The relationship between stroke topography (ie, the regions damaged by the infarct) and functional outcome can aid clinicians in their decision-making at the acute and later stages. However, the side ...(left or right) of the stroke may also influence the identification of clinically relevant regions. We sought to determine which brain regions are associated with good functional outcome at 3 months in patients with left-sided and right-sided stroke treated by endovascular treatment using the diffusion-weighted imaging-Alberta Stroke Program Early CT Score (DWI-ASPECTS).
Patients with ischaemic stroke (n = 405) were included from the ASTER trial and Pitié-Salpêtrière registry. Blinded readers rated ASPECTS on day 1 DWI. Stepwise logistic regression analyses were performed to identify the regions related to 3-month outcome in left (n = 190) and right (n = 215) sided strokes with the modified Rankin scale (0-2) as a binary independent variable and with the 10 regions-of-interest of the DWI-ASPECTS as independent variables.
Median National Institute of Health Stroke Scale (NIHSS) at baseline was 17 (IQR: 12-20), median age was 70 years (IQR: 58-80) and median day-one NIHSS 9 (IQR: 4-18). Not all brain regions have the same weight in predicting good outcome at 3 months; moreover, these regions depend on the affected hemisphere. In left-sided strokes, the multivariate analysis revealed that preservation of the caudate nucleus, the internal capsule and the cortical M5 region were independent predictors of good outcome. In right-sided strokes, the cortical M3 and M6 regions were found to be clinically relevant.
Cortical non-motors areas related to outcome differed between left-sided and right-sided strokes. This difference might reflect the specialisation of the dominant and non-dominant hemispheres for language and attention, respectively. These results may influence decision-making at the acute and later stages.
NCT02523261.
Cerebral infarction is a commonly observed radiological finding in the absence of corresponding, clinical symptomatology, the so-called silent brain infarction (SBI). SBIs are a relatively new ...consideration as improved imaging has facilitated recognition of their occurrence. However, the true incidence, prevalence and risk factors associated with SBI remain controversial.
Systematic searches of the Medline and EMBASE databases from 1946 to December 2013 were performed to identify original studies of population-based adult cohorts derived from community surveys and routine health screening that reported the incidence and prevalence of magnetic resonance imaging (MRI)-determined SBI.
The prevalence of SBI ranges from 5% to 62% with most studies reported in the 10% to 20% range. Longitudinal studies suggest an annual incidence of between 2% and 4%. A strong association was seen to exist between epidemiological estimates of SBI and age of the population assessed. Hypertension, carotid stenosis, chronic kidney disease and metabolic syndrome all showed a strong association with SBI. Heart failure, coronary artery disease, hyperhomocysteinemia and obstructive sleep apnea are also likely of significance. However, any association between SBI and gender, ethnicity, tobacco or alcohol consumption, obesity, dyslipidemia, atrial fibrillation and diabetes mellitus remains unclear.
SBI is a remarkably common phenomenon and endemic among older people. This systematic review supports the association of a number of traditional vascular risk factors, but also highlights disparities between clinically apparent and silent strokes, potentially suggesting important differences in pathophysiology and warranting further investigation.
MicroRNAs play a role in atherosclerosis-related diseases, such as cerebrovascular or cardiovascular disease. However, the effect of miR-146a, miR-149, miR-196a2, and miR-499 polymorphisms on stroke ...and silent brain infarction (SBI) susceptibility has not been reported.
Using polymerase chain reaction-amplified DNA, microRNA polymorphisms were analyzed in 678 patients with ischemic stroke, 373 patients with SBI, and 553 control subjects. The miR-146aC>G polymorphism and miR-146aG/-149T/-196a2C/-499G allele combination was significantly associated with ischemic stroke prevalence. For SBI prevalence, there were no statistically significant genetic markers. However, some allele combinations were associated with increased SBI incidence (C-T-C-G and G-T-T-A of miR-146a/-149/-196a2/-499). In subgroup analyses, miR-146aC>G increased stroke risk in female, normotensive, and nondiabetic groups. There were significant combined effects between microRNA polymorphisms and homocysteine/folate levels on ischemic stroke and SBI prevalence.
The miR-146aG allele and miR-146aG/-149T/-196a2C/-499G allele combination were associated with ischemic stroke pathogenesis. The combined effects between microRNA polymorphisms and homocysteine/folate levels may contribute to stroke and SBI prevalence.
Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP ) proteinopathy has recently been described in ageing and in association with cognitive impairment, ...especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects. We tested the hypotheses that TDP-43 with Alzheimer's disease pathology is a common mixed pathology; is related to increased likelihood of expressing clinical Alzheimer's-type dementia; and that TDP-43 pathologic stage is an important determinant of clinical Alzheimer's-type dementia. Data came from 946 older adults with ( n = 398) and without dementia ( n = 548) from the Rush Memory and Aging Project and Religious Orders Study. TDP-43 proteinopathy (cytoplasmic inclusions) was present in 496 (52%) subjects, and the pattern of deposition was classified as stage 0 (none; 48%), stage 1 (amygdala; 18%), stage 2 (extension to hippocampus/entorhinal; 21%), or stage 3 (extension to neocortex; 14%). TDP-43 pathology combined with a pathologic diagnosis of Alzheimer's disease was a common mixed pathology (37% of all participants), and the proportion of subjects with clinical Alzheimer's-type dementia formerly labelled 'pure pathologic diagnosis of Alzheimer's disease' was halved when TDP-43 was considered. In logistic regression models adjusted for age, sex, and education, TDP-43 pathology was associated with clinical Alzheimer's-type dementia (odds ratio = 1.51, 95% confidence interval = 1.11, 2.05) independent of pathological Alzheimer's disease (odds ratio = 4.30, 95% confidence interval = 3.08, 6.01) or other pathologies (infarcts, arteriolosclerosis, Lewy bodies, and hippocampal sclerosis). Mixed Alzheimer's disease and TDP-43 pathologies were associated with higher odds of clinical Alzheimer's-type dementia (odds ratio = 6.73, 95% confidence interval = 4.18, 10.85) than pathologic Alzheimer's disease alone (odds ratio = 4.62, 95% confidence interval = 2.84, 7.52). In models examining TDP-43 stage, a dose-response relationship with clinical Alzheimer's-type dementia was observed, and a significant association was observed starting at stage 2, extension beyond the amygdala. In this large sample from almost 1000 community participants, we observed that TDP-43 proteinopathy was very common, frequently mixed with pathological Alzheimer's disease, and associated with a higher likelihood of the clinical expression of clinical Alzheimer's-type dementia but only when extended beyond the amygdala.
With advances in brain imaging and completion of randomized clinical trials (RCTs) for primary and secondary stroke prevention, the natural history of central nervous system (CNS) complications in ...sickle cell disease (SCD) is evolving. In order of current prevalence, the primary CNS complications include silent cerebral infarcts (39% by 18 years), headache (both acute and chronic: 36% in children with sickle cell anemia SCA), ischemic stroke (as low as 1% in children with SCA with effective screening and prophylaxis, but ∼11% in children with SCA without screening), and hemorrhagic stroke in children and adults with SCA (3% and 10%, respectively). In high-income countries, RCTs (Stroke Prevention in Sickle Cell Anemia STOP, STOP II) have demonstrated that regular blood transfusion therapy (typically monthly) achieves primary stroke prevention in children with SCA and high transcranial Doppler (TCD) velocities; after at least a year, hydroxycarbamide may be substituted (TCD With Transfusions Changing to Hydroxyurea TWiTCH). Also in high-income countries, RCTs have demonstrated that regular blood transfusion is the optimal current therapy for secondary prevention of infarcts for children with SCA and strokes (Stroke With Transfusions Changing to Hydroxyurea SWiTCH) or silent cerebral infarcts (Silent Infarct Transfusion SIT Trial). For adults with SCD, CNS complications continue to be a major cause of morbidity and mortality, with no evidence-based strategy for prevention.
Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been ...reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment.
Silent brain infarction (SBI) on magnetic resonance imaging has been proposed as a subclinical risk marker for future symptomatic stroke. We performed a systematic review and meta-analysis to ...summarize the association between magnetic resonance imaging-defined SBI and future stroke risk.
We searched the medical literature to identify cohort studies involving adults with SBI detected by magnetic resonance imaging who were subsequently followed up for incident clinically defined stroke. Study data and quality assessment were recorded in duplicate with disagreements in data extraction resolved by a third reader. Strength association between magnetic resonance imaging-detected SBI and future symptomatic stroke was measured by an hazard ratio.
The meta-analysis included 13 studies (14 764 subjects) with a mean follow-up ranging from 25.7 to 174 months. SBI predicted the occurrence of stroke with a random effects crude relative risk of 2.94 (95% confidence interval, 2.24-3.86, P<0.001; Q=39.65, P<0.001). In the 8 studies of 10 427 subjects providing hazard ratio adjusted for cardiovascular risk factors, SBI was an independent predictor of incident stroke (hazard ratio, 2.08 95% confidence interval, 1.69-2.56; P<0.001; Q=8.99; P=0.25). In a subgroup analysis pooling 9483 stroke-free individuals from large population-based studies, SBI was present in ≈18% of participants and remained a strong predictor of future stroke (hazard ratio, 2.06 95% confidence interval, 1.64-2.59; P<0.01).
SBI is present in ≈1 in 5 stroke-free older adults and is associated with a 2-fold increased risk of future stroke. Future studies of in-depth stroke risk evaluations and intensive prevention measures are warranted in patients with clinically unrecognized radiologically evident brain infarctions.
Stroke is one of the most common diseases and a leading cause of death and disability. Cessation of cerebral blood flow (CBF) leads to cell death in the infarct core, but tissue surrounding the core ...has the potential to recover if local reductions in CBF are restored. In these areas, detrimental peri-infarct depolarizations (PIDs) contribute to secondary infarct growth and negatively affect stroke outcome. However, the cellular pathways underlying PIDs have remained unclear. Here, we have used in vivo multiphoton microscopy, laser speckle imaging of CBF, and electrophysiological recordings in a mouse model of focal ischemia to demonstrate that PIDs are associated with a strong increase of intracellular calcium in astrocytes and neurons. We found that astroglial calcium elevations during PIDs are mediated by inositol triphosphate receptor type 2-dependent (IP3R2-dependent) release from internal stores. Importantly, Ip3r2-deficient mice displayed a reduction of PID frequency and overall PID burden and showed increased neuronal survival after stroke. These effects were not related to local CBF changes in response to PIDs. However, we showed that the release and extracellular accumulation of glutamate during PIDs is strongly curtailed in Ip3r2-deficient mice, resulting in ameliorated calcium overload in neurons and astrocytes. Together, these data implicate astroglial calcium pathways as potential targets for stroke therapy.
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