Vascular Dementia Research Articles

Global genomic profile of hippocampal endothelial cells by single-nuclei RNA sequencing in female diabetic mice is associated with cognitive dysfunction.

Type II diabetes mellitus (T2D) is a chronic metabolic disease and a risk factor for cardiovascular disease and cerebrovascular dysfunction including vascular dementia. Sex differences in the prevalence of T2D, dementia, and global genomic changes in the brain have been observed; however, most studies have been performed in males. Therefore, our aim was to evaluate the consequence of T2D on cognitive function and decipher the underlying molecular transcriptomic mechanisms of endothelial cells in an important brain memory center, the hippocampus, using a female murine diabetes model. We assessed cognitive function, metabolic parameters, and then performed hippocampal single-nuclei RNA sequencing (snRNA seq) in adult female db/db and control wild-type (WT) mice. db/db mice exhibited characteristic T2D metabolism with hyperglycemia, hyperinsulinemia, and hyperlipidemia when compared with WT mice. Female db/db mice presented cognitive decline compared with wild-type mice, as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced significant changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, actin cytoskeleton organization, and cell adhesion, suggesting that diabetes increases endothelial cell permeability. Observed genomic changes also correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia. In conclusion, T2D, by transcriptional and posttranscriptional regulation, regulates endothelial cell dysfunction predictive of increased vascular permeability, and negatively impacts cognitive function. Our work has implications for sex-specific molecular therapeutic targets for dementia in females.NEW & NOTEWORTHY Female db/db mice presented cognitive decline as determined by open field and Morris water maze tests. snRNAseq showed that T2D induced changes in the global transcriptomic profile of hippocampal endothelial cells by modulating the expression of not only protein-coding genes but also long noncoding RNAs. These genes regulate cell-cell junctions, cell chemotaxis, or cell adhesion, suggesting increased endothelial permeability. Genomic changes correlated with the genetics of persons with clinical Alzheimer's disease and vascular dementia.

Therapeutic Approach of Phytomedicine for Dementia: A Review

Abstract: Dementia is a brain disorder with progressive neurological disease. It destroys essential brain cells, impairing memory, thinking, and behavior in a severe way to impact health, enduring interests, and social life. Memory, cognition, orientation, learning capacity, language, and judgments gradually get impaired. Dementia results from anatomical and functional abnormalities, cerebral ischemia, energy deficits, calcium excess, glutamate-mediated excitotoxicity, and oxidative stress. Vascular dementia (VaD), which accounts for 10-15% of dementia cases, is the second most frequent form of dementia after Alzheimer's disease (AD). There are currently no approved pharmaceutical treatments for VaD, and traditional anti-AD therapies only offer modest, temporary relief from the symptoms of VaD. Since herbal remedies have a multicomponent and multitarget approach, they may provide effective treatments for VaD. Herbal remedies have been used for centuries to address dementia-like symptoms. This author describes some preliminary research that supports using herbal drugs in managing vascular dementia and dementia.

Pharmacologic Treatments for Dementia and the Risk of Developing Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of blindness among people aged 50 years or older worldwide. There is a need for new strategies for the prevention and treatment of AMD. There is some limited evidence to suggest the possibility of a protective association of dementia medications with the development of some types of AMD, but the evidence is weak. To investigate whether the dementia medications memantine and donepezil are associated with the risk of developing AMD. Three population-based cohort studies were performed using data from the Clinical Practice Research Datalink GOLD and Aurum databases from May 15, 2002, to June 21, 2022. Participants included individuals with dementia (vascular dementia, nonvascular dementia, or Alzheimer disease) aged 40 years or older. Statistical analysis was carried out between February and November 2023. Exposures were dementia medications. Cohort 1 compared patients prescribed donepezil with those prescribed rivastigmine or galantamine using the new-user design. Cohort 2 compared memantine with donepezil, rivastigmine, or galantamine using the prevalent new-user design. In a sensitivity analysis, cohort 3 compared memantine with rivastigmine or galantamine only. New diagnosis of AMD. There were 132 846 individuals (mean [SD] age, 80.4 [7.6] years; 61.8% women; mean [SD] body mass index [BMI], 25.5 [4.6]) with a diagnosis of dementia included in cohort 1, 159 419 individuals (mean [SD] age, 81.2 [7.6] years; 59.7% women; mean [SD] body mass index [BMI], 25.6 [4.7]) with a diagnosis of dementia included in cohort 2, and 92 328 individuals with a diagnosis of dementia included in cohort 3 (mean [SD] age, 80.9 [7.7] years; 58.5% women; mean [SD] body mass index [BMI], 25.5 [4.7]). The adjusted hazard ratio (HR) for donepezil compared with rivastigmine or galantamine (cohort 1) was 0.95 (95% CI, 0.67-1.35). The adjusted HR for memantine compared with donepezil, rivastigmine, or galantamine (cohort 2) was 1.03 (95% CI, 0.83-1.27). The adjusted HR for memantine vs rivastigmine or galantamine only (cohort 3) was 1.24 (95% CI, 0.83-1.86). This cohort study of patients with dementia found no significant associations between memantine or donepezil compared with other dementia medications and the risk of development of AMD. Further research is recommended to examine any possible pathophysiological protective action of memantine and other dementia medications against the development of AMD.

