Crucial neuroprotective roles of the metabolite BH4 in dopaminergic neurons.

Dopa-responsive dystonia (DRD) and Parkinson's disease (PD) are movement disorders caused by the dysfunction of nigrostriatal dopaminergic neurons. Identifying druggable pathways and biomarkers for guiding therapies is crucial due to the debilitating nature of these disorders. Recent genetic studies have identified variants of GTP cyclohydrolase-1 (GCH1), the rate-limiting enzyme in tetrahydrobiopterin (BH4) synthesis, as causative for these movement disorders. Here, we show that genetic and pharmacological inhibition of BH4 synthesis in mice and human midbrain-like organoids accurately recapitulates motor, behavioral and biochemical characteristics of these human diseases, with severity of the phenotype correlating with extent of BH4 deficiency. We also show that BH4 deficiency increases sensitivities to several PD-related stressors in mice and PD human cells, resulting in worse behavioral and physiological outcomes. Conversely, genetic and pharmacological augmentation of BH4 protects mice from genetically- and chemically induced PD-related stressors. Importantly, increasing BH4 levels also protects primary cells from PD-affected individuals and human midbrain-like organoids (hMLOs) from these stressors. Mechanistically, BH4 not only serves as an essential cofactor for dopamine synthesis, but also independently regulates tyrosine hydroxylase levels, protects against ferroptosis, scavenges mitochondrial ROS, maintains neuronal excitability and promotes mitochondrial ATP production, thereby enhancing mitochondrial fitness and cellular respiration in multiple preclinical PD animal models, human dopaminergic midbrain-like organoids and primary cells from PD-affected individuals. Our findings pinpoint the BH4 pathway as a key metabolic program at the intersection of multiple protective mechanisms for the health and function of midbrain dopaminergic neurons, identifying it as a potential therapeutic target for PD.

Acute ischemic stroke and COVID-19 pandemic in Brazil: a comparative study of frequency and risk factors before and during SARS-CoV-2 era.

BACKGROUND: COVID-19 pandemic directly impacted the request for hospital care and medical assistance for several diseases worldwide, as occurred with acute ischemic stroke. The present study sought to compare the incidence and severity of acute ischemic stroke (AIS), in addition to sociodemographic, clinical, and radiological characteristics of patients hospitalized in the prepandemic (2018-2019) and pandemic (2020-2021) eras. METHODS: An incidence case-control, observational, and analytical research was carried out in the Stroke Unit of Hospital Governador Celso Ramos, Florianopolis, Santa Catarina, Brazil, including 171 patients admitted with acute ischemic stroke from April 2018 to April 2019 (prepandemic era) and 148 patients between January 2020 and January 2021 (during pandemic). RESULTS: The mean incidence of AIS hospital admissions was significantly lower in the pandemic period (CI 95%, 0.2 to 5.6; p = 0.04), being lower in the lockdown periods and when the incidence of new COVID-19 cases increased. Besides, referring to AIS severity, the mean areas of AIS were larger during the pandemic period (p < 0.01), especially in August, September, December, and January (p < 0.05). Sociodemographic and clinical variables did not show any difference between the two periods of the study. CONCLUSIONS: Hospital admissions for AIS decreased in the COVID-19 pandemic, mostly during months of higher incidences of new COVID-19 cases. When the incidence of admissions diminished, an increase in the severity of AIS was observed, characterized by larger areas. These findings might contribute to other similar referral centers in managing public policies related to stroke.

Use of non-invasive stimulation in movement disorders: a critical review.

BACKGROUND: Noninvasive stimulation has been widely used in the past 30 years to study and treat a large number of neurological diseases, including movement disorders. OBJECTIVE: In this critical review, we illustrate the rationale for use of these techniques in movement disorders and summarize the best medical evidence based on the main clinical trials performed to date. METHODS: A nationally representative group of experts performed a comprehensive review of the literature in order to analyze the key clinical decision-making factors driving transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in movement disorders. Classes of evidence and recommendations were described for each disease. RESULTS: Despite unavoidable heterogeneities and low effect size, TMS is likely to be effective for treating motor symptoms and depression in Parkinson's disease (PD). The efficacy in other movement disorders is unclear. TMS is possibly effective for focal hand dystonia, essential tremor and cerebellar ataxia. Additionally, it is likely to be ineffective in reducing tics in Tourette syndrome. Lastly, tDCS is likely to be effective in improving gait in PD. CONCLUSIONS: There is encouraging evidence for the use of noninvasive stimulation on a subset of symptoms in selected movement disorders, although the means to optimize protocols for improving positive outcomes in routine clinical practice remain undetermined. Similarly, the best stimulation paradigms and responder profile need to be investigated in large clinical trials with established therapeutic and assessment paradigms that could also allow genuine long-term benefits to be determined.

