Article

Caffeine in Parkinson's Disease: A Pilot Open-Label, Dose-Escalation Study

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Abstract

Epidemiologic studies consistently find an inverse association between caffeine use and PD. Numerous explanations exist, but are difficult to evaluate as caffeine's symptomatic effect and tolerability in PD are unknown. We designed an open-label, 6-week dose-escalation study of caffeine to establish dose tolerability and evaluate potential motor/nonmotor benefits. Caffeine was started at 200 mg daily and was increased to a maximum of 1,000 mg. Of 25 subjects, 20 tolerated 200 mg, 17 tolerated 400 mg, 7 tolerated 800 mg, and 3 tolerated 1,000 mg. The most common adverse events were gastrointestinal discomfort, anxiety, and worsening/emerging tremor. At 400 mg daily, we found potential improvements in motor manifestations and somnolence (UPDRS III: -4.5 ± 4.6, P = 0.003; Epworth: -2.0 ± 3.0, P = 0.015). Maximum dose tolerability for caffeine in PD appears to be 100 to 200 mg BID. We found pilot preliminary evidence that caffeine may improve some motor and nonmotor aspects of PD, which must be confirmed in longer term, placebo-controlled, clinical trials.

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... The full texts of the remaining 92 potentially related studies were obtained. Eighty-eight studies were excluded because of not meeting the inclusion criteria, and the remaining four papers (18)(19)(20)(21) were included in the study. The PRISMA flowchart of the study is shown in Figure 1. ...
... Sample sizes varied from 25 to 61 participants. Of the four included studies, two were RCTs (19,21), and two were non-randomized single-arm studies (18,20). In these four studies, caffeine was evaluated separately and was compared with placebo in the RCTs (19,21). ...
... The treatment duration in studies varied from five days to 18 months (18)(19)(20)(21). The primary outcome of all studies was the effect of caffeine on ESS and UPDRS. ...
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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.
... Third, there is preliminary evidence that caffeine may improve motor manifestations. 2,3 Motor benefit of caffeine is consistent with numerous studies in PD animal models, with human studies documenting benefit from other adenosine 2A antagonists, 4 -7 and with a recent openlabel dose-escalation pilot study that found caffeine reduced motor manifestations of disease. 2 Therefore, we designed a 6-week randomized placebo-controlled double-blind study of caffeine in PD. The principal aims were as follows: ...
... 2,3 Motor benefit of caffeine is consistent with numerous studies in PD animal models, with human studies documenting benefit from other adenosine 2A antagonists, 4 -7 and with a recent openlabel dose-escalation pilot study that found caffeine reduced motor manifestations of disease. 2 Therefore, we designed a 6-week randomized placebo-controlled double-blind study of caffeine in PD. The principal aims were as follows: ...
... Sample size calculations were based on previous clinical trials using the ESS in PD [13][14][15] and assessing motor effects. 2 To obtain power Ն0.80, we calculated that 36 patients (18 each group) were needed to detect a change of 3 Ϯ 2 points in the ESS (significance level ϭ 0.05), and 52 patients (26 in each group) would detect a UPDRS part III change of 4 Ϯ 5 points. To account for potential dropout and deviation of standard error from assumptions, 15% over requirements were recruited. ...
Article
Epidemiologic studies consistently link caffeine, a nonselective adenosine antagonist, to lower risk of Parkinson disease (PD). However, the symptomatic effects of caffeine in PD have not been adequately evaluated. We conducted a 6-week randomized controlled trial of caffeine in PD to assess effects upon daytime somnolence, motor severity, and other nonmotor features. Patients with PD with daytime somnolence (Epworth >10) were given caffeine 100 mg twice daily ×3 weeks, then 200 mg twice daily ×3 weeks, or matching placebo. The primary outcome was the Epworth Sleepiness Scale score. Secondary outcomes included motor severity, sleep markers, fatigue, depression, and quality of life. Effects of caffeine were analyzed with Bayesian hierarchical models, adjusting for study site, baseline scores, age, and sex. Of 61 patients, 31 were randomized to placebo and 30 to caffeine. On the primary intention-to-treat analysis, caffeine resulted in a nonsignificant reduction in Epworth Sleepiness Scale score (-1.71 points; 95% confidence interval [CI] -3.57, 0.13). However, somnolence improved on the Clinical Global Impression of Change (+0.64; 0.16, 1.13, intention-to-treat), with significant reduction in Epworth Sleepiness Scale score on per-protocol analysis (-1.97; -3.87, -0.05). Caffeine reduced the total Unified Parkinson's Disease Rating Scale score (-4.69 points; -7.7, -1.6) and the objective motor component (-3.15 points; -5.50, -0.83). Other than modest improvement in global health measures, there were no changes in quality of life, depression, or sleep quality. Adverse events were comparable in caffeine and placebo groups. Caffeine provided only equivocal borderline improvement in excessive somnolence in PD, but improved objective motor measures. These potential motor benefits suggest that a larger long-term trial of caffeine is warranted. Classification of evidence: This study provides Class I evidence that caffeine, up to 200 mg BID for 6 weeks, had no significant benefit on excessive daytime sleepiness in patients with PD.
... If caffeine is protective via adenosine receptors, it should also be determined whether it has beneficial effects in patients with established PD. In the Harvard Biomarkers Study, a longitudinal study involving 369 patients with PD -of whom 97 were de novo patients -and 197 healthy controls, high caffeine consumption resulted in a delayed need to start levodopa therapy [29] . Patients consumed an average of 296 mg of caffeine per day, and those who consumed less caffeine had a higher prevalence of PD and more rapid disease progression. ...
... Altmanet al., 2011 [30] Caffeine improved both motor and non-motor symptoms in PD patients Bakshiet al., 2020 [29] Harvard Biomarkers Study ...
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Parkinson’s disease (PD) is the second most common neurodegenerative disorder. It is generally accepted that dopamine replacement therapy substantially improves motor symptoms; however, there is a worldwide tendency to include nutrients in treatment strategies. In the present review, caffeine and chocolate are discussed. Caffeine use seems to postpone the occurrence of PD in men, and perhaps also in women who do not take postmenopausal hormone replacement therapy. There are contradictory data concerning possible caffeine-induced improvements in PD symptoms. Given that the basic action of caffeine is the antagonism of adenosine receptors, adenosine antagonists may be a new option for treating PD patients. Furthermore, PD patients tend to have increased chocolate consumption; this may be causally related to ingredients such as phenylethylamine. Thus, nutrients such as caffeine and chocolate may play an important role in postponing and/or improving symptoms in PD.
... In 2011, Altman et al. [250] demonstrated that caffeine may have positive effects on some motor as well as nonmotor aspects in patients suffering from Parkinson's disease. Moreover, the maximum tolerated dose of caffeine in Parkinson's disease subjects was 200-400 mg/day [250]. ...
... In 2011, Altman et al. [250] demonstrated that caffeine may have positive effects on some motor as well as nonmotor aspects in patients suffering from Parkinson's disease. Moreover, the maximum tolerated dose of caffeine in Parkinson's disease subjects was 200-400 mg/day [250]. A year later, Postuma et al. [251] in a randomized, controlled trial showed that administration of caffeine at a dose of 200 mg/day for 3 weeks followed by a further 3 weeks at a dose of 400 mg/day significantly improved the overall unified Parkinson's disease rating scale and motor manifestation (by 4.7 and 3.2 points, respectively). ...
Article
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Coffee is one of the most widely consumed beverages worldwide. It is usually identified as a stimulant because of a high content of caffeine. However, caffeine is not the only coffee bioactive component. The coffee beverage is in fact a mixture of a number of bioactive compounds such as polyphenols, especially chlorogenic acids (in green beans) and caffeic acid (in roasted coffee beans), alkaloids (caffeine and trigonelline), and the diterpenes (cafestol and kahweol). Extensive research shows that coffee consumption appears to have beneficial effects on human health. Regular coffee intake may protect from many chronic disorders, including cardiovascular disease, type 2 diabetes, obesity, and some types of cancer. Importantly, coffee consumption seems to be also correlated with a decreased risk of developing some neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and dementia. Regular coffee intake may also reduce the risk of stroke. The mechanism underlying these effects is, however, still poorly understood. This review summarizes the current knowledge on the neuroprotective potential of the main bioactive coffee components, i.e., caffeine, chlorogenic acid, caffeic acid, trigonelline, kahweol, and cafestol. Data from both in vitro and in vivo preclinical experiments, including their potential therapeutic applications, are reviewed and discussed. Epidemiological studies and clinical reports on this matter are also described. Moreover, potential molecular mechanism(s) by which coffee bioactive components may provide neuroprotection are reviewed.
... Caffeine, a nonselective antagonist of adenosine receptors, has been known to decrease the risk of PD [74], with a greater reduction of the PIGD subtype risk when compared to the TD subtype [12,75,76]. Hence, caffeine has also been used in clinical trials to treat imbalance. ...
... Hence, caffeine has also been used in clinical trials to treat imbalance. Escalating the dose of caffeine over a period of six weeks showed a significant improvement of motor symptoms as measured in terms of the UPDRS score [75,76]. Long-term randomized control trials in the future can help tap the therapeutic benefits of caffeine. ...
Article
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Parkinson’s disease (PD) is a heterogeneous progressive neurodegenerative disorder, which typically affects older adults; it is predicted that by 2030 about 3% of the world population above 65 years of age is likely to be affected. At present, the diagnosis of PD is clinical, subjective, nonspecific, and often inadequate. There is a need to quantify the PD factors for an objective disease assessment. Among the various factors, postural instability (PI) is unresponsive to the existing treatment strategies resulting in morbidity. In this work, we review the physiology and pathophysiology of postural balance that is essential to treat PI among PD patients. Specifically, we discuss some of the reported factors for an early PI diagnosis, including age, nervous system lesions, genetic mutations, abnormal proprioception, impaired reflexes, and altered biomechanics. Though the contributing factors to PI have been identified, how their quantification to grade PI severity in a patient can help in treatment is not fully understood. By contextualizing the contributing factors, we aim to assist the future research efforts that underpin posturographical and histopathological studies to measure PI in PD. Once the pathology of PI is established, effective diagnostic tools and treatment strategies could be developed to curtail patient falls.
... As a possible explanation, the premorbid personality of PD patients might cause a reduced use of caffeine containing products, although a direct relationship cannot be excluded, since caffeine has recently been suggested to have symptomatic and, possibly, neuroprotective effects on the degeneration of dopaminergic neurons [1,2]. Accordingly, the use of caffeine seems to affect positively motor and non-motor symptoms (NMS) of PD [3,4], although the inclusion of populations with heterogeneous disease duration and characteristics has led to somewhat contradictory results across different studies [2]. This might be due also to the methods for assessing caffeine consumption, with most studies focusing either on coffee or tea, whereas multiple caffeine sources should have been included [5]. ...
... With regard to motor symptoms, a higher use of caffeine containing products was associated with lower motor disturbances during the entire study period, suggesting that caffeine consumption might have a symptomatic effect or, ideally, might delay motor disability. Accordingly, there is Class II evidence that motor function in PD can be improved by caffeine [3], and, hence, targeting caffeine pathways is a promising strategy for developing new anti-parkinsonian drugs [4]. Nevertheless, the present study showed for the first time that PD patients with higher caffeine consumption presented a reduced need for dopaminergic treatment and, to be more precise, of L-Dopa, an early marker of motor impairment and disability progression [8]. ...
