Correlations between cognitive function and total SVD scores were analysed in dementia patients. RESULTS: SIVD patients showed poorer performance in information processing speed and better performance in memory, language, and visuospatial function than AD patients, although all cognitive domains were impaired in both groups compared with HCs. Combined cognitive scores showed an area under the curve of 0.727 (95%CI 0.62-0.84, p < 0.001) for differentiating SIVD and AD patients. Auditory Verbal Learning Test recognition scores were negatively correlated with total SVD scores in SIVD patients. CONCLUSIONS: Our results suggested that neuropsychological assessments, specifically combined tests including episodic memory, information processing speed, language and visuospatial ability, are useful in the clinical differentiation between SIVD and AD patients. Moreover, cognitive dysfunction was partly correlated with MRI SVD burden in SIVD patients.

Effects on sedentary behaviour of an approach to reduce sedentary behaviour in patients with minor ischaemic stroke: A randomised controlled trial.

OBJECTIVES: To determine the effects on sedentary behaviour of an approach that promotes reduction in sedentary behaviour in patients with minor ischaemic stroke after intervention and at follow-up. DESIGN: A randomised controlled trial. SETTING: During hospitalisation and after hospital discharge. SUBJECTS: In total, 86 patients with minor ischaemic stroke admitted to an acute care hospital were assigned to the intervention (n = 43) and control (n = 43) groups. INTERVENTION: An intervention group that received an approach to reduce sedentary behaviour upon hospital admission until 3 months after discharge (education, self-monitoring, phone calls, etc.) and a control group that received the usual care during hospitalisation. From 3 to 6 months after discharge, no group received any intervention. MAIN OUTCOME: The primary outcome was the change (%) in sedentary behaviour from baseline to post-intervention (3 months after discharge) and follow-up (6 months after discharge). Sedentary behaviour was measured at baseline (upon hospital admission), post-intervention, and at follow-up using accelerometers. RESULTS: At the post-intervention stage, the intervention group showed a significantly greater change in sedentary behaviour from baseline than that shown by the control group (sedentary behaviour: intervention group, -22.7%; control group, -14.9%; P = 0.013; effect size = 0.58). At follow-up too, the intervention group showed a significantly greater change in sedentary behaviour from baseline than that shown by the control group (sedentary behaviour: intervention group, -20.4%; control group, -13.6%; P = 0.025; effect size = 0.54). CONCLUSIONS: An approach to reduce sedentary behaviour in patients with minor ischaemic stroke effectively reduces sedentary behaviour, which is sustained up to follow-up. TRIAL REGISTRATION: This study is registered at www.umin.ac.jp/ctr/index/htm UMIN000038616.

Neurogranin as an important regulator in swimming training to improve the spatial memory dysfunction of mice with chronic cerebral hypoperfusion.

BACKGROUND: Vascular cognitive impairment caused by chronic cerebral hypoperfusion (CCH) has become a hot issue worldwide. Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities; however, the specific mechanism has remained inconclusive. And recent studies found that neurogranin (Ng) is a potential biomarker for cognitive impairment. This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment. METHODS: To test this hypothesis, the clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (Cas9) system was utilized to construct a strain of Ng conditional knockout (Ng cKO) mice, and bilateral common carotid artery stenosis (BCAS) surgery was performed to prepare the model. In Experiment 1, 2-month-old male and female transgenic mice were divided into a control group (wild-type littermate, n = 9) and a Ng cKO group (n = 9). Then, 2-month-old male and female C57BL/6 mice were divided into a sham group (C57BL/6, n = 12) and a BCAS group (n = 12). In Experiment 2, 2-month-old male and female mice were divided into a sham group (wild-type littermate, n = 12), BCAS group (n = 12), swim group (n = 12), BCAS + Ng cKO group (n = 12), and swim + Ng cKO group (n = 12). Then, 7 days after BCAS, mice were given swimming training for 5 weeks (1 week for adaptation and 4 weeks for training, 5 days a week, 60 min a day). After intervention, laser speckle was used to detect cerebral blood perfusion in the mice, and the T maze and Morris water maze were adopted to test their spatial memory. Furthermore, electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca2+ pathway-related proteins, respectively. Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage, inflammation, and white matter injury. RESULTS: The figures showed that spatial memory impairment was detected in Ng cKO mice, and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS mice. Regular swimming training improved the spatial memory impairment of BCAS mice. This was achieved by preventing long-term potential damage and reversing the decline of Ca2+ signal transduction pathway-related proteins. At the same time, the results suggested that swimming also led to improvements in neuronal death, inflammation, and white matter injury induced by CCH. Further study adopted the use of Ng cKO transgenic mice, and the results indicated that the positive effects of swimming training on cognitive impairments, synaptic plasticity, and related pathological changes caused by CCH could be abolished by the knockout of Ng. CONCLUSION: Swimming training can mediate the expression of Ng to enhance hippocampal synaptic plasticity and improve related pathological changes induced by CCH, thereby ameliorating the spatial memory impairment of vascular cognitive impairment.

