Development Of Post-stroke Cognitive Impairment Research Articles

Peripheral immunity is associated with cognitive impairment after acute minor ischemic stroke and transient ischemic attack

Immunoinflammation is associated with the development of post-stroke cognitive impairment (PSCI), however, peripheral immunity has not been fully explored. We aimed to investigate the association between PSCI and peripheral immune indicators, including neutrophil, lymphocyte, and mononuclear percentages and counts; the systemic immune inflammation index; platelet-to-lymphocyte ratio; neutrophil-to-lymphocyte ratio (NLR); and lymphocyte-to-monocyte ratio. A total of 224 patients with acute minor ischemic stroke or transient ischemic attack with 6–12 months of follow-up were included. PSCI was defined as a Montreal Cognitive Assessment score < 22 during the follow-up period. We performed logistic regression, subgroup analyses based on age and sex, and further established predictive models. We found that increased innate immunity indicators (neutrophils, neutrophil percentage) increased the risk of PSCI, whereas increased adaptive immunity indicator (lymphocytes) were protective against PSCI, especially in patients aged 50–65 years. Neutrophil percentage and NLR improved the predictive efficacy of the models that included demographic, clinical, and imaging information, with the area under the curve increased from 0.765 to 0.804 and 0.803 (P = 0.042 and 0.049, respectively). We conducted a comprehensive analysis of peripheral immunity in PSCI, providing a novel perspective on the early detection, etiology, and treatment of PSCI.

The relationship between the development of post-stroke cognitive impairment and changes in the coagulation component of hemostasis

To evaluate the relationship between the severity of post-stroke cognitive impairment (PSCI) and coagulation parameters assessed using the dynamic thrombophotometry. Thirty-five patients with hemispheric ischemic stroke (IS) with moderate neurological deficit at admission were included. All patients underwent a comprehensive clinical and instrumental assessment according to the current guidelines. On days 10-14, the cognitive status of patients was assessed using the Montreal Cognitive Assessment (MoCA). Coagulation parameters were assessed using the dynamic thrombophotometry at admission, on 6-8th days and 13-15th days from the onset of the disease. A database of laboratory studies of 30 apparently healthy volunteers was used as a comparison group. Data analysis revealed that a number of spatial and temporal parameters were within the reference values, and there were no significant changes over time. Nevertheless, though the optical density of the fibrin clot (D) was within the reference values, it showed a steady increase from the admission by the end of the 1st week of the disease (p=0.007) and by 13-15th days (p=0.009). Correlation and multivariate linear regression, including baseline stroke symptom severity, showed significant associations (p<0.01 in all tests) between the higher optical density of the fibrin clot (D) on days 6-8 and 13-15 and lower MoCA score, confirming the negative effect of altered hemostatic parameters on cognitive function in IS patients. The increase of optical density of the fibrin clot (D) by 6-8th and 13-15th days is a potential prognostic biomarker for the early development of PSCI.

Medical and social consequences of confusion syndrome that developed in the acute period of ischemic stroke

AIM: To assess the dynamics of cognitive functions in patients in whom the acute period of ischemic stroke was accompanied by the confusion syndrome, in comparison with patients in whom the acute period of stroke was not accompanied by the development of confusion. To assess the impact of clinical features of confusion syndrome on the development of post-stroke cognitive impairment, mortality, and patient care burden.&#x0D; MATERIALS AND METHODS: The study involved 99 patients, 55 of whom developed severe confusion during the acute period of stroke, and 44 patients whose ischemic stroke was not complicated by the development of confusion syndrome. The groups were homogeneous in terms of the main etiological factors: age, degree of pre-stroke cognitive impairment. The study assessed the impact of the development of confusional syndrome on the outcome.&#x0D; RESULTS: Confusion syndrome that develops in the acute period of ischemic stroke significantly increases the risk of developing or worsening existing cognitive impairment, mortality, dependence on care, and the burden on caregivers.&#x0D; CONCLUSION: Being a serious complication, confusion syndrome requires monitoring of qualitative and quantitative indicators of consciousness in the acute period of ischemic stroke, prevention and, if detected, immediate correction of confusion syndrome.