Albiflorin Alleviates Neurocognitive Impairment in L-Methionine-Induced Vascular Dementia through FoxO1/SIRT1/RANKL/BDNF Pathway

Albiflorin Alleviates Neurocognitive Impairment in L-Methionine-Induced Vascular Dementia through FoxO1/SIRT1/RANKL/BDNF Pathway

Alterations in Neuronal Nicotinic Acetylcholine Receptors in the Pathogenesis of Various Cognitive Impairments.

Cognitive impairment is a typical symptom of both neurodegenerative and certain other diseases. In connection with these different pathologies, the etiology and neurological and metabolic changes associated with cognitive impairment must differ. Until these characteristics and differences are understood in greater detail, pharmacological treatment of the different forms of cognitive impairment remains suboptimal. Neurotransmitter receptors, including neuronal nicotinic acetylcholine receptors (nAChRs), dopamine receptors, and glutamine receptors, play key roles in the functions and metabolisms of the brain. Among these, the role of nAChRs in the development of cognitive impairment has attracted more and more attention. The present review summarizes what is presently known concerning the structure, distribution, metabolism, and function of nAChRs, as well as their involvement in major cognitive disorders such as Alzheimer's disease, Parkinson's disease, vascular dementia, schizophrenia, and diabetes mellitus. As will be discussed, the relevant scientific literature reveals clearly that the α4β2 and α7 nAChR subtypes and/or subunits of the receptors play major roles in maintaining cognitive function and in neuroprotection of the brain. Accordingly, focusing on these as targets of drug therapy can be expected to lead to breakthroughs in the treatment of cognitive disorders such as AD and schizophrenia.

Combination treatment with cilostazol and isosorbide mononitrate attenuates microemboli-mediated vascular cognitive impairment and improves imaging and plasma biomarkers in diabetic rats

Diabetes is a major risk factor for all types of dementia. The underlying reasons are not fully understood, and preventive therapeutic strategies are lacking. Previously we have shown that diabetic but not control rats developed a progressive cognitive decline in a microemboli (ME) model of vascular contributions to cognitive impairment & dementia (VCID). Given the cerebrovascular dysfunction is a mutual pathological change between diabetes and VCID, we hypothesized that the cognitive impairment in this ME model can be prevented by improving the endothelial function in diabetes. Our treatment paradigm was based on the LACI-2 Trial which assessed the efficacy of isosorbide mononitrate (ISMN) and cilostazol (Cil) treatments in small vessel disease progression. Control and diabetic rats were treated with ISMN/Cil or vehicle for 4 weeks, then injected with cholesterol crystal ME and the behavioral outcomes were monitored. Brain microstructure integrity was assessed by diffusion MRI. Plasma biomarkers were assessed using angiogenesis, neurology and amyloid β 42/40 panels recommended by the MarkVCID consortium. Behavioral deficits and the loss of tissue integrity previously observed in untreated diabetic rats were not noted in the treated animals in this study. Treatment improved tissue perfusion but there were no differences in plasma biomarkers. These results suggest that restoration of endothelial function with ISMN/Cil before ME injection prevented the possible deleterious effects of ME in diabetic rats by improving the endothelial integrity and it is a practical preventive and therapeutic strategy for VCID.

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

Nut consumption is associated with a lower risk of all-cause dementia in adults: a community-based cohort study from the UK Biobank.

This cohort study aimed to analyze the relationship between nut consumption and the risk of all-cause dementia in adults from the United Kingdom (UK). Data from participants in the UK Biobank cohort between 2007-2012 (baseline) and 2013-2023 (follow-up) were analyzed. Baseline information on nut consumption was obtained using the Oxford WebQ 24-h questionnaire. All-cause dementia (i.e. Alzheimer's disease, frontotemporal dementia, or vascular dementia) was assessed at baseline and follow-up through self-reported medical diagnosis, hospitalization, or death records. Hazard regression models were used to estimate the association between nut consumption and the risk of developing all-cause dementia, with adjustments made for sociodemographic, lifestyle, hearing problems, self-rated health, and the number of chronic diseases. Participants with all-cause dementia at baseline were excluded. A total of 50,386 participants (mean age 56.5 ± 7.7years, 49.2% women) were included in the prospective analyses. The incidence of all-cause dementia was 2.8% (n = 1422 cases). Compared with no consumption, daily nut consumption (> 0 to 3 or more handfuls) was significantly associated with a 12% lower risk of all-cause dementia (hazard ratio = 0.88; 95% confidence interval, 0.77-0.99) after 7.1 mean years of follow-up, regardless of the potential confounders considered. No statistically significant interactions were observed between nut consumption and any of the covariates included in the hazard regression models. Stratified analyses revealed that nut consumption of up to 1 handful of 30g/day and consumption of unsalted nuts were associated with the greatest protective benefits. The daily consumption of nuts may play a protective role in the prevention of dementia.

Clinical approach to probable mixed vascular dementia and progressive supranuclear palsy

Probable mixed dementia, combining vascular dementia and progressive supranuclear palsy (PSP), presents diagnostic challenges due to overlapping clinical features and radiological findings. This case report highlights the complexities involved in diagnosing such cases, where clinical manifestations evolve, requiring careful evaluation and periodic reassessment. Imaging plays a crucial role, with characteristic features aiding in distinguishing between different etiologies. Management of mixed dementia poses therapeutic dilemmas, particularly given the lack of effective treatments for PSP. Nonetheless, a comprehensive approach involving education, vascular risk factor control, and family support is essential for optimizing long-term patient and caregiver outcomes. This case underscores the importance of a multidisciplinary clinical and radiological approach in navigating the complexities of mixed dementia cases.

Optimising Emergency Care for Older Adults: A Case Study of the EDITH Service Following a Proximal Humerus Fracture

Abstract Background The Emergency Department in the Home (EDITH) service offers emergency Occupational Therapy and medical assessments to older adults at home, thus negating the need for hospital attendances. Mr X, an 86-year-old with vascular dementia and hypertension, sustained a left proximal humerus fracture from a fall. Following assessment in the ED, Mr X was deemed fit for discharge and was referred to EDITH for an acute functional assessment and clinical review. Methods Within 72 hours of discharge, Mr X was visited at home by an Occupational Therapist (OT) and an Advanced Nurse Practitioner (ANP). The OT conducted a home environment assessment, falls-risk screening, delirium screening, reviewed social supports, and performed a functional assessment. Education on one-handed dressing techniques and falls prevention was provided. The ANP conducted a clinical review, and reviewed Mr X’s medication and analgesia. Mr X had the support of his wife to assist with Activities of Daily Living (ADLs), functional mobility and medication management. Mr X’s son purchased assistive equipment recommended by the OT, to enhance home safety. Referrals were made to the local memory support service, a Physiotherapist, and his Public Health Nurse to organise formal care supports. Results Mr X remained at home with support from his wife, primary care services, and virtual EDITH follow-up. Mr X had a scheduled review at the fracture clinic following his ED attendance. Conclusion Emergency care practitioners play a crucial role in addressing acute functional and clinical changes in older adults attending the ED. Supported ED discharges and service integration during the acute phase can prevent hospital admissions. Collaboration between emergency medicine and primary care is essential for addressing acute medical needs and long-term functional outcomes. With adequate social support and timely services, older adults can recover successfully at home.

Association of dementia with impaired kidney function and plasma biomarkers: A population-based study.

Emerging evidence has linked impaired kidney function with dementia in older adults, but the neuropathological pathways underlying their association remain poorly understood. We sought to examine the relationships of kidney function with dementia and plasma biomarkers in a Chinese rural population. This population-based study used data from the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-China) cohort (March-September 2018; n = 5715). Kidney function was assessed using estimated glomerular filtration rate (eGFR) based on serum creatinine level. Dementia, Alzheimer's disease (AD) and vascular dementia (VaD) were diagnosed according to the international criteria. Plasma biomarkers were measured using the SIMOA platform in a subsample (n = 1446). Data were analyzed using logistic, general linear, and mediation models. Of the 5715 participants, 306 were diagnosed with dementia, including 195 with AD and 100 with VaD. Impaired kidney function (eGFR <60 vs. ≥90 mL/min/1.73 m2) was associated with multivariable-adjusted odds ratios of 2.24 (95% confidence interval [CI] 1.44-3.46) for all-cause dementia, 1.85 (1.07-3.18) for AD, and 2.49 (1.16-5.22) for VaD. In the biomarker subsample, impaired kidney function was significantly associated with higher plasma amyloid-β (Aβ)40 (β-coefficient = 54.36, 95% CI 43.34-65.39), Aβ42 (β-coefficient = 3.14, 95% CI 2.42-3.86), neurofilament light chain (β-coefficient = 10.62, 95% CI 5.62-15.62), and total tau (β-coefficient = 0.68, 95% CI 0.44-0.91), and a lower Aβ42/Aβ40 ratio (β-coefficient = -4.11, 95% CI -8.08 to -0.14). The mediation analysis showed that plasma total tau significantly mediated 21.76% of the association between impaired kidney function and AD (p < 0.05). Impaired kidney function is associated with dementia and plasma biomarkers among rural-dwelling older Chinese adults, and the association with AD is partly mediated by plasma biomarkers for neurodegeneration.

Research Progress of Pharmacological Mechanism of Cistanche in the Treatment of Vascular Dementia

Vascular dementia is one of clinical common type of dementia, its pathogenesis is complex, the incidence of rising trend year by year, the serious influence the patient's life and health. In the category of traditional Chinese medicine, vascular dementia belongs to the category of "dementia", and its etiology and pathogenesis are mostly related to "deficiency of kidney essence". Studies have found that Cistanche deserticola is a traditional Chinese medicine with a high frequency in the treatment of vascular dementia. It has the effects of toning kidney Yang, nourishing essence blood, moistening intestine and purging, and has definite advantages in preventing vascular dementia. C. deserticola chemical composition including echinacea glycosides, mullein indican, c. deserticola total glycosides, phenylethyl alcohol glycosides, flavonoids and polysaccharides, removal of oxygen free radicals and improve antioxidant compounds with resistance to oxidative stress; It plays an anti-vascular dementia role by clearing β-amyloid protein, reducing neuronal apoptosis, protecting hippocampal neurons, and regulating neurotransmitters to protect cholinergic nerves. This article reviews the pharmacological effects of cistanche deserticola on vascular dementia. As to provide theoretical basis for the use of c. deserticola and evidence-based support.

Chronic Stress Exacerbates Cerebral Amyloid Angiopathy Through Promoting Neutrophil Extracellular Traps Formation.

Cerebral amyloid angiopathy (CAA) is the leading cause of vascular dementia among the elderly. Neuropsychiatric symptoms are commonly manifested in cerebral amyloid angiopathy patients but are usually considered as consequences of cerebral amyloid angiopathy pathology. Here, it is reported that chronic stress promotes cerebral amyloid angiopathy progression, which enhances deposition of amyloid protein beta (Aβ) in brain blood vessels and exacerbates subsequent brain injury. Mechanistically, neutrophil is implicated in cerebral amyloid angiopathy development. Aβ that accumulates in brain vasculature induces neutrophil extracellular traps (NETs) by activating STAT6 signaling, which inhibits neutrophil apoptosis and switches the programmed cell death toward NETosis. During chronic stress, circulatory Norepinephrine (NE) strengthens STAT6 activation in neutrophil and promotes NET formation, thus exacerbates the NET-dependent angiopathy. It is demonstrated that inhibiting neutrophil chemotaxis towards brain or suppressing NET formation both ameliorate cerebral amyloid angiopathy severity in the context of chronic stress. Therefore, it is proposed that stress-associated psychological disorders and NETs are promising therapeutic targets in cerebral amyloid angiopathy.

