Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine’s action is largely mediated by the brain adenosine A_2Areceptor (A_2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A_2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for “personalized medicine” in PD.

Background: Nonalcoholic fatty liver disease (NAFLD) is closely associated with Cardiovascular disease (CVD). We aim to examine the association of Life’s Essential 8 (LE8), the recently updated measurement of cardiovascular health (CVH), with the presence of NAFLD among US adults. Methods: This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey in 2017–2018 and included adults 20 years or older. LE8 score (range 0–100) was measured according to American Heart Association definitions and was categorized into low (0–49), moderate (50–79), and high (80–100) CVH. NAFLD was determined by transient elastography measured hepatic steatosis in the absence of other liver diseases and excess alcohol use. Multivariable logistic and restricted cubic spline models were used to assess the associations. Results: Among 3588 participants included (weighted mean age, 48.0 years; 95% confidence interval [CI] 46.4–49.7 years), 1839 were female (weighted percentage, 51.6%; 95% CI 49.0–54.2%) and 1483 were determined to have NAFLD (weighted percentage, 36.5%; 95% CI 33.3–39.7%). The weighted mean LE8 score of the study population was 67.9 (95% CI 66.6–69.2). After the adjustment of potential confounders, higher LE8 scores were associated with reduced odds of NAFLD (odds ratio [OR] for per 10 score increase, 0.67; 95% CI 0.59–0.76) and a nonlinear dose–response relationship was observed. Similar patterns were also identified in the association of health behavior and health factor scores with NAFLD. The inversed association of LE8 score and NAFLD was significantly stronger among younger, Asian, and participants with higher education and income level. Conclusions: LE8 and its subscales scores were negatively associated with the presence of NAFLD in non-linear fashions. Promoting adherence to optimal CVH levels may be beneficial to reduce the burden of NAFLD as well as CVD.

Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils. We demonstrated that chronic caffeine treatment blunted a cascade of pathological events leading to α-synucleinopathy, including pSer129α-Syn-rich aggregates, apoptotic neuronal cell death, microglia, and astroglia reactivation. Importantly, chronic caffeine treatment did not affect autophagy processes in the normal striatum, but selectively reversed α-Syn-induced defects in macroautophagy (by enhancing microtubule-associated protein 1 light chain 3, and reducing the receptor protein sequestosome 1, SQSTM1/p62) and chaperone-mediated autophagy (CMA, by enhancing LAMP2A). These findings support that caffeine—a strongly protective environment factor as suggested by epidemiological evidence—may represent a novel pharmacological therapy for PD by targeting autophagy pathway.

Export Background and Aims: Phenotypic heterogeneity among patients with NAFLD is poorly understood. We aim to identify clinically important phenotypes within NAFLD patients and assess the long-term outcomes among different phenotypes. Methods: We analyzed the clinical data of 2311 participants from the Third National Health and Nutrition Examination Survey (NHANES III) and their linked mortality data through December 2019. NAFLD was diagnosed by ultrasonographic evidence of hepatic steatosis without other liver diseases and excess alcohol use. A 2-stage cluster analysis was applied to identify clinical phenotypes. We used Cox proportional hazard models to explore all-cause and cause-specific mortality between clusters. Results: We identified 3 NAFLD phenotypes. Cluster 1 was characterized by young female patients with better metabolic profiles and lower prevalence of comorbidities; Cluster 2 by obese females with significant insulin resistance, diabetes, inflammation, and advanced fibrosis and Cluster 3 by male patients with hypertension, atherogenic dyslipidemia, and liver and kidney damage. In a median follow-up of 26 years, 989 (42.8%) all-cause mortality occurred. Cluster 1 patients presented the best prognosis, whereas Cluster 2 and 3 had higher risks of all-cause (Cluster 2—adjusted HR: 1.48, 95% CI: 1.16–1.90; Cluster 3—adjusted HR: 1.29, 95% CI: 1.01–1.64) and cardiovascular (Cluster 2—adjusted HR: 2.01, 95% CI: 1.18–3.44; Cluster 3—adjusted HR: 1.75, 95% CI: 1.03–2.97) mortality. Conclusions: Three phenotypically distinct and clinically meaningful NAFLD subgroups have been identified with different characteristics of metabolic profiles. This study reveals the substantial disease heterogeneity that exists among NAFLD patients and underscores the need for granular assessments to define phenotypes and improve clinical practice.