Independent effect of Aβ burden on cognitive impairment in patients with small subcortical infarction

BackgroundThe effect of amyloid-β (Aβ) on cognitive impairment in patients with small subcortical infarction remains controversial, although a growing body of evidence shows a substantial overlap between Alzheimer’s disease (AD) and subcortical ischemic vascular dementia, another form of cerebral small vessel disease (cSVD). Therefore, we investigated the relationships between Aβ positivity and the development of post-stroke cognitive impairment (PSCI) in patients with small subcortical infarction.MethodsWe prospectively recruited 37 patients aged ≥ 50 years, with first-ever small subcortical infarction, who underwent amyloid positron emission tomography, 3 months after stroke at Korea University Guro Hospital. We also enrolled CU participants matched for age and sex with stroke patients for comparison of Aβ positivity. Patients were followed up at 3 and 12 months after the stroke to assess cognitive decline. Logistic and linear mixed-effect regression analyses were performed to identify the effect of Aβ positivity on PSCI development and long-term cognitive trajectories.ResultsAt 3 months after stroke, 12/37 (32.4%) patients developed PSCI, and 11/37 (29.7%) patients had Aβ deposition. Aβ positivity (odds ratio [OR] = 72.2, p = 0.024) was predictive of PSCI development regardless of cSVD burden. Aβ positivity (β = 0.846, p = 0.014) was also associated with poor cognitive trajectory, assessed by the Clinical Dementia Rating-Sum of Box, for 1 year after stroke.ConclusionsOur findings highlight that Aβ positivity is an important predictor for PSCI development and cognitive decline over 1 year. Furthermore, our results provide evidence that anti-AD medications may be a strategy for preventing cognitive decline in patients with small subcortical infarctions.

Possible involvement of inflammasomes on the post-stroke cognitive impairment in a mouse model of embolic cerebral infarct

Post-stroke cognitive impairment (PSCI) of the complications after stroke has been shown to be involved in brain proinflammatory cytokines such as interleukin (IL)-1β (IL-lβ) and IL-18. In the present study, we examined using acetic acid-induced embolic cerebral infarct (ECI) mice whether post-stroke inflammasome activation is involved in the development of PSCI. In behavioral tests, long-term learning and memory assessed using the passive avoidance test were impaired after ECI. On the other hand, the impairment of short-term learning and memory assessed using the Y-maze test was not observed. Furthermore, the phosphorylated α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit glutamate receptor 1 (GluR1) at Ser 831 and Ser 845 protein was found to be significantly decreased in the dorsal hippocampus of ECI mice. In addition, the expression levels of ionized calcium-binding adapter protein 1 (Iba1), glial fibrillary acidic protein (GFAP), apoptosis-associated speck-like protein containing a caspase recruitment domain / target of methylation-induced silencing 1 (ASC/TMS1), Caspase-1, IL-1β, IL-18 and tumor necrosis factor-α (TNF-α) were significantly increased in the dorsal hippocampus of ECI mice. These results indicate that development of PSCI after embolic cerebral infarction is due to a decrease in AMPA receptor subunit GluR1 at Ser831 and Ser845 through the inflammasome activation pathway in the dorsal hippocampus.

Stimulation of Angiotensin II Type 2 Receptor Modulates Pro-Inflammatory Response in Microglia and Macrophages: Therapeutic Implications for the Treatment of Stroke.