Molecular profiling of a rat model of vascular dementia: Evidences from proteomics, metabolomics and experimental validations

Decrease of cerebral blood flow is the primary cause of vascular dementia (VD), but its pathophysiological mechanisms are still not known. This study aims to profile the molecular changes of a rat model of VD induced by bilateral common carotid artery ligation. The Morris water maze and new object recognition tasks were used to test the cognitive function of rats. Hematoxylin and Eosin (HE) staining was used to detect pathological changes in the hippocampus. After confirming the model, proteomics was used to detect differentially expressed proteins in the hippocampus, and metabolomics was used to detect differential metabolites in rat serum. Thereafter, bioinformatics were used to integrate and analyze the potential molecular profile. The results showed that compared with the sham control group, the spatial and recognition memory of the rats were significantly reduced, and pathological changes were observed in the hippocampal CA1 region of the model group. Proteomic analysis suggested 206 differentially expressed proteins in the hippocampus of VD rats, with 117 proteins upregulated and 89 downregulated. Protein-protein interaction network analysis suggested that those differentially expressed proteins might play crucial roles in lipid metabolism, cell adhesion, intracellular transport, and signal transduction. Metabolomics analysis identified 103 differential metabolites, and comparison with the human metabolome database revealed 22 common metabolites, which predicted 265 potential targets. Afterwards, by intersecting the predicted results from metabolomics with the differentially expressed proteins from proteomics, we identified five potential targets, namely ACE, GABBR1, Rock1, Abcc1 and Mapk10. Furthermore, western blotting confirmed that compared with control group, hippocampal GABBR1 and Rock1 were enhanced in the model group. Together, this study showed the molecular profile of VD rats through a combination of proteomics, metabolomics, and experimental confirmation methods, offering crucial molecular targets for the diagnosis and treatment of VD.

Plasma metabolomic signature of healthy lifestyle, structural brain reserve and risk of dementia.

Although the association between healthy lifestyle and dementia risk has been documented, the relationship between a metabolic signature indicative of healthy lifestyle and dementia risk and the mediating role of structural brain impairment remain unknown. We retrieved 136 628 dementia-free participants from UK Biobank. Elastic net regression was used to obtain a metabolic signature that represented lifestyle behaviours. Cox proportional hazard models were fitted to explore the associations of lifestyle-associated metabolic signature with incident dementia. Causal associations between identified metabolites and dementia were investigated using Mendelian randomization. Mediation analysis was also conducted to uncover the potential mechanisms involving 19 imaging-derived phenotypes (brain volume, grey matter volume, white matter volume and regional grey matter volumes). During a follow-up of 12.55 years, 1783 incident cases of all-cause dementia were identified, including 725 cases of Alzheimer's dementia and 418 cases of vascular dementia. We identified 83 metabolites that could represent healthy lifestyle behaviours using elastic net regression. The metabolic signature was associated with a lower dementia risk, and for each standard deviation increment in metabolic signature, the hazard ratio was 0.89 [95% confidence interval (CI): 0.85, 0.93] for all-cause dementia, 0.95 (95% CI: 0.88, 1.03) for Alzheimer's dementia and 0.84 (95% CI: 0.77, 0.91) for vascular dementia. Mendelian randomization revealed potential causal associations between the identified metabolites and risk of dementia. In addition, the specific structural brain reserve, including the hippocampus, grey matter in the hippocampus, parahippocampal gyrus and middle temporal gyrus, were detected to mediate the effects of metabolic signature on dementia risk (mediated proportion ranging from 6.21% to 11.98%). The metabolic signature associated with a healthy lifestyle is inversely associated with dementia risk, and greater structural brain reserve plays an important role in mediating this relationship. These findings have significant implications for understanding the intricate connections between lifestyle, metabolism and brain health.

Barriers of the CNS transfer rate dynamics in patients with vascular cognitive impairment and dementia.

