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.

Extracts of Sideritis scardica and Clinopodium vulgare Alleviate Cognitive Impairments in Scopolamine-Induced Rat Dementia.

Sideritis scardica Griseb. and Clinopodium vulgare L., belonging to the Lamiaceae family, are rich in terpenoids and phenolics and exhibit various pharmacological effects, including antioxidant, anti-inflammatory and anti-cancer activities. While the memory-enhancing impacts of S. scardica are well documented, the cognitive benefits of C. vulgare remain unexplored. This study assessed the potential effect of C. vulgare on learning and memory in healthy and scopolamine (Sco)-induced memory-impaired male Wistar rats, comparing it with the effects of S. scardica. Over a 21-day period, rats orally received extracts of cultivated S. scardica (200 mg/kg) and C. vulgare (100 mg/kg), either individually or in combination, with administration starting 10 days before and continuing 11 days simultaneously with Sco injection at a dose of 2 mg/kg intraperitoneally. The results showed that both extracts effectively mitigated Sco-induced memory impairment. Their combination significantly improved recognition memory and maintained monoaminergic function. S. scardica excelled in preserving spatial working memory, while C. vulgare exhibited comparable retention of recognition memory, robust antioxidant activity and acetylcholinesterase inhibitory activity. The extracts alleviated Sco-induced downregulation of p-CREB/BDNF signaling, suggesting neuroprotective mechanisms. The extract combination positively affected most of the Sco-induced impairments, underscoring the potential for further investigation of these extracts for therapeutic development.

Risk of dementia among antidepressant elderly users: A population-based cohort analysis in Spain.

The use of antidepressants with anticholinergic effects has been associated with an increased risk of dementia. However, the results published are contradictory. The aim of the study is to compare the risk of developing dementia in elderly who were prescribed tricyclic antidepressants (TCA) versus those who were prescribed selective serotonin reuptake inhibitors (SSRIs) and other antidepressants (OA). A prospective population-based cohort study was performed using the Spanish Database for Pharmacoepidemiological Research in Primary Care (BIFAP) data (from 2005 to 2018). The cohort study included 62,928 patients age ≥ 60 without dementia and with antidepressant long-term monotherapy. Patients were divided into exposure antidepressant groups based on ATC system [TCA, SSRIs users and OAs users]. The risk of dementia was calculated by Cox regression models, providing hazard ratios (HR) and 95 % confidence intervals. The Kaplan-Meier model was used for survival analysis. Chi2 test was used as association test. The results showed SSRI users had higher dementia risk than TCA users (HR = 1.864; 95%CI = 1.624-2.140). Moreover, OA users had also significant risk of dementia (HR = 2.103; 95%CI = 1.818-2.431). Several limitations are the variation of the trend in the prescription of antidepressants, the small number of patients that use some antidepressants, the lack of information related to the dose, or socioeconomic characteristics, the use of antidepressant drugs for other indications, or the therapeutic compliance. Our findings showed that older users of SSRI and OA have more risk of developing dementia than TCA elderly users. However, additional studies would be needed.

Antiviral Treatment and Response are Associated With Lower Risk of Dementia Among Hepatitis C Virus-Infected Patients.

OBJECTIVE: Eradication of hepatitis C virus (HCV) infection has been linked with improvement in neurocognitive function, but few studies have evaluated the effect of antiviral treatment/ response on risk of dementia. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we investigated how antiviral therapy impacts the risk of developing dementia among patients with HCV. METHODS: A total of 17,485 HCV patients were followed until incidence of dementia, death, or last follow-up. We used an extended landmark modeling approach, which included time-varying covariates and propensity score justification for treatment selection bias, as well as generalized estimating equations (GEE) with a link function as multinominal distribution for a discrete time-to-event data. Death was considered a competing risk. RESULTS: After 15 years of follow-up, 342 patients were diagnosed with incident dementia. Patients who achieved sustained virological response (SVR) had significantly decreased risk of dementia compared to untreated patients, with hazard ratios (HRs) of 0.32 (95% CI 0.22-0.46) among patients who received direct-acting antiviral (DAA) treatment and 0.41 (95% CI 0.26-0.60) for interferon-based (IFN) treatment. Risk reduction remained even when patients failed antiviral treatment (HR 0.38, 95% CI 0.38-0.51). Patients with cirrhosis, Black/African American patients, and those without private insurance were at significantly higher risk of dementia. CONCLUSION: Antiviral treatment independently reduced the risk of dementia among HCV patients, regardless of cirrhosis. Our findings support the importance of initiation antiviral therapy in chronic HCV-infected patients.

Opioids in geriatric units in 14 Belgian hospitals: prevalence, dosage and associated factors.

Introduction: Adverse effects of opioids are common among older individuals, and undertreatment as well as overuse can be an issue. Epidemiological data on opioid use in older individuals are available, but scarce in hospitalized patients.Aims: The aim of this study is to examine the one-day prevalence of opioid use among older inpatients and identify the factors associated with both opioid use and dosage.Materials and methods: One-day cross-sectional study with data collected from geriatric units across 14 Belgian hospitals. The primary focus of the study is to assess the prevalence of opioid use and dosage, along with identifying associated factors. To achieve this, a multiple binary logistic regression model was fitted for opioid use, and a multiple linear regression model for opioid dose.Results: Opioids were used in 24.4% of 784 patients, of which 57.9% was treated with tramadol, 13.2% with oxycodone or morphine and 28.9% with transdermal buprenorphine or fentanyl. The odds for opioid use were 4.2 times higher in patients in orthogeriatric units compared to other patients (OR=4.2, 95% CI=2.50-7.05). The prevalence of opioid use was 34% higher in patients without dementia compared to patients with dementia (OR=0.66, 95% CI=0.46-0.95). The overall mean daily dosage was 14.07mg subcutaneous morphine equivalent. After adjustment for age, gender and dementia, dosage was only associated with type of opioid: the estimated mean opioid dose was 70% lower with tramadol (mean ratio=0,30,95% CI=0,23-0,39) and 67% lower with oxycodone and morphine (mean ratio=0,33, 95% CI=0,22-0,48) compared to transdermal buprenorphine and transdermal fentanyl.Conclusions: One in four patients received opioid treatment. It is not clear whether this reflects under- or overtreatment, but these results can serve as a benchmark for geriatric units to guide future pain management practices. The utilization of transdermal fentanyl and buprenorphine, resulting in higher doses of morphine equivalent, poses significant risks for side effects.

Association between solid cooking fuel use and dementia in older Chinese adults: the mediating effect of depression.

This study aimed to explore the association between household solid cooking fuel use and dementia prevalence and the mediating effect of depression on this association. A total of 3404 (2018) and 1379 (2015 to 2018) older participants (≥65) from the China Health and Retirement Longitudinal Study (CHARLS) were enrolled in the cross-sectional and retrospective longitudinal analyses, respectively. The results showed that solid cooking fuel use was associated with an increased dementia prevalence (adjusted OR = 1.44) from 2015 to 2018. The indirect effect of depression on this association explained 7.14% and 13.11% variances in the cross-sectional and longitudinal mediating model, respectively. Thus, household solid cooking fuel use is a risk factor for the development of dementia, and depressive symptoms partially accounted for this association. The use of improved cookstoves and clean fuel in households and air cleaners and early intervention in depression may reduce the incidence of dementia.

Association evaluations of oral anticoagulants with dementia risk based on genomic and real-world data.

BACKGROUND: Several observational studies have suggested that oral anticoagulants (OACs) might reduce the risk of dementia in the elderly, but the evidence is inconclusive. And the consistency of this relationship across different OAC classes and dementia subtypes is still uncertain. METHODS: To comprehensively evaluate this association, we applied Mendelian randomization (MR) combined with pharmacovigilance analysis. MR was used to assess the associations between genetic proxies for three target genes of OACs (VKORC1, F2, and F10) and dementia, including Alzheimer's disease (AD) and vascular dementia (VaD). This genetic analysis was supplemented with real-world pharmacovigilance data, employing disproportionality analysis for more reliable causal inference. RESULTS: Increased expression of the VKORC1 gene was strongly associated with increased risk of dementia, especially for AD (OR = 1.28, 95% CI = 1.14-1.43; p value < 0.001). Based on pharmacovigilance data, vitamin K antagonists (VKAs, inhibitors targeting VKORC1) exhibited a protective effect against dementia risk (ROR = 0.43, 95% CI = 0.28-0.67). Additional sensitivity analyses, including different MR models and cohorts, supported these results. Conversely, no strong causal associations of genetically proxied F2 and F10 target genes with dementia and its subtypes were found. CONCLUSIONS: This study reveals that the inhibition of genetically proxied VKORC1 expression or VKAs exposure is associated with a reduced risk of Alzheimer's dementia. However, there is little evidence to support similar associations with direct oral anticoagulants (F2 inhibitors and F10 inhibitors). Further research is warranted to clinically validate our findings.

