A Randomised Placebo-Controlled Study of Purified Anthocyanins on Cognition in Individuals at Increased Risk for Dementia.

IMPORTANCE: Identifying nutritional compounds which can reduce cognitive decline in older people is a hugely important topic. OBJECTIVE: To study the safety and effect of anthocyanins in maintaining cognitive functioning in people at increased risk for dementia. DESIGN, SETTING, AND PARTICIPANTS: Participants (206 individuals, aged 60-80 years) diagnosed with either mild cognitive impairment (MCI) or two or more cardiometabolic disorders (i.e., diabetes, hypertension, obesity) were enrolled at three different centres in Norway. INTERVENTION: Participants were randomly assigned to four capsules with a total of 320 mg/d of naturally purified anthocyanins or placebo 1:1 for 24 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the Quality of Episodic Memory composite measure (0-100) from an online cognitive test battery CogTrack, which was administered at baseline and monthly for the next 24 weeks. Secondary outcomes included other cognitive scores from the CogTrack battery. We applied mixed effects models with a baseline test score, group, time and their interaction as fixed effects, as well as other predefined baseline covariates. The primary comparison was the group difference at week 24 based on a modified intention-to-treat principle. RESULTS: The primary analysis did not show a significant group difference at 24 weeks (78.2 versus 76.8; adjusted mean difference 1.4 (95% confidence interval -0.9-3.7); effect size 0.15; p = 0.23). However, there was a significant difference in slopes during weeks 8-24 (p = 0.007); the anthocyanin group improved while the placebo group worsened. No differences were found for the secondary cognitive outcomes. Anthocyanin capsules were well-tolerated and safe to use. CONCLUSION: Anthocyanin supplementation for 24 weeks was safe and well tolerated in people with MCI or cardiometabolic disorders. We found no significant group difference in episodic memory at the end of the study but statistically significant differences in slopes. Further studies are warranted to explore whether anthocyanins supplementation can reduce cognitive decline in people at increased risk of dementia. TRIAL REGISTRATION: ClinicalTrials.gov, (Identifier NCT03419039). http://www. CLINICALTRIALS: gov/, NCT03419039.

Polypharmacy is associated with functional decline in Alzheimer's disease and Lewy body dementia.

BACKGROUND: In dementia, a number of factors may influence functional decline in addition to cognition. In this study, we aimed to study the potential association of the number of prescribed medications with functional decline trajectories over a five-year follow-up in people diagnosed with mild Alzheimer's disease (AD) or Lewy Body dementia (LBD). METHODS: This is a longitudinal analysis of a Norwegian cohort study entitled "The Dementia Study of Western Norway". We included 196 patients newly diagnosed with AD (n=111) and LBD (n=85), followed annually for 5 years. We conducted linear mixed-effects models to analyse the association of the number of medications with functional decline measured by the Rapid Disability Rating Scale - 2. RESULTS: The mean prescribed medications at baseline was 4.18∓2.60, for AD 3.92∓2.51 and LBD 4.52∓2.70. The number of medications increased during the follow-up; at year five the mean for AD was 7.28∓4.42 and for LBD 8.11∓5.16. Using more medications was associated with faster functional decline in AD (Est 0.04, SE 0.01, p-value 0.003) and LBD (Est 0.08, SE 0.03, p-value 0.008) after adjusting for age, sex, comorbidity, neuropsychiatric symptoms, and cognition. For each medication added during the follow-up, functional trajectories worsened by 1% for AD and 2% for LBD. The number of medications was not associated with cognitive decline. CONCLUSION: We found that higher number of medications was related to a faster functional decline, both in AD and LBD. With disease progression, there was an increase in the number of medications. Prescription in dementia should be carefully assessed, possibly improving the functional prognosis.

Benzodiazepines and antidepressants: Effects on cognitive and functional decline in Alzheimer's disease and Lewy body dementia.

OBJECTIVES: We aim to study the effects of the prescription of benzodiazepines and antidepressants on cognitive and functional decline in older adults living with Alzheimer's disease (AD) and Lewy body dementia (LBD) over a 5-year follow-up. METHODS: This is a longitudinal analysis of a Norwegian cohort study entitled "The Dementia Study of Western Norway" (DemVest). We included 196 patients newly diagnosed with AD (n = 111) and LBD (n = 85), followed annually for 5 years. Three prescription groups were defined: only benzodiazepines (BZD), only antidepressants (ADep), and the combination of benzodiazepines and antidepressants (BZD-ADep). Linear mixed-effects models were conducted to analyze the effect of the defined groups on the outcomes. The outcomes were functional decline, measured by the Rapid Disability Rating Scale-2, and cognition measured with the Mini-Mental State Examination. RESULTS: Prescription of the combination of benzodiazepines and antidepressants in LBD was associated with faster functional decline. In AD, the prescription of BZD and BZD-ADep was associated with greater functional deterioration. ADep alone did not show positive or negative significant associations with the studied outcomes. CONCLUSIONS: BZD and especially the combination of BZD and ADep are associated with functional decline in AD and LBD and should be used cautiously.

Effects of Purified Anthocyanins in People at Risk for Dementia: Study Protocol for a Phase II Randomized Controlled Trial.

Background: The number of people with dementia is increasing, with huge challenges for society and health-care systems. There are no disease-modifying therapies available. There is, therefore, an urgent need to identify strategies to reduce the risk of developing dementia. Anthocyanins are a class of compounds found in dark berries and fruits with some effects that might reduce the risk for cognitive decline and the development of dementia in older people. Aim: This phase II three-center, randomized, 24-week, placebo-controlled study, ongoing in Norway, aims to evaluate the safety, and efficacy of anthocyanins in modifying key dementia-related mechanisms and maintain cognitive functioning in older people at risk for dementia. Methods: Participants (220 individuals aged 60-80 years) who meet the inclusion criteria (either mild cognitive impairment or two or more cardiometabolic disorders) are being enrolled in this study at three different centers in Norway. Participants are block randomized to identically appearing capsules containing 80 mg of naturally purified anthocyanins or placebo 1:1. Dosage is 2 + 2 capsules per day for 24 weeks. The primary outcome will be the quality of episodic memory score, a composite measure from the extensively validated online cognitive test battery CogTrack®, which is administered at baseline and monthly for the next 6 months. Secondary outcomes include other major scores from CogTrack, as well as a range of neuroimaging and other biomarkers. Anthocyanin metabolites will be measured in blood and cerebrospinal fluid. The change from baseline scores will be subject to a mixed model for repeated measures analysis of covariance. The primary comparison will be the contrast (difference in the least-square means) between active and placebo at the end of the study (week 24). The primary study population will be a modified intention-to-treat population (ClinicalTrials.gov, NCT03419039). Discussion: This study aims to demonstrate whether there are beneficial effects of purified anthocyanins on cognition and relevant biological functions in people at increased risk for dementia. Forthcoming results may contribute to further improvement of intervention strategies to prevent or delay the onset of dementia, including a potential decision to take anthocyanins toward phase III trials.

Risk of Hospitalization in Patients with Alzheimer's Disease and Lewy Body Dementia: Time to and Length of Stay.

BACKGROUND: Patients with dementia are at high risk of being hospitalized, but there is little knowledge whether this applies to all forms of dementia. OBJECTIVE: To investigate if there are differences in hospitalization between patients with Alzheimer's disease (AD) and Lewy body dementia (LBD), and further, to compare admission rate with the general age-matched population. METHODS: Patients (age 75.7±7.4) recently diagnosed with mild form of AD (n = 110) or LBD (n = 91) were included from outpatient clinics. The participants were followed from time of diagnosis, for five years or until death. Study outcomes were time to first hospitalization after diagnosis, number of admissions, total number of hospital days, and length of stay. Age-standardized admission ratios were calculated. Time to first admission was analyzed using competing risks regression models, and differences in number of hospitalizations and hospital days were addressed using negative binomial regression models. RESULTS: More than 77% of the patients were admitted, largely as unplanned hospitalizations. Patients with LBD had significantly shorter time until first hospitalization (median 1.28 years, 95% CI 0.93-1.67 versus AD: 2.32 years, 95% CI 1.74-3.31) and more days in hospital (median 13 days, IQR 4, 38), than patients with AD (7 days, IQR 0, 18). CONCLUSION: Our data indicates that patients with LBD have shorter time until first admission and higher admission rate than AD patients. This imposes a great burden on patients, their family, and the health care system. More knowledge about hospital admissions of people with dementia is needed. Future studies should investigate strategies to avoid potentially preventable admissions.

