Article

Prospective study of caffeine consumption and risk of Parkinson's disease in men and women

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Abstract

Results of case-control studies and of a prospective investigation in men suggest that consumption of coffee could protect against the risk of Parkinson's disease, but the active constituent is not clear. To address the hypothesis that caffeine is protective against Parkinson's disease, we examined the relationship of coffee and caffeine consumption to the risk of this disease among participants in 2 ongoing cohorts, the Health Professionals' Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). The study population comprised 47,351 men and 88,565 women who were free of Parkinson's disease, stroke, or cancer at baseline. A comprehensive life style and dietary questionnaire was completed by the participants at baseline and updated every 2–4 years. During the follow-up (10 years in men, 16 years in women), we documented a total of 288 incident cases of Parkinson's disease. Among men, after adjustment for age and smoking, the relative risk of Parkinson's disease was 0.42 (95% CI: 0.23–0.78; p for trend < 0.001) for men in the top one-fifth of caffeine intake compared to those in the bottom one-fifth. An inverse association was also observed with consumption of coffee (p for trend = 0.004), caffeine from noncoffee sources (p for trend < 0.001), and tea (p for trend = 0.02) but not decaffeinated coffee. Among women, the relationship between caffeine or coffee intake and risk of Parkinson's disease was U-shaped, with the lowest risk observed at moderate intakes (1–3 cups of coffee/day, or the third quintile of caffeine consumption). These results support a possible protective effect of moderate doses of caffeine on risk of Parkinson's disease.

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... It has been previously reported that there is a 25% risk reduction in developing PD among coffee drinkers (14). Two large prospective epidemiological studies (27,29), as well as multiple retrospective studies (30), have also shown a reduced risk of developing PD with a relative risk ranging from 0.45 to 0.80 in coffee drinkers versus non-coffee drinkers. A meta-analysis including eight case-control studies and five cohort studies also showed a significantly reduced risk of developing PD in coffee drinkers (RR 0.69) (21). ...
... A meta-analysis including eight case-control studies and five cohort studies also showed a significantly reduced risk of developing PD in coffee drinkers (RR 0.69) (21). Regular tea drinkers also have been reported to have a lower risk of developing PD (29). ...
... Furthermore, there were differences noted between studies with respect to gender. In two cohort studies (27,29), there was a strong inverse correlation between coffee and the development of PD in men, whereas in women this association was weaker. Additionally, in post-menopausal women, the effect of caffeine depended on whether the females were taking hormone replacement therapy including estrogens. ...
Book
Parkinson’s disease is an increasingly common neurodegenerative condition, which causes not only dysfunction of movement but also a broad range of nonmotor features, including mood disturbance, sleep dysfunction, autonomic dysfunction, cognitive deficits, dementia, and neuropsychiatric symptoms. A major conundrum in this condition is understanding its striking clinical variability, which encompasses a spectrum from a benign phenotype with levodopa-responsive symptoms and minimal progression, to a malignant phenotype with rapid progression to severe gait dysfunction, falls and dementia. This book integrates the considerable expertise of a range of authors from different disciplines, from clinicians through to basic scientists, to present a comprehensive and up-to-date overview of Parkinson’s disease. In recent years, we have made significant progress in understanding the pathological and genetic basis of Parkinson’s disease and its heterogeneous forms, and the first section of the book is dedicated to reviewing this. The variable clinical features of Parkinson’s disease and its differential diagnosis are then considered. The final section provides a detailed overview of treatment approaches, including not only pharmacological therapies but also surgical therapies including deep brain stimulation and cell transplantation strategies. The combination of basic biology, clinical knowledge and therapeutics gives this book a very broad appeal. It will be of value to clinicians and health professionals caring for patients with Parkinson’s disease, as well as providing an excellent introduction for junior researchers entering the field.
... Large epidemiological investigations have identified caffeine consumption as a strong inverse predictor of Parkinson's disease (PD) (and independent from the similarly inverse association of cigarette smoking) [1,2]. The risk of PD among men routinely consuming a daily intake of 2-3 cups of coffee is nearly half that of men who do not consume caffeine, whereas decaffeinated coffee affords no such reduced risk [3][4][5][6]. In this review, we first examine the epidemiology of caffeine in PD and follow this by examining evidence for caffeine and other, more selective antagonists of the adenosine A 2A receptor as potential neuroprotective agents. ...
... Other than cigarette smoking, dietary caffeine is the environmental exposure most robustly and reproducibly linked to a lower risk of developing PD [7]. In addition to numerous case-control studies demonstrating lower caffeine intake in association with PD [1,2], well-designed, rigorously conducted epidemiological studies of prospectively followed cohorts have convincingly shown that the risk of PD is significantly and dose-dependently lower among those who consume coffee, tea and other caffeinated beverages [3,6,[8][9][10]. The lack of effect for decaffeinated drinks [3,4] implicates caffeine as the molecular component of coffee driving its inverse correlation with PD; however, other components remain possibilities given that caffeine is not the only molecule removed during the decaffeination process [11]. ...
... In addition to numerous case-control studies demonstrating lower caffeine intake in association with PD [1,2], well-designed, rigorously conducted epidemiological studies of prospectively followed cohorts have convincingly shown that the risk of PD is significantly and dose-dependently lower among those who consume coffee, tea and other caffeinated beverages [3,6,[8][9][10]. The lack of effect for decaffeinated drinks [3,4] implicates caffeine as the molecular component of coffee driving its inverse correlation with PD; however, other components remain possibilities given that caffeine is not the only molecule removed during the decaffeination process [11]. Indeed, although caffeine itself is CNS-active and is reproducibly protective in multiple PD models (vide infra)and possibly in PD if it actually intervenes against its causesother constituents of coffee or tea have shown neuroprotective properties in animal models of the disease [12][13][14]. ...
Article
The adenosine A2A receptor is a major target of caffeine, the most widely used psychoactive substance worldwide. Large epidemiological studies have long shown caffeine consumption is a strong inverse predictor of Parkinson's disease (PD). In this review, we first examine the epidemiology of caffeine use vis-à-vis PD and follow this by looking at the evidence for adenosine A2A receptor antagonists as potential neuroprotective agents. There is a wealth of accumulating biological, epidemiological and clinical evidence to support the further investigation of selective adenosine A2A antagonists, as well as caffeine, as promising candidate therapeutics to fill the unmet need for disease modification of PD.
... Although several studies have shown a dose-dependent inverse relationship between caffeine consumption and the risk of developing PD, more research still seems necessary. The systematic review and metaanalysis of observational studies have demonstrated a 25 -30% reduction in the risk of PD among caffeine consumers, and there is a linear dose-response relation; the higher is the consumption of caffeine, the lower is the risk of PD (6)(7)(8). Caffeine is a nonselective competitive blockade of adenosine receptors, especially adenosine A1 receptors and A2A receptors, and it has stimulant effects on locomotion by the A2A receptor blockade (9,10). Caffeine, as an antag-Copyright © 2021, Author(s). ...
... Parkinson's disease is the second most common neurological disorder (1). Various case-control and cohort studies have suggested a large number of environmental factors for predicting the risk of PD (8,22), of which caffeine intake is one of the most well-established protective factors (6,(23)(24)(25)(26)(27). ...
Article
Full-text available
Objectives: This systematic review of the literature was carried out to see whether coffee consumption could affect Parkinson's disease (PD) symptoms. Methods: Randomized controlled trials (RCTs), crossover studies, and quasi-experimental studies were assessed to evaluate the effect of caffeine on PD. The databases including Medline/PubMed, ProQuest, Embase, Cochrane Library, and ClinicalTrials.gov were systematically searched. The Cochrane Collaboration's tool for assessing the risk of bias in randomized clinical trials and the Cochrane risk of bias assessment tool for non-randomized studies of interventions (ROBINS-I) were used to assess the quality of RCTs and non-randomized clinical trials, respectively. A meta-analysis of the results was not possible because of reporting different outcomes. Results: Four papers were included in this study. Only one study reported the significant effect of caffeine on ESS and UPDRS. Another study observed no significant effect of caffeine on ESS during three-and six-week interventions. However, a significant reduction in ESS scores in the sixth week was reported after excluding four protocol violations. This study reported that the UPDRS score reduced in the third week, but significant changes were observed after six weeks. The other two studies did not show a significant effect of caffeine on ESS and UPDRS. Conclusions: Since a meta-analysis was not conducted, there was insufficient evidence to evaluate the effect of caffeine on PD. Thus, it is recommended to conduct more well-designed RCTs with a larger sample size to assess the effect of caffeine on PD.
... A metaanalysis of 13 study involving total 901,764 participants for coffee intake found a non-linear relationship was found between coffee intake and PD risk, with maximum protection effect at approximately 3 cups/day (Qi and Li, 2014). Systemic analysis of 120 observation studies have firmly established that regular human consumption of caffeine is associated with reduced risk for PD (Ross et al., 2000;Ascherio et al., 2001Ascherio et al., , 2003Saaksjarvi et al., 2008;Grosso et al., 2017) and does not impose significant adverse effects on the cardiovascular system, bone status, or the incidence of cancer (Fredholm et al., 1999b;Winkelmayer et al., 2005;Higdon and Frei, 2006;van Dam et al., 2006;Cadden et al., 2007;Daly, 2007). Interestingly, this inverse relationship of coffee consumption and risker for developing PD is largely attributed to caffeine since that the consumption of caffeinated (but not decaffeinated) coffee is associated with the reduced risk of developing PD in the Health Professional Follow-up Study (Ascherio et al., 2001). ...
... Systemic analysis of 120 observation studies have firmly established that regular human consumption of caffeine is associated with reduced risk for PD (Ross et al., 2000;Ascherio et al., 2001Ascherio et al., , 2003Saaksjarvi et al., 2008;Grosso et al., 2017) and does not impose significant adverse effects on the cardiovascular system, bone status, or the incidence of cancer (Fredholm et al., 1999b;Winkelmayer et al., 2005;Higdon and Frei, 2006;van Dam et al., 2006;Cadden et al., 2007;Daly, 2007). Interestingly, this inverse relationship of coffee consumption and risker for developing PD is largely attributed to caffeine since that the consumption of caffeinated (but not decaffeinated) coffee is associated with the reduced risk of developing PD in the Health Professional Follow-up Study (Ascherio et al., 2001). Notably, this inverse relationship is strong and consistent in men in the Health Professional Follow-up Study (Grosso et al., 2017) and in postmenopausal women who never used hormone replacement therapy in the Cancer Prevention Study II Nutrition Cohort (CPS II-Nutrition) (Palacios et al., 2012), but uncertain in women and postmenopausal women ever users of hormone replacement therapy. ...
Article
Full-text available
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 A2A receptor (A2AR) 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 A2AR 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.
... A2A receptor activation may be one of the major contributors to the pathophysiology of Parkinson's disease in women. Caffeine, another A2A receptor antagonist, was observed to offer neuroprotection from Parkinson's disease in women when consumed in the moderate doses (Ascherio et al., 2001). This relationship was further validated in another study which observed an interaction between the post-menopausal hormonal therapy and intake of caffeine. ...
... However, despite these evidences and its action on A2A receptors, trials involving caffeine haven't led to any clinically relevant end point (Postuma et al., 2017). Results of caffeine intake and women with Parkinson's disease is though more convincing and it has been observed to lower the risk of developing Parkinson's disease in women who did not use post-menopausal hormones (Ascherio et al., 2003;Ascherio et al., 2001). ...
Article
Parkinson’s disease is a neurodegenerative disease which is associated with different motor, cognitive and mood-related problems. Though it has been established that Parkinson’s disease is less prevalent in women in comparison to men, the differences tend to diminish with the advancing age. Different genetic, hormonal, neuroendocrinal and molecular players contribute towards the differences in the Parkinson’s disease pathogenesis. Furthermore, data available with respect to the therapeutic management of Parkinson’s disease in females is limited; women often tend to suffer more from the side effects of the currently available drugs. The present review highlights the sex-specific differences which play a role in the manifestation of these symptoms and side effects of the currently available therapeutic strategies. We have also discussed the current and upcoming therapeutic strategies which are in the clinical trials such as adenosine 2A (A2A) receptor antagonists, estrogen replacement therapy, α-synuclein targeting vaccines and antibodies, Botulinum toxin A, Fas-associated factor-1 (FAF-1) inhibitors, thiazolidinediones, 5-HT1A receptor agonists, dopamine D1/D5 receptor agonists, Glucagon-like peptide 1 (GLP-1) analogues and certain plant based principles for the treatment of Parkinson’s disease in women.
