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Fabiane Caillava-Santos,1,2 Regina Margis,2 Carlos Roberto de Mello Rieder2–4 1Psychology Department, Universidade da Região da Campanha, Bagé, RS, Brazil; 2Curso de Pós-Graduação em Medicina, Ciências Médicas da Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil; 3Movement Disorders Center, Division of Neurology, Universidade Federal de Ciências da Saúde de Porto Alegre, Porto Alegre, RS, Brazil; 4Movement Disorder Clinic, Division of Neurology, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrazilBackground: Levodopa-associated motor fluctuations are common complications observed in Parkinson’s disease (PD) patients. Although nonmotor fluctuations are a significant cause of morbidity, they frequently are not properly identified. Few studies have characterized the nonmotor emotional fluctuations and their relation to motor fluctuations.Aims: The objective of the present study is to analyze the occurrence of fluctuations in anxiety and depression symptoms, as well as in cognitive function (memory, language, executive function, and attention), and their relation to motor fluctuations in PD patients presenting wearing-off phenomenon.Methods: Twenty-four patients were assessed during the wearing on-off periods. The State-Trait Anxiety Inventory (STAI-State) and Beck Depression Inventory (BDI) were used to assess anxiety and depression, respectively, and the Wisconsin Card Sorting Test (WCST), Stroop Test, Rey Auditory Verbal Learning Test (RAVLT), Weschler Memory Scale - digits (WMS) and Controlled Oral Word Association (COWA) for assessing executive functions, verbal memory, attention and work memory and verbal fluency, respectively.Results: Patients presented higher depression and anxiety scores in the wearing-off period (P

Latin Americans are underrepresented in genetic studies, increasing disparities in personalized genomic medicine. Despite available genetic data from thousands of Latin Americans, accessing and navigating the bureaucratic hurdles for consent or access remains challenging. To address this, we introduce the Genetics of Latin American Diversity (GLAD) Project, compiling genome-wide information from 53,738 Latin Americans across 39 studies representing 46 geographical regions. Through GLAD, we identified heterogeneous ancestry composition and recent gene flow across the Americas. Additionally, we developed GLAD-match, a simulated annealing-based algorithm, to match the genetic background of external samples to our database, sharing summary statistics (i.e., allele and haplotype frequencies) without transferring individual-level genotypes. Finally, we demonstrate the potential of GLAD as a critical resource for evaluating statistical genetic software in the presence of admixture. By providing this resource, we promote genomic research in Latin Americans and contribute to the promises of personalized medicine to more people., Competing Interests: Declaration of interests The authors declare no competing interests. D.P.L. is now an employee of AstraZeneca. This is unrelated to the work of this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Identifying hereditary parkinsonism is valuable for diagnosis, genetic counseling, patient prioritization in trials, and studying the disease for personalized therapies. However, most studies were conducted in Europeans, and limited data exist on admixed populations like those from Latin America., Objectives: This study aims to assess the frequency and distribution of genetic parkinsonism in Latin America., Methods: We conducted a systematic review and meta-analysis of the frequency of parkinsonian syndromes associated with genetic pathogenic variants in Latin America. We defined hereditary parkinsonism as those caused by the genes outlined by the MDS Nomenclature of Genetic Movement Disorders and heterozygous carriers of GBA1 pathogenic variants. A systematic search was conducted in PubMed, Web of Science, Embase, and LILACS in August 2022. Researchers reviewed titles and abstracts, and disagreements were resolved by a third researcher. After this screening, five researchers reanalyzed the selection criteria and extracted information based on the full paper. The frequency for each parkinsonism-related gene was determined by the presence of pathogenic/likely pathogenic variants among screened patients. Cochran's Q and I 2 tests were used to quantify heterogeneity. Meta-regression, publication bias tests, and sensitivity analysis regarding study quality were also used for LRRK2-, PRKN-, and GBA1-related papers., Results: We included 73 studies involving 3014 screened studies from 16 countries. Among 7668 Latin American patients, pathogenic variants were found in 19 different genes. The frequency of the pathogenic variants in LRRK2 was 1.38% (95% confidence interval [CI]: 0.52-2.57), PRKN was 1.16% (95% CI: 0.08-3.05), and GBA1 was 4.17% (95% CI: 2.57-6.08). For all meta-analysis, heterogeneity was high and publication bias tests were negative, except for PRKN, which was contradictory. Information on the number of pathogenic variants in the other genes is further presented in the text., Conclusions: This study provides insights into hereditary and GBA1-related parkinsonism in Latin America. Lower GBA1 frequencies compared to European/North American cohorts may result from limited access to gene sequencing. Further research is vital for regional prevalence understanding, enabling personalized care and therapies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Sex differences in Parkinson's disease (PD) risk are well-known. However, the role of sex chromosomes in the development and progression of PD is still unclear., Objective: The objective of this study was to perform the first X-chromosome-wide association study for PD risk in a Latin American cohort., Methods: We used data from three admixed cohorts: (1) Latin American Research consortium on the Genetics of Parkinson's Disease (n = 1504) as discover cohort, and (2) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (3) Bambui Aging cohort (n = 1442) as replication cohorts. We also developed an X-chromosome framework specifically designed for admixed populations., Results: We identified eight linkage disequilibrium regions associated with PD. We replicated one of these regions (top variant rs525496; discovery odds ratio [95% confidence interval]: 0.60 [0.478-0.77], P = 3.13 × 10 -5 replication odds ratio: 0.60 [0.37-0.98], P = 0.04). rs5525496 is associated with multiple expression quantitative trait loci in brain and non-brain tissues, including RAB9B, H2BFM, TSMB15B, and GLRA4, but colocalization analysis suggests that rs5525496 may not mediate risk by expression of these genes. We also replicated a previous X-chromosome-wide association study finding (rs28602900), showing that this variant is associated with PD in non-European populations., Conclusions: Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Handicap is a patient-centered measure of health status that encompasses the impact of social and physical environment on daily living, having been assessed in advanced and late-stage Parkinson's Disease (PD)., Objective: To characterize the handicap of a broader sample of patients., Methods: A cross-sectional study of 405 PD patients during the MDS-UPDRS Portuguese validation study, using the MDS-UPDRS, Unified Dyskinesias Rating Scale, Nonmotor symptoms questionnaire, PDQ-8 and EQ-5D-3L. Handicap was measured using the London Handicap Scale (LHS)., Results: Mean age was 64.42 (±10.3) years, mean disease duration 11.30 (±6.5) years and median HY 2 (IQR, 2-3). Mean LHS was 0.652 (±0.204); "Mobility," "Occupation" and "Physical Independence" were the most affected domains. LHS was significantly worse in patients with longer disease duration, older age and increased disability. In contrast, PDQ-8 did not differentiate age groups. Handicap was significantly correlated with disease duration ( r  = -0.35), nonmotor experiences of daily living (EDL) (MDS-UPDRS-I) ( r  = -0.51), motor EDL (MDS-UPDRS-II) ( r  = -0.69), motor disability (MDS-UPDRS-III) ( r  = -0.49), axial signs of MDS-UPDRS-III ( r  = -0.55), HY ( r  = -0.44), presence of nonmotor symptoms ( r  = -0.51) and PDQ-8 index ( r  = -0.64) (all P  < 0.05). Motor EDL, MDS-UPDRS-III and PDQ-8 independently predicted Handicap (adjusted R 2  = 0.582; P  = 0.007)., Conclusions: The LHS was easily completed by patients and caregivers. Patients were mild-moderately handicapped, which was strongly determined by motor disability and its impact on EDL, and poor QoL. Despite correlated, handicap and QoL seem to differ in what they measure, and handicap may have an added value to QoL. Handicap seems to be a good measure of perceived-health status in a broad sample of PD., (© 2023 International Parkinson and Movement Disorder Society.)

