Risk Of Vascular Dementia Research Articles

Late-onset epilepsy and the risk of dementia: a systematic review and meta-analysis.

Patients with dementia have higher risk of epilepsy. However, it remains not comprehensively evaluated if late-onset epilepsy (LOE) is associated with higher risk of dementia. We, therefore, performed a meta-analysis to systematically evaluate the association. Relevant cohort studies were identified by search of electronic databases including PubMed, Embase, and Web of Science. A randomized-effect model incorporating the possible between-study heterogeneity was used to pool the results. Overall, seven cohort studies including 873,438 adults were included, and 16,036 (1.8%) of them had LOE. With a mean follow-up duration of 8.7years, 33,727 of them were diagnosed as dementia. Pooled results showed that LOE was associated with a higher risk of dementia (risk ratio [RR] 2.39, 95% confidence interval [CI] 2.04-2.81, p < 0.001, I2 = 67%). Results of subgroup analysis showed that the association between LOE and the risk of dementia was stronger in hospital-derived participants (RR 4.23, 95% CI 2.67-6.70, p < 0.001) than that in community-derived population (RR 2.25, 95% CI 1.93-2.63, p < 0.001; p for subgroup difference = 0.01). Pooled results of three studies showed that LOE was associated with a higher risk of Alzheimer's disease (RR 2.35, 95% CI 1.08-5.08, p = 0.03, I2 = 85%). One study suggested a significant association between LOE and risk of vascular dementia (RR 2.0, 95% CI 1.77-2.26, p < 0.001). Evidence from cohort studies suggests that LOE may be a risk factor of dementia.

Triad of minimal antenatal care, pre-eclampsia and dementia in rural women: A deep insight and call for awareness.

Pre-eclampsia, a prominent gestational hypertensive disorder, affects around 2-8% of pregnancies and is the dominating cause of late- life maternal morbidities worldwide. Frequent signs of this disorder such as proteinuria, hypertension, and thrombocytopenia, are detected by physicians during the routine antenatal checkups of expectant women. Pre-eclampsia, if left untreated, delineates with complications like central nervous system dysfunction, microangiopathies, thromboembolism, and cerebrovascular accidents in later life of women.[1] Vascular dementia is noticed as one of the late-life complications in women with a history of preeclampsia. Two cohort analyses disclosed a significantly increased risk of vascular dementia in later life of women with a history of preeclampsia. [2,3] Incidence of vascular dementia was noticed as being thrice more common in these women when compared to the non-pre-eclamptic ones. [2] Like all over the world, high percentage of pre-eclampsia cases are also rampant in the rural areas of Pakistan. An analysis from Sukkar, rural Sindh, Pakistan, showed that Preeclampsia and eclampsia cases in a tertiary care hospital accounted for 112 (5.56%) of total 2012 deliveries. Out of these cases, 6.45% were unbooked, depicting the negligence of antenatal care, and 5.8% were found linked to low education levels. [4] The extensive urban-rural gap in the utilization of antenatal care can be determined by the fact that according to reports, 70% of women in the lower quantile of South Asia undergo labor at home in comparison 40% of them deliver without any professional assistance. In Southeast Asia, only 17.7% of lower area women were recorded to use public maternity facilities.[5] A survey from Interior Sindh of Pakistan reported that most rural women have no access to maternity centres within 10km of their living. The authors further stated that the rural residents believed that medical interventions could pose a threat to pregnancy so they preferred untrained midwives over proper maternity centre visits, which could be one of the prime reasons for undiagnosed gestational disorders in these women.[6] Lack of antenatal care utilization could be due to paucity of awareness amongst rural women or the dearth of maternity centres in such underdeveloped areas. Together these factors presented as the key attributes to vascular dementia favouring pre-eclampsia. In rural areas, where barriers to healthcare services and socioeconomic inequality already prevail, this untended rise is a red flag situation. Respective Governments should channel efforts in expanding the accessible maternity setups in these poorly facilitated areas. --Continue