... Daily consumption of 784 mg/day or more of coffee during mid-life was shown to reduce the risk for developing PD at the age of 65 by fivefold compared to non-coffee drinkers after age-and smoking adjustments [165]. Since then, systemic analysis from over 20 observational studies has firmly established that regular human consumption of caffeine is associated with a fivefold reduction in risk for developing PD [165][166][167][168][169]. A meta-analysis of 13 studies, involving over 900,000 participants, found a non-linear relationship between coffee intake and the risk of PD with maximum protection seen at approximately three cups per day [170]. ...
... (1) The effect may not be due to caffeine-however, the consumption of decaffeinated coffee was not associated with a reduced risk of developing PD in the Health Professional Follow-up Study [166]. (2) The effect is not universal in the population-it is strong and consistent in men in the Health Professional Follow-up Study [169] and in post-menopausal women who have never used hormone replacement therapy in the Cancer Prevention Study II Nutrition Cohort but uncertain in women and post-menopausal women who have used hormone replacement therapy at some point [172]. ...
Article
Full-text available
The adenosine A2A receptor subtype is recognized as a non-dopaminergic pharmacological target for the treatment of neurodegenerative disorders, notably Parkinson’s disease (PD). The selective A2A receptor antagonist istradefylline is approved in the US and Japan as an adjunctive treatment to levodopa/decarboxylase inhibitors in adults with PD experiencing OFF episodes or a wearing-off phenomenon; however, the full potential of this drug class remains to be explored. In this article, we review the pharmacology of adenosine A2A receptor antagonists from the perspective of the treatment of both motor and non-motor symptoms of PD and their potential for disease modification.
... Caffeine belongs to the class of purinergic P1 adenosine (ADO) A 2A receptor inhibitors, which are considered to exert a beneficial action on patients experiencing PD [217], and has been proven to exhibit a neuroprotective role in experimental mouse models experiencing PD [218]. Individuals consuming coffee possess a lower incidence of evolving PD, with a respective incidence varying from 0.45-0.80 in coffee consumers in comparison to individuals not consuming coffee, as per two large prospective epidemiological investigations [217,219], and numerous case-referent studies [220]. Moreover, according to a meta-analysis that comprised five cohort studies and eight case-referent studies, there is a substantially lower incidence of evolving PD (with a risk ratio of 0.69) in individuals consuming coffee [207]. ...
... In addition, gender variations have been observed in several investigations. It has been reported that in 2 cohort studies, coffee has displayed a slightly elevated inversely proportional relationship in the evolution of PD in males as compared to females [217,219]. Moreover, the action of caffeine in post-menopausal women was reliant upon whether the women were or were not on estrogen-containing hormone replacement therapy (HRT). ...
Article
Full-text available
One of the utmost frequently emerging neurodegenerative diseases, Parkinson's disease (PD), comprehend the forfeit of dopamine (DA)-generating nerve cells in the substantia nigra pars compacta (SN-PC). The etiology and pathogenesis underlying the emergence of PD is still obscure. However, expanding corroboration encourages the involvement of genetic and environmental factors in the etiology of PD. The destruction of numerous cellular components, namely oxidative stress, ubiquitin-proteasome system (UPS) dysfunction, autophagy-lysosome system dysfunction, neuroinflammation and programmed cell death, and mitochondrial dysfunction partake in the pathogenesis of PD. Present-day pharmacotherapy can alleviate the manifestations, but no therapy has been demonstrated to cease disease progression. Peroxisome proliferator-activated receptors (PPARs) are ligand-directed transcription factors pertaining to the class of nuclear hormone receptors (NHR), and are implicated in the modulation of mitochondrial operation, inflammation, wound healing, redox equilibrium, and metabolism of blood sugar and lipids. Numerous PPAR agonists have been recognized to safeguard nerve cells from oxidative destruction, inflammation, and programmed cell death in PD and other neurodegenerative diseases. Additionally, various investigations suggest that regular administration of PPAR-activating non-steroidal anti-inflammatory drugs (NSAIDs) (ibuprofen, indomethacin), and leukotriene receptor antagonists (montelukast) were related to the de-escalated evolution of neurodegenerative diseases. The present review elucidates the emerging evidence enlightening the neuroprotective outcomes of PPAR agonists in in vivo and in vitro models experiencing PD. Existing articles up to the present were procured through PubMed, MEDLINE, etc., utilizing specific keywords spotlighted in this review. Furthermore, the authors aim to provide insight into the neuroprotective actions of PPAR agonists by outlining the pharmacological mechanism. As a conclusion, PPAR agonists exhibit neuroprotection through modulating the expression of a group of genes implicated in cellular survival pathways, and may be a propitious target in the therapy of incapacitating neurodegenerative diseases like PD.
... Epidemiological evidence for the neuroprotective effects of caffeine-containing food and beverages, particularly from coffee and tea, emerged in the early 2000s (53)(54)(55)(56)(57)(58)(59)(60)(61) . Meta-analyses which included several of these cohorts in addition to smaller case-control studies, (62)(63)(64)(65)(66)(67)(68)(69) have consistently found an inverse association between caffeine intake and PD risk (70)(71)(72) . ...
Article
Parkinson‟s disease (PD) is the second most common neurodegenerative disease after Alzheimer‟s disease and affects ~1% of the population over the age of 60 years in industrialised countries. The aim of this review is to examine nutrition in PD across three domains: dietary intake and the development of PD; whole body metabolism in PD; and the effects of PD symptoms and treatment on nutritional status. In most cases, PD is believed to be caused by a combination of genetic and environmental factors and whilst there has been much research in the area, evidence suggests that poor dietary intake is not a risk factor for the development of PD. The evidence around body weight changes in both the prodromal and symptomatic phases of PD is inconclusive and is confounded by many factors. Malnutrition in PD has been documented as has sarcopenia, although the prevalence of the latter remains uncertain due to a lack of consensus in the definition of sarcopenia. PD symptoms, including those which are gastrointestinal and non-gastrointestinal, are known to adversely affect nutritional status. Likewise, PD treatments can cause nausea, vomiting and constipation, all of which can adversely affect nutritional status. Given that the prevalence of PD will increase as the population ages, it is important to understand the interplay between PD, comorbidities and nutritional status. Further research may contribute to the development of interventional strategies to improve symptoms, augment care, and importantly, enhance the quality of life for patients living with this complex neurodegenerative disease.
... PD is a multifactorial disease, and both genetic and environmental factors play a role in its development. Some personal habits including cigarette smoking and caffeine consumption, and environmental heavy metal as well as the use of pesticides and herbicides (5)(6)(7)(8)(9)(10)(11) are known to have an influence on the development of PD. Some studies (12)(13)(14)(15) show the role of neuroinflammation in the development of PD by increasing microglial and complement activation and the concentration of pro-inflammatory cytokines in the substantia nigra and striatum. ...
Article
Purpose: To evaluate the relationship between the severity of clinical symptoms and cognitive function of patients with Parkinson's disease (PD) and the serum vitamin D level and nutrition status. Methods: Thirty-three adult PD patient were included in the study (November 2016 to October 2018) and their clinical symptom severity (including the Hoehn and Yahr scale and unified Parkinson's disease rating scale (UPDRS)) and cognitive function (mini-mental state examination) were assessed in two visits (at time of enrollment and one year after the enrollment). In the meanwhile, their renal/liver function, serum level of vitamin D, vitamin B12, Folate and high-sensitive C-reactive protein were also measured for clinical correlation and comparisons. Results: From the two visits, we found our patients divided into two group, the well-nourished status group and at risk or malnutrition status group. In both visits, we uncovered patients at risk of malnutrition status had worse clinical severity and more impaired memory. As for hypovitaminosis D, the vitamin D level alone made no significant correlation with the clinical severity and cognitive function. Conclusion: This study revealed that PD patient with at risk of malnutrition status has impaired cognitive function but patients with abnormal serum vitamin D level did not have such influence. But PD patients with abnormal vitamin D level have a higher hs-CRP level which has an influence on the cognitive function of PD patients. Therefore, abnormal serum vitamin D level may have an indirect influence on the cognitive function of PD patients through the influence on the hs-CRP level. This study is limited by the small case-number and short follow-up time. Further large scale study and longer observation period are needed for a better delineation of the relationship between the serum vitamin D level and nutritional status with the clinical condition of the PD patients.
... This difference between men and women seems unlikely to be related to the amount of flavonoid ingested. A similar sex difference has been reported for other protective factors of PD, such as caffeine intake and plasma urate [127,128], and the risk of PD has been observed only in men but not in women. Considering the age of the women (approximately 50 years), the reduced level of estradiol in menopausal women can be a critical factor contributing to the incidence of neurodegenerative diseases [129]. ...
Article
Background: Parkinson's disease (PD) in elderly patients is the second most prevalent neurodegenerative disease. The pathogenesis of PD is associated with dopaminergic neuron degeneration of the substantia nigra in the basal ganglia, causing classic motor symptoms. Oxidative stress, mitochondrial dysfunction, and neuroinflammation have been identified as possible pathways in laboratory investigations. Nutrition, a potentially versatile factor from all environmental factors affecting PD, has received intense research scrutiny. Methods: A systematic search was conducted in the MEDLINE, EMBASE, and WEB OF SCIENCE databases from 2000 until the present. Only randomized clinical trials (RCTs), observational case-control studies, and follow-up studies were included. Results: We retrieved fifty-two studies that met the inclusion criteria. Most selected studies investigated the effects of malnutrition and the Mediterranean diet (MeDiet) on PD incidence and progression. Other investigations contributed evidence on the critical role of microbiota, vitamins, polyphenols, dairy products, coffee, and alcohol intake. Conclusions: There are still many concerns regarding the association between PD and nutrition, possibly due to underlying genetic and environmental factors. However, there is a body of evidence revealing that correcting malnutrition, gut microbiota, and following the MeDiet reduced the onset of PD and reduced clinical progression. Other factors, such as polyphenols, polyunsaturated fatty acids, and coffee intake, can have a potential protective effect. Conversely, milk and its accessory products can increase PD risk. Nutritional intervention is essential for neurologists to improve clinical outcomes and reduce the disease progression of PD.
... In the present study, we found that modafinil significantly increased dopamine levels in both the striatum and NAc, inducing wakefulness without sleep rebound. Thus, we posit that a combination of modafinil and caffeine at appropriate doses may be useful for increasing dopamine and relieving early non-motor symptoms of Parkinson's disease, such as excessive daytime sleepiness(Ascherio et al., 2001). ...
Article
Background and purpose: Modafinil is a potent wake-promoting agent that is prescribed to treat narcolepsy and has a low incidence of abuse. Although previous studies have shown that modafinil-induced arousal depends on the dopaminergic receptors and transporters, the specific dopaminergic population underlying this mechanism remained unclear. Here, we investigated the role of mesencephalic dopaminergic neurons in modafinil-promoted arousal. Experimental approach: A dopamine indicator (dLight1.1) was employed to detect dopamine changes in the nucleus accumbens (NAc) and dorsal striatum (dStr). We specifically lesioned mesencephalic dopaminergic neurons via diphtheria toxin (DTA) in the dopamine transporter (DAT)-Cre mice. Then, the sleep-wake states were recorded to evaluate the effect of modafinil on arousal. Finally, the extent of DTA-induced lesions was determined by immunohistochemistry. Key results: Modafinil promptly increased dopamine levels in the NAc and dStr in a dose- dependent manner. Lesioning of dopaminergic neurons in the substantia nigra pars compacta (SNc) or ventral tegmental area (VTA) had no significant effects on physiological sleep-wake cycles. Modafinil at 90 mg kg-1 increased continuous wakefulness for 355.3 min in control mice, however, these effects were slightly decreased by 6.7% in the SNc-lesioned mice, and were prominently diminished by 32.8% in VTA-lesioned mice. Furthermore, the modafinil-induced arousal was completely blocked in the SNc-VTA-lesioned mice, whereas lesions of the dorsal raphe nucleus did not alter it. Conclusion and implications: Taken together, our findings indicate that mesencephalic dopaminergic neurons are essential for modafinil-induced arousal.
... The dietary intake of these heavy metals was found to be unrelated to PD prevalence (Mariani et al., 2013). In contrast, occupational exposure to these heavy metal shows increased associated with PD (Gorell et al., 1997;Coon et al., 2006;Lin et al., 2011) Lifestyle Both cigarette smoking (Hernán et al., 2002;Ritz et al., 2007;Noyce et al., 2012;Breckenridge et al., 2016) and coffee drinking (Ascherio et al., 2001;Hernán et al., 2002;Noyce et al., 2012) have been linked to reduced incidences of PD. ...
Thesis
The cerebral pathology of Parkinson’s disease is characterized by a progressive loss of dopaminergic neurons of the substantia nigra, and an accumulation of α-synuclein aggregates. neuroinflammation and genetic predisposition contribute to PD as the main confounding factors. In this PhD thesis, I aimed to evaluate, in vivo and post-mortem, the effects of three factors on the dopaminergic system: 1) α-synuclein overexpression, 2) α-synuclein and LRRK2 co-expression, and 3) mild neuroinflammation, on the dopaminergic system and dopaminergic neuronal cell loss.To this end, positron emission tomography (PET) imaging and behavioural studies have been selected as the main in vivo tools. I have used [18F]LBT999 and [18F]FMT PET imaging to evaluate striatal levels of dopamine transporter (DAT) and the dopamine-synthesising AADC enzyme, respectively. To assess neuroinflammation, I have used [18F]DPA714 to evaluate 18kDa TSPO binding. The in vivo data were validated by post-mortem techniques evaluating the expression of genes (qPCR) and proteins (immunohistochemistry).The results of my work show that overexpression of human WT-α-synuclein in the substantia nigra through viral vectors (AAV2/6-PGK-WT-α-synuclein) does not generate detectable neuronal loss in the substantia nigra, nor does it generate in vivo motor deficits or changes in the dopaminergic system as seen by in vivo PET imaging. On the other hand, I have demonstrated here that overexpression of A53T-α-synuclein in the substantia nigra, using an AAV2/6-PGK-A53T-α-synuclein viral vector approach, resulted in significant α-synuclein aggregation in the substantia nigra as soon as 8wpi, but not in the striatum. Quantitative microscopic analyses show that A53T-α-synuclein aggregation induced a mild but progressive degeneration of dopaminergic neurons in the substantia nigra. The loss of dopaminergic fibres in the striatum as detected by immunohistochemistry of tyrosine hydroxylase (TH) remains, however, moderate. DAT-PET imaging, but not AADC-PET imaging, was able to measure the progressive neuronal loss. Taken together, our in vivo and post-mortem data suggest that DAT-PET does not only reflect neuronal loss induced by α-synuclein accumulation, but also functional compensation mechanisms of the dopaminergic synapse. A reduction in DAT levels, combined with normal TH and AADC levels, could normalise the synaptic dopamine concentrations in the striatum. In addition, this dopaminergic neuronal loss coincided with in initially moderate, followed by a more pronounced microglial response. Finally, in a viral vector model of co-overexpression of AAV2/6-PGK-A53T-α-synuclein and AAV2/6-PGK-G2019S-LRRK2, we did not observe added neurotoxicity of G2019S mutated LRRK2 to A53T-α-synuclein toxicity.In an acute neuroinflammatory model following LPS injection in the striatum, post-mortem analysis revealed the absence of dopaminergic neuronal loss in the substantia nigra and synaptic loss in the striatum. Nevertheless, I observed a significant inverse correlation between inflammation markers (TSPO-PET and IBA1 expression) and markers for dopamine production (TH) and storage (VMAT2). These data support the hypothesis that neuroinflammation may impair the functionality of the dopaminergic system, regardless of the presence dopaminergic neuron loss.In summary, my thesis results confirm the interest of PET in demonstrating functional damage in vivo, which cannot be demonstrated post-mortem in animal models of PD.
... Future work designed to unveil the likely glial targets of chlorogenic acids may pave the way to develop future pharmacological strategies to alleviate the burden of brain diseases. Additionally, it will be important to detail if the present conclusions on the ability of chlorogenic acids to prevent alterations of synaptic function are valid for both sexes, since this preliminary study was carried out in male mice and there are compelling evidences indicating that some neuroprotective effects of coffee differ between men and women 64 ...
Article
Full-text available
The increased healthspan afforded by coffee intake provides novel opportunities to identify new therapeutic strategies. Caffeine has been proposed to afford benefits through adenosine A 2A receptors, which can control synaptic dysfunction underlying some brain disease. However, decaffeinated coffee and other main components of coffee such as chlorogenic acids, also attenuate brain dysfunction, although it is unknown if they control synaptic function. We now used electrophysiological recordings in mouse hippocampal slices to test if realistic concentrations of chlorogenic acids directly affect synaptic transmission and plasticity. 3-(3,4-dihydroxycinnamoyl)quinic acid (CA, 1–10 μM) and 5-O-(trans-3,4-dihydroxycinnamoyl)-D-quinic acid (NCA, 1–10 μM) were devoid of effect on synaptic transmission, paired-pulse facilitation or long-term potentiation (LTP) and long-term depression (LTD) in Schaffer collaterals-CA1 pyramidal synapses. However, CA and NCA increased the recovery of synaptic transmission upon re-oxygenation following 7 min of oxygen/glucose deprivation, an in vitro ischemia model. Also, CA and NCA attenuated the shift of LTD into LTP observed in hippocampal slices from animals with hippocampal-dependent memory deterioration after exposure to β-amyloid 1–42 (2 nmol, icv), in the context of Alzheimer’s disease. These findings show that chlorogenic acids do not directly affect synaptic transmission and plasticity but can indirectly affect other cellular targets to correct synaptic dysfunction. Unraveling the molecular mechanisms of action of chlorogenic acids will allow the design of hitherto unrecognized novel neuroprotective strategies.
... Similarly, prospective studies assessing lifetime coffee and tea consumption and PD highlight a negative correlation between caffeine in coffee or tea and PD risk [76], and the effect is more pronounced among men than women who regularly drink coffee or tea [71,77,78]. Importantly, there is substantial between-study heterogeneity across reported effect estimates. ...
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Purpose Parkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson’s Genetics Study (APGS) seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic, and environmental basis of PD susceptibility, symptoms and progression. Participants In the pilot phase reported here, 1,819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme (PBS) records. The average age at the time of the questionnaire was 64 ± 6 years. We collected patient-reported PD information and socio-demographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred thirty-two participants (84.2%) met all inclusion criteria and 1,499 provided a DNA sample via traditional post. Findings to date 65% of participants were male, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most commonly reported comorbid conditions. Future plans We plan to recruit sex- and age-matched unaffected controls, genotype all participants, and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms and progression, including as part of international PD research consortia. Article summary Strengths and limitations of this study We showed that recruiting Australian participants for PD research through the PBS database is a feasible and highly efficient method that enables us to reach people all over Australia who have been prescribed medications used to treat Parkinson’s symptoms. The Australian Parkinson’s Genetics Study (APGS) is the most extensive nationwide genetic and epidemiological study of Parkinson’s disease (PD) in Australia. It will serve as a platform for advancing PD research in the country. The pilot study questionnaire covered patient-reported outcomes and variables relevant to disease onset, diagnosis, symptoms, medical comorbidities and family history. Information on environmental exposures, lifestyle factors, ethnicity and socio-demographic variables were also included. A significant limitation is that with a 9% response rate, the sample may be prone to self-selection bias. For instance, patient characteristics reflect a younger group of patients with a younger age of onset and higher educational attainment than expected for the larger population of individuals with PD in Australia. Future recruitment efforts will investigate the extent of those biases by recruiting via movement disorders clinics, patient support groups and a public communications campaign.
... Epidemiological studies present that the greater intake of diet, vegetables, legumes and fruits containing anthocyanidins, quercetin, and EC reduced incidence of PD (Gao et al. 2012). An inverse association was reported between coffee and tea consumption with PD in males, but not in females, by Health Professionals Follow-up Study (HPFS) (Ascherio et al. 2001). RPCTs of flavonoids (green tea catechins, EGCG, anthocyanins), resveratrol and curcumin improved cognitive activity and increased serum BDNF in AD, MCI and control subjects (Huhn et al. 2018). ...
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Parkinson’s disease is characterized by typical motor symptoms, loss of dopamine neurons in the substantia nigra, and accumulation of Lewy body composed of mutated α-synuclein. However, now it is considered as a generalized disease with multiple pathological features. Present available treatments can ameliorate symptoms at least for a while, but only a few therapies could delay progressive neurodegeneration of dopamine neurons. Lewy body accumulates in peripheral tissues many years before motor dysfunction becomes manifest, suggesting that disease-modifying therapy should start earlier during the premotor stage. Long-termed regulation of lifestyle, diet and supplement of nutraceuticals may be possible ways for the disease-modification. Diet can reduce the incidence of Parkinson’s disease and phytochemicals, major bioactive ingredients of herbs and plant food, modulate multiple pathogenic factors and exert neuroprotective effects in preclinical studies. This review presents mechanisms underlying neuroprotection of phytochemicals against neuronal cell death and α-synuclein toxicity in Parkinson’s disease. Phytochemicals are antioxidants, maintain mitochondrial function and homeostasis, prevent intrinsic apoptosis and neuroinflammation, activate cellular signal pathways to induce anti-apoptotic and pro-survival genes, such as Bcl-2 protein family and neurotrophic factors, and promote cleavage of damaged mitochondria and α-synuclein aggregates. Phytochemicals prevent α-synuclein oligomerization and aggregation, and dissolve preformed α-synuclein aggregates. Novel neuroprotective agents are expected to develop based on the scaffold of phytochemicals permeable across the blood–brain–barrier, to increase the bioavailability, ameliorate brain dysfunction and prevent neurodegeneration.
... Besides the known risk factors it is discussed that nutrition may be associated with increased (dairy products) or decreased (phytochemicals, Omega-3 fatty acids, tea) risk or progression in PD [55]. Multiple epidemiological studies could already demonstrate an inverse association between coffee drinking and PD and thereby suggest a link to caffeine, and consequently methylxanthines, as A2A receptor antagonists [56][57][58]. Recent studies have confirmed this association (for an overview see Table 3). ...
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Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food, several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling, histone deacetylase activation and gene regulation. By affecting several pathways associated with neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative diseases has been extensively studied and several new aspects have been elucidated. In this review we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing the underlying molecular mechanisms in cell culture experiments and animal studies in order to assess the neuroprotective potential of methylxanthines in these diseases.
... The causal relationship between smoking and PD cannot be verified directly because conducting a trial to test smoking on PD is not ethically feasible. Coffee intake is also associated with a decreased risk of PD in many large cohort studies [18][19][20]. Most believe that pharmacological properties of caffeine, an adenosine receptor antagonist, may have neuroprotective effects on dopaminergic neurons. ...
Article
Atypical parkinsonism or atypical parkinsonian syndromes (APS) refer to a group of neurodegenerative disorders which mimic typical Parkinson's disease but poorly respond to levodopa treatment and deteriorate faster. APS are very rare and among them, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and corticobasal degeneration (CBD) are the three relatively better characterized entities. The prevalence estimates of PSP, MSA, or CBD are mostly <10/105, and the incidence estimates are around 1/105 person-year; both estimates remain stable over the past few decades. The age at onset is relatively young for MSA at late 50s, followed by CBD at early 60s, and then PSP at late 60s. The gender difference is not significant in APS, although slight female predominance in CBD has been reported in literature. Little is known about genetic and environmental risk factors for PSP, MSA, and CBD; although the COQ2 mutation has been identified as a genetic risk for MSA, familial cases are extremely rare. Survival after symptom onset is generally within 10 years, but cases with longer disease duration do exist. Respiratory infection remains the major cause of death for APS, but cardiac arrest should be particularly considered in MSA. In addition to disease rarity, the phenotype-pathology discrepancy in APS makes the epidemiological studies even more challenging. Including biomarkers in future diagnostic criteria and establishing disease registry for collecting sufficient number of APS cases may increase the likelihood of finding modifiable risk factors for prevention and intervention.
... The RR per 3 additional cups/day was 0.75 (CI: 0.64, 0.86) in case-control studies and 0.68 (CI: 0.46, 1.00) in cohort studies [116]. In a prospective study of caffeine consumption and risk of PD, Ascherio et al. [117] found an inverse association of PD risk with consumption of coffee, caffeine from noncoffee sources or tea, but not decaffeinated coffee among men. In the case of women, the relationship between caffeine/coffee intake and risk of PD was U-shaped, with the lowest risk observed at intakes of 1-3 cups of coffee/day. ...
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Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer's and Parkinson's diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.
... As mentioned for caffeine, CA and CGA are coffee components with antioxidant properties and neuroprotective effects against dopaminergic neurotoxicity [216,217] that have been suggested to underlie the decrease in PD risk associated with coffee consumption [218,219]. Interestingly, one of the cardinal symptoms of PD is constipation, and this seems to occur already 10-20 years prior to the presentation of PD motor symptoms [220], with lower bowel movement frequencies predicting the future PD crisis [221]. Moreover, neurodegeneration occurs in PD patients and animal models, and robust evidence suggests that PD could start in the ENS and spread from there to the CNS via the vagal nerve [222,223]. ...
