Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 2.

The field of neuromodulation has evolved significantly over the past decade. Developments include novel indications and innovations of hardware, software, and stimulation techniques leading to an expansion in scope and role of these techniques as powerful therapeutic interventions. In this review, which is the second part of an effort to document and integrate the basic fundamentals and recent successful developments in the field, we will focus on classic paradigms for electrode placement as well as new exploratory targets, mechanisms of neuromodulation using this technique and new developments, including focused ultrasound driven ablative procedures.

O campo da neuromodulação evoluiu significativamente na última década. Esse progresso inclui novas indicações e inovações de hardware, software e técnicas de estimulação, levando a uma expansão das áreas clínicas cobertas e no papel dessas técnicas como intervenções terapêuticas eficazes. Nesta revisão, que é a segunda parte de um esforço para documentar e integrar os fundamentos básicos e os desenvolvimentos recentes e bem-sucedidos no campo, vamos nos concentrar em paradigmas clássicos para colocação de eletrodos, bem como em novos alvos exploratórios, mecanismos de neuromodulação usados por esta técnica e novos desenvolvimentos, incluindo procedimentos ablativos orientados por ultrassom focalizado.

Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 1.

Deep brain stimulation (DBS) is recognized as an established therapy for Parkinson's disease (PD) and other movement disorders in the light of the developments seen over the past three decades. Long-term efficacy is established for PD with documented improvement in the cardinal motor symptoms of PD and levodopa-induced complications, such as motor fluctuations and dyskinesias. Timing of patient selection is crucial to obtain optimal benefits from DBS therapy, before PD complications become irreversible. The objective of this first part review is to examine the fundamental concepts of DBS for PD in clinical practice, discussing the historical aspects, patient selection, potential effects of DBS on motor and non-motor symptoms, and the practical management of patients after surgery.

Nas últimas três décadas, a estimulação cerebral profunda (ECP) se tornou um tratamento bem estabelecido para doença de Parkinson (DP) e outros transtornos do movimento. A eficácia a longo prazo na DP foi bem documentada para a melhora dos sintomas motores cardinais da DP e das complicações induzidas pelo uso do levodopa, como as flutuações motoras e as discinesias. O momento da seleção do paciente é crucial para se obter os benefícios ideais da ECP, antes que as complicações da DP se tornem irreversíveis. O objetivo desta primeira parte da revisão é examinar os conceitos fundamentais da ECP na prática clínica, discutindo os aspectos históricos, a seleção de pacientes, os potenciais efeitos da ECP nos sintomas motores e não motores da doença e o manejo prático dos pacientes após a cirurgia.

Clinical, neuroimaging and genetic findings in Brazilian patients with neurodegeneration with brain iron accumulation.

Neurodegeneration with brain iron accumulation (NBIA) encompasses a clinically and genetically heterogeneous group of rare disorders. Here, we report clinical, neuroimaging and genetic studies in twenty three Brazilian NBIA patients. In thirteen subjects, deleterious variants were detected in known NBIA-causing genes (PANK2, PLA2G6, C9ORF12, WDR45 and FA2H), including previously unreported variants in PANK2 and PLA2G6. Two patients carried rare, likely pathogenic variants in genes not previously associated with NBIA: KMT2A c.11785A > C (p.Ile3929Leu), and TIMM8A c.127T > C (p.Cys43Arg), suggesting an expansion of their associated phenotypes to include NBIA. In eight patients the etiology remains unsolved, suggesting variants undetectable by the adopted methods, or the existence of additional NBIA-causing genes.

An OpenSim-Based Closed-Loop Biomechanical Wrist Model for Subject-Specific Pathological Tremor Simulation.