Bacterial pneumonia and subsequent dementia risk: A nationwide cohort study

BackgroundBacterial pneumonia is associated with an increased risk of dementia. However, the association between different pathogens of bacterial pneumonia and the risk of dementia remains unclear. MethodsUsing the Taiwan National Health Insurance Research Database, we recruited 11,712 patients with bacterial pneumonia and 11,120 controls between 1997 and 2012 and followed them up until the end of 2013. A diagnosis of dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and unspecified dementia were identified during the follow-up period. Cox regression analyses were performed with adjustments for confounders. Sensitivity analysis was conducted to exclude patients with prodromal dementia. ResultsPatients with bacterial pneumonia were more likely to develop dementia (hazard ratio [HR]: 2.83, 95% confidence interval [CI]: 2.53–3.18), AD (HR: 2.44, 95% CI: 1.65–3.61), VaD (HR: 4.15, 95% CI: 3.20–5.38), and unspecified dementia (HR: 2.62, 95% CI: 2.29–3.00) compared with controls after adjusting for potential confounders. Subgroup pathogen analyses showed that the HR of AD was 3.85 (1.66–8.96) for Hemophilus, and the HR of VaD was 5.40 for Staphylococcus. The risks of dementia and VaD were associated with repeated hospitalization due to bacterial pneumonia in a dose-dependent manner. Sensitivity analyses after exclusion of the first three years or first five years of observation and after exclusion case enrollment before 2010 or 2008 showed consistent findings. ConclusionDifferent pathogens are associated with different risks of AD, VaD, and unspecified dementia. Further studies are necessary to investigate the underlying mechanisms of bacterial pneumonia and dementia.

Changes in Physical Activity and the Risk of Dementia in Patients With New-Onset Type 2 Diabetes: A Nationwide Cohort Study

We investigated the association between interval changes in physical activity (PA) and dementia risk among patients with new-onset type 2 diabetes. We identified 133,751 participants newly diagnosed with type 2 diabetes in a health screening (2009-2012), with a follow-up health screening within 2 years (2010-2015). PA level changes were categorized into continuous lack of PA, decreaser, increaser, and continuous PA groups. Dementia was determined using dementia diagnosis codes and antidementia drug prescriptions. During the median follow-up of 4.8 years, 3,240 new cases of all-cause dementia developed. Regular PA was associated with lower risks of all-cause dementia (adjusted hazard ratio [aHR] 0.82; 95% CI 0.75-0.90), Alzheimer disease (AD) (aHR 0.85; 95% CI 0.77-0.95), and vascular dementia (VaD) (aHR 0.78; 95% CI 0.61-0.99). Increasers who started to engage in regular PA had a lower risk of all-cause dementia (aHR 0.86; 95% CI 0.77-0.96). Moreover, the risk was further reduced among those with continuous regular PA: all-cause dementia (aHR 0.73; 95% CI 0.62-0.85), AD (aHR 0.74; 95% CI 0.62-0.88), and VaD (aHR 0.62; 95% CI 0.40-0.94). Consistent results were noted in various subgroup analyses. Regular PA was independently associated with lower risks of all-cause dementia, AD, and VaD among individuals with new-onset type 2 diabetes. Those with continuous regular PA and, to a lesser extent, those who started to engage in regular PA had a lower risk of dementia. Regular PA should be encouraged to prevent dementia in high-risk populations and those with new-onset type 2 diabetes.