Article
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Coffee is one of the most popular beverages consumed worldwide. Roasted coffee is a complex mixture of thousands of bioactive compounds, and some of them have numerous potential health-promoting properties that have been extensively studied in the cardiovascular and central nervous systems, with relatively much less attention given to other body systems, such as the gastrointestinal tract and its particular connection with the brain, known as the brain–gut axis. This narrative review provides an overview of the effect of coffee brew; its by-products; and its components on the gastrointestinal mucosa (mainly involved in permeability, secretion, and proliferation), the neural and non-neural components of the gut wall responsible for its motor function, and the brain–gut axis. Despite in vitro, in vivo, and epidemiological studies having shown that coffee may exert multiple effects on the digestive tract, including antioxidant, anti-inflammatory, and antiproliferative effects on the mucosa, and pro-motility effects on the external muscle layers, much is still surprisingly unknown. Further studies are needed to understand the mechanisms of action of certain health-promoting properties of coffee on the gastrointestinal tract and to transfer this knowledge to the industry to develop functional foods to improve the gastrointestinal and brain–gut axis health.
... Unfortunately, our dataset from the Swedish patient registry does not capture data on smoking. Notably, people who consume on average 1-3 cups of coffee per day have also been shown to have a reduced risk of PD [28]. While it has not been reported that people with RA drink more coffee, there is a correlation between smoking and coffee intake [29]. ...
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Background: Rheumatoid arthritis (RA) and the genetic risk landscape of autoimmune disorders and Parkinson's disease overlap. Additionally, anti-inflammatory medications used to treat RA might influence PD risk. Objective: To use a population-based approach to determine if there is an association between pre-occurring rheumatoid arthritis (RA) and later-life risk of Parkinson's disease (PD). Methods: The study population was 3.6 million residents of Sweden, who were alive during part or all of the follow-up period; 1997-2016. We obtained diagnoses from the national patient registry and identified 30,032 PD patients, 8,256 of whom each was matched to ten controls based on birth year, sex, birth location, and time of follow-up. We determined the risk reduction for PD in individuals previously diagnosed with RA. We also determined if the time (in relation to the index year) of the RA diagnosis influenced PD risk and repeated the analysis in a sex-stratified setting. Results: Individuals with a previous diagnosis of RA had a decreased risk of later developing PD by 30-50% compared to individuals without an RA diagnosis. This relationship was strongest in our conservative analysis, where the first PD diagnosis occurred close to the earliest PD symptoms (odds ratio 0.47 (CI 95% 0.28-0.75, p = 0.0006); with the greatest risk reduction in females (odds ratio 0.40 (CI 95% 0,19 -0.76, p = 0.002). Discussion: Our findings provide evidence that individuals diagnosed with RA have a significantly lower risk of developing PD than the general population. Our data should be considered when developing or repurposing therapies aimed at modifying the course of PD.
... This positive association between the regular intake of moderate doses of coffee and the increased longevity and health quality with ageing is tightly related to the ability of coffee intake to decrease the risk of developing major age-releated chronic disorders, such as diabetes [175][176][177][178][179][180], cardiovascular diseases [150,[181][182][183][184][185][186][187][188], stroke [189][190][191][192], depression and suicide [193][194][195][196][197][198][199][200][201], cognitive decline [202][203][204][205][206][207], and neurodegenerativce diseases, such as Alzheimer's disease [208][209][210][211][212] and Parkinson's disease [213][214][215][216][217][218]. ...
Article
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The health implications of acrylamide in food are a matter of concern based on toxicological studies in rodents, which showed that doses of acrylamide more than 100 times higher than those estimated to result from dietary exposure in humans are carcinogenic; however, the cancer types reported in rodents are species-specific, and whether these results can be extrapolated to humans is still in question. In fact, human epidemiological studies revealed a general lack of association between dietary acrylamide exposure and the incidence of different cancer types. Even occupational exposure to acrylamide, resulting in acrylamide exposure nearly 10 times higher than dietary exposure, did not increase tumor occurrence. Furthermore, the consumption of coffee, which is a main contributor of dietary acrylamide exposure, actually decreases the overall incidence of cancer in humans and afford global health benefits, increasing both lifespan and healthspan on ageing. This paradox clearly illustrates the risk of evaluating an individual molecule independently of its complete food matrix, which may have other components that completely override the effects of the considered molecule.
... Societal discrimination limits career choices, and indeed many career paths are closed to those considered to be obese. Also, societal stigmatization often impairs a person's ability to express his/her intellectual and other talents; that is, they are often termed underachievers [2]. Clinically, obesity is an epidemic in the present world that has caused a lot of health concerns. ...
... In the present study, we observed that coffee consumption predicted an older age at onset and milder motor symptom severity, as measured by MDS-UPDRS part III score. The protective effect of caffeine on PD development has been consistently reported [4,14,15], and recent longitudinal evidence suggests that caffeine is able to slow PD clinical progression [16]. Caffeine (1,3,7-trimethylxanthin) is a natural alkaloid and is an adenosine receptor antagonist [17]. ...
Article
Background Non-genetic risk factors play a relevant role in Parkinson's disease (PD) development but the relationship between these factors and PD clinical features is unknown. Objective The aim of the present multicenter study was to investigate possible relationship between risk factors and clinical motor and non-motor features in a large sample of PD patients. Methods Six hundred ninety-four patients with PD participated. Patients underwent a clinical evaluation assessing motor symptoms and motor complications as well as non-motor symptoms severity. Information regarding pharmacological treatment was also collected. Risk and protective factors were previously identified in the present population and included coffee consumption, cigarette smoking, and physical activity as protective factors and a family history of PD, dyspepsia, and exposure to toxic agents and general anesthesia as risk factors. Multiple regression models were used to investigate the relationship between risk factors and clinical variables. Results Coffee consumption predicted older age at onset (B: 0.527; CI: 0.195; 0.858) and milder motor symptom severity (B: 1.383; CI: 2.646; −0.121). Non-motor symptom severity was more severe in patients with dyspepsia before PD (B: 13.601; CI 5.019; 22.182) and milder in patients who performed physical activity before PD (B: 11.355; CI: 16.443; −6.266). We found no relationship between risk factors and motor complications, motor subtype and pharmacological treatment. Conclusions Risk and protective factors of PD development may influence PD clinical features. This finding may represent the first step in the development of new preventive approaches able to delay disease onset and mitigate the extent of clinical manifestations.
... Our results agree with previous studies that drinking coffee, but not decaffeinated coffee, and tea protect against PD [22]. The protection may be partly due to caffeine, which is both a central nervous system stimulant and neuroprotectant [5,[23][24][25]. ...
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Background Tobacco smokers have reduced Parkinson's disease (PD) risk. Some patients with PD experience constipation long before they develop mobility problems, and constipation is a frequent complaint of people who try to stop smoking. Recently, the gut microbiome has been implicated in PD. Methods In the present study, we analyzed the relationship between smoking and constipation in subjects with PD and controls. We wished to determine whether the effects of smoking and constipation were independent or whether they might be interrelated. To evaluate the relationship, we used a cohort of subjects from the UK Biobank (UKB). Results In 501,174 subjects, the decreased risk of Parkinson's disease with increased smoking was significant (p < 0.001, two-tailed Fisher's exact test). The increased risk of constipation in subjects with PD was significant (p = 0.001, two-tailed Fisher's exact test). Logistic regression was performed; sex, age, constipation, and smoking were the independent variables, and PD present or absent was the dependent variable. The PD odds ratio (OR) for males was 1.790 (95% confidence interval (CI): 1.629-1.966) times that for females, indicating that PD is more common in men. The risk of PD increased by 1.140 (95% CI: 1.131-1.149) with every year of age. Constipation increased the risk of PD by 4.043 (95% CI: 1.901-8.599). Smoking diminished PD risk by 0.772 (95% CI: 0.690-0.863). Drinking coffee was associated with a reduced risk of PD (OR: 0.815 (95% CI: 0.730-0.909). Drinking tea reduced PD risk by 0.979 (95% CI: 0.962-0.997) for each cup per day. The effects of sex, age, constipation, smoking, drinking coffee, and drinking tea were independent and significant. Conclusion Our analysis suggests that the favorable effect of smoking on PD is independent of the detrimental effect of constipation. Smoking reduces PD risk because it not only stimulates the bowel to empty and prevents constipation but also alters the gut microbiome. Another factor, perhaps the tobacco component diterpenoids, may be responsible for the PD risk-reducing effect.
... The largest cross-sectional cohort comprised 512 PD patients, of whom 184 were smokers and 328 never smoked [10]. Likewise, caffeine consumption was associated with lower PD risk, with a dosagedependent level of protection [14]. In terms of AAO, there is evidence that the onset of PD among coffee drinkers is later compared to non-drinkers [11,[15][16][17], also indicating a dosage effect [12,18]. ...
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Parkinson's disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene-environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) and clinical severity in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann-Whitney U test. Non-parametric Spearman correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. Reported p-values remain descriptive because they are not corrected for multiple testing and results are exploratory. We found that smoking (r=0.08, p<0.0001), coffee drinking (r=0.69, p<0.0001) and aspirin intake (r=0.23, p<0.0001) show an exploratory association with AAO in iPD. However, the effect of aspirin diminished as an independent predictor after including comorbidities (heart diseases and arthritis). Smoking was associated with higher (more severe) motor scores, while coffee drinking was linked to lower (less severe) motor scores (p<0.05). In addition, smokers reported anxiety, depression and other non-motor symptoms such as unexplained pains and problems remembering (p<0.05). The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) (n=237 patients with PD), although again the effect diminished after including age in the regression model. Future longitudinal studies are warranted to investigate the clinical severity over time.
... Studies report that disease onset in patients with idiopathic or monogenic PD is later among smokers, dependent on the dosage [7][8][9][10][11][12][13]. The largest crosssectional cohort was comprised of 715 PD patients, of whom 312 were smokers and 404 never smoked [5]. Likewise, caffeine consumption was associated with lower PD risk, with a dosage-dependent level of protection [14]. In terms of AAO, there is evidence that the onset of PD among coffee drinkers is later compared to non-drinkers [11,15,16], also indicating a dosage effect [12,17]. ...
Article
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder. Genetic modifiers, environmental factors and gene–environment interactions have been found to modify PD risk and disease progression. The objective of this study was to evaluate the association of smoking, caffeine and anti-inflammatory drugs with age at onset (AAO) in a large PD cohort. A total of 35,963 American patients with idiopathic PD (iPD) from the Fox Insight Study responded to health and lifestyle questionnaires. We compared the median AAO between different groups using the non-parametric Mann–Whitney U test. Non-parametric Spearman’s correlation was used for correlation assessments and regression analysis was used to assess interaction between variables. We found that smoking ( p < 0.0001), coffee drinking ( p < 0.0001) and aspirin intake ( p < 0.0001) show an exploratory association with AAO in PD, that was further supported by multivariate regression models. The association of aspirin with PD AAO was replicated in another cohort (EPIPARK) ( n = 237 patients with PD).
Article
Background Coffee is one of the most frequently consumed beverages worldwide. Research on effects of coffee drinking has focused on caffeine; however, coffee contains myriad biochemicals that are chemically unrelated to caffeine, including 3,4-dihydroxyphenyl compounds (catechols) such as caffeic acid and dihydrocaffeic acid (DHCA). Objective This prospective within-subjects study examined effects of drinking caffeinated or decaffeinated coffee on plasma free (unconjugated) catechols measured by liquid chromatography with series electrochemical detection (LCED) after batch alumina extraction. To confirm coffee-related chromatographic peaks represented catechols, plasma was incubated with catechol-O-methyltransferase and S-adenosylmethionine before the alumina extraction; reductions in peak heights would identify catechols. Methods Ten healthy volunteers drank 2 cups each of caffeinated and decaffeinated coffee on separate days after fasting overnight. With subjects supine, blood was drawn through an intravenous catheter up to 240 minutes after coffee ingestion and the plasma assayed by alumina extraction followed by LCED. Results Within 15 minutes of drinking coffee of either type, >20 additional peaks were noted in chromatographs from the alumina eluates. Most of the coffee-related peaks corresponded to free catechols. Plasma levels of the catecholamines epinephrine and dopamine increased with both caffeinated and decaffeinated coffee. Levels of other endogenous catechols were unaffected. Plasma DHCA increased bi-phasically, in contrast with other coffee-related free catechols. Interpretation Drinking coffee—whether caffeinated or decaffeinated—results in the rapid appearance of numerous free catechols in the plasma. These might affect the disposition of circulating catecholamines. The bi-phasic increase in plasma DHCA is consistent with production by gut bacteria.
