Effects of schisandrin B on hypoxia-related cognitive function and protein expression in vascular dementia rats.

Vascular dementia (VD) a heterogenous group of brain disorders in which cognitive impairment is attributable to vascular risk factors and cerebrovascular disease. A common phenomenon in VD is a dysfunctional cerebral regulatory mechanism associated with insufficient cerebral blood flow, ischemia and hypoxia. Under hypoxic conditions oxygen supply to the brain results in neuronal death leading to neurodegenerative diseases including Alzheimer's (AD) and VD. In conditions of hypoxia and low oxygen perfusion, expression of hypoxia-inducible factor 1 alpha (HIF-1α) increases under conditions of low oxygen and low perfusion associated with upregulation of expression of hypoxia-upregulated mitochondrial movement regulator (HUMMR), which promotes anterograde mitochondrial transport by binding with trafficking protein kinesin 2 (TRAK2). Schisandrin B (Sch B) an active component derived from Chinese herb Wuweizi prevented ß-amyloid protein induced morphological alterations and cell death using a SH-SY5Y neuronal cells considered an AD model. It was thus of interest to determine whether Sch B might also alleviate VD using a rat bilateral common carotid artery occlusion (BCAO) dementia model. The aim of this study was to examine the effects of Sch B in BCAO on cognitive functions such as Morris water maze test and underlying mechanisms involving expression of HIF-1α, TRAK2, and HUMMR levels. The results showed that Sch B improved learning and memory function of rats with VD and exerted a protective effect on the hippocampus by inhibition of protein expression of HIF-1α, TRAK2, and HUMMR factors. Evidence indicates that Sch B may be considered as an alternative in VD treatment.

Exercise Improves Cerebral Blood Flow and Functional Outcomes in an Experimental Mouse Model of Vascular Cognitive Impairment and Dementia (VCID).

Vascular cognitive impairment and dementia (VCID) are a growing threat to public health without any known treatment. The bilateral common carotid artery stenosis (BCAS) mouse model is valid for VCID. Previously, we have reported that remote ischemic postconditioning (RIPostC) during chronic cerebral hypoperfusion (CCH) induced by BCAS increases cerebral blood flow (CBF), improves cognitive function, and reduces white matter damage. We hypothesized that physical exercise (EXR) would augment CBF during CCH and prevent cognitive impairment in the BCAS model. BCAS was performed in C57/B6 mice of both sexes to establish CCH. One week after the BCAS surgery, mice were randomized to treadmill exercise once daily or no EXR for four weeks. CBF was monitored with an LSCI pre-, post, and 4 weeks post-BCAS. Cognitive testing was performed for post-BCAS after exercise training, and brain tissue was harvested for histopathology and biochemical test. BCAS led to chronic hypoperfusion resulting in impaired cognitive function and other functional outcomes. Histological examination revealed that BCAS caused changes in neuronal morphology and cell death in the cortex and hippocampus. Immunoblotting showed that BCAS was associated with a significant downregulate of AMPK and pAMPK and NOS3 and pNOS3. BCAS also decreased red blood cell (RBC) deformability. EXR therapy increased and sustained improved CBF and cognitive function, muscular strength, reduced cell death, and loss of white matter. EXR is effective in the BCAS model, improving CBF and cognitive function, reducing white matter damage, improving RBC deformability, and increasing RBC NOS3 and AMPK. The mechanisms by which EXR improves CBF and attenuates tissue damage need further investigation.

The Bilateral Carotid Artery Stenosis (BCAS) Model of Vascular Dementia.

Vascular dementia is the second most common form of dementia after Alzheimer's disease. Chronic cerebral hypoperfusion is a key contributor to the development of vascular dementia. In this chapter, we describe the surgical procedures used for bilateral carotid artery stenosis (BCAS) surgery to induce chronic cerebral hypoperfusion. Mice that undergo BCAS surgery develop the hallmarks of vascular dementia including white matter lesions, neuroinflammation, and cognitive impairment. This technique may be used for studies of chronic cerebral hypoperfusion and vascular dementia in mice.