Cholinesterase inhibitors associated with lower rate of mortality in dementia patients with heart failure: a nationwide propensity weighting study.

PURPOSE: This study investigates the potential impact of cholinesterase inhibitors (ChEIs) on patients with heart failure (HF) and dementia. ChEIs are known to boost acetylcholine levels and benefit cognition in patients with dementia; however, their effect on patients with HF is uncertain. This study aimed to assess whether cardiovascular events and mortality among patients with HF and dementia are altered by ChEI therapy. METHODS: Data from the National Health Insurance Research Database in Taiwan were retrospectively analyzed. Dementia patients diagnosed with HF were followed for 5 years until all-cause mortality, cardiovascular mortality, hospitalization for worsening HF, or the end of the study. Multivariable Cox models and inverse probability of treatment weighting (IPTW) were employed. RESULTS: Out of 20,848 patients with dementia, 5138 had HF. Among them, 726 were ChEI users and 4412 were non-users. Based on IPTW, the ChEI users had significantly lower estimated risks of all-cause mortality [hazard ratio (HR) 0.43; 95% confidence interval (CI) 0.38-0.49, p < 0.001] and cardiovascular mortality (HR 0.41; 95% CI 0.33-0.53, p < 0.001) compared with the non-users, but there was no significant difference in hospitalization for worsening HF (HR 0.73; 95% CI 0.51-1.05, p = 0.091) after 5 years. The survival benefits of ChEIs were consistent across subgroups. CONCLUSIONS: The results of this retrospective cohort study suggest that ChEIs may be beneficial in reducing all-cause and cardiovascular mortality in patients with dementia with HF. Further research is needed to validate these findings and explore the potential benefits of ChEIs in all patients with HF, including those without dementia.

Clozapine for the treatment of aggressiveness and agitation in advanced dementia.

BACKGROUND: Distressing behavioural symptoms, particularly agitation and aggressiveness, remain a difficult problem in everyday clinical practice in the treatment of multimorbid patients with dementia. Clozapine may be an effective therapeutic alternative in this context. METHODS: In a retrospective study, patients who had a diagnosis of dementia and had been treated in a specialized geriatric psychiatry unit with clozapine between August 2018 and February 2022 were included, and medical records were systematically reviewed. The Clinical Global Impressions Scale was used to assess improvement, and the Pittsburgh Agitation Scale for symptom reduction. In addition, side effects and clinical features were documented in detail. RESULTS: A total of 31 patients (median age 82 years) were identified with a mean clozapine dose of 47.2 (SD 35.6) mg. A total of 13 patients tolerated clozapine very well, 10 showed tolerable side effects, and in 10 patients side effects were the reason for stopping clozapine. Behavioural symptoms improved significantly, as indicated by the assessment scores. CONCLUSIONS: In summary, clozapine was effective and well tolerated in 23 patients, suggesting that low-dose clozapine may help to alleviate the suffering of difficult-to-treat multimorbid patients with advanced dementia and their caregivers. However, particular attention should be paid to adverse drug reactions, especially in patients with cardiovascular and pulmonary impairment.

A systematic review of quantitative studies exploring staff views on antipsychotic use in residents with dementia in care homes.

BACKGROUND: Despite significant warnings of adverse effects, antipsychotics continue to be prescribed for managing the behavioural and psychological symptoms of dementia (BPSD) in care homes. Information provided by staff working within care homes is a factor that can influence prescribing decisions in residents with BPSD. AIM: The review aimed to capture care home staff views towards antipsychotics for residents with BPSD and separately analyse tools utilized in the studies, mapping them onto the theory of planned behaviour (TPB). METHOD: A comprehensive literature search published in ten databases was conducted between May and July 2020 and updated in July 2021. Studies published in full with no date restriction were included and quality assessed using CROSS checklist. A thematic framework approach was applied to extract data and study tools which were then mapped onto the TPB. RESULTS: Fourteen studies (2059 participants) were included. Findings identified four overarching themes: attitudes toward antipsychotics (e.g. antipsychotics as an appropriate strategy and effectiveness); barriers to deprescribing (e.g. lower staff education, lack of resources and time, poor medication reviews); measures implemented (e.g. nonpharmacological interventions, medication reviews); and perceived needs of staff (e.g. need for training, financial or clinical support). Identified tools addressed seven but not all components of TPB namely, behavioural, normative and control beliefs, attitude, perceived behavioural control, intention and behaviour. CONCLUSION: The positive attitudes toward antipsychotics, the identified barriers to deprescribing and the existing tools not addressing all components of the TPB provide the impetus for further research.

Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study.

BACKGROUND AND OBJECTIVES: Studies on the association between proton pump inhibitor (PPI) use and dementia report mixed results and do not examine the impact of cumulative PPI use. We evaluated the associations between current and cumulative PPI use and risk of incident dementia in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: These analyses used participants from a community-based cohort (ARIC) from the time of enrollment (1987-1989) through 2017. PPI use was assessed through visual medication inventory at clinic visits 1 (1987-1989) to 5 (2011-2013) and reported annually in study phone calls (2006-2011). This study uses ARIC visit 5 as baseline because this was the first visit in which PPI use was common. PPI use was examined 2 ways: current use at visit 5 and duration of use before visit 5 (from visit 1 to 2011, exposure categories: 0 day, 1 day-2.8 years, 2.8-4.4 years, >4.4 years). The outcome was incident dementia after visit 5. Cox proportional hazard models were used, adjusted for demographics, comorbid conditions, and other medication use. RESULTS: A total of 5,712 dementia-free participants at visit 5 (mean age 75.4 ± 5.1 years; 22% Black race; 58% female) were included in our analysis. The median follow-up was 5.5 years. The minimum cumulative PPI use was 112 days, and the maximum use was 20.3 years. There were 585 cases of incident dementia identified during follow-up. Participants using PPIs at visit 5 were not at a significantly higher risk of developing dementia during subsequent follow-up than those not using PPIs (hazard ratio (HR): 1.1 [95% confidence interval (CI) 0.9-1.3]). Those who used PPIs for >4.4 cumulative years before visit 5 were at 33% higher risk of developing dementia during follow-up (HR: 1.3 [95% CI 1.0-1.8]) than those reporting no use. Associations were not significant for lesser durations of PPI use. DISCUSSION: Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that the use of prescribed PPIs for >4.4 years by individuals aged 45 years and older is associated with a higher incidence of newly diagnosed dementia.

Anticholinergic Burden and Cognitive Impairment in Nursing Homes: A Comparison of Four Anticholinergic Scales.

BACKGROUND: Medications with anticholinergic effects are commonly used in nursing homes, and their cumulative effect is of particular concern for the risk of adverse effects on cognition. OBJECTIVE: The relation between cognitive function and anticholinergic burden measured with four scales, the Anticholinergic Cognitive Burden (ACB) Scale, the Anticholinergic Risk Scale, the German Anticholinergic Burden Scale, and the CRIDECO Anticholinergic Load Scale, is assessed according to the hypothesis that a higher anticholinergic burden is associated with reduced cognitive performance. METHODS: This retrospective cross-sectional multicenter study was conducted in a sample of Italian long-term-care nursing homes (NH). Sociodemographic details, diagnosis, and drug treatments of each NH resident were collected using medical records four times during 2018 and 2019. Cognitive status was rated with the Mini-Mental State Examination (MMSE). The prevalence of anticholinergic use and its burden were calculated referring to the last time point for each patient. A longitudinal analysis was done on NH residents with at least two MMSE between 2018 and 2019 to assess the relation between the anticholinergic load and decline in MMSE. The relationship between drug-related anticholinergic burden and cognitive performance was analyzed using Poisson regression model theory. Multivariate analyses were adjusted according to the known risk factors of reduced cognitive performance available [age, sex, history of stroke or transient ischemic attack (TIA), and number of non-anticholinergic drugs] and for cholinesterase inhibitors. In view of the high number of subjects with an MMSE score = 0 among residents with dementia, for this group a zero-inflated Poisson regression model was used to give more consistent results. The association of anticholinergic burden with mortality was examined from each patient's last visit using a multivariate logistic model adjusted for age, sex, and Charlson Comorbidity Index (CCI). RESULTS: Among 1412 residents recruited, a clear direct relationship was found between higher anticholinergic burden and cognitive impairment only for the Anticholinergic Cognitive Burden Scale. Residents taking an anticholinergic who scored 5 or more had 2.5 points more decline than those not taking them (p < 0.001). Among residents without dementia there was a trend toward direct relationship for the Anticholinergic Cognitive Burden Scale and the Anticholinergic Risk Scale. Residents with higher scores had about 2 points more decline than residents not taking anticholinergic drugs. No relation was found between anticholinergic burden and cognitive decline or mortality. CONCLUSIONS: The cumulative effect of medications with modest antimuscarinic activity may influence the cognitive performance of NH residents. The anticholinergic burden measured with the ACB scale should help identify NH residents who may benefit from reducing the anticholinergic burden. A clear direct relationship between anticholinergic burden and cognitive impairment was found only for the ACB Scale.