Use of fish oil supplements is differently related to incidence of all-cause and vascular dementia among people with the distinct APOE ε4 dosage

Previous studies have shown that marine omega-3 PUFAs (fish oil) supplements was associated with improved cognitive function, whereas the association between use of fish oil supplements and risk of incident dementia was still unclear. We aimed to prospectively assess the relations between use of fish oil supplements and risks of all-cause and disease-specific dementia according to the apolipoprotein E (APOE) ε4 dosage. A total of 445,961 participants from UK biobank, who were free of dementia at baseline and completed data on supplement use and genetic information were analyzed in this study. Cox proportional hazards models were used to calculate the hazard ratios (HRs) comparing incident dementia rates in participants who did and did not use fish oil. During a median of 12.2 years of follow-up, a total of 5795 incident cases of dementia were documented, including 1266 cases of vascular dementia and 2382 cases of AD. After adjustment for covariates, use of fish oil supplements was significantly associated with lower risks of all-cause dementia (Hazard ratios, HR, 95% CI, 0.90, 0.85-0.96) and vascular dementia (HR, 0.85; 95% CI, 0.75-0.97), but not AD (HR, 0.99; 95% CI, 0.91-1.09). For all-cause dementia and vascular dementia, we found that the protective associations appeared to be attenuated by the increasing APOE ε4 dosage (P-interaction=0.002 and 0.002, respectively). Notably, the use of fish oil supplements was significantly associated with an 86.0% higher risk of vascular dementia in participants with two APOE-ε4 alleles (HR, 1.86, 95%CI, 1.23-2.80). Our results indicate that use of fish oil supplements is differently associated with risks of all-cause dementia and vascular dementia according to the APOE ε4 dosage.

Migraine and the risk of dementia: a meta-analysis and systematic review.

To conduct a comprehensive systematic review and meta-analysis to explore the correlation between migraine and the risk of dementia. The PubMed, EMBASE, and Cochrane library databases were searched systematically. We selected cohort studies (prospective and retrospective) and case-control studies that reported migraine in patients with dementia, including vascular dementia. The pooled effects were analyzed to evaluate relative risk with 95% confidence intervals. In total, nine studies (two case-control and seven cohort studies) including 291,549 individuals were identified. These studies indicated that people with migraine (relative risk = 1.33; 95% confidence interval: 1.16-1.53) have an increased risk of all-cause dementia. Additionally, the pooled results of four studies showed that migraine is associated with an increased risk of vascular dementia (relative risk = 1.85; 95% confidence interval: 1.22-2.81; P = 0.004). Data from observational studies suggest that migraine may be a risk factor for dementia, particularly vascular dementia. More studies are warranted to explore the association between migraine and dementia and the potential common pathophysiological mechanisms.

Blood pressure screening in midlife aids in prediction of dementia later in life.

BackgroundThere is substantial evidence that midlife hypertension is a risk factor for late life dementia. Our aim was to investigate if even high blood pressure at a single timepoint in midlife can predict an increased risk for all-cause dementia, Alzheimer’s disease (AD), or vascular dementia (VaD) later in life.MethodsThe community-based study population comprised 30,102 dementia-free individuals from the Westmannia Cardiovascular Risk Factors Study. The participants were aged 40 or 50 years when the health examination took place in 1990–2000. Diagnose registers from both hospitals and primary healthcare centers were used to identify individuals who after inclusion to the study developed dementia. The association between midlife high blood pressure (defined as systolic blood pressure >140 and/or diastolic blood pressure >90 mmHg) at a single timepoint and dementia was adjusted for age, gender, body mass index (BMI), fasting blood glucose, education, smoking, and physical activity level. Multivariate binary cox regression analyses were used.ResultsAfter a mean follow-up time of 24 years resulting in 662,244 person/years, 761 (2.5%) individuals had been diagnosed with dementia. Midlife high blood pressure at a single timepoint predicted all-cause dementia (hazard ratio [HR]: 1.22, 95% confidence interval [CI]: 1.02–1.45) and VaD (HR: 2.10, 95% CI: 1.47–3.00) but not AD (HR: 1.06, 95% CI: 0.81–1.38).ConclusionThis study suggests that even midlife high blood pressure at a single timepoint predicts all-cause dementia and more than doubles the risk for VaD later in life independently of established confounders. Even though there was no such association with AD, this strengthens the importance of midlife health examinations in order to identify individuals with hypertension and initiate treatment.

Development of the CogDrisk tool to assess risk factors for dementia.

