Impaired Glymphatic Function and Pulsation Alterations in a Mouse Model of Vascular Cognitive Impairment

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Cortical cerebral microinfarcts on 7T MRI: Risk factors, neuroimaging correlates and cognitive functioning – The Medea-7T study

We determined the occurrence and association of cortical cerebral microinfarcts (CMIs) at 7 T MRI with risk factors, neuroimaging markers of small and large vessel disease, and cognitive functioning. Within the Medea-7T study, a diverse cohort of older persons with normal cognition, patients with vascular disease, and memory clinic patients, we included 386 participants (68 ± 9 years) with available 7 T and 1.5 T/3T brain MRI, and risk factor and neuropsychological data. CMIs were found in 10% of participants and were associated with older age (RR = 1.79 per +10 years, 95%CI 1.28–2.50), history of stroke or TIA (RR = 4.03, 95%CI 2.18–7.43), cortical infarcts (RR = 5.28, 95%CI 2.91–9.55), lacunes (RR = 5.66, 95%CI 2.85–11.27), cerebellar infarcts (RR = 2.73, 95%CI 1.27–5.84) and decreased cerebral blood flow (RR = 1.35 per −100 ml/min, 95%CI 1.00–1.83), after adjustment for age and sex. Furthermore, participants with >2 CMIs had 0.5 SD (95%CI 0.05–0.91) lower global cognitive performance, compared to participants without CMIs. Our results indicate that CMIs on 7 T MRI are observed in vascular and memory clinic patients with similar frequency, and are associated with older age, history of stroke or TIA, other brain infarcts, and poorer global cognitive functioning.

Experimental Rodent Models of Vascular Dementia: A Systematic Review

: Vascular dementia (VaD) occurs due to cerebrovascular insufficiency, which leads to decreased blood circulation to the brain, thereby resulting in mental disabilities. The main causes of vascular cognitive impairment (VCI) are severe hypoperfusion, stroke, hypertension, large vessel disease (cortical), small vessel disease (subcortical VaD), strategic infarct, hemorrhage (microbleed), cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and cerebral amyloid angiopathy (CAA),which leads to decreased cerebrovascular perfusion. Many metabolic disorders such as diabetes mellitus (DM), dyslipidemia, and hyperhomocysteinemia are also related to VaD. The rodent experimental models provide a better prospective for the investigation of the molecular mechanism of new drugs. A plethora of experimental models are available that mimic the pathological conditions and lead to VaD. This review article updates the current knowledge on the basis of VaD, risk factors, pathophysiology, mechanism, advantages, limitations, and the modification of various available rodent experimental models.

Ischemic stroke in human immunodeficiency virus-positive patients: An increasingly age-related comorbidity?

Introduction The global incidence of ischemic stroke among patients with human immunodeficiency virus is increasing. The aim of this controlled case analysis was to study patient characteristics, stroke etiologies, and risk factors in human immunodeficiency virus-positive patients in a medical system with easy access to antiretroviral therapies. Patients and methods We conducted a retrospective, observational study of human immunodeficiency virus-positive patients treated in our stroke unit and outpatient clinic in Germany between 2012 and 2018. A control group of all patients treated for acute ischemic stroke in 2018 was used to elicit possible differences in stroke localization, etiology, and distribution of risk factors. Results Out of 3615 patients with an acute ischemic stroke, 24 (0.7%) were newly or previously diagnosed as human immunodeficiency virus-positive. Strokes in this cohort were caused by large-vessel disease (37.5%), small-vessel disease (20.8%), cryptogenic-embolism (20.8%), vasculitis (16.7%), and cardio-embolism (4.2%). Large-vessel disease-related strokes were more often located in the posterior circulation (77.8%). Compared to the control group, cardio-embolic strokes were less and vasculitis and large-vessel disease more frequent. Human immunodeficiency virus-positive patients were younger at stroke onset (53.7 ± 12.8 vs. 70.2 ± 14.6 years, p = 0.05). Discussion Although the prevalence of human immunodeficiency virus-infection among patients treated for acute ischemic strokes appears low, this collective merits special attention due to a high burden of potentially modifiable risk factors and vasculitis. Conclusion Compared to previous studies, age at stroke onset was one of the highest, supporting the hypothesis that as antiretroviral therapy increases the life expectancy of people living with HIV/AIDS, they will be increasingly affected by cardiovascular disease. Human immunodeficiency virus-related cerebral vasculitis was associated with high mortality (75%).

