Executive dysfunction and blockage of brain microvessels in a rat model of vascular cognitive impairment.
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ABSTRACT:
SUBMITTER: Langdon KD
PROVIDER: S-EPMC6168916 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The identification of biomarkers of vascular cognitive impairment is urgent for its early diagnosis. The aim of this study was to detect and monitor changes in brain structure and connectivity, and to correlate them with the decline in executive function. We examined the feasibility of early diagnostic magnetic resonance imaging (MRI) to predict cognitive impairment before onset in an animal model of chronic hypertension: Spontaneously Hypertensive Rats. Cognitive performance was tested in an operant conditioning paradigm that evaluated learning, memory, and behavioral flexibility skills. Behavioral tests were coupled with longitudinal diffusion weighted imaging acquired with 126 diffusion gradient directions and 0.3 mm(3) isometric resolution at 10, 14, 18, 22, 26, and 40 weeks after birth. Diffusion weighted imaging was analyzed in two different ways, by regional characterization of diffusion tensor imaging (DTI) indices, and by assessing changes in structural brain network organization based on Q-Ball tractography. Already at the first evaluated times, DTI scalar maps revealed significant differences in many regions, suggesting loss of integrity in white and gray matter of spontaneously hypertensive rats when compared to normotensive control rats. In addition, graph theory analysis of the structural brain network demonstrated a significant decrease of hierarchical modularity, global and local efficacy, with predictive value as shown by regional three-fold cross validation study. Moreover, these decreases were significantly correlated with the behavioral performance deficits observed at subsequent time points, suggesting that the diffusion weighted imaging and connectivity studies can unravel neuroimaging alterations even overt signs of cognitive impairment become apparent.
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Project description:Objective:Currently, most models of vascular cognitive impairment are established by occluding the carotid arteries uni- or bilaterally to reduce the cerebral blood flow mimicking chronic cerebral hypoxia. Due to the sudden blood flow interruption, a gradual narrowing of the carotid artery cannot be completely imitated. This paper aims to establish a bilateral carotid stenosis model with mild cognitive dysfunction and mild white matter changes to simulate patients with vascular predementia. Methods:Aged Wistar rats (18 months old) underwent either bilateral common carotid artery stenosis (BCAS) or occlusion (BCAO) surgery or a sham operation (control group). The cerebral blood flow in the frontal cortex was measured using Doppler flowmetry. Thirty days after surgery, cognitive function impairments were determined with the Morris water maze; cerebral magnetic resonance imaging was performed to detect changes in fractional anisotropy to assess white matter injuries, and histological studies were performed. Results:The aged rats in the BCAS group showed a more gradual cerebral blood flow reduction and a lower mortality rate (11%) compared to rats in the BCAO group. The water maze test revealed a more marginal impairment affecting spatial learning and memory in rats with BCAS than in rats with BCAO. Diffusion tensor imaging detected white matter injuries in the hippocampus and cerebral cortex of BCAS rats. Particularly, a small portion of nerve fibers of the lateral somatosensory cortex was significantly different between rats of the BCAO and BCAS groups. In the BCAS group, the microscopic structure of the hippocampal CA1 region changed slightly after 30 days and sustained a slight mitochondrial crista crack. Fluorescence staining indicated that the number of GFAP-positive cells was increased in rat brains of the BCAS group, and this phenomenon was even more pronounced in the BCAO group. The hnRNPA2/B1 and GABAAR-?1 expression levels were significantly decreased in the hippocampus of rats with BCAS compared to those of controls. Conclusion:Severe bilateral carotid stenosis induced mild cognitive dysfunction and slight structural changes in the brains of aged rats. Thus, a chronic cerebral hypoperfusion model was successfully established.
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Project description:Among mild cognitive impairment (MCI) patients, those with memory impairment (amnestic MCI, aMCI) are at a high risk of dementia. However, the precise cognitive domain, beside memory, that predicts dementia conversion is unclear. Therefore, we investigated the cognitive domain that predicts dementia conversion in a longitudinal aMCI cohort. We collected data of 482 aMCI patients who underwent neuropsychological tests and magnetic resonance imaging at baseline and were followed for at least 1 year. The patients were categorized according to number (1-4) and type of impaired cognitive domains (memory, language, visuospatial, and frontal-executive function). We evaluated dementia conversion risk in each group when compared to single-domain aMCI after controlling for age, education, diabetes and dyslipidemia. Baseline cortical thickness of each group was compared to that of 410 cognitively normal controls (NCs) after controlling for age, intracranial volume, diabetes and dyslipidemia. Compared to single-domain aMCI, aMCI patients with frontal-executive dysfunction at baseline had a higher risk of dementia conversion than aMCI patients with visuospatial or language dysfunction. Compared to NCs, aMCI patients with frontal-executive dysfunction had overall cortical thinning including frontal areas. Our findings suggest that aMCI patients with frontal-executive dysfunction have poor prognosis and,thus, should be considered for intervention therapy with a higher priority among aMCI patients.
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Project description:Vascular dementia (VD) is the most common form of dementia in elderly people. However, little is understood about the role of microRNAs (miRNAs) involved in cognitive impairment in early VD. Here, a VD model induced by chronic cerebral ischemia and fetal bovine serum (FBS)-free cell model that detects synapse formation was established to investigate the function of miRNAs in early VD. The microarray analysis and real-time reverse transcription polymerase chain reaction (RT-PCR) showed that miR-210-5p increased significantly in the hippocampus of rats with 4 weeks of ischemia. The VD model rats also displayed significant cognitive deficits and synaptic loss. The overexpression of miR-210-5p decreased the synaptic number in primary hippocampal neurons, whereas specific suppression of miR-210-5p resulted in the formation of more synapses. Additionally, intracerebroventricular (ICV) injection of miR-210-5p agomir to VD rats aggravated phenotypes of cognitive impairment and synaptic loss. These VD-induced phenotypes were effectively attenuated by miR-210-5p antagomir. Moreover, bioinformatic prediction revealed that synaptosomal-associated protein of 25 KDa (Snap25) mRNA is targeted by miR-210-5p. The miR-210-5p decreased the luciferase activities of 3' untranslated region (3'UTR) of Snap25 mRNA. Mutation of predicted miR-210-5p binding sites in the 3' UTR of Snap25 mRNA abolished the miR-210-5p-induced decrease in luciferase activity. Western blot and immunofluorescence staining confirmed that miR-210-5p targets Snap25. Finally, RT-quantitative PCR (qPCR) and immunofluorescence staining detected that miR-210-5p agomir downregulated Snap25 expression in the cornu ammonis1 (CA1) region of hippocampi in VD rats, whereas miR-210-5p antagomir upregulated Snap25 expression. Altogether, miR-210-5p contributes to cognitive impairment in chronic ischemia-induced VD model through the regulation of Snap25 expression, which potentially provides an opportunity to develop a new therapeutic strategy for VD.
| S-EPMC6243094 | biostudies-literature
Project description:Pericytes are unique, multi-functional mural cells localized at the abluminal side of the perivascular space in microvessels. Originally discovered in 19th century, pericytes had drawn less attention until decades ago mainly due to lack of specific markers. Recently, however, a growing body of evidence has revealed that pericytes play various important roles: development and maintenance of blood-brain barrier (BBB), regulation of the neurovascular system (e.g., vascular stability, vessel formation, cerebral blood flow, etc.), trafficking of inflammatory cells, clearance of toxic waste products from the brain, and acquisition of stem cell-like properties. In the neurovascular unit, pericytes perform these functions through coordinated crosstalk with neighboring cells including endothelial, glial, and neuronal cells. Dysfunction of pericytes contribute to a wide variety of diseases that lead to cognitive impairments such as cerebral small vessel disease (SVD), acute stroke, Alzheimer's disease (AD), and other neurological disorders. For instance, in SVDs, pericyte degeneration leads to microvessel instability and demyelination while in stroke, pericyte constriction after ischemia causes a no-reflow phenomenon in brain capillaries. In AD, which shares some common risk factors with vascular dementia, reduction in pericyte coverage and subsequent microvascular impairments are observed in association with white matter attenuation and contribute to impaired cognition. Pericyte loss causes BBB-breakdown, which stagnates amyloid ? clearance and the leakage of neurotoxic molecules into the brain parenchyma. In this review, we first summarize the characteristics of brain microvessel pericytes, and their roles in the central nervous system. Then, we focus on how dysfunctional pericytes contribute to the pathogenesis of vascular cognitive impairment including cerebral 'small vessel' and 'large vessel' diseases, as well as AD. Finally, we discuss therapeutic implications for these disorders by targeting pericytes.
| S-EPMC7171590 | biostudies-literature
Project description:Disruption of the blood-brain barrier has been proposed to be important in vascular cognitive impairment. Increased cerebrospinal fluid albumin and contrast-enhanced MRI provide supporting evidence, but quantification of the blood-brain barrier permeability in patients with vascular cognitive impairment is lacking. Therefore, we acquired dynamic contrast-enhanced MRI to quantify blood-brain barrier permeability in vascular cognitive impairment. Method- We studied 60 patients with suspected vascular cognitive impairment. They had neurological and neuropsychological testing, permeability measurements with dynamic contrast-enhanced MRI, and lumbar puncture to measure albumin index. Patients were separated clinically into subcortical ischemic vascular disease (SIVD), multiple and lacunar infarcts, and leukoaraiosis. Twenty volunteers were controls for the dynamic contrast-enhanced MRI studies, and control cerebrospinal fluid was obtained from 20 individuals undergoing spinal anesthesia for nonneurological problems.Thirty-six patients were classified as SIVD, 8 as multiple and lacunar infarcts, and 9 as leukoaraiosis. The albumin index was significantly increased in the SIVD group compared with 20 control subjects. Permeabilities for the patients with vascular cognitive impairment measured by dynamic contrast-enhanced MRI were significantly increased over control subjects (P<0.05). Patient age did not correlate with either the blood-brain barrier permeability or albumin index. Highest albumin index values were seen in the SIVD group (P<0.05) and were significantly increased over multiple and lacunar infarcts. K(i) values were elevated over control subjects in SIVD but were similar to multiple and lacunar infarcts.There was abnormal permeability in white matter in patients with SIVD as shown by dynamic contrast-enhanced MRI and albumin index. Future studies will be needed to determine the relationship of blood-brain barrier damage and development of white matter hyperintensities.
