Non-motor symptom burden in patients with Parkinson's disease with impulse control disorders and compulsive behaviours : results from the COPPADIS cohort

The study was aimed at analysing the frequency of impulse control disorders (ICDs) and compulsive behaviours (CBs) in patients with Parkinson's disease (PD) and in control subjects (CS) as well as the relationship between ICDs/CBs and motor, nonmotor features and dopaminergic treatment in PD patients. Data came from COPPADIS-2015, an observational, descriptive, nationwide (Spain) study. We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale (QUIP-RS) for ICD/CB screening. The association between demographic data and ICDs/CBs was analyzed in both groups. In PD, this relationship was evaluated using clinical features and treatment-related data. As result, 613 PD patients (mean age 62.47 ± 9.09 years, 59.87% men) and 179 CS (mean age 60.84 ± 8.33 years, 47.48% men) were included. ICDs and CBs were more frequent in PD (ICDs 12.7% vs. 1.6%, p < 0.001; CBs 7.18% vs. 1.67%, p = 0.01). PD patients had more frequent previous ICDs history, premorbid impulsive personality and antidepressant treatment (p < 0.05) compared with CS. In PD, patients with ICDs/CBs presented younger age at disease onset, more frequent history of previous ICDs and premorbid personality (p < 0.05), as well as higher comorbidity with nonmotor symptoms, including depression and poor quality of life. Treatment with dopamine agonists increased the risk of ICDs/CBs, being dose dependent (p < 0.05). As conclusions, ICDs and CBs were more frequent in patients with PD than in CS. More nonmotor symptoms were present in patients with PD who had ICDs/CBs compared with those without. Dopamine agonists have a prominent effect on ICDs/CBs, which could be influenced by dose

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Impacto de las nuevas tecnologías en la neurología en España. Revisión del Comité Ad-Hoc de Nuevas Tecnologías de la Sociedad Española de Neurología

Resumen: Introducción: Las nuevas tecnologías (NT) están cada vez más presentes en el ámbito biomédico. Utilizando la definición de consenso de NT del Comité Ad-Hoc de Nuevas Tecnologías de la Sociedad Española de Neurología (SEN), se evalúa su impacto en la neurología española a través de las comunicaciones de las reuniones anuales de la SEN. Material y métodos: Se define el concepto de NT en neurología como una tecnología novedosa o aplicación de una tecnología anterior, caracterizada por un cierto grado de coherencia persistente en el tiempo, con potencial de tener impacto en el presente y futuro de la neurología. Se plantea un estudio descriptivo tomando como fuente las comunicaciones de las reuniones de la SEN desde 2012 hasta 2018 y analizando los tipos de NT empleadas, la subespecialidad, así como su distribución territorial. Resultados: De las 8.139 comunicaciones presentadas, 299 estaban relacionadas con NT (3,7%), incluyendo 120 pósteres y 179 comunicaciones orales, variando desde el 1,6% en 2012 hasta el 6,8% en 2018. Los tipos de tecnología mayormente representados fueron neuroimagen avanzada (24,7%), biosensores (17,1%), electrofisiología y neuroestimulación (14,7%) y telemedicina (13,7%). Las áreas neurológicas con mayor empleo de NT fueron trastornos del movimiento (18,4%), enfermedades cerebrovasculares (15,7%) y demencias (13,4%). Madrid fue la comunidad que presentó más comunicaciones (32,8%), seguida por Cataluña (26,8%) y Andalucía (9,0%). Conclusiones: Las comunicaciones sobre NT siguen una tendencia creciente. El número de NT empleadas ha ido aumentando de manera paralela a la disponibilidad tecnológica. Se encontraron comunicaciones en todas las subespecialidades neurológicas, con una distribución geográfica heterogénea. Abstract: Introduction: New technologies (NT) are increasingly widespread in biomedicine. Using the consensus definition of NT established by the New Technologies Ad-Hoc Committee of the Spanish Society of Neurology (SEN), we evaluated the impact of these technologies on Spanish neurology, based on communications presented at Annual Meetings of the SEN. Material and methods: We defined the concept of NT in neurology as a novel technology or novel application of an existing technology, characterised by a certain degree of coherence persisting over time, with the potential to have an impact on the present and/or future of neurology. We conducted a descriptive study of scientific communications presented at the SEN's annual meetings from 2012 to 2018, analysing the type of NT, the field of neurology, and the geographical provenance of the studies. Results: We identified 299 communications related with NT from a total of 8,139 (3.7%), including 120 posters and 179 oral communications, ranging from 1.6% of all communications in 2012 to 6.8% in 2018. The technologies most commonly addressed were advanced neuroimaging (24.7%), biosensors (17.1%), electrophysiology and neurostimulation (14.7%), and telemedicine (13.7%). The neurological fields where NT were most widely employed were movement disorders (18.4%), cerebrovascular diseases (15.7%), and dementia (13.4%). Madrid was the region presenting the highest number of communications related to NT (32.8%), followed by Catalonia (26.8%) and Andalusia (9.0%). Conclusions: The number of communications addressing NT follows an upward trend. The number of NT used in neurology has increased in parallel with their availability. We found scientific communications in all neurological subspecialties, with a heterogeneous geographical distribution

Impacto de las nuevas tecnologías en la neurología en España. Revisión del Comité Ad-Hoc de Nuevas Tecnologías de la Sociedad Española de Neurología

Data de publicació electrònica: 21-12-2020Introducción: las nuevas tecnologías (NT) están cada vez más presentes en el ámbito biomédico. Utilizando la definición de consenso de NT del Comité Ad-Hoc de Nuevas Tecnologías de la Sociedad Española de Neurología (SEN), se evalúa su impacto en la neurología española a través de las comunicaciones de las reuniones anuales de la SEN. Material y métodos: se define el concepto de NT en neurología como una tecnología novedosa o aplicación de una tecnología anterior, caracterizada por un cierto grado de coherencia persistente en el tiempo, con potencial de tener impacto en el presente y futuro de la neurología. Se plantea un estudio descriptivo tomando como fuente las comunicaciones de las reuniones de la SEN desde 2012 hasta 2018 y analizando los tipos de NT empleadas, la subespecialidad, así como su distribución territorial. Resultados: de las 8.139 comunicaciones presentadas, 299 estaban relacionadas con NT (3,7%), incluyendo 120 pósteres y 179 comunicaciones orales, variando desde el 1,6% en 2012 hasta el 6,8% en 2018. Los tipos de tecnología mayormente representados fueron neuroimagen avanzada (24,7%), biosensores (17,1%), electrofisiología y neuroestimulación (14,7%) y telemedicina (13,7%). Las áreas neurológicas con mayor empleo de NT fueron trastornos del movimiento (18,4%), enfermedades cerebrovasculares (15,7%) y demencias (13,4%). Madrid fue la comunidad que presentó más comunicaciones (32,8%), seguida por Cataluña (26,8%) y Andalucía (9,0%). Conclusiones: Las comunicaciones sobre NT siguen una tendencia creciente. El número de NT empleadas ha ido aumentando de manera paralela a la disponibilidad tecnológica. Se encontraron comunicaciones en todas las subespecialidades neurológicas, con una distribución geográfica heterogénea

Finding genetically-supported drug targets for Parkinson’s disease using Mendelian randomization of the druggable genome

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

Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Genetic discoveries of Alzheimer’s disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer’s disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer’s disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer’s disease

SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease

Neurological Motor Disorder

Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage

Altres ajuts: Leonard Wolfson Foundation; United Kingdom Medical Research Council (MRC, MR/N008324/1); DRI Limited; UK Medical Research Council; Alzheimer's Society and Alzheimer's Research UK; Medical Research Council (MR/N026004/1); Wellcome Trust (202903/Z/16/Z); Dolby Family Fund; National Institute for Health Research; University College London; Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (00007/COVI/20).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

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Altres ajuts: 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.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 function-associated 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