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Parkinson’s disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson’s disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson’s disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson’s disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson’s disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson’s disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson’s disease drug development., There is currently no disease-modifying treatment for Parkinson’s disease, a common neurodegenerative disorder. Here, the authors use genetic variation associated with gene and protein expression to find putative drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome.

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

Levodopa-carbidopa intestinal gel (LCIG) has shown to be efficacious in motor and non-motor symptoms (NMS). Nevertheless, studies with patient Quality of Life (QoL) as a primary endpoint are scarce. To assess the effect of LCIG on Advanced Parkinson's Disease (APD) patients QoL. Secondarily, the impact on motor symptoms and NMS, emotional well-being, treatment satisfaction, and caregiver QoL, stress, disease burden, anxiety, depression, and work impairment were also investigated. In this prospective, 6-month multicenter postmarketing observational study, LCIG was administered to 59 patients with APD. Endpoints were assessed using validated scales and questionnaires. LOG significantly improved patient QoL (PDQ-39 mean change +/- standard deviation from baseline, -12.8 +/- 14.6; P < 0.0001), motor symptoms (UPDRS-III in "On," -6.5 +/- 11.8; P = 0.0002), NMS (NMSS, -35.7 +/- 31.1; P < 0.0001), mood (Norris/Bond-Lader VAS, -6.6 +/- 21.1; P = 0.0297), fatigue (PFS-16, -0.6 +/- 1.0; P = 0.0003), depression (BDI-II, -5.1 +/- 9.4; P = 0.0002), anxiety (BAI, -6.2 +/- 9.6; P < 0.0001), and patient treatment satisfaction (SATMED-Q, 16.1 +/- 16.8; P < 0.0001). There were significant correlations between the change from baseline to 6 months between PDQ-39 and UPDRS-IV, NMSS, BA', BDI-II, AS, and PFS-16 scores, and Norris/Bond-Lader alertness/sedation factor. Caregiver anxiety also improved (Goldberg anxiety scale, -1.1 +/- 1.0; P = 0.0234), but the clinical relevance of this finding is questionable. The serious adverse events reported were similar to those previously described for LCIG. In patients with APD, LOG improves QoL, motor symptoms and NMS, emotional well-being, and satisfaction with the treatment. Improvement in patient QoL is associated with improvements in motor complications, NMS, anxiety, depression, apathy and fatigue. Improvements in patients' QoL does not correspond with improvements in caregivers' QoL or burden.

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease., Knowledge of genomic features specific to humans may be important for understanding disease. Here the authors demonstrate a potential role for these human-lineage-specific sequences in brain development and neurological disease.

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner. METHODS: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson's Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. RESULTS: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (~ 20%). INTERPRETATION: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients. ANN NEUROL 2021;90:41-48.

Many diseases associated with hyperkinetic movement disorders manifest in women of childbearing age. It is important to understand the risks of these diseases during pregnancy, and the potential risks of treatment for the fetus. This study aims to define the clinical characteristics and the factors affecting the lives of women of childbearing age with dystonia, chorea, Tourette syndrome, tremor, and restless legs syndrome, and to establish guidelines for management of pregnancy and breastfeeding in these patients. This consensus document was developed through an exhaustive literature search and a discussion of the content by a group of movement disorder experts from the Spanish Society of Neurology. We must evaluate the risks and benefits of treatment in all women with hyperkinetic movement disorders, whether pre-existing or with onset during pregnancy, and aim to reduce effective doses as much as possible or to administer drugs only when necessary. In hereditary diseases, families should be offered genetic counselling. It is important to recognise movement disorders triggered during pregnancy, such as certain types of chorea and restless legs syndrome.

The main challenge of Parkinson's disease in women of childbearing age is managing symptoms and drugs during pregnancy and breastfeeding. The increase in the age at which women are having children makes it likely that these pregnancies will become more common in future. This study aims to define the clinical characteristics of women of childbearing age with Parkinson's disease and the factors affecting their lives, and to establish a series of guidelines for managing pregnancy in these patients. This consensus document was developed through an exhaustive literature search and a discussion of the available evidence by a group of movement disorder experts from the Spanish Society of Neurology. Parkinson's disease affects all aspects of sexual and reproductive health in women of childbearing age. Pregnancy should be well planned to minimise teratogenic risk. A multidisciplinary approach should be adopted in the management of these patients in order to take all relevant considerations into account.

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.

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/. © 2020, The Author(s).

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services; project ZO1 AG000949

Special Issue: Focused Ultrasound in Parkinson's Disease., [Background] Single nucleotide polymorphisms (SNPs) in the α‐synuclein (SNCA ) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine‐rich repeat kinase 2 (LRRK2)‐associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored., [Objectives] The mechanistic target of rapamycin (mTOR ) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO., [Methods] Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium., [Results] In the discovery series cohort, we found a 4‐loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P, [Conclusions] These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society, Funding Information; Fundació la Marató de TV3. Grant Number: 60510; Michael J. Fox Foundation for Parkinson's Research. Grant Numbers: Dyskinesia Challenge 2014, MJF_PPMI_10_001, PI044024; National Institutes of Health. Grant Number: LM010098; Secretaría de Estado de Investigación, Desarrollo e Innovación. Grant Number: SAF2014‐57160R and SAF2017‐88812R.

Background Single nucleotide polymorphisms (SNPs) in the alpha-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. Objectives The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Methods Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. Results In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. Conclusions These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. (c) 2019 International Parkinson and Movement Disorder Society

Parkinson's disease (PD), with its characteristic loss of nigrostriatal dopaminergic neurons and deposition of α-synuclein in neurons, is often considered a neuronal disorder. However, in recent years substantial evidence has emerged to implicate glial cell types, such as astrocytes and microglia. In this study, we used stratified LD score regression and expression-weighted cell-type enrichment together with several brain-related and cell-type-specific genomic annotations to connect human genomic PD findings to specific brain cell types. We found that PD heritability attributable to common variation does not enrich in global and regional brain annotations or brain-related cell-type-specific annotations. Likewise, we found no enrichment of PD susceptibility genes in brain-related cell types. In contrast, we demonstrated a significant enrichment of PD heritability in a curated lysosomal gene set highly expressed in astrocytic, microglial, and oligodendrocyte subtypes, and in LoF-intolerant genes, which were found highly expressed in almost all tested cellular subtypes. Our results suggest that PD risk loci do not lie in specific cell types or individual brain regions, but rather in global cellular processes detectable across several cell types.

Objetivo. Basados en estudios anteriores, nuestro propósito es determinar la calidad de vida de los pacientes con aneurismas intracraneales después de haber sido intervenido mediante cirugía o embolización y comparar la calidad de vida de estos dos grupos. Material y métodos. El cuestionario SF-36 fue aplicado retrospectivamente a 93 pacientes con aneurismas tratados mediante cirugía (n=56) o embolización (n=37). Resultados. La calidad de vida de los pacientes tratados con cirugía estaba deteriorada en el 50% y en los pacientes tratados por embolización el 40,5% no mostraron ningún deterioro en ninguno de los dominios del SF-36. Los análisis muestran que el dominio de la función física está menos deteriorada en los pacientes que han sido embolizados que los que han sido intervenidos quirúrgicamente. Conclusiones. Los pacientes con aneurismas intracraneales tratados mediante cirugía o embolización tienen afectada la calidad de vida. El tratamiento endovascular puede causar menos limitaciones en la función física. En la calidad de vida de estos pacientes influyen varios factores, además del tipo de tratamiento. Background. Based on earlier studies, we aimed to determine the quality of life of patients with intracranial aneurysm after their treatment by surgery or embolization and to compare the quality of life of these two groups. Methods. The SF-36 health questionnaire was retrospectively applied to 93 patients with intracranial aneurysm treated with surgery (n=56) or embolization (n=37). Results. The quality of life of some patients was impaired but 50% of patients treated with surgery and 40,5% of patients treated with embolization showed no impairment in any SF-36 domain. The quality of life in the Physical Functioning domain was higher in embolization-treated than in surgery-treated patients. Conclusions. Some patients with intracranial aneurysms treated with surgery or endovascular embolization have an impaired quality of life. Endovascular treatment may cause less limitation in physical function. The quality of life of these patients is affected by numerous factors, in addition to the type of treatment.

To review, from a mainly clinical standpoint, the different strategies applied to regenerate or restore the nigrostriatal dopaminergic system in Parkinson's disease (PD). A previous first part focused on the results of adrenal medulla and human fetal mesencephalic transplants, and this second part addresses transplants of other cell types, administration of trophic factors, and gene therapy.As an alternative to human fetal mesencephalic neurons, other donor cells types (porcine mesencephalic neurons, retinal pigment epithelial cells) with similar 'dopaminergic' action mechanism have been tried, although with heterogeneous results. Transplantation of carotid body cell aggregates may be a promising therapy because of its neurotrophic action mechanism. The perspectives of cell therapies based on genetically modified cells and precursor cells of different origin are also reviewed. Among other neuroregenerative approaches, the clinical outcomes of direct administration of neurotrophic factors and the perspectives for in vivo gene therapy are also addressed.The objective of neuroregenerative therapy for PD should include trophic restoration of damaged neuronal systems, since improvement in striatal dopaminergic function is not sufficient. After the recent failure of the direct (intraventricular or intraputaminal) administration of glial cell line-derived neurotrophic factor (GDNF), attention of researchers has focused on indirect methods, including transplantation of GDNF-producing cells (carotid body cell aggregates or different genetically modified cells), and in vivo gene therapy.

Bilateral deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) have demonstrated efficacy in advanced Parkinson's disease (PD). We aimed to assess the clinical utility of these procedures in terms of the quality of life, and to determine the pre and postsurgical characteristics related to the outcome.A prospective study was conducted on a cohort of 20 patients with advanced PD who underwent bilateral DBS: 14 in STN and 6 in GPi. They were assessed according to the CAPSIT-PD protocol before and after surgery, with a mean follow-up of 9 and 11 months, respectively. The main outcome variables were change in the UPDRS III score in off efficacy and the PDQ-39 quality of life questionnaire score (clinical utility).The STN group improved their UPDRS III in off by a mean of 35% (p = 0.001) and their PDQ-39 by 21% (p = 0.026). The GPi group improved their UPDRS III in off by 21% (p = 0.028) and their PDQ-39 by 37% (p = 0.116). The presurgical levodopa-equivalent dose was a positive predictor of the efficacy and clinical utility of STN DBS and a negative predictor of the efficacy of GPi DBS. In both groups, the clinical utility was determined by improvement in functional disability in off scales.Bilateral DBS demonstrated middle-term efficacy and clinical utility in the treatment of advanced PD. The presurgical levodopa-equivalent dose was a predictor of the efficacy and clinical utility of DBS.

Objetivo. Revisar, desde una perspectiva fundamentalmente clinica, las diferentes estrategias que tienen como finalidad la regeneracion o restauracion del sistema dopaminergico nigroestriatal en la enfermedad de Parkinson (EP). En una primera parte se analizaron los resultados de los trasplantes de medula adrenal y de mesencefalo fetal humano, y en este articulo se continua con los trasplantes de otras estirpes celulares, la administracion de factores troficos y la terapia genica. Desarrollo. Como alternativa al trasplante fetal humano se han planteado otros procedimientos con similar mecanismo de accion ?dopaminergico? (xenotrasplante porcino, celulas retinianas microencapsuladas), aunque con resultados poco consistentes. El trasplante de agregados celulares del cuerpo carotideo podria ser una terapia prometedora por su mecanismo de accion neurotrofico. Se revisan tambien las perspectivas de la terapia celular basada en celulas modificadas geneticamente y en celulas precursoras de distinta procedencia. Entre otras estrategias neurorregenerativas, se analizan los resultados clinicos de la administracion directa de factores neurotroficos y las perspectivas de la terapia genica in vivo. Conclusiones. El objetivo de una autentica terapia neurorregenerativa para la EP deberia ser, no solo incrementar la funcion dopaminergica estriatal, sino promover la restauracion trofica de los sistemas neuronales danados. Tras el reciente fracaso de los metodos de administracion directa (intraventricular e intraputaminal) de factor neurotrofico derivado de una linea celular glial (GDNF), ha cobrado una mayor relevancia la investigacion de otros metodos indirectos, como el trasplante de celulas productoras de GDNF ?agregados celulares del cuerpo carotideo, distintas celulas modificadas geneticamente? y la terapia genica in vivo.

INTRODUCTION Focal cortical dysplasia (FCD) is an unusual cause of refractory epilepsy, in which the morbid anatomy is characterized by cortical laminar dysplasia and the presence of balloon like cells. CLINICAL CASE A 36 year old woman who had had drug-resistant epilepsy since the age of 9 years old, with daily complex partial seizures and seizures in which she fell to the ground. After many therapeutic trials, at the age of 29 years she had a callostomy as palliative treatment for the seizures in which she fell and was completely cured of these. The complex partial seizures increased in frequency, in spite of high doses of multiple drugs, so the possibility of resective surgery was considered. A surface EEG with predominant lateralization and localization to the left temporal lobe, ictal and interictal cerebral SPECT, PET and MR were done. The findings were comparable with two foci of dysplasia in the left cerebral hemisphere, one superior parietal and the other posterior basal temporal in situation. Finally, video-EEG monitoring with foramen ovale electrodes showed ictal activity starting in the left posterior temporal regions and with rapid homolateral anteromesial diffusion. A left temporal lobectomy and amigdalohippocampectomy was done with resection of a posterior basal temporal lesion. This reduced the number of seizures by 90%, with minimal dysnomy as a sequel. The findings on morbid anatomical study were compatible with a FCD. CONCLUSIONS FCD is a cause of refractory epilepsy which may benefit from surgical treatment, with excellent results, after suitable pre-operative surgical evaluation and planning, including hippocampal evaluation since there is a high incidence of associated mesial sclerosis.