IntroductionWe aimed to develop a comprehensive risk assessment tool for Alzheimer's disease (AD), vascular dementia (VaD), and any dementia, that will be applicable in high and low resource settings.MethodRisk factors which can easily be assessed in most settings, and their effect sizes, were identified from an umbrella review, or estimated using meta‐analysis where new data were available.ResultsSeventeen risk/protective factors met criteria for the algorithm to estimate risk for any dementia including age, sex, education, hypertension, midlife obesity, midlife high cholesterol, diabetes, insufficient physical activity, depression, traumatic brain injury, atrial fibrillation, smoking, social engagement, cognitive engagement, fish consumption (diet), stroke, and insomnia. A version for AD excluded atrial fibrillation and insomnia due to insufficient evidence and included pesticide exposure. There was insufficient evidence for a VaD risk score.DiscussionValidation of the tool on external datasets is planned. The assessment tool will assist with implementing risk reduction guidelines.

Prevalence of neuropsychiatric conditions in two parallel, aging study cohorts from rural and urban India

AbstractBackgroundNeuropsychiatric conditions occur more frequently among elderly. With rising proportion of elderly in India, the burden due to neuropsychiatric disorders is bound to escalate. Many of these disorders have been associated with dementia, though the relationship is complex.MethodPrevalence of neuropsychiatric conditions, such as stroke, head injury, depression and early‐life stress were assessed in two parallel, longitudinal, aging cohorts, from rural and urban India, namely, the Srinivaspura Aging Neurosenescence and COGnition (SANSCOG) study and Tata Longitudinal Study of Aging (TLSA), respectively. As part of their baseline clinical assessments, subjects from both cohorts were screened for depression using the self‐rated, Geriatric Depression Scale (GDS) and the clinician‐rated, Hamilton’s Depression Rating Scale (HDRS). Past history of depression and history of early life stressors, such as parental death and parental divorce in childhood were obtained. Self‐reported history of stroke, head injury and risk for vascular dementia using Hatchinski’s Ischemic Index (HIS) were also assessed.ResultProportion of subjects diagnosed with depression using GDS was 9.77% in the rural and 9.66% in the urban cohort, whereas corresponding numbers using HDRS were 6.55% and 3.82%, with female preponderance in both cohorts. Proportion of subjects with past history of depression was 4.82% and 5.07% in the rural and urban cohorts, respectively. Early life parental death was more in the rural 10.91%) as compared with the urban cohort (3.66%). History of stroke was reported in 1.25% and 2.31% of the rural and urban cohorts, respectively. There was no significant difference in proportion of subjects with history of head injury between the rural (4.16%) and urban (4.77%) cohorts. In the rural cohort, 0.23% scored above the threshold for vascular dementia on HIS, whereas none of the subjects scored above the threshold in the urban cohort.ConclusionGDS is a more sensitive tool than HDRS at screening for depression in elderly. Neuropsychiatric conditions such as history of stroke, head injury and risk for vascular dementia did not show any consistent trend of variation between both the cohorts. Further longitudinal assessments of these neuropsychiatric conditions along with parallel monitoring of cognitive changes will help in identifying their causal relationship with dementia.

The role of race/ethnicity, psychiatric history, and substance use in the risk of dementia subtypes: Findings from the NACC

