The association between dietary patterns, plasma lipid profiles, and inflammatory potential in a vascular dementia cohort

Abstract Background Inflammation and altered lipid dyshomeostasis have been implicated in the pathogenesis of Alzheimer's disease and vascular dementia. Objective To determine if there are any associations between dietary patterns, plasma lipid profiles, and inflammatory potential in a vascular dementia cohort. Methods One hundred fifty participants (36 subjects with Vascular Dementia and 114 healthy controls) from two Australian teaching hospitals completed a cross‐sectional survey examining their dietary and lifestyle patterns. Each participant's diet was further evaluated using the Empirical Dietary Inflammatory Index. Some participants also donated blood samples for lipidomic analysis. Results After adjusting for age, education, and socioeconomic status, participants with vascular dementia tend to have higher lipid profiles, do less exercise, and engage less frequently in social interaction, educational, or reading activities. They also tend to consume more deep‐fried food and full‐fat dairy compared to control subjects. However, there was no difference in Empirical Dietary Inflammatory Index between the two groups after adjusting for age, education, and socioeconomic status. Conclusion Our findings suggest a graded inverse association between healthy lifestyle factors and vascular dementia.

The aim of this study was to explore associations between lifestyle factors, diets, and their inflammatory potential, lipid profiles, and VaD. We hypothesize that individuals with VaD will have more pro-inflammatory diets and lipid dysfunction compared with controls. gist. An independent geriatrician's opinion was sought for uncertain cases and such participants would only be included if two clinicians were in consensus of the VaD diagnosis; (4) at least one cerebral imaging modality-CT, SPECT, or MRI was needed to corroborate that the diagnosis was specifically small vessel VaD; and (5) the MMSE score was between 10 and 24 for the diagnosis of mild to moderate dementia. Exclusion criteria that applied to both control and VaD groups were: (1) current diagnosis of malignancy; and (2)  Participants were asked whether they had ever smoked in their lifetime to define ever smokers and never smokers. Ever smokers were asked if they currently smoke or whether and when they had stopped smoking. The number of cigarettes per day was recorded for current or former smokers. Alcohol intake was measured by type of drink (wine vs. beer and other spirits) and quantity (number of glasses/bottles per week). Physical activity was measured by regularity, type of exercise, and incidental physical activity such as housework and gardening. Questionnaires were administered face to face by research assistants.

| Study participants
The questionnaire was mostly completed by close relatives or carers. Any responses given by VaD patients were counter-checked with relatives or carers subsequently.

| Dietary inflammatory index
The EDII was developed by Tabung et al. 11 using eight proinflammatory components (red meats, processed meats, organ meats, other fish, eggs, sugar-sweetened beverages, tomatoes, and refined grains) and eight anti-inflammatory components (leafy green vegetables, dark yellow vegetables, fruit juice, oily fish, coffee, tea, wine, and beer or other alcohol beverages). The scoring system of the EDII was designed using the Mediterranean diet pyramid 12 and other literature. 13 Each pro-inflammatory component was scored 0, 1, or 2 points, and anti-inflammatory components were scored 0, −1, or −2 points. To quantify how pro-inflammatory or anti-inflammatory each participant's diet was, we scored each component of our FFQ using the EDII (Table S1). Food groups from our FFQ that matched perfectly with those in the EDII include red meat, fatty meats, egg, offal, tea, coffee, wine, and other alcoholic beverages. Food groups from our FFQ that were not included in the EDII include beans, curry, cooked foods, deep-fried foods, and full-fat dairy. Food groups from the EDII that were not screened by our FFQ include sugar-sweetened beverages and tomatoes. Some food groups from our FFQ partially matched with those in the EDII: The "fresh vegetables" category from our FFQ included both "leafy green vegetables" and "dark yellow vegetables" from the EDII; the "fresh fruit" category from our FFQ was scored as "fruit juice" from the EDII; the "fish" category from our FFQ included both "oily fish" and "other fish" from the EDII; the "bakery" category from our FFQ was scored as "bread" from the EDII. Where our FFQ's frequency categories did not match exactly with those in the EDII, probability weighted scores were given based on the EDII. Table S1 shows the final scoring system we used. Total scores ranged from −8 to +8, with a higher score indicating a higher inflammatory potential.

| Statistical analysis
All collected data were recorded into a Microsoft Access 2007 database. The data were extracted and analyzed using STATA 16 (StataCorp). Continuous variables were presented as mean values with standard deviation. Dichotomous variables were presented as numbers and percentages. Nonparametric Mann-Whitney U test and Fisher's exact test were used to compare demographic differences between the groups. Ordered logistic regression was used to compare differences in dietary habits between subjects with VaD and healthy controls, and covariate adjustment was performed for age, education, and socioeconomic status. Nonparametric series regression was used to compare EDII between subjects with VaD and healthy controls, and covariate adjustment was performed for age, education, and socioeconomic status. A P value of <0.05 was considered statistically significant.
To determine any association between plasma lipid profiles and dietary intake, we made nine nonparametric series regression models, one for each lipid group. The dependent variable was the lipid group, and the primary predictor variables were the consumption frequency of various food groups such as fresh fruit and vegetables, fish, diary, and deep-fried foods. Covariate adjustment was performed for smoking status, alcohol drinking status, diabetes, age, education, socioeconomic status, and whether the participant had VaD or not. The dietary variables were collapsed into two frequency groups: regular (daily to weekly) versus infrequent (less than weekly/ rarely/almost never). A stricter P value of <0.003 for statistical significance was used in view of the large number of covariates in these nine models.  Table 3). Listening to music, religious activities, and watching television or listening to the radio did not differ in prevalence between the control and VaD groups. Only a minority TA B L E 1 Demographic and selected clinical characteristics.  to those who ate bakery products infrequently. We did not find any association between age and sex with plasma lipid profiles. However, male participants are more likely to eat beans daily compared to females (OR =3.59, 95% CI: 1.08 to 11.97, P = 0.037).

| Pro-inflammatory diet and risk of vascular dementia
The mean EDII score in the control group was −4.03, and the mean EDII score in the VaD group was −3.24 (Figure 1). After adjusting for age, education, and SES, there was no statistically significant difference in mean EDII between the control and VaD group.

| Lipid disorders
We found dyslipidemia was more prevalent among VaD participants.
Elevated low-density lipoproteins have been previously reported to increase the risk for VaD in stroke patients 14,15 and also affects amyloid β processing and deposition causing dementia, in particular Alzheimer's disease. 16

| Exercise
We found VaD participants do less exercise. Higher levels of physical activity seem to be protective for development of VaD, even in the presence of white matter changes, independent of age, education, and other risk factors. 17  patients. 18 A recent trial found that a multidomain intervention (including regular exercise) could improve or maintain cognitive functional abilities in the elderly. 19,20 Our observational study appears to support the idea that exercise is protective against VaD, as regular exercise is less prevalent in the VaD group (OR 0.080). However, our result needs to be interpreted with care since people with VaD might have less capacity to exercise.

| Education
We found VaD participants engage less frequently in social interaction and educational or reading activity. Lower educational level is associated with increased prevalence of VaD. 21 educational level may be protective for motoric function, even in the presence of white matter hyperintensities. Participants with higher education had better motor function, but still had a degree of decline in motoric symptoms. 23 These results are consistent with the passive cognitive reserve hypothesis. 24,25 A study found that there was a delay in onset of dementia in bilingual patients, even in those who are illiterate, in different dementia subtypes. 26 Another study found that factors of life experience and learning other than years of schooling may be protective for the development of cognitive impairment. 27 Recognizing the role of prior and continuing educational activities in cognitive impairment has an importance for the prevention or maintenance of cognitive function as well as the determination of the clinical diagnosis of VaD or other dementia. 27 Our observational study appears to suggest cognitive activities such as socialization with families and friends and reading are protective against VaD, as regular participation in these activities are less prevalent in VaD subjects (OR 0.012 and OR 0.095, respectively). However, people with VaD may have less motivation and cognitive ability to perform these tasks, so our results need to be interpreted with care.

| Diet
In our study, VaD participants reported more frequent consumption of deep-fried food and full-fat dairy ( Higher fish and DHA consumption are associated with lower risk of vascular dementia, cognitive decline, and less development and progression of white matter hyperintensities. Omega 3 polyunsaturated fatty acid (PUFA) therapy is hypothesized to promote brain health by supporting the small blood vessels in the brain. 30,31 Flavonoids, particularly berries, possibly have more antioxidants and may be protective for cognitive impairment. 32,33 Regular cocoa consumption has been shown to improve neurovascular coupling and cognitive function and better neurovascular coupling is associated with greater white matter structural integrity. 34 Dietary soy isoflavone supplementation does not appear to be protective. 35 Ceramides have been reported to regulate the effect of insulin on skeletal muscle and increased levels of ceramide have been reported in obese subjects with type II diabetes. 36 However, lower levels of ceramides have also been associated with increased demyelination 37 and a higher risk of VaD. 38 Bakery products such as whole grain bread and cereals are poor in refined carbohydrates and therefore may inhibit hepatic ceramide synthesis and export.
However, offal products are rich in ceramide content and hence increased consumption of offal-based products can increase plasma ceramide levels. The FRUVEDomic pilot study showed that a diet rich in fruits and vegetables and low in refined carbohydrates improved inflammatory status, which correlated with ceramide levels in in young adults. 39 We recently found significantly higher levels of diglycerides, particularly DG (12:0/20:5) and DG (18:0/18:0) in the plasma of VaD subjects. 38 Mono-and diglycerides, which are present in most breads and baked products, are formed by chemically joining glycerol to fatty acids from animal fats or vegetable oils. These lipids are used as emulsifiers, preventing breads and baked products from crumbling, or becoming stale, and/or maintaining oil and water components in the required viscosity (e.g., in salad dressings). It has been estimated that the percentage of vegetable oil-sourced monoand diglycerides used in the United States is approximately 70%. 40 Diglycerides also act as emulsifiers in alcoholic beverages such as beer and wine and are key ingredients in coffee whiteners. This may likely explain the observed increases in diglycerides in regular alcohol and coffee consumers.

| Dietary inflammatory index
Other studies have reported associations between dietary intake, inflammation, cognitive performance, and risk of dementia, but ours is the first to study specifically VaD. For example, the Supplementation en Vitamines et Minerauz Antioxydants Study reported that higher DII scores at midlife were associated with cognitive decline by at least 13 years later. 41 The Whitehall II study used a set of predefined foods to identify an association between inflammatory dietary intake and IL-6. More specifically, the study found a correlation between higher intake of red meat, processed meat, peas, legumes, and fried food, and lower consumption of whole grains increased inflammatory potential and accelerated cognitive decline. 42

| Strengths and weaknesses
The strength of our study is that we looked into protective factors that are unexplored in vascular dementia and healthy aging. 48 We also ascertain our cases and controls. We were able to classify clinically, not just purely based on radiological appearances of leukoaraiosis, cases of VaD using current validated diagnostic methods.

| CON CLUS ION
Our study demonstrates a graded inverse association between healthy lifestyle factors and VaD in both men and women. A healthy lifestyle may be useful in the primary prevention of VaD, although further prospective studies are needed to confirm this.

CO N FLI C T O F I NTE R E S T S TATE M E NT
Authors were employed by their affiliated organizations (Bankstown-Lidcombe Hospital and University of New South Wales).

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from the corresponding author on special request.