The effect of a high-polyphenol Mediterranean diet (Green-MED) combined with physical activity on age-related brain atrophy: the Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study (DIRECT PLUS)

Abstract

Background: The effect of diet on age-related brain atrophy is largely unproven.

Objectives: We aimed to explore the effect of a Mediterranean diet (MED) higher in polyphenols and lower in red/processed meat (Green-MED diet) on age-related brain atrophy.

Methods: This 18-mo clinical trial longitudinally measured brain structure volumes by MRI using hippocampal occupancy score (HOC) and lateral ventricle volume (LVV) expansion score as neurodegeneration markers. Abdominally obese/dyslipidemic participants were randomly assigned to follow 1) healthy dietary guidelines (HDG), 2) MED, or 3) Green-MED diet. All subjects received free gym memberships and physical activity guidance. Both MED groups consumed 28 g walnuts/d (+440 mg/d polyphenols). The Green-MED group consumed green tea (3-4 cups/d) and Mankai (Wolffia-globosa strain, 100 g frozen cubes/d) green shake (+800 mg/d polyphenols).

Results: Among 284 participants (88% men; mean age: 51 y; BMI: 31.2 kg/m2; APOE-ε4 genotype = 15.7%), 224 (79%) completed the trial with eligible whole-brain MRIs. The pallidum (-4.2%), third ventricle (+3.9%), and LVV (+2.2%) disclosed the largest volume changes. Compared with younger participants, atrophy was accelerated among those ≥50 y old (HOC change: -1.0% ± 1.4% compared with -0.06% ± 1.1%; 95% CI: 0.6%, 1.3%; P < 0.001; LVV change: 3.2% ± 4.5% compared with 1.3% ± 4.1%; 95% CI: -3.1%, -0.8%; P = 0.001). In subjects ≥ 50 y old, HOC decline and LVV expansion were attenuated in both MED groups, with the best outcomes among Green-MED diet participants, as compared with HDG (HOC: -0.8% ± 1.6% compared with -1.3% ± 1.4%; 95% CI: -1.5%, -0.02%; P = 0.042; LVV: 2.3% ± 4.7% compared with 4.3% ± 4.5%; 95% CI: 0.3%, 5.2%; P = 0.021). Similar patterns were observed among younger subjects. Improved insulin sensitivity over the trial was the parameter most strongly associated with brain atrophy attenuation (P < 0.05). Greater Mankai, green tea, and walnut intake and less red and processed meat were significantly and independently associated with reduced HOC decline (P < 0.05). Elevated urinary concentrations of the polyphenols urolithin-A (r = 0.24; P = 0.013) and tyrosol (r = 0.26; P = 0.007) were significantly associated with lower HOC decline.

Conclusions: A Green-MED (high-polyphenol) diet, rich in Mankai, green tea, and walnuts and low in red/processed meat, is potentially neuroprotective for age-related brain atrophy.This trial was registered at clinicaltrials.gov as NCT03020186.

Keywords: Green Mediterranean diet; age-related atrophy; aging; dietary intervention; hippocampal occupancy score; neurodegeneration; polyphenols.

FIGURE 1

Flowchart of Brain DIRECT PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study). Green-MED diet, Mediterranean diet higher in polyphenols and lower in red/processed meat; HDG, healthy dietary guidelines; MED, Mediterranean diet.

FIGURE 2

LVV and HOC across age at baseline. n = 284. Brain MRI-derived data were quantified and segmented in a fully automated manner using NeuroQuant. A change in slope was significant at age 50 y (P-nonlinear trend < 0.0001 for both, analyzed by spline regression). HOC, hippocampal occupancy score; LVV, lateral ventricle volume.

FIGURE 3

Dynamics in volume of different brain structures after 18 mo of lifestyle intervention [DIRECT-PLUS (Dietary Intervention Randomized Controlled Trial Polyphenols Unprocessed Study), n = 224]. (A) Individual response of change in HOC (% of change). A decrease in HOC is represented by black lines, an increase in HOC by blue lines. Among all participants who completed the study with 2 valid MRI brain scans, 148 (66%) exhibited a decrease in HOC after 18 mo. (B) Unbiased standard MRI template brain volume for the normal population, the distance of 4 slices or 4 mm between coronal cross-sections. The color represents the relative change (%) in volume of all available brain structures across the entire cohort and in participants ≥ 50 y of age. The analysis was corrected for multiple comparisons using the false discovery rate (0.05) method. (C) Changes in lateral ventricle volume (red) and hippocampal volume (blue) after 18 mo. Hippocampal atrophy and lateral ventricle expansion were significantly more prominent in older participants than in younger participants (P < 0.001 for both). The slice location is y = 96 in ab unbiased standard MRI template. (D) The relative decrease in HOC was significantly more prominent in older participants than in younger participants (cutoff = age 50 y, P < 0.001, independent-sample t tests). HOC, hippocampal occupancy score.

FIGURE 4

The effect of 18-mo dietary interventions on MRI-derived brain volume structures. (A) No significant difference in change in HOC (from baseline) between groups of the entire study population. The HDG and the MED group participants had a significant decrease in HOC. In contrast, participants in the Green-MED group did not have a significant change in HOC after 18 mo of intervention. (B) Compared with the HDG group, the Green-MED group had attenuated LVV expansion across the entire study population. (C, D) Among participants ≥ 50 y of age, both the MED and Green-MED diet groups demonstrated less HOC decline and LVV expansion than the HDG group. The analysis was performed with general linear modeling. Comparisons of changes in HOC and LVV between intervention groups were analyzed using Bonferroni correction for 3 comparisons. The age-by-group interaction was significant for change in HOC (P-interaction = 0.017) and marginal for change in LVV (P-interaction = 0.07). The time-by-group interaction in change in HOC was significant among participants ≥ 50 y old (P-interaction = 0.032). *Significant change from baseline within groups. **Significant difference between groups. Green-MED diet, Mediterranean diet higher in polyphenols and lower in red/processed meat; HOC, hippocampal occupancy score; LVV, lateral ventricle volume; MED, Mediterranean diet.

FIGURE 5

Relative change in HOC according to specific “green” dietary components (age ≥ 50 y). (A) Weekly walnut consumption: low was defined as ≤2/wk (n = 28), medium as 3–4/wk (n = 33), and high as ≥5/wk (n = 47). (B) Daily green tea consumption: low was defined as ≤1/d (n = 4), medium as 2/d (n = 6), and high as ≥3/d (n = 22). (C) Mankai consumption: low was defined as <3/wk (n = 12), medium as 4–6/wk (n = 13), and high as daily (n = 7). All analyses were performed for data from older participants of the study population (age ≥ 50 y). Mankai and green tea consumption were measured and analyzed only for the Green-MED diet (Mediterranean diet higher in polyphenols and lower in red/processed meat) group. All analyses were nonparametric. HOC, hippocampal occupancy score.