Rapidly progressive dementia due to intravascular lymphoma: A prion disease reference center experience.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare extranodal lymphoma that is characterized by the selective growth of neoplastic cells in blood vessels, representing a potentially treatable cause of rapidly progressive dementia (RPD). Given its diverse clinical and instrumental presentation, it is often misdiagnosed with more common RPD causes, for example, Creutzfeldt-Jakob disease (CJD) or vascular dementia. METHODS: This study presents the clinical and histopathological characteristics of four IVLBCL cases that we diagnosed post-mortem over 20 years among over 600 brain samples received as suspected CJD cases at our prion disease reference center. RESULTS: Our patients exhibited various presenting symptoms, including behavioral disturbances, disorientation, and alertness fluctuations. The diagnostic tests performed at the time, including blood work, cerebrospinal fluid (CSF) analyses, electroencephalography, and neuroimaging, yielded nonspecific and occasionally misleading results. Consequently, the patients were repeatedly diagnosed as variably having CJD, epilepsy, vascular dementia, and encephalitis. The stored CSF samples of two patients tested negative at prion real-time quaking-induced conversion (RT-QuIC), which we performed afterwards for research purposes. Neuropathological analysis revealed a differential involvement of various brain areas, with frontotemporal neocortices being the most affected. CONCLUSIONS: Our results confirm the significant clinical and instrumental heterogeneity of IVLBCL. Neuropathological evidence of the preferential involvement of frontotemporal neocortices, potentially conditioning the clinical phenotype, could be relevant to reach an early diagnosis. Finally, given the therapeutic implications of its misdiagnosis with CJD, we emphasize the utility of prion RT-QuIC as a test for ruling out CJD in these patients.

A Novel Needle Mouse Model of Vascular Cognitive Impairment and Dementia.

Bilateral common carotid artery (CCA) stenosis (BCAS) is a useful model to mimic vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning because of metal implantation. We have established a new low-cost VCID model that better mimics human VCID and is compatible with live-animal MRI. The right and the left CCAs were temporarily ligated to 32- and 34-gauge needles with three ligations, respectively. After needle removal, CCA blood flow, cerebral blood flow, white matter injury (WMI) and cognitive function were measured. In male mice, needle removal led to ∼49.8% and ∼28.2% blood flow recovery in the right and left CCA, respectively. This model caused persistent and long-term cerebral hypoperfusion in both hemispheres (more severe in the left hemisphere), and WMI and cognitive dysfunction in ∼90% of mice, which is more reliable compared with other models. Importantly, these pathologic changes and cognitive impairments lasted for up to 24 weeks after surgery. The survival rate over 24 weeks was 81.6%. Female mice showed similar cognitive dysfunction, but a higher survival rate (91.6%) and relatively milder white matter injury. A novel, low-cost VCID model compatible with live-animal MRI with long-term outcomes was established.SIGNIFICANCE STATEMENT Bilateral common carotid artery (CCA) stenosis (BCAS) is an animal model mimicking carotid artery stenosis to study vascular cognitive impairment and dementia (VCID). However, current BCAS models have the disadvantages of high cost and incompatibility with magnetic resonance imaging (MRI) scanning due to metal implantation. We established a new asymmetric BCAS model by ligating the CCA to various needle gauges followed by an immediate needle removal. Needle removal led to moderate stenosis in the right CCA and severe stenosis in the left CCA. This needle model replicates the hallmarks of VCID well in ∼90% of mice, which is more reliable compared with other models, has ultra-low cost, and is compatible with MRI scanning in live animals. It will provide a new valuable tool and offer new insights for VCID research.

Association between cancer and dementia risk in the UK Biobank: evidence of diagnostic bias.

Epidemiological studies have identified an inverse association between cancer and dementia. Underlying methodological biases have been postulated, yet no studies have systematically investigated the potential for each source of bias within a single dataset. We used the UK Biobank to compare estimates for the cancer-dementia association using different analytical specifications designed to sequentially address multiple sources of bias, including competing risk of death, selective survival, confounding bias, and diagnostic bias. We included 140,959 UK Biobank participants aged ≥ 55 without dementia before enrollment and with linked primary care data. We used cancer registry data to identify cancer cases prevalent before UK Biobank enrollment and incident cancer diagnosed after enrollment. We used Cox models to evaluate associations of prevalent and incident cancer with all-cause dementia, Alzheimer's disease (AD), and vascular dementia. We used time-varying models to evaluate diagnostic bias. Over a median follow-up of 12.3 years, 3,310 dementia cases were diagnosed. All-site incident cancer was positively associated with all-cause dementia incidence (hazard ratio [HR] = 1.14, 95% CI: 1.02-1.29), but prevalent cancer was not (HR = 1.04, 95% CI: 0.92-1.17). Results were similar for vascular dementia. AD was not associated with prevalent or incident cancer. Dementia diagnosis was substantially elevated in the first year after cancer diagnosis (HR = 1.83, 95% CI: 1.42-2.36), after which the association attenuated to null, suggesting diagnostic bias. Following a cancer diagnosis, health care utilization or cognitive consequences of diagnosis or treatment may increase chance of receiving a dementia diagnosis, creating potential diagnostic bias in electronic health records-based studies.

