Diet and nutrition in the progression of Parkinson disease

Restricted (Penn State Only)
- Author:
- Zhang, Xinyuan
- Graduate Program:
- Nutritional Sciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 27, 2022
- Committee Members:
- Gregory C Shearer, Professor in Charge/Director of Graduate Studies
Penny Kris-Etherton, Major Field Member
Xiang Gao, Chair & Dissertation Advisor
Laila Al-Shaar, Outside Unit & Field Member
A Ross, Major Field Member
Alberto Ascherio, Special Member - Keywords:
- Diet quality
Nutrition
Metabolomics
Parkinson disease
Epidemiology - Abstract:
- Parkinson disease (PD), the second common neurodegenerative disease characterized by movement disorders, affected 6.1 million individuals, and contributed to 3.2 million disability-adjusted life-years and 0.2 million deaths worldwide according to the Global Burden of Disease Study in 2016. As PD becomes a leading global health burden, more vigorous strategies for PD prevention, diagnosis, and treatment are needed to achieve the goals of healthy aging. However, to date, PD still lacks robust preclinical diagnostic biomarkers, consensus guidelines on disease-modifying lifestyle behaviors, and effective treatments to slow down disease progression. Dietary factors have been suggested to be associated with altered PD risk. Healthier dietary pattern is usually rich in neuroprotective compounds thus is associated with a lower level of oxidative stress and inflammation, while neuroinflammation is hypothesized as a major factor for neurodegeneration pathology in PD. Dietary intake may also interact with mitochondrial function or genetic expressions that contribute to PD. Moreover, diet may affect the gut microbiome and consequently the gut-brain axis and neuronal functioning that are involved in the pathological development of PD. Epidemiological studies have focused primarily on the prevalence or incidence of PD following clinical diagnosis, whereas evidence of the association between diet and progression of PD both pre-diagnosis and post-diagnosis is scarce. Exploring the role of diet and nutrition in the preclinical, prodromal, and clinical to end-stage phases of PD may provide novel insight into their neuroprotective potentials. The overall objective of this study is to examine diet and related metabolomics profiles in the development and progression phases of PD, including the prodromal stage, symptom onset, and mortality as an outcome of disease prognosis. Integration of the findings in these various stages will allow more accurate risk estimation and targeted prevention for PD incidence and may contribute to treatment strategies for PD post-diagnosis intervention. The objective of the first study (Chapter 3) was to examine the association between diet quality and prodromal symptoms of PD. A total of 71,640 Chinese participants from the Kailuan Study (2006–2014) who were free of PD and completed the semi-quantitative food frequency questionnaire (FFQ) were included in this cross-sectional study. Diet quality was assessed using a modified Alternate Healthy Eating Index (mAHEI) and alternate Mediterranean diet score (aMED). Five prodromal features including probable rapid eye movement sleep behavior disorder (pRBD), hyposmia, excessive daytime sleepiness, constipation, and depressive symptoms were measured using validated questions. Logistic regression was used to calculate the odds ratio (OR) for having a combination of prodromal PD symptoms (0, 1, and 2+ symptoms), adjusting for age, sex, lifestyle factors, total energy intake, and other potential confounders. In the multivariable-adjusted model, the OR for having 2+ versus 0 prodromal PD features was 0.64 (95% confidence interval [CI]: 0.49, 0.85) comparing the highest versus the lowest mAHEI diet quality quartiles with a significant inverse trend (p-trend = 0.003). For individual prodromal PD features, better diet quality was inversely associated with the odds of having excessive daytime sleepiness and constipation (adjusted p-trend <0.05 for both). A similar association was found between aMED and combined prodromal features (adjusted OR comparing the extreme quartiles = 0.74; 95% CI: 0.55, 0.98; p-trend = 0.09). For food and nutrient components, higher intake of vegetables and fruit and lower intake of sugar-sweetened beverages and fruit juice were inversely associated with the odds of having prodromal PD (adjusted p-trend <0.05 for all). No significant interaction between mAHEI and age, sex, or smoking status was found (p-interaction >0.05 for all). We concluded that better diet quality, as assessed by the mAHEI and aMED, was associated with lower overall prevalence of prodromal PD features, mainly constipation and excessive daytime sleepiness, in a Chinese population. Higher intake of fruit and vegetables, and lower intake of SSB and fruit juice were likely to associate with lower prevalence of prodromal PD features. The objective of the second study (Chapter 4) was to investigate the association between the overall diet and physical activity status and mortality among individuals with PD. We included 652 men from the Health Professional Follow-up Study (HPFS, 1986–2018) and 599 women from the Nurses’ Health Study (NHS, 1984–2018) who were diagnosed with PD and had complete baseline dietary assessments. Diet quality was assessed by the AHEI calculated based on validated FFQs every 2–4 years, and overall physical activity was assessed by metabolic-equivalent hours per week (MET-h/wk) based on questionnaires every 2–4 years. To minimize reverse causality due to the severity of motor symptoms after the clinical onset of PD, we separately calculated the pre-diagnosis and post-diagnosis cumulative average of exposures. Mortality was ascertained via the National Death Index and state vital statistics records until 2018. Cox proportional hazard models were used to estimate the association between diet/physical activity and all-cause mortality, individually and jointly, adjusting for age, total energy intake, caffeine intake, and other lifestyle risk factors. Pre-diagnosis exposure levels were further adjusted in post-diagnosis analyses. During 32–34 years of follow-up, we identified 529 deaths in men and 413 deaths in women. Better diet quality was associated with lower mortality rates both before (adjusted p-trend = 0.002) and after (adjusted p-trend <0.001) the diagnosis of PD in both cohorts. In the pooled analysis, compared with the lowest quartile of pre-diagnosis cumulative average AHEI score, the multivariable-adjusted HR of the highest quartile was 0.69 (95% CI: .56, 0.85) without significant difference between men and women. Higher intake of whole grains, nuts and legumes, and lower intake of red/processed meat were each associated with lower mortality rate (adjusted p-trend <0.05 for all). In the post-diagnosis but not the pre-diagnosis analyses, higher adherence to the aMED was inversely associated with mortality rate in PD (post-diagnosis HR = 0.65; 95% CI: 0.48, 0.87; p-trend = 0.009). An inverse association was also found for physical activity (adjusted p-trend = 0.004 and <0.001 for pre-diagnosis and post-diagnosis, respectively). In the joint analysis of AHEI and physical activity before the PD diagnosis, the adjusted hazard ratio was 0.51 (95% confidence interval [CI]: of 0.36, 0.73) for individuals in the highest tertiles for both variables relative to those in the lowest tertiles. The comparable HR for diet quality and physical activity after the diagnosis was 0.35 (95% CI: 0.23, 0.52). In the sensitivity analysis for mortality attributed to PD (HPFS case n = 308 and NHS case n = 211), results remained similar. We did not find interactions between the exposures and age, smoking, or BMI status (p-interaction >0.05 for all). We concluded that following a healthier dietary pattern, such as AHEI, and having frequent physical activities both before and after PD diagnosis, were associated with lower mortality rate. Of note, even after controlling for pre-diagnosis levels, post-diagnosis diet quality and physical activity were still significantly associated with a lower mortality rate. Along the same line, in the third study (Chapter 5), we leveraged the same study population of individuals with PD from the HPFS and the NHS, and used similar data analysis methods as the second study to specifically examine the association between pre-diagnosis and post-diagnosis dietary flavonoid and flavonoid-rich food intakes and mortality in PD. Habitual dietary intake, including major flavonoid-rich foods (tea, apples, berries, orange and orange juice, and red wine), were repeatedly assessed via the validated FFQs and intakes of total flavonoid and its subclasses (flavonols, anthocyanins, flavones, flavanones, flavan-3-ols, and flavonoid polymers) were calculated according to food composition tables. A higher total flavonoid intake before PD diagnosis was associated with a lower future risk for all-cause mortality in men (HR comparing two extreme quartiles = 0.53; 95% CI: 0.39, 0.71; p-trend <0.001) but not in women (HR = 0.93; 95% CI: 0.68, 1.28; p-trend = 0.69), after adjusting for age, smoking status, total energy intake, and other covariates. The pooled HR comparing the extreme quartiles was 0.70 (95% CI: 0.40, 1.22; p-trend = 0.25) with significant heterogeneity (p = 0.01). For flavonoid subclasses, the highest quartile of anthocyanins, flavones, and flavan-3-ols intakes before diagnosis had a lower mortality risk compared to the lowest quartile (pooled HR = 0.66, 0.78, and 0.69, respectively, p <0.05 for all); for berries and red wine, participants consuming ≥3 servings/week had a lower risk (pooled HR = 0.77; 95% CI: 0.58, 1.02 and HR = 0.68; 95% CI: 0.51, 0.91, respectively), compared to <1 serving/month. After PD diagnosis, greater consumptions of total flavonoid, subclasses including flavonols, anthocyanins, flavan-3-ols, and polymers, and berries and red wine, were associated with lower mortality risk (adjusted p <0.05 for all). In both pre-diagnosis and post-diagnosis analyses, the 4-year lagged analyses and models that were further adjusted for vitamin C, vitamin E, and beta-carotene intake did not materially change the results. When looking at PD-specific mortality (n=513), pre-diagnosis total flavonoid intake was inversely associated with PD-specific mortality in men (adjusted HR comparing the extreme quartiles = 0.50, 95% CI: 0.34, 0.75) but not in women (HR = 0.94, 95% CI: 0.61, 1.45) whereas the association was not significant for post-diagnosis total flavonoid intake. We concluded that individuals with PD who habitually consumed more flavonoids and certain subclasses of flavonoids (e.g., anthocyanin and flavan-3-ols) were likely to have a lower risk of all-cause mortality, relative to those with lower intake. Consistently, greater consumption of berries and red wine that are rich in anthocyanins was also associated with lower mortality. The observed associations between flavonoid consumption before PD onset and future risk of mortality were more pronounced in men than in women. In the last study (Chapter 6), we conducted a systematic review to summarize the evidence on metabolomics and PD among human subjects, evaluate the associations and performances, and propose directions for future studies. Original studies reporting metabolomic signatures assessed by high-throughput techniques among individuals with PD were identified by searching PubMed, Web of Science, and PsycINFO through April 2021. Data on study characteristics, quality, individual metabolite-disease associations, and modeling performance of metabolomic panels were extracted and compared. We included 59 articles for a total of 4,458 individuals with PD and 4,536 controls. Metabolic alterations related to caffeine and purine, glutamine and glutamate, branched-chain amino acid (BCAA), glucose, ketone, tricarboxylic acid cycle, niacin, and cell signaling metabolisms were frequently and consistently reported. Metabolic set enrichment analysis also highlighted glutamine and glutamate, BCAA, and glutathione metabolism. Discrimination algorithms showed promising value for assisting with PD diagnosis. Data on preclinical PD and PD progression are limited. In conclusion, better diet quality characterized by higher intake of vegetables, fruit, and whole grains was associated with lower odds of prodromal features among individuals free of PD, and lower rate of mortality among individuals who were diagnosed with PD. Of note, higher intake of flavonoids, especially anthocyanins and flavan-3-ols, and flavonoid-rich food, especially berries and red wine, was associated with lower rate of mortality in PD. Our systematic review of the literature suggests metabolomics as a promising yet challenging tool for disentangling the association between dietary intake, metabolic adaptations, and PD.