Identification of molecular subtypes of dementia by using blood-proteins interaction-aware graph propagational network.

Plasma protein biomarkers have been considered promising tools for diagnosing dementia subtypes due to their low variability, cost-effectiveness, and minimal invasiveness in diagnostic procedures. Machine learning (ML) methods have been applied to enhance accuracy of the biomarker discovery. However, previous ML-based studies often overlook interactions between proteins, which are crucial in complex disorders like dementia. While protein-protein interactions (PPIs) have been used in network models, these models often fail to fully capture the diverse properties of PPIs due to their local awareness. This drawback increases the chance of neglecting critical components and magnifying the impact of noisy interactions. In this study, we propose a novel graph-based ML model for dementia subtype diagnosis, the graph propagational network (GPN). By propagating the independent effect of plasma proteins on PPI network, the GPN extracts the globally interactive effects between proteins. Experimental results showed that the interactive effect between proteins yielded to further clarify the differences between dementia subtype groups and contributed to the performance improvement where the GPN outperformed existing methods by 10.4% on average.

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.

Targeting Astrocyte Signaling Alleviates Cerebrovascular and Synaptic Function Deficits in a Diet-Based Mouse Model of Small Cerebral Vessel Disease.

Despite the indispensable role that astrocytes play in the neurovascular unit, few studies have investigated the functional impact of astrocyte signaling in cognitive decline and dementia related to vascular pathology. Diet-mediated induction of hyperhomocysteinemia (HHcy) recapitulates numerous features of vascular contributions to cognitive impairment and dementia (VCID). Here, we used astrocyte targeting approaches to evaluate astrocyte Ca2+ dysregulation and the impact of aberrant astrocyte signaling on cerebrovascular dysfunction and synapse impairment in male and female HHcy diet mice. Two-photon imaging conducted in fully awake mice revealed activity-dependent Ca2+ dysregulation in barrel cortex astrocytes under HHcy. Stimulation of contralateral whiskers elicited larger Ca2+ transients in individual astrocytes of HHcy diet mice compared with control diet mice. However, evoked Ca2+ signaling across astrocyte networks was impaired in HHcy mice. HHcy also was associated with increased activation of the Ca2+/calcineurin-dependent transcription factor NFAT4, which has been linked previously to the reactive astrocyte phenotype and synapse dysfunction in amyloid and brain injury models. Targeting the NFAT inhibitor VIVIT to astrocytes, using adeno-associated virus vectors, led to reduced GFAP promoter activity in HHcy diet mice and improved functional hyperemia in arterioles and capillaries. VIVIT expression in astrocytes also preserved CA1 synaptic function and improved spontaneous alternation performance on the Y maze. Together, the results demonstrate that aberrant astrocyte signaling can impair the major functional properties of the neurovascular unit (i.e., cerebral vessel regulation and synaptic regulation) and may therefore represent a promising drug target for treating VCID and possibly Alzheimer's disease and other related dementias.SIGNIFICANCE STATEMENT The impact of reactive astrocytes in Alzheimer's disease and related dementias is poorly understood. Here, we evaluated Ca2+ responses and signaling in barrel cortex astrocytes of mice fed with a B-vitamin deficient diet that induces hyperhomocysteinemia (HHcy), cerebral vessel disease, and cognitive decline. Multiphoton imaging in awake mice with HHcy revealed augmented Ca2+ responses in individual astrocytes, but impaired signaling across astrocyte networks. Stimulation-evoked arteriole dilation and elevated red blood cell velocity in capillaries were also impaired in cortex of awake HHcy mice. Astrocyte-specific inhibition of the Ca2+-dependent transcription factor, NFAT, normalized cerebrovascular function in HHcy mice, improved synaptic properties in brain slices, and stabilized cognition. Results suggest that astrocytes are a mechanism and possible therapeutic target for vascular-related dementia.