Anxiety and depression in stroke: An evaluation of these psychopathologies on outcomes of stroke type using the National Inpatient Sample.

BACKGROUND: Anxiety and depression have been reported to complicate the course of stroke. This study evaluated the association of anxiety and depression independently on ischemic vs non-ischemic stroke. METHODS: A cross-sectional survey of 4,983,807 admissions for acute stroke from 1994 to 2013 in the National Inpatient Sample compared stroke patients with depression and anxiety to stroke patients with no psychiatric comorbidities. The database was operationalized based on the inclusion/exclusion criteria approved by the Southern Illinois University School of Medicine Institutional Review Board. RESULTS: Patients with anxiety and depression were more likely to have an ischemic stroke (OR 1.64; 95% CI, 1.61 to 1.68) vs a non-ischemic stroke (OR 1.25; 95% CI, 1.23 to 1.27). Inpatient mortality was significantly less in both the depression and anxiety groups compared to the control group. CONCLUSIONS: Psychiatric disorders (anxiety and depression) may increase the risk of ischemic stroke; however, depressed and anxiety patients with ischemic stroke were less likely to die from stroke. Further well-designed studies are necessary to explore these findings.

Enriched environment priors to TET1 hippocampal administration for regulating psychiatric behaviors via glial reactivity in chronic cerebral hypoperfusion models.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been gradually regarded as a common etiologic mechanism for cognitive and psychiatric disturbances. Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) played an important role in adult hippocampal neurogenesis (AHN), neuronal circuits formation, cognition and psychiatric disorders. Enriched environment (EE) showed a beneficial effect on cognition and depression via effectively regulating AHN and glial reactivity. This study aimed to assess which strategy was feasible to improve cognition and psychiatric disturbances by comparing the TET1 hippocampal microinjection and EE in CCH models and to investigate the possible mechanisms. METHOD: CCH rats were established via permanent bilateral common carotid artery occlusion (2-VO). Rats were stereotaxically injected with the human catalytic domain of TET1 (hTET1) to overexpress the hTET1 in the hippocampus 10 days before 2-VO. 3 days after 2-VO, rats were subjected to standard environment or EE with free access to food and water. Behavioral tests were used to appraise depression and cognition before sacrifice. Epigenetic molecules, adult neurogenesis, synaptic proteins expression, and glial activation were analyzed using immunofluorescent staining, qRT-PCR and western blot. RESULTS: In the present study, we found both EE and genetical treatment with overexpressing hTET1 were sufficient for stimulating AHN. However, promoting ANH could not deal with the cognitive dysfunction and depressive-like behaviors in CCH rats. Notably, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. Meanwhile, astrocytes were involved in the cognitive regulating process of neurons, presynaptic function and microglia. In general, we held that depressive disturbances were determined by BDNF levels, neuronal and presynaptic function, as well as glial activation containing astrocytes and microglia. To further support this point, we investigated severe depressive symptoms that were strongly correlated with the activation of astroglia and microglia. Importantly, causal mediation analysis showed significant mediation by the presence of reactive glial cells in the relation between neural plasticity and depressive symptoms. Finally, we showed EE performed better than hTET1 treatment for cognitive deficits and depression. EE with less glial reactivity was much more resistant to depression, while hTET1 with more glial activation was more vulnerable to depressive disorders. CONCLUSIONS: EE was likely to be superior to TET1 hippocampal administration for cognition and psychiatric behaviors in CCH rats. Furthermore, a healthy local brain environment with elevated BDNF and astrocytes was conducive to improving cognitive dysfunction. More glial activation, and more vulnerable to depressive disorders. These results were important for our understanding of disease mechanisms and provided valuable tools for the overall management of CCH patients.