Article
Introduction: Higher caffeine consumption has been associated with reduced risk of Parkinson's disease (PD), and with a more benign progression of motor and non-motor symptoms (NMS). The present observational cohort study investigated motor and non-motor correlates of caffeine consumption in de novo PD. Methods: 79 newly diagnosed, drug naïve PD patients have been included and followed up for 4 years. The total caffeine use was calculated with the Caffeine Consumption Questionnaire. Following study variables were recorded at baseline, and after 2 and 4 years: UPDRS part III, UPDRS part IV, l-dopa Equivalent Daily Dose (LEDD), NMS Questionnaire (NMSQuest), and the time occurring from PD diagnosis to the need for l-dopa treatment. Age, gender and disease duration were included as covariates in the statistical models. Results: The average daily caffeine consumption was 296.1 ± 157.2 mg. At Cox regression models, higher caffeine consumption was associated with a lower rate of starting l-Dopa treatment (HR = 0.630; 95%CI = 0.382-0.996). At the mixed-effects linear regression models considering the whole study period, each additional espresso cup per day (50 mg of caffeine) was more likely associated with 5-point lower UPDRS part III total score (Coef = -0.01; 95%CI = -0.02 to 0.00), with 50% reduced LEDD (Coef = -0.01; 95%CI = -0.15 to 0.00; p = 0.021), and with 5-point lower NMSQuest total score (Coef = -0.01; 95%CI = -0.01 to 0.00), but not with UPDRS part IV total score (Coef = -0.00; 95%CI = -0.00 to 0.00). Conclusion: Caffeine consumption was associated with a reduced accrual of motor and non-motor disability during 4-year follow-up in de novo PD, highlighting the rationale for using adenosine A2A antagonists since the early phases of PD.
... It is a bioactive component of coffee which is one of the world most consumed beverages. Several clinical trials and metaanalysis studies have shown that its consumption is associated to a lower risk of Parkinson's disease development [5][6][7][8][9][10]. Coffee is a major source of dietary antioxidants and has been shown to inhibit inflammation, thereby reducing the risk of cardiovascular and other inflammatory diseases in postmenopausal women [11]. ...
... A great number of studies, carried out in the last decade and also earlier, points out to the beneficial effect of coffee consumption in PD prevention [6][7][8]10,55,66,67]. These studies showed an inverse association between coffee consumption and PD and most of them present evidences that caffeine can improve motor and non-motor symptoms of PD. ...
... Current clinical benefits of caffeine have been demonstrated in the treatment of several diseases in patients such as Parkinson's disease (PD) and sleep-apnea of prematurity. Caffeine was shown to negatively associate with the risk of developing PD and clinical trials reports that PD patients who received caffeine treatment showed motor-and nonmotorassociated improvements [14][15][16]. Other disease in which caffeine exerts positive effects includes stroke, traumatic brain injury, Alzheimer's disease, Huntington's disease and multiple sclerosis [17]. ...
... In the case of PD, the maximum tolerability dose of caffeine was reported to be 100 to 200 mg bis in diem (i.e. twice a day) [15]. In this current study, medium dose (2.5 mM) of caffeine treatment in colitic mice is effective in suppressing CHI3L1 expression accompanied by an ameliorative effect on colitis phenotype. ...
Article
The initial trigger of inflammatory bowel disease (IBD) can be partly attributed towards the interaction and invasion of intestinal epithelial cells (IECs) and submucosal compartments. Identifying safe and economical methods to block these interactions may help prevent the onset of early colitis. Chitinase 3-like 1 (CHI3L1) is an inducible host protein that facilitates bacterial attachment and invasion on/into IECs. Therefore, we test the hypothesis of inhibiting CHI3L1 using the pan-chitinase inhibitor caffeine to reduce the likelihood of early colitis onset. IEC lines were treated with caffeine (2.5 or 5 mM) and analyzed for CHI3L1 expression and the impact on bacterial invasion. In vivo, mice were treated with 2.5 mM caffeine and induced with 3.5 % dextran sulfate sodium (DSS)-mediated colitis and subsequently analyzed colitis development. In vitro, caffeine treatment in IEC lines down-regulated CHI3L1 mRNA expression, which resulted in the reduction of bacterial invasion in a caffeine dose-dependent manner. In vivo, mice treated with caffeine displayed a delayed response towards DSS-induced colitis, characterized by lower body weight loss, clinical and histological scores. Bacterial translocation into other organs and pro-inflammatory cytokines production were also reduced in the caffeine-treated mice with DSS-induced colitis. Caffeine treatment also resulted in the loss of CHI3L1-associated AKT signaling pathway activation both in vitro and in vivo. Development of acute colitis is reduced upon caffeine treatment. The mechanism involves the down-regulation of CHI3L1 expression and its associated bacterial interaction effect. Therefore, caffeine is proposed as a safe and economical candidate for successful IBD management.
... In patients with Parkinson's disease, consumption of caffeine for 6 weeks in doses of at least 200 mg/day was associated with an improvement in motor symptoms, and a slowing of the progression of dyskinesia was observed [60,61]. Based on these observations, the benefits of caffeine were evaluated in a placebo-controlled phase 3 trial, with no improvement in motor symptoms observed after 6 months of daily consumption of 400 mg of caffeine [62]. ...
Article
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Caffeine is the most frequently used substance with a central nervous system stimulant effect, but its consumption is most often due to the intake of foods and drinks that contain it (coffee, tea, chocolate, food supplements with plant extracts of Guarana, Mate herba, Cola nuts). Due to its innocuity, caffeine is a safe xanthine alkaloid for human consumption in a wide range of doses, being used for its central nervous stimulating effect, lipolytic and diuresis-enhancing properties, but also as a permitted ergogenic compound in athletes. In addition to the mechanisms that explain the effects of caffeine on the targeted organ, there are many proposed mechanisms by which this substance would have antioxidant effects. As such, its consumption prevents the occurrence/progression of certain neurodegenerative diseases as well as other medical conditions associated with increased levels of reactive oxygen or nitrogen species. However, most studies that have assessed the beneficial effects of caffeine have used pure caffeine. The question, therefore, arises whether the daily intake of caffeine from food or drink has similar benefits, considering that in foods or drinks with a high caffeine content, there are other substances that could interfere with this action, either by potentiating or decreasing its antioxidant capacity. Natural sources of caffeine often combine plant polyphenols (phenol-carboxylic acids, catechins) with known antioxidant effects; however, stimulant drinks and dietary supplements often contain sugars or artificial sweeteners that can significantly reduce the effects of caffeine on oxidative stress. The objective of this review is to clarify the effects of caffeine in modulating oxidative stress and assess these benefits, considering the source and the dose administered.
... The symptomatic effect of caffeine in PD was first tested in 1970s (Shoulson and Chase, 1975), but has been revisited by several clinical studies recently. The motor benefit of caffeine were documented in a pilot open-label, 6-week dose-escalation study (Altman et al., 2011) and a 6-week randomized controlled trial of caffeine (200-400 mg daily) involving 61 PD patients (Postuma et al., 2012). These clinical studies suggest that caffeine improved objective motor deficits in PD with the reduced total Unified PD Rating Scale score and the objective motor component. ...
Article
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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.
... Furthermore, caffeine downregulates NO production, inflammatory cytokines and microglial activation [217]. Chronic low doses have been evaluated in clinical trials, witnessing partial, symptomatic relief of bradykinesia, rigidity, freezing and depression [218,219]. Such findings gave new hope to investigate the potential of more selective A2a receptor antagonists, such as istradefylline, as a therapeutic adjunct in PD management, with clinical trials demonstrating a modest amelioration of PD symptoms and levodopa-induced dyskinesias in treated patients [220][221][222]. ...
Article
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Increasing evidence gives support for the idea that extra‐-neuronal factors may affect brain physiology and its predisposition to neurodegenerative diseases. Epidemiological and experimental studies show that nutrition and metabolic disorders such as obesity and type 2 diabetes increase the risk of Alzheimer’s and Parkinson’s diseases after midlife, while the relationship with amyotrophic lateral sclerosis is uncertain, but suggests a protective effect of features of metabolic syndrome. The microbiota has recently emerged as a novel factor engaging strong interactions with neurons and glia, deeply affecting their function and behavior in these diseases. In particular, recent evidence suggested that gut microbes are involved in the seeding of prion‐-like proteins and their spreading to the central nervous system. Here, we present a comprehensive review of the impact of metabolism, diet and microbiota in neurodegeneration, by affecting simultaneously several aspects of health regarding energy metabolism, immune system and neuronal function. Advancing technologies may allow researchers in the future to improve investigations in these fields, allowing the buildup of population‐-based preventive interventions and development of targeted therapeutics to halt progressive neurologic disability.
... Although phase 0, I and II trials are mostly used in relation to testing of pharmaceuticals, these designs (or variants of these designs) often cover exposures falling under EFSA remit. An example of such studies include a phase 0 trial studying the pharmacokinetics of bisphenol-A (V € olkel et al., 2002), a phase I dose escalation trial of caffeine (Altman et al., 2011) andadvantame (Warrington et al., 2011) and in the area of novel foods a phase II trial examining the possible therapeutic effects of flavanol-containing cocoa (Balzer et al., 2008). ...
Article
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Abstract EFSA requested its Scientific Committee to prepare a guidance document on appraising and integrating evidence from epidemiological studies for use in EFSA's scientific assessments. The guidance document provides an introduction to epidemiological studies and illustrates the typical biases of the different epidemiological study designs. It describes key epidemiological concepts relevant for evidence appraisal. Regarding study reliability, measures of association, exposure assessment, statistical inferences, systematic error and effect modification are explained. Regarding study relevance, the guidance describes the concept of external validity. The principles of appraising epidemiological studies are illustrated, and an overview of Risk of Bias (RoB) tools is given. A decision tree is developed to assist in the selection of the appropriate Risk of Bias tool, depending on study question, population and design. The customisation of the study appraisal process is explained, detailing the use of RoB tools and assessing the risk of bias in the body of evidence. Several examples of appraising experimental and observational studies using a Risk of Bias tool are annexed to the document to illustrate the application of the approach. This document constitutes a draft that will be applied in EFSA's assessments during a 1‐year pilot phase and be revised and complemented as necessary. Before finalisation of the document, a public consultation will be launched.
... Considering the clinical use of these drugs for treatment of PD, TCP-FA4, a derivate of tranylcypromine (Desino et al., 2009), flunarizine (Agarwal et al., 1996), and bromocriptine (Friis et al., 1979), have good blood-brain barrier permeability. Caffeine, a nonselective adenosine receptor antagonist, has been reported to lower the risk of PD (Altman et al., 2011;Postuma et al., 2012). Currently, an adenosine A2A receptor antagonist is used as treatment for PD, but A3A-R antagonists have not yet been used. ...
Article
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Parkinson disease (PD) is a neurodegenerative disorder caused by the progressive loss of midbrain dopaminergic neurons, and mitochondrial dysfunction is involved in its pathogenesis. This study aimed to establish an imaging-based, semi-automatic, high-throughput system for the quantitative detection of disease-specific phenotypes in dopaminergic neurons from induced pluripotent stem cells (iPSCs) derived from patients with familial PD having Parkin or PINK1 mutations, which exhibit abnormal mitochondrial homeostasis. The proposed system recapitulates the deficiency of mitochondrial clearance, ROS accumulation, and increasing apoptosis in these familial PD-derived neurons. We screened 320 compounds for their ability to ameliorate multiple phenotypes and identified four candidate drugs. Some of these drugs improved the locomotion defects and reduced ATP production caused by PINK1 inactivation in Drosophila and were effective for idiopathic PD-derived neurons with impaired mitochondrial clearance. Our findings suggest that the proposed high-throughput system has potential for identifying effective drugs for familial and idiopathic PD.
... Several clinical trials and meta-analyzes have showed that caffeine consumption is associated with a decreased risk of developing PD and dementia (Ross, Petrovitch, 2001;Ascherio et al., 2001;Costa et al., 2010;Altman, Lang, Postuma, 2011;Palacios et al., 2012;Liu et al., 2012;Kolahdouzan, Hamadeh, 2017). ...
Article
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The effects of new derivatives of caffeine-8-thioglycolic acid (100 µM) on isolated rat brain synaptosomes, human neuroblastoma cell line SH-SY5Y and human recombinant MAOB enzyme (hMAOB) (1 µM) were evaluated. Most of the compounds, administered alone, didn’t show statistically significant neurotoxic effects on SH-SY5Y, when compared to the control (non-treated cells). Of all studied structures JTA-2Ox, JTA-11, JTA-12 and JTA-13 decreased cell viability. In combination with 6-hydroxydopamine (6-OHDA) (100 µM), only JTA-1 and JTA-2 revealed neuroprotective effects, stronger than those of caffeine. All compounds administered alone revealed, neurotoxic effects on synaptosomes, as compared to non-treated synaptosomes. JTA-1, JTA-2 and JTA-3 showed lowest neurotoxic effects and were investigated in a model of 6-OHDA-induced oxidative stress. In this model of neurotoxicity, only JTA-1 and JTA-2 showed statistically significant neuroprotective effect, by preserving the synaptosomal viability and the level of reduced glutathione. Inhibition of hMAOB, was revealed by JTA-1 and JTA-2. They inhibited the enzyme by 23% and 25% respectively, thus approaching the selegiline activity, which was 42%. The possible mechanisms of neuroprotection of JTA-1 and JTA-2 might be a result from the inhibition of hMAOB, which catalyze the production of neurotoxic p-quinone from 6-OHDA.
... Previous evidence showed that NICO and CAF are negatively related to PD risk and have DA neuron protective potency [25,57]. The NICO and CAF were supposed to protect DA neurons via multiple mechanisms [28][29][30][31][32][33][34][35]. ...
Article
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: Accumulative evidence indicated that the pathologically accumulated metal ions (iron species and Mn3+) and abnormally up-regulated monoamine oxidase B (MAOB) activity induced oxidation of endogenous dopamine (DA) can lead to mitochondria impairment, lysosome dysfunction, proteasome inhibition, and selective DA neuron vulnerability, which is implicated in the pathogenesis of Parkinson’s disease (PD). The DA oxidation can generate deleterious reactive oxygen species (ROS) and highly reactive DA quinones (DAQ) to induce DA-related toxicity, which can be alleviated by DA oxidation suppressors, ROS scavengers, DAQ quenchers, and MAOB inhibitors. On the other hand, the nuclear factor erythroid 2-related factor 2 (Nrf2)-Keap1 and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) anti-oxidative and proliferative signaling pathways play roles in anti-oxidative cell defense and mitochondria biogenesis, which is implicated in DA neuron protections. Therefore, agents with capabilities to suppress DA-related toxicity including inhibition of DA oxidation, scavenge of ROS, detoxification of DAQ, inhibition of MAOB, and modulations of anti-oxidative signaling pathways can be protective to DA neurons. Accumulative evidence shows that tea or coffee consumptions and smoking are related to deceased PD prevalence with unknown mechanisms. In this study, we investigate the protective capabilities of tea polyphenols and other PD relevant agents to inhibit DA-related toxicity and protect against environmental or genetic factors induced DA neuron degeneration in vitro and in vivo. We find that tea polyphenols can significantly suppress DA-related toxicity to protect DA neurons. The tea polyphenols can protect DA neurons via inhibition of DA oxidation, conjugation with DAQ, scavenge of ROS, inhibition of MAOB, and modulations of Nrf2-Keap1 and PGC-1α anti-oxidative signaling pathways. The tea polyphenols with more phenolic hydroxyl groups and ring structures have stronger protective functions. The protective capabilities of tea polyphenols is further strengthened by evidence that phenolic hydroxyl groups can directly conjugate with DAQ. However, GSH and other sulfhydyl groups containing agents have weaker capabilities to abrogate DA oxidation, detoxify ROS and DAQ and inhibit MAOB; whereas nicotine (NICO) and caffeine (CAF) can only modulate Nrf2-Keap1 and PGC-1α pathways to protect DA neurons weakly. The tea polyphenols are identified to protect against overexpression of mutant A30P α-synuclein (α-syn) induced DA neuron degeneration and PD-like symptoms in transgenic Drosophila. Based on achievements from current studies, the excellent and versatile protective capabilities of tea polyphenols are highlighted, which will contribute and benefit to future anti-PD therapy.
... Es gibt verschiedene Hinweise auf eine inverse Beziehung zwischen täglichem Kaffeekonsum und dem reduzierten Risiko für die Entwicklung eines Morbus Parkinson [21,22]. Koffein verbessert offensichtlich motorische Symptome durch eine Antagonisierung von Adenosin-A-Rezeptoren [23][24][25] und wird aufgrund einer jüngsten Untersuchung bereits als möglicher früher Biomarker für das Parkinson-Syndrom diskutiert [26]. ...
Article
Summary: Several studies have shown that coffee drinkers live longer due to having a lower risk of many diseases. The strongest effect is seen for 3–5 cups per day. But the health effects of regular coffee consumption are quite controversial. Depending on the research context, it is either a healthy beverage or in some cases harmful. Coffee is high in antioxidants and linked to a reduced risk of many diseases. However, it also contains the main active compound caffeine, a stimulant that can cause a short-term boost in energy levels, brain function, metabolic rate and exercise performance but various problems in some people as well, especially in those with known cardiovascular risks or diseases. Coffee may lower the risk of type 2 diabetes and is beneficial in blood pressure regulation in the longterm. Coffee drinkers have a significantly lower risk of cirrhosis and liver cancer. The more coffee they drink, the lower the risk. Recently caffeine and metabolites have been detected as reliable biomarkers of early Parkinson disease. Caffeine exposure during gestation may affect the fetal brain and program for behavioral disorders later in life. The review takes a detailed look at regular coffee consumption and its health effects, examining both the pros and cons.
... Recently, istradefylline, an adenosine A 2A receptor antagonist, has been proposed as a new anti-parkinsonian drug (Mizuno et al. 2013). In addition, several reports indicate that caffeine may also improve Parkinsonian symptoms (Altman et al. 2011;Postuma et al. 2012), and that coffee consumption may have protective effects against the development of Parkinson's disease (PD) (Schwarzschild et al. 2002). Furthermore, anti-parkinsonian effects of caffeine have been observed in rat PD models (Herrera-Marschitz et al. 1988, Machado-Filho et al. 2014, which may be explained by the A 2A antagonistic effect of caffeine. ...
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Caffeine, an adenosine receptor antagonist, is known to affect sleep–awake cycles, the stress response, and learning and memory. It has been suggested that caffeine influences synaptic plasticity, but the effects of caffeine on synaptic plasticity in the human brain remain unexplored. The present study aimed to investigate the effects of caffeine on long-term potentiation (LTP)-like effects in the primary motor cortex of healthy humans. Twelve healthy participants (six women and six men; mean age: 44.8 ± 1.5 years) underwent quadripulse magnetic stimulation with an inter-stimulus interval of 5 ms (QPS5) to induce LTP-like effects, 2 h after administration of either a caffeine (200 mg) or placebo tablet in a double-blind crossover design. We recorded motor-evoked potentials (MEPs) before and after QPS5. The degree of MEP enhancement was compared between the placebo and caffeine conditions. Neither active nor resting motor thresholds were influenced by caffeine administration. Following caffeine administration, the degree of potentiation significantly decreased in “significant responders”, whose average MEP ratios were greater than 1.24 in the placebo condition. The observed reduction in potentiation following caffeine administration is consistent with the A2A receptor antagonistic effect of caffeine. This is the first report of an effect of caffeine on neural synaptic plasticity in the human brain, which is consistent with the caffeine-induced plasticity reduction observed in primate studies. Because we studied only a small number of subjects, we cannot firmly conclude that caffeine reduces LTP in humans. The present results will, however, be helpful when considering further or new clinical uses of caffeine.
... Kaffee enthält neben Koffein u. a. Theophylin, verschiedene Flavonoide und Gerbstoffe mit antioxidativem Effekt. In einer offenen Studie mit Parkinsonpatienten verbesserten sich nichtmotorische Symptome ohne Geschlechtsunterschied [33]. In mehreren epidemiologischen Studien fand sich ein größerer Effekt hinsichtlich des MP-Risikos bei Männern [34]. ...
Article
Zusammenfassung Daten aus epidemiologischen Studien, die mögliche Assoziationen bestimmter Nahrungsmittel mit dem Risiko an der Parkinson’schen Krankheit zu erkranken untersucht haben, suggerieren, dass manche Nahrungsmittel, wie z. B. nikotinreiche Paprika, dieses modifizieren können. Auch scheinen nach der Analyse einer Reihe von Medikamenten-Zulassungsstudien positive Effekte auf den Krankheitsverlauf durch Coffein (Kaffee) und höhere Harnsäure-, sowie Gesamtcholesterinspiegel vor allem bei Männern vorhanden zu sein. Noch ist aber ungewiss, ob eine Diät oder besondere diätetische Konzepte und eventuell auch die Auswirkungen der Mikrobiota des Darmes auf den menschlichen Stoffwechsel, eine Rolle für den Krankheitsverlauf spielen könnten. Angesichts fehlender prospektiver Ernährungsstudien können nur allgemeine Empfehlungen gegeben werden: eine „ausgewogene“ saisonal-regional frische Ernährung mit Schwerpunkten auf Gemüse, Obst, Nüssen, Fisch, wenig rotem Fleisch und wenig hochverarbeiteter Nahrung mit nur einem geringen Anteil einfacher Kohlenhydrate könnte hilfreich sein. Speziell für ältere Menschen ist eine eiweißarme Diät nicht sinnvoll. Vielmehr muss, um der Entwicklung von Sarkopenie und Malnutrition im Alter vorzubeugen, besonders auf ausreichende Eiweißzufuhr geachtet werden. Die Versorgung mit den Vitaminen B12 und D3 muss sichergestellt werden – gleichzeitig muss von der unkritischen Anwendung von Nahrungsergänzungsmitteln, insbesondere von Mikronährstoffen mit vermuteten anti-oxidativen Eigenschaften, abgeraten werden.
... Clinically, caffeine appears to improve motor symptoms by antagonizing adenosine 2A receptors (A2A-Rs). [7][8][9] One of the biological effects of caffeine is the nonselective antagonism of A2A-Rs, which is encoded by the A2A-R gene (ADORA2A). Caffeine is primarily metabolized by 2 cytochrome P450 enzymes, cytochrome P450 family 1 subfamily A member 2 (CYP1A2) and cytochrome P450 family 2 subfamily E member 1 (CYP2E1). ...
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Objective: To investigate the kinetics and metabolism of caffeine in serum from patients with Parkinson disease (PD) and controls using liquid chromatography-mass spectrometry. Methods: Levels of caffeine and its 11 metabolites in serum from 108 patients with PD and 31 age-matched healthy controls were examined by liquid chromatography-mass spectrometry. Mutations in caffeine-associated genes were screened by direct sequencing. Results: Serum levels of caffeine and 9 of its downstream metabolites were significantly decreased even in patients with early PD, unrelated to total caffeine intake or disease severity. No significant genetic variations in CYP1A2 or CYP2E1, encoding cytochrome P450 enzymes primarily involved in metabolizing caffeine in humans, were detected compared with controls. Likewise, caffeine concentrations in patients with PD with motor complications were significantly decreased compared with those without motor complications. No associations between disease severity and single nucleotide variants of the ADORA2A gene encoding adenosine 2A receptor were detected, implying a dissociation of receptor sensitivity changes and phenotype. The profile of serum caffeine and metabolite levels was identified as a potential diagnostic biomarker by receiver operating characteristic curve analysis. Conclusion: Absolute lower levels of caffeine and caffeine metabolite profiles are promising diagnostic biomarkers for early PD. This is consistent with the neuroprotective effect of caffeine previously revealed by epidemiologic and experimental studies. Classification of evidence: This study provides Class III evidence that decreased serum levels of caffeine and its metabolites identify patients with PD.
... 5 Moreover, an open-label study of caffeine demonstrated reduced somnolence. 4 This accords with the well-described effects of caffeine in the general population. Therefore, the balance of evidence suggests that caffeine probably has a modest effect on daytime somnolence or the sensation of alertness, which may wear off with prolonged exposure. ...
Article
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Objective: To assess effects of caffeine on Parkinson disease (PD). Methods: In this multicenter parallel-group controlled trial, patients with PD with 1-8 years disease duration, Hoehn & Yahr stages I-III, on stable symptomatic therapy were randomized to caffeine 200 mg BID vs matching placebo capsules for 6-18 months. The primary research question was whether objective motor scores would differ at 6 months (Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale [MDS-UPDRS]-III, Class I evidence). Secondary outcomes included safety and tolerability, motor symptoms (MDS-UPDRS-II), motor fluctuations, sleep, nonmotor symptoms (MDS-UPDRS-I), cognition (Montreal Cognitive Assessment), and quality of life. Results: Sixty patients received caffeine and 61 placebo. Caffeine was well-tolerated with similar prevalence of side effects as placebo. There was no improvement in motor parkinsonism (the primary outcome) with caffeine treatment compared to placebo (difference between groups -0.48 [95% confidence interval -3.21 to 2.25] points on MDS-UPDRS-III). Similarly, on secondary outcomes, there was no change in motor signs or motor symptoms (MDS-UPDRS-II) at any time point, and no difference on quality of life. There was a slight improvement in somnolence over the first 6 months, which attenuated over time. There was a slight increase in dyskinesia with caffeine (MDS-UPDRS-4.1+4.2 = 0.25 points higher), and caffeine was associated with worse cognitive testing scores (average Montreal Cognitive Assessment = 0.66 [0.01, 1.32] worse than placebo). Conclusion: Caffeine did not provide clinically important improvement of motor manifestations of PD (Class I evidence). Epidemiologic links between caffeine and lower PD risk do not appear to be explained by symptomatic effects. Clinicaltrialsgov identifier: NCT01738178. Classification of evidence: This study provides Class I evidence that for patients with PD, caffeine does not significantly improve motor manifestations.
... Although the efficacy of caffeine increased with increasing concentrations of the drug, doses >2 mM were toxic to normal gastric cells (data not shown). Previously, dose-escalation studies have been performed in order to establish potentially suitable oral administration doses for caffeine in clinical treatments or animal experiments (59,60). The relationship between everyday caffeine intake and the risk of cancer is currently undefined (61,62). ...
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Caffeine is one of the most widely consumed substances found in beverages, and has demonstrated anticancer effects in several types of cancer. The present study aimed to examine the anticancer effects of caffeine on gastric cancer (GC) cells (MGC‑803 and SGC‑7901) in vitro, and to determine whether the apoptosis‑related caspase‑9/-3 pathway is associated with these effects. The sustained antiproliferative effects of caffeine on gastric cancer were also investigated. GC cell viability and proliferation were evaluated using cell counting and colony forming assays, following treatment with various concentrations of caffeine. Flow cytometry was performed to assess cell cycle dynamics and apoptosis. Western blot analysis was conducted to detect the activity of the caspase‑9/-3 pathway. The results indicated that caffeine treatment significantly suppressed GC cell growth and viability and induced apoptosis by activating the caspase‑9/-3 pathway. Furthermore, the anticancer effects of caffeine appeared to be sustained, as the caspase‑9/-3 pathway remained active following caffeine withdrawal. In conclusion, caffeine may function as a sustained anticancer agent by activating the caspase‑9/-3 pathway, which indicates that it may be useful as a therapeutic candidate in gastric cancer.
... In a randomized, placebocontrolled, double-blind trial of caffeine administered at the dose of 200 mg twice daily, sleepiness was improved as assessed by the Clinical Global Impression of Change without significant improvements of the ESS score. 93 Sodium oxybate improved the ESS score and increased slow-wave sleep time in an openlabel study of 30 patients with PD. 33 The dose range was 2.25 g twice nightly to 4.5 g twice nightly. The medication was reasonably well tolerated and associated with a mild increase in the apnea-hypopnea index. ...
Article
Parkinson's disease (PD) and multiple system atrophy (MSA) are disorders associated with α synuclein-related neurodegeneration. Nonmotor symptoms are common hallmarks of these disorders, and disturbances of the sleep–wake cycle are among the most common nonmotor symptoms. It is only recently that sleep disturbances have received the attention of the medical and research community. Significant progress has been made in understanding the pathophysiology of sleep and wake disruption in alphasynucleinopathies during the past few decades. Despite these advancements, treatment options are limited and frequently associated with problematic side effects. Further studies that center on the development of novel treatment approaches are very much needed. In this article, the author discusses the current state of the management of disturbed sleep and alertness in PD and MSA. © 2017 International Parkinson and Movement Disorder Society
... In the other two patients studied, the effect was inconclusive, due in one case it only being possible to complete two crossovers, which limited the power of that study. Insomnia and tremor were identified as potential adverse events that should be of special interest in clinical practice or when planning further studies (18). This study is the second (19) to report on a set of n-of-1 trials conducted in PD patients, reinforcing that it is feasible to conduct this type of trial in the PD population. ...
Article
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There is limited information available concerning the treatment of daytime somnolence associated with Parkinson’s disease (PD); the most frequently applied therapeutic strategies include decreasing the dose of dopamine agonists or adding potential wake-promoting agents. There is recent data from a placebo-controlled trial concluding on a non-significant trend in favor of caffeine. We aimed to evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD. To evaluate the efficacy of espresso-coffee in the treatment of daytime somnolence in PD, we have conducted multiple single-patient (n-of-1) clinical trials comparing regular espresso coffee to decaffeinated coffee in PD patients presenting moderate to severe daytime somnolence defined as an Epworth Sleepiness Scale (ESS) score >9. Each single-patient (n-of-1) trial included a sequence of three crossovers (two treatment periods separated by two days of washout). Four patients were included in the studies and three completed the three pairs of treatment periods. In two of the four patients, espresso coffee was considered beneficial. This study concludes that multiple single patient trials are feasible in PD and suggests that espresso-coffee may have a beneficial effect on daytime somnolence in some patients. These results cannot be generalized beyond the patients included in these trials.
... Altman et al. aiming to evaluate tolerability of caffeine by PD patients and its efficacy on alleviating motor and non-motor features of the disease found that 400 mg of caffeine daily could improve motor symptoms and sleep quality, and diminish daytime somnolence. The authors also found higher daily doses of caffeine to be difficult to tolerate by PD patients (Altman et al. 2011). ...
Chapter
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Parkinson's disease (PD)—the second most common neurodegenerative condition worldwide—has no proven neuroprotective intervention. However PD belongs to the ever-growing group of diseases that occur less frequently in coffee-drinkers. Coffee is the major dietary source of caffeine—an adenosine A 2A receptor antagonist. This is presumed to be the main mechanism responsible for the decreased risk of developing PD among coffee drinkers. Furthermore, in view of other biochemical and cellular actions attributed to caffeine, it has been proposed based on basic science results that caffeine may have a neuroprotective role in PD. Animal data is supportive of this hypothesis by showing that caffeine is able to prevent neurode-generation in PD animal models. Still, human data is lacking precluding the establishment of firm conclusions on the role of caffeine as a disease-modifying agent in PD.
... 22 In an open-label 6-week study conducted in 25 PD patients, caffeine 200 mg twice-daily (BID) was found to be well tolerated and to have a beneficial effect on the UPDRS Part III. 23 In a randomized, double-blind, placebo-controlled 6-week study where 200 mg BID caffeine was administered, UPDRS part III score was modestly reduced. ...
Article
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Background Treatment of motor fluctuations in Parkinson's disease (PD) remains an unmet challenge. Adenosine 2A (A2A) receptors are located along the indirect pathway and represent a potential target to enhance l-3,4-dihydroxyphenylalanine (l-DOPA) antiparkinsonian action.Methods This article summarizes the preclinical and clinical literature on A2A antagonists in PD, with a specific focus on their effect on off time, on time, and dyskinesia.FindingsSeveral A2A receptor antagonists have been tested in preclinical studies and clinical trials. In preclinical studies, A2A antagonists enhanced l-DOPA antiparkinsonian action without exacerbating dyskinesia, but A2A antagonists were generally administered in combination with a subthreshold dose of l-DOPA, which is different to the paradigms used in clinical trials, where A2A antagonists were usually added to an optimal antiparkinsonian regimen. In clinical settings, A2A antagonists generally reduced duration of off time, by as much as 25% in some studies. The effect of on time duration is less clear, and in a few studies an exacerbation of dyskinesia was reported. Two A2A antagonists have been tested in phase III settings: istradefylline and preladenant. Istradefylline was effective in two phase III trials, but ineffective in another; the drug has been commercially available in Japan since 2013. In contrast, preladenant was ineffective in a phase III trial and the drug was discontinued. A phase III study with tozadenant will begin in 2015; the drug was effective at reducing off time in a phase IIb study. Other A2A antagonists are in development at the preclinical and early clinical levels.
... tion time [3][4][5]. In addition, recent studies have found that consumption of caffeine could improve the motor manifestations in Parkinson disease [6][7][8][9][10]. However, some studies have reported inconsistent balance control results regarding the effect of caffeine on physical performance. ...
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To evaluate the effect of caffeine on balance control of hemiparetic stroke patients, we investigated the difference in postural stability before and after drinking coffee by observing changes in stability index (SI) from posturography. Thirty patients with history of stroke and 15 age-matched healthy subjects participated in this study. Effect of group factor (of the control and stroke groups) and treatment factor (pre- and post-drinking of coffee) on SI were tested in three conditions: with eyes opened, with eyes closed, and with a pillow support. The effects of these factors on visual deprivation and somatosensory change of subjects were also tested. Under all conditions, SI was higher in the stroke group than in the control group. Under eyes-open condition, the treatment factor was not statistically significant. Under eyes-closed condition, the interaction between group and treatment factor was statistically significant. After the subjects drank coffee, SI in the control group was increased. However, SI in the stroke group was decreased. Under pillow-supported condition, the interaction between group and treatment factor appeared marginally significant. For visual deprivation effect, the interaction between treatment and group factor was statistically significant. After caffeine consumption, the visual deprivation effect was increased in control group but decreased in the stroke group. For somatosensory change effect, the interaction between group and treatment factor was not statistically significant. Postural stability of hemiparetic stroke patients related to somatosensory information was improved after intake of usual dose of caffeine.
... Epidemiological studies have firmly established that coffee drinking is inversely associated with risk of developing Parkinson disease (PD) [1], and clinical trials of caffeine for treatment of PD have shown symptomatic benefit [2][3][4]. Identifying genes that modulate the efficacy of coffee may therefore have pharmacogenomic potential for prevention and treatment. ...
... Together these studies suggest that the beneficial effects of caffeine may be limited to men and post-menopausal women not receiving hormone-replacement therapy. However, an open-label study examining caffeine's symptomatic effects and tolerability in patients demonstrated improved non-motor aspects of PD with no gender differences (Altman et al., 2011). Currently adenosine A 2A antagonists and caffeine are in phase II and III clinical trials for the symptomatic treatment of PD (Barkhoudarian and Schwarzschild, 2011). ...
Article
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Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in ageing individuals. It is now clear that genetic susceptibility and environmental factors play a role in disease etiology and progression. Because environmental factors are involved with the majority of the cases of PD, it is important to understand the role nutrition plays in both neuroprotection and neurodegeneration. Recent epidemiological studies have revealed the promise of some nutrients in reducing the risk of PD. In contrast, other nutrients may be involved with the etiology of neurodegeneration or exacerbate disease progression. This review summarizes the studies that have addressed these issues and describes in detail the nutrients and their putative mechanisms of action in PD.
... It is a bioactive component of coffee which is one of the world most consumed beverages. Several clinical trials and metaanalysis studies have shown that its consumption is associated to a lower risk of Parkinson's disease development5678910. Coffee is a major source of dietary antioxidants and has been shown to inhibit inflammation, thereby reducing the risk of cardiovascular and other inflammatory diseases in postmenopausal women [11]. ...
Data
press as: Filho JAM, et al. Caffeine neuroprotective effects on 6-OHDA-lesioned rats are medi-ated by several factors, including pro-inflammatory cytokines and histone deacetylase inhibitions. Behav Brain Res (2014), j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b b r Research report Caffeine neuroprotective effects on 6-OHDA-lesioned rats are mediated by several factors, including pro-inflammatory cytokines and histone deacetylase inhibitions h i g h l i g h t s • The striatal DA depletion observed in the untreated 6-OHDA group. • The decreased locomotor activity and increased apomorphine-induced behavior. • The decreased immunoreactivity for TH in the striatum of 6-OHDA-lesioned rats. • The increased IL-1beta and TNF-alpha immunoreactivity in the substantia nigra and striatum of 6-OHDA-lesioned rats. • The increased HDAC immunoreactivity in the striatum and CA1 and CA3 areas of the hippocampus of 6-OHDA-lesioned groups. Available online xxx Keywords: Caffeine Neuroprotection Parkinson's disease Pro-inflammatory cytokine 6-OHDA model Behavior a b s t r a c t Several lines of evidences have shown the inversion association between coffee consumption and Parkin-son's disease (PD) development. Caffeine is a methylxanthine known as a non-selective inhibitor of A2A and A1 adenosine receptors in the brain and shown to be a neuroprotective drug. The objectives were to study caffeine effects in a unilateral 6-OHDA model of PD in rats. Male rats were divided into the following groups: sham-operated (SO), striatal 6-OHDA-lesioned and 6-OHDA-lesioned and treated for 2 weeks with caffeine (10 and 20 mg/kg, p.o.). Then, animals were subjected to behavioral (open field and apomorphine-induced rotations), neurochemical (striatal determinations of DA and DOPAC), histo-logical (cresyl violet staining) and immunohistochemical (TH, TNF-␣, IL-1␤ and HDAC) evaluations. The results showed that while the 6-OHDA group presented a decreased locomotor activity and a high num-ber of apomorphine-induced rotations, these behaviors were partially blocked by caffeine. Caffeine itself increased DA contents and reversed the decrease in striatal DA observed in the 6-OHDA-lesioned group. Furthermore, it improved the hippocampal neuronal viability and significantly increased TH immunore-activity in the striatum of the 6-OHDA-lesioned group. In addition, caffeine treatment also decreased the number of immunopositive cells for HDAC and pro-inflammatory cytokines TNF-␣ and IL-1␤. All these effects points out to a neuroprotective effect of caffeine and its potential benefit in the prevention and treatment of PD.
... Epidemiological data suggest that dementia (AD in particular) risk is reduced in coffee (Coffea arabica L. [Rubiaceae])/caffeine (59) drinkers, compared with no or low coffee intake [186][187][188], although other studies do not support this conclusion since any protective effect of coffee or caffeine consumption against AD was not evident [189,190]. Studies also suggest a high intake of coffee or caffeine is associated with a lower incidence of PD [2,191], and an open-label pilot study with 25 PD subjects also indicated caffeine may improve some motor and nonmotor symptoms of PD [192]. Any effect of coffee on neurodegenerative disease risk therefore requires further evaluation, and the phytochemicals in coffee that might contribute to such an effect would also need to be assessed. ...
Chapter
Neurodegenerative diseases include a range of disorders that involve dysfunction of the central nervous system, due to degeneration of neurons and associated pathological processes. These diseases include Lewy body dementia, vascular dementia, Huntington’s, Parkinson’s (PD), and Alzheimer’s diseases (AD). Treatment strategies are limited and frequently only provide symptomatic relief through the use of drugs that modulate neurotransmitter disturbances. Of the five drugs developed to treat symptoms of AD, the most common form of dementia, two are derived from plant alkaloids: galantamine, originally from Galanthus woronowii, and rivastigmine, which is based on the chemical structure of physostigmine from Physostigma venenosum. These drugs inhibit acetylcholinesterase to improve cholinergic neuronal dysfunction and the associated cognitive symptoms that occur in AD. Many other alkaloids and their derivatives have been investigated for their ability to modulate cholinergic functions in AD and other dementias. Other alkaloids have been explored as potential treatments for the motor symptoms that occur in PD, via modulation of dopaminergic neurotransmission. Lead compounds for drug discovery include ergot alkaloids from Claviceps purpurea, which provided templates for the development of synthetic drugs such as bromocriptine, used to alleviate PD symptoms. Numerous other alkaloids and their derivatives have been investigated for their ability to alleviate symptoms in neurodegenerative diseases, with some also emerging as disease-modifying agents. Other alkaloids, such as nicotine and caffeine, have been suggested to provide protective effects against the development of some neurodegenerative diseases and are discussed from an epidemiological perspective, with consideration of their mechanistic effects.
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The question whether life style may impair the advent or course of the disease in patients with Parkinsonism is of great importance for patients and physicians alike. We present here comprehensive information on the influence of the environment, diet (especially caffeine, nicotine, alcohol, chocolate and dairy products), physical activity and sleep on risk and course of Parkinson’s disease.
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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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.
Article
The aim of this study was to determine the interactive effect of caffeine and attention focus on the postural stability in subjects with different levels of physical activity. 20 male students were divided into two equal groups (physically active and inactive) by the international physical activity questionnaire. Their postural sways were gathered from a force plate system during two 30-second trials with a 1-minute rest interval with no interventions in the pretest and in internal attention focus (attention to the lower extremity) and external attention focus (attention to a point on the front wall) conditions. On the second day of the experiment, subjects in both groups received 5 mg of caffeine per kg of body weight and the postural stability test was conducted under internal and external attention focus conditions after 30 minutes. The results of ANOVA with repeated measures at α=0.05 showed significant increases in the postural sways of both groups in internal and external conditions. Also, caffeine intervention significantly increased the postural sways of both groups in internal and external conditions. Furthermore, active subjects showed less postural sways in different conditions than the inactive group. Regardless of the focus of attention, caffeine causes more postural sways in both groups with different levels of physical activity through affecting the sympathetic system and increased muscle contractions and tremor. In future studies, other factors such as individual differences in response to caffeine intake or its effect on tasks along with postural disturbances should be considered.
Article
Parkinson's disease (PD) is a neurodegenerative and debilitating disease that affects 1% of elderly population. Patient's motor disability results in an extreme difficulty to deal with daily activities. Conventional treatment is limited to dopamine replacement therapy, which fails to delay disease's progression and is often associated with a number of adverse reactions. Recent progress in understanding the mechanisms involved in PD has revealed new molecular targets for therapeutic approaches. Among them, caffeine and xanthine derivatives are promising drug candidates, because of the possible symptomatic benefits in PD. In fact, consumption of coffee correlates with a reduced risk of PD. Over the last decades, a lot of efforts have been made to uncover the therapeutic potential of xanthine structures. The substituted xanthine molecule is used as a scaffold for the synthesis of new compounds with protective effects in neurodegenerative diseases, including PD, asthma, cancer, and others. The administration of the xanthines has been proposed as a non-dopaminergic strategy for neuroprotection in PD and the mechanisms of protection have been associated with antagonism of adenosine A2A receptors and monoamine oxidase type B (MAO-B) inhibition. The current review summarizes frequently suspected non-dopaminergic neuroprotective mechanisms and the possible beneficial effects of the xanthine derivatives in PD, along with some synthetic approaches to produce perspective xanthine derivatives as non-dopaminergic agents in PD treatment.
Article
Current therapies for Parkinson's disease are problematic because they are symptomatic and have adverse effects. New drugs have failed in clinical trials because of inadequate efficacy. At the core of the problem is trying to make one drug work for all Parkinson's disease patients, when we know this premise is wrong because (1) Parkinson's disease is not a single disease, and (2) no two individuals have the same biological makeup. Precision medicine is the goal to strive for, but we are only at the beginning stages of building the infrastructure for one of the most complex projects in the history of science, and it will be a long time before Parkinson's disease reaps the benefits. Pharmacogenomics, a cornerstone of precision medicine, has already proven successful for many conditions and could also propel drug discovery and improve treatment for Parkinson's disease. To make progress in the pharmacogenomics of Parkinson's disease, we need to change course from small inconclusive candidate gene studies to large-scale rigorously planned genome-wide studies that capture the nuclear genome and the microbiome. Pharmacogenomic studies must use homogenous subtypes of Parkinson's disease or apply the brute force of statistical power to overcome heterogeneity, which will require large sample sizes achievable only via internet-based methods and electronic databases. Large-scale pharmacogenomic studies, together with biomarker discovery efforts, will yield the knowledge necessary to design clinical trials with precision to alleviate confounding by disease heterogeneity and interindividual variability in drug response, two of the major impediments to successful drug discovery and effective treatment. © 2017 International Parkinson and Movement Disorder Society.
Chapter
Parkinson’s disease (PD) is traditionally recognized as a motor disease. However, non-motor symptoms associated with PD are frequent and currently difficult to manage, being reported by patients to represent a significant burden. We now review the ability of adenosine A2A receptor (A2AR) antagonist to attenuate several non-motor PD symptoms including olfactory impairments, anxiety, depression and cognitive deficits. This paves the way to consider A2AR antagonists as novel holistic drugs for PD patients since they not only ameliorate the efficacy of L-DOPA and attenuate its dyskinetic effects, but also afford neuroprotection and attenuate mood and cognitive dysfunctions associated with PD. This clearly prompts the need to detail the underlying mechanisms to understand when and how A2AR should be exploited to maximize benefits for PD patients.
Article
Background: Adenosine A2A receptor antagonists reduce or prevent the development of dyskinesia in animal models of levodopa-induced dyskinesia. Methods: We examined the association between self-reported intake of the A2A receptor antagonist caffeine and time to dyskinesia in the Comparison of the Agonist Pramipexole with Levodopa on Motor Complications of Parkinson's Disease (CALM-PD) and CALM Cohort extension studies, using a Cox proportional hazards model adjusting for age, baseline Parkinson's severity, site, and initial treatment with pramipexole or levodopa. Results: For subjects who consumed >12 ounces of coffee/day, the adjusted hazard ratio for the development of dyskinesia was 0.61 (95% CI, 0.37-1.01) compared with subjects who consumed <4 ounces/day. For subjects who consumed between 4 and 12 ounces/day, the adjusted hazard ratio was 0.73 (95% CI, 0.46-1.15; test for trend, P = .05). Conclusions: These results support the possibility that caffeine may reduce the likelihood of developing dyskinesia.
Article
Neurotransmitters other than dopamine are recognized as having modulatory roles within the basal ganglia and can influence the basal ganglia dopaminergic system to alter activity of the direct and indirect pathways. Many nondopaminergic neurotransmitter systems have been implicated in the mechanisms contributing to the motor features of Parkinson's disease (PD). Thus, it is now well established that neurotransmitter systems, including glutamatergic, GABAergic, cholinergic, noradrenergic, serotonergic, opioidergic, histaminergic, and adenosinergic systems, are affected in the pathogenesis of PD. Nondopaminergic neurotransmitter systems are thus targets for the development of novel therapies for motor symptoms and motor complications in PD. Over the last 5 years, more than 20 randomized, control trials (RCTs) in PD investigating drugs that target several of these nondopaminergic neurotransmitter systems for the treatment of motor features have been completed. There are at least 15 additional RCTs that are ongoing or planned. Here, we review these RCTs to highlight the potential nondopaminergic pharmacological therapies for treatment of motor features of PD. Nondopaminergic drugs are not expected to replace dopaminergic strategies, but further development of these drugs will likely yield novel approaches with positive clinical implications. © 2012 Movement Disorder Society.
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Somnolence is a recognized adverse effect of dopamine agonists. Two new dopamine agonists, pramipexole and ropinirole, have been reported to cause sudden-onset sleep spells in patients with Parkinson disease (PD) while they were driving. The frequency of these spells and whether driving should be restricted has yet to be established. To determine the frequency of and predictors for sudden-onset sleep and, particularly, episodes of falling asleep while driving among patients with PD. Prospective survey conducted between January and April 2000 in 18 clinics directed by members of the Canadian Movement Disorders Group; 638 consecutive highly functional PD patients without dementia were enrolled, of whom 420 were currently drivers. Excessive daytime sleepiness and sudden-onset sleep as assessed by the Epworth Sleepiness Scale and the Inappropriate Sleep Composite Score. The latter score, designed for this study, addressed falling asleep in unusual circumstances. The 2 scales were combined in 3 separate formats: dozing off, sudden unexpected sleep, and sudden blank spells. Excessive daytime sleepiness was present overall in 327 (51%) of the 638 patients and in 213 (51%) of the 420 drivers. Patients taking a variety of different dopamine agonists had no differences in Epworth sleepiness scores, in the composite score, or in the risk of falling asleep while driving. Sixteen patients (3.8%) had experienced at least 1 episode of sudden onset of sleep while driving (after the diagnosis of PD); in 3 (0.7%), it occurred without warning. The 2 risk factors associated with falling asleep at the wheel were the Epworth Sleepiness Scale score (odds ratio [OR], 1.14; 95% confidence interval [CI], 1.06-1.24) and the Inappropriate Sleep Composite Score (OR, 2.54; 95% CI, 1.76-3.66). A standard Epworth Sleepiness Scale score of 7 or higher predicted 75% of episodes of sleep behind the wheel at a specificity of 50% (exclusion of the question related to driving provided 70% sensitivity and 52% specificity), whereas a score of 1 on the Inappropriate Sleep Composite Score generated a sensitivity of 52% and specificity of 82%. Excessive daytime sleepiness is common even in patients with PD who are independent and do not have dementia. Sudden-onset sleep without warning is infrequent. The Epworth score has adequate sensitivity for predicting prior episodes of falling asleep while driving and its specificity can be increased by use of the Inappropriate Sleep Composite Score. It is unknown if routinely performing these assessments could be more effective in predicting future risk for these rare sleep attacks. Patients should be warned not to drive if they doze in unusual circumstances.
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Disorders affecting the basal ganglia can have a severe effect on speech motor control. The effect can vary depending on the pathophysiology of the basal ganglia disease but in general terms it can be classified as hypokinetic or hyperkinetic dysarthria. Despite the role of basal ganglia on speech, there is a marked discrepancy between the effect of medical and surgical treatments on limb and speech motor control. This is compounded by the complex nature of speech and communication in general, and the lack of animal models of speech motor control. The emergence of deep brain stimulation of basal ganglia structures gives us the opportunity to record systematically the effects on speech and attempt some assumptions on the role of basal ganglia on speech motor control. The aim of the present work was to examine the impact of bilateral subthalamic nucleus deep brain stimulation (STN-DBS) for Parkinson’s disease (PD) and globus pallidus internus (GPi-DBS) for dystonia on speech motor control. A consecutive series of PD and dystonia patients who underwent DBS was evaluated. Patients were studied in a prospective longitudinal manner with both clinical assessment of their speech intelligibility and acoustical analysis of their speech. The role of pre-operative clinical factors and electrical parameters of stimulation, mainly electrode positioning and voltage amplitude was systematically examined. In addition, for selected patients, tongue movements were studied using electropalatography. Aerodynamic aspects of speech were also studied. The impact of speech therapy was assessed in a subgroup of patients. The clinical evaluation of speech intelligibility one and three years post STN-DBS in PD patients showed a deterioration of speech, partly related to medially placed electrodes and high amplitude of stimulation. Pre-operative predictive factors included low speech intelligibility before surgery and longer disease duration. Articulation rather than voice was most frequently affected with a distinct dysarthria type emerging, mainly hyperkinetic-dystonic, rather than hypokinetic. Traditionally effective therapy for PD dysarthria had little to no benefit following STN-DBS. Speech following GPi-DBS for dystonia did not significantly change after one year of stimulation. A subgroup of patients showed hypokinetic features, mainly reduced voice volume and fast rate of speech more typical of Parkinsonian speech. Speech changes in both STN-DBS and GPi-DBS were apparent after six months of stimulation. This progressive deterioration of speech and the critical role of the electrical parameters of stimulation suggest a long-term effect of electrical stimulation of basal ganglia on speech motor control.
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Several studies conducted worldwide report an inverse association between caffeine/coffee consumption and the risk of developing Parkinson's disease (PD). However, heterogeneity and conflicting results between studies preclude a correct estimation of the strength of this association. We conducted a systematic review and meta-analysis of published epidemiological studies to better estimate the effect of caffeine exposure on the incidence of PD. Data sources searched included Medline, LILACS, Scopus, Web of Science and reference lists, up to September 2009. Cohort, case-control and cross-sectional studies were included. Three independent reviewers selected the studies and extracted the data on to standardized forms. Twenty-six studies were included: 7 cohort, 2 nested case-control, 16 case-control, and 1 cross-sectional study. Quantitative data synthesis of the most precise estimates from each study was accomplished through random effects meta-analysis. Heterogeneity was quantified using the I2 statistic. The summary RR for the association between caffeine intake and PD was 0.75 [[95% Confidence Interval (95%CI): 0.68-0.82], with low to moderate heterogeneity (I2= 28.8%). Publication bias for case-control/cross-sectional studies may exist (Egger's test, p=0.053). When considering only the cohort studies, the RR was 0.80 (95%CI: 0.71-90; I2=8.1%). The negative association was weaker when only women were considered (RR=0.86, 95%CI: 0.73-1.02; I2=12.9%). A linear relation was observed between levels of exposure to caffeine and the RR estimates: RR of 0.76 (95%CI: 0.72-0.80; I2= 35.1%) per 300 mg increase in caffeine intake. This study confirm an inverse association between caffeine intake and the risk of PD, which can hardly by explained by bias or uncontrolled confounding.
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The importance of lipids in cell signaling and tissue physiology is demonstrated by the many CNS pathologies involving deregulated lipid metabolism. One such critical metabolic event is the activation of phospholipase A(2) (PLA(2)), which results in the hydrolysis of membrane phospholipids and the release of free fatty acids, including arachidonic acid, a precursor for essential cell-signaling eicosanoids. Reactive oxygen species (ROS, a product of arachidonic acid metabolism) react with cellular lipids to generate lipid peroxides, which are degraded to reactive aldehydes (oxidized phospholipid, 4-hydroxynonenal, and acrolein) that bind covalently to proteins, thereby altering their function and inducing cellular damage. Dissecting the contribution of PLA(2) to lipid peroxidation in CNS injury and disorders is a challenging proposition due to the multiple forms of PLA(2), the diverse sources of ROS, and the lack of specific PLA(2) inhibitors. In this review, we summarize the role of PLA(2) in CNS pathologies, including stroke, spinal cord injury, Alzheimer's, Parkinson's, Multiple sclerosis-Experimental autoimmune encephalomyelitis and Wallerian degeneration.
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This study compared vocal sound pressure level (SPL) and self-perception of speech and voice in men and women with idiopathic Parkinson disease (PD) and in healthy men and women. Thirty subjects with PD (15 men, 15 women) and 14 healthy comparison (HC) subjects (7 men, 7 women) participated in the study. They performed a variety of speech and voice tasks and carried out perceptual self-ratings of nine speech and voice characteristics. To assess performance stability, subjects repeated the data collection procedures on 3 different days. Results revealed that subjects with PD were statistically significantly lower in vocal SPL (2.0-4.0 dB SPL; 30 cm) during speech and voice tasks than HC subjects. Repeated measures across sessions revealed that subjects with PD were not significantly more unstable than HC subjects in their day-to-day performance for all variables examined. In addition, subjects with PD rated themselves as statistically significantly more severely impaired than HC subjects on all nine self-rated perceptual variables examined. These data provide additional descriptive information on speech and voice characteristics in people with PD and may be useful in assessment and treatment planning for this population.
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The difficulties inherent in obtaining consistent and adequate diagnoses for the purposes of research and therapy have been pointed out by a number of authors. Pasamanick12 in a recent article viewed the low interclinician agreement on diagnosis as an indictment of the present state of psychiatry and called for "the development of objective, measurable and verifiable criteria of classification based not on personal or parochial considerations, but on behavioral and other objectively measurable manifestations."Attempts by other investigators to subject clinical observations and judgments to objective measurement have resulted in a wide variety of psychiatric rating scales.4,15 These have been well summarized in a review article by Lorr11 on "Rating Scales and Check Lists for the Evaluation of Psychopathology." In the area of psychological testing, a variety of paper-and-pencil tests have been devised for the purpose of measuring specific
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The study reports the effect of subthalamic deep brain stimulation (STN DBS) on vocal function in Parkinson’s disease (PD). Specifically, the effect was evaluated in relation to the vibratory characteristics of the vocal folds during sustained vowelphonation using two different methods: one measures jitter and shimmer, while the other measures the correlation dimension D2, a nonlinear dynamicanalysis. Twenty right‐handed individuals with advanced PD and dysarthria underwent unilateral STN DBS. Ten were operated on the right hemisphere and ten on the left hemisphere. The side receiving STN DBS had more affected motor function. Speech was evaluated before surgery and three‐to‐six months after surgery with stimulator‐off and with stimulator‐on; all were off anti‐Parkinsonian medication for 12 h before evaluation. Evaluators and subjects were blinded to the subjects stimulator status at the postsurgery evaluations. Nonspeech motor performance was assessed with UPDRS‐III. Each subject produced six maximally sustained ‘‘ah’’ phonations (MSVPs) at his/her habitual loudness level. Two‐second samples extracted from the MSVPs were used for both analyses. In addition, the maximum vocal intensity, duration, mean F0, and cycle‐to‐cycle F0 variation were also obtained. The results were discussed with regard to Chaos theory and the phonationcharacteristics in PD.
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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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The objective of this study was to evaluate the efficacy, safety, and tolerability of istradefylline 20 mg once daily versus placebo as an adjunct to levodopa in subjects with Parkinson's disease (PD) who have motor fluctuations. Istradefylline (KW-6002) is an adenosine A2A receptor antagonist that in primate models of PD improves motor function without causing or worsening dyskinesia. This 12-week, multicenter, double-blind, placebo-controlled, randomized, Phase 3 study of istradefylline was conducted in subjects experiencing an average daily OFF time of at least 3 hours (116 randomized to istradefylline; 115 to placebo). All were on stable levodopa regimens; 90% were also on stable regimens of other anti-Parkinson's medications. Istradefylline-treated subjects had significant placebo-corrected reductions in daily OFF time from baseline to endpoint: 4.6% (P = 0.03) and 0.7 hours (P = 0.03). For ON time with troublesome dyskinesia, the changes between istradefylline and placebo were not significant. Istradefylline was well tolerated, with 6 (5.2%) istradefylline-treated and 7 (6.1%) placebo-treated subjects withdrawing from the study because of adverse events. Dyskinesia, lightheadedness, tremor, constipation, and weight decrease were reported more often with istradefylline than placebo. We conclude that istradefylline is well tolerated and significantly reduces OFF time as an adjunct to levodopa in PD subjects with motor fluctuations. © 2008 Movement Disorder Society
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Subsyndromal symptoms of depression (SSD) in patients with schizophrenia are common and clinically important. While treatment of depression in major depressive disorder may partially ameliorate cognitive deficits, the cognitive effects of antidepressant medications in patients with schizophrenia or schizoaffective disorder and SSD are unknown. The goal of this study was to assess the impact of SSD and their treatment on cognition in participants with schizophrenia or schizoaffective disorder aged ≥40 years. Participants were randomly assigned to a flexible dose treatment with citalopram or placebo augmentation of their current medication for 12 weeks. An ANCOVA compared improvement in the cognitive composite scores, and a linear model determined the moderation of cognition on treatment effects based on the Hamilton Depression Rating Scale and the Calgary Depression Rating Scale scores between treatment groups. There were no differences between the citalopram and placebo groups in changes in cognition. Baseline cognitive status did not moderate antidepressant treatment response. Although there are other cogent reasons why SSD in schizophrenia warrant direct intervention, treatment does not substantially affect the level of cognitive functioning. Given the effects of cognitive deficits associated with schizophrenia on functional disability, there remains an ongoing need to identify effective means of directly ameliorating them.
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The development of a 21-item self-report inventory for measuring the severity of anxiety in psychiatric populations is described. The initial item pool of 86 items was drawn from three preexisting scales: the Anxiety Checklist, the Physician’s Desk Reference Checklist, and the Situational Anxiety Checklist. A series of analyses was used to reduce the item pool. The resulting Beck Anxiety Inventory (BAI) is a 21-item scale that showed high internal consistency (α = .92) and test—retest reliability over 1 week, r (81) = .75. The BAI discriminated anxious diagnostic groups (panic disorder, generalized anxiety disorder, etc.) from nonanxious diagnostic groups (major depression, dysthymic disorder, etc). In addition, the BAI was moderately correlated with the revised Hamilton Anxiety Rating Scale, r (150) = .51, and was only mildly correlated with the revised Hamilton Depression Rating Scale, r (153) = .25.
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In 1686, Thomas Sydenham described a syndrome of chorea occurring in youth which was subsequently shown to be a complication of rheumatic fever. An association between chorea and antiphospholipid antibodies has been reported since 1985. We report two females presenting with chorea, aged 17 and 22, who fulfilled the Jones' criteria for rheumatic fever and concurrently had antiphospholipid antibodies detected in serum. A third patient presented at the age of 16 with two bouts of Sydenham's chorea; no assays for antiphospholipid antibodies were performed at the time but 13 years later she was found to have high titres of anticardiolipin antibodies. No patient had abnormalities in the basal ganglia detected on magnetic resonance imaging. Sydenham's chorea may be part of the spectrum of antiphospholipid-associated neurological disease.
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The safety and efficacy of istradefylline, a selective adenosine A(2A) receptor antagonist, was evaluated in a 12-week, double-blind study in levodopa-treated Parkinson disease (PD) subjects with motor complications. Levodopa-treated PD subjects (n = 395) received istradefylline 20 mg/day (n = 163), istradefylline 60 mg/day (n = 155), or placebo (n = 77) at 40 sites. The primary efficacy variable was the change in the percentage of time per day spent in the OFF state. Secondary measurements assessed change in ON time, Unified Parkinson's Disease Rating Scale, and Clinical Global Impression. Safety monitoring included clinical laboratory, electrocardiograms, vital signs, physical/neurologic examinations, and adverse events (AEs). Changes from baseline to endpoint in the percentage OFF time in the active groups compared with placebo were -4.35% (95% CI -8.16 to -0.54; p = 0.026) for istradefylline 20 mg/day and -4.49% (95% CI -8.35 to -0.62; p = 0.024) for 60 mg/day; these changes were significant (analysis of covariance). For total hours, istradefylline demonstrated mean differences from placebo of -0.64 hours (95% CI -1.30 to 0.01) for 20 mg/day and -0.77 hours (95% CI -1.44 to -0.11) for 60 mg/day (p = 0.065; overall treatment effect). Clinical response occurred by the second week and was maintained throughout the study. Istradefylline was well tolerated. The common AEs were dyskinesia, nausea, dizziness, and hallucinations. Istradefylline demonstrated a significant reduction in the percentage of awake time per day spent in the OFF state, which resulted in a clinically meaningful reduction in OFF time, without an increase in ON time with troublesome dyskinesia, and was well tolerated as adjunctive treatment to levodopa in Parkinson disease.
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Holmes' tremor refers to an unusual combination of rest, postural and kinetic tremor of extremities. Common causes of Holmes' tremor include stroke, trauma, vascular malformations and multiple sclerosis, with lesions involving the thalamus, brain stem or cerebellum. Although some drugs (eg, levodopa and dopaminergic drugs, clonazepam and propranolol) have been occasionally reported to give some benefit, medical treatment of Holmes' tremor is unsatisfactory, and many patients require thalamic surgery to achieve satisfactory control. We report a patient in whom post-ischaemic Holmes' tremor dramatically responded to levetiracetam treatment.
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Restless legs syndrome (RLS) and other sleep abnormalities are common in Parkinson's Disease (PD). We prospectively examined sleep measures in PD patients undergoing subthalamic nucleus (STN) deep brain stimulation (DBS). An RLS questionnaire, Epworth Sleepiness Scale (ESS), and Parkinson's Disease Sleep Scale (PDSS) were administered through telephone interviews preoperatively and postoperatively. Seventeen patients were included. Mean preoperative and 4 weeks postoperative ESS scores were 11.6 and 6.4 respectively (p < 0.001) and PDSS scores were 94.2 and 122.9 respectively (p < 0.001). The improvement was sustained at 6 months. Six patients were diagnosed with RLS preoperatively. Mean preoperative International Restless Legs Syndrome Study Group rating scale score was 23.0. Mean 4 week and 6 month postoperative IRLSSG rating scale scores were 14.8 and 13.8 respectively, significantly improved compared to preoperative scores (p = 0.027 and p = 0.037 respectively). No patients developed new-onset RLS postoperatively. STN DBS improves daytime sleepiness, sleep quality, and RLS.
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The presence of either excessive tonic chin EMG activity during REM sleep, or excessive phasic submental or limb EMG twitching is required to diagnose REM sleep behavior disorder (RBD). The aim was to identify cut-off values and to assess the sensitivity and specificity of these values taken separately or combined to diagnose idiopathic RBD patients. Eighty patients presenting with a clinical diagnosis of idiopathic RBD and 80 age- and gender-matched normal controls were studied in the sleep laboratory. Receiver operating characteristic curves were drawn to find optimal cut-off values for three REM sleep EMG parameters. Tonic and phasic EMG activity were measured in the chin, but not in the limbs. Videos were examined during the recording but were not systematically reviewed by the authors. Total correct classification of 81.9% was found for tonic chin EMG density ≥30%; 83.8% for phasic chin EMG density ≥15% and 75.6% for ≥24 leg movements per hour of REM sleep. Five patients did not fulfill any of these three polysomnographic (PSG) criteria. Conversely, one subject of the control group met the PSG criteria for RBD. This study estimates the diagnostic value of a visual scoring method for the diagnosis of idiopathic RBD and establishes cut-off values to be used in clinical and research set-ups. For the five RBD patients who did not show chin EMG abnormalities, it cannot be excluded that they had increased phasic EMG activity in the upper limbs and presented visible motor activity.
Article
Seven autosomal recessive genes associated with juvenile and young-onset Levodopa-responsive parkinsonism have been identified. Mutations in PRKN, DJ-1, and PINK1 are associated with a rather pure parkinsonian phenotype, and have a more benign course with sustained treatment response and absence of dementia. On the other hand, Kufor-Rakeb syndrome has additional signs, which distinguish it clearly from Parkinson's disease including supranuclear vertical gaze palsy, myoclonic jerks, pyramidal signs, and cognitive impairment. Neurodegeneration with brain iron accumulation type I (Hallervorden-Spatz syndrome) due to mutations in PANK2 gene may share similar features with Kufor-Rakeb syndrome. Mutations in three other genes, PLA2G6 (PARK14), FBXO7 (PARK15), and Spatacsin (SPG11) also produce clinical similar phenotypes in that they presented with rapidly progressive parkinsonism, initially responsive to Levodopa treatment but later, developed additional features including cognitive decline and loss of Levodopa responsiveness. Here, using homozygosity mapping and sequence analysis in families with complex parkinsonisms, we identified genetic defects in the ATP13A2 (1 family), PLA2G6 (1 family) FBXO7 (2 families), and SPG11 (1 family). The genetic heterogeneity was surprising given their initially common clinical features. On careful review, we found the FBXO7 cases to have a phenotype more similar to PRKN gene associated parkinsonism. The ATP13A2 and PLA2G6 cases were more seriously disabled with additional swallowing problems, dystonic features, severe in some, and usually pyramidal involvement including pyramidal weakness. These data suggest that these four genes account for many cases of Levodopa responsive parkinsonism with pyramidal signs cases formerly categorized clinically as pallido-pyramidal syndrome.
Article
Over 50% of persons with idiopathic REM sleep behavior disorder (RBD) will develop Parkinson disease (PD) or dementia. At present, there is no way to predict who will develop disease. Since polysomnography is performed in all patients with idiopathic RBD at diagnosis, there is an opportunity to analyze if baseline sleep variables predict eventual neurodegenerative disease. In a longitudinally studied cohort of patients with idiopathic RBD, we identified those who had developed neurodegenerative disease. These patients were matched by age, sex, and follow-up duration to patients with RBD who remained disease-free and to controls. Polysomnographic variables at baseline (i.e., before development of neurodegenerative disease) were compared between groups. Twenty-six patients who developed neurodegenerative disease were included (PD 12, multiple system atrophy 1, dementia 13). The interval between polysomnogram and disease onset was 6.7 years, mean age was 69.5, and 81% were male. There were no differences between groups in sleep latency, sleep time, % stages 2-4, % REM sleep, or sleep efficiency. However, patients with idiopathic RBD who developed neurodegenerative disease had increased tonic chin EMG activity during REM sleep at baseline compared to those who remained disease-free (62.7 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.020). This effect was seen only in patients who developed PD (72.9 +/- 6.0% vs 41.0 +/- 6.0%, p = 0.002), and not in those who developed dementia (54.3 +/- 10.3, p = 0.28). There was no difference in phasic submental REM EMG activity between groups. In patients with REM sleep behavior disorder initially free of neurodegenerative disease, the severity of REM atonia loss on baseline polysomnogram predicts the development of Parkinson disease.
Article
The drug treatment of Parkinson's disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression. As a consequence, novel approaches to therapy are sought, and adenosine A(2A) receptors (A(2A)ARs) provide a viable target. A(2A)ARs are highly localized to the basal ganglia and specifically to the indirect output pathway, which is highly important in the control of voluntary movement. A(2A)AR antagonists can modulate gamma-aminobutyric acid (GABA) and glutamate release in basal ganglia and other key neurotransmitters that modulate motor activity. In both rodent and primate models of PD, A(2A)AR antagonists produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD. In clinical trials, the A(2A)AR antagonist istradefylline reduces "off" time in patients with PD receiving optimal dopaminergic therapy. However, these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class. Based on preclinical studies, A(2A)AR antagonists may also be neuroprotective and have utility in the treatment of neuropsychiatric disorders. We are only now starting to explore the range of potential uses of A(2A)AR antagonists in central nervous system disorders, and their full utility is still to be uncovered.
