The Parkinson's Disease genome-wide association study locus browser

Background: Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. Methods: We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data. Results: We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets. Conclusions: Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered

Advancing personalized medicine in common forms of Parkinson’s disease through genetics : current therapeutics and the future of individualized management

Parkinson’s disease (PD) is a condition with heterogeneous clinical manifestations that vary in age at onset, rate of progression, disease course, severity, motor and non-motor symptoms, and a variable response to antiparkinsonian drugs. It is considered that there are multiple PD etiological subtypes, some of which could be predicted by genetics. The characterization and prediction of these distinct molecular entities provides a growing opportunity to use individualized management and personalized therapies. Dissecting the genetic architecture of PD is a critical step in identifying therapeutic targets, and genetics represents a step forward to sub-categorize and predict PD risk and progression. A better understanding and separation of genetic subtypes has immediate implications in clinical trial design by unraveling the different flavors of clinical presentation and development. Personalized medicine is a nascent area of research and represents a paramount challenge in the treatment and cure of PD. This manuscript summarizes the current state of precision medicine in the PD field and discusses how genetics has become the engine to gain insights into disease during our constant effort to develop potential etiological based interventions

Tracing the distribution of european lactase persistence genotypes along the Americas

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the –13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the –13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries’ dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of –13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the –13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the –13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the –13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent

Clinimetrics of the 9- and 19-item wearing-off questionnaire : a systematic review

The treatment of Parkinson’s disease (PD) with dopaminergic therapy improves functionality and quality of life. However, as the disease progresses, the wearing-off phenomenon develops, which necessitates complex posology adjustment or adjuvant therapy. This phenomenon may not be well recognized, especially if it is mild or involves nonmotor symptoms. Questionnaires were developed to improve the recognition of the wearing-off phenomenon. The questionnaires consist of a list of symptoms that patients must check if they have and if the symptoms improve with medication. A recent review by the Movement Disorder Society suggested the 19-item (WOQ-19) and 9-item (WOQ-9) questionnaires as screening tools for the wearing-off phenomenon. However, there has not been a systematic review to assess the questionnaires’ clinimetric properties, such as sensitivity, specificity, test-retest reliability, and responsiveness. We conducted an extensive search for studies using these two tools. We identified 3 studies using WOQ-19 and 5 studies using WOQ-9. Both questionnaires seem to have good sensitivity (0.81–1). WOQ-19 has variable specificity (0.39–0.8), depending on the number of positive items, while WOQ-9 lacks specificity (0.1–0.69). Only one study using WOQ-19 reported test-retest, and only two studies reported responsiveness. Thus, this report describes the first independent systematic review to exam quantitatively the clinimetric properties of these two questionnaires

A case-control study of the effects of Chimarrão ( Ilex paraguariensis) and coffee on Parkinson's disease

Introduction: Coffee has been inversely associated with Parkinson's disease (PD) in many studies, and caffeine is the leading candidate to mediate this effect. Mate (Ilex paraguariensis, IP), a caffeinated beverage rich in antioxidants consumed in South America, was also inversely associated with PD in one study from Argentina. Other varieties of IP infusion, such as chimarrão, were never studied in PD. Chimarrão is a common caffeinated beverage consumed in Brazil made with the leaves and stems of IP. Methods: A case–control study was conducted to evaluate the relationship between chimarrão ingestion and PD in southern Brazil. All subjects answered a questionnaire about the frequency of chimarrão and coffee intake. A multiple regression analysis adjusted for age and sex was performed to assess the association between PD and chimarrão consumption. Results: We included 200 PD patients and 200 healthy controls. High consumption of chimarrão was inversely associated with PD (OR = 0.44, 95% CI = 0.24–0.81, P = 0.008). High consumption of coffee was also inversely associated with PD, as expected. Chimarrão remained associated when adjusted for coffee consumption, smoking history, and age (OR 0.46, 95% CI = 0.25–0.86, P = 0.014). These two exposures showed an additive effect. Conclusion: Chimarrão consumption was inversely associated with PD, even after adjusting for coffee intake, suggesting a possible protective role. IP's effect can be mediated by caffeine and through its antioxidant components. Chimarrão has a lower concentration of caffeine compared with coffee and has numerous substances with antioxidative effects that may be important to PD protection. Further studies are needed to test this hypothesis

Associação da educação com a ocorrência de delirium em pacientes de um serviço de emergência