Inhibition of Glial Activation and Subsequent Reduction in White Matter Damage through Supplementation with a Combined Extract of Wheat Bran, Citrus Peel, and Jujube in a Rat Model of Vascular Dementia.

Vascular dementia (VaD) is the second most common type of dementia after Alzheimer's disease. In our previous studies, we showed that wheat bran extract (WBE) reduced white matter damage in a rat VaD model and improved memory in a human clinical trial. However, starch gelatinization made the large-scale preparation of WBE difficult. To simplify the manufacturing process and increase efficacy, we attempted to find a decoction containing an optimum ratio of wheat bran, sliced citrus peel, and sliced jujube (WCJ). To find an optimal ratio, the cell survival of C6 (rat glioma) cultured under hypoxic conditions (1% O2) was measured, and apoptosis was assessed. To confirm the efficacies of the optimized WCJ for VaD, pupillary light reflex, white matter damage, and the activation of astrocytes and microglia were assessed in a rat model of bilateral common carotid artery occlusion (BCCAO) causing chronic hypoperfusion. Using a combination of both searching the literature and cell survival experiments, we chose 6:2:1 as the optimal ratio of wheat bran to sliced citrus peel to sliced jujube to prepare WCJ. We showed that phytic acid contained only in wheat bran can be used as an indicator component for the quality control of WCJ. We observed in vitro that the WCJ treatment improved cell survival by reducing apoptosis through an increase in the Bcl-2/Bax ratio. In the BCCAO experiments, the WCJ-supplemented diet prevented astrocytic and microglial activation, mitigated myelin damage in the corpus callosum and optic tract, and, consequently, improved pupillary light reflex at dosages over 100 mg/kg/day. The results suggest that the consumption of WCJ can prevent VaD by reducing white matter damage, and WCJ can be developed as a safe, herbal medicine to prevent VaD.

Effect of Different Durations of Treatment With Antihypertensive Drugs With Anticholinergic Effects on the Risk of Dementia: A Target Trial Emulation Study.

Studying the effect of duration of treatment on prognostic outcomes using real-world data is challenging because only people who survive for a long time can receive a treatment for a long time. Specifying a target trial helps overcome such challenge. We aimed to estimate the effect of different durations of treatment with antihypertensive drugs with anticholinergic properties (AC AHT) on the risk of vascular dementia and Alzheimer's disease by emulating a target trial using the UK CPRD GOLD database (2001-2017). Comparing treatment for 3-6 years versus ≤3 years yielded null results for both types of dementia. Comparing a longer duration of treatment, >6 years versus ≤3 years, yielded a 10-year risk ratio of 0.69 (95% CI, 0.54-0.90) for vascular dementia and 0.91 (95% CI, 0.77-1.10) for Alzheimer's disease. For illustration, we performed an analysis that failed to emulate a target trial by assigning exposure categories using post-baseline information, obtaining implausible beneficial estimates. Our findings indicate a modest benefit of longer duration of treatment with AC AHT on vascular dementia and highlight the value of the target trial emulation to avoid selection bias in the evaluation of the effect of different durations of treatment.

Investigating the nexus of metabolic syndrome, serum uric acid, and dementia risk: a prospective cohort study.

BACKGROUND: The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. METHODS: Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. RESULTS: Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19-1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51-2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 µmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02-1.21; VD: HR = 1.50, 95% CI = 1.28-1.77). CONCLUSIONS: Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Specification curve analysis to identify heterogeneity in risk factors for dementia: findings from the UK Biobank.

