Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur's effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.

Despite its importance as the leading cause of vascular dementia, the primary pathogenic mechanisms in subcortical ischemic vascular dementia (SIVD) have remained elusive. Because of the lack of approved therapeutic agents for SIVD, there is a pressing need to identify novel therapeutic targets. Comparative lipidomic analyses of SIVD and mixed dementia (i.e., SIVD and Alzheimer's disease, MixD) may also confer new insights pertaining to the possible interaction between neurodegenerative and vascular mechanisms in the pathogenesis of dementia. Liquid chromatography coupled to mass spectrometry was used to comprehensively analyze the lipidomes of white and gray matter from the temporal cortex of nondemented controls, SIVD, and MixD subjects. Detailed molecular profiles highlighted the pathologic relevance of gray matter sphingolipid fatty acyl chain heterogeneity in dementia. In addition, the levels of sulfatides and lysobisphosphatidic acids were progressively increased in the temporal cortex gray matter from control to SIVD to MixD. White matter phospholipid profiles indicated possible adaptive mechanisms (i.e., increased unsaturation) to chronic ischemia in SIVD and elevated membrane degradation in MixD.

Since groundbreaking studies demonstrated the presence of progenitor cells in the adult human brain, there have been intense interests in their potential therapeutic application, but to date only limited data has been obtained in man. An immunohistological study was performed in order to examine neurogenesis in both the subventricular and peri-infarct zones of vascular dementia patients compared to age-matched controls. The results were striking, showing a significant increase of progenitor cells in both the subventricular zone and in peri-infarct area in patients with vascular dementia compared to controls, which was sustained even in patients with infarcts occurring more than three months prior to autopsy. Moreover, the peri-infarct response appeared to be unified with that of the subventricular zone via a stream of cells, with some of them differentiating into immature neurons. We conclude that neurogenesis is stimulated in vascular dementia patients and, specifically, in patients with visible infarcts. Progenitors may migrate from the neurogenic niche to areas of infarction and differentiate into neurons, even three months after cerebrovascular damage, thus implicating the feasibility of enhancing neurogenesis as a novel treatment approach.

Dementia is a chronic brain disorder classified by four distinct diseases that impact cognition and mental degeneration. Each subgroup exhibits similar brain deficiencies and mutations. This review will focus on four dementia subgroups: Alzheimer's disease, vascular dementia, frontotemporal dementia and dementia Lewy body.

Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100 kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N=11), mixed Alzheimer's disease (AD) and VaD (N=8), VaD (N=7), and stroke no dementia (SND, N=8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD (-50%). Furthermore, levels of Dynamin1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular glutamate transporter 1. This work indicates that Dynamin1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target.

Tetrandrine is one of the major active ingredients in Menispermaceae Stephania tetrandra S. Moore, and has specific therapeutic effects in ischemic cerebrovascular disease. Its use in vascular dementia has not been studied fully. Here, we investigated whether tetrandrine would improve behavioral and cellular impairments in a two-vessel occlusion rat model of chronic vascular dementia. Eight weeks after model establishment, rats were injected intraperitoneally with 10 or 30 mg/kg tetrandrine every other day for 4 weeks. Behavioral assessment in the Morris water maze showed that model rats had longer escape latencies in training trials, and spent less time swimming in the target quadrant in probe trials, than sham-operated rats. However, rats that had received tetrandrine showed shorter escape latencies and longer target quadrant swimming time than untreated model rats. Hematoxylin-eosin and Nissl staining revealed less neuronal necrosis and pathological damage, and more living cells, in the hippocampus of rats treated with tetrandrine than in untreated model rats. Western blot assay showed that interleukin-1β expression, and phosphorylation of the N-methyl-D-aspartate 2B receptor at tyrosine 1472, were lower in model rats that received tetrandrine than in those that did not. The present findings suggest that tetrandrine may be neuroprotective in chronic vascular dementia by reducing interleukin-1β expression, N-methyl-D-aspartate receptor 2B phosphorylation at tyrosine 1472, and neuronal necrosis.

Subcortical vascular dementia is a clinical entity, widespread, even challenging to diagnose and correctly treat. Patients with this diagnosis are old, frail, often with concomitant pathologies, and therefore, with many drugs in therapy. We tried to diagnose and follow up for three years more than 600 patients. Study subjects were men and women, not bedridden, aged 68-94 years, outpatients, recruited from June, 1st 2007 to June, 1st 2010. We examined them clinically, neurologically, with specific consideration on drug therapies. Our aim has been to define gait and imbalance problem, if eventually coexistent with the pathology of white matter and/or with the worsening of the deterioration. Drug intake interference has been detected and considered.