Dementia risk in patients with type 2 diabetes: Comparing metformin with no pharmacological treatment.

INTRODUCTION: Metformin has been suggested as a therapeutic agent for dementia, but the relevant evidence has been partial and inconsistent. METHODS: We established a national cohort of 210,237 type 2 diabetes patients in the UK Clinical Practice Research Datalink. Risks of incident dementia were compared between metformin initiators and those who were not prescribed any anti-diabetes medication during follow-up. RESULTS: Compared with metformin initiators (n = 114,628), patients who received no anti-diabetes medication (n = 95,609) had lower HbA1c and better cardiovascular health at baseline. Both Cox regression and propensity score weighting analysis showed metformin initiators had lower risk of dementia compared to those non-users (adjusted hazard ratio = 0.88 [95% confidence interval: 0.84-0.92] and 0.90 [0.84-0.96]). Patients on long-term metformin treatment had an even lower risk of dementia. DISCUSSION: Metformin may act beyond its glycemic effect and reduce dementia risk to an even lower level than that of patients with milder diabetes and better health profiles. HIGHLIGHTS: Metformin initiators had a significantly lower risk of dementia compared with patients not receiving anti-diabetes medication. Compared with metformin initiators, diabetes patients not receiving pharmacological treatment had better glycemic profiles at baseline and during follow-up. Patients on long-term metformin treatment had an even lower risk of subsequent dementia incidence. Metformin may act beyond its effect on hyperglycemia and has the potential of being repurposed for dementia prevention.

Therapeutic dilemma's: antipsychotics use for neuropsychiatric symptoms of dementia, delirium and insomnia and risk of falling in older adults, a clinical review.

PURPOSE: Because of the common and increasing use of antipsychotics in older adults, we aim to summarize the current knowledge on the causes of antipsychotic-related risk of falls in older adults. We also aim to provide information on the use of antipsychotics in dementia, delirium and insomnia, their adverse effects and an overview of the pharmacokinetic and pharmacodynamic mechanisms associated with antipsychotic use and falls. Finally, we aim to provide information to clinicians for weighing the benefits and harms of (de)prescribing. METHODS: A literature search was executed in CINAHL, PubMed and Scopus in March 2022 to identify studies focusing on fall-related adverse effects of the antipsychotic use in older adults. We focused on the antipsychotic use for neuropsychiatric symptoms of dementia, insomnia, and delirium. RESULTS: Antipsychotics increase the risk of falls through anticholinergic, orthostatic and extrapyramidal effects, sedation, and adverse effects on cardio- and cerebrovascular system. Practical resources and algorithms are available that guide and assist clinicians in deprescribing antipsychotics without current indication. CONCLUSIONS: Deprescribing of antipsychotics should be considered and encouraged in older people at risk of falling, especially when prescribed for neuropsychiatric symptoms of dementia, delirium or insomnia. If antipsychotics are still needed, we recommend that the benefits and harms of antipsychotic use should be reassessed within two to four weeks of prescription. If the use of antipsychotic causes more harm than benefit, the deprescribing process should be started.

In the prevention of dementia, the focus should be on early and consistent treatment of hypertension.

The brain is among the target organs of hypertension. Patients with hypertension have a higher risk of developing stroke as well as experiencing a decline in cognitive functions and dementia. Changes in the white matter and atrophy of the grey matter of the brain induced by high blood pressure develop insidiously since the onset of hypertension, even in young individuals. The effect of high blood pressure on the vessel wall cumulates in time; therefore, hypertension in younger people implies an increased risk of dementia in older age. Hypertension in young age cannot be considered a benign condition. Hypertension in middle age increases the risk of dementia by 61 %. Consistent and early hypertension control can reverse the adverse development towards dementia and lack of self-sufficiency in the patient. Data comparing individual antihypertensive drugs in terms of preventing dementia are scarce. However, renin angiotensin system blockers have been found to protect against Alzheimer's disease more than other classes of antihypertensive drugs. To achieve rapid and effective hypertension control, a combination of antihypertensive drugs is usually required. Using a fixed-dose triple combination of perindopril, indapamide, and amlodipine, blood pressure targets of < 130/80 mm Hg can be achieved within three months in 93 % of patients.