BACKGROUND: In 2020, the Lancet Commission identified 12 risk factors as priorities for prevention of dementia, and other studies identified APOE e4/e4 genotype and family history of Alzheimer's disease strongly associated with dementia outcomes; however, it is unclear how robust these relationships are across dementia subtypes and analytic scenarios. Specification curve analysis (SCA) is a new tool to probe how plausible analytical scenarios influence outcomes. METHODS: We evaluated the heterogeneity of odds ratios for 12 risk factors reported from the Lancet 2020 report and two additional strong associated non-modifiable factors (APOE e4/e4 genotype and family history of Alzheimer's disease) with dementia outcomes across 450,707 UK Biobank participants using SCA with 5357 specifications across dementia subtypes (outcomes) and analytic models (e.g., standard demographic covariates such as age or sex and/or 14 correlated risk factors). RESULTS: SCA revealed variable dementia risks by subtype and age, with associations for TBI and APOE e4/e4 robust to model specification; in contrast, diabetes showed fluctuating links with dementia subtypes. We found that unattributed dementia participants had similar risk factor profiles to participants with defined subtypes. CONCLUSIONS: We observed heterogeneity in the risk of dementia, and estimates of risk were influenced by the inclusion of a combination of other modifiable risk factors; non-modifiable demographic factors had a minimal role in analytic heterogeneity. Future studies should report multiple plausible analytic scenarios to test the robustness of their association. Considering these combinations of risk factors could be advantageous for the clinical development and evaluation of novel screening models for different types of dementia.

Early-Onset Ocular Motor Cranial Neuropathy Is a Strong Predictor of Dementia: A Nationwide, Population-Based Cohort Study.

PURPOSE: To assess the risk of dementia in individuals with newly diagnosed ocular motor cranial neuropathy (OMCN). DESIGN: A nationwide, population-based cohort study using authenticated data from the Korean National Health Insurance Service (KNHIS). PARTICIPANTS: This study included 60 781 patients with OMCN who received a diagnosis between 2010 and 2017 and were followed up through 2018, with an average follow-up of 3.37 ± 2.21 years with a 1-year lag. After excluding patients with disease related to oculomotor dysfunction preceding the OMCN diagnosis, a total of 52 076 patients with OMCN were established. Of these, 23 642 patients who had participated in the National Health Screening Program (NHSP) within 2 years before the OMCN diagnosis were included. After applying the exclusion criteria, the final cohort comprised 19 243 patients and 96 215 age and sex-matched control participants without OMCN. METHODS: We identified patients with newly diagnosed OMCN in the KNHIS database and collected participant characteristics from the health checkup records of the NHSP. The study end point was determined by the first claim with a dementia diagnostic code and antidementia medications. The association of OMCN with dementia risk was examined using Cox proportional hazards regression analysis, adjusting for potential confounding factors. MAIN OUTCOME MEASURES: The main outcome measures were hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause dementia (ACD), Alzheimer's disease (AD), and vascular dementia (VaD) development in patients with OMCN relative to those without OMCN. RESULTS: Patients with newly diagnosed OMCN demonstrated higher metabolic comorbidities than those without OMCN. New OMCN was associated with an elevated risk of ACD (HR, 1.203; 95% CI, 1.113-1.300), AD (HR, 1.137; 95% CI, 1.041-1.243), and VaD (HR, 1.583; 95% CI, 1.286-1.948), independent of potential confounding factors. The younger age groups exhibited a stronger association between OMCN and ACD (HR, 8.690 [< 50 years] vs. 1.192 [≥ 50 years]; P = 0.0004; HR, 2.517 [< 65 years] vs. 1.099 [≥ 65 years]; P < 0.0001). CONCLUSIONS: This nationwide population-based study assessed the association between OMCN and dementia risk. Our results demonstrated a robust relationship between OMCN and the risk of dementia, particularly in the younger population. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Causal relationship between psoriasis vulgaris and dementia: Insights from Mendelian randomization analysis.