No abstract available

Vascular dementia appears rarer than previously thought, but the contribution of vascular lesions to cognitive impairment in Alzheimer's disease (AD) affected patients (mixed dementias) is now recognized as frequent. The role of strategic areas of the brain involved in the cognitive decline induced by vascular lesions and their relative contributions to the severity of the dementing process remain poorly understood. We determined the relationship between the severity of clinical dementia and the volume of different brain areas affected by infarcts in a prospective clinicopathological study in elderly patients. A volumetric study of the functional zones of Mesulam's human brain map affected by vascular lesions was made and correlations between quantified neuropathological data and the severity of dementia were performed in cases with large vascular lesions only, pure AD, and both lesions. The severity of cognitive impairment was significantly correlated with the total volume of infarcts but in a multi-variate model the volume destroyed in the limbic and heteromodal association areas, including the frontal cortex and in the white matter explained 50% of the variability in MMSE and GDS. The total volume of ischemic lesions explained only 0.1-5% of the variability in MMSE and GDS. Age only explained an extra of 0.1-1.6%. This study confirms that infarcts located in strategic areas have a role in the mechanism of cognitive impairment and brings a key for their quantification. It may be useful for developing neuropathological criteria in multi-infarct and mixed dementias.

Apelin receptor (APJ), a member of family A of the G protein-coupled receptors (GPCRs), is a potential pharmaceutical target for diseases of the nervous system. Our previous work revealed that human APJ can form a homodimer that has different functional characteristics than the monomer. To investigate the effects of APJ homodimers on neuroprotection in vascular dementia (VD), we established VD model in rats and treated the animals by injecting apelin-13 into the lateral ventricle. In addition, we established an oxygen-glucose deprivation/reoxygenation (OGD/R) model in SH-SY5Y cells treated with apelin-13. After apelin-13 stimulation in the VD rat, the level of APJ and APJ homodimer were elevated. Furthermore, APJ homodimer decreased the level of cleaved caspase-3 and cleaved caspase-9 via the Gαi3 and Gαq signaling pathway, thereby increasing the number of neurons and inhibiting apoptosis. Consequently, APJ homodimers may serve as a unique mechanism for neuroprotection against VD and provide new pharmaceutical targets for VD.

Vascular dementia (VaD) is a challenging illness that affects the lives of older adults and caregivers. It is unclear how multiple vascular risk factor exposures (polyvascular disease) affect VaD.

We determined whether the possible roles of oxidative stress differ in the pathophysiology and cognitive decline of Alzheimer's disease (AD), vascular dementia (VaD) and mixed Alzheimer's/vascular dementia (MD).

Vascular dementia (VaD) constitutes the second most prevalent cause of dementia in the world after Alzheimer's disease (AD). VaD regroups heterogeneous neurological conditions in which the decline of cognitive functions, including executive functions, is associated with structural and functional alterations in the cerebral vasculature. Among these cerebrovascular disorders, major stroke, and cerebral small vessel disease (cSVD) constitute the major risk factors for VaD. These conditions alter neurovascular functions leading to blood-brain barrier (BBB) deregulation, neurovascular coupling dysfunction, and inflammation. Accumulation of neurovascular impairments over time underlies the cognitive function decline associated with VaD. Furthermore, several vascular risk factors, such as hypertension, obesity, and diabetes have been shown to exacerbate neurovascular impairments and thus increase VaD prevalence. Importantly, air pollution constitutes an underestimated risk factor that triggers vascular dysfunction via inflammation and oxidative stress. The review summarizes the current knowledge related to the pathological mechanisms linking neurovascular impairments associated with stroke, cSVD, and vascular risk factors with a particular emphasis on air pollution, to VaD etiology and progression. Furthermore, the review discusses the major challenges to fully elucidate the pathobiology of VaD, as well as research directions to outline new therapeutic interventions.

Although cerebral white matter lesions (WMLs) are considered as a risk factor for vascular dementia, data on their impact on cerebral hemodynamics are scarce. We test and compare transcranial Doppler (TCD) features in WML patients with or without associated cognitive impairment.

To investigate whether midlife atherosclerosis is associated with different dementia subtypes and related underlying pathologies.

