Benzodiazepine use in relation to long-term dementia risk and imaging markers of neurodegeneration: a population-based study.

BACKGROUND: Benzodiazepine use is common, particularly in older adults. Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain. METHODS: We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models. RESULTS: Of all 5443 participants, 2697 (49.5%) had used benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of benzodiazepines or cumulative dose. CONCLUSIONS: In this population-based sample of cognitively healthy adults, overall use of benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.

Beneficial effect of lupeol and metformin in mouse model of intracerebroventricular streptozotocin induced dementia.

This study examines the effectiveness of lupeol and metformin in a mouse model of dementia generated by intracerebroventricular streptozotocin (i.c.v., STZ). Dementia was induced in Swiss mice with the i.c.v. administration of STZ at a dosage of 3 mg/kg on the first and third day. The assessment of dementia involved an examination of the Morris Water Maze (MWM) performance, as well as a number of biochemical and histological studies. STZ treatment resulted in significant decrease in MWM performance; various biochemical alterations (increase in brain acetyl cholinesterase (AChE) activity, thiobarbituric acid reactive species (TBARS), nitrite/nitrate, and reduction in nuclear factor erythroid 2 related factor-2 (Nrf-2), reduced glutathione (GSH) levels) and neuroinflammation [increased myeloperoxidase (MPO) activity & neutrophil infiltration]. The administration of Lupeol (50 mg/kg & 100 mg/kg; p.o.) and Metformin (150 mg/kg & 300 mg/kg; p.o.) demonstrated a considerable reduction in the behavioral, biochemical, and histological alterations produced by STZ. Low dose combination of lupeol (50 mg/kg; p.o.) and Metformin (150 mg/kg; p.o.) produced more pronounced effect than that of high doses of either agent alone. It is concluded that Lupeol and Metformin has shown efficacy in dementia with possible synergism between the two and can be explored as potential therapeutic agents for managing dementia of Alzheimer's disease (AD) type.

Association between gabapentin use and risk of dementia in adults with chronic pain: A nested case-control study.

STUDY OBJECTIVE: To explore the association between gabapentin use and the risk of dementia in patients with chronic pain, considering the rising concerns of dementia in an aging population and the potential cognitive impacts of chronic pain management. DESIGN: A nested case-control study utilizing data from a longitudinal health insurance database. SETTING: The study is based on a longitudinal health insurance database spanning 2000-2019 in Taiwan. PATIENTS: A total of 201,492 patients aged 50 years and older diagnosed with chronic pain between 2001 and 2017 were included. The study focused on individuals with chronic pain, excluding those diagnosed with dementia a year before or after their chronic pain diagnosis. INTERVENTION: Analysis of gabapentin prescription history was conducted, considering the cumulative dose from the chronic pain diagnosis date to the dementia diagnosis date or equivalent period for controls. MEASUREMENT: Data included demographics, gabapentin prescription history, and comorbidities. Logistic regression was used to estimate odds ratios for dementia risk. MAIN RESULTS: No significant difference in the risk of dementia was found between low and high cumulative doses of gabapentin. The adjusted odds ratio for dementia risk associated with gabapentin use was 0.91 (95 % C.I. 0.83-1.01), indicating no substantial increase in risk. CONCLUSION: Long-term Gabapentin therapy for chronic pain is not associated with a differential risk of dementia across dosage levels, irrespective of age or gender. Further study into its potential cognitive impacts is essential.

Association between colchicine use and the risk of dementia among patients with gout: A nationwide retrospective cohort study.

BACKGROUND: Recent findings suggest a link between gout and the development of dementia. Early treatment with colchicine is recommended as a first-line therapy for gout flares. Animal studies demonstrate that colchicine could induce cognitive impairment. This cohort study aimed to investigate the association between colchicine use and the risk of developing dementia. METHODS: In this nationwide cohort study, we performed comparative analysis on 6147 patients ≥40 years, with gout and colchicine new users against 6147 controls to assess subsequent dementia risk. The colchicine group and the control group (urate lowering therapy group) were matched on the bases of age, sex, index year, and comorbidities. All participants were followed for up to 14 years for a diagnosis of dementia considering medical records were retrospectively checked over this period. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Sensitivity analyses were performed to validate our findings. RESULTS: The adjusted hazard ratio (aHR) of dementia for colchicine users was 1.45 (95% CI = 1.05, 1.99) relative to comparison group after adjusting for sex, age, and comorbidities. Sensitivity analysis aiming to minimize underdiagnosed occult dementia at the time of index year yielded consistent positive association. In higher accumulative dose colchicine group (cumulative defined daily dose [cDDD] >30), the aHR of dementia risk for colchicine users was 1.42 (95% CI = 1.03, 1.97) compared with nonusers. For those duration of colchicine use >30 days, the aHR was 1.53 (95% CI = 1.01-2.32) compared to the nonuser group. CONCLUSIONS: A significant risk of dementia was observed in this study in patients with gout using colchicine at higher cDDD and for a longer period. Further research is needed to elucidate the relationship between colchicine, gout, and dementia.

The longitudinal associations between ambient air pollution exposure and dementia in the UK: results from the cognitive function and ageing study II and Wales.

BACKGROUND: Air pollution has been recognised as a potential risk factor for dementia. Yet recent epidemiological research shows mixed evidence. The aim of this study is to investigate the longitudinal associations between ambient air pollution exposure and dementia in older people across five urban and rural areas in the UK. METHODS: This study was based on two population-based cohort studies of 11329 people aged ≥ 65 in the Cognitive Function and Ageing Study II (2008-2011) and Wales (2011-2013). An algorithmic diagnosis method was used to identify dementia cases. Annual concentrations of four air pollutants (NO2, O3, PM10, PM2.5) were modelled for the year 2012 and linked via the participants' postcodes. Multistate modelling was used to examine the effects of exposure to air pollutants on incident dementia incorporating death and adjusting for sociodemographic factors and area deprivation. A random-effect meta-analysis was carried out to summarise results from the current and nine existing cohort studies. RESULTS: Higher exposure levels of NO2 (HR: 1.04; 95% CI: 0.94, 1.14), O3 (HR: 0.90; 95% CI: 0.70, 1.15), PM10 (HR: 1.17; 95% CI: 0.86, 1.58), PM2.5 (HR: 1.41; 95% CI: 0.71, 2.79) were not strongly associated with dementia in the two UK-based cohorts. Inconsistent directions and strengths of the associations were observed across the two cohorts, five areas, and nine existing studies. CONCLUSIONS: In contrast to the literature, this study did not find clear associations between air pollution and dementia. Future research needs to investigate how methodological and contextual factors can affect evidence in this field and clarity the influence of air pollution exposure on cognitive health over the lifecourse.

[Drug-induced cognitive impairment and dementia]. / Lekarstvenno-indutsirovannye kognitivnye narusheniya i dementsiya.

One of the reasons for the development or worsening of cognitive impairment (CI) may be the use of a number of drugs: non-steroidal anti-inflammatory drugs, antiarrhythmics, antidepressants, glucocorticosteroids, antitumor drugs and a number of others. The negative effect of drugs on cognitive functions is realized due to many pathophysiological mechanisms: disruption of hormonal regulation, decreased neuronal excitability, increased activity of gamma-aminobutyric acid receptors, decreased cerebral circulation, atrophic changes in the brain; many mechanisms have not been fully established. Risk factors for the development of drug-induced CIs are: old age or childhood, brain damage, chronic diseases, genetic factors, the patient's initial CI, polypharmacy, dose and duration of drug use, acute infectious diseases, metabolic disorders, dehydration, acute urinary retention, etc. To diagnose and differentially diagnose drug-induced CI, it is necessary to establish a connection between the start of taking a suspected drug-inducer and a decrease in cognitive functions. The first step in the treatment of drug-induced CI is the abolition of an inducer drug or a reduction in its dose, in cases where it is impossible to discontinue the drug and there is no replacement, special slow-release dosage forms can be considered. The main measures to prevent drug-induced CI include the use of drugs with the lowest risk of their development, assessment of drug interactions, and the use of modern scales to assess the risk of developing this side-effect (anticholinergic burden scale, etc.).

Association of Exposure to Ambient Air Pollutants With Cognitive Performance and Dementia Risk and the Mediating Role of Pulmonary Function: Evidence From the UK Biobank.

BACKGROUND: The pathways by which air pollution affects cognition remain to be explored. This study aimed to explore how single air pollutants [including nitrogen oxide (NOX), nitrogen dioxide (NO2), particulate matter with a diameter of 2.5 micrometers (PM2.5), PM10, and PM2.5-10], and air pollution mixture could affect cognitive function and the incidence of dementia, and determine whether pulmonary function (PF) could play a mediating role in the relationship. METHODS: Multiple statistical methods were employed to evaluate association of 5 air pollutants (NOX, NO2, PM2.5, PM10, and PM2.5-10) with cognitive function. Bootstrap method was used to estimate mediating role of PF in the association of air pollutants with cognition or the incidence of dementia. RESULTS: A mixture of air pollutants was associated with performance on 5 cognitive tests, and global cognition (p < .05). Significantly negative association was also identified between mixture of air pollutants and PF (ß= -0.020, 95% confidence interval (CI) = -0.029 to -0.011). In addition, as PF scores increase, performance on all cognitive tests significantly improve, although the risk of dementia correspondingly decreases. It was noted that PF was shown to mediate the effects of air pollution mixtures on all cognitive tests as well as global cognition. For global cognition, PF mediated 6.08% of the association. PF was also found to have a mediating role in the association between NOX, NO2, PM2.5, and the risk of dementia. CONCLUSIONS: Mixed air pollution may impact cognitive function, with PF potentially mediating this relationship.

Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.