AbstractBackgroundDementia is characterized by significant declines in cognitive and physical functioning and includes multiple subtypes that differ in etiology. There is limited evidence of the influence of psychiatric and substance use history on the risk of dementia subtypes among underrepresented racial/ethnic minorities. The study explored the role of psychiatric and substance use history on the risk of etiology‐specific dementias: Alzheimer’s disease (AD) and vascular dementia (VaD), in the context of a racially and ethnically diverse sample based on national data in the US.MethodWe conducted secondary data analyses based on the National Alzheimer’s Coordinating Center Uniform Data Set (N = 17,592). Participants completed at least two visits and were dementia‐free at baseline, and were assessed for history of five psychiatric and substance use disorders (depression, traumatic brain injury, other psychiatric disorders, alcohol use, and other substance use). Cox proportional hazard models were estimated to examine the influence of psychiatric and substance use history on the risk of two dementia subtypes, and the interactions between psychiatric and substance use history and race/ethnicity with adjustment for demographic and health‐related factors.ResultIn addition to other substance use, having any one type of psychiatric and substance use history increased the risk of developing AD by 22‐51% and VaD by 22‐53%. The risk of other psychiatric disorders on AD and VaD risk varied by race/ethnicity. For Non‐Hispanic White, history of other psychiatric disorders increased AD risk by 27% and VaD risk by 116%. For African Americans, AD risk increased by 28% and VaD risk increased by 108% when other psychiatric disorder history was present.ConclusionThe findings indicate that having psychiatric and substance use history increases the risk of developing AD and VaD in later life. Preventing the onset and recurrence of such disorders may prevent or delay the onset AD and VaD dementia subtypes. Prevention efforts should pay particular attention to Non‐Hispanic White and African American older adults who have history of other psychiatric disorders.

Ischemia‐triggered, immune‐mediated neurodegeneration as a component of VCID

AbstractBackgroundPost‐stroke cognitive decline is an important component of vascular dementia. Ischemia and vascular disease is present in the brains of the majority of both Alzheimer’s Disease and VCID cases, and brain ischemia alone, in the form of a clinical stroke, doubles the risk of later cognitive impairment independently of known vascular dementia risk factors. In stroke survivors one of the most distressing complications is post‐stroke cognitive decline, which occurs in up to a third of individuals within five years and impacts significantly on quality of life.MethodsTo disentangle the effects of ischemia from other vascular mechanisms of dementia, we utilize mouse models of post‐stroke cognitive decline in adult and aged mice, mouse behavior, immunohistochemistry, and gene expression. In addition, we utilize prospective longitudinal cohort studies in human stroke survivors to examine how immune phenotyping of peripheral blood predicts cognitive decline at one year and chronically.ResultsWe found that normal wildtype mice develop delayed cognitive decline after stroke that is associated with a chronic neuroimmune response characterized by B and T lymphocyte infiltration of the stroke. Both genetic and drug studies demonstrate that B lymphocytes are necessary for post‐stroke cognitive decline. In humans with stroke and dementia, we find similar B and T cell infiltration. In a prospective longitudinal cohort of stroke survivors tested with a comprehensive cognitive test battery we see a high rate of cognitive impairment in at least one cognitive domain among the participants. In keeping with an autoimmune‐like mechanism, humans with immune alterations in the acute phase after stroke are more likely to have cognitive decline after stroke.ConclusionsTaken together we have demonstrated that normal mice exhibit ischemia‐triggered immune‐mediated neurodegeneration after stroke. Human studies demonstrate similar mechanisms, however more work remains to be done to identify immune mechanisms and biomarkers that predict cognitive decline in living humans after stroke. It will then be important to determine how much these post‐ischemia maladaptive immune responses contribute to VCID.

Blood Pressure Levels and Risks of Dementia: a Nationwide Study of 4.5 Million People

There are inconsistent results on the impacts of controlling blood pressure (BP) on the risk of dementia. We investigated the association between BP and risk of dementia subtypes by antihypertensive treatment and comorbidities. Using the Korean National Health Insurance Service-Health Screening Database from 2009 to 2012, a total of 4 522 447 adults aged 60+ years without a history of dementia were analyzed and followed up for a mean of 5.4 years. Individuals were classified according to their baseline systolic BP (SBP) and diastolic BP; SBP 130 to <140 mm Hg and diastolic BP 80 to <90 mm Hg were used as reference groups. The risk of overall dementia and probable Alzheimer disease was significantly higher in the SBP≥160 and lower SBP groups. These U-shaped associations were consistent regardless of antihypertensive use or comorbidities. The risk of probable vascular dementia (VaD) was not higher among lower SBP groups and increased gradually as SBP increased. Although there was a linear association between SBP and the risk of probable VaD in individuals not taking antihypertensives or without comorbidities, there was a U-shaped association in individuals taking antihypertensives or with comorbidities. Patterns of association between diastolic BP and risk of probable Alzheimer disease or probable VaD were similar to those with SBP, except for the risk of probable VaD in individuals taking antihypertensives. In conclusion, risks of probable Alzheimer disease and probable VaD were different among lower BP groups. Although the risk of dementia appears higher in people with lower BP receiving antihypertensives, this finding may be affected by comorbidities.

Effect of Metabolic Syndrome on the Incidence of Dementia Based on National Insurance Data in Korea.

Background: To evaluate the association between metabolic syndrome (MetS) and the incidence of dementia using big data from national health claims and health examinations. Methods: This study involved 3,619,388 subjects categorized with MetS of three status based on the results of health examinations conducted in 2009. This was a longitudinal study of the incidence of dementia based on the national health claims from the date of health examinations in 2009 until December 31, 2018. This study was conducted for men and women aged 50 to 69 years living in Korea. A Cox proportional hazard regression was performed to analyze the risk of dementia according to the status of MetS. Results: The cumulative incidence of Alzheimer dementia was 0.41% in the non-Mets group, 0.54% in the pre-MetS group, and 0.67% in the MetS group. The cumulative incidence of vascular dementia was 0.19% in the non-Mets group, 0.27% in the pre-MetS group, and 0.34% in the MetS group. The risk of Alzheimer dementia in the pre-MetS group compared to the non-Mets group was 1.20-fold greater (95% confidence interval, CI: 1.14-1.26) and was 1.39-fold (95% CI: 1.31-1.48) greater in the MetS group. The risk of vascular dementia in the pre-MetS group compared to the non-Mets group was 1.30-fold greater (95% CI: 1.21-1.40) and the risk of vascular dementia was 1.53-fold (95% CI: 1.44 1.71) greater. Conclusions: This study showed that pre-MetS and MetS were related to an increased incidence of Alzheimer dementia and vascular dementia. Also, these results support efforts to decrease the incidence of Alzheimer dementia and vascular dementia through managing the Mets.

Effects of Nutrients on Platelet Function: A Modifiable Link between Metabolic Syndrome and Neurodegeneration?

Metabolic syndrome increases the risk of vascular dementia and other neurodegenerative disorders. Recent studies underline that platelets play an important role in linking peripheral with central metabolic and inflammatory mechanisms. In this narrative review, we address the activation of platelets in metabolic syndrome, their effects on neuronal processes and the role of the mediators (e.g., serotonin, platelet-derived growth factor). Emerging evidence shows that nutritional compounds and their metabolites modulate these interactions—specifically, long chain fatty acids, endocannabinoids and phenolic compounds. We reviewed the role of activated platelets in neurovascular processes and nutritional compounds in platelet activation.

Meta-analysis of association between migraine and risk of dementia.

The association between migraine and dementia has rarely been investigated, and available results are conflicting. Thus, the aim of this meta-analysis was to evaluate whether an association exists between migraine and dementia. We searched for cohort studies from databases including PubMed, EBSCO, Web of Science, and EMBASE database from inception to April 1, 2021, using subject and free words. RevMan 5.1software was used to calculate the risk ratio (RR) of dementia in patients with migraine. Subgroup and sensitivity analyses were conducted to assess the source of heterogeneity. A random-effects model was used when heterogeneity was present. The Funnel plot and Egger's test were used to evaluate publication bias. Five published cohort studies covering a total of 249,303 individuals were identified. Pooled analysis showed that migraine was associated with increased risk of all-cause dementia (RR: 1.34, 95% CI: 1.13-1.59) and Alzheimer's disease (AD) (RR: 2.49, 95% CI: 1.16-5.32). However, we did not found any association between migraine and risk of vascular dementia (VaD) (RR: 1.51, 95% CI: 0.77-2.96). Our results revealed that migraine was a potential risk indicator for AD and all-cause dementia.