OBJECTIVE: A pathological tremor (PT) is an involuntary rhythmic movement of varying frequency and amplitude that affects voluntary motion, thus compromising individuals' independence. A comprehensive model incorporating PT's physiological and biomechanical aspects can enhance our understanding of the disorder and provide valuable insights for therapeutic approaches. This study aims to build a biomechanical model of pathological tremors using OpenSim's realistic musculoskeletal representation of the human wrist with two degrees of freedom. METHODS: We implemented a Matlab/OpenSim interface for a forward dynamics simulation, which allows for the modeling, simulation, and design of a physiological H∞ closed-loop control. This system replicates pathological tremors similar to those observed in patients when their arm is extended forward, the wrist is pronated, and the hand is subject to gravity forces. The model was individually tuned to five subjects (four Parkinson's disease patients and one diagnosed with essential tremor), each exhibiting distinct tremor characteristics measured by an inertial sensor and surface EMG electrodes. Simulation agreement with the experiments for EMGs, central frequency, joint angles, and angular velocities were evaluated by Jensen-Shannon divergence, histogram centroid error, and histogram intersection. RESULTS: The model emulated individual tremor statistical characteristics, including muscle activations, frequency, variability, and wrist kinematics, with greater accuracy for the four Parkinson's patients than the essential tremor. CONCLUSION: The proposed model replicated the main statistical features of subject-specific wrist tremor kinematics. SIGNIFICANCE: Our methodology may facilitate the design of patient-specific rehabilitation devices for tremor suppression, such as neural prostheses and electromechanical orthoses.

The impact of the socioeconomic factor on Parkinson's disease medication adherence: a scoping review.

BACKGROUND: Therapeutic adherence is a decisive issue on chronic disease management in patients requiring long-term pharmacotherapy, such as Parkinson's disease (PD). Although it is well known that socioeconomic factor is a barrier to medication adherence in many chronic diseases, its impacts on PD still need to be investigated. OBJECTIVE: Explore what and how socioeconomic factors impact medication adherence in people with PD. METHODS: We carried out a scoping review across three databases to identify studies exploring what and how socioeconomic factors impact medication adherence in people with PD considering eight attributes: 1. educational level, 2. disease-related knowledge, 3. income, 4. cost of medication, 5. drug subsidy (meaning presence of subsidies in the cost of medication), 6. employability, and 7. ethnicity (black, indigenous, immigrants). RESULTS: Of the 399 identified studies (Embase = 294, Medline = 88, LILACS = 17), eight met inclusion criteria. We identified factors covering the eight attributes of socioeconomic impact, and all of them negatively impacted the medication adherence of people with PD. The most prevalent factor in the studies was low patient educational level (four studies), followed by costs of medications (three studies), income (three studies), and disease-related knowledge (three studies). Distinctly from most of the studies selected, one of them evidenced suboptimal adherence in individuals receiving the medication free of charge, and another one could not find correlation between suboptimal adherence and educational level. CONCLUSION: Socioeconomic factors negatively impact medication adherence in PD patients. This review provides basis for developing patient and population-based interventions to improve adherence to treatment in PD.

ANTECEDENTES: A adesão à medicação é um componente crucial no manejo correto da doença de Parkinson (DP) e, embora esteja bem estabelecido que o fator socioeconômico é uma barreira à adesão medicamentosa em muitas doenças crônicas, seus impactos na DP ainda precisam ser investigados. OBJETIVO: Explorar quais são e como os fatores socioeconômicos afetam a adesão à medicação em pessoas com DP. MéTODOS: Realizamos uma revisão de escopo em três bases de dados para identificar estudos que explorassem quais e como os fatores socioeconômicos impactam na adesão à medicação em pessoas com DP, considerando oito atributos: 1. nível educacional, 2. conhecimento relacionado à doença, 3. renda, 4. custo de medicamentos, 5. subsídio de medicamentos (ou seja, presença de subsídios no custo dos medicamentos), 6. empregabilidade e 7. etnia (negra, indígena, imigrantes). RESULTADOS: Dos 399 estudos identificados (Embase = 294, Medline = 88, LILACS = 17), oito preencheram os critérios de inclusão. Identificamos fatores que abrangem os oito atributos de impacto socioeconômico e todos impactaram negativamente na adesão medicamentosa de pessoas com DP. Foram mais prevalentes o baixo nível educacional do paciente (quatro estudos), custos dos medicamentos, nível de renda e conhecimento relacionado à doença (três estudos cada). Diferentemente da maioria dos estudos selecionados, um deles evidenciou adesão subótima em indivíduos que receberam a medicação gratuitamente, e outro não encontrou correlação entre adesão subótima e nível educacional. CONCLUSãO: Fatores socioeconômicos impactam negativamente a adesão ao tratamento medicamentoso em pessoas com DP. Esta revisão fornece base para o desenvolvimento de intervenções baseadas em pacientes e populações no intuito de melhorar a adesão ao tratamento farmacológico de pessoas com DP.

Task-related brain activity in upper limb dystonia revealed by simultaneous fNIRS and EEG.

OBJECTIVE: The aim of this study was to explore differences in brain activity and connectivity using simultaneous electroencephalography and near-infrared spectroscopy in patients with focal dystonia during handwriting and finger-tapping tasks. METHODS: Patients with idiopathic right upper limb focal dystonia and controls were assessed by simultaneous near-infrared spectroscopy and electroencephalography during the writing and finger-tapping tasks in terms of the mu-alpha, mu-beta, beta and low gamma power and effective connectivity, as well as relative changes in oxyhemoglobin (oxy-Hb) and deoxyhemoglobin using a channel-wise approach with a mixed-effect model. RESULTS: Patients exhibited higher oxy-Hb levels in the right and left motor cortex and supplementary motor area during writing, but lower oxy-Hb levels in the left sensorimotor and bilateral somatosensory area during finger-tapping compared to controls. During writing, patients showed increased low gamma power in the bilateral sensorimotor cortex and less mu-beta and beta attenuation compared to controls. Additionally, patients had reduced connectivity between the supplementary motor area and the left sensorimotor cortex during writing. No differences were observed in terms of effective connectivity in either task. Finally, patients failed to attenuate the mu-alpha, mu-beta, and beta rhythms during the finger-tapping task. CONCLUSIONS: Cortical blood flow and EEG spectral power differ between controls and dystonia patients, depending on the task. Writing increased blood flow and altered connectivity in dystonia patients, and it also decreased slow-band attenuation. Finger-tapping decreased blood flow and slow-band attenuation. SIGNIFICANCE: Simultaneous fNIRS and EEG may show relevant information regarding brain dynamics in movement disorders patients in unconstrained environments.

The impact of the socioeconomic factor on Parkinson's disease medication adherence: a scoping review / O impacto do fator socioeconômico na adesão à medicação na doença de Parkinson: uma revisão de escopo

Abstract Background Therapeutic adherence is a decisive issue on chronic disease management in patients requiring long-term pharmacotherapy, such as Parkinson's disease (PD). Although it is well known that socioeconomic factor is a barrier to medication adherence in many chronic diseases, its impacts on PD still need to be investigated. Objective Explore what and how socioeconomic factors impact medication adherence in people with PD. Methods We carried out a scoping review across three databases to identify studies exploring what and how socioeconomic factors impact medication adherence in people with PD considering eight attributes: 1. educational level, 2. disease-related knowledge, 3. income, 4. cost of medication, 5. drug subsidy (meaning presence of subsidies in the cost of medication), 6. employability, and 7. ethnicity (black, indigenous, immigrants). Results Of the 399 identified studies (Embase = 294, Medline = 88, LILACS = 17), eight met inclusion criteria. We identified factors covering the eight attributes of socioeconomic impact, and all of them negatively impacted the medication adherence of people with PD. The most prevalent factor in the studies was low patient educational level (four studies), followed by costs of medications (three studies), income (three studies), and disease-related knowledge (three studies). Distinctly from most of the studies selected, one of them evidenced suboptimal adherence in individuals receiving the medication free of charge, and another one could not find correlation between suboptimal adherence and educational level. Conclusion Socioeconomic factors negatively impact medication adherence in PD patients. This review provides basis for developing patient and population-based interventions to improve adherence to treatment in PD.