Advances in in vivo MRI techniques enable cerebral barrier transfer rates (K trans ) measurement in patients with vascular cognitive impairment and dementia (VCID). However, a consensus has not been reached on the dynamic contribution and importance of cerebral barrier abnormalities to the differential diagnosis of dementia subtypes. Our goal was to investigate the dynamics of blood-brain barrier (BBB) and blood-CSF barrier (BCSFB) K trans in patients with VCID longitudinally and determine the effect of aging. We studied subjects at two time points over two years; they were 65.5 years of age (SD = 15.94, M/F = 24/14) at the first visit. We studied 38 patients, 18 of whom had two visits. We calculated the BBB and BCSFB K trans with dynamic contrast-enhanced T1 MR, and we used 1H-MR spectroscopy to measure N-acetylaspartate (NAA) levels in the white matter as a marker of injury. In addition, we measured CSF levels of active-matrix metalloproteinase-3 (MMP3) as an inflammatory biomarker to aid in patient clustering. Longitudinal BBB measurements revealed variable dynamic behavior: after two years, the BBB K trans increased in 55% of patients and decreased in the remaining 45% unpredictably. We did not find a significant linear model of BBB K trans versus age for VCID. For healthy controls, the model was K trans = 0.0014 + 0.0002 × age, which was significant (p = 0.046). VCID patients showed a reduction in BCSFB K trans compared to healthy controls (p = 0.01). Combining NAA, CSF MMP3, and K trans in a clustering analysis separated patients into groups. These results suggest that BBB K trans in VCID is dynamic and BCSFB K trans reduced by age. By combining inflammatory biomarkers with BBB K trans data, it is possible to separate VCID patients into distinct groups with different underlying pathologies.

Unraveling of Molecular Mechanisms of Cognitive Frailty in Chronic Kidney Disease: How Exercise Makes a Difference.

As our population ages, the medical challenges it faces become increasingly acute, with chronic kidney disease (CKD) becoming more prevalent among older adults. Frailty is alarmingly more common in CKD patients than in the general populace, putting the elderly at high risk of both physical and cognitive decline. CKD not only accelerates physical deterioration, but also heightens vascular dysfunction, calcification, arterial rigidity, systemic inflammation, oxidative stress, and cognitive impairment. Cognitive frailty, a distinct syndrome marked by cognitive deficits caused by physiological causes (excluding Alzheimer's and other dementias), is a critical concern. Although cognitive impairment has been well-studied, the molecular mechanisms driving cognitive frailty remain largely uncharted. Comprehensive interventions, including cutting-edge pharmaceuticals and lifestyle changes, are pivotal and effective, especially in the early stages of CKD. Recent research suggests that systematic exercise could counteract cognitive decline by improving brain blood flow, boosting neuroplasticity through the brain-derived neurotrophic factor (BDNF), and by triggering the release of neurotrophic factors such as insulin-like growth factor (IGF-1). This review delves into the molecular pathways of cognitive frailty in CKD, identifies key risk factors, and highlights therapeutic approaches, particularly the potent role of exercise in enhancing cognitive health.

Acute Kidney Injury and Its Association With Dementia and Specific Dementia Types: Findings From a Population-Based Study in Sweden.

Preclinical studies suggest that acute kidney injury (AKI) results in biochemical and pathologic changes in the brain. We aimed to explore the association between experiencing AKI and subsequent risks of developing dementia. We conducted a study involving individuals aged 65 years and older in Stockholm from 2006 to 2019, who were free from dementia diagnosis and had data on kidney function. The exposure was an episode of AKI (time varying), ascertained by issued clinical diagnoses and transient creatinine elevations according to Kidney Disease Improving Global Outcomes criteria. The outcome was all-cause dementia and specific types of dementia, ascertained by clinically confirmed cases in the Swedish registry of cognitive/dementia disorders, the presence of 2 issued dementia diagnoses in outpatient care, or initiation of specific antidementia medications. We investigated associations with dementia through Cox proportional hazard regression by AKI, severity levels of AKI, AKI recurrence, and setting (community-acquired or hospital-acquired AKI). We included 305,122 individuals with a median age of 75 ± 8 years (56.6% women). During a median follow-up of 12.3 (interquartile range 8.7-13.3) years, there were 79,888 individuals (26%) suffering from at least 1 episode of AKI and 47,938 incident cases (16%) of dementia. The rate of dementia cases was 37.0 per 1,000 person-years (95% CI 36.2-37.8) after developing AKI, which was approximately 2 times higher than the rate observed during the periods before AKI (17.3, 95% CI 17.2-17.5). After multivariable adjustment, developing AKI was associated with a 49% higher rate of subsequent dementia (adjusted hazard ratio hazard ratio [HR] 1.49, 95% CI 1.45-1.53). This pattern was consistent across dementia types, with HRs of 1.88 (95% CI 1.53-2.32), 1.47 (1.38-1.56), and 1.31 (1.25-1.38) for dementia with Lewy bodies and Parkinson disease with dementia, vascular dementia, and Alzheimer dementia, respectively. Risk associations were stronger in magnitude across more severe AKIs and in hospital-acquired vs community-acquired AKI. Individuals who experienced an AKI were at increased risk of receiving a diagnosis of dementia.