Many clinical studies have demonstrated a correlation between psoriasis vulgaris and dementia, yet this correlation remains controversial. Our study employed the Mendelian randomization (MR) method to investigate the causal relationship between psoriasis vulgaris and dementia. Data were obtained from the summary statistics of the genome-wide association studies from IEU-OpenGWAS project database. In univariate Mendelian randomization (UVMR) analysis, psoriasis vulgaris was used as exposure. Alzheimer disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson's disease with dementia (PDD) and frontotemporal dementia (FTD) served as the outcomes. In multivariate Mendelian randomization (MVMR) analysis, VaD served as the outcome. The first MVMR analysis used psoriasis vulgaris, mean platelet volume (MPV), platelet distribution width (PDW) and platelet count (PLT) as exposures. The second MVMR analysis used psoriasis vulgaris, vitamin D level and 25 hydroxyvitamin D level as exposures. The main analysis employed the inverse variance weighted method, and the outcomes were evaluated by odds ratio (OR) and 95% confidence interval (95% CI). In UVMR analysis, the results depicted that psoriasis vulgaris was associated with VaD (OR: 0.903, 95% CI: 0.818-0.996, p = 0.041). The results revealed insignificant associations between psoriasis vulgaris and other dementia types. After adjusting the effects of MPV, PDW and PLT in MVMR analysis, the association between psoriasis vulgaris and VaD was no longer significant (p = 0.164). Similarly, after adjusting the effects of vitamin D level and 25 hydroxyvitamin D level in MVMR analysis, the association between psoriasis vulgaris and VaD was also no longer significant (p = 0.533). Our study suggests that psoriasis vulgaris may potentially decrease VaD incidence. However, the causal association between psoriasis vulgaris and VaD may be impeded by platelet-related indices, vitamin D level and 25 hydroxyvitamin D level.

Clinical biomarker-based biological ageing and future risk of neurological disorders in the UK Biobank.

BACKGROUND: Many common neurological disorders are associated with advancing chronological age, but their association with biological age (BA) remains poorly understood. METHODS: We studied 325 870 participants in the UK Biobank without a diagnosed neurological condition at baseline and generated three previously-described measures of BA based on 18 routinely measured clinical biomarkers (PhenoAge, Klemera-Doubal method age (KDMAge), homeostatic dysregulation age). Using survival models, we assessed the effect of advanced BA on incident neurological diagnoses, including all-cause and cause-specific dementia, ischaemic stroke, Parkinson's disease and motor neuron disease. RESULTS: During a mean follow-up of 9.0 years, there were 1397 incident cases of dementia and 2515 of ischaemic stroke, with smaller case numbers of other diagnoses. The strongest associations with a 1 SD in BA residual were seen for all-cause dementia (KDMAge HR=1.19, 95% CI=1.11 to 1.26), vascular dementia (1.41, 1.25 to 1.60) and ischaemic stroke (1.39, 1.34 to 1.46). Weaker associations were seen for Alzheimer's disease and motor neuron disease, while, in contrast, HRs for Parkinson's disease tended to be <1. Results were largely consistent after adjustment for disease-specific covariates including common cardiometabolic risk factors. CONCLUSIONS: Advanced BA calculated from routine clinical biomarker results increases the risk of subsequent neurological diagnoses including all-cause dementia and ischaemic stroke.

Hypercholesterolemia and the Increased Risk of Vascular Dementia: a Cholesterol Perspective.

PURPOSE OF REVIEW: Vascular dementia (VaD) is the second most prevalent type of dementia after Alzheimer's disease.Hypercholesterolemia may increase the risk of dementia, but the association between cholesterol and cognitive function is very complex. From the perspective of peripheral and brain cholesterol, we review the relationship between hypercholesterolemia and increased risk of VaD and how the use of lipid-lowering therapies affects cognition. RECENT FINDINGS: Epidemiologic studies show since 1980, non-HDL-C levels of individuals has increased rapidly in Asian countries.The study has suggested that vascular risk factors increase the risk of VaD, such as disordered lipid metabolism. Dyslipidemia has been found to interact with chronic cerebral hypoperfusion to promote inflammation resulting in cognitive dysfunction in the brain.Hypercholesterolemia may be a risk factor for VaD. Inflammation could potentially serve as a link between hypercholesterolemia and VaD. Additionally, the potential impact of lipid-lowering therapy on cognitive function is also worth considering. Finding strategies to prevent and treat VaD is critical given the aging of the population to lessen the load on society. Currently, controlling underlying vascular risk factors is considered one of the most effective methods of preventing VaD. Understanding the relationship between abnormal cholesterol levels and VaD, as well as discovering potential serum biomarkers, is important for the early prevention and treatment of VaD.

