Heterogeneous Disease Progression in a Mouse Model of Vascular Cognitive Impairment.

Recently, an asymmetric vascular compromise approach that replicates many aspects of human vascular cognitive impairment (VCI) has been reported. The present study aimed to first investigate on the reproducibility in the disease progression of this newly reported VCI model using wild-type C57BL6/J mice. The second aim was to assess how this approach will affect the disease progression of transgenic Alzheimer's disease (AD) 5XFAD mice subjected to VCI. C57BL6/J and 5XFAD mice were subjected to VCI by placing an ameroid constrictor on the right CCA and a microcoil on the left CCA. Infarcts and hippocampal neuronal loss did not appear predominantly in the right (ameroid side) as expected but randomly in both hemispheres. The mortality rate of C57BL6/J mice was unexpectedly high. Inducing VCI reduced amyloid burden in the hippocampi of 5XFAD mice. Since VCI is known to be complex and complicated, the heterogeneous disease progression observed from this current study shares close resemblance to the clinical manifestation of VCI. This heterogeneity, however, makes it challenging to test novel treatment options using this model. Further study is warranted to tackle the heterogeneous nature of VCI.

Survival and life-expectancy in a young-onset dementia cohort with six years of follow-up: the NeedYD-study.

OBJECTIVES: The aim of this study was to investigate survival time and life-expectancy in people with young-onset dementia (YOD) and to examine the relationship with age, sex, dementia subtype and comorbidity. DESIGN, SETTING AND PARTICIPANTS: Survival was examined in 198 participants in the Needs in Young-onset Dementia study, including participants with Alzheimer's dementia (AD), vascular dementia (VaD) and frontotemporal dementia (FTD). MEASURES: The primary outcomes were survival time after symptom onset and after date of diagnosis. Cox proportional hazards models were used to explore the relationship between survival and age, sex, dementia subtype and comorbidity. Additionally, the impact on remaining life expectancy was explored. RESULTS: During the six-year follow-up, 77 of the participants died (38.9%), 78 participants survived (39.4%) and 43 were lost to follow-up (21.7%). The mean survival time after symptom onset and diagnosis was 209 months (95% CI 185-233) and 120 months (95% CI 110-130) respectively. Participants with AD had a statistically significant shorter survival compared with VaD participants, both regarding survival after symptom onset (p = 0.047) as well as regarding survival after diagnosis (p = 0.049). Younger age at symptom onset or at diagnosis was associated with longer survival times. The remaining life expectancy, after diagnosis, was reduced with 51% for males and 59% for females compared to the life expectancy of the general population in the same age groups. CONCLUSION/IMPLICATIONS: It is important to consider the dementia subtype when persons with YOD and their families are informed about the prognosis of survival. Our study suggests longer survival times compared to other studies on YOD, and survival is prolonged compared to studies on LOD. Younger age at symptom onset or at diagnosis was positively related to survival but diagnosis at younger ages, nevertheless, still diminishes life expectancy dramatically.

Incident depression and mortality among people with different types of dementia: results from a longitudinal cohort study.

PURPOSE: The aim of this study was to investigate the independent and combined association of incident depression and dementia with mortality and to explore whether the magnitude of the association varies according to different types of dementia, including Alzheimer's disease and vascular dementia. METHODS AND DESIGN: The study was based on a population-based longitudinal cohort consisting of 9940 participants at baseline and followed for over 14 years. The sample used for the analyses included 6114 participants with available information on diagnosis of incident dementia and depression. For survival analyses, Cox regression models with incident dementia (n = 293; 5%) and incident depression (n = 746; 12%) as time-dependent variables were used. RESULTS: Cox models adjusted for relevant confounders indicated that comorbidity of incident vascular dementia and incident depression was associated with a much higher mortality risk (HR 6.99; 95% CI 3.84-12.75) than vascular dementia in the absence of depression (HR 2.80; 95% CI 1.92-4.08). In contrast, estimates for comorbidity of Alzheimer's disease and depression were slightly lower than those for Alzheimer in absence of depression (HR 3.56; 95% CI 1.83-6.92 and HR 4.19; 95% CI 2.97-5.90, respectively). Incident depression in the absence of incident dementia was only weakly associated with mortality. CONCLUSIONS: These findings indicate that depression and vascular dementia might have synergistic effects on mortality. The results have relevant public health implications for prevention, routine screening for and early treatment of depression among older people, especially those at risk of vascular dementia.