Cerebrovascular pulsatility indicates preoperative subcortical cognitive impairment and an increased risk for postoperative delirium in elderly patients undergoing elective spine surgery.

Advances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD. This prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics. POD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p < 0.01) but did not differ by gender (p = 0.51). ICA PI significantly predicted POD risk (OR = 5.46 [95%CI: 1.81-16.49], p = 0.003), which remained significant after adjustment for age and duration of surgery (ORadj = 6.38 [95% CI: 1.77-23.03], p = 0.005). TAPV did not inform the POD risk (p = 0.68). ICA PI Pre-operative cognitive scores were significantly associated with ICA PI (mean CERAD score: r = -0.32, p < 0.001). ICA PI was also significantly associated with total white matter lesion volume (τ = 0.19, p = 0.012) and periventricular white matter lesion volume (τ = 0.21, p = 0.007). This is the first study to demonstrate that cerebrovascular duplex sonography can assess the risk for POD in elderly spine surgery patients. Increased ICA PI may indicate subcortical impairment, larger white matter lesion load, and lower white matter volume, predisposing factors for POD. Pre-operative cerebrovascular duplex sonography of the ICA is widely available, easy-to-use, and efficient, offering a promising screening method for POD risk. Increased ICA PI could supplement established predictors like age to adjust surgical and peri-operative procedures to individual risk profiles.

Glyoxalase 1 overexpression improves neurovascular coupling and limits development of mild cognitive impairment in a mouse model of type 1 diabetes.

Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO-detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment. Diabetes was induced with streptozotocin. Fasting blood glucose, cognitive function, cerebral blood flow, neurovascular coupling (NVC), Glo1 activity, MGO and AGEs were assessed. In diabetes, MGO-derived hydroimidazolone-1 increased in the cortex, and was decreased in Glo1-overexpressing mice compared to controls. Visuospatial memory was decreased in diabetes, but not in Glo1/diabetes. NVC response time was slightly increased in diabetes, and normalised in the Glo1-overexpressing group. No impact of diabetes or Glo1 overexpression on blood-brain barrier integrity or vascular density was observed. Diabetes induced a mild visuospatial memory impairment and slightly reduced NVC response speed and these effects were mitigated by Glo1. This study shows a link between MGO-related AGE accumulation and cerebrovascular/cognitive functions in diabetes. Modulation of the MGO-Glo1 pathway may be a novel intervention strategy in patients with diabetes who have cerebrovascular complications. KEY POINTS: Diabetes is associated with an increased risk of stroke, cognitive decline, depression and Alzheimer's disease, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a highly reactive by-product of glycolysis, plays an important role in the development of diabetes-associated microvascular dysfunction in the periphery and is detoxified by the enzyme glyoxalase 1. Diabetes reduced visuospatial memory in mice and slowed the neurovascular coupling response speed, which was improved by overexpression of glyoxalase 1. MGO formation and MGO-derived advanced glycation endproduct (AGE) accumulation in the brain of diabetic mice are associated with a slight reduction in neurovascular coupling and mild cognitive impairment. The endogenous formation of MGO, and the accumulation of MGO-derived AGEs, might be a potential target in reducing the risk of vascular cognitive impairment in people with diabetes.