Association Between the AHA Life's Essential 8 Score and Incident All-Cause Dementia: A Prospective Cohort Study from UK Biobank.

This study aimed to investigate the association between the Life's Essential 8 (LE8) score and incident all-cause dementia (including Alzheimer's disease [AD] and vascular dementia) in UK Biobank. A total of 259,718 participants were included in this prospective study. Smoking, non-HDL cholesterol, blood pressure, body mass index, HbA1c, physical activity, diet, and sleep were used to create the Life's Essential 8 (LE8) score. Associations between the score (both continuous and as quartiles) and outcomes were investigated using adjusted Cox proportional hazard models. The potential impact fractions of 2 scenarios and the rate advancement periods were also calculated. Over a median follow-up of 10.6 years, 4958 participants were diagnosed with any dementia. Higher LE8 scores were associated with lower risk of all-cause and vascular dementia in an exponential decay pattern. Compared with individuals in the healthiest quartile, those in the least healthy quartile had a higher risk of all-cause dementia (HR: 1.50 [95% CI: 1.37-1.65] and vascular dementia (HR: 1.86 [1.44-2.42]). A targeted intervention that increased the score by 10-points among individuals in the lowest quartile could have prevented 6.8% of all-cause dementia cases. Individuals in the least healthy LE8 quartile might develop all-cause dementia 2.45 years earlier than their counterparts. In conclusion, individuals with higher LE8 scores had lower risk of all-cause and vascular dementia. Because of nonlinear associations, interventions targeted at the least healthy individuals might produce greater population-level benefits.

Abnormal Spontaneous Discharges of Primary Sensory Neurons and Pain Behavior in a Rat Model of Vascular Dementia.

Patients with vascular dementia experience more pain than healthy elders, potentially due to the presence of central neuropathic pain. However, the mechanisms underlying neuropathic pain in vascular dementia remain poorly understood, and there is currently a lack of effective treatment available. In this study, a rat model of vascular dementia was induced by permanently occluding the common carotid arteries bilaterally (2-VO). The cognitive impairments in the 2-VO rats were evaluated using the Morris Water Maze test, while HE and LBF staining were employed to assess brain tissue lesions in the hippocampal, cerebral cortex, and white matter regions known to be associated with severe memory and learning deficits. Furthermore, pain-related behavioral tests, including mechanical and thermal stimuli assessments, were conducted, and in vivo electrophysiological recordings of primary sensory neurons were performed. Compared to sham-operated and pre-operative rats, rats with vascular dementia exhibited mechanical allodynia and thermal hyperalgesia 30 days after surgery. Furthermore, in vivo electrophysiology revealed a significant increase in the occurrence of spontaneous activity of Aß- and C-fiber sensory neurons in the rat model of vascular dementia. These results indicate that neuropathic pain behaviors developed in the rat model of vascular dementia, and abnormal spontaneous discharges of primary sensory neurons may play a crucial role in the development of pain after vascular dementia.

Efficacy of Artemisia annua Linné in improving cognitive impairment in a chronic cerebral hypoperfusion-induced vascular dementia animal model.