Resumo Antecedentes A adesão à medicação é um componente crucial no manejo correto da doença de Parkinson (DP) e, embora esteja bem estabelecido que o fator socioeconômico é uma barreira à adesão medicamentosa em muitas doenças crônicas, seus impactos na DP ainda precisam ser investigados. Objetivo Explorar quais são e como os fatores socioeconômicos afetam a adesão à medicação em pessoas com DP. Métodos Realizamos uma revisão de escopo em três bases de dados para identificar estudos que explorassem quais e como os fatores socioeconômicos impactam na adesão à medicação em pessoas com DP, considerando oito atributos: 1. nível educacional, 2. conhecimento relacionado à doença, 3. renda, 4. custo de medicamentos, 5. subsídio de medicamentos (ou seja, presença de subsídios no custo dos medicamentos), 6. empregabilidade e 7. etnia (negra, indígena, imigrantes). Resultados Dos 399 estudos identificados (Embase = 294, Medline = 88, LILACS = 17), oito preencheram os critérios de inclusão. Identificamos fatores que abrangem os oito atributos de impacto socioeconômico e todos impactaram negativamente na adesão medicamentosa de pessoas com DP. Foram mais prevalentes o baixo nível educacional do paciente (quatro estudos), custos dos medicamentos, nível de renda e conhecimento relacionado à doença (três estudos cada). Diferentemente da maioria dos estudos selecionados, um deles evidenciou adesão subótima em indivíduos que receberam a medicação gratuitamente, e outro não encontrou correlação entre adesão subótima e nível educacional. Conclusão Fatores socioeconômicos impactam negativamente a adesão ao tratamento medicamentoso em pessoas com DP. Esta revisão fornece base para o desenvolvimento de intervenções baseadas em pacientes e populações no intuito de melhorar a adesão ao tratamento farmacológico de pessoas com DP.

Fundamentals of deep brain stimulation for Parkinson's disease in clinical practice: part 1 / Princípios da estimulação cerebral profunda na doença de Parkinson na prática clínica: parte 1

Abstract Deep brain stimulation (DBS) is recognized as an established therapy for Parkinson's disease (PD) and other movement disorders in the light of the developments seen over the past three decades. Long-term efficacy is established for PD with documented improvement in the cardinal motor symptoms of PD and levodopa-induced complications, such as motor fluctuations and dyskinesias. Timing of patient selection is crucial to obtain optimal benefits from DBS therapy, before PD complications become irreversible. The objective of this first part review is to examine the fundamental concepts of DBS for PD in clinical practice, discussing the historical aspects, patient selection, potential effects of DBS on motor and non-motor symptoms, and the practical management of patients after surgery.

Resumo Nas últimas três décadas, a estimulação cerebral profunda (ECP) se tornou um tratamento bem estabelecido para doença de Parkinson (DP) e outros transtornos do movimento. A eficácia a longo prazo na DP foi bem documentada para a melhora dos sintomas motores cardinais da DP e das complicações induzidas pelo uso do levodopa, como as flutuações motoras e as discinesias. O momento da seleção do paciente é crucial para se obter os benefícios ideais da ECP, antes que as complicações da DP se tornem irreversíveis. O objetivo desta primeira parte da revisão é examinar os conceitos fundamentais da ECP na prática clínica, discutindo os aspectos históricos, a seleção de pacientes, os potenciais efeitos da ECP nos sintomas motores e não motores da doença e o manejo prático dos pacientes após a cirurgia.

Floor and ceiling effects on the Montreal Cognitive Assessment in patients with Parkinson's disease in Brazil.

Parkinson's disease (PD) is a common neurodegenerative disease associated with cognitive impairment. The Montreal Cognitive Assessment (MoCA) has been used as a recommended global cognition scale for patients with PD, but there are some concerns about its application, partially due to the floor and ceiling effects. Objective: To explore the floor and ceiling effects on the MoCA in patients with PD in Brazil. Methods: Cross-sectional study with data from patients with PD from five Brazilian Movement Disorders Clinics, excluding individuals with a possible diagnosis of dementia. We analyzed the total score of the MoCA, as well as its seven cognitive domains. The floor and ceiling effects were evaluated for the total MoCA score and domains. Multivariate analyses were performed to detect factors associated with floor and ceiling effects. Results: We evaluated data from 366 patients with PD and approximately 19% of individuals had less than five years of education. For the total MoCA score, there was no floor or ceiling effect. There was a floor effect in the abstraction and delayed memory recall domains in 20% of our sample. The ceiling effect was demonstrated in all domains (80.8% more common in naming and 89% orientation), except delayed recall. Education was the main factor associated with the floor and ceiling effects, independent of region, sex, age at evaluation, and disease duration. Conclusion: The floor and ceiling effects are present in specific domains of the MoCA in Brazil, with a strong impact on education. Further adaptations of the MoCA structure for underrepresented populations may reduce these negative effects.

A doença de Parkinson (DP) é uma doença neurodegenerativa comum associada ao declínio cognitivo. A Avaliação Cognitiva de Montreal (Montreal Cognitive Assessment ­ MoCA) tem sido usada como uma escala de cognição global recomendada para pacientes com DP, mas existem algumas preocupações sobre sua aplicação, em parte pelos efeitos solo e teto. Objetivo: Explorar os efeitos solo e teto na MoCA em pacientes com DP no Brasil. Métodos: Estudo transversal com dados de pacientes com DP oriundos de cinco Clínicas de Distúrbios de Movimento no Brasil, excluindo-se pessoas com possível diagnóstico de demência. Nós analisamos a pontuação total da MoCA, assim como a de seus sete domínios cognitivos. Os efeitos solo e teto foram avaliados para a pontuação total da MoCA e seus domínios. Foram feitas análises multivariadas para a detecção de fatores associados os efeitos solo e teto. Resultados: Nós avaliamos dados de 366 pacientes com DP, e aproximadamente 19% das pessoas tinham menos que cinco anos de escolaridade. Para a pontuação total do MoCA, não houve efeito solo ou teto. Houve efeito solo nos domínios abstração e memória de evocação tardia em 20% de nossa amostra. O efeito teto foi demonstrado em todos os domínios (80,8% mais comum em nomeação e 89% orientação), com exceção de memória de evocação tardia. A educação foi o principal fator associado aos efeitos solo e teto, independentemente de região, sexo, idade na avaliação e duração da doença. Conclusão: Os efeitos solo e teto estão presentes em domínios específicos da MoCA no Brasil, com forte impacto da educação. Adaptações adicionais à estrutura da MoCA para populações vulneráveis podem reduzir esses efeitos negativos.

Omics profile of iPSC-derived astrocytes from Progressive Supranuclear Palsy (PSP) patients.