Article
Adenosine derived from the degradation of ATP/AMP functions as a signalling molecule in the nervous system through the occupation of A1, A2, and A3 adenosine receptors. Adenosine A(2A) receptors have a selective localization to the basal ganglia and specifically to the indirect output pathway, and as a consequence offer a unique opportunity to modulate the output from the striatum that is believed critical to the occurrence of motor components of PD. Indeed, the ability of A(2A) antagonists to modulate basal ganglia neurotransmission has been shown to be associated with improved motor function in experimental models of PD. This suggests that A(2A) antagonists would be effective as a symptomatic treatment in humans without provoking marked dyskinesia. Indeed, the A(2A) antagonist istradefylline reduces OFF time in moderate- to late-stage patients with PD already receiving dopaminergic therapy, with an increase in non-troublesome dyskinesia. Adenosine and adenosine receptors also exert actions relevant to pathogenesis in PD, raising the possibility of their use as neuroprotective agents. Both epidemiologic evidence and the current preclinical data strongly support a role for A(2A) antagonists in protecting dopaminergic neurons and influencing the onset and progression of PD.
Article
Parkinson's disease (PD) is a common neurodegenerative disorder marked by movement impairment caused by a selective degeneration of dopaminergic neurons. The mechanism for dopaminergic neuronal degeneration in PD is not completely clear, but it is believed that oxidative and nitrosative stress plays an important role during the pathogenesis of PD. This notion is supported by various studies that several indices of oxidative and nitrosative stress are increased in PD patients. In recent years, different pathways that are known to be important for neuronal survival have been shown to be affected by oxidative and nitrosative stress. Apart from the well-known oxidative free radicals induced protein nitration, lipid peroxidation and DNA damage, increasing evidence also suggests that some neuroprotective pathways can be affected by nitric oxide through S-nitrosylation. In addition, the selective dopaminergic neurodegeneration suggests that generation of oxidative stress associated with the metabolism of dopamine is an important contributor. Thorough understanding of how oxidative stress can contribute to the pathogenesis of PD will help formulate potential therapy for the treatment of this neurodegenerative disorder in the future.
Article
PLA2G6 mutations are known to be responsible for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA). In addition, novel mutations in PLA2G6 have recently been associated with dystonia-parkinsonism in two unrelated consanguineous families. Direct sequencing analysis of the PLA2G6 gene. Here, we report the segregation of R632W with disease in an Iranian consanguineous dystonia-parkinsonism pedigree. The identical mutation was previously observed in a patient affected with NBIA. We conclude that different and even identical PLA2G6 mutations may cause neurodegenerative diseases with heterogeneous clinical manifestations, including INAD, NBIA and dystonia-parkinsonism.
Article
To describe the clinical features, treatment, and outcomes of patients with antiphospholipid antibody (aPL)-associated chorea. The study cohort consisted of consecutive patients with chorea evaluated between 1990 and 2005 with documented aPL at time of their neurologic diagnosis. Eighteen patients were identified, 4 with systemic lupus erythematosus (SLE). The 14 non-SLE patients experienced 1.6 vascular thromboses/pregnancy losses per person, while patients with SLE experienced 0.5 events/person. Four non-SLE patients (29%) and no SLE patients met criteria for antiphospholipid antibody syndrome (APS). None of these 4 tested positive for IgM anticardiolipin antibody (aCL). In contrast, 10 (71%) non-APS patients tested positive for IgM aCL. Chorea was most often bilateral, mild to moderate, and occurred once with a median age at onset of 44 and 33 years in non-SLE and SLE patients, respectively. Therapy included immunosuppression in 3 (21%) non-SLE patients and in all SLE patients. Antidopaminergic agents were used in 7 (39%). All patients responded to treatment. Five patients received anticoagulation for thrombosis and 2 died of bleeding complications, both non-SLE patients. aPL-associated chorea occurs most often in women and severity is mild to moderate. Clinical expression of chorea does not differ between those with and without SLE. Anticoagulation should be reserved for thrombosis treatment and not simply for chorea in the presence of aPL, as 2 patients died of bleeding. The absence of IgM aCL in patients with APS supports prior evidence that IgG aCL and lupus anticoagulant may be the more clinically relevant antibodies for thrombosis. However, IgM aCL may be important in patients with chorea.
Article
Deep brain stimulation (DBS) is a surgical procedure that has been shown effective in improving the cardinal motor signs of advanced Parkinson's disease, however, declines in cognitive function have been associated with bilateral subthalamic nucleus (STN) DBS. Despite the fact that most activities of daily living clearly have motor and cognitive components performed simultaneously, postoperative assessments of cognitive and motor function occur, in general, in isolation of one another. The primary aim of this study was to determine the effects of unilateral and bilateral STN DBS on upper extremity motor function and cognitive performance under single- and dual-task conditions in advanced Parkinson's disease patients. Data were collected from eight advanced Parkinson's disease patients between the ages of 48 and 70 years (mean 56.5) who had bilaterally placed STN stimulators. Stimulation parameters for DBS devices were optimized clinically and were stable for at least 6 months prior to study participation. Data were collected while patients were Off anti-parkinsonian medications under three stimulation conditions: Off stimulation, unilateral DBS and bilateral DBS. In each stimulation condition patients performed a cognitive (n-back task) and motor (force tracking) task under single- and dual-task conditions. During dual-task conditions, patients performed the n-back and force-maintenance task simultaneously. Under relatively simple dual-task conditions there were no differences in cognitive or motor performance under unilateral and bilateral stimulation. As dual-task complexity increased, cognitive and motor performance was significantly worse with bilateral compared with unilateral stimulation. In the most complex dual-task condition (i.e. 2-back + force tracking), bilateral stimulation resulted in a level of motor performance that was similar to the Off stimulation condition. Significant declines in cognitive and motor function under modest dual-task conditions with bilateral but not with unilateral STN DBS suggest that unilateral procedures may be an alternative to bilateral DBS for some patients, in particular, those with asymmetric symptomology. From a clinical perspective, these results underscore the need to assess cognitive and motor function simultaneously during DBS programming as these conditions may better reflect the context in which daily activities are performed.
Article
Subthalamic nucleus deep brain stimulation (STN-DBS) is particularly effective in improving limb symptoms in Parkinson's disease. However, speech shows a variable response. Contact site and amplitude of stimulation have been suggested as possible factors influencing speech. In this double blind study, we assessed 14 patients post bilateral STN-DBS, without medication. Six conditions were studied in random order as follows: stimulation inside the STN at low voltage (2 V) and at high voltage (4 V); above the STN at 2 V and at 4 V, at usual clinical parameters, and off-stimulation. The site of stimulation was defined on the postoperative stereotactic MRI data. Speech protocol consisted of the assessment of intelligibility of the dysarthric speech, maximum sustained phonation, and a 1-minute monologue. Movement was assessed using the UPDRS-III. Stimulation at 4 V significantly reduced the speech intelligibility (P = 0.004) independently from the site of stimulation. Stimulation at 4 V significantly improved the motor function. Stimulation inside the nucleus was significantly more effective than outside the nucleus (P = 0.0006). The significant improvement in movement coupled with significant deterioration in speech intelligibility when patients are stimulated inside the nucleus at high voltage indicates a critical role for electrical stimulation parameters in speech motor control.
Article
Orthostatic tremor (OT) is a disabling movement disorder associated with postural and gait impairment in the elderly. Medical therapy often yields insufficient benefit. We report the clinical and electrophysiological data on two patients with medication-refractory OT treated with deep brain stimulation of the ventral intermediate thalamic nucleus (Vim DBS). Patient 1 underwent bilateral deep brain stimulation (DBS) and Patient 2 unilateral Vim DBS following 28 and 30 years of disease duration, respectively. Both patients showed increased latency to symptom onset after rising from a seated position, improved tolerance for prolonged standing, and slower crescendo of tremor severity when remaining upright. Postoperative evaluation demonstrated decreased amplitude of electromyographic activity with persistence of well-defined oscillatory behavior showing strong coherence at 15 Hz between all muscles tested in the upper and lower limbs. Postural sway was unchanged. Clinical benefits have been sustained for over 18 months in Patient 1, and receded after 3 months in Patient 2. These findings support the consideration of bilateral Vim DBS implantation as a therapeutic option in patients with medically refractory OT. Further efficacy studies on chronic stimulation to disrupt the abnormal oscillatory activity in this disorder are warranted.
Article
Parkinson's disease (PD) is acknowledged as the second most common neurodegenerative disorder after Alzheimer's Disease. Older age may be the only unequivocal risk factor for PD although the male to female ratio is consistently greater than 1 in populations of European ancestry. Characteristic features of PD include dopaminergic neuron death in the substantia nigra (SN) pars compacta, accumulation of alpha-synuclein inclusions known as Lewy bodies in the SN, and brain iron accumulation beyond that observed in non-PD brains of a similar age. In this review article, we will provide an overview of human and animal studies investigating the contributions of iron in PD, a summary of human studies of iron-related genes in PD, a review of the literature on the genetics of iron metabolism, and some hypotheses on possible roles for iron in the pathogenic processes of PD including potential interactions between iron and other factors associated with Parkinson's disease.
Article
We report it patient with severe orthostatic tremor (OT) unresponsive to pharmacological treatments that was successfully controlled with thalamic (Vim. ventralis intermedius nucleus) deep brain stimulation (DBS) over a 4-year period. Cortical activity associated with the 0,17 revealed by EEG back-averaging and fluoro-deoxi-glucose PET were also suppressed in parallel with tremor arrest. This case suggests that Vim-DBS may be a useful therapeutic approach for patients highly disabled by OT. (C) 2008 Movement Disorder Society.
Article
A rare complication of oral contraceptive therapy is the induction of chorea. We here describe five cases of chorea in patients receiving low- or high-dose estrogen-containing contraceptives. All patients were nulliparous, young (average age 19 years), and became symptomatic shortly (average of 5 weeks) after initiation of contraceptive therapy. Two patients previously suffered an episode of Syndenham chorea; one experienced chorea in the course of Henoch-Schönlein purpura; and two had a history of congenital cyanotic heart disease without chorea. Dyskinesia resolved in all patients upon discontinuing the medication. Patients with preexisting striatal abnormalities appear more susceptible to oral contraceptive-induced chorea which is reversible on drug discontinuation. The mechanism of oral contraceptive-induced chorea is unknown, but clinical and experimental data suggest that it involves altered central dopaminergic activity.
Article
In this study, the frequency of occurrence of speech and voice symptoms in 200 Parkinson patients was defined by two expert listeners from high-fidelity tape recordings of conversational speech samples and readings of the sentence version of the Fisher-Logemann Test of Articulation Competence. Specific phonemes that were misarticulated were catalogued. Other vocal-tract dysfunctions, including laryngeal disorders, rate disorders, and hypernasality, were also recorded. Cooccurrence of symptoms in each patient was tabulated. Examination of the patterns of cooccurring dysfunctions permitted classifying the 200 patients into five groups: Group 1 (45% of the patients) with laryngeal dysfunction as their only vocal-tract symptom; Group 2 (13.5% of the patients) with laryngeal and back-tongue involvement; Group 3 (17% of the patients) with laryngeal, back-tongue, and tongue-blade dysfunction; Group 4 (5.5% of the patients) with laryngeal dysfunction, back-tongue involvement, tongue-blade dysfunction, and labial misarticulations; and Group 5 (9% of the patients) with laryngeal dysfunction and misarticulations of the back tongue, tongue blade, lips, and tongue tip. Disfluencies and hypernasality did not follow a systematic pattern of cooccurrence with other vocal-tract dysfunctions.