IL-1α and IL-6 predict vascular events or death in patients with cerebral small vessel disease-Data from the SHEF-CSVD study.

PURPOSE: The natural clinical course of cerebral small vessel disease (CSVD) was not thoroughly described. The aim of this single center cohort study was to establish biochemical predictors of vascular events and death in CSVD patients during a 24-month follow-up. PATIENTS AND METHODS: A total of 130 functionally independent patients with marked MRI features of CSVD and recent lacunar stroke (n = 52,LS), vascular Parkinsonism (n = 28,VaP) or dementia (n = 50,VaD) were prospectively recruited. Serum markers of endothelial dysfunction, inflammation and hemostasis were determined at baseline. The primary outcome was defined as occurrence of death or any vascular events during the observation. RESULTS: The mean age was 72 ± 8.1 years, and 37.6% of the patients were women. The mean follow-up time was 22.3 ± 4.3 months, and 84.6% of patients had extensive white matter lesions on baseline MRI. The overall mortality rate was 6.9%, and vascular events or death occurred in 27% of the patients. Kaplan-Meier survival curves revealed no significant differences between CSVD groups (log rank p = 0.49). Cox regression analysis revealed that IL-1α (HR 1.4; 95%CI 1.09-1.8), IL-6 (1.4;1.1-2.2), hs-CRP (1.1;1.06-1.9), homocysteine (1.4;1.1-1.8), fibrinogen (1.4;1.05-2), and d-dimer (2.7;1.6-4.5) were significantly associated with the primary outcome. IL-1α (1.3;1.07-1.8), IL-6 (1.4;1.02-2.2), d-dimer (2.8;1.6-5) and homocysteine (1.4;1.1-1.8) remained significant after adjusting for age, sex and CSVD radiological markers. CONCLUSIONS: Our study demonstrated the important prognostic role of various circulation markers of inflammation in individuals with different clinical signs and radiological markers of CSVD. The strongest association occurred between IL-1α, IL-6 and recurrent stroke, other vascular events and death.

Association of hyperglycemia episodes on long-term mortality in type 2 diabetes mellitus with vascular dementia: A population-based cohort study.

AIM: This study investigated the effect of severe hyperglycemia episodes on survival and associated factors related to risk of mortality in type 2 diabetes mellitus (DM) patients with dementia. METHODS: We enrolled all type 2 DM patients newly diagnosed as having dementia in Taiwan from 1998 to 2005. These patients were categorized into those who had hyperglycemia episodes and those who did not based on whether or not they had been hospitalized for hyperglycemia after dementia diagnosis. Factors independently associated with mortality were evaluated. RESULTS: Of 5314 patients identified, 303 (5.7%) had at least one hyperglycemia hospitalization. Patients with at least one hyperglycemia hospitalization had a 30% greater risk of mortality than those who had no such admissions (adjusted hazard ratio: 1.30, 95% confidence interval: 1.09-1.55). Other variables, including age, sex, geographical region, insurance amount, patient with congestive heart failure, cerebrovascular disease, renal disease, use of anti-hypertensive drugs, use of anti-lipid drugs, and use of insulin were independently associated with risk of mortality. CONCLUSION: Severe hyperglycemia is common in type 2 DM patients with dementia and it substantially shortens their life. The findings of this study suggest a great need to improve care in DM patients with dementia.

Tube feeding decreases pneumonia rate in patients with severe dementia: comparison between pre- and post-intervention.

BACKGROUND: It is widely supposed that there is no benefit, including extended survival and decreased rate of pneumonia, in patients with severe dementia receiving enteral tube feeding (TF). However, there have been few studies comparing the frequency of pneumonia before and after TF in severe dementia. METHODS: Nine psychiatric hospitals in Okayama Prefecture participated in this retrospective survey. All inpatients fulfilling the entry criteria were evaluated. All subjects suffered from difficulty in oral intake. Attending physicians thought that the patients could not live without long-term artificial nutrition, and they decided whether or not to make use of long-term artificial nutrition from January 1, 2014 to December 31, 2014. RESULTS: We evaluated 58 patients including 46 with TF and 12 without. The mean age of all patients was 79.6 ± 9.0 years old. Patients with probable Alzheimer's disease (n = 38) formed the biggest group, and those with vascular dementia the second (n = 14). Median survival times were 23 months among patients with TF and two months among patients without TF. The start of TF decreased the frequency of pneumonia and the use of intravenous antibiotics. CONCLUSIONS: TF decreased pneumonia and antibiotic use, even in patients with severe dementia. The results of this study do not necessarily indicate that we should administer TF to patients with severe dementia. We should consider the quality of life of patients carefully before deciding the use or disuse of TF for patients with severe dementia.

Observational study of vascular dementia in the Spanish elderly population according to type 2 diabetes status: trends in incidence, characteristics and outcomes (2004-2013).

OBJECTIVES: To examine trends overtime in the incidence and in-hospital outcomes of vascular dementia (VaD) hospitalisations in patients aged 70 years or over suffering and not suffering from type 2 diabetes mellitus (T2DM) between 2004 and 2013 in Spain. DESIGN: Retrospective study. SETTING: Spain. PARTICIPANTS: National hospital discharge data were used; patients aged ≥70, discharged from a hospital with VaD as a primary diagnosis, were selected. MAIN OUTCOME MEASURES: Overall incidence, therapeutic and diagnostic procedures, comorbidities, infectious complications, duration of hospital stays and in-hospital mortality (IHM). RESULTS: In total, 170 607 admissions for VaD (34.3% with T2DM) were identified. We found a significant upward linear trend in the incidence of VaD for men and women with and without diabetes between 2004 and 2013. The adjusted incidence was higher among people with T2DM over the study period. We found a higher incidence in men than women in all years under study. A positive association between T2DM and VaD hospitalisation was found among both men (IRR 2.14, 95% CI 2.11 to 2.16) and women (incidence rate ratio (IRR) 2.22; 95% CI 2.19 to 2.25). Pneumonia was significantly associated with a higher mortality (OR 2.59, 95% CI 2.52 to 2.67). We found that percutaneous endoscopic gastrostomy was associated with lower IHM (OR 0.37, 95% CI 0.31 to 0.45), while parenteral nutrition had the opposite effect (OR 1.29, 95% CI 1.18 to 1.41). There was no association between diabetes and higher IHM (OR 0.99, 95% CI 0.93 to 1.06). The time-trend analyses of the entire sample showed a significant reduction in mortality in patients with VaD (OR 0.98, 95% CI 0.97 to 0.99). CONCLUSIONS: Incidence rates for VaD hospitalisations were twice as high in patients with diabetes compared with those without. Men had significantly higher incidence rates than women, regardless of diabetes status. In both groups studied, pneumonia and parenteral nutrition were associated with mortality while percutaneous endoscopic gastrostomy was associated with survival. Having diabetes was not associated with higher IHM after hospitalisation with VaD.

Lower Death Risk for Vascular Dementia Than for Alzheimer's Disease With Postmenopausal Hormone Therapy Users.

Context: There are conflicting data on postmenopausal hormone therapy (HT) and the risk of vascular dementia (VD) and Alzheimer's disease (AD). Objective: We analyzed the mortality risk attributable to VD or AD in women with a history of HT use. Design, Patients, Interventions, and Main Outcome Measures: Finnish women (n = 489,105) using systemic HT in 1994 to 2009 were identified from the nationwide drug reimbursement register. Of these women, 581 died of VD and 1057 of AD from 1998 to 2009. Observed deaths in HT users with <5 or ≥5 years of exposure were compared with deaths that occurred in the age-standardized female population. Furthermore, we compared the VD or AD death risk of women who had started HT at <60 vs ≥60 years of age. Results: Risk of death from VD was reduced by 37% to 39% (<5 or ≥5 years of exposure) with the use of any systemic HT, and this reduction was not associated with the duration or type (estradiol only or estradiol-progestin combination) of HT. Risk of death from AD was not reduced with systemic HT use <5 years, but was slightly reduced (15%) if HT exposure exceeded 5 years. Age at systemic HT initiation (<60 vs ≥60 years) did not affect the death risk reductions. Conclusion: Estradiol-based HT use is associated with a reduced risk of death from both VD and AD, but the risk reduction is larger and appears sooner in VD than AD.

Causes of Death According to Death Certificates in Individuals with Dementia: A Cohort from the Swedish Dementia Registry.