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Project description:Vascular dementia (VaD) is a progressive cognitive impairment caused by a reduced blood supply to the brain. Chronic cerebral hypoperfusion (CCH) is one cause of VaD; it induces oxidative stress, neuroinflammation, and blood-brain barrier (BBB) disruption, damaging several brain regions. Vitamin C plays a vital role in preventing oxidative stress-related diseases induced by reactive oxygen species, but it is easily oxidized and loses its antioxidant activity. To overcome this weakness, we have developed a vitamin C/DNA aptamer complex (NXP031) that increases vitamin C's antioxidant efficacy. Aptamers are short single-stranded nucleic acid polymers (DNA or RNA) that can interact with their corresponding target with high affinity. We established an animal model of VaD by permanent bilateral common carotid artery occlusion (BCCAO) in 12 week old Wistar rats. Twelve weeks after BCCAO, we injected NXP031 into the rats intraperitoneally for two weeks at moderate (200 mg/4 mg/kg) and high concentrations (200 mg/20 mg/kg). NXP031 administration alleviates cognitive impairment, microglial activity, and oxidative stress after CCH. NXP031 increased the expression of basal lamina (laminin), endothelial cell (RECA-1, PECAM-1), and pericyte (PDGFRβ); these markers maintain the BBB integrity. We found that NXP031 administration activated the Nrf2-ARE pathway and increased the expression of SOD-1 and GSTO1/2. These results suggest that this new aptamer complex, NXP031, could be a therapeutic intervention in CCH-induced VaD.
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Project description:To study the neuroprotective mechanism of minocycline against vascular cognitive impairment after cerebral ischemia.The rat model with vascular cognitive impairment was established by permanent bilateral common carotid artery occlusion (BCCAO). The observing time-points were determined at 4, 8 and 16 weeks after BCCAO. Animals were randomly divided into sham-operated group (n = 6), model group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6), and minocycline group (subdivided into 3 groups: 4 weeks after BCCAO, n = 6; 8 weeks after BCCAO, n = 6; and 16 weeks after BCCAO, n = 6). Minocycline was administered by douche via stomach after BCCAO until sacrifice. Glial fibrillary acidic protein (GFAP) was examined by Western blotting and immunohistochemistry. Levels of cyclooxygenase-2 (COX-2) and nuclear factor-kappaB (NF-kappaB) were measured by immunohistochemistry. IL-1beta and TNF-alpha levels were tested with ELISA method.Levels of GFAP, COX-2, NF-kappaB, IL-1beta and TNF-alpha were all up-regulated after permanent BCCAO, which could be significantly inhibited by minocycline.Minocycline could ameliorate the inflammation and oxidative stress in the hippocampus of the vascular cognitive impairment rat model.
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Project description:Vascular cognitive impairment (VCI) is the second most prevalent type of dementia in the world. The white matter damage that characterizes the common subcortical ischemic form of VCI can be modeled by ligating both common carotid arteries in the Wistar rat to induce protracted cerebral hypoperfusion. In this model, we find that repetitive intranasal administration of recombinant E-selectin to induce mucosal tolerance and to target immunomodulation to activating blood vessels potently suppresses both white matter (and possibly gray matter) damage and markers of vessel activation (tumor necrosis factor and E-selectin); it also preserves behavioral function in T-maze spontaneous alternation, T-maze spatial discrimination memory retention, and object recognition tests. Immunomodulation may be an effective novel strategy to prevent progression of VCI.
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Project description:A better understanding of the functioning of the brain, particularly executive functions, of the prison population could aid in reducing crime rates through the reduction of recidivism rates. Indeed, reoffending appears to be related to executive dysfunction and it is known that executive functions are crucial for self-regulation. In the current paper, studies to executive functions in regular adult prisoners compared to non-offender controls were reviewed. Seven studies were found. Specific executive functions were found to be impaired in the general prison population, i.e., attention and set-shifting, as well as in separate subgroups of violent (i.e., set-shifting and working memory) and non-violent offenders (i.e., inhibition, working memory and problem solving). We conclude that the limited number of studies is remarkable, considering the high impact of this population on society and elaborate on the implications of these specific impairments that were found. Further empirical research is suggested, measuring executive functioning within subjects over time for a group of detainees as well as a control group.
| S-EPMC4311616 | biostudies-literature