Frequency of Hereditary and GBA1-Related Parkinsonism in Latin America: A Systematic Review and Meta-Analysis.

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 I2 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.

History of high household pesticide use and Parkinson's disease in Brazil.

The prevalence of Parkinson's disease (PD) is growing worldwide and household pesticides exposure may be related to this phenomenon. We showed that individuals with high exposure to household pesticides have two times more risk of developing PD. Household pesticide exposure did not impact age at PD onset.

Life-space mobility, balance, and self-efficacy in Parkinson disease: A cross-sectional study.

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 (R2  = 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.

Systematic review and meta-analysis of Sniffin Sticks Test performance in Parkinson's disease patients in different countries.

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.

Postoperative Confusion in Patients with Parkinson Disease Undergoing Deep Brain Stimulation of the Subthalamic Nucleus.

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.

Regional Amyloid-ß Load and White Matter Abnormalities Contribute to Hypometabolism in Alzheimer's Dementia.

We investigated the association between amyloid-ß 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 [18F]FDG and [18F]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-ß deposition. In the AD patients, [18F]FDG hypometabolism in the striatum, mesiobasal temporal, orbitofrontal, precuneus, and cingulate cortices were associated with the interaction between high levels of [18F]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-ß 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.

Impairments in gait kinematics and postural control may not correlate with dopamine transporter depletion in individuals with mild to moderate Parkinson's disease.

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).

Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

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.

Wearing-off in Parkinson's disease: neuropsychological differences between on and off periods.

BACKGROUND: 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<0.05). Differences were also found in the semantic verbal fluency (P=0.017) and executive function (P=0.008) tests performance. CONCLUSIONS: Nonmotor symptoms such as anxiety and depression, verbal fluency, and executive function performance are influenced by motor fluctuations.

A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease.

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.

Evidence that folic acid deficiency is a major determinant of hyperhomocysteinemia in Parkinson's disease.

In the present work we measured blood levels of total homocysteine ((t)Hcy), vitamin B(12) and folic acid in patients with Parkinson s disease (PD) and in age-matched controls and searched for possible associations between these levels with smoking, alcohol consumption, L-DOPA treatment and disease duration in PD patients. We initially observed that plasma (t)Hcy levels were increased by around 30 % in patients affected by PD compared to controls. Linear correlation, multiple regression and comparative analyses revealed that the major determinant of the increased plasma concentrations of (t)Hcy in PD patients was folic acid deficiency, whereas in controls (t)Hcy levels were mainly determined by plasma vitamin B(12) concentrations. We also observed that alcohol consumption, gender and L-DOPA treatment did not significantly alter plasma (t)Hcy, folic acid and vitamin B(12) levels in parkinsonians. Furthermore, disease duration was positively associated with (t)Hcy levels and smoking was linked with a deficit of folic acid in PD patients. Considering the potential synergistic deleterious effects of Hcy increase and folate deficiency on the central nervous system, we postulate that folic acid should be supplemented to patients affected by PD in order to normalize blood Hcy and folate levels, therefore potentially avoiding these risk factors for neurologic deterioration in this disorder.