Sustained microglial activation contributes to the development of post-stroke cognitive impairment (PSCI). Compound 21 (C21), an angiotensin II type 2 receptor agonist, has shown some neurovascular protection after stroke. This study aimed to investigate the direct anti-inflammatory effects of C21 on macrophages, as well as brain innate immune cells. Murine microglial cell line (C8-B4) and RAW 264.7 macrophages were exposed to lipopolysaccharide (LPS) and co-treated with C21. Pro-inflammatory mediators were assessed via RT-qPCR and ELISA. Cellular reactive oxygen species (ROS) were evaluated via CellROXGreen staining, and nitrate production was assessed using Griess assay. C21 suppressed LPS-induced inflammation and ROS generation in both cells. In microglia, C21 blunted LPS-induced mRNA expression of IL-1β, IL-12b, COX-1, iNOS, and IL-6. A similar pattern was observed in macrophages, where C21 suppressed LPS-induced IL-1β, TNF-α, and CXCL1 expression. These anti-inflammatory effects in microglia and macrophages were associated with increased neuroprotective gene expression, including GDNF and BDNF, in a dose-dependent manner. Our findings suggest a protective effect of C21 against the inflammatory response, in both macrophages and microglia, via suppression of the release of pro-inflammatory cytokines/chemokines and the generation of ROS while stimulating the production of neurotrophic factors.

Risk factors of cognitive impairment post-ischemic stroke

BackgroundStroke is still remarked as one of the major ailments in Indonesia. Cognitive impairment occurs frequently after stroke events and its predictors are needed to identify patients with a high risk of cognitive impairment. However, the researches done in Indonesia still vary in results. This retrospective cohort study evaluated 236 ischemic stroke patients in Bethesda Hospital Yogyakarta from January–November 2020 through medical records. Cognitive impairment was measured by MMSE and CDT, defined as MMSE score le 20 for patients with the educational attainment of 1–6 years; le 24 for the educational attainment of > 6 years and/ or CDT < 4. All data were analyzed with univariate test and Chi-square test, followed by logistic regression.ResultsOf 236 subjects, the frequency of cognitive impairment was 67.4% and the risk factors are age > 80 years old (RR: 1,545; CI 0.136–17.542; p: 0.026), educational attainment ≤ 6 years (RR: 20.016; CI 1.951–222.120; p: 0.012), temporal (RR: 4.238; CI 2.266–7.926; p: 0.007) or multiple site lesion location (RR: 7.522; CI: 3.522–17.532; p: 0.047) and multiple (> 1) lesions (RR: 1,819; CI 0.822–4.022; p: 0.040).ConclusionsThe prevalence of post-stroke cognitive impairment is high, affecting up to 2 out of 3 people in this study. The risk factors of post-stroke cognitive impairment are age > 80 years, educational attainment le 6 years, temporal or multiple site lesion, and > 1 lesion. Strict stroke prevention strategies are needed to halt the development of post-stroke cognitive impairment.

Changes in gene expression and neuroinflammation in the hippocampus of rats with poststroke cognitive impairment.

Poststroke cognitive impairment (PSCI) often occurs during the stroke recovery period and greatly increases the difficulty of rehabilitation. Activation of neuroinflammation and long-term changes in gene expression patterns in the hippocampus could be essential in the development of PSCI. Therefore, this study aimed to identify neuroinflammation and changes in gene expression patterns in the hippocampus in rats with PSCI. Rats underwent transient middle cerebral artery occlusion (tMCAO) or sham surgery. The infarct volume was measured on day 3 after surgery. The Morris water maze (MWM) test was used to assess cognitive function. Microglial activation and white matter (WM) lesions in the hippocampus were evaluated on day 28 after surgery. In addition, we compared differentially expressed genes (DEGs) in the hippocampus between tMCAO group rats and sham group rats by RNA sequencing. Then, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) network analyses were conducted to investigate these DEGs. The results showed that the tMCAO group rats showed extensive infarction and cognitive dysfunction compared with the sham group rats. Microglial activation and WM damage were obvious in the hippocampus of tMCAO group rats. We found 43 DEGs by RNA sequencing: 29 genes with upregulated expression and 14 genes with downregulated expression. The GO analysis indicated that DEGs were mainly involved in cell proliferation and differentiation, cholesterol synthesis, and metabolism. The KEGG pathway analysis suggested that the DEGs were significantly enriched in intestinal immune network for IgA production and steroid biosynthesis. Acta2, Calb2, and Cxcl12 were notable in the PPI analysis. Our results suggest that microglial activation and WM damage are maintained in rats with PSCI. The mechanism may be related to the regulation of steroid biosynthesis, intestinal immunity, and potential key genes such as Acta2, Calb2, and Cxcl12 in the hippocampus.