INTRODUCTION: Progressive Supranuclear Palsy (PSP) is a neurodegenerative tauopathy and, to date, the pathophysiological mechanisms in PSP that lead to Tau hyperphosphorylation and neurodegeneration are not clear. In some brain areas, Tau pathology in glial cells appears to precede Tau aggregation in neurons. The development of a model using astrocyte cell lines derived from patients has the potential to identify molecules and pathways that contribute to early events of neurodegeneration. We developed a model of induced pluripotent stem cells (iPSC)-derived astrocytes to investigate the pathophysiology of PSP, particularly early events that might contribute to Tau hyperphosphorylation, applying omics approach to detect differentially expressed genes, metabolites, and proteins, including those from the secretome. METHODS: Skin fibroblasts from PSP patients (without MAPT mutations) and controls were reprogrammed to iPSCs, further differentiated into neuroprogenitor cells (NPCs) and astrocytes. In the 5th passage, astrocytes were harvested for total RNA sequencing. Intracellular and secreted proteins were processed for proteomics experiments. Metabolomics profiling was obtained from supernatants only. RESULTS: We identified hundreds of differentially expressed genes. The main networks were related to cell cycle re-activation in PSP. Several proteins were found exclusively secreted by the PSP group. The cellular processes related to the cell cycle and mitotic proteins, TriC/CCT pathway, and redox signaling were enriched in the secretome of PSP. Moreover, we found distinct sets of metabolites between PSP and controls. CONCLUSION: Our iPSC-derived astrocyte model can provide distinct molecular signatures for PSP patients and it is useful to elucidate the initial stages of PSP pathogenesis.

Handicap as a Measure of Perceived-Health Status in Parkinson's Disease.

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.

Prevalence of Intestinal Parasites, Risk Factors and Zoonotic Aspects in Dog and Cat Populations from Goiás, Brazil.

Gastrointestinal diseases caused by parasites are frequently diagnosed in the clinical routine of domestic animals, especially dogs and cats. In general, they trigger factors that can affect human health due to zoonoses. Therefore, this study aims to identify the main intestinal parasites obtained from the fecal samples of dogs and cats in the municipality of Jata, Brazil, and their associated risk factors. Between October 2020 and March 2022, fecal samples were collected from 359 dogs and 55 cats through spontaneous defecation and subsequently subjected to coproparasitological analyses using the Willis fluctuation and Hoffman spontaneous sedimentation techniques. The following parasitic species were identified: Ancylostoma spp., Toxocara spp., Trichuris vulpis, Dipylidium caninum; Giardia spp., Entamoeba spp., Cystoisospora spp., and Platynosomum fastosum. The risk factors associated with parasitism include age, average income of owners, access to garbage, sewage, waste, outdated deworming, and contact with animals. The results demonstrate the need to establish public policies and implement preventive and control measures to reduce the occurrence of parasites in animals and the exposure of humans to pathogenic agents.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson's Disease.

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.

Role of cardiac ß1-adrenergic and A1-adenosine receptors in severe arrhythmias related to Parkinson's disease.

AIMS: Although reduced life expectancy in Parkinson's Disease (PD) patients has been related to severe cardiac arrhythmias due to autonomic dysfunctions, its molecular mechanisms remain unclear. To investigate the role of cardiac ß1-Adrenergic (ß1AR) and A1-Adenosine (A1R) receptors in these dysfunctions, the pharmacological effects of stimulation of cardiac ß1AR (isoproterenol, ISO), in the absence and presence of cardiac ß1AR (atenolol, AT) or A1R (1,3-dipropyl-8-cyclopentyl xanthine, DPCPX) blockade, on the arrhythmias induced by Ischemia/Reperfusion (CIR) in an animal PD model were studied. METHODS: PD was produced by dopaminergic lesions (confirmed by immunohistochemistry analysis) caused by the injection of 6-hydroxydopamine (6-OHDA, 6 µg) in rat striatum. CIR was produced by a surgical interruption for 10 min followed by reestablishment of blood circulation in the descendent left coronary artery. On the incidence of CIR-Induced Ventricular Arrhythmias (VA), Atrioventricular Block (AVB), and Lethality (LET), evaluated by Electrocardiogram (ECG) analysis, the effects of intravenous treatment with ISO, AT and DPCPX (before CIR) were studied. RESULTS: VA, AVB and LET incidences were significantly higher in 6-OHDA (83%, 92%, 100%, respectively) than in control rats (58%, 67% and 67%, respectively). ISO treatment significantly reduced these incidences in 6-OHDA (33%, 33% and 42%, respectively) and control rats (25%, 25%, 33%, respectively), indicating that stimulation of cardiac ß1AR induced cardioprotection. This response was prevented by pretreatment with AT and DPCPX, confirming the involvement of cardiac ß1AR and A1R. CONCLUSION: Pharmacological modulation of cardiac ß1AR and A1R could be a potential therapeutic strategy to reduce severe arrhythmias and increase life expectancy in PD patients.