Residential exposure to transportation noise in Denmark and incidence of dementia: national cohort study

ObjectiveTo investigate the association between long term residential exposure to road traffic and railway noise and risk of incident dementia.DesignNationwide prospective register based cohort study.SettingDenmark.Participants1 938 994 adults aged ≥60...

Cerebral microangiopathy at the type 2 diabetes mellitus: A histopathological update

Background and Aims: An estimated experts more than 90% of diabetes mellitus (DM) cases in the wide world correspond to type 2 diabetes (DM). Type 2 diabetes and its associated factors predispose patients to microvascular and macrovascular complications at the brain and increased risk of vascular dementia or development of a stroke. Our aim was to examine brain small vessels histological changes in patients with type 2 diabetes mellitus and diabetic encephalopathy.

The Neurovascular Unit in Dementia: An Opinion on Current Research and Future Directions.

Dementia is a burgeoning public health crisis, with 50 million people currently affected worldwide (Prince et al., 2015). As the population ages, this figure is set to rise dramatically by 40% over the next 12 years (Prince et al., 2015). Dementia is an umbrella term for several disorders which result in the progressive loss of memory or other cognitive functions (Scott and Barrett, 2007). It remains an incurable disease, and current therapeutics have limited efficacy at slowing disease progression for one third of patients (Rockwood et al., 2008). Of the dementia sub-types, Alzheimer's disease (AD) remains the most prevalent, accounting for ~60–70% cases (Alzheimer's-Society, 2016). Vascular dementia (VaD) is the second most common form and is responsible for ~20% of cases, with a further 10% being a combination of these two diseases (Alzheimer's-Society, 2016). However, in practise these distinctions are somewhat arbitrary given the significant overlap in altered vascular structure and function in both of these major sub-types (Kalaria and Ballard, 1999). At least 30% of patients with AD have evidence of cerebrovascular disease on post-mortem examination, and almost all have evidence of cerebral amyloid angiopathy, microvascular degeneration, and white matter lesions (Kalaria and Ballard, 1999). Similarly, one-third of patients with VaD exhibit pathology consistent with AD (e.g., hippocampal or temporal lobe atrophy) (Kalaria and Ballard, 1999). Longitudinal studies have demonstrated that vascular risk factors (e.g., hypertension), significantly increase the risk of both AD and VaD (Rius-Perez et al., 2018). In genetically at-risk individuals positive for apolipoprotein E4 (APOE4), atherosclerosis can increase the risk of AD by three-fold (Hoffmann et al., 2010). This article provides an opinion on the current evidence on the role of the neurovascular unit in dementia, for further information, several recent reviews are available on this topic (Nelson et al., 2016; Kisler et al., 2017).

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.

While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

Risks and Prognoses of Alzheimer's Disease and Vascular Dementia in Patients With Insomnia: A Nationwide Population-Based Study.

This study aimed to investigate the risk and prognosis of Alzheimer's disease (AD) and vascular dementia (VaD) in patients with insomnia using the National Health Insurance Service database covering the entire population of the Republic of Korea from 2007 to 2014. In total, 2,796,871 patients aged 40 years or older with insomnia were enrolled, and 5,593,742 controls were matched using a Greedy digit match algorithm. Mortality and the rate of admission to a long-term care facility were estimated using multivariable Cox analysis. Of all patients with insomnia, 138,270 (4.94%) and 26,706 (0.96%) were newly diagnosed with AD and VaD, respectively. The incidence rate ratios for AD and VaD were 1.73 and 2.10, respectively, in patients with insomnia compared with those without. Higher mortality rates and long-term care facility admission rates were also observed in patients with dementia in the insomnia group. Known cardiovascular risk factors showed interactions with the effects of insomnia on the risk of AD and VaD. However, the effects of insomnia on the incidence of AD and VaD were consistent between the groups with and without cardiovascular risk factors. Insomnia is a medically modifiable and policy-accessible risk factor and prognostic marker of AD and VaD.