Inhibition of Long non-coding RNA zinc finger antisense 1 improves functional recovery and angiogenesis after focal cerebral ischemia via microRNA-144-5p/fibroblast growth factor 7 axis.

Long non-coding RNA zinc finger antisense 1 (ZFAS1) has been probed in cerebral ischemia, while the regulatory mechanism of ZFAS1 in focal cerebral ischemia (FCI) via binding to microRNA (miR)-144-5p remains rarely explored. This study aims to decipher the function of ZFAS1 on FCI via sponging miR-144-5p to modulate fibroblast growth factor 7 (FGF7). The focal cerebral ischemia rat model was established by occlusion of the middle cerebral artery (MCAO) Lentivirus vectors altering ZFAS1, miR-144-5p or FGF7 expression were injected into rats before MCAO. Then, ZFAS1, miR-144-5p, and FGF7 levels were detected, the inflammatory factor level, oxidative stress level, angiogenesis, neurological function injury and neuronal apoptosis were assessed. The binding relations among ZFAS1, miR-144-5p and FGF7 were validated. ZFAS1 and FGF7 expression was elevated, while miR-144-5p expression was reduced in FCI rats. Decreased ZFAS1 or FGF7 or enriched miR-144-5p repressed the inflammatory response, oxidative stress, neuronal apoptosis, while it improved angiogenesis, and neurological function recovery; while up-regulated ZFAS1 exerted opposite effects. The augmented miR-144-5p or silenced FGF7 reversed the effects of enriched ZFAS1. ZFAS1 sponged miR-144-5p that targeted FGF7. Inhibition of lncRNA ZFAS1 improves functional recovery and angiogenesis after FCI via miR-144-5p/FGF7 axis. This study provides novel therapeutic targets for FCI treatment.

Influence of Melatonin on Behavioral and Neurological Function of Rats with Focal Cerebral Ischemia-Reperfusion Injury via the JNK/FoxO3a/Bim Pathway.

OBJECTIVE: To investigate the influence of melatonin on behavioral and neurological function of rats with focal cerebral ischemia-reperfusion injury via the JNK/FoxO3a/Bim pathway. METHODS: One hundred and twenty healthy male SD rats were randomized into the model group (Model: the middle cerebral artery occlusion (MCAO) model was constructed and received an equal volume of normal saline containing 5% DMSO), sham operation group (Sham: received no treatment except normal feeding), and low, medium, and high dose of melatonin group (L-MT, M-MT, and H-MT intraperitoneally injected 10, 20, and 40 mg/kg melatonin 30 min after IR, respectively), with 24 rats in each group. Following 24 h of reperfusion, the rats in each of the above groups were tested for neurological deficit symptoms and behavioral changes to screen the rats included in the study. HE and TUNEL stainings were performed to observe pathological changes. Levels of oxidative stress-related indexes, inflammatory factor-related indexes, nuclear factor-κB p65 (NF-κB p65), and interferon-γ (IFN-γ) in the rat brain were measured by ELISA. The JNK/FoxO3a/Bim pathway-related proteins as well as Bcl-2, Caspase-3, and Bax were examined using Western blot. RESULTS: Detection of behavioral indicators showed that the MACO model was successfully constructed in rats. L-MT, M-MT, and L-MT groups presented reduced malondialdehyde (MDA), reactive oxygen species (ROS), tumor necrosis factor- (TNF-) α, interleukin- (IL-) 6, IL-1ß, IFN-γ, NF-κB p65, and apoptosis compared with the Model group (P < 0.05), and the improvement degree was better in the M-MT group versus the L-HT group. Bcl-2 protein expression in the brain tissue of L-MT, M-MT, and H-MT groups increased significantly, while Bax, Caspase-3, p-JNK, p-FoxO3a, and Bim protein expression declined markedly, versus the Model group (P < 0.05). The changes of indexes were greater in the M-MT group compared with that in the L-MT group. No significant difference was observed in all the above indexes between the M-MT group and the H-MT group (P > 0.05). CONCLUSIONS: In the MACO rat model, melatonin can effectively reduce Bax and Caspase-3 levels by modulating the JNK/FoxO3a/Bim pathway, inhibit neuronal apoptosis, and alleviate neurological deficits by reducing the release of proinflammatory mediators, with anti-inflammatory and antioxidant effects. In addition, 20 mg/kg is the optimal melatonin concentration.

Combined Preconditioning Reduces the Negative Influence of Cerebral Ischemia on the Morphofunctional Condition of CNS.

We studied the influence of combined preconditioning (compound pQ-4 and moderate hypoxia) on morphometrical parameters of neuronal populations in hippocampal fields CA1 and CA3 in rats after bilateral ligation of the common carotid artery. Preconditioning produced a neuroprotective effect, improved survival of pyramidal neurons in the early and delayed periods of modeled ischemia, prevented the formation of necrotic and apoptotic neurons and hyperactivation of microglia, and protected endotheliocytes. The positive influence of preconditioning factors on the morphometric parameters of the brain under ischemic conditions agrees with the results of behavioral tests (open field and elevated plus maze) that demonstrated increased locomotor activity and exploratory behavior of animals.

Enriched environment remedies cognitive dysfunctions and synaptic plasticity through NMDAR-Ca2+-Activin A circuit in chronic cerebral hypoperfusion rats.

Chronic cerebral ischemia (CCI) is one of the critical factors in the occurrence and development of vascular cognitive impairment (VCI). Apoptosis of nerve cells and changes in synaptic activity after CCI are the key factors to induce VCI. Synaptic stimulation up-regulates intraneuronal Ca2+ level through N-methyl-D-aspartic acid receptor (NMDAR) via induction of the activity-regulated inhibitor of death (AID) expression to produce active-dependent neuroprotection. Moreover, the regulation of synaptic plasticity could improve cognition and learning ability. Activin A (ActA), an exocrine protein of AID, can promote NMDAR phosphorylation and participate in the regulation of synaptic plasticity. We previously found that exogenous ActA can improve the cognitive function of rats with chronic cerebral ischemia and enhance the oxygenated glucose deprivation of intracellular Ca2+ level. In addition to NMDAR, the Wnt pathway is critical in the positive regulation of LTP through activation or inhibition. It plays an essential role in synaptic transmission and activity-dependent synaptic plasticity. The enriched environment can increase ActA expression during CCI injury. We speculated that the NMDAR-Ca2+-ActA signal pathway has a loop-acting mode, and the environmental enrichment could improve chronic cerebral ischemia cognitive impairment via NMDAR-Ca2+-ActA, Wnt/ß-catenin pathway is involved in this process. For the hypothesis verification, this study intends to establish chronic cerebral hypoperfusion (CCH) rat model, explore the improvement effect of enriched environment on VCI, detect the changes in plasticity of synaptic morphology and investigate the regulatory mechanism NMDAR-Ca2+-ActA-Wnt/ß-catenin signaling loop, providing a therapeutic method for the treatment of CCH.

Pre-hospital causes for delayed arrival in acute ischemic stroke before and during the COVID-19 pandemic: A study at two stroke centers in Egypt.

BACKGROUND: In the current study we investigated the causes of pre-hospital delay as this can compromise the patient's chance to receive thrombolytic therapy and thus impact stroke outcome. METHODS: We surveyed 254 patients regarding reasons for delayed and early arrival to hospital after acute ischemic stroke. The survey was performed over five months, spanning a period pre- and during COVID-19 (between December 7, 2019 and May 10, 2020). RESULTS: A total of 71.2% of patients arrived beyond four hours of onset of ischemic stroke. The commonest cause for delay pre-Covid-19 was receiving treatment in a non-stroke hospital, while that during COVID-19 was fear of infection and lock down issues. Not realizing the urgency of the condition and stroke during sleep were common in both periods. Early arrival because of the patient's previous experience with stroke accounted for approximately 25% of cases in both periods. The effect of media was more evident during COVID-19, accounting for 47.7% of cases. CONCLUSION: Pre-hospital delay secondary to misperception of the urgency of stroke and management in a non-stroke hospital reflect the lack of awareness among the public and medical staff. This concept is emphasized by early arrival secondary to previous experience with stroke and the pronounced effect of media in the time of COVID-19.

When to Assess: Cognitive Impact of Ventriculoperitoneal Shunt Operation in Elderly Adults with Normal Pressure Hydrocephalus.

OBJECTIVE: Normal pressure hydrocephalus (NPH) has clinical manifestations with different cognitive difficulties. Despite the intense interest, the change in cognitive functions after ventriculoperitoneal shunt (VPS) treatment varies widely. The aims of this study were to monitor the effect of NPH on cognition in elderly and the progress of cognitive abilities after VPS surgery. METHODS: Patients diagnosed with idiopathic NPH (iNPH) who had ventriculomegaly with narrow callosal angle and/or periventricular signal changes not attributable to ischemic changes were included in study. All patients (n = 30) underwent comprehensive neuropsychological assessment and received programmable VPS. After VPS placement, 2 consecutive examinations were performed at approximately 6-month intervals. RESULTS: At the baseline evaluation, patients with iNPH displayed poorer performance in executive functions (EFs) compared with the matched control group (n = 30). Among those patients, significant improvement was observed in semantic fluency (M = 13.94; standard deviation, 4.95) and clock drawing (M = 3.67; standard deviation, 1.57) at the second follow-up evaluation (P = 0.015 and P = 0.024, respectively). The other prominent finding was in memory process: patients with iNPH showed improvement in delayed recall (P = 0.011), recognition (P = 0.033), and learning scores (P = 0.041) at the second follow-up compared with evaluation before VPS placement. CONCLUSIONS: iNPH seems to have a detrimental effect predominantly on EFs. As EFs become corrupted, decline occurs in learning and recall processes of memory. VPS provides an improvement of cognitive deterioration; however, efficacy of this treatment on cognitive abilities is shows in a longer period compared with other iNPH symptoms.

Positive effects of roflumilast on behavior, neuroinflammation, and white matter injury in mice with global cerebral ischemia.

Inhibition of phosphodiesterase 4 (PDE4) is a promising pharmacological strategy for the treatment of cerebral ischemic conditions. To increase the relevance and increase the translational value of preclinical studies, it is important to conduct experiments using different animal species and strains, different animal models, and to evaluate long-term functional outcomes after cerebral ischemia. In the present study, the effects of the selective PDE4 inhibitor roflumilast were evaluated in vivo and in vitro. Balb/c mice were subjected to bilateral common carotid artery occlusion (BCCAO) and tested during 21 days in multiple behavioral tasks to investigate the long-term effects of roflumilast on functional recovery. The effects of roflumilast were also investigated on hippocampal cell loss, white matter injury, and expression of neuroinflammatory markers. Roflumilast prevented cognitive and emotional deficits induced by BCCAO in mice. Roflumilast also prevented neurodegeneration and reduced the white matter damage in the brain of ischemic animals. Besides, roflumilast decreased Iba-1 (microglia marker) levels and increased Arginase-1 (Arg-1; microglia M2 phenotype marker) levels in the hippocampus of these mice. Likewise, roflumilast suppressed inducible nitric oxide synthase (microglia M1 phenotype marker) expression and increased Arg-1 levels in a primary mouse microglia culture. These findings support evidence that PDE4 inhibition by roflumilast might be beneficial in cerebral ischemic conditions. The neuroprotective effects of roflumilast appear to be mediated by a decrease in neuroinflammation.

Intermittent fasting attenuates inflammasome-associated apoptotic and pyroptotic death in the brain following chronic hypoperfusion.

Chronic cerebral hypoperfusion (CCH) has been shown to initiate several inflammatory pathways that can contribute to cognitive deficits and memory loss in vascular cognitive impairment (VCI). Multi-protein complexes termed inflammasomes that may be involved in the inflammatory response to CCH has already been shown to contribute to the inflammatory process and cell death following acute cerebral ischemia. Intermittent fasting (IF) has already been shown to decrease inflammasome activation and protect the brain from ischemic stroke; however, its effects during CCH remains unknown. The present study investigated the impact of IF (16 h of food deprivation daily) for four months on inflammasome-mediated cell death in the cerebellum following CCH in a mouse model of VCI using fourteen to sixteen-week-old male C57BL/6NTac mice. Here we demonstrated that IF decreased inflammasome activation, and initiation of apoptotic and pyroptotic cell death pathways as reflected by the reduction (20-30%) in the expression levels of key effector proteins and cell death markers in the cerebellum following CCH. In summary, our results indicate that IF can attenuate the inflammatory response and cell death pathways in the brain following chronic hypoperfusion in a mouse model of VCI.

Dexmedetomidine exerts a protective effect on ischemic brain injury by inhibiting the P2X7R/NLRP3/Caspase-1 signaling pathway.

Dexmedetomidine (Dex) has been suggested to exert a protective function in ischemic brain injury. In this study, we aimed to elucidate the intrinsic mechanisms of Dex in regulating microglia pyroptosis in ischemic brain injury via the purinergic 2X7 receptor (P2X7R)/NLRP3/Caspase-1 signaling pathway. First, permanent middle cerebral artery occlusion (p-MCAO) rat model was established, followed by the measurement of behavioral deficit, neuronal injury, the volume of brain edema and the infarct size. Dex treatment was suggested to alleviate the neurological deficits in p-MCAO rats and reduce the brain water content and infarct size. Additionally, rat microglia were cultured in vitro and a model of oxygen and glucose (OGD) was established. Microglia cell activity and ultrastructure were detected. Dex could increase cell activity and reduce LDH activity, partially reversing the changes in cell morphology. Furthermore, the activation of P2X7R/NLRP3/Caspase-1 pathway was tested. The obtained findings indicated Dex suppressed microglial pyroptosis by inhibiting the P2X7R/NLRP3/Caspase-1 pathway. Inhibition of P2X7R or NLRP3 could inhibit Caspase-1 p10 expression, improve cell activity, and reduce LDH activity. The same result was verified in vivo experiments. This study indicated that Dex inhibited microglia pyroptosis by blocking the P2X7R/NLRP3/Caspase-1 pathway, thus playing a protective role against ischemic brain injury.

Consecutive and temporally distant perseverations after right brain damage: A prospective study.

Objective: Right brain-damaged patients may show omissions and/or additional marks in target cancellation. The latter is classified as perseverative behavior and has been attributed to defective response inhibition or attentional disengagement deficit. This study aimed at (a) verifying that consecutive (immediate) and return (temporally distant) motor perseverations could be due to different mechanisms; (b) investigating the relationships among different types of perseveration (e.g., consecutive, return, scribble), spatial neglect and the impairment in specific components of executive functioning. Method: Seventeen right brain-damaged patients underwent letter, star, bell, and apple cancellation tasks. A global index for each type of perseveration found and Mean Position of Hits, as a neglect index, were calculated. The following components of executive functioning were evaluated: motor programming (Frontal Assessment Battery [FAB] subtest), inhibitory control FAB, interference sensitivity (FAB and Stroop color-word interference test), set-shifting (Weigl sorting test, Phonemic/semantic alternate fluencies), and working memory (Backward Digit span). Results: Ten patients out of 17 showed some degree of perseveration. Regularized linear regression analyses demonstrated that interference sensitivity and Stroop test performances were related to return perseverations and backward digit to scribble ones. No significant relationships were found for consecutive perseverations and between neglect and any type of perseverations. Conclusions: The present study showed that return perseverations might have a distinct etiology from consecutive ones, being related to an inability to update and shift between action programs according to the visual stimuli. A finer classification of perseverations could help in unveiling the neuropsychological mechanisms underlying each type of behavior. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

MiRNA-34c-5p protects against cerebral ischemia/reperfusion injury: involvement of anti-apoptotic and anti-inflammatory activities.

MicroRNAs (miRNAs) are known as important regulators of gene expression and play important roles in diverse biological activities. However, the involvement of miRNAs in cerebral ischemia remains elusive. In the present study, using the middle cerebral artery occlusion (MCAO) model and oxygen-glucose deprivation/reperfusion (OGD/RP)-induced cell injury model, we found that the expression levels of miR-34c-5p were significantly reduced in MCAO rats and OGD/RP cells. Overexpression of miR-34c-5p could improve the increased brain infarction, brain water content and neurological scores in MCAO rats, as well as the abnormal expression of inflammatory cytokines (TNF-α, IL-6, COX-2, iNOS, IL-10) in OGD/RP cells. Moreover, overexpression of miR-34c-5p was found to inhibit the activity of nuclear factor-kappa B (NF-κB) by regulating the expression of nuclear receptor coactivator 1 (NCOA1), and increase the apoptotic rate of cortical neurons by inhibiting the expression of Caspase-3 and Bax and upregulating the expression of Bcl-2. Taken together, our findings demonstrated that miR-34c-5p plays an important role in cerebral ischemia/reperfusion injury, which may be mediated through inflammatory and apoptotic signaling pathways.

Gadd45b is a novel mediator of depression-like behaviors and neuroinflammation after cerebral ischemia.

BACKGROUND: Poststroke depression (PSD) is an important consequence after stroke, with a negative impact on stroke outcome. Recent evidence points to a modulatory role of Growth arrest and DNA-damage-inducible protein 45 beta (Gadd45b) in depression. Herein, we evaluated the antidepressant efficacy and mechanism underlying the potent therapeutic effects of Gadd45b after cerebral ischemia. METHODS: Adult male Sprague-Dawley rats were subjected to cerebral ischemia by permanent middle cerebral artery occlusion (MCAO). The sucrose preference test (SPT), forced swim test (FST), and tail suspension test (TST) were performed after completing MCAO to study the antidepressant-like effects. The expression of brain-derived neurotrophic factor (BDNF) and neuroinflammation were determined in the hippocampus. RESULTS: We showed that Gadd45b knockdown induced depression-like behaviors after cerebral ischemia, including increased immobility time in the FST and TST and reduced sucrose preference. Gadd45b knockdown enhanced the expression of pro-inflammatory cytokines IL-6 and TNF-α, accompanying with decreased protein levels of BDNF in the hippocampus. Moreover, the levels of phosphorylated ERK and CREB, which have been implicated in events downstream of BDNF signaling, were also decreased after cerebral ischemia. CONCLUSION: Hence, the results showed that Gadd45b is a promising drug candidate for treating PSD and possibly other nervous system diseases associated with neuroinflammation. Gadd45b may have therapeutic potential for PSD through BDNF-ERK-CREB pathway and neuroinflammation.

Abatement of neurobehavioral and neurochemical dysfunctions in cerebral ischemia/reperfusion injury by Tetrapleura tetraptera fruit extract.

ETHNOPHARMACOLOGICAL RELEVANCE: Tetrapleura tetraptera Taub. (family Fabaceae), is generally found in the lowland forest of tropical Africa. Its leaves and fruits are traditionally used in West Africa for the management of brain disorders. AIM OF THE STUDY: This study evaluated the effect of Tetrapleura tetraptera methanol fruit extract (TT) on bilateral common carotid artery occlusion-induced cerebral ischemia/reperfusion (I/R) injury in male Wistar rats. MATERIALS AND METHODS: Rats pretreated with TT for 7 days before a 30 min bilateral common carotid artery occlusion and reperfusion for 24 h were assessed for neurobehavioural deficits. Cortical, striatal and hippocampal oxidative stress, pro-inflammatory events, electrolyte imbalance and neurochemical dysfunctions, as well as hippocampal histopathological alterations, were also evaluated. HPLC-DAD analysis was performed to identify likely compounds contributing to the bioactivity of the extract. RESULTS: TT reduced I/R-induced behavioral deficits and ameliorated I/R-induced oxidative stress by restoring reduced glutathione level, increasing catalase and superoxide dismutase activities, and also reducing both lipid peroxidation and xanthine oxidase activity in the brain. TT attenuated I/R-increased myeloperoxidase and lactate dehydrogenase activities as well as disturbances in Na+ and K+ levels. Alterations elicited by I/R in the activities of Na+/K+ ATPase, complex I, glutamine synthetase, acetylcholinesterase, and dopamine metabolism were abated by TT pretreatment. TT prevented I/R-induced histological changes in the hippocampus. HPLC-DAD analysis revealed the presence of aridanin, a marker compound for Tetrapleura tetraptera, and other phytochemicals. CONCLUSIONS: These findings indicate that Tetrapleura tetraptera fruit has a protective potential against stroke through modulation of redox and electrolyte imbalances, and attenuation of neurotransmitter dysregulation and other neurochemical dysfunctions. Tetrapleura tetraptera fruit could be a promising source for the discovery of bioactives for stroke therapy.