7, 8-dihydroxyflavone Ameliorates Cholinergic Dysfunction, Inflammation, Oxidative Stress, and Apoptosis in a Rat Model of Vascular Dementia.

Vascular dementia (VD) is a degenerative cerebrovascular disorder associated with progressive cognitive decline. Previous reports have shown that 7,8-dihydroxyflavone (7,8-DHF), a well-known TrkB agonist, effectively ameliorates cognitive deficits in several disease models. Therefore, this study investigated the protective effects of 7,8-DHF against 2-VO-induced VD. VD was established in rats using the permanent bilateral carotid arteries occlusion (two-vessel occlusion, 2-VO) model. 7,8-DHF (5, 10, and 20 mg/kg) and Donepezil (10 mg/kg) were administered for 4 weeks. Memory function was assessed by the novel objective recognition task (NOR) and Morris water maze (MWM) tests. Inflammatory (TNF-α, IL-1ß, and NF-kß), oxidative stress, and apoptotic (BAX, BCL-2, caspase-3) markers, along with the activity of choline acetylcholinesterase (AChE) was assessed. p-AKT, p-CREB, BDNF, and neurotransmitter (NT) (GLU, GABA, and ACh) levels were also analyzed in the hippocampus of 2-VO rats. Our results show that 7,8-DHF effectively improved memory performance and cholinergic dysfunction in 2-VO model rats. Furthermore, 7,8-DHF treatment also increased p-AKT, p-CREB, and BDNF levels, suppressed oxidative, inflammatory, and apoptotic markers, and restored altered NT levels in the hippocampus. These findings imply that 7, 8-DHF may act via multiple mechanisms and as such serve as a promising neuroprotective agent in the context of VD.

Single-cell RNA Sequencing Identifies a Novel Subtype of Microglia with High Cd74 Expression that Facilitates White Matter Inflammation During Chronic Cerebral Hypoperfusion.

Vascular dementia (VaD) causes progressive cognitive decline in the elderly population, but there is short of available therapeutic measures. Microglia-mediated neuroinflammation is vigorously involved in the pathogenesis of VaD, but the traditional classification of microglial M1/M2 phenotypes remains restrictive and controversial. This study aims to investigate whether microglia transform into novel subtypes in VaD. Chronic cerebral hypoperfusion (CCH) rat model was constructed to mimic VaD. Microglia were isolated via magnetic-activated cell sorting and analyzed by single-cell RNA sequencing (scRNA-seq) and bioinformatics. The findings inferred from scRNA-seq and bioinformatics were further validated through in vivo experiments. In this study, microglia were divided into eight clusters. The proportion of MG5 cluster was significantly increased in the white matter of the CCH group compared with the Sham group and was named chronic ischemia-associated microglia (CIAM). Immunity- and inflammation-related genes, including RT1-Db1, RT1-Da, RT1-Ba, Cd74, Spp1, C3, and Cd68, were markedly upregulated in CIAM. Enrichment analysis illustrated that CIAM possessed the function of evoking neuroinflammation. Further studies unveiled that Cd74 is associated with the most abundant GO terms involved in inflammation as well as cell proliferation and differentiation. In addition, microglia-specific Cd74 knockdown mediated by adeno-associated virus decreased the abundance of CIAM in the white matter, thereby mitigating inflammatory cytokine levels, alleviating white matter lesions, and improving cognitive impairment for CCH rats. These findings indicate that Cd74 is the core molecule of CIAM to trigger neuroinflammation and induce microglial differentiation to CIAM, suggesting that Cd74 may be a potential therapeutic target for VaD.