Is Matrix Metalloproteinase-9 Associated with Post-Stroke Cognitive Impairment or Dementia?

Matrix metalloproteinase-9 (MMP-9) is a significant protease required for synaptic plasticity, learning, and memory. Yet, the role of MMP-9 in the occurrence and development of cognitive decline after ischemic stroke is not fully understood. In this study, we used clinical data experiments to further investigate whether MMP-9 and genetic polymorphism are associated with post-stroke cognitive impairment or dementia (PSCID). A total of 148 patients with PSCID confirmed by the Montreal Cognitive Assessment (MoCA) 3 months after onset (PSCID group) were included in the study. The MMP-9 rs3918242 polymorphisms were analyzed using polymerase chain reaction coupled with restriction fragment length polymorphism, and the serum level of MMP-9 was measured using enzyme-linked immunosorbent assay (ELISA). The same manipulations have been done on 169 ischemic stroke patients without cognitive impairment (NCI group) and 150 normal controls (NC group). The expression level of serum MMP-9 in the PSCID group and NCI group was higher compared to the NC group, and the levels in the PSCID group were higher than that in the NCI group (all p < 0.05). Diabetes mellitus, hyperhomocysteinemia, and increased serum MMP-9 levels were the main risk factors of cognitive impairment after ischemic stroke. The serum level of MMP-9 was negatively correlated with the MoCA score, including visual-spatial executive, naming, attention, language, and delayed recall. Genetic polymorphism showed that TC genotype with MMP-9 rs3918242 and CC genotype were associated with a significantly increased risk of PSCID; moreover, the TC genotype significantly increased the risk of cognitive impairment. In the TCCC genotype of MMP-9 rs3918242, diabetes mellitus and hyperhomocysteinemia were associated with the increased risk of PSCID; also, hyperhomocysteinemia could increase the risk of cognitive impairment. MMP-9 level and MMP-9 rs3918242 polymorphism have an important role in the occurrence and development of post-stroke cognitive impairment or dementia (PSCID).

The involvement of inflammasomes on the learning and memory impairment in a mouse model of embolic stroke

Post-stroke cognitive impairment (PSCI) is one of the major complications after a stroke and affects quality of life. Recently, several studies demonstrated that elevated brain proinflammatory cytokines such as TNF-α, IL-6 and IL-1β can induce cognitive impairment. However, the mechanisms underlying PSCI remain unclear. In the present study, we investigated whether post-stroke inflammasomes are involved in the development of PSCI using acetic acid-induced embolic cerebral infarct mice. Long-term learning and memory assessed by the passive avoidance test was impaired on days 7 and 14 after stroke, whereas short-term learning and memory assessed by Y-maze test showed no changes. Also, the expression of the phosphorylated AMPA receptor subunits GluR1 at serine 831 and serine 845 in the dorsal hippocampus were significantly decreased. Under these conditions, inflammasome-related proteins, including caspase-1, ASC/TMS1, IL-1β, TNF-α and IL-18, were significantly increased in the dorsal hippocampus 14 days after stroke. The present findings suggest that a decrease in phosphorylated GluR1 at ser831 and ser845 via the inflammasome activation pathway in the dorsal hippocampus may be involved in the development of learning and memory impairment after embolic stroke.