Aspirin Resistance Affects Medium-Term Recurrent Vascular Events after Cerebrovascular Incidents: A Three-Year Follow-up Study

Background: The aim of this prospective, a three-year follow-up study, was to establish the role of high on-treatment platelet reactivity (HTPR) in predicting the recurrence of vascular events in patients after cerebrovascular incidents, particularly in the aspect of stroke etiology. Methods: The study included 101 subjects with non-embolic cerebral ischemia (69 patients with ischemic stroke and 32 patients with transient ischemic attack) treated with 150 mg of acetylsalicylic acid (aspirin) a day. The platelet reactivity was tested in the first 24 h after the onset of cerebral ischemia by impedance aggregometry. Recurrent vascular events, including recurrent ischemic stroke, transient ischemic attack, myocardial infarction, systemic embolism, or sudden death of vascular reason, were assessed 36 months after the onset of cerebral ischemia. Results: Recurrent vascular events occurred between 3 and 9 months after onset in 8.5% of all subjects; in the HTPR subgroup, recurrent vascular events occurred in 17.9%; in the normal on-treatment platelet reactivity (NTPR) subgroup, they occurred in 4.6%. We did not notice early or long-term recurrent events. Aspirin resistant subjects had a significantly higher risk of recurrent vascular events than did aspirin sensitive subjects (Odds ratio (OR) = 4.57, 95% Confidence interval (CI) 1.00–20.64; p = 0.0486). Cox proportional hazard models showed that large-vessel disease (Hazard ratio (HR) 12.04, 95% CI 2.43–59.72; p = 0.0023) and high on-treatment platelet reactivity (HR 4.28, 95% CI 1.02–17.93; p = 0.0465) were independent predictors of recurrent vascular events. Conclusion: Aspirin resistance in the acute phase of cerebral ischemia was associated with a higher risk of recurrent medium-term vascular events, coexisting with large-vessel etiology of stroke. Platelet function-guided personalized antiplatelet treatment should be considered for patients with recurrent strokes, especially when due to large-vessel disease.

Pre-micro RNA polymorphism detection in small versus large vessel disease in stroke patients

Article Outline Abstract Introduction Patients and methods Procedure Statistical analysis Results Discussion Conclusion References Background Cerebrovascular accidents are the second leading cause of death and the third leading cause of disability worldwide. The methods currently available for diagnosis and prognosis of cerebral ischaemia still require further improvements. Micro-RNAs (small non-coding RNAs) have been recently reported as useful biomarkers in diseases such as cancer and diabetes. Further research concerned with microRNA (miRNA) profiling from peripheral blood to detect and identify characteristic patterns in ischaemic stroke is crucial. Aim of the work This study aims to investigate the association between three potentially functional polymorphisms in pre-miRNAs and stroke subtypes (small vessel disease and large vessel disease) in a sample of Egyptian stroke patients. Patients and Methods This is a cross sectional study conducted in Ain Shams University Hospitals in which 81 patients presenting with cerebrovascular stroke fulfilling criteria of small vessel disease (SVD) or large vessel disease (LVD) according to TOAST [2] classification in the period from March 2018 to August 2018 were included. Blood samples were withdrawn for DNA extraction to investigate the association between three potentially functional polymorphisms (rs2910164, rs11614913, and rs3746444) in pre-miRNAs (hsamiR-146a, hsa-miR-196a2, and hsa-miR-499, respectively). Results Smoking, hypertension and diabetes were significant value in both stroke subtypes. Meanwhile, age and gender showed no significance between both stroke subtypes. Conclusion Ischemic stroke has polygenic basis, but identification of stroke susceptibility gene and quantification of associated risks has been hindered by conflicting results from different studies.