Chapter
Globally, coffee is consumed as a functional beverage due to its nutraceutical value and positive physiological effects. Coffee is an important source of several nutritious and therapeutic phytoconstituents including lipids, carbohydrates, minerals, vitamins, and nitrogenous compounds, along with bioactive compounds like cafestol and kahweol diterpenes, caffeine, and chlorogenic acid (CGA), which all possess great therapeutic potential. Coffee is claimed to be an ancient wonder drug that is endowed with a variety of phytobiomolecules of therapeutic potential. The bioavailability of green coffee beans (GCB) and their active principles need to be ameliorated by modern nanoencapsulation and coffee capsule techniques. The role of CGA, caffeine, and other components in a variety of ailments such as cancer, inflammatory diseases, hepatitis, obesity, neurodegenerative disorders, and cardiovascular diseases has been well documented and supported using a mechanistic rationale. Furthermore, the risk–benefit ratio and health assessment need to be speculated on in the light of toxicological interventions and fortification of GCB with different permutations and combinations that could be obtained in the future.
Article
Zusammenfassung Hintergrund Patienten mit einem idiopathischen Parkinson-Syndrom können offenbar vom Koffeinkonsum profitieren, wie bereits eine Reihe experimenteller und klinischer Studien belegen. Methodik Die Übersichtsarbeit untersuchte die vorliegende Literatur zu Koffein und Parkinson. Ergebnisse Koffein kann die Blut-Hirn-Schranke durchdringen und übt seine biologischen Effekte überwiegend durch Antagonisierung von Adenosin-Rezeptoren aus. Zahlreiche Studien weisen darauf hin, dass Koffein und seine Derivate Theobromin und Theophylin mit einem reduzierten Parkinsonrisiko verbunden sind. Koffein und Adenosin-Antagonisten verringern die Exzitotoxizität durch Glutamat. Evidenz aus Tiermodellen untermauert das Potential des A2A Rezeptorantagonismus als innovative Krankheits-verändernde Zielstruktur bei Parkinson Schlussfolgerung Die vorliegenden Ergebnisse zeigen, dass die Untersuchung und Synthese von Xanthin-Derivaten sowie deren Analyse in klinischen Studien ein vielversprechender Ansatz in der Therapie neurodegenerativer Erkrankungen sein könnten.
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Coffee is one of the most widely consumed beverages worldwide. It is a complex chemical mixture composed of thousands of physiologically active compounds, including caffeine, chlorogenic acid, and diterpenes (cafestol and kahweol). Recently, coffee has emerged as a beverage with various health benefits, in particular in liver disease. Several epidemiological and observational studies demonstrated an inverse association between coffee consumption and primary liver cancer risk. The biological mechanisms underlying the hepatoprotective effect of coffee are still not completely understood. This article reviews the current available literature about the association between coffee consumption and hepatocellular carcinoma risk and the proposed mechanisms by which coffee exerts its chemopreventive properties.
Thesis
Neurodegenerative diseases are characterised by progressive neuronal loss due to the accumulation of misfolded proteins into the brain, underpinned by complex gene-environment interactions. Among them, Parkinson's disease (PD) and other related conditions are defined by slowness of movement, tremor and rigidity, i.e. parkinsonism. This is caused by a progressive degeneration of dopaminergic neurons and impaired function of the basal ganglia. While diagnostic criteria are mainly based on clinical appraisal and definite diagnosis relies on post-mortem evaluation, structural and functional brain imaging allows to assess the intricate pathophysiological processes underlying neurodegeneration in vivo. Notably, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging can estimate the pathogenic pathways involved in degenerative parkinsonisms. This includes impaired density of neurotransmitters receptors and transporters (e.g. dopamine and serotonin), altered brain metabolism, abnormal protein aggregation as well as neuroinflammation, all of which can be detected in early forms or even before the onset of motor symptoms in high-risk populations. My line of research aims at improving the diagnostic performance of degenerative parkinsonisms, notably by using PET/SPECT in addition to structural brain imaging. Moreover, my objectives include to better understand the pathophysiological role of tau deposition and brain inflammation in these conditions. Neurodegenerative diseases lead to motor, cognitive and emotional disability, and have a major impact on patients' quality of life. They also place a tremendous burden on families, caregivers, and society. Although dopamine-replacement therapy and deep brain stimulation are valid therapeutic options, they are symptomatic and thus do not halt disease progression. In combination with clinical and other biological markers, molecular imaging will certainly contribute to gain further insight into the complex pathophysiological mechanisms involved in neurodegeneration and to help developing disease-modifying treatments. 3 ACKNOWLEDGEMENTS
Article
Parkinson's Disease (PD) is a pervasive, chronic, progressively debilitating neurodegenerative disorder that commonly presents with a series of motor-related symptoms, including resting tremor, stiffness, bradykinesia, and issues with balance and reflexes leading to postural instability and an impaired gait. Since it's official classification, much has been studied regarding the clinical features, etiology, and neuropathophysiology of PD. An array of similar conditions, known as Parkinsonian syndromes, have also been identified. In addition to the clinical presentation of motor and non-motor related symptoms, histological analyses have revealed the presence of protein clusters and cellular changes in the brain that are indicative of PD. Since histology is necessarily performed post-mortem on the patients sectioned brain, it is not of use in diagnostic purposes. However, with the use of medical imaging technologies, particularly magnetic resonance imaging (MRI) and nuclear medicine imaging techniques, characteristic morphological and metabolic changes in the brain, which occur in the earlier stages of the disease, have been uncovered. Despite these technological advancements, PD is still typically diagnosed via clinical analysis. With the uncertainty associated with this technique, and the development of observable motor-related symptoms occurring after a significant amount of neurodegeneration, diagnosis of PD in its early stages is not possible. A review of the diagnostic imaging approaches to assessing PD could spread awareness of their efficacy and their potential for earlier diagnosis. Not only could this information inform public health policy in a similar manner to the recommendations for mammographic scans, the early diagnosis of PD is necessary for the implementation of any potential interventions.
Article
The present study aimed to investigate the beneficial effects of coffee on the liver. The results show that coffee has beneficial effects on the liver and can reduce liver disease progression due to its antioxidant properties. Coffee contains antioxidant capacities of chlorogenic acid, hydrophilic components, hydrophobic components, lactones, and diterpenes. There are also rich amounts of potassium and magnesium in coffee. Roasting of the green coffee beans at high temperatures will make unique components due to the chemical reactions between carbohydrates and amino acids as Maillard reactions. Caffeine with a purine derivative is found in several dietary sources, including tea, chocolate bars, coffee, cocoa beverages, energy, and soft drinks. Caffeine can pass all biological membranes due to the hydrophobic properties of caffeine. Three primary metabolites, such as theophylline, theobromine, and paraxanthine, are caused by metabolizing caffeine in the liver. Caffeine at normal consumption doses mainly acts among humans as an antagonist of adenosine receptors. Two cups of coffee per day should be consumed to show its beneficial effects. Coffee drinkers experience a lower incidence of advanced cirrhosis and fibrosis. There are also differences between males and females in their responses to caffeine due to changes in circulating steroid hormones. This article investigates the beneficial effects of coffee on the liver and summarizes the potential preventive or positive effects of coffee on the liver. Coffee has beneficial effects on the liver and can reduce the progression of liver disease due to its antioxidant properties.
Article
Background Tamoxifen, a selective estrogen receptor modulator, has been shown to variably affect Parkinson's disease (PD) risk. Objective The aim of this study was to review epidemiological literature and evaluate the rate of PD in women with breast cancer with tamoxifen exposure in a US population. Methods A literature search was conducted to identify relevant studies. We performed a retrospective cohort analysis using the Nurses' Health Study Version One to report descriptive statistics. Results Most studies suggest there may be a time‐dependent effect of tamoxifen on PD risk, with the risk increasing with time from exposure. However, rates of PD in persons exposed to tamoxifen overall appear to be low. In our cohort, PD was evident in 6.2 per 1,000 of those with tamoxifen use and 3.6 per 1,000 of those without tamoxifen use. Time from breast cancer to PD diagnosis was 9.7 years among women with tamoxifen exposure and 11.7 among women without. Conclusions Tamoxifen may be associated with an increased risk for PD. Further research is needed to elucidate the role of estrogen and selective estrogen antagonism in PD. © 2021 International Parkinson and Movement Disorder Society
Article
Background: Existing limited evidence suggests that smoking and tea consumption may be associated with a lower risk of Parkinson's disease (PD). However, less is known about the independent and joint roles of these two habits, which are often clustered among Chinese, on PD risk. Objective: To prospectively examine the independent and joint association of tea consumption and smoking with the risk of PD. Methods: The China Kadoorie Biobank (CKB) study recruited 512,725 participants aged 30 to 79 years from ten areas across China since 2004. Information on smoking and tea consumption was collected at baseline, and PD cases were ascertained by linkage to the national health insurance system and death registry. Cox proportional hazards models were used to estimate the multivariable-adjusted hazard ratios (HRs) and corresponding 95%confidence intervals (CIs). Results: During a median of 10.8 years of follow-up, 922 PD cases were recorded. Compared with participants who never consumed tea, the HR (95%CI) for daily consumers was 0.68 (0.55, 0.84). Compared with participants who never or occasionally smoked, the HR (95%CI) for current smokers was 0.66 (0.53, 0.82). Those who had a clustering habit of smoking and tea consumption had a 38%(HR = 0.62; 95%CI: 0.49, 0.79) lower PD risk than those who consumed none. However, there were no statistically significant multiplicative or additive interaction for tea consumption and smoking on PD risk. Conclusion: We found that smoking and daily tea consumption were independently inversely associated with the risk of PD.
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Purpose Parkinson’s disease (PD) is a neurodegenerative disorder associated with progressive disability. While the precise aetiology is unknown, there is evidence of significant genetic and environmental influences on individual risk. The Australian Parkinson’s Genetics Study seeks to study genetic and patient-reported data from a large cohort of individuals with PD in Australia to understand the sociodemographic, genetic and environmental basis of PD susceptibility, symptoms and progression. Participants In the pilot phase reported here, 1819 participants were recruited through assisted mailouts facilitated by Services Australia based on having three or more prescriptions for anti-PD medications in their Pharmaceutical Benefits Scheme records. The average age at the time of the questionnaire was 64±6 years. We collected patient-reported information and sociodemographic variables via an online (93% of the cohort) or paper-based (7%) questionnaire. One thousand five hundred and thirty-two participants (84.2%) met all inclusion criteria, and 1499 provided a DNA sample via traditional post. Findings to date 65% of participants were men, and 92% identified as being of European descent. A previous traumatic brain injury was reported by 16% of participants and was correlated with a younger age of symptom onset. At the time of the questionnaire, constipation (36% of participants), depression (34%), anxiety (17%), melanoma (16%) and diabetes (10%) were the most reported comorbid conditions. Future plans We plan to recruit sex-matched and age-matched unaffected controls, genotype all participants and collect non-motor symptoms and cognitive function data. Future work will explore the role of genetic and environmental factors in the aetiology of PD susceptibility, onset, symptoms, and progression, including as part of international PD research consortia.
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Considerando-se a importância de desenvolver uma fórmula de sorvete mais saudável para um público com restrição ao açúcar, optou-se pelo uso do adoçante estévia na elaboração de um sorvete de café, que tem propriedades antioxidantes, além de vitaminas, e o óleo de coco que também tem vários benefícios para a saúde. O objetivo deste trabalho é avaliar a aceitabilidade sensorial de um sorvete sabor café junto ao óleo de coco em substituição à gordura e a estévia como edulcorante. Foram formuladas três receitas de sorvetes: uma formulação padrão da fábrica de sorvetes Maipu, já testada, com textura, cremosidade e cor, apenas sem a melhoria do sabor e aroma do café, porém utilizou-se açúcar e gordura hidrogenada, com saborizante de café; a segunda foi substituído o açúcar pelo adoçante estévia, acrescentado o óleo de coco e mantido o mescla de café saborizante; já a terceira amostra foi formulada uma receita mais saudável com óleo de coco, estévia e café expresso. Estas 3 formulações de sorvetes foram submetidas à análise sensorial para atributos de cor, textura, sabor, aroma por meio de uma escala hedônica estruturada de nove pontos, com 50 provadores não treinados. Observou-se que a adição de 100% estévia, do óleo de coco e do café expresso, alterou significativamente a textura dos sorvetes testados e apresentaram melhor aceitabilidade com relação ao sabor agradável do café marcante.