Implementing the National Heart, Lung, and Blood Institute's Strategic Vision in the Division of Cardiovascular Sciences-2022 Update.

Spurred by the 2016 release of the National Heart, Lung, and Blood Institute's Strategic Vision, the Division of Cardiovascular Sciences developed its Strategic Vision Implementation Plan-a blueprint for reigniting the decline in cardiovascular disease (CVD) mortality rates, improving health equity, and accelerating translation of scientific discoveries into better cardiovascular health (CVH). The 6 scientific focus areas of the Strategic Vision Implementation Plan reflect the multifactorial nature of CVD and include (1) addressing social determinants of CVH and health inequities, (2) enhancing resilience, (3) promoting CVH and preventing CVD across the lifespan, (4) eliminating hypertension-related CVD, (5) reducing the burden of heart failure, and (6) preventing vascular dementia. This article presents an update of strategic vision implementation activities within Division of Cardiovascular Sciences. Overarching and cross-cutting themes include training the scientific workforce and engaging the extramural scientific community to stimulate transformative research in cardiovascular sciences. In partnership with other NIH Institutes, Federal agencies, industry, and the extramural research community, Division of Cardiovascular Sciences strategic vision implementation has stimulated development of numerous workshops and research funding opportunities. Strategic Vision Implementation Plan activities highlight innovative intervention modalities, interdisciplinary systems approaches to CVD reduction, a life course framework for CVH promotion and CVD prevention, and multi-pronged research strategies for combatting COVID-19. As new knowledge, technologies, and areas of scientific research emerge, Division of Cardiovascular Sciences will continue its thoughtful approach to strategic vision implementation, remaining poised to seize emerging opportunities and catalyze breakthroughs in cardiovascular sciences.

Long-Term Impact of Delirium on the Risk of Dementia in Hospitalized Older Patients: A Real-World Multicenter Study.

BACKGROUND: The association between delirium and dementia has been suggested, but mostly in the postoperative setting. This study aims to explore this relationship in a broader inpatient population, leveraging extensive real-world data to provide a more generalized understanding. METHODS: In this retrospective cohort study, electronic health records of 11,970,475 hospitalized patients aged over 60 from nine institutions in South Korea were analyzed. Patients with and without delirium were identified, and propensity score matching (PSM) was used to create comparable groups. A 10-year longitudinal analysis was conducted using the Cox proportional hazards model, which calculated the hazard ratio (HR) and 95% confidence interval (CI). Additionally, a meta-analysis was performed, aggregating results from all nine medical institutions. Lastly, we conducted various subgroup and sensitivity analyses to demonstrate the consistency of our study results across diverse conditions. RESULTS: After 1:1 PSM, a total of 47,306 patients were matched in both the delirium and nondelirium groups. Both groups had a median age group of 75-79 years, with 43.1% being female. The delirium group showed a significantly higher risk of all dementia compared with the nondelirium group (HR: 2.70 [95% CI: 2.27-3.20]). The incidence risk for different types of dementia was also notably higher in the delirium group (all dementia or mild cognitive impairment, HR: 2.46 [95% CI: 2.10-2.88]; Alzheimer's disease, HR: 2.74 [95% CI: 2.40-3.13]; vascular dementia, HR: 2.55 [95% CI: 2.07-3.13]). This pattern was consistent across all subgroup and sensitivity analyses. CONCLUSIONS: Delirium significantly increases the risk of onset for all types of dementia. These findings highlight the importance of early detection of delirium and prompt intervention. Further research studies are warranted to investigate the mechanisms linking delirium and dementia.

Risk of Dementia in Different Types of Cancer Survivors: A Nationwide Cohort Study.

