Edited by: Joseph Baur, University of Pennsylvania, United States
Reviewed by: Indika Edirisinghe, Illinois Institute of Technology, United States; Wieslaw Wiczkowski, Institute of Animal Reproduction and Food Research (PAN), Poland
This article was submitted to Genetics of Aging, a section of the journal Frontiers in Genetics
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Anthocyanins may protect against cardiovascular related cognitive decline and dementia.
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) (
There was a significant difference between groups for monocyte chemoattractant protein (MCP-1) and fasting glucose. 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.
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.
Anthocyanins, a subclass of the flavonoids, are found in foods such as berries and fruits and information regarding their content in food can be found in an online phenol-explorer (
In this exploratory open-label pilot study, we aimed as a primary endpoint to examine potential changes in dementia-relevant mechanisms after 16 weeks of treatment with purified anthocyanin containing capsules, in people with increased risk of dementia. As a secondary endpoint we also explored the potential change in a battery of cognitive tests.
Participants were recruited from the outpatient Memory and Cardiology clinics at Stavanger University Hospital in Norway during 2015 and 2016. Eligible for this study were patients with MCI or mild dementia and/or stable non-obstructive coronary artery disease (CAD). Potential participants identified at the respective outpatient clinics were contacted for a telephone interview by a study doctor, regarding inclusion and exclusion criteria. Participants were also recruited from the dementia disease initiation (DDI) study (
Exclusion criteria were moderate to severe dementia [operationalized as a mini-mental status exam (MMSE) (
All participants provided written informed consent, and the study has been approved by the Regional Ethics Committee (Approval 2014/1966). The study has been registered at
The participants were given open-label Medox® capsules, provided free of charge by the manufacturer Medpalett AS, Sandnes, Norway. Medox® capsules, which contain specific quantities of natural purified anthocyanins from bilberry (
The capsules were dispensed at inclusion in the study, and the participants were instructed to consume two 80 mg anthocyanin capsules twice daily for a total daily intake of 320 mg anthocyanins for 16 weeks. This dosage was chosen because it has previously been shown to have biological effects (
Participants were instructed to maintain their dietary and lifestyle habits in order to avoid interferences in the study results.
At inclusion, all participants underwent a physical examination, including standardized blood pressure measurement, electrocardiogram (ECG), and blood tests. In addition a cognitive test battery (see below) was administered, including the MMSE and GDS-15. Following standardized procedures, participants provided blood samples in the morning after having been fasting for at least 8 h, before and after 16 weeks of treatment. They were contacted by telephone after 8 weeks regarding safety and compliance.
Blood was collected, centrifugated, and stored at −80 °C until analysis according to standardized procedures. The serum samples were analyzed for lipids (total cholesterol, triglycerides, HDL- and LDL cholesterol) and fasting glucose using Architect c16000 TM (Abbott Diagnostics, Chicago, IL, United States) and HbA1c using Variant II turbo (BioRad, Hercules, CA, United States) at Stavanger University Hospital.
Markers of inflammation were analyzed after completion of the study by The Lipid Research Group, Department of Clinical Sciences, University of Bergen, Bergen, Norway. Concentrations of cytokines were measured in serum using the Bio-Plex ProTM Human Cytokine 8-plex assay (Cat.: M50000007A) which included GM-CSF, IFN-γ, IL-2, IL-4, IL-6, IL-8, IL-10, and TNF-α, in addition to five Bio-Plex Pro Human Cytokine single-plexes: MCP-1 (Cat.: 171B5021M), RANTES (Cat.: 171B5025M), G-CSF (Cat.: 171B5017M), IL-17 (Cat.: 171B5014M), and IL-Iβ (Cat.:171B5001M). All plexes were manufactured by Bio-Rad (Hercules, CA, United States). The cytokines were detected by the Bio-PlexTM 200 System and determined with the Bio-Plex Manager Software 6.1. The samples were prepared as described in the protocol (Cat.: 10014905) with a dilution factor of three.