Alzheimer's disease (AD) and vascular dementia (VaD) present with similar clinical symptoms of cognitive decline, but the underlying pathophysiological mechanisms differ. To determine whether clinical electroencephalography (EEG) can provide information relevant to discriminate between these diagnoses, we used quantitative EEG analysis to compare the spectra between non-medicated patients with AD (n = 77) and VaD (n = 77) and healthy elderly normal controls (NC) (n = 77). We use curve-fitting with a combination of a power loss and Gaussian function to model the averaged resting-state spectra of each EEG channel extracting six parameters. We assessed the performance of our model and tested the extracted parameters for group differentiation. We performed regression analysis in a multivariate analysis of covariance with group, age, gender, and number of epochs as predictors and further explored the topographical group differences with pair-wise contrasts. Significant topographical differences between the groups were found in several of the extracted features. Both AD and VaD groups showed increased delta power when compared to NC, whereas the AD patients showed a decrease in alpha power for occipital and temporal regions when compared with NC. The VaD patients had higher alpha power than NC and AD. The AD and VaD groups showed slowing of the alpha rhythm. Variability of the alpha frequency was wider for both AD and VaD groups. There was a general decrease in beta power for both AD and VaD. The proposed model is useful to parameterize spectra, which allowed extracting relevant clinical EEG key features that move toward simple and interpretable diagnostic criteria.

Circular RNAs (circRNAs) are a class of endogenous noncoding RNA molecules that lack free 5' and a 3' end poly(A) tail. CircRNAs are enriched in neural tissues, and have been found to be associated with various diseases of the central nervous system. This study aimed to examine key circRNAs involved in vascular dementia(VD) model rats.

The tight junctions (TJs) are key players in the control of blood-brain barrier (BBB) properties, the most complex TJs in the vascular system being found in the endothelial cells of brain capillaries. One of the main TJs proteins is occludin, which anchors plasma membranes of neighbour cells and is present in large amounts in the brain endothelia. Previous studies demonstrated that disruption of BBB in various pathological situations associates with changes in occludin expression, and this change could be responsible for malfunction of BBB. Therefore in this study, applying an immunohistochemical approach, we decided to explore the occludin expression in frontal cortex (FC) and basal ganglia in ageing control, Alzheimer's disease (AD), and vascular dementia (VD) brains, as far as all these pathologies associate microangiopathy and disruption of BBB. Strikingly, we found selected neurons, astrocytes and oligodendrocytes expressing occludin, in all cases studied. To estimate the number of occludin-expressing neurons, we applied a stereological approach with random systematic sampling and the unbiased optical fractionator method. We report here a significant increase in ratio of occludin-expressing neurons in FC and basal ganglia regions in both AD and VD as compared to ageing controls. Within the cerebral cortex, occludin was selectively expressed by pyramidal neurons, which are the ones responsible for cognitive processes and affected by AD pathology. Our findings could be important in unravelling new pathogenic pathways in dementia disorders and new functions of occludin and TJs.

Hippocampal mitochondrial dysfunction due to oxidative stress has been considered to play a major role in the pathogenesis of vascular dementia (VD). Previous studies suggested that acupuncture could improve cerebral hypoperfusion-induced cognitive impairments. However, whether hippocampal mitochondria are associated with this cognitive improvement remains unclear. In this study, an animal model of VD was established via bilateral common carotid arteries occlusion (BCCAO) to investigate the alterations of cognitive ability and hippocampal mitochondrial function. BCCAO rats showed impairments in hippocampal mitochondrial function, overproduction of reactive oxygen species (ROS) and learning and memory deficits. After two-week acupuncture treatment, BCCAO-induced spatial learning and memory impairments as shown in Morris water maze were ameliorated. Hippocampal mitochondrial respiratory complex enzymes (complex I, II, IV) activities and cytochrome c oxidase IV expression significantly increased, which might contribute to the reduction of hippocampal ROS generation. In addition, acupuncture significantly improve mitochondrial bioenergy parameters such as mitochondrial respiratory control rate and membrane potential not PDH A1 expression. Placebo-acupuncture did not produce similar therapeutic effects. These findings suggested that acupuncture reversed BCCAO-induced hippocampal mitochondrial dysfunction, which might contribute to its prevention on cognitive deficits.

Despite acupuncture having been successfully used for the clinical treatment for vascular dementia in Asian countries for centuries, scientifically rigorous evidence is lacking for standardizing therapeutic parameters. To address this problem, it is necessary to examine the parameters of acupuncture using scientific methodology. The goal of this study is to investigate various therapeutic parameters, including manipulation, retention, and frequency of acupuncture, and their contribution to the efficacy of acupuncture in VD.