Experimental and Modeling High-Pressure Study of Ammonia-Methane Oxidation in a Flow Reactor.

The present work deals with an experimental and modeling analysis of the oxidation of ammonia-methane mixtures at high pressure (up to 40 bar) in the 550-1250 K temperature range using a quartz tubular reactor and argon as a diluent. The impact of temperature, pressure, oxygen stoichiometry, and CH4/NH3 ratio has been analyzed on the concentrations of NH3, NO2, N2O, NO, N2, HCN, CH4, CO, and CO2 obtained as main products of the ammonia-methane mixture oxidation. The main results obtained indicate that increasing either the pressure, CH4/NH3 ratio, or stoichiometry results in a shift of NH3 and CH4 conversion to lower temperatures. The effect of pressure is particularly significant in the low range of pressures studied. The main products of ammonia oxidation are N2, NO, and N2O while NO2 concentrations are below the detection limit for all of the conditions considered. The N2O formation is favored by increasing the CH4/NH3 ratio and stoichiometry. The experimental results are simulated and interpreted in terms of an updated detailed chemical kinetic mechanism, which, in general, is able to describe well the conversion of both NH3 and CH4 under almost all of the studied conditions. Nevertheless, some discrepancies are found between the experimental results and model calculations.

The enduring enigma of sporadic chorea: A single center case series.

Chorea can have a wide variety of causes including neurodegenerative, pharmacological, structural, metabolic, infectious, immunologic and paraneoplastic processes. We reviewed the clinical records of patients with apparently sporadic choreic movements and no relevant family history, who presented to our neurology department (Hospital Fundación Jimenez Diaz) between 1991 and 2022. We detected 38 cases of apparent sporadic chorea (ASC); Our analysis revealed 5 cases of genetic chorea (including 3 cases with Huntington's disease) while 6 cases were autoimmune/hematological; 6 drug-related chorea, 5 metabolic-vascular, 5 due to miscellaneous conditions and 4 were of mixed etiology. No clear etiology was identified in 8 cases. The differential diagnosis of ASC is extensive and challenging. Highlights: Chorea can have a wide variety of genetic and sporadic causesWe reviewed the clinical records of patients with apparently sporadic chorea (ASC), who presented to our neurology department over the last 30 yearsWe detected 38 cases of apparent ASC; Our analysis revealed a wide array of different sporadic conditions and 5 cases of genetic choreaThe differential diagnosis of ASC is extensive and challenging.

Homocysteine, vitamin B metabolites, dopamine-substituting compounds, and symptomatology in Parkinson's disease: clinical and therapeutic considerations.

Emerging studies suggest a correlation between elevated plasma homocysteine (hcy) levels and the risk of atherosclerosis, vascular disorders, and neurodegenerative diseases, including Parkinson's disease (PD). This narrative review delves into the intricate relationships between Hcy, vitamin B metabolites, dopamine-substituting compounds, and various symptoms of PD. Patients undergoing a long-term L-dopa/dopa-decarboxylase inhibitor (DDI) regimen, especially without a concurrent catechol-O-methyl transferase (COMT) inhibitor or methyl group-donating vitamin supplementation, such as vitamins B6 and B12, exhibit an elevation in Hcy and a decline in vitamin B metabolites. These altered concentrations appear to be associated with heightened risks of developing non-motor symptoms, including peripheral neuropathy and cognitive disturbances. The review underscores the impact of levodopa metabolism via COMT on homocysteine levels. In light of these findings, we advocate for the supplementation of methyl group-donating vitamins, notably B6 and B12, in patients undergoing a high-dose L-dopa/DDI regimen, particularly those treated with L-dopa/carbidopa intestinal gel (LCIG) infusion.

Perampanel: Medical Alternative for Essential Tremor?

OBJECTIVES: The aim of this study was to assess the safety and efficacy of perampanel in patients with refractory essential tremor (ET). METHODS: We recruited patients from our movement disorders clinic with the diagnosis of severe refractory ET, and perampanel 4 mg at night was initiated.Assessments were conducted at baseline and after 1 month of treatment with perampanel 4 mg/d. Details about tolerance and effectiveness were collected. Clinical evaluation was conducted with the Fahn-Tolosa-Marín scale, and statistical analysis was carried out with Wilcoxon matched pairs signed rank test. RESULTS: This study included 18 patients with severe ET (11 females, 7 males; mean age: 75.1 ± 12.03 years; mean duration of ET: 17.4 ± 17.03 years). Perampanel significantly improved patients' average score with refractory ET ( P ≤ 0.0001). This improvement has been occasionally quite relevant. However, a proportion of patients did not tolerate perampanel because of several adverse effects including dizziness, ataxia, irritability, and instability. CONCLUSIONS: Perampanel had a markedly positive antitremor effect in patients with ET and could be an alternative treatment. However, this drug is not devoid of adverse effects.

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease.

BACKGROUND AND PURPOSE: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. METHODS: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. RESULTS: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (ß = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. CONCLUSION: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge.

Considerations about the Continuous Assay Methods, Spectrophotometric and Spectrofluorometric, of the Monophenolase Activity of Tyrosinase.

With the purpose to obtain the more useful tyrosinase assay for the monophenolase activity of tyrosinase between the spectrofluorometric and spectrophotometric continuous assays, simulated assays were made by means of numerical integration of the equations that characterize the mechanism of monophenolase activity. These assays showed that the rate of disappearance of monophenol (VssM,M) is equal to the rate of accumulation of dopachrome (VssM,DC) or to the rate of accumulation of its oxidized adduct, originated by the nucleophilic attack on o-quinone by a nucleophile such as 3-methyl-2-benzothiazolinone (MBTH), (VssM, A-ox), despite the existence of coupled reactions. It is shown that the spectrophotometric methods that use MBTH are more useful, as they do not have the restrictions of the L-tyrosine disappearance measurement method, of working at pH = 8 and not having a linear response from 100 µM of L-tyrosine. It is possible to obtain low LODM (limit of detection of the monophenolase activity) values with spectrophotometric methods. The spectrofluorimetric methods had a lower LODM than spectrophotometric methods. In the case of 4-hydroxyphenil-propionic acid, the LODM obtained by us was 0.25 U/mL. Considering the relative sensitivities of 4-hydroxyanisole, compared with 4-hydroxyphenil-propionic acid, LODM values like those obtained by fluorescent methods would be expected.

Present and Future of Parkinson's Disease in Spain: PARKINSON-2030 Delphi Project.

Parkinson's disease (PD) is a chronic progressive and irreversible disease and the second most common neurodegenerative disease worldwide. In Spain, it affects around 120.000-150.000 individuals, and its prevalence is estimated to increase in the future. PD has a great impact on patients' and caregivers' lives and also entails a substantial socioeconomic burden. The aim of the present study was to examine the current situation and the 10-year PD forecast for Spain in order to optimize and design future management strategies. This study was performed using the modified Delphi method to try to obtain a consensus among a panel of movement disorders experts. According to the panel, future PD management will improve diagnostic capacity and follow-up, it will include multidisciplinary teams, and innovative treatments will be developed. The expansion of new technologies and studies on biomarkers will have an impact on future PD management, leading to more accurate diagnoses, prognoses, and individualized therapies. However, the socio-economic impact of the disease will continue to be significant by 2030, especially for patients in advanced stages. This study highlighted the unmet needs in diagnosis and treatment and how crucial it is to establish recommendations for future diagnostic and therapeutic management of PD.

Regulatory rare variants of the dopaminergic gene ANKK1 as potential risk factors for Parkinson's disease.

Parkinson's disease (PD) is characterized by cerebral dopamine depletion that causes motor and cognitive deficits. The dopamine-related gene ANKK1 has been associated with neuropsychiatric disorders with a dopaminergic deficiency in the striatum. This study aims to define the contribution of ANKK1 rare variants in PD. We found in 10 out of 535 PD patients 6 ANKK1 heterozygous rare alleles located at the 5'UTR, the first exon, intron 1, and the nearby enhancer located 2.6 kb upstream. All 6 ANKK1 single nucleotide variants were located in conserved regulatory regions and showed significant allele-dependent effects on gene regulation in vitro. ANKK1 variant carriers did not show other PD-causing Mendelian mutations. Nevertheless, four patients were heterozygous carriers of rare variants of ATP7B gene, which is related to catecholamines. We also found an association between the polymorphic rs7107223 of the ANKK1 enhancer and PD in two independent clinical series (P = 0.007 and 0.021). rs7107223 functional analysis showed significant allele-dependent effects on both gene regulation and dopaminergic response. In conclusion, we have identified in PD patients functional variants at the ANKK1 locus highlighting the possible relevance of rare variants and non-coding regulatory regions in both the genetics of PD and the dopaminergic vulnerability of this disease.

Electroconvulsive Therapy and Movement Disorders. New Perspectives on A Time-Tested Therapy.

Electroconvulsive therapy (ECT) has been a very well known therapy in Psychiatry for over 80 years. ECT is considered useful in treating acute mania, severe depression and other psychiatric conditions. Over time, this therapy has also been used in several movement disorders including Parkinson disease (PD) and Huntington disease (HD). In this brief review, I summarize the recent History and evolution of ECT, its proven and potential applications in movement disorders as well as its potential mechanisms.

Consensus guidelines for botulinum toxin therapy: general algorithms and dosing tables for dystonia and spasticity.

Botulinum toxin (BT) therapy is a complex and highly individualised therapy defined by treatment algorithms and injection schemes describing its target muscles and their dosing. Various consensus guidelines have tried to standardise and to improve BT therapy. We wanted to update and improve consensus guidelines by: (1) Acknowledging recent advances of treatment algorithms. (2) Basing dosing tables on statistical analyses of real-life treatment data of 1831 BT injections in 36 different target muscles in 420 dystonia patients and 1593 BT injections in 31 different target muscles in 240 spasticity patients. (3) Providing more detailed dosing data including typical doses, dose variabilities, and dosing limits. (4) Including total doses and target muscle selections for typical clinical entities thus adapting dosing to different aetiologies and pathophysiologies. (5) In addition, providing a brief and concise review of the clinical entity treated together with general principles of its BT therapy. For this, we collaborated with IAB-Interdisciplinary Working Group for Movement Disorders which invited an international panel of experts for the support.

Mutational spectrum of GNAL, THAP1 and TOR1A genes in isolated dystonia: study in a population from Spain and systematic literature review.

OBJECTIVE: We aimed to investigate the prevalence of TOR1A, GNAL and THAP1 variants as the cause of dystonia in a cohort of Spanish patients with isolated dystonia and in the literature. METHODS: A population of 2028 subjects (including 1053 patients with different subtypes of isolated dystonia and 975 healthy controls) from southern and central Spain was included. The genes TOR1A, THAP1 and GNAL were screened using a combination of high-resolution melting analysis and direct DNA resequencing. In addition, an extensive literature search to identify original articles (published before 10 August 2020) reporting mutations in TOR1A, THAP1 or GNAL associated to dystonia was performed. RESULTS: Pathogenic or likely pathogenic variants in TOR1A, THAP1 and GNAL were identified in 0.48%, 0.57% and 0.29% of our patients, respectively. Five patients carried the variation p.Glu303del in TOR1A. A very rare variant in GNAL (p.Ser238Asn) was found as a putative risk factor for dystonia. In the literature, variations in TOR1A, THAP1 and GNAL accounted for about 6%, 1.8% and 1.1% of published dystonia patients, respectively. CONCLUSIONS: There is a different genetic contribution to dystonia of these three genes in our patients (about 1.3% of patients) and in the literature (about 3.6% of patients), probably due the high proportion of adult-onset cases in our cohort. As regards age at onset, site of dystonia onset, and final distribution, in our population there is a clear differentiation between DYT-TOR1A and DYT-GNAL, with DYT-THAP1 likely to be an intermediate phenotype.

A genetic analysis of a Spanish population with early onset Parkinson's disease.

INTRODUCTION: Both recessive and dominant genetic forms of Parkinson's disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson's disease in a cohort from central Spain. METHODS/PATIENTS: We analyzed a cohort of 117 unrelated patients with early onset Parkinson's disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson's disease and other Parkinsonisms and CNV screening. RESULTS: Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes. CONCLUSIONS: Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson's disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson's disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson's disease.

Sexual Dysfunction in Early-Onset Parkinson's Disease: A Cross-Sectional, Multicenter Study.

BACKGROUND: Sexual dysfunction (SD) is one of the least studied non-motor symptoms in Parkinson's disease (PD). OBJECTIVES: To assess sexual function in a cohort of patients with early-onset PD (EOPD) and compare it to a group of healthy controls. METHODS: In this cross-sectional multicenter study, SD was assessed with gender-specific multi-dimensional self-reported questionnaires: The Brief Male Sexual Function Inventory (BSFI-M) and the Female Sexual Function Index (FSFI). Scores between patients and controls were compared and associations between SD and demographical and clinical variables were studied. RESULTS: One hundred and five patients (mean age 47.35±7.8, disease duration 6 (3-11) years, UPDRS part III 17 (10-23) and 90 controls were recruited. The BSFI-M total score was lower in EOPD men than in controls, and specific items were also significantly lower, such as drive, erections, ejaculation, and satisfaction. EOPD women had lower scores than controls in totalFSFI, and certain domains such as lubrication and pain. SD was present in 70.2% of patients and 52.5% of controls. Sexual satisfaction in 35.2% of patients and 81.2% of controls. By gender, male and female patients had more SD than controls but only male patients had more dissatisfaction than controls. Gender, higher depression scores and urinary dysfunction were associated with SD in multivariate analysis; and gender, UPDRS and urinary dysfunction with sexual satisfactionConclusion:In this Spanish cohort, SD and sexual dissatisfaction was more prevalent in EOPD patients than in the general population. Gender and urinary disfunction were associated with SD and sexual dissatisfaction.

Benign versus malignant Parkinson disease: the unexpected silver lining of motor complications.

OBJECTIVE: We sought to evaluate demographic, clinical, and habits/occupational variables between phenotypic extremes in Parkinson's disease (PD). METHODS: Databases from nine movement disorders centers across seven countries were retrospectively searched for subjects meeting criteria for very slowly progressive, benign, PD (bPD) and rapidly progressive, malignant, PD (mPD). bPD was defined as Hoehn and Yahr (H&Y) stage ≤ 3, normal cognitive function, and Schwab and England (S&E) score ≥ 70 after ≥ 20 years of PD (≥ 10 years if older than 60 at PD onset); mPD as H&Y > 3, S&E score < 70, and cognitive impairment within 10 years from PD onset. We performed between-group analysis of demographic, habits/occupational, and clinical features at baseline and follow-up and unsupervised data-driven analysis of the clinical homogeneity of bPD and mPD. RESULTS: At onset, bPD subjects (n = 210) were younger, had a single limb affected, lower severity and greater asymmetry of symptoms, and lower prevalence of depression than mPD (n = 155). bPD was associated with active smoking and physical activity, mPD with agricultural occupation. At follow-up, mPD showed higher prevalence of depression, hallucinations, dysautonomia, and REM behaviour disorder. Interestingly, the odds of mPD were significantly reduced by the presence of dyskinesia and wearing-off. Data-driven analysis confirmed the independent clustering of bPD and mPD, with age at onset emerging as a critical discriminant between the two groups (< 46-year-old vs. > 68-year-old). CONCLUSIONS: Phenotypic PD extremes showed distinct demographic, clinical, and habits/occupational factors. Motor complications may be conceived as markers of therapeutic success given their attenuating effects on the odds of mPD.

Utility of the Parkinson's disease-Cognitive Rating Scale for the screening of global cognitive status in Huntington's disease.

BACKGROUND: Cognitive impairment is an essential feature of Huntington's disease (HD) and dementia is a predictable outcome in all patients. However, validated instruments to assess global cognitive performance in the field of HD are lacking. OBJECTIVES: We aimed to explore the utility of the Parkinson's disease-Cognitive Rating Scale (PD-CRS) for the screening of global cognition in HD. METHODS: A multicenter cohort of 132 HD patients at different disease stages and 33 matched healthy controls were classified as having preserved cognition, mild cognitive impairment (HD-MCI) or dementia (HD-Dem) according to the Clinical Dementia Rating and Functional Independence Score. The PD-CRS and the Mini-Mental State Examination were administered. Receiver operating characteristic curve analysis was used to determine optimal cutoffs to differentiate patients according to their cognitive status. RESULTS: A PD-CRS cutoff score ≤ 81/82 was optimal to detect HD-MCI (sensitivity = 93%; specificity = 80%; area under the curve (AUC) = 0.940), and ≤ 63/64 was optimal to detect HD-Dem (sensitivity = 90%; specificity = 87%; AUC = 0.933). MMSE scores failed to show robust psychometric properties in this context. DISCUSSION: The PD-CRS is a valid and reliable instrument to assess global cognition in HD in routine clinical care and clinical trials.