Stimulation of angiotensin II receptor 2 preserves cognitive function and is associated with an enhanced cerebral vascular density after stroke

Angiotensin signaling is known to be sexually dimorphic. Although it is a well-studied target for intervention in stroke and cognitive impairment, female studies are rare. With females suffering a disproportionately greater negative impact of stroke and dementia vs. males, effective interventions are of utmost urgency. The aim of the current study was to determine the impact of activation of the angiotensin II type 2 receptor (AT2R) with the agonist compound 21 (C21) on the development of post-stroke cognitive impairment, after experimental ischemic stroke. Ovariectomized (OVX) spontaneously hypertensive rats (SHRs) were subjected to 1 h of middle cerebral artery occlusion (MCAO). At 24 h, rats with a significant neurologic deficit were randomized to receive either saline or C21 (0.03 mg/kg/day) intraperitoneally (IP) for 5 days, then orally (0.12 mg/kg/day) for a total of 6 weeks. Cognitive function, brain structure by MRI and vascular architecture by microCT angiography were measured. C21 preserved cognitive function, specifically spatial memory, and improved vascular density in the ischemic hemisphere at 6 weeks, reflecting both arteriogenesis and angiogenesis. In conclusion, C21 prevented cognitive impairment after stroke, likely through a mechanism involving vascular protection and restoration.

High Neutrophil-Lymphocyte Ratio Predicts Post-stroke Cognitive Impairment in Acute Ischemic Stroke Patients.

Background and Aims: Systemic inflammation is associated with an increased risk of cognitive impairment and dementia, but the associations between them in stroke patients are less clear. We examined the impact of systemic inflammation represented as the neutrophil-lymphocyte ratio (NLR) on the development of post-stroke cognitive impairment (PSCI) and domain-specific cognitive outcomes 3-month after ischemic stroke.Methods: Using prospective stroke registry data, we consecutively enrolled 345 participants with ischemic stroke whose cognitive functions were evaluated 3-month after stroke. Their cognition was assessed with the Korean version of the Vascular Cognitive Impairment Harmonization Standards and the Korean-Mini Mental Status Examination. PSCI was defined as a z-score of < -2 standard deviations for age, sex, and education adjusted means in at least one cognitive domain. The participants were categorized into five groups according to the quintiles of NLR (lowest NLR, Q1). The cross-sectional association between NLR and PSCI was assessed using multiple logistic regression, adjusting for age, sex, education, vascular risk factors, and stroke type.Results: A total of 345 patients were enrolled. The mean age was 63.0 years and the median NIHSS score and NLR were 2 [1–4] and 2.26 [1.65–2.91], respectively. PSCI was identified in 71 (20.6%) patients. NLR was a significant predictor for PSCI both as a continuous variable (adjusted OR, 1.14; 95% CI, 1.00–1.31) and as a categorical variable (Q5, adjusted OR, 3.26; 95% CI, 1.17–9.08). Patients in the Q5 group (NLR ≥ 3.80) showed significantly worse performance in global cognition and in visuospatial and memory domains.Conclusions: NLR in the acute stage of ischemic stroke was independently associated with PSCI at 3 months after stroke, and high NLR was specifically associated with cognitive dysfunction in the memory and visuospatial domains. Thus, systemic inflammation may be a modifiable risk factor that may influence cognitive outcomes after stroke.

Association between Geriatric Nutritional Risk Index and Post-Stroke Cognitive Outcomes.

Background: It is not yet clear whether nutritional status is associated with post-stroke cognitive impairment (PSCI). We examined the geriatric nutritional risk index (GNRI) on the domain-specific cognitive outcomes 3 months after a stroke. Methods: A total of 344 patients with acute ischemic stroke were included for the analysis. The GNRI was calculated as 1.489 × serum albumin (g/L) + 41.7 × admission weight (kg)/ideal body weight (kg) and was dichotomized according to the prespecified cut-off points for no risk and any risks. The primary outcome was PSCI, defined as having adjusted z-scores of less than −2 standard deviations in at least one cognitive domain: executive/activation, memory, visuospatial and language. Multiple logistic regression and linear regression analyses were performed to investigate the association between the GNRI and cognitive outcomes. Results: Seventy (20.3%) patients developed PSCI 3 months after a stroke. The mean GNRI was 106.1 ± 8.6, and 59 (17.2%) patients had low (<98) GNRI scores. A low GNRI was independently associated with the PSCI after adjusting for age, sex, education, initial stroke severity, stroke mechanism and left hemispheric lesion (odds ratio, 2.04; 95% confidence interval, 1.00–4.14). The GNRI scores were also significantly associated with the z-scores from the mini-mental status examination and the frontal domain (β = 0.04, p-value = 0.03; β = 0.03, p-value = 0.03, respectively). Conclusions: A low GNRI was independently associated with the development of PSCI at 3 months after an ischemic stroke. The GNRI scores were specifically associated with the z-scores of the global cognition and frontal domain cognitive outcomes.

Effects of Glycemic Gap on Post-Stroke Cognitive Impairment in Acute Ischemic Stroke Patients.

Background: Post-stroke hyperglycemia is a frequent finding in acute ischemic stroke patients and is associated with poor functional and cognitive outcomes. However, it is unclear as to whether the glycemic gap between the admission glucose and HbA1c-derived estimated average glucose (eAG) is associated with post-stroke cognitive impairment (PSCI). Methods: We enrolled acute ischemic stroke patients whose cognitive functions were evaluated three months after a stroke using the Korean version of the vascular cognitive impairment harmonization standards neuropsychological protocol (K-VCIHS-NP). The development of PSCI was defined as having z-scores of less than −2 standard deviations in at least one cognitive domain. The participants were categorized into three groups according to the glycemic gap status: non-elevated (initial glucose − eAG ≤ 0 mg/dL), mildly elevated (0 mg/dL < initial glucose − eAG < 50 mg/dL), and severely elevated (50 mg/dL ≤ initial glucose − eAG). Results: A total of 301 patients were enrolled. The mean age was 63.1 years, and the median National Institute of Health Stroke Scale (NIHSS) score was two (IQR: 1–4). In total, 65 patients (21.6%) developed PSCI. In multiple logistic regression analyses, the severely elevated glycemic gap was a significant predictor for PSCI after adjusting for age, sex, education level, initial stroke severity, Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification, and left hemispheric lesion (aOR: 3.65, p-value = 0.001). Patients in the severely elevated glycemic gap group showed significantly worse performance in the frontal and memory domains. Conclusions: In conclusion, our study demonstrated that an elevated glycemic gap was significantly associated with PSCI three months after a stroke, with preferential involvement of frontal and memory domain dysfunctions.

Raised high-sensitivity C-reactive protein and cognitive impairment among African stroke survivors within the first three months following stroke

Stroke remains a major factor causing death and disabilities such as cognitive impairment. There is conflicting evidence on the role and dynamics of high sensitivity C-reactive protein (hsCRP), an acute phase pro-inflammatory protein, in post-stroke cognitive impairment. This study evaluated cognitive impairment and examined its relationship with serum hsCRP in the first three months following stroke. Cognition was assessed using Montreal Cognitive Assessment test, while serum hsCRP concentrations were assessed using enzyme link immunosorbent assay kit. Data were processed using SPSS Statistics version 20.0. Sixty subjects, comprising of 30 stroke patients and 30 healthy subjects, matched for age, sex and level of education were studied. Cognitive impairment was observed among the stroke patients, while the healthy subjects showed normal cognitive function; and the difference in the cognitive scores of the two groups was highly significant (P = 0.001). There was higher prevalence of cognitive impairment among the stroke survivors compared to the non-stroke subjects. Serum hsCRP was significantly higher among the stroke survivors compared to the healthy subjects (P = 0.001). The high hsCRP level correlates well with duration of stroke and working memory domain of cognition. The data revealed a high prevalence of cognitive impairment and concurrent high serum hsCRP levels among stroke survivors in the first three months following stroke, in contrast with normal subjects. The high hsCRP level correlates with duration of stroke and working memory domain of cognition. The data suggest a role for serum hsCRP and inflammation in the development of post-stroke cognitive impairment.

Post-stroke Neurogenesis: Friend or Foe?

The substantial clinical burden and disability after stroke injury urges the need to explore therapeutic solutions. Recent compelling evidence supports that neurogenesis persists in the adult mammalian brain and is amenable to regulation in both physiological and pathological situations. Its ability to generate new neurons implies a potential to contribute to recovery after brain injury. However, post-stroke neurogenic response may have different functional consequences. On the one hand, the capacity of newborn neurons to replenish the damaged tissue may be limited. In addition, aberrant forms of neurogenesis have been identified in several insult settings. All these data suggest that adult neurogenesis is at a crossroads between the physiological and the pathological regulation of the neurological function in the injured central nervous system (CNS). Given the complexity of the CNS together with its interaction with the periphery, we ultimately lack in-depth understanding of the key cell types, cell–cell interactions, and molecular pathways involved in the neurogenic response after brain damage and their positive or otherwise deleterious impact. Here we will review the evidence on the stroke-induced neurogenic response and on its potential repercussions on functional outcome. First, we will briefly describe subventricular zone (SVZ) neurogenesis after stroke beside the main evidence supporting its positive role on functional restoration after stroke. Then, we will focus on hippocampal subgranular zone (SGZ) neurogenesis due to the relevance of hippocampus in cognitive functions; we will outline compelling evidence that supports that, after stroke, SGZ neurogenesis may adopt a maladaptive plasticity response further contributing to the development of post-stroke cognitive impairment and dementia. Finally, we will discuss the therapeutic potential of specific steps in the neurogenic cascade that might ameliorate brain malfunctioning and the development of post-stroke cognitive impairment in the chronic phase.

The role of the inflammatory process in the development of post-stroke cognitive impairment

Post-stroke cognitive impairment (PCI) is a common complication of stroke. PCI in most cases is associated with an increased risk of progression to dementia, with a progression rate of 8-15% per year. When post-stroke cognitive impairment reaches dementia, patients lose independence, professional and social maladjustment occurs, which, in turn, significantly worsen the quality of life and reduce the rehabilitation potential. According to many experimental and clinical studies, the inflammatory process has an important role in the development of PCI. Several previous studies have looked at the association between inflammatory markers and PCI, with some results conflicting with specific biomarkers. Based on the results of studies, inflammatory markers such as IL-8, IL-12 and ESR were closely associated with PCI, high ESR values are associated with worse cognitive impairment, especially memory. The relationship was not confirmed between the markers IFN-gamma, TNF-α and PCI. With regard to IL-1β, IL-6, IL-10, CRP, the results obtained are not unambiguous. Thus, the inflammatory process in the development of PCI has an important role, including a series of complex reactions, the combined effect of which induces neuronal damage and loss of synapses that ultimately leads to cognitive impairment.

Neuropsychological screening in the acute phase of cerebrovascular diseases.

Cognitive impairment is a common and disabling consequence of stroke. Its prevalence, the best way to screen for it in the acute setting, and its relation with premorbid status have not been thoroughly clarified. Ischemic and hemorrhagic stroke patients admitted to our stroke unit underwent a baseline assessment that included a clinical and neuroimaging assessment, two cognitive tests (clock-drawing test, CDT; Montreal Cognitive Assessment-Basic, MoCA-B) and measures of premorbid function (including the Clinical Dementia Rating Scale). A follow-up examination was repeated 3-4months after the acute event. Two hundred and twenty-three patients (52.5% women, mean age±SD 75.8years±12.3) were evaluated. Prestroke cognitive impairment was present in 91 patients (40.8%). At follow-up, the prevalence of cognitive impairment was 49%, while its incidence among patients who did not have any prestroke cognitive impairment was 38.8%. Of the originally admitted 223 patients (71 were lost to follow-up), only 60 (26.9%) were still cognitively intact at follow-up. On regression analysis, age and baseline CDT were associated with worsening of cognitive status at follow-up. In patients without cognitive impairment at baseline, a cutoff of 23 for MoCA-B and of 8.7 for CDT scores predicted the diagnosis of post-stroke cognitive impairment with sufficient accuracy. Prestroke and post-stroke cognitive impairment affect a large proportion of patients with stroke. Our findings suggest that a neuropsychological screening during the acute phase might be predictive of the development of post-stroke cognitive impairment.

Microglia knockdown reduces inflammation and preserves cognition in diabetic animals after experimental stroke

IntroductionUnfortunately, over 40% of stroke victims have pre-existing diabetes which not only increases their risk of stroke up to 2–6 fold, but also worsens both functional recovery and the severity of cognitive impairment. Our lab has recently linked the chronic inflammation in diabetes to poor functional outcomes and exacerbated cognitive impairment, also known as post-stroke cognitive impairment (PSCI). Although we have shown that the development of PSCI in diabetes is associated with the upregulation and the activation of pro-inflammatory microglia, we have not established direct causation between the two. To this end, we evaluated the role of microglia in the development of PSCI.MethodsAt 13 weeks of age, diabetic animals received bilateral intracerebroventricular (ICV) injections of short hairpin RNA (shRNA) lentiviral particles targeting the colony stimulating factor 1 receptor (CSF1R). After 14 days, animals were subjected to 60 min middle cerebral artery occlusion (MCAO) or sham surgery. Adhesive removal task (ART), novel object recognition (NOR), and 2-trial Y-maze were utilized to evaluate sensorimotor and cognitive function. Tissue from freshly harvested brains was analyzed by flow cytometry and immunohistochemistry.ResultsCSF1R silencing resulted in a 94% knockdown of residential microglia to relieve inflammation and improve myelination of white matter in the brain. This prevented cognitive decline in diabetic animals.ConclusionMicroglial activation after stroke in diabetes may be causally related to the development of delayed neurodegeneration and PSCI.

MiR-217-regulated MEF2D-HDAC5/ND6 signaling pathway participates in the oxidative stress and inflammatory response after cerebral ischemia

Multiple factors are known to contribute to the pathogenesis of cerebral ischemic injury, including microRNAs (miRNAs). However, the precise mechanism of miRNAs involvement in cerebral ischemia remains largely unclear. In the current study, we found that miR-217 was significantly upregulated in ischemic stroke models, and the upregulation of miR-217 was associated with the development of post-stroke cognitive impairment. Further investigation revealed that myocyte enhancer factor 2D (MEF2D) was the direct target of miR-217. In vitro experiments showed that miR-217 promoted aggregation of histone deacetylase 5 (HDAC5) in cell nuclei by targeting MEF2D, which led to decreased expression of interleukin (IL)-10. In addition, miR-217 inhibited the expression of NADH dehydrogenase subunit 6 (ND6) in a MEF2D-dependent manner. Overexpression of MEF2D can reverse oxygen-glucose deprivation (OGD)-induced downregulation of ND6 and OGD-mediated neuronal apoptosis, and also reduce the elevated generation of reactive oxygen species (ROS) induced by OGD. Additionally, we found that in vivo administration of MEF2D overexpression plasmids increased IL-10 production and ameliorated cognitive impairment after cerebral ischemia. Taken together, these findings reveal a novel pathogenetic mechganism of cerebral ischemia-related brain injury involving the miR-217/MEF2D/HDAC5 axis and the miR-217/MEF2D/ND6 axis.