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Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies., This research was funded by National Institute of Mental Health (NIMH) grant R01MH092293 (to GAH and JAT) and NJCTS (New Jersey Center for Tourette Syndrome and Associated Disorders; to GAH and JAT). This work was also supported by grants from the Judah Foundation, the Tourette Association of America, National Institute of Health (NIH) Grants NS40024, NS016648, MH079489, MH073250, the American Recovery and Re-investment Act (ARRA) Grants NS040024-07S1; NS16648-29S1; NS040024-09S1; MH092289; MH092290; MH092291; MH092292; R01MH092293; MH092513; MH092516; MH092520; MH071507; MH079489; MH079487; MH079488; and MH079494. Dr. Mir has received grants from the Instituto de Salud Carlos III (PI10/01674, PI13/01461), the Consejería de Economía, Innovación, Ciencia y Empresa de la Junta de Andalucía (CVI-02526, CTS-7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI-0741/2010, PI-0437-2012, PI-0471-2013), the Sociedad Andaluza de Neurología, the Fundación Alicia Koplowitz, the Fundación Mutua Madrileña and the Jaques and Gloria Gossweiler Foundation. Dr. Morer has received grants from the Fundacion Alicia Koplowitz and belongs to the research group of the Comissionat per Universitats i Recerca del Departmanent d’Innovacio (DIUE) 2009SGR1119. Dr. Münchau has received grants from the Deutsche Forschungsgemeinschaft (DFG: MU 1692/3-1, MU 1692/4-1 and FOR 2698). This study was also supported by a Grant from the National Institute for Environmental Health Science (R01 ES021462).

Background: Rare variants in PLCG2 (p.P522R), ABI3 (p.S209F), and TREM2 (p.R47H, p.R62H) have been associated with late onset Alzheimer’s disease (LOAD) risk in Caucasians. After the initial report, several studies have found positive results in cohorts of different ethnic background and with different phenotype. Objective: In this study, we aim to evaluate the association of rare coding variants in PLCG2, ABI3, and TREM2 with LOAD risk and their effect at different time points of the disease. Methods: We used a European American cohort to assess the association of the variants prior onset (using CSF Aβ42, tau, and pTau levels, and amyloid imaging as endophenotypes) and after onset (measured as rate of memory decline). Results: We confirm the association with LOAD risk of TREM2 p.R47H, p.R62H and ABI3 p.S209F variants, and the protective effect of PLCG2 p.P522R. In addition, ABI3 and TREM2 gene-sets showed significant association with LOAD risk. TREM2 p.R47H and PLCG2 p.P522R variants were also statistically associated with increase of amyloid imaging and AD progression, respectively. We did not observe any association of ABI3 p.S209F with any of the other AD endophenotypes. Conclusion: The results of this study highlight the importance of including biomarkers and alternative phenotypes to better understand the role of novel candidate genes with the disease.

CCL23 is a chemokine implicated in inflammation and host defense responses. It has been recently associated with acquired brain damage and stroke outcomes. In this study, we reported the role of CCL23 in Alzheimer's disease (AD). We evaluated the levels of CCL23 in 659 individuals: cognitively normal, mild cognitive impaired (MCI), and AD patients. Two cross-sectional (study 1, n = 53; study 2, n = 200) and two longitudinal (study 3, n = 74; study 4, n = 332) studies were analyzed separately. CCL23 levels in the blood and/or cerebrospinal fluid (CSF) of each study were measured by immunoassays. Globally, our results suggest a predictive role of CCL23 protein levels both in the plasma in study 3 (hazard ratio (HR) = 2.5 (confidence interval (CI) 95% : 1.2-5.3), p = 0.02) and in the CSF in study 4 (HR = 3.05 (CI 95% : 1.02-5), p = 0.04) in cases of MCI that progress to AD. Moreover, we observed that the APOE ϵ4 allele was associated with higher levels of CCL23 in study 2 (470.33 pg/mL (interquartile range (IQR): 303.33-597.76) versus 377.94 pg/mL (IQR: 267.16-529.19), p = 0.01) (APOE genotypes were available in studies 2 and 4). Together, these findings support the role of CCL23 in neuroinflammation in the early stages of AD, suggesting that CCL23 might be a candidate blood biomarker for MCI to AD progression.

Alzheimer’s disease is a complex and multifactorial condition regulated by both genetics and lifestyle, which ultimately results in the accumulation of β-amyloid (Aβ) and tau proteins in the brain, loss of gray matter, and neuronal death [...]

Alzheimer’s disease (AD) has become a common disease of the elderly for which no cure currently exists. After over 30 years of intensive research, we have gained extensive knowledge of the genetic and molecular factors involved and their interplay in disease. These findings suggest that different subgroups of AD may exist. Not only are we starting to treat autosomal dominant cases differently from sporadic cases, but we could be observing different underlying pathological mechanisms related to the amyloid cascade hypothesis, immune dysfunction, and a tau-dependent pathology. Genetic, molecular, and, more recently, multi-omic evidence support each of these scenarios, which are highly interconnected but can also point to the different subgroups of AD. The identification of the pathologic triggers and order of events in the disease processes are key to the design of treatments and therapies. Prevention and treatment of AD cannot be attempted using a single approach; different therapeutic strategies at specific disease stages may be appropriate. For successful prevention and treatment, biomarker assays must be designed so that patients can be more accurately monitored at specific points during the course of the disease and potential treatment. In addition, to advance the development of therapeutic drugs, models that better mimic the complexity of the human brain are needed; there have been several advances in this arena. Here, we review significant, recent developments in genetics, omics, and molecular studies that have contributed to the understanding of this disease. We also discuss the implications that these contributions have on medicine.

This review summarizes the current state of the art of polygenic risk scores (PRSs) in the assessment of risk for neurodegenerative diseases. Polygenic risk scores have been used to identify the shared genetic architecture between comorbid complex traits, disease presentations, and disease endophenotypes. The pathological and symptomatologic overlap between neurodegenerative diseases is strikingly high. In some cases, the diagnostic decision is arbitrary depending on the first appearance of symptomatology. Genetic studies have demonstrated that the genetic architecture of each of these diseases is different, but has a high degree of overlap. The creation of polygenic risk scores has allowed a more accurate calculation of this overlap. However, the power of the PRS is dependent on the power of the genome-wide association studies (GWAS) used to describe the genetic architecture. Even though not all neurodegenerative disease GWAS have the same sample size, and thus the same power, the use of polygenic risk scores has been successful in demonstrating the genetic overlap that has been observed phenotypically.

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 PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci.

Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86–0.94]; q value=7.43×10 − 5 ), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92–0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65–0.77]; q value=5.11×10 − 14 ); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06–1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

Background and Purpose: Large-scale observational studies of acute ischemic stroke (AIS) promise to reveal mechanisms underlying cerebral ischemia. However, meaningful quantitative phenotypes attainable in large patient populations are needed. We characterize a dynamic metric of AIS instability, defined by change in National Institutes of Health Stroke Scale score (NIHSS) from baseline to 24 hours baseline to 24 hours (NIHSS baseline – NIHSS 24hours = ΔNIHSS 6-24h ), to examine its relevance to AIS mechanisms and long-term outcomes. Methods: Patients with NIHSS prospectively recorded within 6 hours after onset and then 24 hours later were enrolled in the GENISIS study (Genetics of Early Neurological Instability After Ischemic Stroke). Stepwise linear regression determined variables that independently influenced ΔNIHSS 6 –24h . In a subcohort of tPA (alteplase)-treated patients with large vessel occlusion, the influence of early sustained recanalization and hemorrhagic transformation on ΔNIHSS 6–24h was examined. Finally, the association of ΔNIHSS 6 –24h with 90-day favorable outcomes (modified Rankin Scale score 0–2) was assessed. Independent analysis was performed using data from the 2 NINDS-tPA stroke trials (National Institute of Neurological Disorders and Stroke rt-PA). Results: For 2555 patients with AIS, median baseline NIHSS was 9 (interquartile range, 4–16), and median ΔNIHSS 6 –24h was 2 (interquartile range, 0–5). In a multivariable model, baseline NIHSS, tPA-treatment, age, glucose, site, and systolic blood pressure independently predicted ΔNIHSS 6 –24h (R 2 =0.15). In the large vessel occlusion subcohort, early sustained recanalization and hemorrhagic transformation increased the explained variance (R 2 =0.27), but much of the variance remained unexplained. ΔNIHSS 6 –24h had a significant and independent association with 90-day favorable outcome. For the subjects in the 2 NINDS-tPA trials, ΔNIHSS 3 –24h was similarly associated with 90-day outcomes. Conclusions: The dynamic phenotype, ΔNIHSS 6–24h , captures both explained and unexplained mechanisms involved in AIS and is significantly and independently associated with long-term outcomes. Thus, ΔNIHSS 6 –24h promises to be an easily obtainable and meaningful quantitative phenotype for large-scale genomic studies of AIS.

During the first hours after stroke onset neurological deficits can be highly unstable: some patients rapidly improve, while others deteriorate. This early neurological instability has a major impact on long-term outcome. Here, we aimed to determine the genetic architecture of early neurological instability measured by the difference between NIH stroke scale (NIHSS) within six hours of stroke onset and NIHSS at 24h (ΔNIHSS). A total of 5,876 individuals from seven countries (Spain, Finland, Poland, United States, Costa Rica, Mexico and Korea) were studied using a multi-ancestry meta-analyses. We found that 8.7% of ΔNIHSS variance was explained by common genetic variations, and also that early neurological instability has a different genetic architecture than that of stroke risk. Seven loci (2p25.1, 2q31.2, 2q33.3, 4q34.3, 5q33.2, 6q26 and 7p21.1) were genome-wide significant and explained 2.1% of the variability suggesting that additional variants influence early change in neurological deficits. We used functional genomics and bioinformatic annotation to identify the genes driving the association from each loci. eQTL mapping and SMR indicate that ADAM23 (log Bayes Factor (LBF)=6.34) was driving the association for 2q33.3. Gene based analyses suggested that GRIA1 (LBF=5.26), which is predominantly expressed in brain, is the gene driving the association for the 5q33.2 locus. These analyses also nominated PARK2 (LBF=5.30) and ABCB5 (LBF=5.70) for the 6q26 and 7p21.1 loci. Human brain single nuclei RNA-seq indicates that the gene expression of ADAM23 and GRIA1 is enriched in neurons. ADAM23, a pre-synaptic protein, and GRIA1, a protein subunit of the AMPA receptor, are part of a synaptic protein complex that modulates neuronal excitability. These data provides the first evidence in humans that excitotoxicity may contribute to early neurological instability after acute ischemic stroke.RESEARCH INTO CONTEXTEvidence before this studyNo previous genome-wide association studies have investigated the genetic architecture of early outcomes after ischemic stroke.Added Value of this studyThis is the first study that investigated genetic influences on early outcomes after ischemic stroke using a genome-wide approach, revealing seven genome-wide significant loci. A unique aspect of this genetic study is the inclusion of all of the major ethnicities by recruiting from participants throughout the world. Most genetic studies to date have been limited to populations of European ancestry.Implications of all available evidenceThe findings provide the first evidence that genes implicating excitotoxicity contribute to human acute ischemic stroke, and demonstrates proof of principle that GWAS of acute ischemic stroke patients can reveal mechanisms involved in ischemic brain injury.

Alpha-Synuclein (α-Syn) is the main protein component of Lewy bodies (LB), the pathological hallmark of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of α-Syn are not currently used as a clinical biomarker but may be a proxy for pathological α-Syn accumulation in the brain. Therefore, identifying genetic modifiers of CSF α-Syn levels could provide insights into the underlying molecular mechanisms leading to PD. However, genetic modifiers of CSF α-Syn levels remain unknown. CSF levels of amyloid beta1-42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau181) are standard biomarkers for the diagnosis of Alzheimer disease (AD); its use as quantitative traits in genetic studies have provided novel insights into AD pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in PD has not been conducted. Here, genome-wide association studies (GWAS) were performed using CSF biomarker levels as quantitative traits in four PD cases and control cohorts (combined N=1,960). CSF biomarker (α-Syn, Aβ42, t-tau, and p-tau181) levels were significantly lower in PD cases compared with controls. An SNP, proxy for APOE ε4, was associated with CSF Aβ42 levels (effect=-0.5, p=9.2×10−19). Several genome-wide suggestive loci associated with CSF α-Syn, t-tau, or p-tau181 were found. Polygenic risk scores (PRS) were constructed using the latest PD risk meta-analysis (49,731 PD cases and 784,343 controls) and the largest CSF biomarkers GWAS (N=3,146). PRS calculated using META-PD were associated with PD status in the four cohorts included in the present study (p= 2.2×10−16). A highly significant correlation (Nagelkerke pseudo-R2 =2.29%; p=2.5×10−11) of the genomic architecture between CSF Aβ42 and PD risk was also found. Higher PRS scores were associated with lower CSF Aβ42 levels (p=7.3×10−04). Two-sample Mendelian Randomization (MR) approach revealed that CSF Aβ42 plays a role in PD risk (p=1.4×10−05) and age at onset (p=7.6×10−06), an effect mainly mediated by variants in the APOE locus. Subsequently, the APOE ε4 allele was associated with significantly lower levels of CSF Aβ42 (p=3.8×10−06), higher mean cortical binding potentials (cortical binding of Pittsburgh compound B PET) (p=5.8×10−08) and higher Braak Aβ score (p=4.4×10−04) in PD participants. Together these results from high-throughput and hypothesis-free approaches (GWAS, PRS and MR) converge on a genetic link between PD with CSF Aβ42 and APOE.

Expression quantitative trait loci (eQTL) mapping has successfully resolved some genome-wide association study (GWAS) loci for complex traits1–6. However, there is a need for implementing additional “omic” approaches to untangle additional loci and provide a biological context for GWAS signals. We generated a detailed landscape of the genomic architecture of protein levels in multiple neurologically relevant tissues (brain, cerebrospinal fluid (CSF) and plasma), by profiling thousands of proteins in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. We demonstrated that cis-pQTL are more likely to be shared across tissues but trans-pQTL are tissue-specific. Between 78% to 87% of pQTL are not eQTL, indicating that protein levels have a different genetic architecture than gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. In the context of personalized medicine, these results highlight the need for implementing additional functional genomic approaches beyond gene expression in order to understand the biology of complex traits, and to identify novel biomarkers and potential drug targets for those traits.

Aim: Genetic variants on metabolic and transport enzymes are good candidates to explain inter-individual differences in response to antipsychotics. The aim of this study is to evaluate and compare the influence of the CYP2D6, CYPC19, CYP1A2 and ABCB1 variants on plasma levels, treatment response and side effects of antipsychotics. Methods: Twenty polymorphisms in selected genes were genotyped in 318 patients diagnosed with schizophrenia, schizoaffective or delusional disorder treated with antipsychotics (clozapine, olanzapine, paliperidone, risperidone, aripiprazole and quetiapine). Plasma drug levels were determined after 6 weeks of treatment. The Positive and Negative Symptoms Scale (PANSS) and UKU scale of side effects were recorded at baseline and after 12 weeks of treatment. The effect of gene variants on plasma drug levels, treatment response and adverse effects were examined by multinomial regression. Results:CYP1A2 was found to be associated with psychic side effects (P = 0.02), with variants predicting higher enzyme activity associated with lower adverse effects, and was the strongest predictor for this adverse effect of all the studied factors. Functional variants in CYP genes were associated with plasma level differences, with higher activity variants associated with lower plasma levels. No association with improvement of the condition, as measured by the PANSS score, was found in this study. Conclusion: The results suggest that increased CYP1A2 activity protects against psychic side effects. Few studies have evaluated the impact of genetic factors on treatment response or side effects, and only in relation to a selection of adverse reactions. These results are a step towards better understanding of the factors behind the different aspects of clinical outcomes, such as various adverse effects.

[Background and Purpose] Immune cells play a key role in the first 24h poststroke (acute phase), being associated with stroke outcome. We aimed to find genetic risk factors associated with leukocyte counts during the acute phase of stroke., [Methods] Ischemic stroke patients with leukocyte counts data during the first 24h were included. Genome-wide association study and gene expression studies were performed., [Results] Our genome-wide association study, which included 2064 (Discovery) and 407 (Replication) patients, revealed a new locus (14q24.3) associated with leukocyte counts. After Joint analysis (n=2471) 5 more polymorphisms reached genome-wide significance (P, [Conclusions] We have found the first locus associated with leukocyte counts in ischemic stroke, also associated with acute outcome. Genetic analysis of acute endophenotypes could be useful to find the genetic factors associated with stroke outcome. Our findings suggested a different modulation of immune cells in stroke compared with healthy conditions.

Antipsychotic drugs fail to achieve adequate response in 30–50% of treated patients and about 50% of them develop severe and lasting side effects. Treatment failure results in poorer prognosis with devastating repercussions for the patients, carers and broader society. Our study evaluated the clinical benefits of a pharmacogenetic intervention for the personalisation of antipsychotic treatment. Pharmacogenetic information in key CYP polymorphisms was used to adjust clinical doses in a group of patients who started or switched treatment with antipsychotic drugs (PharmG+, N = 123), and their results were compared with those of a group of patients treated following existing clinical guides (PharmG−, N = 167). There was no evidence of significant differences in side effects between the two arms. Although patients who had their antipsychotic dose adjusted according to CYPs polymorphisms (PharmG+) had a bigger reduction in side effects than those treated as usual (PharmG−), the difference was not statistically significant (p > 0.05 for all comparisons). However, PharmG+ patients treated with CYP2D6 substrates that were carriers of CYP2D6 UMs or PMs variants showed a significantly higher improvement in global, psychic and other UKU side effects than PharmG− patients (p = 0.02, p = 0.05 and p = 0.01, respectively). PharmG+ clozapine treated patients with CYP1A2 or CYP2C19 UM and PMs variants also showed higher reductions in UKU scores than PharmG− clozapine patients in general. However, those differences were not statistically significant. Pharmacogenetic interventions may improve the safety of antipsychotic treatments by reducing associated side effects. This intervention may be particularly useful when considering treatment with antipsychotics with one major metabolic pathway, and therefore more susceptible to be affected by functional variants of CYP enzymes., This research was funded by grants from the Institute Carlos III (FIS PI11/02006; FIS PI16/01029). A.G.-R. was partially funded by a private grant from the Jové family. Genotyping was partially conducted by the CEGEN-PRB2-ISCIII node, which is supported by grant PT13/001, ISCIIISGEFI/ FEDER.

Comment inThe yin and yang of magnesium and calcium: New genetic insights for stroke? [Neurology. 2019]; International audience; Objective To determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach. Methods Analyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases). Results In standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10 −4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10 −4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype. Conclusions This study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

ObjectiveTo validate the Genot-PA score, a clinical-genetic logistic regression score that stratifies the thrombolytic therapy safety, in a new cohort of patients with stroke.MethodsWe enrolled 1,482 recombinant tissue plasminogen activator (rtPA)-treated patients with stroke in Spain and Finland from 2003 to 2016. Cohorts were analyzed on the basis of ethnicity and therapy: Spanish patients treated with IV rtPA within 4.5 hours of onset (cohort A and B) or rtPA in combination with mechanical thrombectomy within 6 hours of onset (cohort C) and Finnish participants treated with IV rtPA within 4.5 hours of onset (cohort D). The Genot-PA score was calculated, and hemorrhagic transformation (HT) and parenchymal hematoma (PH) risks were determined for each score stratum.ResultsGenot-PA score was tested in 1,324 (cohort A, n = 726; B, n = 334; C, n = 54; and D, n = 210) patients who had enough information to complete the score. Of these, 213 (16.1%) participants developed HT and 85 (6.4%) developed PH. In cohorts A, B, and D, HT occurrence was predicted by the score (p = 2.02 × 10−6, p = 0.023, p = 0.033); PH prediction was associated in cohorts A through C (p = 0.012, p = 0.034, p = 5.32 × 10−4). Increased frequency of PH events from the lowest to the highest risk group was found (cohort A 4%–15.7%, cohort B 1.5%–18.2%, cohort C 0%–100%). The best odds ratio for PH prediction in the highest-risk group was obtained in cohort A (odds ratio 5.16, 95% confidence interval 1.46–18.08, p = 0.009).ConclusionThe Genot-PA score predicts HT in patients with stroke treated with IV rtPA. Moreover, in an exploratory study, the score was associated with PH risk in mechanical thrombectomy-treated patients.

Background: The prevalence of dementia in Parkinson disease (PD) increases dramatically with advancing age, approaching 80% in patients who survive 20 years with the disease. Increasing evidence suggests clinical, pathological and genetic overlap between Alzheimer disease, dementia with Lewy bodies and frontotemporal dementia with PD. However, the contribution of the dementia-causing genes to PD risk, cognitive impairment and dementia in PD is not fully established. Objective: To assess the contribution of coding variants in Mendelian dementia-causing genes on the risk of developing PD and the effect on cognitive performance of PD patients. Methods: We analyzed the coding regions of the amyloid-beta precursor protein (APP), Presenilin 1 and 2 (PSEN1, PSEN2), and Granulin (GRN) genes from 1,374 PD cases and 973 controls using pooled-DNA targeted sequence, human exome-chip and whole-exome sequencing (WES) data by single variant and gene base (SKAT-O and burden tests) analyses. Global cognitive function was assessed using the Mini-Mental State Examination (MMSE) or the Montreal Cognitive Assessment (MoCA). The effect of coding variants in dementia-causing genes on cognitive performance was tested by multiple regression analysis adjusting for gender, disease duration, age at dementia assessment, study site and APOE carrier status. Results: Known AD pathogenic mutations in the PSEN1 (p.A79V) and PSEN2 (p.V148I) genes were found in 0.3% of all PD patients. There was a significant burden of rare, likely damaging variants in the GRN and PSEN1 genes in PD patients when compared with frequencies in the European population from the ExAC database. Multiple regression analysis revealed that PD patients carrying rare variants in the APP, PSEN1, PSEN2, and GRN genes exhibit lower cognitive tests scores than non-carrier PD patients (p = 2.0 × 10−4), independent of age at PD diagnosis, age at evaluation, APOE status or recruitment site. Conclusions: Pathogenic mutations in the Alzheimer disease-causing genes (PSEN1 and PSEN2) are found in sporadic PD patients. PD patients with cognitive decline carry rare variants in dementia-causing genes. Variants in genes causing Mendelian neurodegenerative diseases exhibit pleiotropic effects.

Many genetic studies for Alzheimer’s Disease (AD) have been focused on the identification of common genetic variants associated with AD risk and not on other aspects of the disease, such as age at onset or rate of dementia progression. There are multiple approaches to untangling the genetic architecture of these phenotypes. We hypothesized that the genetic architecture of rate of progression is different than the risk for developing AD dementia. To test this hypothesis, we used longitudinal clinical data from ADNI and the Knight-ADRC at Washington University and we calculated PRS (polygenic risk score) based on the IGAP study to compare the genetic architecture of AD risk and dementia progression. Dementia progression was measured by the change of Clinical Dementia Rating Sum of Boxes (CDR)-SB per year. Out of the 21 loci for AD risk, no association with the rate of dementia progression was found. The PRS rate was significantly associated with the rate of dementia progression (β=0.146, p.value= 0.03). In the case of rare variants, TREM2 (β=0.309, p.value=0.02) was also associated with the rate of dementia progression. TREM2 variant carriers showed a 23% faster rate of dementia compared with non-variant carriers. In conclusion, our results indicate that the recently identified common and rare variants for AD susceptibility have a limited impact on the rate of dementia progression in AD patients.

Background The genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau). Methods The weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry. Results The PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS. Conclusion Our study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk. Electronic supplementary material The online version of this article (10.1186/s12883-017-0978-z) contains supplementary material, which is available to authorized users.

Objective:To determine whether the genetic architecture of sporadic late-onset Alzheimer’s Disease (sLOAD) has an effect on familial late-onset AD (fLOAD), sporadic early-onset (sEOAD) and autosomal dominant early-onset (eADAD).Methods:Polygenic risk scores (PRS) were constructed using previously identified 21 genome-wide significant loci for LOAD risk.Results:We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27; p=1.29×10-7), followed by fLOAD (OR=1.75; p=1.12×10-7) and sLOAD (OR=1.40; p=1.21×10-3). PRS is associated with cerebrospinal fluid ptau181-Aβ42on eADAD.Conclusion:Our analysis confirms that the genetic factors identified for sLOAD also modulate risk in fLOAD and sEOAD cohorts. Furthermore, our results suggest that the burden of these risk variants is associated with familial clustering and earlier-onset of AD. Although these variants are not associated with risk in the eADAD, they may be modulating age at onset.

A study on familial Parkinson disease (PD) described four variants in the gene TMEM230 (Chr. 20p13) as cause of PD (1). The aim of this study was to test if variants in the TEMEM230 gene are associated with PD in two independent American European datasets. No variants in the TMEM230 region were found associated with PD, age at onset or cerebrospinal fluid α-synuclein levels.

OBJECTIVES: We aim to describe rates and risk factors of Hepatitis C Virus (HCV) diagnoses, follow-up HCV testing and HCV seroconversion from 2004-2011 in a cohort of HIV-positive persons in Spain. METHODS: CoRIS is a multicentre, open and prospective cohort recruiting adult HIV-positive patients naïve to antiretroviral therapy. We analysed patients with at least one negative and one follow-up HCV serology. Incidence Rates (IR) were calculated and multivariate Poisson regression was used to estimate adjusted Rates Ratios (aIRR). RESULTS: Of 2112 subjects, 53 HCV diagnoses were observed, IR = 0.93/100 py (95%CI: 0.7-1.2). IR increased from 0.88 in 2004-05 to 1.36 in 2010-11 (aIRR = 1.55; 95%CI: 0.37-6.55). In men who have sex with men (MSM) from 0.76 to 1.10 (aIRR = 1.45; 95%CI: 0.31-6.82); in heterosexual (HTX) subjects from 1.19 to 1.28 (aIRR = 1.08; 95%CI: 0.11-10.24). HCV seroconversion rates decreased from 1.77 to 0.65 (aIRR = 0.37; 95%CI: 0.12-1.11); in MSM from 1.06 to 0.49 (aIRR = 0.46; 95%CI: 0.09-2.31); in HTX from 2.55 to 0.59 (aIRR = 0.23; 95%CI: 0.06-0.98). HCV infection risk was higher for injecting drug users (IDU) compared to HTX (aIRR = 9.63;95%CI: 2.9-32.2); among MSM, for subjects aged 40-50 compared to 30 or less (IRR = 3.21; 95%CI: 1.7-6.2); and among HTX, for female sex (aIRR = 2.35; 95%CI: 1.03-5.34) and

To describe tuberculosis (TB) incidence, risk factors, clinical presentation, disease management and outcomes in human immunodeficiency virus (HIV) infected patients from the CoRIS cohort, Spain, 2004-2010.Open multicentre cohort of antiretroviral treatment (ART) naïve patients at entry. Incidence and risk factors were evaluated using multivariate Poisson regression.Among 6811 patients, 271 were eligible for the study and 198 for the estimation of the incidence rate; TB incidence ranged from 12.1 to 14.1/1000 person-years. TB was associated with low education level (rate ratio [RR] 2.65, 95%CI 1.73-4.07), being sub-Saharan African (RR 3.14, 95%CI 1.81-5.45), heterosexual (RR 2.01, 95%CI 1.22-3.29) or an injecting drug user (RR 2.11, 95%CI 1.20-3.69), not undergoing ART (RR 3.33, 95%CI 2.22-4.76), CD4200 cells/mm(3) (RR 5.20, 95%CI 3.25-8.33) and log-viral load of 4-5 (RR 5.44, 95%CI 3.28-9.02) or5 (RR 13.10, 95%CI 8.27-20.76). Overall, 87% were new cases and 13% were previously treated cases; 175 (65%) were bacteriologically confirmed. Drug susceptibility testing was performed in 146 (83%) patients: resistance to first-line drugs was 11.1% in new and 36.4% in previously treated cases. Standard anti-tuberculosis treatment with four or three drugs was prescribed in respectively 55% and 36% of cases. Treatment default was 11%, and was higher among previously treated cases; 80% received ART during anti-tuberculosis treatment, 80% of new and 50% of previously treated cases were cured or completed treatment, and 18 (6.6%) died.TB incidence in HIV-infected patients remains high. Interventions should include early HIV diagnosis and access to ART, enhanced bacteriological confirmation, wider use of four-drug regimens and reduction in treatment default.

Background Higher prevalence of atherosclerosis and higher cardiovascular risk is observed in HIV-infected individuals. The biological mechanisms underlying these processes are unclear. Several studies have implicated genetic variants in the inflammatory genes in cardiovascular disease and in HIV natural course infection. Methods & Findings In this study we have tested the possible association between genetic variants in several inflammatory genes and asymptomatic cardiovascular disease measured by carotid intima media thickness (cIMT) and atherosclerotic plaque presence as dependent variables in 213 HIV-infected individuals. A total of 101 genetic variants in 25 candidate genes have been genotyped. Results were analyzed using Plink and SPSS statistical packages. We have found several polymorphisms in the genes ALOX5 (rs2115819 p = 0.009), ALOX5AP (rs9578196 p = 0.007; rs4769873 p = 0.004 and rs9315051 p = 0.0004), CX3CL1 (rs4151117 p = 0.040 and rs614230 p = 0.015) and CCL5 (rs3817655 p = 0.018 and rs2107538 p = 0.018) associated with atherosclerotic plaque. cIMT mean has been associated with CRP (1130864 p = 0.0003 and rs1800947 p = 0.008), IL1RN (rs380092 p = 0.002) and ALOX5AP (rs3885907 p = 0.02) genetic variants. Conclusions In this study we have found modest associations between genetic variants in several inflammatory genes and atherosclerotic plaque or cIMT. Nevertheless, our study adds evidence to the association between inflammatory pathway genetic variants and the atherosclerotic disease in HIV-infected individuals.

Background. The clinical relevance of ultrasensitive human immunodeficiency virus type 1 (HIV-1) genotypicresistance testing in antiretroviral treatment (ART)-experienced individuals remains unknown.Methods. Thiswasa retrospective,multicentre,cohortstudy inART-experienced, HIV-1-infectedadultswho ini-tiated salvage ART including, at least 1 ritonavir-boosted protease inhibitor, raltegravir or etravirine. Presalvage ARTSangerand454sequencingofplasmaHIV-1wereusedtogenerateseparategenotypicsensitivityscores(GSS)usingtheHIVdb, ANRS, and REGA algorithms. Virological failure (VF) was defined as 2 consecutive HIV-1 RNA levels ≥200copies/mL at least 12 weeks after salvage ART initiation, whereas subjects remained on the same ART. The ability ofSangerand454-GSStopredictVFwasassessedbyreceiveroperatingcharacteristic(ROC)curvesandsurvivalanalyses.Results. Thestudyincluded132evaluablesubjects;28(21%)developedVF.UsingHIVdb,454predictedVFbetterthanSangersequencingintheROCcurveanalysis(areaunderthecurve:0.69vs0.60,DelongtestP=.029).TimetoVFwas shorter for subjects with 454-GSS

Currently, neuropsychological impairment among HIV+ patients on antiretroviral therapy leads to a reduction in the quality of life and it is an important challenge due to the high prevalence of HIV-associated neurocognitive disorders and its concomitant consequences in relation to morbidity and mortality- including those HIV+ patients with adequate immunological and virological status. The fact that the virus is established in CNS in the early stages and its persistence within the CNS can help us to understand HIV-related brain injury even when highly active antiretroviral therapy is effective. The rising interest in HIV associated neurocognitive disorders has let to development new diagnostic tools, improvement of the neuropsychological tests, and the use of new biomarkers and new neuroimaging techniques that can help the diagnosis. Standardization and homogenization of neurocognitive tests as well as normalizing and simplification of easily accessible tools that can identify patients with increased risk of cognitive impairment represent an urgent requirement. Future efforts should also focus on diagnostic keys and searching for useful strategies in order to decrease HIV neurotoxicity within the CNS.

To analyze the impact of late presentation (LP) on overall mortality and causes of death and describe LP trends and risk factors (2004-2013). Cox models and logistic regression were used to analyze data from a nation-wide cohort in Spain. LP is defined as being diagnosed when CD4 4 years, aHRLP.vs.nLP = 1.5(0.7-3.1). First-year's main cause of death was HIV/AIDS (73%); and malignancies among those surviving >4 years (32%). HIV/AIDS-related deaths were more likely in LP (59.2% vs. 25.0%; p 50.vs.

Prevalence of transmitted drug resistance (pTDR) to antiretroviral drugs in Spain (2007–2012) was estimated using the CoRIS cohort, adjusting its territorial distribution and transmission route to the reference population from the Spanish Information System on New human immunodeficiency virus diagnoses. A total of 2702 patients from ten autonomous communities and with naive FASTA sequence within 6 months of human immunodeficiency virus diagnosis were selected. Weighted pTDR, estimated using the inverse probability of selection in the sample by autonomous communities and transmission group, was 8.12% (95% CI 6.44–9.80), not significantly different from unweighted pTDR. We illustrate how proportional weighting can maximize representativeness of cohort-based data, and its value to monitor pTDR at country level.