Background: Life-space mobility (LSM) is a mobility measure that assesses the physical and social environments through which people move during their daily lives., Objective: To characterize LSM among individuals with Parkinson disease and explore the relationship between LSM, self-efficacy, and balance., Design: A cross-sectional study., Settings: Movement disorder clinic at a teaching hospital., Participants: Eighty-eight participants with Parkinson disease., Interventions: Not applicable., Main Outcome Measures: The dependent variable (LSM) was assessed using the Life-Space Assessment (LSA) instrument. Balance evaluation and balance self-efficacy were assessed using the Mini Balance Evaluation Systems Test (Mini-BESTest) and the Activities-Specific Balance Confidence Scale, respectively. Other variables, such as age, disease staging (Hoehn-Yahr staging system), cognition (Montreal Cognitive Assessment), and depressive symptoms (Beck Depression Inventory-II), were also measured., Results: The mean LSA score was 65.2 (SD: 22.8) and mean age was 63.2 years (SD: 10.5 years). Among the 88 patients, 32 (36.4%) were classified as restricted LSM. Age (p = .03), disease severity (p = .02), cognition (p = .02), and motor subtype (p = .006) were associated with more restricted LSM among participants. A multiple linear regression model demonstrated that LSM can be predicted by balance performance (R 2  = 0.377; p < .001)., Conclusion: Age, disease severity, cognition, motor subtype, balance self-efficacy, and balance performance are associated with LSM. Understanding and improving balance and self-efficacy in people with Parkinson disease could facilitate community mobility and promote functional independence and health maintenance., (© 2022 American Academy of Physical Medicine and Rehabilitation.)

Background: Large-scale Parkinson's disease (PD) genome-wide association studies (GWAS) have, until recently, only been conducted on subjects with European-ancestry. Consequently, polygenic risk scores (PRS) constructed using PD GWAS data are likely to be less predictive when applied to non-European cohorts., Methods: Using GWAS data from the largest study to date, we constructed a PD PRS for a Latino PD cohort (1497 subjects from LARGE-PD) and tested it for association with PD status and age at onset. We validated the PRS performance by testing it in an independent Latino cohort (448 subjects) and by repeating the analysis in LARGE-PD with the addition of 440 external Peruvian controls. We also tested SNCA haplotypes for association with PD risk in LARGE-PD and a European-ancestry PD cohort., Results: The GWAS-significant PD PRS had an area under the receiver-operator curve (AUC) of 0.668 (95% CI: 0.640-0.695) in LARGE-PD. The inclusion of external Peruvian controls mitigated this result, dropping the AUC 0.632 (95% CI: 0.607-0.657). At the SNCA locus, haplotypes differ by ancestry. Ancestry-specific SNCA haplotypes were associated with PD status in both LARGE-PD and the European-ancestry cohort (p-value < 0.05). These haplotypes both include the rs356182 G-allele, but only share 14% of their variants overall., Conclusion: The PD PRS has potential for PD risk prediction in Latinos, but variability caused by admixture patterns and bias in a European-ancestry PD PRS data limits its utility. The inclusion of diverse subjects can help elucidate PD risk loci and improve risk prediction in non-European cohorts., Competing Interests: Declaration of competing interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Olfaction impairment occurs in about 90% of patients with Parkinson's disease. The Sniffin Sticks Test is a widely used instrument to measure olfactory performance and is divided into three subtests that assess olfactory threshold, discrimination and identification. However, cultural and socioeconomic differences can influence test performance., Objectives: We performed a systematic review and meta-analysis of the existent data about Sniffin Sticks Test performance of Parkinson's disease patients and healthy controls in different countries and investigated if there are other cofactors which could influence the olfactory test results. A subgroup analysis by country was performed as well as a meta-regression using age, gender and air pollution as covariates., Results: Four hundred and thirty studies were found and 66 articles were included in the meta-analysis. Parkinson's disease patients showed significantly lower scores on the Sniffin Sticks Test and all its subtests than healthy controls. Overall, the heterogeneity among studies was moderate to high as well as the intra-country heterogeneity. The subgroup analysis, stratifying by country, maintained a high residual heterogeneity., Conclusion: The meta-regression showed a significant correlation with age and air pollution in a few subtests. A high heterogeneity was found among studies which was not significantly decreased after subgroup analysis by country. This fact signalizes that maybe cultural influence has a small impact on the Sniffin Sticks Test results. Age and air pollution have influence in a few olfactory subtests., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Guimarães Alves, Sukow, Adelman Cipolla, Mendes, Leal, Petzl-Erler, Lehtonen Rodrigues Souza, Rainha de Souza, Sanchez, Santolalla, Loesch, Dean, Machado, Moon, Kaplan, North, Weiss, Barreto, Lima-Costa, Guio, Cáceres, Padilla, Tarazona-Santos, Mata, Dieguez, Raggio, Lescano, Tumas, Borges, Ferraz, Rieder, Schumacher-Schuh, Santos-Lobato, Chana-Cuevas, Fernandez, Arboleda, Arboleda, Arboleda-Bustos, O’Connor, Beltrame and Borda.)

Objective: This work was undertaken in order to identify Parkinson's disease (PD) risk variants in a Latino cohort, to describe the overlap in the genetic architecture of PD in Latinos compared to European-ancestry subjects, and to increase the diversity in PD genome-wide association (GWAS) data., Methods: We genotyped and imputed 1,497 PD cases and controls recruited from nine clinical sites across South America. We performed a GWAS using logistic mixed models; variants with a p-value <1 × 10 -5 were tested in a replication cohort of 1,234 self-reported Latino PD cases and 439,522 Latino controls from 23andMe, Inc. We also performed an admixture mapping analysis where local ancestry blocks were tested for association with PD status., Results: One locus, SNCA, achieved genome-wide significance (p-value <5 × 10 -8 ); rs356182 achieved genome-wide significance in both the discovery and the replication cohorts (discovery, G allele: 1.58 OR, 95% CI 1.35-1.86, p-value 2.48 × 10 -8 ; 23andMe, G allele: 1.26 OR, 95% CI 1.16-1.37, p-value 4.55 × 10 -8 ). In our admixture mapping analysis, a locus on chromosome 14, containing the gene STXBP6, achieved significance in a joint test of ancestries and in the Native American single-ancestry test (p-value <5 × 10 -5 ). A second locus on chromosome 6, containing the gene RPS6KA2, achieved significance in the African single-ancestry test (p-value <5 × 10 -5 )., Interpretation: This study demonstrated the importance of the SNCA locus for the etiology of PD in Latinos. By leveraging the demographic history of our cohort via admixture mapping, we identified two potential PD risk loci that merit further study. ANN NEUROL 2021;90:353-365., (© 2021 American Neurological Association.)

Background: Parkinson's disease is the second most common neurodegenerative disorder and affects people from all ethnic backgrounds, yet little is known about the genetics of Parkinson's disease in non-European populations. In addition, the overall identification of copy number variants at a genome-wide level has been understudied in Parkinson's patients. The objective of this study was to understand the genome-wide burden of copy number variants in Latinos and its association with Parkinson's disease., Methods: We used genome-wide genotyping data from 747 Parkinson's disease patients and 632 controls from the Latin American Research Consortium on the Genetics of Parkinson's disease., Results: Genome-wide copy number burden analysis showed that patients were significantly enriched for copy number variants overlapping known Parkinson's disease genes compared with controls (odds ratio, 3.97; 95%CI, 1.69-10.5; P = 0.018). PRKN showed the strongest copy number burden, with 20 copy number variant carriers. These patients presented an earlier age of disease onset compared with patients with other copy number variants (median age at onset, 31 vs 57 years, respectively; P = 7.46 × 10 -7 )., Conclusions: We found that although overall genome-wide copy number variant burden was not significantly different, Parkinson's disease patients were significantly enriched with copy number variants affecting known Parkinson's disease genes. We also identified that of 250 patients with early-onset disease, 5.6% carried a copy number variant on PRKN in our cohort. Our study is the first to analyze genome-wide copy number variant association in Latino Parkinson's disease patients and provides insights about this complex disease in this understudied population. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

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.

We investigated the association between amyloid-β deposition and white matter (WM) integrity as a determinant of brain glucose hypometabolism across the Alzheimer's disease (AD) spectrum. We assessed ninety-six subjects (27 cognitively normal, 49 mild cognitive impairment, and 20 AD dementia) who underwent [ 18 F]FDG and [ 18 F]Florbetapir positron emission tomography (PET) as well as magnetic resonance imaging (MRI) with diffusion tensor imaging. Among the regions with reduced fractional anisotropy (FA) in the AD group, we selected a voxel of interest in the angular bundle bilaterally for subsequent analyses. Using voxel-based interaction models at voxel level, we tested whether the regional hypometabolism is associated with FA in the angular bundle and regional amyloid-β deposition. In the AD patients, [ 18 F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [ 18 F]Florbetapir standard uptake value ratios (SUVR) in these regions and low FA in the angular bundle. We found that the interaction between, rather than the independent effects of, high levels of amyloid-β deposition and WM integrity disruption determined limbic hypometabolism in patients with AD. This finding highlights a more integrative model for AD, where the interaction between partially independent processes determines the glucose hypometabolism.

Parkinson's disease (PD) is a progressive neurodegenerative disorder caused by the loss of dopamine, an important neurotransmitter involved in regulating movement. Nuclear medicine imaging methods such as single-photon emission computed tomography (SPECT) combined with radiotracers can obtain the density of this neurotransmitter. This reduced density leads to classic PD symptoms, such as bradykinesia, tremor and stiffness, consequently affecting walking and postural control. The aim of this study was to verify the correlation between disorders of gait kinematics and postural instability with dopamine depletion in individuals with mild to moderate PD. This is a descriptive, observational cross-sectional study. Subjects were assessed for spatiotemporal gait parameters by a three-dimensional motion capture system, for postural control by stabilometry on a force plate. Dopamine depletion was verified through 99mTc-TRODAT-1 (SPECT-CT) examination. The subjects were in the off-stage of levodopa in all analysis. We evaluated 71 individuals, 32 with mild to moderate PD (HY 2 and 2.5) and 39 healthy individuals matched for gender, age, and height. There was a significant difference between the groups regarding the spatiotemporal variables of gait, as well as in the stabilometric variables. However, there was no correlation between these disturbances and the uptake values of 99mTc-TRODAT-1. The results indicate that there is no correlation between gait impairments and postural instability of individuals with mild to moderate PD and the dopaminergic depletion measured through the 99mTc-TRODAT-1 (SPECT-CT)., (© 2018 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an established treatment for patients with Parkinson disease. One adverse event is the development of postoperative confusion. The aim of this study was to report the incidence and associated factors of postoperative confusion after STN DBS surgery., Methods: This was a retrospective cohort study by chart review of patients with Parkinson disease who underwent STN DBS in a Brazilian public academic hospital from January 2013 to October 2017. The primary outcome was the incidence of postoperative confusion. The association of the outcome and imaging and clinical variables was evaluated., Results: Among 49 patients who underwent STN DBS for Parkinson disease, the incidence of postoperative confusion was 26.5% (95% confidence interval 15%-41.1%). Univariate analysis identified the following variables associated with development of confusion: age (63.2 ± 7.8 years vs. 55.4 ± 9.1 years, P = 0.009), disease duration (16.5 ± 5.1 years vs. 13.2 ± 4.2 years, P = 0.027), Charlson comorbidity index (2 [interquartile range 1-3] vs. 1 [0-1 interquartile range], P = 0.002), width of the third ventricle (5.4 ± 2.1 mm vs. 4 ± 1.6 mm, P = 0.018), and cella media index (5 ± 1 vs. 5.6 ± 0.8, P = 0.018). After adjustment, Charlson comorbidity index remained significant (adjusted relative risk 1.64, 95% confidence interval 1.17-2.3, P = 0.004)., Conclusions: The incidence of postoperative confusion in this cohort was 26.5%. After analysis of confounding factors, the Charlson comorbidity index was significantly associated with postoperative confusion., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The role of neuroinflammation in Parkinson's disease (PD) has been demonstrated through several different approaches. It was suggested an inflammation-derived oxidative stress and cytokine-dependent toxicity role in the nigrostriatal pathway degeneration and hasten progression of disease. Tumor necrosis factor alpha (TNFA) gene promoter polymorphisms might alter the expression of this cytokine contributing to the pro- and anti-inflammatory polarization. An increased TNFA expression might lead to inflammatory profile predominance. The aim of study was to determine if TNFA haplotypes are associated with PD age at onset. Five polymorphisms in TNFA gene were investigated in 226 patients with idiopathic PD in relation to age at onset. Haplotype grouping was based on allele expression. Logistic binary regression analysis showed that the genetic background leading to higher TNF-α expression confers a higher risk to develop PD earlier. Gender and ancestry did not differ between groups. High TNFA expression may contribute for faster dopaminergic neuron degeneration. In this context, a higher genetic pro-inflammatory profile confers a higher risk to develop PD earlier., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a polyglutamine disorder with no current disease-modifying treatment. Conformational changes in mutant ataxin-3 trigger different pathogenic cascades, including reactive oxygen species (ROS) generation; however, the clinical relevance of oxidative stress elements as peripheral biomarkers of SCA3/MJD remains unknown. We aimed to evaluate ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/MJD individuals and correlate these markers with clinical and molecular data with the goal of assessing their properties as disease biomarkers., Methods: Molecularly confirmed SCA3/MJD carriers and controls were included in an exploratory case-control study. Serum ROS, measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) antioxidant enzyme activities, levels were assessed., Results: Fifty-eight early/moderate stage symptomatic SCA3/MJD, 12 presymptomatic SCA3/MJD, and 47 control individuals were assessed. The DCFH-DA levels in the symptomatic group were 152.82 nmol/mg of protein [95% confidence interval (CI), 82.57-223.08, p  < 0.001] higher than in the control and 243.80 nmol/mg of protein (95% CI, 130.64-356.96, p  < 0.001) higher than in the presymptomatic group. The SOD activity in the symptomatic group was 3 U/mg of protein (95% CI, 0.015-6.00, p  = 0.048) lower than in the presymptomatic group. The GSH-Px activity in the symptomatic group was 13.96 U/mg of protein (95% CI, 5.90-22.03, p  < 0.001) lower than in the control group and 20.52 U/mg of protein (95% CI, 6.79-34.24, p  < 0.001) lower than in the presymptomatic group and was inversely correlated with the neurological examination score for spinocerebellar ataxias ( R  = -0.309, p  = 0.049)., Conclusion: Early/moderate stage SCA3/MJD patients presented a decreased antioxidant capacity and increased ROS generation. GSH-Px activity was the most promising oxidative stress disease biomarker in SCA3/MJD. Further longitudinal studies are necessary to identify both the roles of redox parameters in SCA3/MJD pathophysiology and as surrogate outcomes for clinical trials.

We compare the effects of Nordic walking training (NW) and Free walk (FW) on functional parameters (motor symptoms, balance) and functional mobility (Timed Up and Go at Self-selected Speed - TUGSS, and at forced speed, TUGFS; Self-selected Walking Speed, SSW; locomotor rehabilitation index, LRI) of Parkinson's disease (PD) patients. The study included 33 patients with clinical diagnosis of idiopathic PD, and staging between 1 and 4 in the Hoehn and Yahr scale (H&Y) randomized into two groups: NW (N = 16) and FW (N = 17) for 6 weeks. Baseline characteristics were compared trough a one-way ANOVA. Outcomes were analyzed using the Generalized Estimation Equations (GEE) with a Bonferroni post-hoc. Data were analyzed using SPSS v.20.0. Improvements in UPDRS III (P < 0.001), balance scores (P < 0.035), TUGSS distance (P < 0.001), TUGFS distance (P < 0.001), SSW (P < 0.001), and LRI (P < 0.001) were found for both groups. However, the NW group showed significant differences (P < 0.001) when compared to the FW group for the functional mobility. We conclude the NW improves functional parameters and walking mobility demonstrating that NW is as effective as the FW, including benefits for FW on the functional mobility of people with PD., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Parkinson's disease (PD) is a common and complex neurodegenerative disorder, the second most prevalent, only behind Alzheimer's disease. Recent studies suggest that environmental factors may contribute for neurodegeneration through induction of epigenetic modifications, such as DNA methylation, that is carried out by enzymes, such as DNMT1 and DNMT3B. This present study targeted to investigate the association among DNMT1 and DNMT3B polymorphisms with PD. Five hundred and twenty-two participants (214 PD patients following UK Brain Bank criteria and 308 healthy individuals) were evaluated. DNA was obtained from whole blood and genotypes were detected by an allelic discrimination assay using TaqMan ® MGB probes on a real-time PCR system. The polymorphisms studied were rs2162560 and rs759920 (DNMT1) and rs2424913, rs998382 and rs2424932 (DNMT3B). Was found association between DNMT3B rs2424913 in T allele carriers with PD. The presence of the T allele was associated with PD (OR=1.80, 95% CI 1.16-2.81, p=0.009). No significant difference was observed for others DNMT3B SNPs. Also, no association between PD and the control group were observed for DNMT1 polymorphisms. This is the first study addressing an association between DNMT3B polymorphism and PD. The polymorphism may play a role in the pathogenesis of PD., (Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.)

Aims . To verify the effectiveness of the maneuver application in swallowing therapy with PD. Materials and Method . We performed an open-label trial, with three groups compounds by PD individuals: the experimental group, control group, and orientation group. The study included PD patients with dysphagia. A cognitive screening, through a questionnaire about depression and quality of life, was conducted. Swallowing assessment was performed through (1) fiberoptic endoscopic evaluation of swallowing (FEES); (2) clinical evaluation and Functional Oral Intake Scale (FOIS); and (3) assessment of the quality life related to swallowing (SWALQOL). A therapeutic program, which consisted of chin-down postural maneuver and orientations on feeding, was applied. Both groups (EG and OG) received on-month therapeutic program. Results . A significant improvement in swallowing, evaluated by clinical assessment, was observed in solid ( p < 0.001) and liquid ( p = 0.022) consistencies in EG when compared to OG and CG. Patients in EG presented improvement in QoL, with the significant difference in comparison with the other groups, about domain frequency of symptoms ( p = 0.029) in SWALQOL questionnaire. Conclusion . The postural maneuver chin-down improved swallowing performance and self-perception, but not the laryngeal signs. This trial is registered with registration number NCT02973698., Competing Interests: The authors declare no conflict of interests.

Background: Parkinson's disease (PD) shows symptoms involving motor and non-motor complications, including cognitive and behavioral changes, such changes might to contraindicate deep brain stimulation surgery (DBS)., Objective: The aim of study was to investigate the neuropsychological profile of patients with PD in a waiting list for DBS., Methods: The neuropsychological evaluation was held in 30 patients of the ISCMPA Movement Disorders Clinic, with surgical indication based on the criteria of the responsible neurologists, in the period of 12 months. Instruments used: MMSE, FAB, MoCA, BDI, Semantic Verbal Fluency, PDQ-39, PDSS; and the UPDRS and Hoehn-Yahr scale., Results: The patients were mostly male (66.7%) with a mean age of 59.37 (SD 10.60) and disease duration 9.33 (SD 4.08). There was cognitive impairment in 56.7% of patients by FAB and 76.7% by MoCA., Conclusion: Even in the earliest stages of the disease, there is the incidence of non-motor symptoms, especially in those subjects who had an early onset of the disease., Competing Interests: Disclosure: The authors report no conflicts of interest.

Objective: Correlate the occurrence of falls and the activity of rolling over in bed with performance on the Trunk Mobility Scale (TMS) in patients with PD, and determine whether this instrument score can predict the risk of falls., Method: This is a cross-sectional study. Assessed patients reported the frequency of falls in the previous year and whether they had difficulties rolling over in bed. Then, the following scales were applied: TMS, Hoehn and Yahr, Unified Parkinson's Disease Rating Scale-III and Schwab and England Activities of Daily Living., Results: Eighty-five patients were analyzed. Patients with a history of falling showed worse performance in the TMS (p < 0.01). There is a significant correlation between TMS and the activity of rolling over in bed (p < 0.01)., Conclusion: PD fallers present worse scores in TMS, and there is a significant correlation between difficulty rolling over in bed and TMS score.

Introduction: Deep Brain Stimulation (DBS) has been satisfactorily used to control the cardinal motor symptoms of Parkinson's disease (PD), but little is known about its impact on communication., Purpose: This study aimed to characterize the aspects of cognition, language, speech, voice, and self-perception in two patients with PD, pre- and post- DBS implant surgery., Methods: The patients were assessed using a cognitive screening test, a brief language evaluation, a self-declared protocol, and an analysis of the aspects of voice and speech, which was conducted by a specialized Speech-language Therapist who was blinded for the study., Results: At the pre-surgery assessment, Case I showed impairment regarding the aspects of cognition, language and voice, whereas Case II showed impairment only with respect to the voice aspect. The post-surgery evaluation of the cases showed an opposite pattern of the effect of DBS after analysis of the communication data: Case I, who presented greater impairment before the surgery, showed improvement in some aspects; Case II, who presented lower communicative impairment before the surgery, showed worsening in other aspects., Conclusion: This study shows that DBS may influence different communication aspects both positively and negatively. Factors associated with the different effects caused by DBS on the communication of patients with PD need to be further investigated.

Introduction: Dysphagia is a common symptom in Parkinson's disease (PD) and it has been associated with poor quality of life (QoL), anxiety, depression., Objective: The aim of this study was to evaluate the quality of life in individuals with PD before and after SLP therapy., Methods: The program consisted of four individual therapy sessions. Each session comprised guidelines regarding food and postural maneuvers (chin down). The Quality of Life in Swallowing Disorders (SWAL-QOL) questionnaire was applied before and after therapy., Results: The sample comprised of 10 individuals (8 men), with a mean (SD) age of 62.2 (11.3) years, mean educational attainment of 7.5 (4.3) years, and mean disease duration of 10.7 (4.7) years. Thirty percent of patients were Hoehn and Yahr (H&Y) stage 2, 50% were H&Y stage 3, and 20% were H&Y stage 4. Mean scores for all SWAL-QOL domains increased after the intervention period, with significant pre- to post-therapy differences in total score (p = 0.033) and domain 4 (symptom frequency) (p = 0.025). There was also a bias significance for domain 5 (food selection) (p = 0.095)., Conclusion: Patients exhibited improvement in swallowing-related quality of life after a SLP therapy program. The earlier in the course of PD, greater the improvement observed after therapy.

Aim: Levodopa is first-line treatment of Parkinson's disease motor symptoms but, dose response is highly variable. Therefore, the aim of this study was to determine how much levodopa dose could be explained by biological, pharmacological and genetic factors., Patients & Methods: A total of 224 Parkinson's disease patients were genotyped for SV2C and SLC6A3 polymorphisms by allelic discrimination assays. Comedication, demographic and clinical data were also assessed., Results: All variables with p < 0.20 were included in a multiple regression analysis for dose prediction. The final model explained 23% of dose variation (F = 11.54; p < 0.000001)., Conclusion: Although a good prediction model was obtained, it still needs to be tested in an independent sample to be validated.

Parkinson's disease (PD) is one of the most common neurodegenerative diseases worldwide. Besides characteristic PD motor features, the disease has important non-motor characteristics such as cognitive impairment. The role of genetic factors in cognitive impairment associated with PD is still unclear. In this study, we examined whether BDNF Val66Met was associated with impaired cognition in Parkinson's disease. One hundred and seventy five patients with a clinical diagnosis of Parkinson's disease were included. Global cognitive abilities of the patients were measured by the Mini-Mental State Examination (MMSE). Poisson Regression models were used to test for association between 66Met carriers and cognitive impairment controlling for covariates. Carriers of at least one BDNF 66Met allele presented a higher prevalence of cognitive impairment (p=0.005 RR=1.45 IC=95% [1.1-1.8]). These results suggest a role for BDNF Val66Met polymorphism on cognitive impairment in PD., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD)., Methods: The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies., Results: We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD., Interpretation: Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis., (© 2016 American Neurological Association.)

Parkinson's disease (PD) is characterized by progressive motor impairment attributed to progressive loss of dopaminergic neurons in the substantia nigra (SN) pars compacta. In addition to an accumulation of iron, there is also an increased production of reactive oxygen/nitrogen species (ROS/RNS) and inflammatory markers. These observations suggest that iron dyshomeostasis may be playing a key role in neurodegeneration. However, the mechanisms underlying this metal-associated oxidative stress and neuronal damage have not been fully elucidated. To determine peripheral levels of iron, ferritin, and transferrin in PD patients and its possible relation with oxidative/nitrosative parameters, whilst attempting to identify a profile of peripheral biomarkers in this neurological condition. Forty PD patients and 46 controls were recruited to compare serum levels of iron, ferritin, transferrin, oxidative stress markers (superoxide dismutase (SOD), catalase (CAT), nitrosative stress marker (NOx), thiobarbituric acid reactive substances (TBARS), non-protein thiols (NPSH), advanced oxidation protein products (AOPP), ferric reducing ability of plasma (FRAP) and vitamin C) as well as inflammatory markers (NTPDases, ecto-5'-nucleotidase, adenosine deaminase (ADA), ischemic-modified albumin (IMA) and myeloperoxidase). Iron levels were lower in PD patients, whereas there was no difference in ferritin and transferrin. Oxidative stress (TBARS and AOPP) and inflammatory markers (NTPDases, IMA, and myeloperoxidase) were significantly higher in PD, while antioxidants FRAP, vitamin C, and non-protein thiols were significantly lower in PD. The enzymes SOD, CAT, and ecto-5'-nucleotidase were not different among the groups, although NOx and ADA levels were significantly higher in the controls. Our data corroborate the idea that ROS/RNS production and neuroinflammation may dysregulate iron homeostasis and collaborate to reduce the periphery levels of this ion, contributing to alterations observed in the pathophysiology of PD.

Background. Changes in proprioception may contribute to postural instability in individuals with neurological disorders. Objectives. Evaluate proprioception in the lower limbs of patients with Parkinson's disease (PD) and the association between proprioception and cognitive ability, motor symptoms, postural instability, and disease severity. Methods. This is a cross-sectional, controlled study that evaluated proprioception in PD patients and healthy age- and sex-matched individuals. Kinetic postural proprioception of the knee was evaluated using an isokinetic dynamometer (Biodex® Multi-Joint System 4 Pro). Participants were evaluated using the Montreal Cognitive Assessment (MoCA), the Hoehn and Yahr rating scale and postural instability (pull test and stabilometric analysis), and motor function (UPDRS-III) tests. Results. A total of 40 individuals were enrolled in the study: 20 PD patients and 20 healthy controls (CG). The PD patients had higher angular errors on the proprioceptive ratings than the CG participants (p = 0.002). Oscillations of the center of pressure (p = 0.002) were higher in individuals with PD than in the controls. Proprioceptive errors in the PD patients were associated with the presence of tremors as the dominant symptom and more impaired motor performance. Conclusion. These findings show that individuals with PD have proprioceptive deficits, which are related to decreased cognitive ability and impaired motor symptoms.

Introduction. Deep brain stimulation of the subthalamic nucleus (STN-DBS) in Parkinson's disease (PD) has been linked to a decline in verbal fluency. The decline can be attributed to surgical effects, but the relative contributions of the stimulation parameters are not well understood. This study aimed to investigate the impact of the frequency of STN-DBS on the performance of verbal fluency tasks in patients with PD. Methods. Twenty individuals with PD who received bilateral STN-DBS were evaluated. Their performances of verbal fluency tasks (semantic, phonemic, action, and unconstrained fluencies) upon receiving low-frequency (60 Hz) and high-frequency (130 Hz) STN-DBS were assessed. Results. The performances of phonemic and action fluencies were significantly different between low- and high-frequency STN-DBS. Patients showed a decrease in these verbal fluencies for high-frequency STN-DBS. Conclusion. Low-frequency STN-DBS may be less harmful to the verbal fluency of PD patients., Competing Interests: The authors declare that they have no competing interests.

Background: In a recent phase 2 clinical trial in spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), a neurogenetic disorder without specific therapy, benefits of lithium carbonate were found only on secondary efficacy outcomes, all related to ataxic features. In order to help designing future studies, we further analyzed the trial data searching for treatment response modifiers and metric properties of spinocerebellar ataxia (SCA) scales., Methods: Efficacy analysis was performed with the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) subscores and with the subgroup of patients with independent gait according to the 8-meter walking-time (8MW). Interactions of clinical/molecular findings with treatment response, minimally important differences (MIDs), and sample size estimations for NESSCA, SARA, Spinocerebellar Ataxia Functional Index (SCAFI) and Composite Cerebellar Functional Score (CCFS) were evaluated., Results: 62 SCA3/MJD patients had been randomly assigned (1:1) for the double-blind, placebo-controlled trial. While cerebellar NESSCA (range: 0-7 points) differed between groups 0.64 points (95% CI 0.23 to 1.05, p<0.001) over the whole 48weeks of study, favoring lithium, no effect was found on non-ataxia subscores. Among patients able to perform the 8MW on baseline, NESSCA (p=0.010) and SCAFI (p=0.015) differed between groups favoring lithium. Finally, estimated sample sizes for the scales were provided., Conclusion: Lithium efficacy on cerebellar NESSCA, and on SCAFI and CCFS in the primary analysis, together with the lack of effect on non-ataxia features suggests that lithium should be tested in phase 3 trials in SCA3/MJD and that ataxia scales should be preferred to multisystem neurological instruments as the primary outcome. The inclusion of early stage patients is advisable in future clinical trials in SCA3/MJD., Trial Registration: clinicaltrials.gov identifier: NCT01096082., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Calcium-binding protein B (S100B), a primary product of astrocytes, is a proposed marker of Parkinson's Disease (PD) pathophysiology, diagnosis and progression. However, it has also been implicated in sleep disruption, which is very common in PD. To explore the relationship between S100B, disease severity, sleep symptoms and polysomnography (PSG) findings, overnight changes in serum S100B levels were investigated for the first time in PD. 17 fully treated, non-demented, moderately advanced PD patients underwent PSG and clinical assessment of sleep symptoms. Serum S100B samples were collected immediately before and after the PSG. Results are shown as median [interquartile range]. Night and morning S100B levels were similar, but uncorrelated (rs=-0.277, p=0.28). Morning S100B levels, as opposed to night levels, positively correlated with the Unified Parkinson's Disease rating scale (UPDRS) subsections I and II (rs=0.547, p=0.023; rs=0.542, p=0.025). Compared to those with overnight S100B reduction, patients with overnight S100B elevation had higher H&Y scores (2.5 [0.87] vs. 2 [0.25], p=0.035) and worse total Pittsburgh Sleep Quality Index (PSQI) and Parkinson's Disease Sleep Scores (10 [3.2] vs. 8 [4.5], p=0.037; 92.9 [39] vs. 131.4 [28], p=0.034). Correlation between morning S100B levels and total UPDRS score was strengthened after controlling for total PSQI score (rs=0.531, p=0.034; partial rs=0.699, p=0.004, respectively). Overnight S100B variation and morning S100B were associated with PD severity and perceived sleep disruption. S100B is proposed as a putative biomarker for sleep-related neuroinflammation in PD. Noradrenergic-astrocytic dysfunction is hypothesized as a possible mechanism underlying these findings., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Sleep EEG spectral patterns were investigated in eight newly diagnosed, non-depressed, non-demented, drug-naïve Parkinson's disease patients compared to nine controls., Methods: Mean relative spectral power density calculated for 0.25 Hz frequency bins and for classical EEG frequency bands., Results: Differences between patients and controls were most prominent in non-REM sleep, specially around 8.6 Hz (slow alpha), 12.5 Hz (fast alpha/slow sigma) and 15 Hz (fast sigma). Slow alpha showed lower p-values over frontal and occipital electrodes, whereas fast sigma activity was more important on central and parietal sites. Significantly increased NREM sleep alpha activity was found in left and right frontal (Mann-Whitney U=12,000, p=.021; U=14,000, p=.036), left and right central (U=14,000, p=.036), left parietal and left occipital (U=13,000, p=.027; U=15,000, p=.046) areas. Increased sigma activity was found in right frontal (U=14,000, p=.036), left central (U=12,000, p=.021), left and right parietal (U=12,000, p=.021; U=13,000, p=.027) and left occipital (U=15,000, p=.046) areas., Conclusions: Concomitantly increased scalp EEG alpha and sigma activity was found during NREM sleep in initial Parkinson's disease., Significance: These non-REM sleep microstructure changes may represent evidence for altered electrophysiological mechanisms leading to sleep-wake instability in early disease stages., (Copyright © 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Aim: Levodopa is first line treatment of Parkinson's disease (PD). However, its use is associated with the presence of motor fluctuations and dyskinesias. In recent years, adenosine A2A receptor (A2AR) is rising as a therapeutic target for PD. The aim of the present study was to investigate whether ADORA2A is associated with levodopa adverse effects., Patients & Methods: Two hundred and eight PD patients on levodopa therapy were investigated. rs2298383 and rs3761422 at the ADORA2A gene were genotyped by allelic discrimination assays., Results: A trend for association was observed for both polymorphism and diplotypes with dyskinesia., Conclusion: The present results should be considered as positive preliminary evidence. Further studies are needed to determine the association between ADORA2A and dyskinesia. Original submitted 3 December 2014; Revision submitted 13 February 2015.

Objective. To assess the presence of nonverbal and verbal apraxia in patients with Parkinson's disease (PD) and analyze the correlation between these conditions and patient age, education, duration of disease, and PD stage, as well as evaluate the correlation between the two types of apraxia and the frequency and types of verbal apraxic errors made by patients in the sample. Method. This was an observational prevalence study. The sample comprised 45 patients with PD seen at the Movement Disorders Clinic of the Clinical Hospital of Porto Alegre, Brazil. Patients were evaluated using the Speech Apraxia Assessment Protocol and PD stages were classified according to the Hoehn and Yahr scale. Results. The rate of nonverbal apraxia and verbal apraxia in the present sample was 24.4%. Verbal apraxia was significantly correlated with education (p ≤ 0.05). The most frequent types of verbal apraxic errors were omissions (70.8%). The analysis of manner and place of articulation showed that most errors occurred during the production of trill (57.7%) and dentoalveolar (92%) phonemes, consecutively. Conclusion. Patients with PD presented nonverbal and verbal apraxia and made several verbal apraxic errors. Verbal apraxia was correlated with education levels.

Background. Prognosis of PD is variable. Most studies show higher mortality rates in PD patients compared to the general population. Clinical and epidemiologic factors predicting mortality are poorly understood. Methods. Clinical and epidemiologic features including patient history and physical, functional, and cognitive scores were collected from a hospital-based cohort of PD patients using standardized protocols and clinical scales. Data on comorbidities and mortality were collected on follow-up. Results. During a mean follow-up of 4.71 years (range 1-10), 43 (20.9%) of the 206 patients died. Those who died had higher mean age at disease onset than those still alive at the last follow-up (67.7 years versus 56.3 years; p < 0.01). In the univariate analysis, age at baseline was associated with decreased survival. In the adjusted Cox proportional hazards model, age at disease onset and race/ethnicity were predictors of mortality. Conclusions. Late age at disease onset and advanced chronological age are associated with decreased survival. Comorbidities and PD characteristics were not associated with decreased survival in our sample. Race/ethnicity was found in our study to be associated with increased hazard of mortality. Our findings indicate the importance of studying survival among different populations of PD patients.

The aim of this study was to identify the relative frequency of Huntington's disease (HD) and HD-like (HDL) disorders HDL1, HDL2, spinocerebellar ataxia type 2 (SCA2), SCA17, dentatorubral-pallidoluysian degeneration (DRPLA), benign hereditary chorea, neuroferritinopathy and chorea-acanthocytosis (CHAC), in a series of Brazilian families. Patients were recruited in seven centers if they or their relatives presented at least chorea, besides other findings. Molecular studies of HTT, ATXN2, TBP, ATN1, JPH3, FTL, NKX2-1/TITF1 and VPS13A genes were performed. A total of 104 families were ascertained from 2001 to 2012: 71 families from South, 25 from Southeast and 8 from Northeast Brazil. There were 93 HD, 4 HDL2 and 1 SCA2 families. Eleven of 104 index cases did not have a family history: 10 with HD. Clinical characteristics were similar between HD and non-HD cases. In HD, the median expanded (CAG)n (range) was 44 (40-81) units; R(2) between expanded HTT and age-at-onset (AO) was 0.55 (p=0.0001, Pearson). HDL2 was found in Rio de Janeiro (2 of 9 families) and Rio Grande do Sul states (2 of 68 families). We detected HD in 89.4%, HDL2 in 3.8% and SCA2 in 1% of 104 Brazilian families. There were no cases of HDL1, SCA17, DRPLA, neuroferritinopathy, benign hereditary chorea or CHAC. Only six families (5.8%) remained without diagnosis., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.

Parkinson's disease (PD) is unique among neurodegenerative disorders because a highly effective pharmacological symptomatic treatment is available. The marked variability in drug response and in adverse profiles associated with this treatment led to the search of genetic markers associated with these features. We present a review of the literature on PD pharmacogenetics to provide a critical discussion of the current findings, new approaches, limitations and recommendations for future research. Pharmacogenetics studies in this field have assessed several outcomes and genes, with special focus on dopaminergic genes, mainly DRD2, which is the most important receptor in nigrostriatal pathway. The heterogeneity in methodological strategies employed by different studies is impressive. The question of whether PD pharmacogenetics studies will improve clinical management by causing a shift from a trial-and-error approach to a pharmacological regimen that takes into account the individual variability remains an open question. Collaborative longitudinal studies with larger sample sizes, better outcome definitions and replication studies are required.

Background: Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5-0.8 milliequivalents per liter) in patients with Machado-Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3])., Methods: For this phase 2, single-center, double-blind, parallel, placebo-controlled trial (ClinicalTrials.gov identifier NCT01096082), 62 patients who had MJD/SCA3 with a disease duration ≤10 years and an independent gait were randomly assigned (1:1) to receive either lithium or placebo., Results: After 24 weeks, 169 adverse events were reported, including 50.3% in the lithium group (P = 1.00; primary safety outcome). Sixty patients (31 in the placebo group and 29 in the lithium group) were analyzed for efficacy (intention-to-treat analysis). Mean progression between groups did not differ according to scores on the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) after 48 weeks (-0.35; 95% confidence interval, -1.7 to 1.0; primary efficacy outcome). The lithium group exhibited minor progression on the PATA speech-rate (P = 0.002), the nondominant Click Test (P = 0.023), the Spinocerebellar Ataxia Functional Index (P = 0.003), and the Composite Cerebellar Functional Score (P = 0.029)., Conclusions: Lithium was safe and well tolerated, but it had no effect on progression when measured using the NESSCA in patients with MJD/SCA3. This slowdown in secondary outcomes deserves further clarification., (© 2014 International Parkinson and Movement Disorder Society.)