OBJECTIVES: The causes of death in dementia are not established, particularly in rarer dementias. The aim of this study is to calculate risk of death from specific causes for a broader spectrum of dementia diagnoses. DESIGN: Cohort study. SETTING: Swedish Dementia Registry (SveDem), 2007-2012. PARTICIPANTS: Individuals with incident dementia registered in SveDem (N = 28,609); median follow-up 741 days. Observed deaths were 5,368 (19%). MEASUREMENTS: Information on number of deaths and causes of mortality was obtained from death certificates. Odds ratios for the presence of dementia on death certificates were calculated. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox hazards regression for cause-specific mortality, using Alzheimer's dementia (AD) as reference. Hazard ratios for death for each specific cause of death were compared with hazard ratios of death from all causes (P-values from t-tests). RESULTS: The most frequent underlying cause of death in this cohort was cardiovascular (37%), followed by dementia (30%). Dementia and cardiovascular causes appeared as main or contributory causes on 63% of certificates, followed by respiratory (26%). Dementia was mentioned less in vascular dementia (VaD; 57%). Compared to AD, cardiovascular mortality was higher in individuals with VaD than in those with AD (HR = 1.82, 95% CI = 1.64-2.02). Respiratory death was higher in individuals with Lewy body dementia (LBD, including Parkinson's disease dementia and dementia with Lewy bodies, HR = 2.16, 95% CI = 1.71-2.71), and the risk of respiratory death was higher than expected from the risk for all-cause mortality. Participants with frontotemporal dementia were more likely to die from external causes of death than those with AD (HR = 2.86, 95% CI = 1.53-5.32). CONCLUSION: Dementia is underreported on death certificates as main and contributory causes. Individuals with LBD had a higher risk of respiratory death than those with AD.

Reporting of clinically diagnosed dementia on death certificates: retrospective cohort study.

BACKGROUND: mortality statistics are a frequently used source of information on deaths in dementia but are limited by concerns over accuracy. OBJECTIVE: to investigate the frequency with which clinically diagnosed dementia is recorded on death certificates, including predictive factors. METHODS: a retrospective cohort study assembled using a large mental healthcare database in South London, linked to Office for National Statistics mortality data. People with a clinical diagnosis of dementia, aged 65 or older, who died between 2006 and 2013 were included. The main outcome was death certificate recording of dementia. RESULTS: in total, 7,115 people were identified. Dementia was recorded on 3,815 (53.6%) death certificates. Frequency of dementia recording increased from 39.9% (2006) to 63.0% (2013) (odds ratio (OR) per year increment 1.11, 95% CI 1.07-1.15). Recording of dementia was more likely if people were older (OR per year increment 1.02, 95% CI 1.01-1.03), and for those who died in care homes (OR 1.89, 95% CI 1.50-2.40) or hospitals (OR 1.14, 95% CI 1.03-1.46) compared with home, and less likely for people with less severe cognitive impairment (OR 0.95, 95% CI 0.94-0.96), and if the diagnosis was Lewy body (OR 0.30, 95% CI 0.15-0.62) or vascular dementia (OR 0.79, 95% CI 0.68-0.93) compared with Alzheimer's disease. CONCLUSIONS: changes in certification practices may have contributed to the rise in recorded prevalence of dementia from mortality data. However, mortality data still considerably underestimate the population burden of dementia. Potential biases affecting recording of dementia need to be taken into account when interpreting mortality data.

Influence of pneumonia complications on the prognosis of patients with autopsy-confirmed Alzheimer's disease, dementia with Lewy bodies, and vascular dementia.

BACKGROUND: Pneumonia is a major, complicated disease in patients with dementia. However, the influence of pneumonia on the prognosis of patients with varying types of dementia has not been fully evaluated. METHODS: We retrospectively analyzed the data from medical and autopsy reports. All study patients had been hospitalized and underwent brain autopsy in a hospital in Toyohashi, Japan, between 2005 and 2014. The patients with subtypes of dementia, specifically Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or vascular dementia (VaD), were neuropathologically diagnosed and examined. Pneumonia incidence, cause of death, and the clinical time-course of dementia were compared among the dementia subtypes. The time to death from dementia onset (survival time) was compared by the Kaplan-Meier method among subtypes of dementia with or without pneumonia. Risk factors for survival time on all study patients were analyzed with the Cox proportional hazard model. RESULTS: Of the 157 eligible patients, 63 (40.1%) had AD, 42 (26.8%) had DLB, and 52 (33.1%) had VaD. Pneumonia complication was observed with high incidence in each subtype of dementia, especially in DLB (90.5%). The median total duration from dementia onset to death was 8 years in AD and DLB, and 5 years in VaD. The VaD subtype had more male patients than AD or DLB (P = 0.010), and age of death in this group was the youngest among the three groups (P = 0.018). A significant difference was observed in the survival time by the Kaplan-Meier method among the three groups (P < 0.001) and among the groups with pneumonia (P = 0.002). The factors associated with shorter survival time were male gender, pneumonia complications, diabetes mellitus, age of dementia onset ≥ 75 years, and VaD. CONCLUSIONS: Pneumonia complications shortened the survival time of patients with AD, DLB, and VaD.

Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory.

Rats subjected to bilateral common carotid arteries (CCAs) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia (SIVD). However, these models possess an inherent limitation in that cerebral blood flow (CBF) drops sharply and substantially after ligation of CCAs without vascular risk factors and causative small vessel changes. We previously reported a novel rat model of 2-vessel gradual occlusion (2VGO) in which ameroid constrictors (ACs) were placed bilaterally in the CCAs of Wistar-Kyoto rats. To simulate SIVD pathology more closely, we applied ACs in spontaneously hypertensive rats (SHRs), which naturally develop small vessel pathology, and compared their phenotypes with SHR-2VO and sham-operated rats. The mortality rate of the SHR-2VGO was 0% while that of the SHR-2VO was 56.5%. The CBF of the SHR-2VO dropped to 50% of the baseline level at 3 h, whereas the SHR-2VGO showed a gradual CBF reduction reaching only 68% of the baseline level at seven days. The SHR-2VGO showed slowly evolving white matter abnormalities and subsequent spatial working memory impairments of a similar magnitude to the remaining SHR-2VO at 28 days. We suggest the SHR-2VGO robustly replicates selective aspects of the pathophysiology of SIVD with low mortality rate.

Survival in Subcortical Vascular Dementia: Predictors and Comparison to Probable Alzheimer's Disease in a Tertiary Memory Clinic Population.

BACKGROUND: Subcortical vascular dementia (SVaD) is one of the most common dementias, after Alzheimer's disease (AD) dementia. Few survival analyses in SVaD patients have been reported. METHODS: The dates and causes of death of 146 SVaD and 725 AD patients were included. We used the Cox proportional hazards model to compare survival between SVaD and AD patients and to explore possible factors related to survival of SVaD patients. RESULTS: The median survival time after the onset of SVaD (109 months) was shorter than that recorded for AD (152 months). The most common cause of death in SVaD was stroke (47.1%). Factors associated with shorter survival in SVaD were late onset, male sex, worse baseline cognition, absence of hypertension and a family history of stroke. CONCLUSIONS: Stroke prevention may be important in SVaD treatment because 47.1% of SVaD patients died of stroke. A family history of stroke and absence of hypertension were associated with a shorter survival in SVaD, suggesting the existence of genetic or unknown risk factors.

Heart failure and dementia: survival in relation to types of heart failure and different dementia disorders.

AIMS: Heart failure (HF) and dementia frequently coexist, but little is known about their types, relationships to each other and prognosis. The aims were to (i) describe patients with HF and dementia, assess (ii) the proportion of specific dementia disorders in types of HF based on ejection fraction and (iii) the prognostic role of types of HF and dementia disorders. METHODS AND RESULTS: The Swedish Heart Failure Registry (RiksSvikt) and The Swedish Dementia Registry (SveDem) were record-linked. Associations between dementia disorders and HF types were assessed with multinomial logistic regression and survival was investigated with Kaplan-Meier analysis and multivariable Cox regression. We studied 775 patients found in both registries (55% men, mean age 82 years). Ejection fraction was preserved in 38% of patients, reduced in 34%, and missing in 28%. The proportions of dementia disorders were similar across HF types. Vascular dementia was the most common dementia disorder (36%), followed by other dementias (28%), mixed dementia (20%), and Alzheimer disease (16%). Over a mean follow-up of 1.5 years, 76% of patients survived 1 year. We observed no significant differences in survival with regard to HF type (P = 0.2) or dementia disorder (P = 0.5). After adjustment for baseline covariates, neither HF types nor dementia disorders were independently associated with survival. CONCLUSIONS: Heart failure with preserved ejection fraction was the most common HF type and vascular dementia was the most common dementia disorder. The proportions of dementia disorders were similar across HF types. Neither HF types nor specific dementia disorders were associated with survival.

The natural history of dementia.

This review summarizes studies on the natural history of dementia with a focus on Alzheimer's disease and vascular dementia. Understanding the course of dementia is important not only for patients, caregivers, and health professionals, but also for health policy-makers, who have to plan for national resources needed in the management of an increasing number of dementia cases. From the available published data, the life expectancy of elderly people with dementia is shorter than that of non-demented elderly. Reports on survival after a diagnosis of dementia vary from 3 to 12 years. The wide variation is partly due to the diagnostic criteria used in the studies and the sites where they were conducted (i.e. hospitals, clinics, or homes). There is an apparent difference in survival between Alzheimer's disease patients with onset of illness before 75 years and those after 75 years: the younger patients have a longer life expectancy. However, there are conflicting data on survival (in years) comparing male and female patients and comparing patients of different ethnicities. For vascular dementia, published papers on life expectancy vary between 3 to 5 years. Vascular dementia appears to have a poorer prognosis than Alzheimer's disease. The stages of severity of dementia were compared in a follow-up of a sample of Alzheimer's disease patients in Singapore, and the mean duration of the mild phase (clinical dementia rating 1) was 5.6 years, the moderate phase (clinical dementia rating 2) was 3.5 years, and the severe phase (clinical dementia rating 3) was 3.2 years. At the various phases of the disease, the demand on health-care services and economic cost are different.

Association between risk factors for vascular dementia and adiponectin.

Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia.

Associations between risk of mortality and atypical antipsychotic use in vascular dementia: a clinical cohort study.

OBJECTIVES: People with vascular dementia (VaD) are frequently prescribed atypical antipsychotics to treat behavioural and psychological symptoms, but there is an alarming lack of evidence regarding their safety or efficacy in VaD. This study sought to identify the mortality risk associated with the most commonly prescribed atypical antipsychotics in people with VaD compared with people not exposed to these drugs. METHODS: A clinical cohort study of 1531 people with VaD performed using anonymised versions of full electronic health records from the Clinical Record Interactive Search application at the South London and Maudsley NHS Foundation Trust. Patients were identified from 2007 to 2010, of whom 337 were exposed to quetiapine, risperidone or olanzapine. The main outcome measure was mortality. RESULTS: Patients exposed to atypical antipsychotics were not at increased risk of mortality [hazard ratio (HR) 1.05, 95% confidence interval (CI): 0.87-1.26]. Exposure to risperidone did not result in an increased risk of mortality (HR = 0.85; 95% CI: 0.59-1.24), and patients exposed to quetiapine had a non-significant numerical increase in mortality risk (HR = 1.14; 95% CI: 0.93-1.39; p-value = 0.20) compared with untreated patients. Too few patients were exposed to olanzapine alone to provide reliable results. CONCLUSIONS: The absence of a significant increase in mortality risk associated with atypical antipsychotics in people with VaD indicates that a clinical trial of antipsychotics focussing on the treatment of aggression and agitation in this patient group will be justified and feasible following further consideration of possible confounders, which will be critical to determine the role of antipsychotics in treatment of VaD.

Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF-VEGFR2 signaling pathway in a rat model of vascular dementia.

Bone marrow mononuclear cells (BMMNCs) are important for angiogenesis after stroke. We investigated the effects of BMMNCs on cognitive function, angiogenesis, and the vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling pathway in a rat model of vascular dementia. We transplanted BMMNCs into rats that had undergone permanent bilateral occlusion of the common carotid arteries (2VO) and observed their migration in vivo. On day 28, we assessed cognitive function with the Morris Water Maze test and examined vascular density and white matter damage within the corpus striatum by staining with fluorescein lycopersicon esculentum (tomato) lectin or Luxol fast blue. We evaluated expression of VEGF, rapidly accelerated fibrosarcoma 1 (Raf1), and extracellular-signal-regulated kinases 1 and 2 (ERK1/2) in the ischemic hemisphere by Western blot analysis on day 7 after cell transplantation. Contribution of the VEGF-VEGFR2 signaling pathway was confirmed by using VEGFR2 inhibitor SU5416. BMMNCs penetrated the blood-brain barrier and reached the ischemic cortex and white matter or incorporated into vascular walls of 2VO rats. BMMNC-treated 2VO rats had better learning and memory, higher vascular density, and less white matter damage than did vehicle-treated rats. The beneficial effects of BMMNCs were abolished by pretreatment of rats with SU5416. Protein expression of VEGF and phosphorylated Raf1 and ERK1/2 was also significantly increased by BMMNC treatment, but this upregulation was reversed by SU5416. BMMNCs can enhance angiogenesis, reduce white matter damage, and promote cognitive recovery in 2VO rats. The angiogenic effect may result from upregulation of the VEGF-VEGFR2 signaling pathway.