Background: Delirium is a neuropsychiatric syndrome with multiple etiological factors. Evaluation of delirium in different settings, especially the Emergency Department (ED) pertaining to different regions of the world with patients from different cultural and educational backgrounds is needed. Objective: To determine the prevalence of delirium and its association with education in an ED in Brazil during a 6-month period. Methods: Patients aged >18 years were randomly selected from ED admissions. The instruments Confusion Assessment Method (CAM) scale, Mini-Mental State Examination (MMSE), Wechsler Logical Memory (WLM) and Charlson comorbidity score were applied to evaluate delirium, cognitive status, and comorbidities. Results: The prevalence of delirium was10.7%. Delirium patients had significantly lower education, MMSE and WLM (immediate and delayed) scores, with 97.4% presenting episodic memory impairment. Patients with delirium had more history of neurological disorders. Three logistic regression models evaluating the association of variables with delirium were developed. Age and MMSE were retained in the first model, WLM scores in the second, and education in the third. Conclusion: To the best of our knowledge, this is the first study estimating the prevalence of delirium in a Brazilian ED. Lower education was associated with the occurrence of delirium.Introdução: Delirium é uma síndrome neuropsiquiátrica, com fatores etiológicos múltiplos. A avaliação de delirium em diferentes ambientes, especialmente no Serviço de Emergência (SE) de diferentes regiões do mundo e com diferentes características culturais e educacionais é necessária. Objetivo: Determinar a prevalência de delirium e associação com educação em um SE no Brasil, durante seis meses. Métodos: Foram randomizados aleatoriamente no SE os pacientes com idade acima de 18 anos. Escala Confusion Assessment Method (CAM), Mini Exame do Estado Mental (MEEM), o teste de Memória Lógica de Wechsler (MLW), e o escore de comorbidade de Charlson foram aplicados para avaliar delirium, status cognitivo, e comorbidades. Resultados: A prevalência de delirium foi 10,7%. Os pacientes com delirium apresentaram significativamente menor escolaridade, escores mais baixos no MEEM e MLW (imediato e tardio), sendo que 97,4% apresentava comprometimento de memória episódica. Pacientes com delirium apresentaram mais história de transtorno neurológico prévio. Três modelos de regressão logística para delirium foram realizados. No primeiro, idade e MEEM foram mantidos no modelo final. No segundo, MLW imediato e tardio; e no terceiro, apenas educação. Conclusão: Este é o primeiro estudo brasileiro, de acordo com nosso melhor conhecimento, a estimar a prevalência de delirium em serviço de emergência. Nível educacional mais baixo foi associado com ocorrência de delirium

Validação do questionário de 19 itens de wearing-off (WOQ-19) para a língua portuguesa

Background: The treatment of Parkinson disease with dopaminergic therapy improves functionality and quality of life. However, as the disease progresses, the wearing-off phenomenon develops. To improve the recognition of this phenomenon, the 19-item wearing-off questionnaire (WOQ-19) was developed. Objective: To translate and validate the WOQ-19 into Portuguese. Methods: The questionnaire was translated into Portuguese and, subsequently, back-translated into English and analyzed. The final version was tested in Parkinson disease patients for reliability through the test-retest paradigm and internal consistency. Also, sensitivity and specificity were obtained in different cut-off positive items. Results: The WOQ-19 showed good test stability, with an intraclass correlation coefficient of 0.877 (95%CI 0.690-0.951; p<0.001), and good internal consistency, with Cronbach alpha of 0.815. Two items of positive cut-off showed the best accuracy: 0.873 (95%CI 0.791-0.954). Sensitivity was 0.975 (95%CI 0.892-1) and specificity was 0.714 (95%CI 0.565-0.863). Conclusion: The Portuguese version of the WOQ-19 showed excellent diagnostic properties and can be used to diagnose wearing-off phenomena.Introdução: O tratamento da doença de Parkinson com terapia dopaminérgica melhora a funcionalidade e a qualidade de vida. Entretanto, com a progressão da doença, os fenômenos de flutuação motora e não motora se desenvolvem. Para melhorar o reconhecimento dessa situação, foi desenvolvido o questionário de 19 itens de wearing-off (WOQ-19) Objetivo: Traduzir e validar o questionário WOQ-19 para a língua portuguesa. Métodos: O questionário foi traduzido do inglês para o português. Em seguida, foi retrotraduzido para o inglês e analisado. A versão final foi testada em pacientes parkinsonianos com paradigma teste-reteste e consistência interna. A sensibilidade e especificidade foram medidas em relação a vários pontos de cortes de itens positivos. Resultados: O questionário apresenta boa estabilidade de teste, com coeficiente de correlação intraclasse de 0,877 (IC95% 0,690-0,951; p<0,001), e boa consistência interna, com alfa de Cronbach de 0,815. O ponto de corte com dois itens positivos teve a melhor acurácia: 0,873 (IC95% 0,791-0,954). A sensibilidade foi de 0,975 (IC95% 0,892-1) e a especificidade foi 0,714 (0,565-0,863). Conclusão: A versão em português do WOQ-19 mostrou excelentes propriedades diagnósticas e pode ser utilizada para diagnosticar as condições de flutuações motoras e não motoras na doença de Parkinson

