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CORONAVIRUS COVID-19 Global Cases by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) ...

sábado, 23 de febrero de 2019

Procesos de neurorreparación tras la asfixia perinatal

Neonatal hypoxia-ischemia: cellular and molecular brain damage and therapeutic modulation of neurogenesis

INTRODUCTION:

Perinatal asphyxia remains a major cause of both mortality and neurological morbidity. Neonatal encephalopathy affects to 1-3/1,000 newborns, leading to significant brain damage and childhood disability. The only standard therapy is moderate hypothermia, whose efficacy, despite proved, is limited, being partially effective.

DEVELOPMENT:

The capacity of hypothermia in promoting cell proliferation in the neurogenic niches of the central nervous system remains subject of investigation. The use of therapeutic agents such as erythropoietin and cannabinoids and mesenchymal stem cells have shown promising results in experimental models of perinatal asphyxia, being able of modulate neurogenesis, neuronal plasticity and neuroreparation processes after hypoxic-ischemic brain injury.

CONCLUSIONS:

The effects of these therapies in clinics are still unknown, so as if the newborn cells will be able to effectively integrate in the existing neuronal networks or if they will develop their proper functions in a brain-damaged microenvironment, thus being necessary new works focused on the evaluation of the real potential of these therapies in the modulation of neurogenesis after neonatal hypoxia-ischemia.

Vinculan astrocitos defectuosos con la enfermedad de Parkinson

Patient-Specific iPSC-Derived Astrocytes Contribute toNon-Cell-Autonomous Neurodegeneration in Parkinson's Disease

Summary

Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

La falta y la mala calidad de sueño aumentan el riesgo cardiovascular

Association of Sleep Duration and Quality With Subclinical Atherosclerosis

Abstract

Background

Sleep duration and quality have been associated with increased cardiovascular risk. However, large studies linking objectively measured sleep and subclinical atherosclerosis assessed in multiple vascular sites are lacking.

Objectives

The purpose of this study was to evaluate the association of actigraphy-measured sleep parameters with subclinical atherosclerosis in an asymptomatic middle-aged population, and investigate interactions among sleep, conventional risk factors, psychosocial factors, dietary habits, and inflammation.

Methods

Seven-day actigraphic recording was performed in 3,974 participants (age 45.8 ± 4.3 years; 62.6% men) from the PESA (Progression of Early Subclinical Atherosclerosis) study. Four groups were defined: very short sleep duration <6 6="" 7="" 8="" and="" duration="" h="" long="" reference="" short="" sleep="" to="">8 h. Sleep fragmentation index was defined as the sum of the movement index and fragmentation index. Carotid and femoral 3-dimensional vascular ultrasound and cardiac computed tomography were performed to quantify noncoronary atherosclerosis and coronary calcification.

Results

When adjusted for conventional risk factors, very short sleep duration was independently associated with a higher atherosclerotic burden with 3-dimensional vascular ultrasound compared to the reference group (odds ratio: 1.27; 95% confidence interval: 1.06 to 1.52; p = 0.008). Participants within the highest quintile of sleep fragmentation presented a higher prevalence of multiple affected noncoronary territories (odds ratio: 1.34; 95% confidence interval: 1.09 to 1.64; p = 0.006). No differences were observed regarding coronary artery calcification score in the different sleep groups.

Conclusions

Lower sleeping times and fragmented sleep are independently associated with an increased risk of subclinical multiterritory atherosclerosis. These results highlight the importance of healthy sleep habits for the prevention of cardiovascular disease.

Central Illustration

Un trasplante de células madre podría frenar la progresión de la esclerosis múltiple remitente recurrente

Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis

Abstract
Importance  Hematopoietic stem cell transplantation (HSCT) represents a potentially useful approach to slow or prevent progressive disability in relapsing-remitting multiple sclerosis (MS).
Objective  To compare the effect of nonmyeloablative HSCT vs disease-modifying therapy (DMT) on disease progression.
Design, Setting, and Participants  Between September 20, 2005, and July 7, 2016, a total of 110 patients with relapsing-remitting MS, at least 2 relapses while receiving DMT in the prior year, and an Expanded Disability Status Scale (EDSS; score range, 0-10 [10 = worst neurologic disability]) score of 2.0 to 6.0 were randomized at 4 US, European, and South American centers. Final follow-up occurred in January 2018 and database lock in February 2018.
Interventions  Patients were randomized to receive HSCT along with cyclophosphamide (200 mg/kg) and antithymocyte globulin (6 mg/kg) (n = 55) or DMT of higher efficacy or a different class than DMT taken during the previous year (n = 55).
Main Outcomes and Measures  The primary end point was disease progression, defined as an EDSS score increase after at least 1 year of 1.0 point or more (minimal clinically important difference, 0.5) on 2 evaluations 6 months apart, with differences in time to progression estimated as hazard ratios.
Results  Among 110 randomized patients (73 [66%] women; mean age, 36 [SD, 8.6] years), 103 remained in the trial, with 98 evaluated at 1 year and 23 evaluated yearly for 5 years (median follow-up, 2 years; mean, 2.8 years). Disease progression occurred in 3 patients in the HSCT group and 34 patients in the DMT group. Median time to progression could not be calculated in the HSCT group because of too few events; it was 24 months (interquartile range, 18-48 months) in the DMT group (hazard ratio, 0.07; 95% CI, 0.02-0.24; P < .001). During the first year, mean EDSS scores decreased (improved) from 3.38 to 2.36 in the HSCT group and increased (worsened) from 3.31 to 3.98 in the DMT group (between-group mean difference, −1.7; 95% CI, −2.03 to −1.29; P < .001). There were no deaths and no patients who received HSCT developed nonhematopoietic grade 4 toxicities (such as myocardial infarction, sepsis, or other disabling or potential life-threatening events).
Conclusions and Relevance  In this preliminary study of patients with relapsing-remitting MS, nonmyeloablative HSCT, compared with DMT, resulted in prolonged time to disease progression. Further research is needed to replicate these findings and to assess long-term outcomes and safety.

Se evidencia el vínculo entre obesidad, senescencia y ansiedad

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis

Summary


Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16Ink4a-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesisoccurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed “accumulation of lipids in senescence.” Clearing senescent cells from high fat-fed or leptin receptor-deficient obese micerestored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.

Keywords

aging
senescence
obesity
anxiety
anxiety-like behavior
neurogenesis
high-fat diet
brain
stem cells
lipid droplets

sábado, 16 de febrero de 2019

Vinculan la pérdida auditiva con depresión en la vejez

Association of Audiometric Age-Related Hearing Loss With Depressive Symptoms Among Hispanic Individuals

Abstract
Importance  Age-related hearing loss is highly prevalent and has recently been associated with numerous morbid conditions of aging. Late-life depression is also prevalent and can be resistant to available treatments. Preliminary studies examining the association between hearing loss and late-life depression have been limited by subjective hearing measures, small sample sizes, and primarily white populations.
Objective  To assess whether a cross-sectional association exists between objective audiometric hearing loss and depressive symptoms in older Hispanic adults.
Design, Setting, and Participants  This cross-sectional study uses 2008-2011 Hispanic Community Health Study/Study of Latinos data collected in Miami, Florida, San Diego, California, Chicago, Illinois, or the Bronx, New York, from 5328 Hispanic adults 50 years or older who had exposure, outcome, and covariate data. Data analyses were conducted from March 2018 to September 2018.
Exposure  Audiometric hearing loss (pure-tone average).
Main Outcomes and Measures  Center for Epidemiologic Studies Depression Scale, 10-item version (CESD-10) score of 10 or higher, which indicates clinically significant depressive symptoms.
Results  The median age (interquartile range) of the 5328 participants was 58 (53-63) years, and 3283 participants (61.6%) were female. The mean (SD) CESD-10 score was 7.7 (6.4). Of the 5328 included participants, 1751 (32.9%) had clinically significant depressive symptoms. The odds of having these symptoms increased 1.44 (95% CI, 1.27-1.63) times for every 20 dB of hearing loss, adjusting for hearing aid use, age, sex, educational level, study site, geographic background, cardiovascular disease, and antidepressant use. Compared with those for individuals with normal hearing (0 dB), the odds of having clinically significant depressive symptoms was 1.81 (95% CI, 1.48-2.22) times as high in individuals with mild hearing loss (median threshold, 32.5 dB), 2.38 (95% CI, 1.77-3.20) times as high in individuals with moderate hearing loss (median threshold, 47.5 dB), and 4.30 (95% CI, 2.61-7.09) times as high in individuals with severe hearing loss (median threshold, 80 dB).
Conclusions and Relevance  Objective hearing loss appears to be associated with clinically significant depressive symptoms in older Hispanic people, with greater hearing loss seemingly associated with greater odds of having depressive symptoms. Given the high prevalence of untreated hearing loss in older adults, hearing loss may be a potentially modifiable risk factor for late-life depression.
Reduced non–rapid eye movement sleep is associated with tau pathology in early Alzheimer’s disease


Losing sleep over Alzheimer’s disease


In patients with Alzheimer’s disease (AD), amyloid-β (Aβ) plaques and tau protein tangles accumulate in the brain long before the appearance of clinical symptoms Early intervention is critical for slowing neurodegeneration and disease progression. Therefore, reliable markers of early AD are needed. Lucey et al. analyzed sleep patterns in aging cognitively normal subjects and showed that non–rapid eye movement (NREM) sleep negatively correlated with tau pathology and Aβ deposition in several brain areas. The results show that alterations in NREM sleep may be an early indicator of AD pathology and suggest that noninvasive sleep analysis might be useful for monitoring patients at risk for developing AD.



El rituximab podría retrasar la discapacidad en pacientes con esclerosis múltiple secundaria progresiva

Association of Rituximab Treatment With Disability Progression Among Patients With Secondary Progressive Multiple Sclerosis

Abstract
Importance  Therapeutic options for patients with secondary progressive multiple sclerosis (SPMS) are limited.
Objective  To analyze disability progression in patients with SPMS treated with rituximab compared with matched control patients never treated with rituximab.
Design, Setting, and Participants  This retrospective cohort study analyzed data obtained from patients with SPMS at 3 multiple sclerosis centers located in Basel and Lugano, Switzerland, and Amsterdam, the Netherlands, from 2004 to 2017. Patients were included for analysis if they had received a diagnosis of SPMS, were treated (57 eligible; 54 included) or never treated (504 eligible; 59 included) with rituximab, and had at least 1 follow-up visit. The variables used for propensity score matching were sex, age, Expanded Disability Status Scale (EDSS) score, and disease duration. Follow-up duration was up to 10 years, with a mean (SD) of 3.5 (2.6) years for rituximab-treated patients and 5.4 (2.4) years for controls in the total cohort and a mean (SD) of 3.5 (2.7) years for rituximab-treated patients and 4.8 (2.2) years for controls in the matched cohort.
Exposures  Comparing EDSS score progression in patients with SPMS (treated with rituximab vs not treated with rituximab) using propensity score matching.
Main Outcomes and Measures  The primary end point was progression of EDSS score after baseline, and the secondary end point was time to confirmed disability progression.
Results  After 1:1 propensity score matching, 44 matched pairs (88 patients) were included in the analysis. At baseline, patients treated with rituximab had a mean (SD) age of 49.7 (10.0) years, mean (SD) disease duration of 18.2 (9.4) years, and mean (SD) EDSS score of 5.9 (1.4), and 26 (59%) were women, whereas controls had a mean (SD) age of 51.3 (7.4) years, mean (SD) disease duration of 19.4 (8.7) years, and mean (SD) EDSS score of 5.70 (1.29), and 27 (61%) were women. In the covariate-adjusted analysis of the matched set, patients with SPMS who were treated with rituximab had a significantly lower EDSS score during a mean (SD) follow-up of 3.5 (2.7) years (mean difference, −0.52; 95% CI, −0.79 to −0.26; P < .001). Time to confirmed disability progression was significantly delayed in the rituximab-treated group (hazard ratio, 0.49; 95% CI, 0.26-0.93; P = .03).
Conclusions and Relevance  In this study, patients with SPMS treated with rituximab had a significantly lower EDSS score for up to 10 years of follow-up and a significantly delayed confirmed progression compared with matched controls, suggesting that B-cell depletion by rituximab may be therapeutically beneficial in these patients. A prospective randomized clinical trial with a better level of evidence is needed to confirm the efficacy of rituximab in such patients.

Un mecanismo dendrítico permite al cerebro seleccionar información clave para el aprendizaje y la memoria

Learning-Related Plasticity in Dendrite-Targeting Layer 1 Interneurons

Summary

A wealth of data has elucidated the mechanisms by which sensory inputs are encoded in the neocortex, but how these processes are regulated by the behavioral relevance of sensory information is less understood. Here, we focus on neocortical layer 1 (L1), a key location for processing of such top-down information. Using Neuron-Derived Neurotrophic Factor (NDNF) as a selective marker of L1 interneurons(INs) and in vivo 2-photon calcium imaging, electrophysiology, viral tracing, optogenetics, and associative memory, we find that L1 NDNF-INs mediate a prolonged form of inhibition in distal pyramidal neuron dendrites that correlates with the strength of the memory trace. Conversely, inhibition from Martinotti cells remains unchanged after conditioning but in turn tightly controls sensory responses in NDNF-INs. These results define a genetically addressable form of dendritic inhibition that is highly experience dependent and indicate that in addition to disinhibition, salient stimuli are encoded at elevated levels of distal dendritic inhibition.

Video Abstract

Aplicaciones móviles en la esclerosis múltiple

Mobile applications related to multiple sclerosis: a systematic review

INTRODUCTION:


New treatment options are emerging within the information and communication technologies field through smartphones in order to treat multiple sclerosis (MS) patients.

AIM:


To carry out a systematic review about the information related to mobile applications specifically designed in the field of MS, in order to classify them and carry out a description of their main characteristics.

SUBJECTS AND METHODS:


A literature search of articles published in English and Spanish has been carried out from 2012 until 2017 that presents, analyzes and validates a system based on an application with utility or specific design for MS. In turn, a search for mobile applications has been conducted in mobile application markets.

RESULTS:


A total of 46 mobile applications were found in the field of MS, classified as 19 information apps, 3 assessment apps, 4 treatment apps, 6 communication apps and 14 were considered combined. Four apps had costs and 37 were only found in English.

CONCLUSIONS:


All papers included in this systematic review showed mobile applications designed specifically for MS, but the low methodological quality of the articles included and the fact that there are no coincidences between the apps found in the scientific literature and in the apps markets mean that their use could not be recommended in a generalized way.

Mujeres con migraña muestran un riesgo más bajo de diabetes tipo 2

Associations Between Migraine and Type 2 Diabetes in Women

Abstract
Importance  Little is known about the associations between migraine and type 2 diabetes and the temporality of the association between these 2 diseases.
Objective  To evaluate the association between migraine and type 2 diabetes incidence as well as the evolution of the prevalence of active migraine before and after type 2 diabetes diagnosis.
Design, Setting, and Participants  We used data from the E3N cohort study, a French prospective population-based study initiated in 1990 on a cohort of women born between 1925 and 1950. The E3N study participants are insured by a health insurance plan that mostly covers teachers. From the eligible women in the E3N study, we included those who completed the 2002 follow-up questionnaire with information available on migraine. We then excluded prevalent cases of type 2 diabetes, leaving a final sample of women who were followed up between 2004 and 2014. All potential occurrences of type 2 diabetes were identified through a drug reimbursement database. Statistical analyses were performed in March 2018.
Exposures  Self-reported migraine occurrence.
Main Outcomes and Measures  Pharmacologically treated type 2 diabetes.
Results  From the 98 995 women in the study, 76 403 women completed the 2002 follow-up survey. Of these, 2156 were excluded because they had type 2 diabetes, leaving 74 247 women. Participants had a mean (SD) age of 61 (6) years at baseline, and all were free of type 2 diabetes. During 10 years of follow-up, 2372 incident type 2 diabetes cases occurred. A lower risk of type 2 diabetes was observed for women with active migraine compared with women with no migraine history (univariate hazard ratio, 0.80 [95% CI, 0.67-0.96], multivariable-adjusted hazard ratio, 0.70 [95% CI, 0.58-0.85]). We also observed a linear decrease in active migraine prevalence from 22% (95% CI, 16%-27%) to 11% (95% CI, 10%-12%) during the 24 years prior to diabetes diagnosis, after adjustment for potential type 2 diabetes risk factors. A plateau of migraine prevalence around 11% was then observed for 22 years after diagnosis.
Conclusions and Relevance  We observed a lower risk of developing type 2 diabetes for women with active migraine and a decrease in active migraine prevalence prior to diabetes diagnosis. Further targeted research should focus on understanding the mechanisms involved in explaining these findings.

Estudian las principales vías genéticas alteradas en la fibromialgia

A predictive algorithm to identify genes that discriminate individuals with fibromyalgia syndrome diagnosis from healthy controls

Objectives

Fibromyalgia syndrome (FMS) is a chronic and often debilitating condition that is characterized by persistent fatigue, pain, bowel abnormalities, and sleep disturbances. Currently, there are no definitive prognostic or diagnostic biomarkers for FMS. This study attempted to utilize a novel predictive algorithm to identify a group of genes whose differential expression discriminated individuals with FMS diagnosis from healthy controls.

Methods

Secondary analysis of gene expression data from 28 women with FMS and 19 age-and race-matched healthy women. Expression of discriminatory genes were identified using fold-change differential and Fisher’s ratio (FR). Discriminatory accuracy of the differential expression of these genes was determined using leave-one-out-cross-validation. Functional networks of the discriminating genes were described from the Ingenuity’s Knowledge Base.

Results

The small-scale signature contained 57 genes whose expressions were highly discriminatory of the FMS diagnosis. The combination of these high discriminatory genes with FR higher than 1.45 provided a leave-one-out-cross-validation accuracy for the FMS diagnosis of 85.11%. The discriminatory genes were associated with 3 canonical pathways: hepatic stellate cell activation, oxidative phosphorylation, and airway pathology related to COPD.

Conclusion

The discriminating genes, especially the 2 with the highest accuracy, are associated with mitochondrial function or oxidative phosphorylation and glutamate signaling. Further validation of the clinical utility of this finding is warranted.
Keywords: chronic pain, machine learning, medically unexplained symptoms, microarray

El ejercicio de resistencia aeróbica sería preferible para ralentizar el envejecimiento celular

Differential effects of endurance, interval, and resistance training on telomerase activity and telomere length in a randomized, controlled study

Abstract


Aims
It is unknown whether different training modalities exert differential cellular effects. Telomeres and telomere-associated proteins play a major role in cellular aging with implications for global health. This prospective training study examines the effects of endurance training, interval training (IT), and resistance training (RT) on telomerase activity and telomere length (TL).
Methods and results
One hundred and twenty-four healthy previously inactive individuals completed the 6 months study. Participants were randomized to three different interventions or the control condition (no change in lifestyle): aerobic endurance training (AET, continuous running), high-intensive IT (4 × 4 method), or RT (circle training on 8 devices), each intervention consisting of three 45 min training sessions per week. Maximum oxygen uptake (VO2max) was increased by all three training modalities. Telomerase activity in blood mononuclear cells was up-regulated by two- to three-fold in both endurance exercise groups (AET, IT), but not with RT. In parallel, lymphocyte, granulocyte, and leucocyte TL increased in the endurance-trained groups but not in the RT group. Magnet-activated cell sorting with telomerase repeat-ampliflication protocol (MACS-TRAP) assays revealed that a single bout of endurance training—but not RT—acutely increased telomerase activity in CD14+ and in CD34+ leucocytes.
Conclusion
This randomized controlled trial shows that endurance training, IT, and RT protocols induce specific cellular pathways in circulating leucocytes. Endurance training and IT, but not RT, increased telomerase activity and TL which are important for cellular senescence, regenerative capacity, and thus, healthy aging.

sábado, 9 de febrero de 2019

Observan conexiones cerebrales más prolongadas en adultos con autismo

Evaluation of Differences in Temporal Synchrony Between Brain Regions in Individuals With Autism and Typical Development

Abstract
Importance  Despite reports of widespread but heterogeneous atypicality of functional connectivity in individuals with autism, little is known regarding the temporal dynamics of functional brain connections and how they relate to autistic traits.
Objective  To investigate differences in temporal synchrony between brain regions in individuals with autism and those with typical development.
Design, Setting, and Participants  This cohort study, conducted at the University of Utah, included 90 adolescent and adult male participants. A larger sample from the multisite Autism Brain Imaging Data Exchange (ABIDE) was also used as a replication sample. The study includes data acquired between December 2016 and April 2018. Aggregate data included in the replication sample were released to the public in August 2012 (ABIDE I) and June 2016 (ABIDE II). Data analysis were conducted between January 2018 and April 2018.
Exposures  Male individuals diagnosed as having autism (n = 52) and typically developing male individuals (n = 38).
Main Outcomes and Measures  Long duration (30 minutes/individual) of multiband, multiecho functional magnetic resonance imaging was acquired to estimate functional connectivity between brain regions. Sustained connectivity, a measure of functional connectivity duration, as well as lagged temporal dynamics related to functional connectivity, were compared between groups for 361 gray matter regions of interest and a 17-network parcellation. Lagged findings were replicated in the larger ABIDE sample (n = 1402). Sustained connectivity findings were also associated with behavioral and cognitive variables.
Results  In 52 males with autism (mean [SD] age, 27.73 [8.66] years) and 38 control males with typical development (mean [SD] age, 27.09 [7.49] years), increases in both sustained and functional connectivity at several lags were found in individuals with autism compared with the control group. Group differences in functional connectivity were replicated in the larger ABIDE data set at a 6-second lag. Measures of symptom severity in individuals with autism were positively associated with sustained connectivity values. In the control group, sustained connectivity was negatively associated with cognitive processing. A replication sample (n = 1402) composed of 579 individuals with autism (80 female and 499 male; mean [SD] age, 15.08 [6.89] years) and 823 in the control group (211 female and 612 male; mean [SD] age, 15.06 [6.79] years) from the ABIDE data set was also analyzed.
Conclusions and Relevance  Whereas the magnitude of functional connectivity in autism is variable across brain regions, participant samples, and development, prolonged temporal synchrony of functional connections is reproducibly observed in autism, suggesting a potential mechanism for core symptoms

Se Identifica un gen esencial en la recuperación funcional tras un ictus isquémico

PATJ Low Frequency Variants Are Associated With Worse Ischemic Stroke Functional Outcome

Abstract

Rationale:

Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome.

Objective:

Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date.

Methods and Results:

A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10−9).

Conclusions:

Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJin stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci