A randomized, placebo-controlled trial of purified anthocyanins on cognitive function in individuals at elevated risk for dementia: Analysis of inflammatory biomarkers toward personalized interventions.

BACKGROUND: Dementia poses a significant global health challenge. Anthocyanins neutralize free radicals, modulate signaling pathways, inhibit pro-inflammatory genes, and suppress cytokine production and may thus have positive cognitive effects in people at increased risk of dementia. We aim to investigate the effects of purified anthocyanins on cognitive function in people at increased risk of dementia according to their inflammation status based on blood-based inflammatory biomarkers. METHODS: This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial. Cluster analysis was performed to categorize two groups based on their individual inflammatory biomarker profile using multiplex sandwich ELISA for the quantitative measurement of cytokines. Descriptive statistics and longitudinal models assessed cognitive outcomes. The primary comparison was the group difference at week 24 based on a modified intention-to-treat analysis. RESULTS: Cluster analysis revealed two distinct inflammatory biomarker profiles. In Cluster 1 (high levels of inflammation biomarkers), anthocyanin treatment showed a statistically significant improvement on cognitive function compared to placebo at 24 weeks. No significant differences were observed in Cluster 2 (low levels of inflammation biomarkers). The demographic characteristics, cognitive scores, and biomarker distributions were similar between treatment groups at baseline. However, cluster 1 exhibited higher BMI, diabetes prevalence, medication usage, and lower HDL cholesterol levels. CONCLUSION: Individuals with elevated levels of inflammation markers benefited from anthocyanin treatment to enhance cognitive performance, whereas those with lower levels did not. The anti-inflammatory and antioxidant properties of anthocyanins make them a promising intervention, and future prospective trials in people with increased inflammation are warranted.

Corrigendum: Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

[This corrects the article DOI: 10.3389/fgene.2019.00536.].

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.

Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer's Disease.

BACKGROUND: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence ß- and γ-secretase activities and thus contribute to Alzheimer's disease (AD) pathology. OBJECTIVE: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. METHODS: We identified 261 plasma lipids using reversed-phase liquid chromatography/mass spectrometry in cerebrospinal fluid amyloid positive (Aß+) or negative (Aß-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years. RESULTS: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aß+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aß+ individuals compared to MCI Aß-. No plasma lipids were associated with performance on primary neuropsychological tests at baseline or between the two time points after correction for multiple testing. CONCLUSION: Reduced plasma concentrations of SM were associated with AD.

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.

Effects of Anthocyanin Supplementation on Serum Lipids, Glucose, Markers of Inflammation and Cognition in Adults With Increased Risk of Dementia - A Pilot Study.

BACKGROUND: Anthocyanins may protect against cardiovascular related cognitive decline and dementia. OBJECTIVE: Open-label study to measure changes in serum lipids, glucose, glycosylated hemoglobin (HbA1c), and markers of inflammation after anthocyanin supplementation in people with increased risk of dementia. As a secondary endpoint we examined potential changes in a battery of cognitive test in the anthocyanin group (AG). A total of 27 individuals with mild cognitive impairment (MCI) (n = 8) or stable non-obstructive coronary artery disease (CAD) (n = 19) consumed two Medox® capsules, each containing 80 mg of natural purified anthocyanins, twice daily for 16 weeks. They provided blood samples and performed a short battery of cognitive tests. Twenty healthy normal controls (NC) (n = 20) provided blood samples, but did not receive any intervention and did not perform cognitive tests. RESULTS: There was a significant difference between groups for CCL-5/RANTES [regulated on activation, normal T-cell expressed and secreted (RANTES)]. In addition, total cholesterol and triglycerides were significantly increased in the AG. Improvements in memory and executive test scores were observed. No adverse effects were reported. CONCLUSION: The results of this pilot study were largely inconclusive with regard to the potential protective effects of anthocyanin supplementation. However, anthocyanins were well tolerated, and compliance was high. Larger, placebo-controlled studies to explore the potential effects of anthocyanins on dementia risk are encouraged. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, identifier NCT02409446.

Effect of Vascular Risk Factors on the Progression of Mild Alzheimer's Disease and Lewy Body Dementia.

BACKGROUND: Vascular risk factors (VRF) are associated with an increased risk of neurodegenerative disease. OBJECTIVE: To examine the association between VRF and cognitive decline in patients with Alzheimer's disease (AD) and Lewy body dementia (LBD). METHODS: We included consecutive referrals with mild AD or LBD to dementia clinics in western Norway from 2005 to 2013. The Mini-Mental Status Exam (MMSE) and Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) were administered at baseline and then annually for up to five years. The VRF include diabetes mellitus, hypertension, hypercholesterolemia, overweight and smoking. Generalized Estimating Equations (GEE) were used to examine the potential association between VRF scores and the change in MMSE and CDR-SB scores, adjusting for age, sex, and the apolipoprotein ɛ4 allele (APOE4). RESULTS: A total of 200 patients were included (113 AD, 87 LBD) (mean age 76 years, mean baseline MMSE 24.0, mean follow-up time 3.5 years). Smoking was the only VRF significantly associated with a more rapid cognitive decline, however only in the AD group. Being overweight at baseline was associated with a slower cognitive decline. Moreover, hypertension at baseline predicted a slower decline in MMSE scores. In the LBD group diabetes mellitus was found to be associated with a slower increase in CDR-SB scores. CONCLUSION: With the exception of smoking, VRF at time of dementia diagnosis were not associated with a more rapid cognitive decline.