Impaired dopamine metabolism is linked to fatigability in mice and fatigue in Parkinson's disease patients.

Fatigue is a common symptom of Parkinson's disease that compromises significantly the patients' quality of life. Despite that, fatigue has been under-recognized as symptom, its pathophysiology remains poorly understood, and there is no adequate treatment so far. Parkinson's disease is characterized by the progressive loss of midbrain dopaminergic neurons, eliciting the classical motor symptoms including slowing of movements, muscular rigidity and resting tremor. The dopamine synthesis is mediated by the rate-limiting enzyme tyrosine hydroxylase, which requires tetrahydrobiopterin as a mandatory cofactor. Here, we showed that reserpine administration (1 mg/kg, two intraperitoneal injections with an interval of 48 h) in adult Swiss male mice (8-10 weeks; 35-45 g) provoked striatal depletion of dopamine and tetrahydrobiopterin, and intolerance to exercise. The poor exercise performance of reserpinized mice was not influenced by emotional or anhedonic factors, mechanical nociceptive thresholds, electrocardiogram pattern alterations or muscle-impaired bioenergetics. The administration of levodopa (100 mg/kg; i.p.) plus benserazide (50 mg/kg; i.p.) rescued reserpine-induced fatigability-like symptoms and restored striatal dopamine and tetrahydrobiopterin levels. Remarkably, it was observed, for the first time, that impaired blood dopamine metabolism inversely and idependently correlated with fatigue scores in eighteen idiopathic Parkinson's disease patients (male n = 13; female n = 5; age 61.3 ± 9.59 years). Altogether, this study provides new experimental and clinical evidence that fatigue symptoms might be caused by the impaired striatal dopaminergic neurotransmission, pointing to a central origin of fatigue in Parkinson's disease.

Evolução das manifestações clínicas de pacientes com doença de parkinson / Evolution of clinical manifestations of parkinson's disease patients

Objetivos: Avaliar o perfil clínico e epidemiológico dos pacientes parkinsonianos acompanhados no ambulatório de Distúrbios do Movimento do Hospital Governador Celso Ramos utilizando-se escaladas validadas. Métodos: Estudo longitudinal onde foram incluídos 167 pacientes consecutivos, em diferentes estágios da doença de Parkinson, atendidos no ambulatório de distúrbios do movimento do HGCR e reavaliados 20 pacientes em consulta, 5 anos após a primeira. Aplicou-se questionário e avaliou-se o primeiro sintoma motor cardinal entre as associações independentes e entre os escores de sintomas neurológicos motores avaliados através da escala UPDRS-MDS e Schwab and England Activities of Daily Living Scale. Resultados: Tremor foi o primeiro sintoma motor percebido mais frequentemente pelos pacientes (64,9%), dor foi a primeira queixa de 5,2% dos pacientes. A idade de início do primeiro sintoma foi inversamente proporcional à escolaridade. Quanto maior a pontuação nas escalar UPDRS-MDS ­ III (p=0,004) e Schwab and England Activities of Daily Living Scale (p=0,001) maior a tendência a inatividade. Conclusão: A doença de Parkinson geralmente é percebida por seus sintomas motores clássicos, entretanto, uma série de sintomas não motores iniciam e acompanham a evolução da doença conforme mostra a piora do perfil ao longo de 5 anos.