The impact of cognitive performance on quality of life in individuals with Parkinson's disease

Background: Evidence points to the occurrence of cognitive impairment in all stages of PD, constituting a frequent and debilitating symptom, due to high impact on quality of life and mortality of patients. Objective: To correlate cognitive performance with quality of life in PD. Methods: The sample was drawn from a Movement Disorders Clinic of a reference hospital in Porto Alegre. Inclusion criteria were: PD diagnosis, according to the United Kingdom Parkinson’s Disease Society Brain Bank criteria for idiopathic PD (Hughes et al. 1992) and patient consent to participate. Patients with other neurological pathologies and those submitted to deep brain stimulation were excluded. The evaluation consisted of a cognitive testing battery (composed of eight tests for assessing cognitive performance), and a questionnaire on quality of life (PDQ-39) and depression (BDI). Results: The sample comprised 85 individuals with PD, with a mean age of 62.9 years (±10.7), mean disease duration of 10.4 years (±5.7), and mean educational level of four years (±4.3). There was a significant relationship between total score on the PDQ and all cognitive tests, showing that poor cognitive performance was correlated with poor quality of life. Moreover, a significant correlation was observed between cognitive tests and depression, H&Y, education level, and age. Conclusion: It may be concluded that the individuals with PD in this sample showed a correlation between poorer quality of life and worse cognitive performance. Poor performance was also correlated with more advanced stage, older age, low level of education and depression.Embasamento: As evidências apontam a ocorrência de comprometimento cognitivo em todas as fases da doença de Parkinson (DP), sendo este um sintoma não motor frequente e incapacitante, devido ao alto impacto na qualidade de vida e mortalidade dos pacientes. Objetivo: correlacionar a performance cognitiva com qualidade de vida na DP. Métodos: A amostra foi oriunda de um Ambulatório de Distúrbios do Movimento de um hospital referência de Porto Alegre. Os critérios de inclusão utilizados foram ter diagnóstico de DP e consentir em participar do estudo. Exclui-se pacientes com outras patologias neurológicas ou pacientes com estimulação cerebral profunda. A avaliação foi composta por uma anamnese, bateria de testes cognitivos (composta por oito testes), questionários sobre qualidade de vida (PDQ-39) e depressão (BDI). Resultados: A amostra foi composta por 85 indivíduos com DP, com média de idade de 62,9 anos (±10,7), média do tempo de doença de 10,4 anos (±5,7) e média de escolaridade de 7,4 anos (±4,3). Verificou-se relação significativa entre escore total do PDQ com todos os testes cognitivos, demonstrando que pior performance cognitiva está relacionada com pior qualidade de vida. Além disso, foi observado correlação significativa entre os testes cognitivos com depressão, H&Y, escolaridade e idade. Conclusão: Pode-se concluir que na presente amostra indivíduos com DP apresentaram correlação entre pior qualidade de vida com pior desempenho cognitivo. Isto também foi observado com estágio avançado da doença, idade avançada, baixa escolaridade e depressão

Occupational pesticide exposure and the risk of death in patients with Parkinson’s disease : an observational study in southern Brazil

Background: Multiple studies have suggested that various pesticides are associated with a higher risk of developing Parkinson’s disease (PD) and may influence the progression of the disease. However, the evidence regarding the impact of pesticide exposure on mortality among patients with PD is equivocal. This study examines whether pesticide exposure influences the risk of mortality among patients with PD in Southern Brazil. Methods: A total of 150 patients with idiopathic PD were enrolled from 2008 to 2013 and followed until 2019. In addition to undergoing a detailed neurologic evaluation, patients completed surveys regarding socioeconomic status and environmental exposures. Results: Twenty patients (13.3%) reported a history of occupational pesticide exposure with a median duration of exposure of 10 years (mean = 13.1, SD = 11.2). Patients with a history of occupational pesticide exposure had higher UPDRS-III scores, though there were no significant differences in regards to age, sex, disease duration, Charlson Comorbidity Index, and age at symptom onset. Patients with occupational pesticide exposure were more than twice as likely to die than their unexposed PD counterparts (HR = 2.32, 95% CI [1.15, 4.66], p = 0.018). Occupational pesticide exposure was also a significant predictor of death in a cox-proportional hazards model which included smoking and caffeine intake history (HR = 2.23, 95% CI [1.09, 4.59], p = 0.03)) and another which included several measures of socioeconomic status (HR = 3.91, 95% CI [1.32, 11.58], p = 0.01). Conclusion: In this prospective cohort study, we found an increased all-cause mortality risk in PD patients with occupational exposure to pesticides. More studies are needed to further analyze this topic with longer follow-up periods, more detailed exposure information, and more specific causes of mortality

Mechanisms of brain aging regulation by insulin : implications for neurodegeneration in late-onset Alzheimer’s disease

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer’s disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation