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Resumen: Introducción: Se ha comunicado la asociación de ictus isquémico y COVID-19, con mayor frecuencia en aquellos pacientes más graves. Sin embargo, se desconoce en qué medida podría estar en relación con la inflamación sistémica y la hipercoagulabilidad producidas en el contexto de la infección. Métodos: Descripción de 4 pacientes atendidos en nuestro centro por ictus isquémico y diagnóstico de COVID-19, clasificándolos según el grado de probabilidad causal entre el estado de hipercoagulabilidad y el ictus isquémico. Revisión de la literatura sobre los posibles mecanismos implicados en la etiopatogenia del ictus isquémico en este contexto. Resultados: Dos pacientes se consideraron con alta probabilidad causal: presentaban infartos corticales, sin enfermedad cardioembólica ni arterial significativa, con parámetros de inflamación sistémica e hipercoagulabilidad; las otras 2 pacientes eran de edad avanzada y el ictus isquémico se consideró cardioembólico, con una probable asociación casual de COVID-19. Conclusiones: La inflamación sistémica, junto con la posible acción directa del virus, provocaría disfunción endotelial, generando un estado de hipercoagulabilidad que podría considerarse una causa potencial de ictus isquémico. Sin embargo, puesto que los mecanismos del ictus pueden ser múltiples, se precisan estudios más amplios que evalúen esta hipótesis. Mientras tanto, el estudio etiológico del ictus en pacientes con COVID-19 debe ser sistemático atendiendo a los protocolos vigentes, con las adaptaciones necesarias en relación con las circunstancias clínicas y epidemiológicas de la actual pandemia. Abstract: Introduction: Ischaemic stroke has been reported in patients with COVID-19, particularly in more severe cases. However, it is unclear to what extent this is linked to systemic inflammation and hypercoagulability secondary to the infection. Methods: We describe the cases of 4 patients with ischaemic stroke and COVID-19 who were attended at our hospital. Patients are classified according to the likelihood of a causal relationship between the hypercoagulable state and ischaemic stroke. We also conducted a review of studies addressing the possible mechanisms involved in the aetiopathogenesis of ischaemic stroke in these patients. Results: The association between COVID-19 and stroke was probably causal in 2 patients, who presented cortical infarcts and had no relevant arterial or cardioembolic disease, but did show signs of hypercoagulability and systemic inflammation in laboratory analyses. The other 2 patients were of advanced age and presented cardioembolic ischaemic stroke; the association in these patients was probably incidental. Conclusions: Systemic inflammation and the potential direct action of the virus may cause endothelial dysfunction, resulting in a hypercoagulable state that could be considered a potential cause of ischaemic stroke. However, stroke involves multiple pathophysiological mechanisms; studies with larger samples are therefore needed to confirm our hypothesis. The management protocol for patients with stroke and COVID-19 should include a complete aetiological study, with the appropriate safety precautions always being observed.

[Introduction] Acute ischemic stroke therapy has improved in recent decades, decreasing the rates of disability and death among stroke patients. Unfortunately, all health care systems have geographical disparities in infrastructure for stroke patients. A centralized telestroke network might be a low-cost strategy to reduce differences in terms of geographical barriers, equitable access, and quality monitoring across different hospitals., [Aims] We aimed to quantify changes in stroke patients’ geographic access to specialized evaluation by neurologists and to intravenous acute stroke reperfusion treatments following the rapid implementation of a centralized telestroke network in the large region of Andalusia (8.5 million inhabitants)., [Methods] We conducted an observational study using spatial and analytical methods to examine how a centralized telestroke network influences the quality and accessibility of stroke care for a large region., [Results] In the pre-implementation period, 5,005,477 (59.72% of the Andalusian population) had access to specialized stroke care in less than 30 min. After the 5-month process of implementing the telestroke network, 7,832,988 (93.5%) inhabitants had an access time of less than 30 min, bridging the gap in acute stroke care in rural hospitals., [Conclusions] A centralized telestroke network may be an efficient tool to reduce the differences in stroke care access and quality monitoring across different hospitals, especially in large regions with low population density.

Background: Neurologic impairment persisting months after acute severe SARS-CoV-2 infection has been described because of several pathogenic mechanisms, including persistent systemic inflammation. The objective of this study is to analyze the selective involvement of the different cognitive domains, it impacts on quality of life and the possible existence of related biomarkers.Methods: Cross-sectional study of patients who survived severe infection with SARS-CoV-2 consecutively recruited from 13 neurology services in Spain between 90 and 120 days after hospital discharge. All patients underwent an exhaustive study of cognitive functions as well as plasma determination of pro-inflammatory factors (chemokines), and neurotrophic factors and light-chain neurofilaments. A Principal Component Analysis extracted the main independent characteristics of the syndrome.Results: 152 patients were recruited. The results of our study show a pattern of cognitive impairment with preferential involvement of episodic and working memory, executive functions, and attention and relatively less affectation of information processing speed, denomination, verbal fluency, and other cortical functions. In addition, psychiatric affectation such as anxiety and depression pictures are constant in our cohort. Several plasma chemokines concentrations were elevated compared with both, a non-SARS-Cov2 infected cohort of neurological outpatients or a control healthy general population, suggesting a pro-inflammatory chronic state derived of viral infection.Conclusion: The neurologic Subacute Impairment in severe Covid-19 consist in an amnesic and dysexecutive syndrome with neuropsychiatric manifestations. We do not know if the deficits detected can persist in the long term and, in this case, if this can trigger or accelerate the onset of neurodegenerative diseases.

[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., This work was supported by the Carlos III Health Institute-European Regional Development Fund (ISCIII-FEDER) [PI14/01823, PI16/01575, PI18/01898, PI19/01576], the Andalusian Regional Ministry of Economics, Innovation, Science and Employment [CVI-02526, CTS-7685], the Andalusian Regional Ministry of Health and Welfare [PI-0741-2010, PI-0471-2013, PE-0210-2018, PI-0459-2018, PE-0186-2019], and the Alicia Koplowitz and Mutua Madrileña Foundations. Pilar Gómez-Garre was supported by the "Miguel Servet" program [MSII14/00018] (from ISCIII-FEDER) and “Nicolás Monardes” program [C-0048-2017] (from the Andalusian Regional Ministry of Health). Silvia Jesús was supported by the "Juan Rodés" program [B-0007-2019] and Daniel Macías-García by the “Río Hortega” program [CM18/00142] (both from ISCIII-FEDER). María Teresa Periñán was supported by the Spanish Ministry of Education [FPU16/05061]. Cristina Tejera was supported by VPPI-US from the University of Seville.

Objectives: Stroke is a very common cause of death, especially in southern Spain. The present study analyses in-hospital mortality associated with stroke in an Andalusian tertiary care hospital. Methods: We gathered the files of all patients who had died at Hospital Universitario Virgen de las Nieves in Granada in 2013 and whose death certificates indicated stroke as the cause of death. We also gathered stroke patients discharge data and compared them to that of patients with acute coronary syndrome (ACS). Results: A total of 825 patients had a diagnosis of stroke (96 deaths, 11.6%); of these, 562 had ischaemic stroke (IS) (44 deaths, 7.8%) and 263 haemorrhagic stroke (HS) (52 deaths, 19.7%). Patients with HS therefore showed greater mortality rate (odds ratio, OR 2.9). Patients in this group died after a shorter time in hospital (median, 4 vs. 7 days; mean, 6 days). However, patients with IS were older and presented with more comorbidities. On the other hand, 617 patients had a diagnosis of ACS (36 deaths, 5.8%). The mortality odds ratio was 2.1 (stroke/SCA). Around 23% of the patients who died from stroke were taking anticoagulants. 60% of the deceased patients with IS and 20% of those with HS had atrial fibrillation (AF); 35% of the patients with IS and AF were taking anticoagulants. Conclusions: Stroke is associated with higher admission and in-hospital mortality rates than SCA. Likewise, patients with HS showed higher mortality rates than those with IS. Patients with fatal stroke usually had a history of long-term treatment with anticoagulants; two-thirds of the patients with fatal IS and AF were not receiving anticoagulants. According to our results, optimising prevention in patients with AF may have a positive impact on stroke-related in-hospital mortality. Resumen: Objetivos: El ictus constituye una causa muy frecuente de muerte, especialmente en el sur de España; se analiza la mortalidad intrahospitalaria asociada a ictus en un hospital andaluz de tercer nivel. Métodos: Registro de pacientes con ictus como diagnóstico en su informe de defunción en el Hospital Virgen de las Nieves de Granada durante 2013. Se utilizan además datos globales sobre altas en ictus y se comparan con iguales variables en síndrome coronario agudo (SCA). Resultados: Altas con diagnóstico de ictus 825 (96 defunciones, 11,6%); 562 isquémicos (44 fallecidos, 7,8%); 263 hemorrágicos (52 muertes, 19,7%). Los hemorrágicos, por tanto, tuvieron mayor mortalidad (OR = 2,9) y más precoz durante el ingreso (mediana 4 vs. 7 días, global 6 días), aunque los isquémicos fueron más ancianos y más pluripatológicos. Altas con SCA 617 (36 fallecidos, 5,8%); OR de mortalidad en ictus/SCA = 2,1. Un 23% de los fallecidos con ictus estaban anticoagulados cuando lo presentaron. El 60% de los ictus isquémicos y el 20% de los ictus hemorrágicos fallecidos tenían fibrilación auricular; solo el 35% de los pacientes con ictus isquémico y fibrilación auricular estaban anticoagulados. Conclusiones: El ictus supera al SCA en ingresos y mortalidad intrahospitalaria. El ictus hemorrágico supera al isquémico en mortalidad asociada. La anticoagulación crónica es frecuente en pacientes con ictus fatal; 2 tercios de los pacientes con ictus isquémico mortal y fibrilación auricular no estaban anticoagulados. Según nuestros resultados, optimizar la prevención en pacientes con fibrilación auricular podría impactar favorablemente sobre la mortalidad intrahospitalaria asociada al ictus. Keywords: Stroke, In-hospital mortality, Ischaemic stroke, Haemorrhagic stroke, Acute coronary syndrome, Oral anticoagulants, Palabras clave: Ictus, Mortalidad intrahospitalaria, Ictus isquémico, Ictus hemorrágico, Síndrome coronario agudo, Anticoagulación oral

International Parkinson’s Disease Genomics Consortium (IPDGC), UK Brain Expression Consortium (UKBEC)., Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/., Mina Ryten, David Zhang, and Karishma D’Sa were supported by the UK Medical Research Council (MRC) through the award of Tenure-track Clinician Scientist Fellowship to Mina Ryten (MR/N008324/1). Sebastian Guelfi was supported by Alzheimer’s Research UK through the award of a PhD Fellowship (ARUK-PhD2014-16). Regina Reynolds was supported through the award of a Leonard Wolfson Doctoral Training Fellowship in Neurodegeneration.

BackgroundWhile the LRRK2 p.G2019S mutation has been demonstrated to be a strong risk factor for Parkinson’s Disease (PD), factors that contribute to penetrance among carriers, other than aging, have not been well identified.ObjectivesTo evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers.MethodsWe included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two datasets: one from a case-control setting without selection of mutation carriers, and the other from a population sampling. The associations between PRS constructed from 89 variants reported in Nalls et al. and PD were tested and meta-analyzed. We also explored the interaction of age and PRS.ResultsAfter excluding 8 homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. PRS was associated with a higher penetrance of PD (OR 1.34, 95% C.I. [1.09, 1.64] per +1 SD, P = 0.005). In addition, associations with PRS and penetrance were stronger in the younger participants (main effect: OR 1.28 [1.04, 1.58] per +1 SD, P = 0.022; interaction effect: OR 0.78 [0.64, 0.94] per +1 SD and +10 years of age, P = 0.008).ConclusionsOur results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiologic consequences and potential impact on the selection of subjects for clinical trials.

ObjectivesTo analyse the association between aminosalicylate-treated inflammatory bowel disease (IBD) and Parkinson’s disease (PD) at population level.DesignCross-sectional study.SettingThe study was performed based on electronic drug prescription and dispensation records of the Andalusian Public Health System.ParticipantsAll individuals aged ≥50 years with at least one drug dispensation during December 2014 were identified from the records.Primary and secondary outcome measuresGroups were formed: ‘possible PD’ group, including all who received an anti-Parkinson agent; ‘possible IBD’ group, those treated with mesalazine and/or derivatives (5-aminosalicylic acid (5-ASA)); and ‘possible PD and IBD’, including those receiving both anti-Parkinson agent and 5-ASA. Prevalence of possible PD was determined among those with possible IBD and among those without this condition. The age-adjusted and sex-adjusted OR was calculated.ResultsWe recorded 2 020 868 individuals (68±11 years, 56% female), 19 966 were included in possible PD group (75±9 years, 53% female) and 7485 in possible IBD group (64±10 years, 47% female); only 56 were included in both groups (76±8 years, 32% female). The prevalence of possible PD was 0.7% among those with possible IBD and 1% among those without this condition (adjusted OR=0.94; 95% CI 0.72 to 1.23; p=0.657). OR was 0.28 in individuals aged ≤65 years (95% CI 0.10 to 0.74; p=0.01) and 1.17 in older individuals (95% CI 0.89 to 1.54; p=0.257).ConclusionsWithin the limitations of this study, the results suggest a protective role for IBD and/or 5-ASA against PD development, especially among under 65-year olds. Further studies are warranted to explore this association given its scientific and therapeutic implications.

BackgroundClassical randomisation of clinical trial patients creates a source of genetic variance that may be contributing to the high failure rate seen in neurodegenerative disease trials. Our objective was to quantify genetic difference between randomised trial arms and determine how imbalance can affect trial outcomes.Methods5851 patients with Parkinson’s disease of European ancestry data and two simulated virtual cohorts based on public data were used. Data were resampled at different sizes for 1000 iterations and randomly assigned to the two arms of a simulated trial. False-negative and false-positive rates were estimated using simulated clinical trials, and per cent difference in genetic risk score (GRS) and allele frequency was calculated to quantify variance between arms.Results5851 patients with Parkinson’s disease (mean (SD) age, 61.02 (12.61) years; 2095 women (35.81%)) as well as simulated patients from virtually created cohorts were used in the study. Approximately 90% of the iterations had at least one statistically significant difference in individual risk SNPs between each trial arm. Approximately 5%–6% of iterations had a statistically significant difference between trial arms in mean GRS. For significant iterations, the average per cent difference for mean GRS between trial arms was 130.87%, 95% CI 120.89 to 140.85 (n=200). Glucocerebrocidase (GBA) gene-only simulations see an average 18.86%, 95% CI 18.01 to 19.71 difference in GRS scores between trial arms (n=50). When adding a drug effect of −0.5 points in MDS-UPDRS per year at n=50, 33.9% of trials resulted in false negatives.ConclusionsOur data support the hypothesis that within genetically unmatched clinical trials, genetic heterogeneity could confound true therapeutic effects as expected. Clinical trials should undergo pretrial genetic adjustment or, at the minimum, post-trial adjustment and analysis for failed trials.