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Parkinson’s disease (PD) is a neurodegenerative disease with multifactorial aetiology that influences the quality of life. However, the association of possible factors with PD is need to be investigated in Indian population, hence we aimed to determine the association of lifestyle, environmental factors, biochemical parameters and genetic insights of MT-ND1 gene in PD patients. Using a standardised questionnaire, PD patients and control group of about 146 subjects were interviewed on demographic, lifestyle and environmental factors. The subjects includes n = 73 Parkinson’s patients [juvenile (n = 4); early-onset (n = 8); late-onset (n = 61)] with equal number of age and sex matched controls, further we had obtained institutional ethical clearance and informed consent from study participants. Biomarker investigations and MT-ND1 alterations were investigated by appropriate molecular techniques. During the average follow-up years of 5.1, significant association was observed among smoking, alcohol, caffeinated drinks, surgery, pesticide exposure at p < 0.05 in varied PD age groups. Occupational exposure to agriculture and industry showed an increased risk among the late-onset group. The biomarkers uric acid (UA) and dopamine (DA) were significant at p < 0.05 in all the three PD age groups. The MT-ND1 alteration with A3843 G variant was significant at p < 0.05 for AG allele in all the three PD groups but the highest prevalence was observed in late-onset group. From our study, smoking, alcohol, caffeinated drinks, occupational influence of agriculture and industry and pesticide exposure had more association with PD occurrence. Hence, to the best of our knowledge, this is the first kind of study in Tamil Nadu population, India to validate the various factors with PD. Therefore we suggest that further research is mandatory to detect other possible associations among PD, using comprehensive larger sample size.
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Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects more than 10 million people worldwide. Oxidative stress and mitochondrial dysfunction play a significant role in altering the homeostasis of energy production and free radical generation. Current PD therapies are focused on reducing the cardinal symptoms rather than preventing disease progression in the patients. Adenosine A2A receptor (A2A R) antagonist (Istradephylline) combined with levodopa shows a promising therapy for PD. In animal studies, caffeine administration showed to improve motor functions and neuroprotective effect in the neurons. Caffeine is probably the most extensively used psychoactive substance. In this current study, we investigated the neuroprotective effect of caffeine against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration. Here, we demonstrate that caffeine improves behavioral and neurotransmitter recovery against MPTP-induced toxicity. Caffeine restores endogenous antioxidant levels and suppresses neuroinflammation. Our finding suggests that the blockage of A2AR is a promising disease-modifying therapy for PD. Target engagement strategies could be more beneficial in preventing disease progression rather than symptomatic reliefs in PD patients.
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The purine alkaloid caffeine is the most widely consumed psychostimulant drug in the world and has multiple beneficial pharmacological activities, for example, in neurodegenerative diseases. However, despite being an extensively studied bioactive natural product, the mechanistic understanding of caffeine's pharmacological effects is incomplete. While several molecular targets of caffeine such as adenosine receptors and phosphodiesterases have been known for decades and inspired numerous medicinal chemistry programs, new protein interactions of the xanthine are continuously discovered providing potentially improved pharmacological understanding and a molecular basis for future medicinal chemistry. In this Perspective, we gather knowledge on the confirmed protein interactions, structure activity relationship, and chemical biology of caffeine on well-known and upcoming targets. The diversity of caffeine's molecular activities on receptors and enzymes, many of which are abundant in the CNS, indicates a complex interplay of several mechanisms contributing to neuroprotective effects and highlights new targets as attractive subjects for drug discovery.
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Background and Objectives Although flavonoids have the potential to exert neuroprotective benefits, evidence of their role in improving survival rates among individuals with Parkinson disease (PD) remains lacking. We aimed to prospectively study the association between pre- and post-diagnosis flavonoid intakes and risk of mortality among individuals with PD identified from two large ongoing cohorts of US men and women. Methods Included in the current analysis were 599 women from the Nurses’ Health Study and 652 men from the Health Professionals Follow-up Study who were newly diagnosed with PD during follow-up. Dietary intakes of total flavonoid and its subclasses together with major flavonoid-rich foods (tea, apples, berries, orange and orange juice, and red wine) were repeatedly assessed based on a validated food frequency questionnaire every 4 years. Mortality was ascertained via the National Death Index and state vital statistics records. Results We documented 944 deaths during 32–34 years of follow-up. A higher total flavonoid intake before PD diagnosis was associated with a lower future risk for all-cause mortality in men (hazard ratio [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 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 (p<0.05 for all). Discussion Among individuals with PD, higher consumption of flavonoids, especially anthocyanins and flavan-3-ols, and flavonoid-rich food such as berries and red wine, was likely to be associated with a lower risk of mortality.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide, characterized by symptoms of bradykinesia, rigidity, postural instability, and tremor. Recently, there has been a growing focus on the relationship between the gut and the development of PD. Emerging to the forefront, an interesting concept has developed suggesting that the initial pathophysiological changes occur in the gastrointestinal tract before changes are seen within the brain. This review is aimed at highlighting the relationship between PD and the gastrointestinal tract, along with the supporting evidence for this. Firstly, we will focus on the gastrointestinal conditions and symptoms which commonly affects patients, including both upper and lower gastrointestinal issues. Secondly, the impact of nutrition and diet on neurological health and PD physiology, with particular emphasis on commonly consumed items including macronutrients and micronutrients. Finally, variability of the gut microbiome will also be discussed and its link with both the symptoms and signs of PD. The evidence presented in this review highly suggests that the initial pathogenesis in the gut may proceed the development of prodromal PD subtypes, and therefore building on this further could be imperative and lead to earlier diagnosis with new and improved therapeutics.
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BACKGROUND: Parkinson’s disease (PD) is a chronic neurodegenerative disorder, and previous studies have shown that the Mediterranean diet (MeDi) can be effective in reducing the incidence and progression of the disease. OBJECTIVE: The purpose of this study was to determine an association between adherence to MeDi and the risk of PD in adults by meta-analysis of cohort studies. METHODS: Online databases including Scopus, PubMed, Web of Science, and Google Scholar were searched up to March 2021. Cohort studies that examined the association of PD risk with adherence to MeDi were included. A pooled relative risk with a 95% confidence interval was calculated by a random effects meta-analysis. As well, bias assessment, assessment of heterogeneity, sensitivity, and subgroup analyses were carried out. The primary outcome was Parkinson’s incidence. RESULTS: Overall four papers on PD risk were included in the present systematic review and meta-analysis. The effect size of the summary for the risk of overall PD, comparing the highest with the lowest adherence to MeDi, was 0.76 (95% CI: 0.59, 0.98), indicating a significant inverse association. CONCLUSIONS: Adherence to MeDi has a protective role against PD. Also, adhering to this dietary pattern at a younger age may be more beneficial in reducing the risk of PD. However, we suggest more prospective cohort studies in this regard.
Article
Introduction The relationship of prodromal markers of PD with PD mortality is unclear. Electronic health records (EHRs) provide a large source of raw data that could be useful in the identification of novel relevant prognostic factors in PD. We aimed to provide a proof of concept for automated data mining and pattern recognition of EHRs of PD patients and to study associations between prodromal markers and PD mortality. Methods Data from EHRs of PD patients (n = 2522) were collected from the Turku University Hospital database between 2006 and 2016. The data contained >27 million words/numbers and >750000 unique expressions. The 5000 most common words were identified in three-year time period before PD diagnosis. Cox regression was used to investigate the association of expressions with the 5-year survival of PD patients. Results During the five-year period after PD diagnosis, 839 patients died (33.3%). If expressions associated with psychosis/hallucinations were identified within 3 years before the diagnosis, worse survival was observed (hazard ratio = 1.71, 95%CI = 1.46–1.99, p < 0.001). Similar effects were observed for words associated with cognition (1.23, 1.05–1.43, p = 0.009), constipation (1.34, 1.15–1.56, p = 0.0002) and pain (1.34, 1.12–1.60, p = 0.001). Conclusions Automated mining of EHRs can predict relevant clinical outcomes in PD. The approach can identify factors that have previously been associated with survival and detect novel associations, as observed in the link between poor survival and prediagnostic pain. The significance of early pain in PD prognosis should be the focus of future studies with alternate methods.
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Background Caffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l -dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice. Results In behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l -dopa + COF. l -Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l -dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l -dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l -dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ. Conclusions Our findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l -dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.
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In the absence of efficient disease-modifying treatments for Parkinson’s disease (PD), research has focused on identifying potential environmental factors whose modulation may prevent or slow the progression of this neurodegenerative disorder. Compelling epidemiological evidence suggests that caffeine consumption is inversely associated with the risk of developing PD. Further experimental findings demonstrated that caffeine, by particularly targeting adenosine A2A (A2AR) receptors, protected PD animal models against the loss of dopaminergic neurons. The antagonistic action of caffeine on adenosine receptors not only slowed PD-related neurodegeneration, but also improved motor and nonmotor symptoms of PD in animal models. Here, we review the potential action mechanisms by which caffeine might play a role in reducing the risk of PD. We also review current evidence of the benefits of caffeine consumption in motor and nonmotor symptoms of PD. Finally, we point out how these promising findings could lead to the identification of new approaches for effective treatment of PD.
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Caffeine is the most widely consumed centralnervous-system stimulant. Three main mechanisms of action of caffeine on the central nervous system have been described. Mobilization of intracellular calcium and inhibition of specific phosphodiesterases only occur at high non-physiological concentrations of caffeine. The only likely mechanism of action of the methylxanthine is the antagonism at the level of adenosine receptors. Caffeine increases energy metabolism throughout the brain but decreases at the same time cerebral blood flow, inducing a relative brain hypoperfusion. Caffeine activates noradrenaline neurons and seems to affect the local release of dopamine. Many of the alerting effects of caffeine may be related to the action of the methylxanthine on serotonine neurons. The methylxanthine induces dose-response increases in locomotor activity in animals. Its psychostimulant action on man is, however, often subtle and not very easy to detect. The effects of caffeine on learning, memory, performance and coordination are rather related to the methylxanthine action on arousal, vigilance and fatigue. Caffeine exerts obvious effects on anxiety and sleep which vary according to individual sensitivity to the methylxanthine. However, children in general do not appear more sensitive to methylxanthine effects than adults. The central nervous system does not seem to develop a great tolerance to the effects of caffeine although dependence and withdrawal symptoms are reported.
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The authors assessed the reproducibility and validity of an expanded 131-item semiquantitative food frequency questionnaire used in a prospective study among 51,529 men. The form was administered by mail twice to a sample of 127 participants at a one-year interval. During this interval, men completed two one-week diet records spaced approximately 6 months apart. Mean values for intake of most nutrients assessed by the two methods were similar. Intraclass correlation coefficients for nutrient intakes assessed by questionnaires one year apart ranged from 0.47 for vitamin E without supplements to 0.80 for vitamin C with supplements. Correlation coefficients between the energy-adjusted nutrient intakes measured by diet records and the second questionnaire (which asked about diet during the year encompassing the diet records) ranged from 0.28 for iron without supplements to 0.86 for vitamin C with supplements (mean r = 0.59). These correlations were higher after adjusting for week-to-week variation in diet record intakes (mean r = 0.65). These data indicate that the expanded semiquantitative food frequency questionnaire is reproducible and provides a useful measure of intake for many nutrients over a one-year period.
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Caffeine is a natural constituent of more than 60 plant species and as such is present in the human diet through drinks based on plant extracts. It has also been used as a flavoring agent in food (baked goods, dairy desserts, puddings and fillings, candy) and beverages (Dr. Pepper, Coca-Cola, Pepsi-Cola, Royal Crown Cola) and also in a variety of over-the-counter pharmaceuticals (1). In such pharmaceuticals, caffeine is present in combination with drugs used as stimulants, pain relievers, diuretics, cold remedies, weight control products, bronchial and cardiac stimulants as well as in drugs for the treatment of acne and other skin disorders. The pharmaceutical properties of caffeine described in this report explain its use in these drugs. These multiple sources of caffeine reflect the human search and interest for psychotropic drugs and stimulants from the plant world.
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The Nurses' Health Study was designed as a prospective follow-up study to examine relations between contraception and breast cancer. With follow-up questionnaires mailed every 2 years, investigators have added extensive details of lifestyle practices. The study, currently in its 20th year, has maintained high follow-up with > 90% of participants responding to each of the follow-up cycles since 1988. The relations between use of hormones, diet, exercise, and other lifestyle practices have been related to the development of a wide range of chronic illnesses among women. This review describes the methods used to follow up the study participants and summarizes the major findings that have been described over the first 20 years of the study. We highlight additional areas added to the study in recent years to address emerging issues in women's health. Special emphasis is placed on the recent findings from the study, including relations between weight gain and heart disease, diabetes, and mortality, the lack of relation between calcium and osteoporotic fractures, and the positive relation between postmenopausal use of hormones and risk of breast cancer.