BACKGROUND: Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. Currently, no FDA-approved drugs are available for the treatment of VaD. Artemisia annua Linné (AA) is known to have antioxidant properties, but its effects and mechanisms of action on cognitive impairment are still unknown. PURPOSE: In this study, the improvement in cognitive impairment by AA in terms of protection against oxidative stress, neuroinflammation, and preservation of the integrity of the neurovascular unit (NVU) was assessed in an animal model of VaD with bilateral common carotid artery occlusion (BCCAO). METHODS: Eight-week-old male Wistar rats were allowed to adapt for four weeks, and BCCAO was induced at 12 weeks of age. The rats were randomly assigned into four groups, with seven rats in each group: sham group without BCCAO, VaD group that received oral administration of distilled water after BCCAO surgery, and two AA groups that received oral administration of 150 mg/kg or 750 mg/kg AA after BCCAO surgery for 8 weeks. Nine weeks after BCCAO surgery, the cognitive function of the rats was evaluated and accumulated oxidative stress was assessed by immunohistochemistry, immunofluorescence, and western blotting. Damage to the components of the NVU was evaluated, and sirtuin (Sirt) 1 and 2 expression and nuclear factor-erythrocyte 2-associated factor 2 (Nrf2)/Kelch-like ECH-associated protein1 (Keap1) activation were investigated to assess the reduction in cell signaling and antioxidant pathways. RESULTS: BCCAO-induced cerebral perfusion decreased memory function and induced neuroinflammation and oxidative stress. But AA treatment mitigated cognitive impairment and reduced neuroinflammation and oxidative stress caused by chronic cerebral hypoperfusion. AA extracts activated the Nrf2/Keap1/activating antioxidant response elements pathway and maintained Sirt 1 and 2, subsequently leading to the maintenance of neurons, improved construct of microvessels, increased platelet-derived growth factor receptor beta, and platelet-endothelial cell adhesion molecule-1 associated with the blood-brain barrier integrity. CONCLUSION: AA is effective in alleviating BCCAO-induced cognitive decline and its administration may be a useful therapeutic approach for VaD.

Gardenia jasminoides Extract GJ-4 Alleviates Memory Deficiency of Vascular Dementia in Rats through PERK-Mediated Endoplasmic Reticulum Stress Pathway.

Endoplasmic reticulum stress (ERS) is involved in the pathological process of vascular dementia (VD). GJ-4 is extracted from Gardenia jasminoides J. Ellis and has been reported to have protective roles in ischemia-related brain damage. However, the role of GJ-4 in ERS has not been elucidated. We established a VD rat model through bilateral common carotid arteries occlusion (2-VO). The rats were intragastrically administrated with GJ-4 (10, 25, and 50[Formula: see text]mg/kg) and nimodipine (10[Formula: see text]mg/kg). Data from a Morris water maze test showed that GJ-4 could significantly alleviate learning and memory deficits in VD rats. Nissl and cleaved caspase-3 staining revealed that GJ-4 can inhibit apoptosis and thus exert a protective role in the brain of 2-VO rats. Western blot results suggested that GJ-4 significantly reduced ERS-related protein expression and inhibited apoptosis through suppression of the PERK/eIF2[Formula: see text]/ATF4/CHOP signaling pathway. For in vitro studies, the oxygen-glucose deprivation (OGD) SH-SY5Y model was employed. Western blot and Hoechst 33342/PI double staining were utilized to explore the effects of crocetin, the main active metabolite of GJ-4. Like GJ-4 in vivo, crocetin in vitro also decreased ERS-related protein expression and inhibited the activation of the PERK/eIF2[Formula: see text]/ATF4/CHOP signaling pathway. Thus, crocetin exerted similar protective roles on OGD challenged SH-SY5Y cells in vitro. In summary, GJ-4 and crocetin reduce the ERS in the brain of VD rats and SY5Y cells subjected to OGD and inhibit neuronal apoptosis through suppression of the PERK/eIF2[Formula: see text]/ATF4/CHOP pathway, suggesting that GJ-4 may be useful for the treatment of VD.

Chronic exposure to 2.45 GHz microwave radiation improves cognition and synaptic plasticity impairment in vascular dementia model.