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.

Blepharospasm Patients after Botulinum Toxin - Sleep Approach.

Background Blepharospasm is a focal dystonia that affects the orbicularis oculi muscles. The interest in nonmotor symptoms is due to their impact on quality of life. Objective We evaluated the frequency of sleep disorders and circadian rhythm in a sample of Brazilian blepharospasm patients. Methods A total of 51 patients, who met the clinical criteria for blepharospasm, evaluated by 2 specialists in movement disorders, were recruited from the outpatient clinic for movement disorders of two reference centers in the city of São Paulo: Universidade Federal de São Paulo and Hospital do Servidor Público do Estado de São Paulo. The selected 13 patients were evaluated from 13 days before to 13 days after using botulinum toxin. They were interviewed, underwent physical examination and actigraphy, and completed sleep diaries. Results After using botulinum toxin, the group that reported sleep improvement exhibited a 50% decrease in sleep latency. There was no change in restless leg syndrome or circadian rhythm. Patients who reported no sleep improvement after using botulinum toxin presented poorer synchronization of the light-dark cycle. Conclusion Blepharospasm patients have poor sleep quality. About 50% of the patients had sleep improvement after using botulinum toxin. The synchronization of the light-dark cycle should be influenced by this finding.

Development and Validation of the Dystonia-Pain Classification System: A Multicenter Study.

BACKGROUND: Dystonia is associated with disabling nonmotor symptoms like chronic pain (CP), which is prevalent in dystonia and significantly impacts the quality of life (QoL). There is no validated tool for assessing CP in dystonia, which substantially hampers pain management. OBJECTIVE: The aim was to develop a CP classification and scoring system for dystonia. METHODS: A multidisciplinary group was established to develop the Dystonia-Pain Classification System (Dystonia-PCS). The classification of CP as related or unrelated to dystonia was followed by the assessment of pain severity score, encompassing pain intensity, frequency, and impact on daily living. Then, consecutive patients with inherited/idiopathic dystonia of different spatial distribution were recruited in a cross-sectional multicenter validation study. Dystonia-PCS was compared to validated pain, mood, QoL, and dystonia scales (Brief Pain Inventory, Douleur Neuropathique-4 questionnaire, European QoL-5 Dimensions-3 Level Version, and Burke-Fahn-Marsden Dystonia Rating Scale). RESULTS: CP was present in 81 of 123 recruited patients, being directly related to dystonia in 82.7%, aggravated by dystonia in 8.8%, and nonrelated to dystonia in 7.5%. Dystonia-PCS had excellent intra-rater (Intraclass Correlation Coefficient - ICC: 0.941) and inter-rater (ICC: 0.867) reliability. In addition, pain severity score correlated with European QoL-5 Dimensions-3 Level Version's pain subscore (r = 0.635, P < 0.001) and the Brief Pain Inventory's severity and interference scores (r = 0.553, P < 0.001 and r = 0.609, P < 0.001, respectively). CONCLUSIONS: Dystonia-PCS is a reliable tool to categorize and quantify CP impact in dystonia and will help improve clinical trial design and management of CP in patients affected by this disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Spontaneous intracranial hypotension: from cerebral venous thrombosis to neurosurgical treatment: a case series experience from a Brazilian tertiary health care center.

BACKGROUND: Spontaneous intracranial hypotension (SIH) is a secondary cause of headache and an underdiagnosed disease. The clinical presentation can be highly variable. It typically presents with isolated classic orthostatic headache complaints, but patients can develop significant complications such as cerebral venous thrombosis (CVT). OBJECTIVE: To report 3 cases of SIH diagnosis admitted and treated in a tertiary-level neurology ward. METHODS: Review of the medical files of three patients and description of clinical and surgical outcomes. RESULTS: Three female patients with SIH with a mean age of 25.6 ± 10.0 years old. The patients had orthostatic headache, and one of them presented with somnolence and diplopia because of a CVT. Brain magnetic resonance imaging (MRI) ranges from normal findings to classic findings of SIH as pachymeningeal enhancement and downward displacement of the cerebellar tonsils. Spine MRI showed abnormal epidural fluid collections in all cases, and computed tomography (CT) myelography could determine an identifiable cerebrospinal fluid (CSF) leak in only one patient. One patient received a conservative approach, and the other two were submitted to open surgery with laminoplasty. Both of them had uneventful recovery and remission in surgery follow-up. CONCLUSION: The diagnosis and management of SIH are still a challenge in neurology practice. We highlight in the present study severe cases of incapacitating SIH, complication with CVT, and good outcomes with neurosurgical treatment.

ANTECEDENTES: Hipotensão intracraniana espontânea (HIE) é uma causa secundária de cefaleia e uma doença subdiagnosticada. A apresentação clínica pode ser muito variável. Tipicamente, se apresenta com queixas isoladas de cefaleia ortostática clássica, porém pode evoluir com complicações significativas como trombose venosa cerebral (TVC). OBJETIVO: Relatar 3 casos de diagnóstico de hipotensão intracraniana espontânea manejados em uma enfermaria de neurologia de nível terciário. MéTODOS: Revisão dos prontuários de três pacientes e descrição dos resultados clínicos e cirúrgicos. RESULTADOS: Três pacientes do sexo feminino com média de idade de 25.6 ± 10.0 anos. As pacientes apresentavam cefaleia ortostática e uma delas apresentou sonolência e diplopia devido a TVC. A ressonância magnética (RM) do encéfalo varia de achados normais até achados clássicos de HIE como realce paquimeníngeo e deslocamento inferior das tonsilas cerebelares. A RM da coluna mostrou coleções anormais de líquido epidural em todos os casos e a mielografia por tomografia computadorizada (TC) foi capaz de determinar fístula liquórica identificável em apenas uma paciente. Uma paciente recebeu abordagem conservadora e as outras duas foram submetidas a cirurgia aberta com laminoplastia. Ambas tiveram recuperação e remissão sem intercorrências no seguimento cirúrgico. CONCLUSãO: O diagnóstico e manejo da hipotensão intracraniana ainda são desafios na prática neurológica. Destacamos no presente estudo casos graves, complicação com TVC e bons resultados com tratamento neurocirúrgico.

X-Chromosome Association Study in Latin American Cohorts Identifies New Loci in Parkinson Disease.

Sex differences in Parkinson Disease (PD) risk are well-known. However, it is still unclear the role of sex chromosomes in the development and progression of PD. We performed the first X-chromosome Wide Association Study (XWAS) for PD risk in Latin American individuals. We used data from three admixed cohorts: (i) Latin American Research consortium on the GEnetics of Parkinson's Disease (n=1,504) as discover cohort and (ii) Latino cohort from International Parkinson Disease Genomics Consortium (n = 155) and (iii) Bambui Aging cohort (n= 1,442) as replication cohorts. After developing a X-chromosome framework specifically designed for admixed populations, we identified eight linkage disequilibrium regions associated with PD. We fully replicated one of these regions (top variant rs525496; discovery OR [95%CI]: 0.60 [0.478 - 0.77], p = 3.13 × 10 -5 ; replication OR: 0.60 [0.37-0.98], p = 0.04). rs525496 is an expression quantitative trait loci for several genes expressed in brain tissues, including RAB9B, H2BFM, TSMB15B and GLRA4 . We also replicated a previous XWAS finding (rs28602900), showing that this variant is associated with PD in non-European populations. Our results reinforce the importance of including X-chromosome and diverse populations in genetic studies.