Repetitive transcranial magnetic stimulation impacts the executive function of patients with vascular cognitive impairment: a systematic review and meta-analysis.

Objective: Executive dysfunction is a core symptom of vascular cognitive impairment (VCI), which seriously affects patients' prognosis. This paper aims to investigate the effectiveness of rTMS on executive function in VCI. Methods: The databases selected for this study included Pubmed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, China Science and Technology Journal Database (VIP), and China Biology Medicine Disc (CBM). The screening times were conducted from the time of library construction until August 23, 2023. The inclusion criteria for this meta-analysis were randomized controlled trials (RCTs) on rTMS for VCI, which include executive function scores. The primary metrics were executive subscale scores of the Cognitive Comprehensive Scale and total scores of the Executive Specificity Scale. The secondary metrics were subscale scores of the Executive Specificity Scale. The quality of each eligible study was assessed using the Cochrane Risk of Bias tool. Meta-analysis and bias analysis were performed using Stata (version 16.0) and RevMan (version 5.3). Results: A total of 20 high-quality clinical RCTs with 1,049 samples were included in this paper. The findings from the primary outcomes revealed that within the rTMS group, there were significantly higher scores observed for the executive sub-item on the cognitive composite scale (SMD = 0.93, 95% CI = 0.77-1.08, p < 0.00001, I 2 = 14%) and the total score on the executive specific scale (SMD = 0.69, 95% CI = 0.44-0.94, p < 0.00001, I 2 = 0%) compared to the control group. As for the secondary outcome measures, as shown by the Trail Making Test-A (time) (MD = -35.75, 95% CI = -68.37 to -3.12, p = 0.03, I 2 = 55%), the Stroop-C card (time) (SMD = -0.46, 95% CI = -0.86 to -0.06, p = 0.02, I 2 = 0%) and the Stroop-C card (correct number) (SMD = 0.49, 95% CI = 0.04-0.94, p = 0.03, I 2 = 0%), the experimental group shorts time and enhances accuracy of executive task in comparison to the control group. Subgroup analysis of the main outcome demonstrated that intermittent theta burst stimulation (iTBS), higher frequency, lower intensity, longer duration, and combined comprehensive therapy exhibited superior efficacy. Conclusion: rTMS is effective in the treatment of the executive function of VCI. The present study has some limitations, so multi-center, large-sample, objective indicators and parameters are needed to further explore in the future.Systematic review registration:https://www.crd.york.ac.uk/prospero/, CRD42023459669.

Changes in Alzheimer's disease blood biomarkers in kidney failure before and after kidney transplant.

INTRODUCTION: Alzheimer's disease (AD) blood biomarkers show promise for clinical diagnosis but their reliability in chronic kidney disease (CKD) is debated. This study investigates the impact of kidney transplant (KT) on AD biomarkers in CKD. METHODS: We assessed AD biomarkers in 46 CKD patients pre-KT, at 12 weeks and 12 months post-KT, with baseline measures from 13 non-CKD controls. Using linear mixed models, we examined associations with participant groups, estimated glomerular filtration rate (eGFR) and cognition. RESULTS: CKD patients showed elevated levels of neurofilament light (117 ± 72 vs. 11 ± 5 pg/mL), phosphorylated tau 181 (75 ± 42 vs. 13 ± 8 pg/mL), glial fibrillary acidic protein (193 ± 127 vs. 94 ± 39 pg/mL), amyloid ß 42 (17 ± 5 vs. 5 ± 1 pg/mL), and amyloid ß 40 (259 ± 96 vs. 72 ± 17 pg/mL) compared to controls. Post-KT, biomarker levels approached normal with improved eGFR, paralleled by enhanced cognitive function. DISCUSSION: AD blood biomarker elevations in CKD are reversible with improved kidney function through KT. Highlights: AD biomarker levels are extremely high in severe CKD.AD biomarker levels are higher in patients with kidney failure on dialysis when compared to CKD patients not on dialysis.These elevations in AD biomarker levels in kidney failure are reversable and decrease dramatically after kidney transplantation.The change in biomarker levels after transplantation align with changes in kidney function.The change in biomarker levels after transplantation align with changes in cognitive function.

Activation of glutamatergic neurons in the somatosensory cortex promotes remyelination in ischemic vascular dementia.

Chronic cerebral hypoperfusion can cause progressive demyelination as well as ischemic vascular dementia, however no effective treatments are available. Here, based on magnetic resonance imaging studies of patients with white matter damage, we found that this damage is associated with disorganized cortical structure. In a mouse model, optogenetic activation of glutamatergic neurons in the somatosensory cortex significantly promoted oligodendrocyte progenitor cell (OPC) proliferation, remyelination in the corpus callosum, and recovery of cognitive ability after cerebral hypoperfusion. The therapeutic effect of such stimulation was restricted to the upper layers of the cortex, but also spanned a wide time window after ischemia. Mechanistically, enhancement of glutamatergic neuron-OPC functional synaptic connections is required to achieve the protection effect of activating cortical glutamatergic neurons. Additionally, skin stroking, an easier method to translate into clinical practice, activated the somatosensory cortex, thereby promoting OPC proliferation, remyelination and cognitive recovery following cerebral hypoperfusion. In summary, we demonstrated that activating glutamatergic neurons in the somatosensory cortex promotes the proliferation of OPCs and remyelination to recover cognitive function after chronic cerebral hypoperfusion. It should be noted that this activation may provide new approaches for treating ischemic vascular dementia via the precise regulation of glutamatergic neuron-OPC circuits.

Does Transcranial Direct Current Stimulation Affect Potential P300-Related Events in Vascular Dementia? Considerations from a Pilot Study.

Vascular dementia, the second most common type of dementia, currently lacks a definitive cure. In the pursuit of therapies aimed at slowing its progression and alleviating symptoms, transcranial direct current stimulation (tDCS) emerges as a promising approach, characterized by its non-invasive nature and the ability to promote brain plasticity. In this study, the primary objective was to investigate the effects of a two-week cycle of tDCS on the dorsolateral prefrontal cortex (DLPFC) and neurophysiological functioning in thirty patients diagnosed with vascular dementia. Each participant was assigned to one of two groups: the experimental group, which received anodal tDCS to stimulate DPCFL, and the control group, which received sham tDCS. Neurophysiological functions were assessed before and after tDCS using P300 event-related potentials (ERPs), while neuropsychological function was evaluated through a Mini-Mental State Examination (MMSE). The results showed a reduction in P300 latency, indicating a faster cognitive process; an increase in P300 amplitude, suggesting a stronger neural response to cognitive stimuli; and a significant improvement in MMSE scores compared to the control group, indicating an overall enhancement in cognitive functions. These findings suggest that tDCS could represent a promising therapeutic option for improving both neurophysiological and cognitive aspects in patients with vascular dementia.

The Role of Zinc in the Development of Vascular Dementia and Parkinson's Disease and the Potential of Carnosine as Their Therapeutic Agent.

Synaptic zinc ions (Zn2+) play an important role in the development of vascular dementia (VD) and Parkinson's disease (PD). In this article, we reviewed the current comprehension of the Zn2+-induced neurotoxicity that leads to the pathogenesis of these neuronal diseases. Zn2+-induced neurotoxicity was investigated by using immortalised hypothalamic neurons (GT1-7 cells). This cell line is useful for the development of a rapid and convenient screening system for investigating Zn2+-induced neurotoxicity. GT1-7 cells were also used to search for substances that prevent Zn2+-induced neurotoxicity. Among the tested substances was a protective substance in the extract of Japanese eel (Anguilla japonica), and we determined its structure to be like carnosine (ß-alanylhistidine). Carnosine may be a therapeutic drug for VD and PD. Furthermore, we reviewed the molecular mechanisms that involve the role of carnosine as an endogenous protector and its protective effect against Zn2+-induced cytotoxicity and discussed the prospects for the future therapeutic applications of this dipeptide for neurodegenerative diseases and dementia.

The human SMAD9 (GCC) repeat links to natural selection and late-onset neurocognitive disorders.

INTRODUCTION: Whereas (GCC)-repeats are overrepresented in genic regions, and mutation hotspots, they are largely unexplored with regard to their link with natural selection. Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches highest level of expression in the human brain. This gene contains a (GCC)-repeat in the interval between + 1 and + 60 of the transcription start site, which is in the high-ranking (GCC)-repeats with respect to length. METHODS: Here we sequenced this (GCC)-repeat in 396 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 181) and controls (N = 215). RESULTS: We detected two predominantly abundant alleles of 7 and 9 repeats, forming 96.2% of the allele pool. The (GCC)7/(GCC)9 ratio was in the reverse order in the NCD group versus controls (p = 0.005), resulting from excess of (GCC)7 in the NCD group (p = 0.003) and (GCC)9 in the controls (p = 0.01). Five genotypes, predominantly consisting of (GCC)7 and lacking (GCC)9 were detected in the NCD group only (p = 0.008). The patients harboring those genotypes received the diagnoses of Alzheimer's disease (AD) and vascular dementia (VD). Five genotypes consisting of (GCC)9 and lacking (GCC)7 were detected in the control group only (p = 0.002). The group-specific genotypes formed approximately 4% of the genotype pool in the human samples studied. CONCLUSION: We propose natural selection and a novel locus for late-onset AD and VD at the SMAD9 (GCC)-repeat in humans.

Vascular endothelial growth factor is an effective biomarker for vascular dementia, not for Alzheimer's disease: A meta-analysis.

INTRODUCTION: Vascular pathology is known to contribute to dementia and vascular endothelial growth factor (VEGF) is a well-established biomarker associated with vascular alterations. Nonetheless, research findings on VEGF in Alzheimer's disease (AD) and vascular dementia (VaD) are inconsistent across various studies. METHODS: We conducted a meta-analysis to elucidate relationships between VEGF and AD/VaD. RESULTS: Twenty-four studies were included. Pooled data showed that both blood and cerebrospinal fluid (CSF) VEGF levels were higher in VaD patients, whereas no significant difference was found between AD patients and healthy controls. However, the correlation between blood VEGF and AD was found among studies with AD pathology verification. And blood VEGF levels were higher in AD patients than controls in "age difference < 5 years" subgroup and CSF samples for European cohorts. DISCUSSION: This study highlights that VEGF is more effective for the diagnosis of VaD and vascular factors are also an important contributor in AD. Highlights: Vascular endothelial growth factor (VEGF) levels were higher in the vascular dementia group, but not in the overall Alzheimer's disease (AD) group.Correlation between VEGF and AD was found among studies with clear AD pathological verification.Elevated VEGF in the cerebrospinal fluid might be a diagnostic marker for AD in European populations.

Post-stroke cognitive impairment and brain hemorrhage are augmented in hypertensive mice.

Hypertension is a major risk factor for both stroke and cognitive impairment, but it is unclear whether it may specifically affect post-stroke cognitive impairment. We assessed the effect of hypertension and/or stroke on brain injury, cognitive outcome, and the brain transcriptomic profile. C57BL/6J mice (n = 117; 3-5 mo.) received s.c. infusion of either saline or angiotensin II followed by sham surgery or photothrombotic stroke targeting the prefrontal cortex seven days later. Cognitive function was assessed with the Barnes maze and RNA sequencing was used to quantify transcriptomic changes in the brain. Angiotensin II treatment produced spontaneous hemorrhaging after stroke. In the Barnes maze, hypertensive mice that received stroke surgery had an increased escape latency compared to other groups (day 3: hypertensive + stroke = 166.6 ± 6.0 s vs. hypertensive + sham = 122.8 ± 13.8 s vs. normotensive + stroke = 139.9 ± 10.1 s vs. normotensive + sham = 101.9 ± 16.7 s), consistent with impaired cognition. RNA sequencing revealed >1500 differentially expressed genes related to neuroinflammation in hypertensive + stroke vs. normotensive + stroke, which included genes associated with apoptosis, microRNAs, autophagy, anti-cognitive biomarkers and Wnt signaling. Overall, we show that the combination of hypertension and stroke resulted in greater learning impairment and brain injury.

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.

Exploring the Regulatory Landscape of Dementia: Insights from Non-Coding RNAs.

Dementia, a multifaceted neurological syndrome characterized by cognitive decline, poses significant challenges to daily functioning. The main causes of dementia, including Alzheimer's disease (AD), frontotemporal dementia (FTD), Lewy body dementia (LBD), and vascular dementia (VD), have different symptoms and etiologies. Genetic regulators, specifically non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), are known to play important roles in dementia pathogenesis. MiRNAs, small non-coding RNAs, regulate gene expression by binding to the 3' untranslated regions of target messenger RNAs (mRNAs), while lncRNAs and circRNAs act as molecular sponges for miRNAs, thereby regulating gene expression. The emerging concept of competing endogenous RNA (ceRNA) interactions, involving lncRNAs and circRNAs as competitors for miRNA binding, has gained attention as potential biomarkers and therapeutic targets in dementia-related disorders. This review explores the regulatory roles of ncRNAs, particularly miRNAs, and the intricate dynamics of ceRNA interactions, providing insights into dementia pathogenesis and potential therapeutic avenues.

Snoring and risk of dementia: a prospective cohort and Mendelian randomization study.

STUDY OBJECTIVES: The association between snoring, a very common condition that increases with age, and dementia risk is controversial. We aimed to investigate the observational and causal relationship between snoring and dementia, and to elucidate the role of body mass index (BMI). METHODS: Using data from 451,250 participants who were dementia-free at baseline, we examined the association between self-reported snoring and incident dementia using Cox proportional-hazards models. Causal relationship between snoring and Alzheimer's disease (AD) was examined using bidirectional two-sample Mendelian randomization (MR) analysis. RESULTS: During a median follow-up of 13.6 years, 8,325 individuals developed dementia. Snoring was associated with a lower risk of all-cause dementia (hazard ratio [HR] 0.93; 95% confidence interval [CI] 0.89 to 0.98) and AD (HR 0.91; 95% CI 0.84 to 0.97). The association was slightly attenuated after adjusting for BMI, and was stronger in older individuals, APOE ε4 allele carriers, and during shorter follow-up periods. MR analyses suggested no causal effect of snoring on AD, however, genetic liability to AD was associated with a lower risk of snoring. Multivariable MR indicated that the effect of AD on snoring was primarily driven by BMI. CONCLUSIONS: The phenotypic association between snoring and lower dementia risk likely stems from reverse causation, with genetic predisposition to AD associated with reduced snoring. This may be driven by weight loss in prodromal AD. Increased attention should be paid to reduced snoring and weight loss in older adults as potential early indicators of dementia risk.

The Effect of Acupuncture on Brain Iron Deposition and Body Iron Metabolism in Vascular Cognitive Impairment: Protocol for a Randomized Controlled Trial.

BACKGROUND: Vascular cognitive impairment (VCI) persistently impairs cognition and the ability to perform activities of daily living, seriously compromising patients' quality of life. Previous studies have reported that disorders of serum iron metabolism and iron deposition in the brain can lead to inflammation, abnormal protein aggregation and degeneration, and massive neuronal apoptosis in the central nervous system, which in turn leads to a progressive decline in cognitive processes. Our previous clinical studies have found acupuncture to be a safe and effective intervention for treating VCI, but the specific mechanisms require further exploration. OBJECTIVE: The objective of the trial is to evaluate the clinical efficacy of Tongdu Xingshen acupuncture and to investigate whether it can improve VCI by regulating brain iron deposition and body iron metabolism. METHODS: In total, 42 patients with VCI and 21 healthy individuals will participate in this clinical trial. The 42 patients with VCI will be randomized into acupuncture and control groups, while the 21 healthy individuals will be in the healthy control group. Both the control and acupuncture groups will receive conventional medical treatment and cognitive rehabilitation training. In addition, the acupuncture group will receive electroacupuncture treatment with Tongdu Xingshen for 30 minutes each time, 6 times a week for 4 weeks. Meanwhile, the healthy control group will not receive any intervention. All 3 groups will undergo baseline assessments of brain iron deposition, serum iron metabolism, and neuropsychological tests after enrollment. The acupuncture and control groups will be evaluated again at the end of 4 weeks of treatment, as described earlier. By comparing neuropsychological test scores between groups, we will examine the efficacy of Tongdu Xingshen acupuncture in treating VCI. Additionally, we will test the correlations between neuropsychological test scores, brain iron deposition, and body iron metabolism indexes to explore the possible mechanisms of Tongdu Xingshen acupuncture in treating VCI. RESULTS: Participants are currently being recruited. The first participant was enrolled in June 2023, which marked the official start of the experiment. As of the submission of the paper, there were 23 participants. The recruitment process is expected to continue until June 2025, at which point the processing and analysis of data will begin. As of May 15, 2024, up to 30 people have been enrolled in this clinical trial. CONCLUSIONS: This study will provide data on the effects of Tongdu Xingshen acupuncture on cerebral iron deposition as well as somatic iron metabolism in patients with VCI. These results will help to prove whether Tongdu Xingshen acupuncture can improve VCI by regulating brain iron deposition and body iron metabolism, which will provide the clinical and theoretical basis for the wide application of acupuncture therapy in VCI rehabilitation. TRIAL REGISTRATION: China Clinical Registration Agency ChiCTR2300072188; https://tinyurl.com/5fcydtkv. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56484.

The life cycle of a capillary: Mechanisms of angiogenesis and rarefaction in microvascular physiology and pathologies.

Capillaries are the smallest blood vessels (<10 µm in diameter) in the body and their walls are lined by endothelial cells. These microvessels play a crucial role in nutrient and gas exchange between blood and tissues. Capillary endothelial cells also produce vasoactive molecules and initiate the electrical signals that underlie functional hyperemia and neurovascular coupling. Accordingly, capillary function and density are critical for all cell types to match blood flow to cellular activity. This begins with the process of angiogenesis, when new capillary blood vessels emerge from pre-existing vessels, and ends with rarefaction, the loss of these microvascular structures. This review explores the mechanisms behind these processes, emphasizing their roles in various microvascular diseases and their impact on surrounding cells in health and disease. We discuss recent work on the mechanisms controlling endothelial cell proliferation, migration, and tube formation that underlie angiogenesis under physiological and pathological conditions. The mechanisms underlying functional and anatomical rarefaction and the role of pericytes in this process are also discussed. Based on this work, a model is proposed in which the balance of angiogenic and rarefaction signaling pathways in a particular tissue match microvascular density to the metabolic demands of the surrounding cells. This negative feedback loop becomes disrupted during microvascular rarefaction: angiogenic mechanisms are blunted, reactive oxygen species accumulate, capillary function declines and eventually, capillaries disappear. This, we propose, forms the foundation of the reciprocal relationship between vascular density, blood flow, and metabolic needs and functionality of nearby cells.

The protocol for an observational Australian cohort study of CADASIL: The AusCADASIL study.

Introduction: Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a rare genetic condition with a broad phenotypic presentation. This study aims to establish the first Australian cohort of individuals affected by CADASIL (AusCADASIL) and examine its clinical features and longitudinal course, and to investigate neuroimaging and blood biomarkers to assist in early diagnosis and identify disease progression. Methods: Participants will be recruited from six study centres across Australia for an observational study of CADASIL. We aim to recruit 150 participants with diagnosed CADASIL, family history of CADASIL or suspected CADASIL symptoms, and 150 cognitively normal NOTCH3 negative individuals as controls. Participants will complete: 1) online questionnaires on medical and family history, mental health, and wellbeing; 2) neuropsychological evaluation; 3) neurological examination and brain MRI; 4) ocular examination and 5) blood sample donation. Participants will have annual follow-up for 4 years to assess their progression and will be asked to invite a study partner to corroborate their self-reported cognitive and functional abilities.Primary outcomes include cognitive function and neuroimaging abnormalities. Secondary outcomes include investigation of genetics and blood and ocular biomarkers. Data from the cohort will contribute to an international consortium, and cohort participants will be invited to access future treatment/health intervention trials. Discussion: AusCADASIL will be the first study of an Australian cohort of individuals with CADASIL. The study will identify common pathogenic variants in this cohort, and characterise the pattern of clinical presentation and longitudinal progression, including imaging features, blood and ocular biomarkers and cognitive profile.

Association between elevated systemic inflammatory markers and the risk of cognitive decline progression: a longitudinal study.

BACKGROUND: Chronic systemic inflammation is linked to cognitive decline pathogenesis. This study investigates the association between systemic inflammation markers and cognitive decline progression in a clinical cohort. METHODS: This prospective observational cohort study enrolled 295 participants. Cognitive decline progression was defined by an increase in clinical dementia rating (CDR) scores. The study examines the correlation between systemic inflammation markers, including systemic Inflammation Response Index (SIRI), systemic Immune-Inflammation Index (SII), prognostic Inflammatory and Nutritional Index (PIV), and cognitive impairment progression. RESULTS: The presence of the APOE 4 allele and diabetes mellitus was associated with elevated PIV levels (P < 0.05). Additionally, AD patients had the highest SII levels, indicating increased inflammation compared to individuals with MCI and SCD (P < 0.05). After a mean follow-up of 17 months, 117 patients (51.31%) experienced cognitive decline progression. AD diagnosis, CDR, and SII were significant predictors of cognitive decline progression (All P < 0.05). CONCLUSION: This study highlights the clinical significance of elevated systemic inflammation markers in identifying individuals at risk of cognitive decline. Addressing inflammation may offer a promising approach to improving cognitive health and mitigating age-related cognitive decline.

Associations between toxicity-weighted concentrations and dementia risk: Results from the Cardiovascular Health Cognition Study.

BACKGROUND: Air pollution is a modifiable risk factor for dementia. Yet, studies on specific sources of air pollution (i.e., toxic chemical emissions from industrial facilities) and dementia risk are scarce. We examined associations between toxicity-weighted concentrations of industrial pollution and dementia outcomes among a large, multi-site cohort of older adults. METHODS: Participants (n = 2770) were ≥ 65 years old (Mean = 75.3, SD = 5.1 years) from the Cardiovascular Health Cognition Study (1992-1999). Toxicity-weighted concentrations were estimated using the Risk Screening Environmental Indicator (RSEI) model which incorporates total reported chemical emissions with toxicity, fate, and transport models. Estimates were aggregated to participants' baseline census tract, averaged across 1988-1992, and log2-transformed. Dementia status was clinically adjudicated in 1998-1999 and categorized by subtype (Alzheimer's, vascular, mixed). We assessed whether RSEI-estimated toxicity-weighted concentrations were associated with 1) odds of prevalent dementia and 2) incident dementia risk by subtype. RESULTS: After adjusting for individual and census-tract level covariates, a doubling in toxicity-weighted concentrations was associated with 9 % higher odds of prevalent dementia (OR = 1.09, 95 % CI: 1.00, 1.19). In discrete-time survival models, each doubling in toxicity-weighted concentrations was associated with a 16 % greater hazard of vascular dementia (HR = 1.16, 95 % CI: 1.01, 1.34) but was not significantly associated with all-cause, Alzheimer's disease, or mixed dementia (p's > 0.05). DISCUSSION: Living in regions with higher toxicity-weighted concentrations was associated with higher odds of prevalent dementia and a higher risk of incident vascular dementia in this large, community-based cohort of older adults. These findings support the need for additional studies to examine whether toxic chemical emissions from industrial and federal facilities may be a modifiable target for dementia prevention.

Causal relationships between gut microbiota and dementia: A two-sample, bidirectional, Mendelian randomization study.

BACKGROUND: Existing evidence suggests that gut microbiota represent a significant environmental risk factor for various forms of dementia, including Alzheimer's dementia, vascular dementia, and dementia in other diseases classified elsewhere. However, the exact causal relationships between gut microbiota and the different forms of dementia or their subtypes remain unclear. AIM: To investigate putative causal relationships between gut microbiota and dementia or its subtypes using Mendelian randomization (MR) analysis. METHODS: A bidirectional, two-sample, MR analysis was conducted utilizing publicly available gut microbiota-related genome-wide association study (GWAS) summary data from the MiBioGen consortium alongside GWAS summary statistics for dementia and its subtypes from the FinnGen consortium. Instrumental variables were selected according to the fundamental tenets of MR and their strengths were evaluated using the F-statistic. Five MR methods were employed, and the robustness of our findings was validated. To account for multiple comparisons, we applied the Bonferroni method for P-value adjustment. RESULTS: We identified several gut microbiota taxa exhibiting putative causal relationships with dementia or its subtypes, potentially serving as risk or protective factors for the disease. In addition, reverse MR analysis indicated that the relative abundance of several gut microbiota taxa might be influenced by dementia or its subtypes. An exhaustive sensitivity analysis confirmed the absence of heterogeneity and horizontal pleiotropy. After applying correction for multiple testing, we observed that the order Bacillales (odds ratio: 0.830, 95% confidence interval: 0.740-0.932, P = 0.00155, Padjust = 0.0311) exhibited a strong association with Alzheimer's disease-related dementia. CONCLUSION: The results suggest that gut microbiota is causally associated with dementia. Our findings provide novel insights into the pathophysiology of dementia and have important implications for its treatment and prevention.

Association between COVID-19 and the Risk of Vascular Dementia: A Mendelian Randomisation Study of the Potential Cognitive Sequela of COVID-19.

A growing body of observational studies and Mendelian Randomisation analyses suggest an increased risk of Alzheimer's disease and dementia following COVID-19 infection. However, evidence on the potential association between COVID-19 and vascular dementia, which is plausible given the vascular complications of COVID-19 infection, is still limited. In this study, we conducted a two-sample Mendelian Randomisation analysis to examine the potential causal relationship between COVID-19 phenotypes and the risk of vascular dementia, using summary data from large-scale GWASs. The two-sample Mendelian Randomisation analysis did not detect any significant associations of COVID-19 infection, COVID-19 hospitalisation, or critical COVID-19 with the risk of vascular dementia, with weighted average ß values of -0.29 (95% CI: -0.84, 0.26; p = 0.301), -0.12 (95% CI: -0.36, 0.13; p = 0.345), and -0.07 (95% CI: -0.23, 0.09; p = 0.374), respectively. Our findings do not support the hypothesis that vascular dementia is one of the long-term sequelae of COVID-19.

Taohong Siwu decoction alleviates cognitive impairment by suppressing endoplasmic reticulum stress and apoptosis signaling pathway in vascular dementia rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Taohong Siwu Decoction (TSD), a classic traditional Chinese medicine formula, is used for the treatment of vascular diseases, including vascular dementia (VD). However, the mechanisms remain unclear. AIM OF STUDY: This study aimed to investigate whether TSD has a positive effect on cognitive impairment in VD rats and to confirm that the mechanism of action is related to the Endoplasmic Reticulum stress (ERs) and cell apoptosis signaling pathway. MATERIALS AND METHODS: A total of 40 male adult Sprague-Dawley rats were divided into four groups: sham-operated group (Sham), the two-vessel occlusion group (2VO), the 2VO treated with 4.5 g/kg/d TSD group (2VO + TSD-L), the 2VO treated with 13.5 g/kg/d TSD group (2VO + TSD-H). The rats underwent either 2VO surgery or sham surgery. Postoperative TSD treatment was given for 4 consecutive weeks. Behavioral tests were initiated at the end of gastrulation. Open-field test (OFT) was used to detect the activity level. The New Object Recognition test (NOR) was used to test long-term memory. The Morris water maze (MWM) test was used to examine the foundation of spatial learning and memory. As a final step, the hippocampus was taken for molecular testing. The protein levels of GRP78 (Bip), p-PERK, PERK, IRE1α, p-IRE1α, ATF6, eIF2α, p-eIF2α, ATF4, XBP1, Bcl-2 and Bax were determined by Western blot. Immunofluorescence visualizes molecular expression. RESULTS: In the OFT, residence time in the central area was significantly longer in both TSD treatment groups compared to the 2VO group. In the NOR, the recognition index was obviously elevated in both TSD treatment groups. The 2VO group had a significantly longer escape latency and fewer times in crossing the location of the platform compared with the Sham group in MWM. TSD treatment reversed this notion. Pathologically, staining observations confirmed that TSD inhibited hippocampal neuronal loss and alleviated the abnormal reduction of the Nissl body. In parallel, TUNEL staining illustrated that TSD decelerated neuronal apoptosis. Western Blot demonstrated that TSD reduces the expression of ERs and apoptotic proteins. CONCLUSION: In this study, the significant ameliorative effect on cognitive impairment of TSD has been determined by comparing the behavioral data of the 4 groups of rats. Furthermore, it was confirmed that this effect of TSD was achieved by suppressing the ERs-mediated apoptosis signaling pathway.