Purpose: In this study, we evaluated the effects of 2.45 GHz microwave radiation on cognitive dysfunction induced by vascular dementia (VaD).Methods: The VaD was induced by bilateral-common carotid occlusion (2-VO). The rats were divided into 4 groups including: control (n = 6), sham (n = 6), 2-VO (n = 8), and 2-VO + Wi-Fi (n = 10) groups. Wi-Fi modem centrally located at the distance of 25 cm from the animal's cages and the animals were continuously exposed to Wi-Fi signal while they freely moved in the cage (2 h/day for forty-five days). Therefore, the power density (PD) and specific absorption rate value (SAR) decreased at a distance of 25 to 60 cm (PD = 0.018 to 0.0032 mW/cm2, SAR = 0.0346 to 0.0060 W/Kg). The learning, memory, and hippocampal synaptic-plasticity were evaluated by radial arm maze (RAM), passive avoidance (PA), and field-potential recording respectively. The number of hippocampal CA1 cells was also assessed by giemsa staining.Results: Our results showed that VaD model led to impairment in the spatial learning and memory performance in RAM and PA that were associated with long-term potentiation (LTP) impairment, decrease of basal-synaptic transmission (BST), increase of GABA transmission, and decline of neurotransmitter release-probability as well as hippocampal cell loss. Notably, chronic Wi-Fi exposure significantly recovered the learning-memory performance, LTP induction, and cell loss without any effect on BST.Conclusions: The LTP recovery by Wi-Fi in the 2-VO rats was probably related to significant increases in the hippocampal CA1 neuronal density, partial recovery of neurotransmitter release probability, and reduction of GABA transmissiSon as evident by rescue of paired-pulse ratio 10 ms.

Arterial Spin-Labeling Parameters and Their Associations with Risk Factors, Cerebral Small-Vessel Disease, and Etiologic Subtypes of Cognitive Impairment and Dementia.

BACKGROUND AND PURPOSE: Cerebral small-vessel disease may alter cerebral blood flow (CBF) leading to brain changes and, hence, cognitive impairment and dementia. CBF and the spatial coefficient of variation can be measured quantitatively by arterial spin-labeling. We aimed to investigate the associations of demographics, vascular risk factors, location, and severity of cerebral small-vessel disease as well as the etiologic subtypes of cognitive impairment and dementia with CBF and the spatial coefficient of variation. MATERIALS AND METHODS: Three hundred ninety patients with a diagnosis of no cognitive impairment, cognitive impairment no dementia, vascular cognitive impairment no dementia, Alzheimer disease, and vascular dementia were recruited from the memory clinic. Cerebral microbleeds and lacunes were categorized into strictly lobar, strictly deep, and mixed-location and enlarged perivascular spaces into the centrum semiovale and basal ganglia. Total and region-specific white matter hyperintensity volumes were segmented using FreeSurfer. CBF (n = 333) and the spatial coefficient of variation (n = 390) were analyzed with ExploreASL from 2D-EPI pseudocontinuous arterial spin-labeling images in white matter (WM) and gray matter (GM). To analyze the effect of demographic and vascular risk factors as well as the location and severity of cerebral small-vessel disease markers on arterial spin-labeling parameters, we constructed linear regression models, whereas logistic regression models were used to determine the association between arterial spin-labeling parameters and cognitive impairment no dementia, vascular cognitive impairment no dementia, Alzheimer disease, and vascular dementia. RESULTS: Increasing age, male sex, hypertension, hyperlipidemia, history of heart disease, and smoking were associated with lower CBF and a higher spatial coefficient of variation. Higher numbers of lacunes and cerebral microbleeds were associated with lower CBF and a higher spatial coefficient of variation. Location-specific analysis showed mixed-location lacunes and cerebral microbleeds were associated with lower CBF. Higher total, anterior, and posterior white matter hyperintensity volumes were associated with a higher spatial coefficient of variation. No association was observed between enlarged perivascular spaces and arterial spin-labeling parameters. A higher spatial coefficient of variation was associated with the diagnosis of vascular cognitive impairment no dementia, Alzheimer's disease, and vascular dementia. CONCLUSIONS: Reduced CBF and an increased spatial coefficient of variation were associated with cerebral small-vessel disease, and more specifically lacunes, whereas cerebral microbleeds and white matter hyperintensities were associated with WM-CBF and GM spatial coefficient of variation. The spatial coefficient of variation was associated with cognitive impairment and dementia, suggesting that hypoperfusion might be the key underlying mechanism for vascular brain damage.

Risk of dementia according to the smoking habit change after ischemic stroke: a nationwide population-based cohort study.