OBJECTIVES: The association between specific types of malignancies and the subsequent risk of dementia remains unknown. DESIGN: A retrospective population-based cohort study based on data from Taiwan National Health Insurance Research Database. SETTING AND PARTICIPANTS: We recruited 32,250 patients who survived malignancies and 322,500 controls between 1998 and 2011 and followed them up until the end of 2013. MEASUREMENTS: Diagnoses of dementia (including Alzheimer's disease (AD), vascular dementia (VaD), and unspecified dementia) was made during the follow-up period. Cox regression analyses were performed after adjusting for potential confounders. A sensitivity analysis was conducted to exclude patients with prodromal dementia. RESULTS: Cancer survivors were more likely to develop AD (hazard ratio [HR]: 1.68, 95% confidence interval [CI]: 1.38-2.06), unspecified dementia (HR: 1.19, 95% CI: 1.07-1.32), and any dementia (HR: 1.26, 95% CI: 1.16-1.37) compared with controls after adjusting for potential confounders. Importantly, cancers of the digestive and genitourinary organs seem to be associated with AD, unspecified dementia, and any dementia, whereas only malignant neoplasms of the brain are more likely to develop into VaD. Sensitivity analyses after exclusion of the first three or five years of observation and after exclusion of case enrollment before 2009 or 2007 showed consistent findings. CONCLUSION: Cancer survivors are at higher risk of subsequent dementia. Different types of cancer survivors may contribute to variable risks of specific dementias. Further studies are necessary to investigate the underlying mechanisms in cancer survivors and patients with dementia.

Living Alone With Mild-to-Moderate Dementia Over a Two-Year Period: Longitudinal Findings From the IDEAL Cohort.

OBJECTIVES: To compare the experiences of people with dementia living alone or with others and how these may change over two years. DESIGN: We analysed longitudinal data from three assessment waves, one year apart, in the British IDEAL cohort. SETTING: Participants with mild-to-moderate dementia were recruited through National Health Service providers, where possible with a family caregiver, and interviewed at home. PARTICIPANTS: The current analyses include 281 people with dementia living alone and 1,244 living with others at baseline; follow-up data were available for 200 and 965 respectively at time 2 and 144 and 696 respectively at time 3. For those living alone, 140 nonresident caregivers contributed at baseline, 102 at time 2 and 81 at time 3. For those living with others, 1,127 family caregivers contributed at baseline, 876 at time 2 and 670 at time 3. MEASUREMENTS: Assessments covered: cognitive and functional ability; self-reported perceptions of health, mood, social engagement, quality of life, satisfaction with life and well-being; use of in-home and community care; and transitions into residential care. RESULTS: People living alone tended to have better cognitive and functional ability and were more frequent users of in-home care. However, they experienced poorer physical, social, and psychological health and reduced quality of life, satisfaction with life, and well-being. These differences persisted over time and rates of transition into residential care were higher. CONCLUSIONS: To facilitate continuing in place for people with dementia living alone, a dual focus on supporting functional ability and addressing psychosocial needs is essential in the context of an enabling policy framework.

Microvascular disease and its association with dementia in patients with type 2 diabetes: A nationwide cohort study in Taiwan.

AIM: To assess the likelihood of dementia in individuals with type 2 diabetes (T2D), distinguishing between those with and without microvascular diseases. METHODS: Leveraging the National Health Insurance Research Database in Taiwan, we identified individuals newly diagnosed with T2D from 1 January 2009 through 31 December 2014. Multivariable Cox proportional hazard models were used to compare the risk of outcomes. RESULTS: Individuals with microvascular disease had a significantly higher risk of all-cause dementia (adjusted hazard ratio [95% confidence interval] 1.13 [1.09, 1.17]) compared with matched individuals without microvascular disease. In addition, individuals with diabetic kidney disease and diabetic neuropathy were associated with a significantly increased risk of Alzheimer's disease (1.16 [1.02, 1.32] and 1.14 [1.03, 1.27]), vascular dementia (1.21 [1.06, 1.38] and 1.14 [1.02, 1.28]) and other dementia (1.11 [1.04, 1.19] and 1.10 [1.04, 1.16]), respectively, compared with those without microvascular disease. CONCLUSIONS: This nationwide cohort study showed that patients with T2D and microvascular disease, particularly diabetic kidney disease and diabetic neuropathy, were associated with a significantly higher risk of Alzheimer's disease, vascular dementia, other dementia and all-cause dementia than those without microvascular disease.

Diabetes, antidiabetic medications and risk of dementia: A systematic umbrella review and meta-analysis.

AIMS: The objective of this umbrella review and meta-analysis was to evaluate the effect of diabetes on risk of dementia, as well as the mitigating effect of antidiabetic treatments. MATERIALS AND METHODS: We conducted a systematic umbrella review on diabetes and its treatment, and a meta-analysis focusing on treatment. We searched MEDLINE/PubMed, Embase, PsycINFO, CINAHL and the Cochrane Library for systematic reviews and meta-analyses assessing the risk of cognitive decline/dementia in individuals with diabetes until 2 July 2023. We conducted random-effects meta-analyses to obtain risk ratios and 95% confidence intervals estimating the association of metformin, thiazolidinediones, pioglitazone, dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, meglitinides, insulin, sulphonylureas, glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) with risk of dementia from cohort/case-control studies. The subgroups analysed included country and world region. Risk of bias was assessed with the AMSTAR tool and Newcastle-Ottawa Scale. RESULTS: We included 100 reviews and 27 cohort/case-control studies (N = 3 046 661). Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with significant reduction in risk of dementia. When studies examining metformin were divided by country, the only significant effect was for the United States. Moreover, the effect of metformin was significant in Western but not Eastern populations. No significant effect was observed for dipeptidyl peptidase-4 inhibitors, α-glucosidase inhibitors, or insulin, while meglitinides and sulphonylureas were associated with increased risk. CONCLUSIONS: Metformin, thiazolidinediones, pioglitazone, GLP1RAs and SGLT2is were associated with reduced risk of dementia. More longitudinal studies aimed at determining their relative benefit in different populations should be conducted.

Genetic Susceptibility Variants of Vascular Dementia among Asians: A Systematic Review and Meta-Analysis.

INTRODUCTION: Vascular dementia (VaD), a neurocognitive impairment directly related to vascular injury, is the second most common cause of age-related dementia. Although numerous studies have investigated candidate genetic polymorphisms associated with VaD in Asia, the genetics of VaD remains unclear. METHODS: This review provides an updated meta-analysis of genetic polymorphisms associated with VaD in Asians, using the PRISMA guidelines. Published literature up to May 2021 was extracted from the PubMed, Scopus, Ovid, and EBSCOhost databases. Meta-analysis was conducted using the Open Meta analyst, Review Manager, and MedCalc® Statistical Software. Trial sequential analysis (TSA) was performed using TSA viewer software. RESULTS: A total of 46 eligible studies, comprising 23 genes and 35 single nucleotide polymorphisms, were retrieved. The meta-analysis was conducted on the following genetic polymorphisms, APOE ε2/3/4, MTHFR rs1801131, ACE rs4340 (I/D) gene polymorphism, and a PSEN1 intron 8 variant. The pooled odds ratio (ORs) revealed a significant increase in the risk of VaD in the apolipoprotein E (APOE) ε4 allelic model (OR, 1.79, p < 0.001), and the methylenetetrahydrofolate reductase (MTHFR) rs1801133 polymorphism T allele in the allelic model (OR, 1.23, p = 0.013). CONCLUSION: Our findings provide evidence that genetic polymorphisms of the APOE ε4 allele and MTHFR rs1801133 T allele increase the risk of developing VaD in Asians. However, future large-scale investigations examining particularly on South-Eastern and West-Asian populations are highly recommended.