Potentially inappropriate medications and drug-drug interactions in home-dwelling people with mild dementia.

OBJECTIVES: The objectives of this study were to describe the use of psychotropic drugs among home-dwelling people with mild dementia, to identify potentially inappropriate medications (PIM) and drug-drug interactions (DDI), and to analyze potential variables associated with having PIM and DDI. METHODS: Patients (n = 251) with a first-time diagnosis of mild dementia (defined as a mini-mental state examination score >20) were included from outpatient clinics. Prevalence of psychotropic drug use, polypharmacy, and psychotropic polypharmacy were investigated. The prevalence of PIM and DDI were defined using the Norwegian general practice criteria and an interactions database, respectively. Variables associated with having PIM and DDI were assessed using a multivariable logistic regression analysis adjusting for relevant demographic and clinical variables. RESULTS: Almost 96% of the patients used one or more medications. Polypharmacy was found in 45% of the patients, and nearly 70% of the patients were using one or more psychotropic drugs. Psychotropic polypharmacy was found in seven patients. PIM were identified in 35 patients (14%), while only four severe DDI were found. Female sex and number of medications were significantly associated with having PIM, whereas only number of medications was significantly associated with having DDI. CONCLUSION: Few patients had PIM or severe DDI, indicating that the quality of prescribing was acceptable. However, psychotropic drug use was common in home-dwelling people with mild dementia despite limited evidence of benefit in dementia. More knowledge is needed about the potential risks associated with psychotropic drug use and having PIM and DDI in people with mild dementia. Copyright © 2016 John Wiley & Sons, Ltd.

Cognitive decline in dementia with Lewy bodies: a 5-year prospective cohort study.

OBJECTIVES: We report the cognitive decline in persons diagnosed with mild dementia with Lewy bodies (DLB) and mild Alzheimer's disease (AD) during 5 years of annual follow-ups. METHODS: Patients were recruited into the study from geriatric, psychiatric and neurology clinics in Western Norway during 2005-2013. They were diagnosed according to clinical consensus criteria, based on standardised clinical rating scales. Autopsy-based diagnoses were available for 20 cases. Cognitive decline for up to 5 years was assessed using the Clinical Dementia Rating (CDR) scale and the Mini-Mental State Examination (MMSE). Survival analysis including Cox regression (time to reach severe dementia) and linear mixed-effects (lme) modelling were used to model the decline on MMSE. RESULTS: At least one follow-up assessment was available for 67 patients with DLB and 107 patients with AD, with a median follow-up time of 4.3 years. The time to reach severe dementia was significantly shorter in DLB (median 1793 days) compared with AD (1947 days; p=0.033), and the difference remained significant in the multiple Cox regression analysis (HR=2.0, p<0.02). In the adjusted lme model, MMSE decline was faster in DLB (annual decline 4.4 points) compared with AD (3.2 points; p<0.008). CONCLUSIONS: Our findings show that from the mild dementia stage, patients with DLB have a more rapid cognitive decline than in AD. Such prognostic information is vital for patients and families and crucial for planning clinical trials and enabling health economic modelling.

Long-term mortality in a cohort of home-dwelling elderly with mild Alzheimer's disease and Lewy body dementia.

OBJECTIVE: To study mortality in subjects with mild dementia in Norway with a special focus on patients with Lewy body dementia (LBD) compared to Alzheimer's disease (AD). METHODS: All referrals of mild dementia patients to dementia clinics in western Norway from March 2005 to March 2007 were included and followed until December 2012. Diagnoses were based on a comprehensive standardized assessment program. RESULTS: Of 209 patients, 137 (66%) had AD and 53 (25%) had LBD. Dementia was associated with increased mortality (standardized mortality ratio = 1.8, AD 1.5, LBD 2.6). The median survival time was 6.2 years (95% CI 5.4-6.9). Predictors of mortality were age at diagnosis (HR 1.1 per year) and LBD diagnosis (HR 2.4). CONCLUSION: Dementia patients had an increased mortality, particularly those with LBD.