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In a hospital based case-control study, we investigated the role of environmental factors in the aetiology of Parkinson's disease. This paper describes our results on smoking habits. The smoking histories of 380 Parkinson's disease (PD) patients recruited from nine German clinics were compared to those of age- and sex-matched control subjects (379 neighbourhood controls and 376 controls from the same region). Detailed information on smoking behaviour was collected in structured personal interviews in order to calculate the number of pack-years smoked up to the time of diagnosis. Conditional logistic regression was used to calculate odds ratios (OR) and control for potential confounders. Among PD patients, 44% had ever smoked, as compared to 59% in both control groups. Among ever-smoking patients, 74% quit prior to the date of diagnosis, as compared to roughly 45% of the ever-smoking control subjects. The OR for ever having smoked was 0.5 (95% confidence interval [CI]: 0.3-0.7), P trend < 0.00005). The results are considered in terms of criteria for causality. Plausible explanations for the observed inverse association between smoking and PD include: 1. A genetic predisposition that increases the risk for PD (such as defective detoxification enzymes) simultaneously decreases the likelihood of smoking. 2. Inherently lower dopamine levels in predestined PD patients cause them to be less prone to addiction. 3. Smoking is neuroprotective.
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The projected expansion in the next several decades of the elderly population at highest risk for Parkinson disease (PD) makes identification of factors that promote or prevent the disease an important goal. To explore the association of coffee and dietary caffeine intake with risk of PD. Data were analyzed from 30 years of follow-up of 8004 Japanese-American men (aged 45-68 years) enrolled in the prospective longitudinal Honolulu Heart Program between 1965 and 1968. Incident PD, by amount of coffee intake (measured at study enrollment and 6-year follow-up) and by total dietary caffeine intake (measured at enrollment). During follow-up, 102 men were identified as having PD. Age-adjusted incidence of PD declined consistently with increased amounts of coffee intake, from 10.4 per 10,000 person-years in men who drank no coffee to 1.9 per 10,000 person-years in men who drank at least 28 oz/d (P<.001 for trend). Similar relationships were observed with total caffeine intake (P<.001 for trend) and caffeine from non-coffee sources (P=.03 for trend). Consumption of increasing amounts of coffee was also associated with lower risk of PD in men who were never, past, and current smokers at baseline (P=.049, P=.22, and P=.02, respectively, for trend). Other nutrients in coffee, including niacin, were unrelated to PD incidence. The relationship between caffeine and PD was unaltered by intake of milk and sugar. Our findings indicate that higher coffee and caffeine intake is associated with a significantly lower incidence of PD. This effect appears to be independent of smoking. The data suggest that the mechanism is related to caffeine intake and not to other nutrients contained in coffee. JAMA. 2000;283:2674-2679.
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Two populations of limbic neurons are likely neurophysiological substrates for cognitive operations required for spatial orientation and navigation: hippocampal pyramidal cells discharge selectively when the animal is in a certain place (the "firing field") in the environment, whereas head direction cells discharge when the animal orients its head in a specific, "preferred" direction. Cressant et al. (1997) showed that the firing fields of hippocampal place cells reorient relative to a group of three-dimensional objects only if these are at the periphery, but not the center of an enclosed platform. To test for corresponding responses in head direction cells, three objects were equally spaced along the periphery of a circular platform. Preferred directions were measured before and after the group of objects was rotated. (The rat was disoriented in total darkness between sessions). This was repeated in the presence or absence of a cylinder enclosing the platform. When the enclosure was present, the preferred directions of all 30 cells recorded shifted by the same angle as the objects. In the absence of the enclosure, the preferred directions did not follow the objects, remaining fixed relative to the room. These results provide a possible neurophysiological basis for observations from psychophysical experiments in humans that background, rather than foreground, cues are preferentially used for spatial orientation.
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The etiology of Parkinson's disease has been enigmatic to clinicians, epidemiologists, and basic scientists since the clinical syndrome was first described in 1817. Mendelian inheritance probably accounts fur a small proportion of Parkinson's disease. Apart from an increasing risk with age, the most consistent epidemiologic observation has been an inverse relation with cigarette smoking. Neither selective survival of nonsmokers nor behavioral characteristics of smokers can explain this seemingly protective association, interest in environmental exposures, particularly pesticides, metals, and industrial solvents, heightened substantially following the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant, as a cause of human parkinsonism. Epidemiologic and toxicologic research has since been guided to a great extent, although not exclusively, by mechanisms of MPTP toxicity. Efforts to characterize gene/environment interactions have also intensified in recent years. In this review, we evaluate recent evidence concerning the etiology of Parkinson's disease, with emphasis on environmental and lifestyle exposures and their potential interactions with genetic susceptibility traits. The most challenging aspects of epidemiologic research into Parkinson's disease causation include methodologic difficulties surrounding case definition, completeness of case ascertainment, selection of appropriate controls in case-control studies, and assessment of environmental exposures. We conclude with recommendations for future research directions.
Book
This book is intended to increase understanding of the complex relationships between diet and the major diseases of western civilization, such as cancer and atherosclerosis. The book starts with an overview of research strategies in nutritional epidemiology-a relatively new discipline which combines the knowledge compiled by nutritionists during this century with the methodology developed by epidemiologists to study the determinants of disease with multiple etiologies and long latent periods. A major part of the book is devoted to methods of dietary assessment using data on food intake, biochemical indicators of diet, and measures of body size and composition. The reproducibility and validity of each approach and the implications of measurement error are considered in detail. The analysis, presentation, and interpretation of data from epidemiologic studies of diet and disease are discussed. Particular attention is paid to the important influence of total energy intake on findings in such studies. As examples of methodologic issues in nutritional epidemiology, three substantive topics are examined in depth: the relations of diet and coronary heart disease, fat intake and breast cancer, and Vitamin A and lung cancer.
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A standard analysis of the Framingham Heart Study data is a generalized person-years approach in which risk factors or covariates are measured every two years with a follow-up between these measurement times to observe the occurrence of events such as cardiovascular disease. Observations over multiple intervals are pooled into a single sample and a logistic regression is employed to relate the risk factors to the occurrence of the event. We show that this pooled logistic regression is close to the time dependent covariate Cox regression analysis. Numerical examples covering a variety of sample sizes and proportions of events display the closeness of this relationship in situations typical of the Framingham Study. A proof of the relationship and the necessary conditions are given in the Appendix.
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The ability of orally administered caffeine to modify the antiparkinsonian efficacy of levodopa of piribedil, a putative dopamine receptor against, was studied in six patients. At doses that induced unequivocal central nervous system stimulation, caffeine produced no change in the therapeutic response to either antiparkinsonian agent. On the other hand, patients with levodopa dyskinesias reported an increase in the duration of their involuntary movements with caffeine coadministration. Since caffeine is known to stimulate both dopaminergic mechanisms and motor activity in the experimental animal, the results of this study cast doubt on the value of these factors as predictors of therapeutic efficacy in parkinsonian patients.
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Caffeine was administered to six patients with idiopathic parkinsonism in an attempt to potentiate the therapeutic response of bromocriptine, a dopamine (DA) receptor agonist, by inhibition of phosphodiesterase. In a double-blind study at doses of 1,000 mg daily, caffeine failed to enhance the antiparkinsonian action of bromocriptine (40 mg daily) given concomitantly. Although effective in potentiating the action of levodopa and other agonists in animal models of parkinsonism, caffeine is inactive in parkinsonism in man.
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A number of studies have reported lower cigarette consumption in patients with Parkinson's disease (PD) previous to onset of the disease. In an attempt to determine whether there existed a "premorbid attitude" by patients against the use of socially accepted "drugs," the premorbid tobacco, alcohol, and coffee consumption habits were compared in 128 PD patients and 256 controls. Patients and controls were selected by case control method and were recruited from the same health area and socioeconomic stratum. In males, the habits of smoking more than 10 cigarettes/day (p < 0.001) and drinking more than 50 g/day of alcohol (p < 0.001) were significantly less frequent in the PD patients than in the controls, but the differences in coffee consumption were nonsignificant. In females behavior did not differ significantly between the PD group and the controls for any of the three habits. There was no correlation between the amount of smoking and alcohol drinking and age at onset of PD or current Hoehn and Yahr's staging. Our results suggest the existence of a premorbid personality in males with PD, possibly conditioning a restrictive attitude toward the consumption of such toxic substances as tobacco and alcohol, yet a more tolerant attitude toward habits more widely accepted socially, like coffee consumption.
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Smokers are less likely to develop Parkinson's disease (PD) than is true of non-smokers, and PD is the only disease inversely related to smoking. PD is associated with a reduced level of dopamine. Although nicotine can affect the receptors, including dopamine receptors, it seems unlikely that use of nicotine is protective in PD. An alternative explanation is that just as PD is associated with a lower than normal level of dopamine, addiction to smoking is linked with a higher than normal level of dopamine. This high innate level of dopamine facilitates addiction to nicotine.
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Additional epidemiologic studies may provide important insights into the etiology of Parkinson's disease. Moreover as the elderly population of Europe and the United States grows, accurate public health planning requires accurate incidence and prevalence estimates. The recent development of a therapy that may slow disease progression (see article by Tetrud elsewhere in this issue) makes early identification and treatment of Parkinson's disease particularly important. Investigations of early markers of Parkinson's disease or markers of disease susceptibility are critical areas of future research, requiring careful collaboration between epidemiologists and laboratory scientists.
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Abstract— The administration of reserpine with α-methyl-p-tyrosine (2.5 and 200 mg kg−1 i.p., 24 and 3 h before the test, respectively) induced a marked akinesia in mice. This effect was significantly and dose-dependently reversed by the methylxanthine, caffeine. The anti-akinetic effect of caffeine within a pattern of catecholamine depletion has been interpreted as a dopamine mimetic activity of this drug. The possible involvement of the adenosine system in this effect of caffeine is discussed.
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The reproducibility and validity of responses for 55 specific foods and beverages on a self-administered food frequency questionnaire were evaluated. One hundred and seventy three women from the Nurses' Health Study completed the questionnaire twice approximately 12 months apart and also recorded their food consumption for seven consecutive days, four times during the one-year interval. For the 55 foods, the mean of correlation coefficients between frequencies of intake for first versus second questionnaire was 0.57 (range = 0.24 for fruit punch to 0.93 for beer). The mean of correlation coefficients between the dietary records and first questionnaire was 0.44 (range = 0.09 for yellow squash to 0.83 for beer and tea) and between the dietary records and the second questionnaire was 0.52 (range = 0.08 for spinach to 0.90 for tea). Ratios of within- to between-person variance for the 55 foods were computed using the mean four one-week dietary records for each person as replicate measurements. For most foods this ratio was greater than 1.0 (geometric mean of ratios = 1.88), ranging from 0.25 (skimmed milk) to 14.76 (spinach). Correlation coefficients comparing questionnaire and dietary record for the 55 foods were corrected for the within-person variation (mean corrected value = 0.55 for dietary record versus first questionnaire and 0.66 versus the second). Mean daily amounts of each food calculated by the questionnaire and by the dietary record were also compared; the observed differences suggested that responses to the questionnaire tended to over-represent socially desirable foods. This analysis documents the validity and reproducibility of the questionnaire for measuring specific foods and beverages, as well as the large within-person variation for food intake measured by dietary records. Differences in the degree of validity for specific foods revealed in this type of analysis can be useful in improving questionnaire design and in interpreting findings from epidemiological studies that use the instrument.
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The purpose of this study was to examine whether caffeine stimulates dopamine (DA) receptors. The effects of caffeine on the binding of [3H]spiperone to membranes from the striatum, accumulation of L-DOPA in the striatum in mice receiving gamma-butyrolactone, and regional levels of 3,4-dihydroxyphenylacetic acid in the brain of the rat were investigated and compared with those elicited by DA receptor agonists. Caffeine did not inhibit the binding of [3H]spiperone to membranes or the accumulation of L-DOPA in the striatum, produced by gamma-butyrolactone. Caffeine decreased the levels of 3,4-dihydroxyphenylacetic acid significantly in the striatum, olfactory tubercle and nucleus accumbens and slightly in the frontal cortex of rats, whereas it delayed utilization of DA in all those regions except the frontal cortex. Taken together these results suggest that caffeine fails to stimulate pre- or postsynaptic DA receptors. The possible mechanism by which caffeine mimics DA receptor in DA metabolism and behavior are discussed.