Anthocyanin metabolites were measured in plasma after completion of the study at Department of Nutritional Sciences, School of Life Course Sciences, Faculty of Medicine and Life Sciences, King’s College London, using a method based on microelution solid phase extraction followed by liquid chromatography and mass spectrometry, using authentic standards, as previously described with some modifications (
Verbal memory function was assessed using the Norwegian adaptation of the Ten Word List Learning and Recall from the CERAD battery (
Executive functioning was assessed by the Trail Making Test (TMT) A and B (
Participants were contacted by phone at week 8 to ask about potential side-effects and adverse events (AE).
The safety blood tests included hemoglobin, thrombocytes, kidney function and liver function tests, which were measured at both baseline and study-end.
Participants were contacted by phone at week 8 and asked about adherence to the protocol. Specifically, they were asked whether they had been taking Medox® capsules as instructed, and they were reminded about keeping the empty blister packages. Protocol adherence was also assessed by collecting and counting the empty blister packages and left-over capsules at study-end.
Descriptive statistics are presented as medians and interquartile ranges (IQR), and illustrated using Box plots. Most data were not normally distributed and thus the main analyses were non-parametric. The Mann–Whitney
Supplementary parametric analyses were performed, from which we present means, standard deviations (SD), and
The IBM SPSS statistical package version 24 was used for all statistical analyses.
During the period May 2015 to September 2016, 33 participants started anthocyanin supplementation, of whom 27 (8 MCI and 19 CAD) completed the study (6 were excluded for administrative and logistical reasons) (
Enrolment of participants. N, number.
Baseline characteristics are shown in
Baseline characteristics.
Active ( |
Controls ( |
|
---|---|---|
Median (IQR) | Median (IQR) | |
Women, count (%) | 9 (33) | 11 (55) |
Age (years) | 61 (55–70) | 58 (55–62) |
CAD, count (%) | 19 (70) | |
Education (years) | 11.5 (10–14) | |
BMI | 27.7 (26.0–30.3) | |
Lipid lowering therapy, count (%) | 19 (70) | |
Acetylsalicylic acid, count (%) | 17 (63) | |
Oral antidiabetic treatment count (%) | 3 (11) | |
Dietary supplement, count (%) | 18 (67) |
Only IL-8, MCP-1, CCL-5/RANTES [regulated on activation, normal T-cell expressed and secreted (RANTES)] and TNF were available for statistical analyses, as the other inflammation markers did not reach measurement thresholds. The findings are summarized in
Changes from baseline to 16 weeks follow-up in serum variables, for participants with supplementation (active) and for control participants.
Pre | 4.0 (3.1 to 5.5) | 5.1 (4.5 to 5.5) | |||
Post | 4.6 (3.3 to 6.0) | 5.1 (4.6 to 5.6) | |||
Diff | 0.2 (0.1 to 0.7) | 0.009 | 0.1 (−0.2 to 0.5) | 0.29 | 0.34 |
Pre | 1.2 (1.0 to 1.4) | 1.5 (1.1 to 1.7) | |||
Post | 1.2 (1.1 to 1.5) | 1.4 (1.2 to 1.8) | |||
Diff | 0.0 (−0.1 to 0.1) | 0.81 | 0.1 (−0.1 to 0.1) | 0.21 | 0.23 |
Pre | 2.4 (1.8 to 3.9) | 3.3 (2.9 to 3.9) | |||
Post | 3.0 (1.8 to 4.3) | 3.3 (2.8 to 4.0) | |||
Diff | 0.1 (−0.1 to 0.3) | 0.21 | 0.0 (−0.1 to 0.4) | 0.62 | 0.72 |
Pre | 1.0 (0.7 to 1.4) | 0.9 (0.6 to 1.3) | |||
Post | 1.0 (0.7 to 1.7) | 0.9 (0.6 to 1.8) | |||
Diff | 0.1 (0.7 to 1.7) | 0.016 | 0.0 (−0.1 to 0.4) | 0.072 | 0.84 |
Pre | 5.4 (4.9 to 5.6) | 5.3 (5.0 to 5.6) | |||
Post | 5.5 (5.3 to 6.3) | 5.0 (4.8 to 5.7) | |||
Diff | 0.2 (−0.1 to 0.4) | 0.058 | −0.2 (−0.4 to −0.03) | 0.009 | |
Pre | 5.8 (5.6 to 6.1) | 5.6 (5.4 to 5.8) | |||
Post | 5.8 (5.6 to 6.1) | 5.4 (5.2 to 5.6) | |||
Diff | 0.0 (−0.1 to 0.1) | 0.87 | −0.05 (−0.2 to 0.0) | 0.057 | |
Pre | 9.0 (7.7 to 10.3) | 7.5 (7.2 to 8.4) | |||
Post | 9.2 (6.9 to 11.1) | 7.8 (7.2 to 8.9) | |||
Diff | 0.0 (−1.5 to 1.2) | 0.80 | 0.2 (−1.0 to 1.5) | 0.79 | |
Pre | 42.2 (10.3 to 59.4) | 51.7 (40.9 to 70.2) | |||
Post | 41.3 (11.1 to 60.2) | 52.8 (45.1 to 93.7) | |||
Diff | 0.0 (−5.4 to 1.7) | 0.55 | 1.9 (0.2 to 17.5) | 0.014 | |
Pre | 9206 (8172 to 9833) | 8800 (8370 to 9761) | |||
Post | 8918 (8046 to 9942) | 9164 (8651 to 10027) | |||
Diff | −161 (−730 to 677) | 0.81 | 19.09 (−633 to 1105) | 0.41 | |
Pre | 10.1 (7.8 to 13.3) | 6.5 (6.1 to 10.9) | |||
Post | 9.9 (6.5 to 13.9) | 8.0 (5.8 to 11.4) | |||
Diff | 0.9 (−2.8 to 2.9) | 0.74 | −0.4 (−1.5 to 3.9) | 0.66 |
The only significant between-group difference was for difference were for ΔMCP-1 (difference from baseline to study end) (
When analyzing the groups separately, significant increases were found in total cholesterol and triglycerides in the anthocyanin supplementation group (AG) from baseline to study end (
No significant changes were found for fasting glucose and HbA1c in the AG group.
A total of 29 plasma anthocyanin metabolites were quantified (
Changes from baseline to 16 weeks follow-up in plasma anthocyanin metabolites, for participants with supplementation (active) and for control participants.
Active ( |
Control ( |
Active vs. control |
|||
---|---|---|---|---|---|
nmol/L | Median (IQR) | Median (IQR) | |||
Pre | 33.1 (17.5 to 52.5) | 26.2 (10.2 to 67.6) | |||
Post | 45.5 (24.1 to 104.2) | 20.6 (7 to 65.3) | |||
Diff | 15.6 (−3.3 to 70.7) | 0.068 | −1.7 (−23.8 to 13.0) | 0.85 | 0.14 |
Pre | 36.4 (17.2 to 110.5) | 58.4 (20.4 to 102.4) | |||
Post | 63.8 (41.5 to 199.1) | 35.2 (21.2 to 93.1) | |||
Diff | 17.5 (−8.3 to 106.4) | 0.001 | −12.3 (−82.4 to 32.1) | 0.41 | 0.89 |
Pre | 3.5 (0.3 to 11.1) | 5.4 (1.6 to 10.1) | |||
Post | 11.0 (5.5 to 26.5) | 6.5 (0.3 to 16.4) | |||
Diff | 6.2 (0.0 to 21.6) | 0.007 | 0.8 (−6.3 to 10.1) | 0.81 | 0.071 |
Pre | 44.7 (29.2 to 77.3) | 60.8 (34.8 to 123) | |||
Post | 52.7 (33.6 to 97.2) | 71.8 (30.3 to 106) | |||
Diff | 12.8 (−19.6 to 32.7) | 0.14 | 10.4 (−27.8 to 65.5) | 0.60 | 0.70 |
Pre | 14.0 (5.6 to 23.8) | 13.1 (8.5 to 28.7) | |||
Post | 12.8 (7.1 to 24.6) | 12.3 (7.3 to 21.1) | |||
Diff | 1.6 (−7.8 to 14.3) | 0.65 | −5.5 (−15.6 to 12.0) | 0.35 | 0.25 |
Pre | 2027 (1211 to 4284) | 2664 (1455 to 3764) | |||
Post | 1704 (772 to 3597) | 1723 (420 to 4354) | |||
Diff | −97 (−1039 to 234) | 0.14 | −924 (−2691 to 1046) | 0.26 | 0.67 |
Pre | 164 (93 to 272) | 145 (117 to 275) | |||
Post | 123 (94 to 283) | 111 (91 to 163) | |||
Diff | 6 (−84 to 44) | 0.84 | −33 (−236 to 33) | 0.079 | 0.21 |
Pre | 57.5 (22.0 to 106.8) | 66.6 (35.5 to 127) | |||
Post | 51.3 (29.4 to 114.2) | 48.7 (5.0 to 76.9) | |||
Diff | 1.6 (−49.7 to 51.3) | 0.75 | −22.0 (−85.2 to 17.2) | 0.049 | 0.057 |
Pre | 25.6 (15.3 to 61.2) | 55.1 (25.3 to 106.5) | |||
Post | 52.9 (25.5 to 97.6) | 63.8 (41.4 to 94.4) | |||
Diff | 18.8 (1.5 to 68.4) | 0.006 | −2.9 (−36.3 to 45.7) | 0.85 | 0.093 |
Pre | 174 (100 to 237) | 122 (85 to 197) | |||
Post | 106 (84 to 213) | 98 (75 to 163) | |||
Diff | −26 (−135 to 69) | 0.20 | −33 (−67 to 2) | 0.044 | 0.97 |
Pre | 5518 (2718 to 8056) | 5986 (4284 to 7527) | |||
Post | 4640 (3183 to 7843) | 4690 (3576 to 5627) | |||
Diff | 367 (−2569 to 1608) | 0.61 | −937 (−3502 to 2010) | 0.25 | 0.67 |
Pre | 30.6 (9.5 to 47.8) | 24.6 (9.6 to 39.6) | |||
Post | 26.2 (9.8 to 42.3) | 22.6 (7.9 to 34.7) | |||
Diff | −6.5 (−27.6 to 10.8) | 0.20 | −5.2 (−15.0 to 23.8) | 1.0 | 0.41 |
Pre | 709 (191 to 3060) | 451 (269 to 1343) | |||
Post | 339 (63 to 1233) | 162 (35 to 599) | |||
Diff | −503 (−1246 to −55) | 0.002 | −183 (−1117 to 196) | 0.10 | 0.28 |
Pre | 0.29 (0.00 to 0.52) | 0.23 (0.00 to 0.46) | |||
Post | 0.21 (0.11 to 0.41) | 0.17 (0.00 to 0.30) | |||
Diff | −0.07 (−0.26 to 0.24) | 0.92 | 0.01 (−0.20 to 0.20) | 0.94 | 0.84 |
Pre | 2.3 (0.0 to 8.3) | 5.5 (0.0 to 19.1) | |||
Post | 2.8 (0.0 to 11.3) | 5.7 (0.3 to 14.4) | |||
Diff | 0.0 (−3.5 to 11.3) | 0.90 | −1.1 (−10.6 to 3.6) | 0.50 | 0.48 |
Pre | 1.7 (0.0 to 9.2) | 2.2 (0.1 to 8.0?) | |||
Post | 4.6 (1.6 to 14.2) | 1.1 (0.1 to 6.6) | |||
Diff | 1.5 (−1.5 to 8.8) | 0.075 | 0.1 (−2.2 to 1.7) | 0.97 | 0.14 |
Pre | 4.3 (0.4 to 33.4) | 7.7 (1.0 to 19.4) | |||
Post | 19.4 (2.6 to 59.3) | 5.8 (1.1 to 21.5) | |||
Diff | 5.5 (0.2 to 31.4) | 0.013 | −0.3 (−5.9 to 15.4) | 0.98 | 0.064 |
Pre | 17680 (9444 to 55008) | 24075 (11958 to 39646) | |||
Post | 15225 (8654 to 40673) | 12211 (11086 to 28936) | |||
Diff | −3572 (−18398 to 1041) | 0.068 | −2788 (−15907 to 4975) | 0.33 | 0.68 |
Pre | 1630 (815 to 3580) | 1209 (753 to 1889) | |||
Post | 1228 (691 to 2722) | 997 (647 to 1899) | |||
Diff | −182 (−1087 to 733) | 0.47 | −221 (−617 to 255) | 0.28 | 0.95 |
Pre | 72.6 (40.3 to 130) | 81.2 (58.4 to 105) | |||
Post | 53.5 (48.9 to 93.3) | 48.7 (39.5 to 75.5) | |||
Diff | −24.8 (−56.1 to 6.5) | 0.029 | −34.3 (−52.8 to −6.8) | 0.019 | 0.78 |
Pre | 2.3 (0.5 to 7.0) | 4.0 (0.0 to 12.3) | |||
Post | 1.9 (0.8 to 23.8) | 6.1 (1.6 to 9.7) | |||
Diff | 0.5 (−2.9 to 21.1) | 0.20 | 1.1 (−7.7 to 9.1) | 0.55 | 0.69 |
Pre | 7.2 (0.0 to 17.5) | 4.9 (0.0 to 14.1) | |||
Post | 9.2 (2.1 to 23.7) | 7.6 (1.0 to 19.4) | |||
Diff | 1.0 (−7.5 to 8.6) | 0.47 | 0.9 (−6.9 to 13.0) | 0.69 | 0.94 |
Pre | 1.1 (0.3 to 2.3) | 0.8 (0.4 to 5.7) | |||
Post | 4.5 (0.4 to 13.7) | 1.5 (0.3 to 8.6) | |||
Diff | 0.6 (−1.7 to 10.2) | 0.25 | 0.4 (−1.6 to 2.4) | 0.55 | 0.67 |
Pre | 19.1 (7.2 to 45.7) | 25.8 (2.5 to 82.4) | |||
Post | 20.7 (8.1 to 60.8) | 16.1 (5.4 to 43.4) | |||
Diff | 1.2 (−15.4 to 34.5) | 0.47 | −4.9 (−70.9 to 27.7) | 0.55 | 0.31 |
Pre | 22.3 (5.2 to 67.5) | 21.2 (1.8 to 54.6) | |||
Post | 27.3 (8.5 to 136.4) | 21.3 (5.7 to 58.6) | |||
Diff | 24.4 (−18.0 to 96.2) | 0.044 | 2.7 (−10.1 to 36.8) | 0.55 | 0.21 |
Pre | 3.7 (1.2 to 8.3) | 1.9 (0.2 to 3.6) | |||
Post | 1.6 (0.9 to 5.1) | 2.7 (1.4 to 5.2) | |||
Diff | −1.5 (−3.1 to −0.3) | 0.006 | 0.8 (−0.9 to 2.9) | 0.31 | 0.010 |
Pre | 805 (44 to 2377) | 350 (14 to 1479) | |||
Post | 470 (72 to 4306) | 414 (112 to 1624) | |||
Diff | 29 (−495 to 831) | 0.43 | 36 (−917 to 345) | 0.74 | 0.76 |
Pre | 111 (35 to 146) | 84 (63 to 110) | |||
Post | 55 (38 to 78) | 58 (53 to 85) | |||
Diff | −62 (−82 to 16) | 0.014 | −28 (−58 to 2) | 0.093 | 0.33 |
Pre | 218 (81 to 356) | 125 (81 to 234) | |||
Post | 87 (47 to 158) | 81 (50 to 162) | |||
Diff | −116 (−230 to −35) | <0.001 | −36 (−111 to −1) | 0.006 | 0.019 |
In the AG, there was a statistically significant increase in five of the metabolites (Pyrogallol-2-
In the NC group, there was a statistically significant decrease in four metabolites (Protocatechuic acid, 3,4-Dihydroxyphenylacetic acid, 4-Hydroxybenzaldehyde and
The cognitive test scores improved in the intervention group, with improvements for CERAD learning (
Changes from baseline to 16 weeks follow-up in cognitive variables, for participants with supplementation (active).
Active ( |
||
---|---|---|
Median (IQR) | ||
Pre | 20 (16 to 22) | |
Post | 21 (17 to 25) | |
Diff | 2 (−1 to 3) | 0.016 |
Pre | 6 (4 to 8) | |
Post | 7 (5 to 9) | |
Diff | 1 (0 to 2) | <0.001 |
Pre | 20 (16 to 20) | |
Post | 20 (19 to 20) | |
Diff | 0 (0 to 1) | 0.047 |
Pre | 32 (21 to 53) | |
Post | 34 (23 to 39) | |
Diff | −2 (−6 to 2) | 0.081 |
Pre | 85.50 (62.25 to 118) | |
Post | 69.50 (56 to 100.75) | |
Diff | −2.0 (−19.75 to 2.25) | 0.16 |
Pre | 87 (72 to 67) | |
Post | 87 (80 to 103) | |
Diff | 6 (1 to 10) | <0.001 |
Pre | 61 (52 to 67) | |
Post | 62 (54 to 69) | |
Diff | 2 (−1 to 6) | 0.044 |
Pre | 34 (29 to 41) | |
Post | 34 (28 to 41) | |
Diff | 0 (−3 to 5) | 0.67 |
Overall, findings using parametric analyses differed only marginally from the non-parametric findings reported above (
The compliance was good. More than 85% of the participants returned at least 90% of the empty blister packages. The anthocyanins were well tolerated, and none of the participants withdrew due to adverse effects. Blood tests taken for safety reasons were all within a clinically acceptable range. Increased bleeding tendency was not observed.
In this pilot study anthocyanin supplementation was well tolerated, without any AE, and the compliance was good. This indicates that larger RCTs might be feasible, to confirm exploratory results in the current pilot study.
Our findings are somewhat inconclusive. While some cognitive improvements were observed in the AG, there were no significant changes in serum levels of some risk factors for dementia; i.e., fasting glucose, HbA1c or pro-inflammatory cytokines. There was a non-significant increase in serum levels of MCP-1 in the AG and a significant increase in the NC during the study period. The between-group difference in Δ serum levels of MCP-1 was statistically significant.
Furthermore, we observed a significant increase in serum levels of total cholesterol and triglycerides in AG. The lipid profile of the NC group did not change significantly, and since we have no information about statin use or use of other lipid lowering medications in the NC group, the observed difference should be interpreted cautiously.
Previous studies using Medox® have shown a statistically significant increase in HDL-cholesterol (
The differences in the findings between our study and these previous studies might be due to differences in participants, as well as in anthocyanin supplementation dose and duration, or other factors. Furthermore, other studies included dyslipidemic and hypercholesterolemic participants not using statins or any other lipid lowering treatment (
Regarding the inflammation markers, RANTES promotes activation and migration of leukocytes and mediates neuroinflammation and brain microvascular dysfunction (
The beneficial effect of anthocyanins might possibly be due to their degradation products and metabolites (
In our study, we were able to measure a total of 29 anthocyanin metabolites. The results were conflicting, as we found various anthocyanin metabolites to be both significantly increasing and decreasing in the AG. In the NC group as well, we found significant changes. This is in line with findings in another study reporting an increase of some metabolites, and a decrease in others after ingestion of anthocyanins over time (
The improvement on several cognitive tests should be interpreted cautiously due to potential learning effects related to the relatively short test–retest interval, and the lack of a comparison group. Nonetheless, our results are in line with previous smaller studies involving participants with MCI, reporting improved cognition after ingestion of anthocyanins (
Intake of anthocyanin capsules in the dosage of 320 mg/day appears to be well tolerated and safe. None of the safety blood tests were found to be out of a clinically acceptable range or necessitating medical follow-up after study-end. This is consistent with previous studies (
The major limitations of this pilot study are the non-randomized open-label design, the small sample size, and the relatively short intervention period. Although all the participants were told not to change their lifestyle during the intervention period, we have no data on this. Further we had no detailed dietary assessment, and thus we cannot exclude the possibility of differences in the background diet between the groups before or during the study. However, the participants were instructed to maintain their dietary and lifestyle habits during the study period, and to take the capsules 30 min before or 120 min after meals, as concomitant ingestion of certain types of food may counteract the effect of flavonoids (
The NC were recruited separately and differed from the participants by being a healthy group that did not receive any intervention, and did not perform cognitive testing. Thus power calculations for further studies might be compromised. However, we provide descriptive statistics including variance measurements which may be helpful in planning sample size in later studies.
An important strength of our study is the well characterized combination of nutraceuticals used, which facilitates comparison with other studies regarding both source of anthocyanins and dosage. Of note, this is, to our knowledge, the first study on cognitive function in adults with increased risk of dementia where Medox® is being used as the source of anthocyanin. Thus our study might also facilitate investigation of the effect of different proprietary blueberry formulatons, shown by Whyte et al. to be of importance (
All things considered, adequately powered, randomized studies are warranted to better understand how anthocyanins and their metabolites may affect relevant mechanisms, including their possible protective role in epigenetic modifications that potentially benefit the aging brain and reduce the risk for dementia.
All participants provided written informed consent, and the study has been approved by the Regional Ethics Committee (Approval 2014/1966). The study has been registered at
DA, HS, AB, and AL planned and designed the study. AB conducted the study and collected the data. RB performed the serum analyses. MT and AR-M performed the plasma analyses. AB and ID conducted the statistical analyses. All authors wrote the manuscript and critically reviewed the manuscript.
AB has received support for conference participation from Evonik. DA has received research support and/or honoraria from Astra-Zeneca, H. Lundbeck, Novartis Pharmaceuticals, and GE Health, and serves as paid consultant for H. Lundbeck and Axovant. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
We would like to thank the research nurses Reidun Sikveland Meling and Jorunn Margrete Nilsen for their contribution in the conduction of the study. We also thank Hellen Svalestad for her contribution to participant recruitment from the cardiology department, and Bjarne Hervik for his contribution in recruiting healthy normal controls.
The Supplementary Material for this article can be found online at:
Changes from baseline to 16 weeks follow-up in serum lipids, for participants with anthocyanin supplementation. mmol/L, millimole/liter.
Changes from baseline to 16 weeks follow-up in serum fasting glucose and HbA1c, for participants with anthocyanin supplementation. HbA1a, glycosylated hemoglobin; mmol/L, millimole/liter.
Changes from baseline to 16 weeks follow-up in serum cytokines, for participants with anthocyanin supplementation. RANTES;CCL-5/RANTES (regulated on activation, normal T-cell expressed and secreted). pg/mL, picomolar/milliliter.
Changes from baseline to 16 weeks follow-up in plasma anthocyanin metabolites, for participants with and without anthocyanin supplementation. Measurement unit: nmol/L, nanomolar/liter, except for hippuric acid (nmol/10L) and coumaric acid-4-
Changes from baseline to 16 weeks follow-up in CERAD.
Changes from baseline to 16 weeks follow-up in Trail Making Test (TMT). Sec, seconds.
Changes from baseline to 16 weeks follow-up in Stroop test.
Changes from baseline to 16 weeks follow-up in serum variables, for participants with supplementation (active) and for control participants.
Changes from baseline to 16 weeks follow-up in cognitive variables, for participants with supplementation (active).