There is a paucity of research regarding the association between the risk of incident dementia and changes in smoking habits in the acute ischemic stroke population. We aimed to investigate the effects of smoking habit change on the risk of incident dementia in an ischemic stroke population using data from the Korean National Health Insurance Services Database. This nationwide population-based cohort study included 197,853 patients with ischemic stroke. The patients were divided into never smokers, former smokers, smoking quitters, sustained smokers, and new smokers, based on the 2-year change in smoking status between the two consecutive health examinations before and after the index stroke. The patients were followed up from the index date to 2018 to assess the development of dementia. Dementia was further categorized into Alzheimer's, vascular, and other types of dementia according to the International Classification of Diseases, Tenth Revision diagnosis. Multivariable Cox proportional hazards models were used to assess the association between changes in smoking habits and the risk of dementia. After a median of 4.04 years of follow-up, 19,595 (9.9%) dementia cases were observed. Among them, 15,189 (7.7%) were diagnosed with Alzheimer's disease dementia and 2719 (1.4%) were diagnosed with vascular dementia. After adjusting for covariates, including age, sex, alcohol intake habits, cigarette pack-year, regular physical activity, income, history of hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease, new smokers, sustained smokers, and smoking quitters were significantly associated with a higher risk of all-cause dementia than never smokers (adjusted hazard ratio [aHR] 1.395, 95% confidence interval [CI] 1.254-1.552; aHR 1.324, 95% CI 1.236-1.418; and aHR 1.170, 95% CI 1.074-1.275, respectively). Similar trends were observed for both Alzheimer's dementia and vascular dementia, but the association between new smokers and vascular dementia was not significant. The impact of smoking habit change was more prominent in the 40-65-year-old group. New and sustained smokers had a substantially higher risk of incident dementia after ischemic stroke than never smokers. Smoking quitters also had an elevated risk of incident dementia, but the detrimental effects were lower than those in new and sustained smokers.

Palm Oil Derived Tocotrienol-Rich Fraction Attenuates Vascular Dementia in Type 2 Diabetic Rats.

Vascular dementia (VaD) is a serious global health issue and type 2 diabetes mellitus (T2DM) patients are at higher risk. Palm oil tocotrienol-rich fraction (TRF) exhibits neuroprotective properties; however, its effect on VaD is not reported. Hence, we evaluated TRF effectiveness in T2DM-induced VaD rats. Rats were given a single dose of streptozotocin (STZ) and nicotinamide (NA) to develop T2DM. Seven days later, diabetic rats were given TRF doses of 30, 60, and 120 mg/kg orally for 21 days. The Morris water maze (MWM) test was performed for memory assessment. Biochemical parameters such as blood glucose, plasma homocysteine (HCY) level, acetylcholinesterase (AChE) activity, reduced glutathione (GSH), superoxide dismutase (SOD) level, and histopathological changes in brain hippocampus and immunohistochemistry for platelet-derived growth factor-C (PDGF-C) expression were evaluated. VaD rats had significantly reduced memory, higher plasma HCY, increased AChE activity, and decreased GSH and SOD levels. However, treatment with TRF significantly attenuated the biochemical parameters and prevented memory loss. Moreover, histopathological changes were attenuated and there was increased PDGF-C expression in the hippocampus of VaD rats treated with TRF, indicating neuroprotective action. In conclusion, this research paves the way for future studies and benefits in understanding the potential effects of TRF in VaD rats.

Ambient air pollution and risk of incident dementia in older men living in a region with relatively low concentrations of pollutants: The Health in Men Study.

BACKGROUND: In areas with moderate to severe air pollution, pollutant concentrations are associated with dementia risk. It is unclear whether the same relationship is present in regions with lower ambient air pollution. OBJECTIVE: To determine whether exposure to air pollution is associated with risk of incident dementia in general, and Alzheimer's disease and vascular dementia in particular, in older men living in a relatively low ambient air pollution region. METHODS: The cohort comprised 11,243 men residing in Perth, Australia. Participants were aged ≥65 years and free of a dementia diagnosis at time of recruitment in 1996-1999. Incident dementia was identified from recruitment to 2018 via ICD diagnosis codes and subsequent study waves. Concentrations for three air pollutants, nitrogen dioxide (NO2), fine particulate matter less than 2.5 µm in diameter (PM2.5), and black carbon (BC) were estimated at participants' home addresses using land-use regression models. We used Cox proportional hazards regression models adjusting for smoking status, physical activity, BMI, education, and socio-economic status. RESULTS: Of 3053 (27.2%) incident cases of dementia, 1670 (54.7%) and 355 (11.6%) had documented Alzheimer's disease and vascular dementia. The average concentration of NO2 was 13.5 (SD 4.4) µg/m3, of PM2.5 was 4.54 (SD 1.6) µg/m3 and of BC was 0.97 (SD 0.29) ×10-5 m-1. None of the air pollutants were associated with incident dementia or Alzheimer's disease. In the unadjusted model, increased exposure to PM2.5 was associated with an increased risk of vascular dementia (for a 5 µg/m3 increase: HR 1.62, 95% CI 1.13, 2.31). However, this association was attenuated following adjustment for confounders (HR 1.39, 95% CI 0.93, 2.08). NO2 and BC were not associated with vascular dementia incidence. DISCUSSION: Exposure to air pollution is not associated with increased risk of incident dementia in older men living in a region with relatively low ambient air pollution.

The Attenuating Effect of Beta-Carotene on Streptozotocin Induced Diabetic Vascular Dementia Symptoms in Rats.

This study investigated the ameliorative effects of beta-carotene (BC) on diabetes-associated vascular dementia and its action against biomolecule oxidation. The diabetic vascular dementia (VaD) was induced by administration of nicotinamide (NA; 50 mg/kg; i.p.) and streptozotocin (STZ; 50 mg/kg; i.p.). The test compound, BC (50 and 100 mg/kg; p.o.), and the reference compound, donepezil (DP) (1 mg/kg; p.o.), were administered for 15 consecutive days. Changes in learning and memory were assessed by escape latency time (ELT) and times spent in target quadrant (TSTQ) in the Morris water maze (MWM) test. The changes in neurotransmitter, i.e., acetylcholinesterase (AChE) and oxidative stress markers, i.e., thiobarbituric acid reactive substance (TBARS) and reduced glutathione (GSH), were estimated in hippocampal tissue of the rat brain. The administration of STZ caused significant deterioration of cognitive function (decreased ELT and raised the TSTQ) as compared to the normal group. Treatment with BC and DP diminished the increased AChE activity, TBARS level and decreased GSH level caused by STZ. Thus, BC ameliorates the diabetic vascular complications in VaD due to its potential anticholinergic, antioxidative and free radical scavenging actions.

Total and regional fat-to-muscle mass ratio and risks of incident all-cause dementia, Alzheimer's disease, and vascular dementia.

BACKGROUND: The fat-to-muscle mass ratio (FMR), which integrates the antagonistic effects of fat and muscle mass, has been proposed as a useful indicator to assess disease risk independent of overall obesity. However, little is known about the association between FMR and dementia risk. We aimed to prospectively investigate the sex-specific associations between total and regional FMR and incident dementia. METHODS: A total of 491 420 participants (223 581 men and 267 839 women; mean age 56.7 ± 8.2 and 56.3 ± 8.0 years old, respectively) free of dementia at baseline from the UK Biobank were included. Fat mass and muscle mass were measured using a bioelectrical impedance assessment device. Cox regression analyses were used to examine the associations of total and regional FMR with incident all-cause dementia, Alzheimer's disease (AD) and vascular dementia (VD). The shape of the associations of the continuous scale of FMR and incident dementia were examined using restricted cubic spline analysis. RESULTS: During a median 8.65 years of follow-up, we documented 2 225 incident all-cause dementia cases, including 836 AD and 468 VD cases. There was an L-shaped association between whole body FMR and all-cause dementia risk in both sexes after adjusting body mass index (BMI) and other covariates (P for non-linear <0.001 in men and women), where all-cause dementia risk decreased steeply with increasing FMR and levelled off at around the medians (0.35 in men, 0.61 in women) with a hazard ratio (HR) of 0.78 (95% CI: 0.64, 0.96; P = 0.019) and 0.60 (0.47, 0.77; <0.001) per 1 standard deviation (SD) increase in men and women, respectively. Compared with other body parts, FMR of the leg showed the strongest inverse associations [HR (95% CI; P) per 1 SD below the medians: 0.60 (0.48, 0.75; <0.001); 0.61 (0.47, 0.79; <0.001) in men and women, respectively]. Specifically, the inverse associations of whole body FMR on all-cause dementia risk were significant only among participants over the age of 60 (P for trend <0.001). Multivariable adjusted Cox models showed inverse associations of whole body FMR with AD in men only (P for trend = 0.003), whereas no statistically significant decrease was detected in VD among men and women. CONCLUSIONS: Our analyses provide strong evidence for L-shaped associations of total and regional FMR with the development of dementia among participants aged 60 years or older independent of overall obesity.

Salubrious effects of ulinastatin and quercetin alone or in combination in endothelial dysfunction and vascular dementia.

BACKGROUND: Vascular dementia is the second most prevalent form of dementia. Hypertension is the leading risk factor for endothelial dysfunction and the progression of dementia that is of vascular origin. This study investigates the role of ulinastatin (UTI) and quercetin alone as well as in combination in hypertension-induced endothelial dysfunction and vascular dementia (VaD). METHOD: Two-kidney one-clip (2K1C) renovascular model was set up to induce hypertension in the Albino Wistar rats (males). Rats were assessed for mean arterial blood pressure, behavioral function (Morris water maze, attention set-shifting tests), vascular endothelial function, and biochemical levels (aortic superoxide anion and serum nitrite/nitrate), as well as brains' thiobarbituric acid reactive species-TBARS, reduced glutathione-GSH, interleukin-6, 10, tumor necrosis factor-TNF-α and acetylcholinesterase-AChE). UTI (10,000 U/kg, ip) and quercetin (60 mg/kg) were used alone and in combination for treatment. Donepezil (0.5 mg/kg) was used as a positive control. RESULTS: 2K1C rats showed impairment in learning, memory, executive functioning, and reversal learning. These rats further showed endothelial dysfunction as well as an increase in mean arterial blood pressure, brains' oxidative stress, inflammation, and AChE-activity. Treatment with UTI and quercetin alone as well in combination significantly attenuated the 2K1C model induced impairments in the behavioural, biochemical, and endothelial parameters. CONCLUSION: 2K1C renovascular hypertension-induced impairment in behavioural, biochemical, and endothelial parameters were attenuated by the treatment with UTI and quercetin alone as well as in combination. Therefore, the utility of these agents might be studied further to understand their full potential in hypertension-induced VaD.

Comparative Study of Risk Factors and Cognitive Profile of Small- and Large-Vessel Vascular Dementia - A Clinic Based Study.

Background: Vascular dementia (VaD) is a clinically heterogeneous entity. There is a dearth of studies for comparison of the cognitive profile of cerebral small-vessel disease (SVD) with large-vessel disease. Objective: We planned to evaluate and compare the cognitive profile of SVD and large-vessel VaD and evaluate various risk factors associated with them. Materials and Methods: Patients of VaD were recruited after excluding mixed and ambiguous cases. Patients were classified into SVD and large-vessel VaD and analyzed for their clinic-epidemiological and cognitive profiles. Results: Among 76 patients, 48 (62.5%) have SVD and 28 (37.5%) have large-vessel disease. Hypertension (93.4%) was the commonest risk factor, followed by smoking (34.21%), hyperlipidemia (26.31%), and diabetes mellitus (DM, 22.36%). Hypertension (P < 0.05) and DM were common in SVD, whereas smoking, hyperlipidaemia, and cardiac diseases were common in large-vessel disease. Attention (77.1% vs 25%), executive function (68.8% vs 28.6%), and calculation (58.3% vs 32.1%) were significantly more impaired in SVD compared to large-vessel disease, whereas visuoperceptual (21.4% vs 6.3%), praxis (28.6% vs 4.2%), and gnosis (14.3% vs 2.1%) were significantly more impaired in large-vessel disease than in SVD. Disruption of frontal-subcortical connection was responsible for the cognitive profile in SVD, but in large-vessel disease, it resulted from the cumulative loss of function from different lesions. Conclusions: Despite having common vascular risk factors, few are more common in SVD than in large-vessel disease. The different clinical and cognitive profile is due to the diverse anatomical lesions in these two subclasses of VaD.

Resolving inflammatory links between myocardial infarction and vascular dementia.

Myocardial infarction is associated with increased risk for vascular dementia. In both myocardial infarction and vascular dementia, there is evidence that elevated inflammatory biomarkers are associated with worsened clinical outcomes. Myocardial infarction leads to a systemic inflammatory response, which may contribute to recruitment or activation of myeloid cells, including monocytes, microglia, and perivascular macrophages, within the central nervous system. However, our understanding of the causative roles for these cells linking cardiac injury to the development and progression of dementia is incomplete. Herein, we provide an overview of inflammatory cellular and molecular links between myocardial infarction and vascular dementia and discuss strategies to resolve inflammation after myocardial infarction to limit neurovascular injury.