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The aim of this study was to evaluate the reproducibility and validity of a 61-item semiquantitative food frequency questionnaire used in a large prospective study among women. This form was administered twice to 173 participants at an interval of approximately one year (1980-1981), and four one-week diet records for each subject were collected during that period. Intraclass correlation coefficients for nutrient intakes estimated by the one-week diet records (range = 0.41 for total vitamin A without supplements to 0.79 for vitamin B6 with supplements) were similar to those computed from the questionnaire (range = 0.49 for total vitamin A without supplements to 0.71 for sucrose), indicating that these methods were generally comparable with respect to reproducibility. With the exception of sucrose and total carbohydrate, nutrient intakes from the diet records tended to correlate more strongly with those computed from the questionnaire after adjustment for total caloric intake. Correlation coefficients between the mean calorie-adjusted intakes from the four one-week diet records and those from the questionnaire completed after the diet records ranged from 0.36 for vitamin A without supplements to 0.75 for vitamin C with supplements. Overall, 48% of subjects in the lowest quintile of calorie-adjusted intake computed from the diet records were also in the lowest questionnaire quintile, and 74% were in the lowest one of two questionnaire quintiles. Similarly, 49% of those in the highest diet record quintile were also in the highest questionnaire quintile, and 77% were in the highest one or two questionnaire quintiles. These data indicate that a simple self-administered dietary questionnaire can provide useful information about individual nutrient intakes over a one-year period.
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It is suggested here that in most cases of Parkinson's disease the cause may be an environmental factor, possibly toxic, superimposed on a background of slow, sustained neuronal loss due to advancing age.
Article
Four persons developed marked parkinsonism after using an illicit drug intravenously. Analysis of the substance injected by two of these patients revealed primarily 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) with trace amounts of 1-methyl-4-phenyl-4-propionoxy-piperidine (MPPP). On the basis of the striking parkinsonian features observed in our patients, and additional pathological data from one previously reported case, it is proposed that this chemical selectively damages cells in the substantia nigra.
Article
Few food frequency questionnaires have been evaluated for their ability to assess intakes of individual foods that may be related to disease independently of their nutrient content. The reproducibility and validity of food intake measurements by a 131-item semiquantitative food frequency questionnaire were evaluated in a sample of 127 men from the Health Professionals Follow-up Study, a large longitudinal study of diet and disease. Each subject completed two questionnaires 1 year apart and two 1-week diet records 6 months apart during the intervening year. Pearson correlations assessing reproducibility between food intakes from the two questionnaires ranged from .31 for pie to .92 for coffee (mean = .59). Validity was measured by comparing food intakes from the second questionnaire with those from the diet records. Pearson correlations corrected for within-person weekly variation in diet record data ranged from .17 for other nuts to .95 for bananas (mean = .63). Large within-person variation precluded the calculation of accurate validity correlations for 29 foods. As we previously observed in women, the foods most often overreported were fruits and vegetables, and meats and dairy products were most often underreported. With few exceptions, reasonable levels of reproducibility and validity were observed for intake of individual foods in this extensive food frequency questionnaire.
Article
To determine patterns of lifetime caffeinated and decaffeinated coffee use, focusing on frequency and determinants for curtailing caffeinated coffee. Residents of Rancho Bernardo, a white, upper-middle class Southern California community, were surveyed about their lifetime coffee-drinking behavior; completed questionnaires were received from 69% (n = 2955; mean age was 64 years, age range: 30-105 years). Chi-square tests of differences between proportions in categorical data and t-tests for continuous data were used. Due to the large number of comparisons, statistical significance was defined as p<or=0.01. Respondents began drinking caffeinated coffee around age 20, and decaffeinated coffee around age 50. A few gender-related differences were observed; more women than men curtailed caffeinated coffee (p<0.001), or did so due to sleep problems (p<0.01), while more men curtailed coffee because their spouses stopped drinking it (p<0.001). Most who curtailed caffeinated coffee did so on their own initiative (80% for health concerns); but only 10% of coffee drinkers curtailed caffeinated coffee on advice of a physician. Past combined intake of caffeinated and decaffeinated coffees approached >or=5 cups/day only in those who curtailed caffeinated coffee on advice of a physician or for heart/circulatory problems. Curtailing of caffeinated coffee in this adult cohort was primarily due to health concerns, but few of those who curtailed caffeinated coffee attribute the change to the advice of a physician.
Article
There is now good reason to believe that blockade of the adenosine A2A receptor could be of value in the treatment of Parkinson's disease. Peter J. Richardson, Hiroshi Kase and Peter G. Jenner review the actions of this receptor in the striatum, emphasizing its ability to modulate the neuronal activity of striatal GABA-releasing output neurones, and showing that recently developed A2A receptor antagonists are capable of reducing the disabling effects of nigral cell degeneration in primates. They conclude that such antagonists may be useful as novel therapeutic agents for the treatment of Parkinson's disease.
Article
Both adenosine A1 and A2 receptor populations are located in the striatum and can modify locomotor activity, and they may form a therapeutic target for Parkinson's disease (PD). Administration of the selective adenosine A2A antagonist (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-pu rine-2,6-dione (KW-6002) to MPTP-treated common marmosets increased locomotor activity. In contrast, administration of the selective A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxantine (DPCPX) had no effect on locomotion. Administration of the adenosine A2A receptor agonist 2-[p-[2-(2-aminoethylamino) carbonylethyl] phenethyl amino]-5'-N-ethylcarboxamidoadenosine (APEC) dose dependently suppressed basal locomotor activity. A minimally effective dose of APEC (0.62 mg/kg, i.p) completely reversed the increase in locomotor activity produced by administration of KW-6002. The adenosine A2A receptor appears to be an important target for the treatment of basal ganglia disorders, particularly PD.
Article
To investigate the possible impact of nutritional and environmental risk factors for idiopathic Parkinson's disease (IP), a case-control study was performed in the county of Ostergötland in southeastern Sweden. The study involved 113 cases of IP and 263 control subjects. Dietary, drinking, and smoking habits, as well as previous occupation, were requested in a structured questionnaire. No increased risk was found for any of the nutritional items in which information was requested. A reduced risk was found for coffee, wine, and liquor at various consumption levels but also for fried or broiled meat, smoked ham or meat, eggs, French loaf or white bread, and tomatoes. All these food and drink items contain niacin. As in many studies, the frequency of preceding and present smoking was reduced in IP patients. Various occupational groups and exposures were analyzed and increased risks of IP in men were found for agricultural work along with pesticide exposure; this was also the case for male carpenters and female cleaners. The findings indicate that nutritional factors and occupational exposures, especially to pesticides, could be of etiologic importance in IP.
Article
Previous cohort studies of fat intake and risk of coronary heart disease (CHD) have been inconsistent, probably due in part to methodological differences and various limitations, including inadequate dietary assessment and incomplete adjustment for total energy intake. The authors analyzed repeated assessment of diet from the Nurses' Health Study to examine the associations between intakes of four major types of fat (saturated, monounsaturated, polyunsaturated, and trans fats) and risk of CHD during 14 years of follow-up (1980-1994) by using alternative methods for energy adjustment. In particular, the authors compared four risk models for energy adjustment: the standard multivariate model, the energy-partition model, the nutrient residual model, and the multivariate nutrient density model. Within each model, the authors compared four different approaches for analyzing repeated dietary measurements: baseline diet only, the most recent diet, and two different algorithms for calculating cumulative average diets. The substantive results were consistent across all models; that is, higher intakes of saturated and trans fats were associated with increased risk of CHD, while higher intakes of monounsaturated and polyunsaturated fats were associated with reduced risk. When nutrients were considered as continuous variables, the four energy-adjustment methods yielded similar associationS. However, the interpretation of the relative risks differed across models. In addition, within each model, the methods using the cumulative averages in general yielded stronger associations than did those using either only baseline diet or the most recent diet. When the nutrients were categorized according to quintiles, the residual and the nutrient density models, which gave similar results, yielded statistically more significant tests for linear trend than did the standard and the partition models.
Article
The etiology of Parkinson's disease has been enigmatic to clinicians, epidemiologists, and basic scientists since the clinical syndrome was first described in 1817. Mendelian inheritance probably accounts for a small proportion of Parkinson's disease. Apart from an increasing risk with age, the most consistent epidemiologic observation has been an inverse relation with cigarette smoking. Neither selective survival of nonsmokers nor behavioral characteristics of smokers can explain this seemingly protective association. Interest in environmental exposures, particularly pesticides, metals, and industrial solvents, heightened substantially following the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a street drug contaminant, as a cause of human parkinsonism. Epidemiologic and toxicologic research has since been guided to a great extent, although not exclusively, by mechanisms of MPTP toxicity. Efforts to characterize gene/environment interactions have also intensified in recent years. In this review, we evaluate recent evidence concerning the etiology of Parkinson's disease, with emphasis on environmental and lifestyle exposures and their potential interactions with genetic susceptibility traits. The most challenging aspects of epidemiologic research into Parkinson's disease causation include methodologic difficulties surrounding case definition, completeness of case ascertainment, selection of appropriate controls in case-control studies, and assessment of environmental exposures. We conclude with recommendations for future research directions.
Article
To study the association of PD with preceding smoking, alcohol, and coffee consumption using a case-control design. The authors used the medical records linkage system of the Rochester Epidemiology Project to identify 196 subjects who developed PD in Olmsted County, MN, during the years 1976 to 1995. Each incident case was matched by age (+/-1 year) and sex to a general population control subject. The authors reviewed the complete medical records of cases and control subjects to abstract exposure information. For coffee consumption, the authors found an OR of 0.35 (95% CI = 0.16 to 0.78, p = 0.01), a dose-effect trend (p = 0.003), and a later age at PD onset in cases who drank coffee compared with those who never did (median 72 versus 64 years; p = 0.0002). The inverse association with coffee remained significant after adjustment for education, smoking, and alcohol drinking and was restricted to PD cases with onset at age <72 years and to men. The OR for cigarette smoking was 0.69 (95% CI = 0.45 to 1.08, p = 0.1). The authors found no association between PD and alcohol consumption. Extreme or unusual behaviors such as tobacco chewing or snuff use and a diagnosis of alcoholism were significantly more common in control subjects than cases. These findings suggest an inverse association between coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered.
Article
NMDA receptors (NMDARs) are highly calcium-permeable and are negatively regulated by intracellular calcium during prolonged exposure to agonist. We have investigated whether calcium-mediated feedback occurs during transient exposure to glutamate during single synaptic events. Examination of miniature EPSCs (mEPSCs) indicated that the decay kinetics of the NMDAR component was markedly slowed by the intracellular perfusion of exogenous calcium buffers (BAPTA or Fluo-3). In contrast, the AMPA receptor component of the miniature EPSC was unaffected. Slow on-rate calcium buffers, such as EGTA, did not alter kinetics of the NMDAR component of the mEPSC. Addition of exogenous fast calcium buffers did not slow the decay kinetics of glutamate-evoked currents mediated by NR1/NR2A heteromers expressed in HEK 293 cells, suggesting that the effect we observed in neurons may be specific to processes associated with synaptically activated receptors. Trial-to-trial amplitude variability of miniature calcium transients mediated by NMDARs increased with the injection of exogenous calcium buffers, suggesting that the amplitude of synaptic calcium transients are maintained at a rather constant level by a calcium-mediated feedback mechanism.
Article
Recent epidemiological studies have established an association between the common consumption of coffee or other caffeinated beverages and a reduced risk of developing Parkinson's disease (PD). To explore the possibility that caffeine helps prevent the dopaminergic deficits characteristic of PD, we investigated the effects of caffeine and the adenosine receptor subtypes through which it may act in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin model of PD. Caffeine, at doses comparable to those of typical human exposure, attenuated MPTP-induced loss of striatal dopamine and dopamine transporter binding sites. The effects of caffeine were mimicked by several A(2A) antagonists (7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine (SCH 58261), 3,7-dimethyl-1-propargylxanthine, and (E)-1,3-diethyl-8 (KW-6002)-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione) (KW-6002) and by genetic inactivation of the A(2A) receptor, but not by A(1) receptor blockade with 8-cyclopentyl-1,3-dipropylxanthine, suggesting that caffeine attenuates MPTP toxicity by A(2A) receptor blockade. These data establish a potential neural basis for the inverse association of caffeine with the development of PD, and they enhance the potential of A(2A) antagonists as a novel treatment for this neurodegenerative disease.
Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's dis-ease
  • Richardson Pj H Kase
  • Jenner
Richardson PJ, Kase H, Jenner PG. Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's dis-ease. Trends Pharmacol Sci 1997;18:338 –344.
Reproducibil-ity and validity of a expanded self-administered semiquantita-tive food frequency questionnaire among male health profes-sionals
  • Rimm Eb Giovannucci El
  • Stampfer
  • Mj
Rimm EB, Giovannucci EL, Stampfer MJ, et al. Reproducibil-ity and validity of a expanded self-administered semiquantita-tive food frequency questionnaire among male health profes-sionals. Am J Epidemiol 1992;135:1114 –1126.
Caffeine and the central ner-Fig
  • J-L A Nehlig
  • Debry
Nehlig A, Daval J-L, Debry G. Caffeine and the central ner-Fig
Nutritional and occupational factors influencing the risk of Parkinson's disease: a case-control study in southeastern Sweden
  • Fall
Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements (see comments)