Objectives: To evaluate symptoms, establish a profile for the Parkinsonian patient of HGCR's Movement Disorders's Service. Method: Longitudinal study. 167 consecutive patients, in different stages of Parkinson's disease, and treated at HGCR movement disorders service were inclueded. 20 of them were reevaluated after 5 yers. A questionnaire was administered and the first cardinal motor symptoms was evaluated and associated with independent associations and with the scores of neurological symptoms measured by UPDRS-MDS and through the Schwab and England Activities of Daily Living Scale. Results: Tremor was the first motor symptom perceived most frequently by patients (64.9%), pain was the first complaint of 5,2% of patients. The age of onset of the first symptom was inversely proportional to schooling. The higher the scores in the UPDRS-MDS-III scale (p=0,004) and the Schwab and England Activities of the Daily Living Scale (p = 0,001) the greater the tendency to inactivity. Conclusion: Parkinson's disease is usually noticed by its classic motor symptoms, however, a series of non-motor symptoms begin and accompany the disease's progression. This study evaluated the profile of the clinical and epidemiological patients attending our service and showed important clinical worsening in the evolution of 5 years of disease.

Variables associated with physical health-related quality of life in Parkinson's disease patients presenting for deep brain stimulation.

Deep brain stimulation (DBS) benefits Parkinson's disease (PD) patient's quality of life specially in domains as mobility, activities of daily living (ADL) and bodily discomfort (BD), but little is known about the variables associated with these HRQOL domains in patients presenting for DBS. The objective is to evaluate variables associated with of HRQOL in a Brazilian sample of PD patients presenting for DBS treatment, specifically in the domains related with motor symptoms. In a cross-sectional study of 59 PD patients evaluated at outpatient Unit for Movement Disorders, multiple linear regression analysis was performed to identify independent variables associated with mobility, ADL and BD domains of the 39-item Parkinson's disease questionnaire (PDQ-39). UPDRS III "on" scores, duration of the disease, age, presence of comorbidities and anxiety and depressive symptoms quantified by hospital anxiety and depression scale (HADS), were the independent variables. In our results, HADS scores were independently associated to mobility domain: ß coefficient 1.36 (95 % CI 0.55-2.15) and BD domain: ß coefficient 1.57 (95 % CI 0.67-2.48). UPDRS III "on" scores were independently associated to mobility domain: 0.42 (95 % CI 0.03-0.81). The model of each multiple linear regression analysis explains 25 % of the mobility domain variability (p < 0.01) and 24 % of the BD domain variability (p < 0.01). Psychiatric symptoms were at least as relevant to quality of life as motor symptoms in PD patients presenting for DBS treatment. The effect of treating these psychiatric symptoms on patients' HRQOL deserves further investigation.

Hospital mortality of patients with severe traumatic brain injury is associated with serum PTX3 levels.

BACKGROUND: Traumatic brain injury (TBI) is a worldwide cause of morbidity and mortality. Pentraxin 3 (PTX3) is a humoral component of the innate immune system which has been studied as a marker of inflammatory, infections or cardiovascular pathologies. To investigate the association between serum levels of PTX3 and the hospital mortality of patients with severe TBI. METHODS: The independent association between serum PTX3 levels after severe TBI (Glasgow Coma Scale, GCS ≤ 8) and hospital mortality was analyzed in a prospective study of 83 consecutive patients by a multiple logistic regression analysis. The leukocyte count in the same sample was analyzed as another marker of inflammatory response. RESULTS: The mean age of patients was 35 years and 85% were male. Serum PTX3 levels were determined 18.0 (SD ± 17.0) h after TBI. Patients who died showed a mean serum PTX3 level of 9.95 µg/ml (SD ± 6.42) in comparison to 5.46 µg/ml (SD ± 4.87) of the survivor group (P = 0.007). Elevated serum PTX3 levels remain significantly associated with mortality (P = 0.04) in the subset of patients with isolated TBI (n = 34). There were no differences in the leukocytes count measured in the same blood sample used for PTX3 determination in survivors and non-survivors (P = 0.56). The final multiple logistic regression model including age, pupillary examination, GCS, associated trauma, and PTX3 levels shows that serum levels of PTX3 which were higher than 10 µg/ml were independently associated with the patients mortality (adjusted OR 3.06, CI 95% 1.03-9.15, P = 0.04). CONCLUSIONS: Serum PTX3 levels after severe TBI are independently associated with higher hospital mortality and may be a useful marker of TBI and its prognosis.