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The lack of knowledge about the onset and progression of Parkinson’s disease (PD) hampers its early diagnosis and treatment. Metabolomics might shed light on the PD imprint seeking a broader view of the biochemical remodeling induced by this disease in an early and pre-symptomatic stage and unveiling potential biomarkers. To achieve this goal, we took advantage of the great potential of the European Prospective Study on Nutrition and Cancer (EPIC) cohort to apply metabolomics searching for early diagnostic PD markers. This cohort consisted of healthy volunteers that were followed for around 15 years until June 2011 to ascertain incident PD. For this untargeted metabolomics-based study, baseline preclinical plasma samples of 39 randomly selected individuals that developed PD (Pre-PD group) and the corresponding control group were analyzed using a multiplatform approach. Data were statistically analyzed and exposed alterations in 33 metabolites levels, including significantly lower levels of free fatty acids (FFAs) in the preclinical samples from PD subjects. These results were then validated by adopting a targeted HPLC-QqQ-MS approach. After integrating all the metabolites affected, our finding revealed alterations in FFAs metabolism, mitochondrial dysfunction, oxidative stress, and gut–brain axis dysregulation long before the development of PD hallmarks. Although the biological purpose of these events is still unknown, the remodeled metabolic pathways highlighted in this work might be considered worthy prognostic biomarkers of early prodromal PD. The findings revealed by this work are of inestimable value since this is the first study conducted with samples collected many years before the disease development.

Background and purpose: This study examined whether the 786 NOS3 polymorphism is associated with the risk of hemorrhagic transformation (HT) in stroke patients with anterior large vessel occlusion (ALVO) treated using endovascular thrombectomy (EVT).Methods: We performed an observational cohort study that included 118 patients with ALVO who underwent EVT. HT was assessed in follow-up CT and MRI. HT and non-HT patients were compared in terms of the 786 NOS3 polymorphism, flow mediated dilation (FMD) values within 3 days after the stroke, and collateral status based on three grading scales. Demographics, vascular risk factors, additional radiological data including ASPECT score, thrombus length and infarct size, and EVT procedure and outcome variables were also included.Results: Radiological HT occurred in 55 (46.6%) patients and the 786T/T NOS3 polymorphism was associated with HT (unadjusted OR of 2.33, 95%CI: 1.05-5.20, adjusted OR of 3.14, 95%CI: 1.16-8.54). Collateral status and systemic endothelial function assessed by FMD were not mediators of this relationship as no differences were seen in the median FMD percentage values or collateral status between NOS3 genotypes.Conclusions: Our results suggest that genetic variations affecting the NO pathway, such as the 786 NOS3 poly-morphism, may contribute to individual variability in the occurrence of HT and these results support involve-ment of this pathway in the pathogenesis of ischemia-reperfusion injury after EVT.

Background: The identification of biomarkers for the early diagnosis of Parkinson’s Disease (PD) might improve treatment and avoid complications. However, the search of such biomarkers is a real challenge. The main reason for this is that finding samples for that purpose is not an easy task. In this work, we propose a set of reliable samples for the identification of biomarkers for the early diagnosis of PD. In fact, the original source of these samples can be searched for similar purposes when dealing with other diseases.Materials and methods: Case-control study included 12 plasma samples of subjects that subsequently developed PD and 21 plasma samples of matched healthy controls from the Spanish EPIC-Navarra cohort, part of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain study. All the case samples were provided by healthy volunteers who were followed up for a mean of 15.9 (± 4.1) years and developed PD disease later on. Therefore, these sample are ideal for the search of early biomarkers of PD. We used an analytical multiplatform based on liquid chromatography and tandem mass spectrometry in order to find significant differences in the amounts of previously reported metabolites that are altered when the disease has been established and diagnosed. Results: Out of all 40 analytes that were studied, seven significant metabolites were observed. Benzoic acid, palmitic acid, oleic acid, stearic acid, myo-inositol, sorbitol and quinolinic acid were significantly changed in subjects that developed PD. These metabolites are closely related to mitochondrial dysfunction, the oxidative stress and the mechanisms of energy production, which might indicate that these mechanisms are already affected before disease onset.Conclusions: We propose the samples from the EPIC study as reliable and priceless samples for the search of early biomarkers of PD, although many other diseases can be also studied as long as the information stored about the participants recorded such details. As a proof of concept, we showed that these samples were useful for the study of metabolites that may be altered before the participants developed PD. This might also be a starting point in the establishment of a well-founded panel of metabolites that can be used for the early detection of this disease.

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1–2% of all cases of Parkinson’s disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2—either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10Thr73) was measured by quantitative multiplexed immunoblotting for pRab10Thr73/total Rab10 as well as targeted mass-spectrometry for absolute pRab10Thr73 occupancy. We found a significant over fourfold increase in pRab10Thr73 phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10Thr73 phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10Thr73 phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors.

ObjectiveThe lack of knowledge about the onset and progression of Parkinson’s disease (PD) hampers its early diagnosis and treatment. Our aim was to determine the biochemical remodeling induced by PD in a really early and pre-symptomatic stage and unveiling early potential diagnostic biomarkers adopting a multiplatform (LC-MS, GC-MS, CE-MS) untargeted metabolomics approach.Methods41,437 healthy volunteers from the European Prospective Study on Nutrition and Cancer (EPIC)-Spain cohort were followed for around 15 years to ascertain incident PD. For this study, baseline pre-clinical plasma samples of 39 randomly selected individuals (46% females, 41– 69 years old) that developed PD (Pre-PD group) and the corresponding control group (n=39, 46% females, 41–69 years old) were analyzed. The metabolic differences were investigated by univariate and multivariate data analyses, followed by pathway-based metabolite analyses to obtain possible clues on biological functions.ResultsOur results exposed significantly lower levels of seven free fatty acids in the pre-PD subjects, together with alterations in other metabolite classes. Our finding revealed alterations in fatty acids metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation.ConclusionsAlthough the biological purpose of these events is still unknown, the mechanisms involved in the remodelling of the suggested metabolic pathways seem to appear long before the development of PD hallmarks. These findings might be considered as worthy potential markers whose alteration might lead to the development of PD hallmarks in the future. Consequently, this study is of inestimable value since this is the first study conducted with samples collected many years before the disease development.

Gain-of kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause Parkinson’s disease (PD), albeit with incomplete and age-dependent penetrance, offering the prospect of disease-modifying treatment strategies via LRRK2 kinase inhibition. LRRK2 phosphorylates a subgroup of RabGTPases including Rab10 and pathogenic mutations enhance LRRK2-mediated phosphorylation of Rab10 at Thr73.In this study we analyse LRRK2 dependent Rab10Thr73 phosphorylation in human peripheral blood neutrophils isolated from 101 individuals using quantitative immunoblotting and mass spectrometry. Our cohort includes 42 LRRK2 mutation carriers (21 with the G2019S mutation that resides in the kinase domain and 21 with the R1441G mutation that lies within the ROC-COR domain), 27 patients with idiopathic PD, and 32 controls.We show that LRRK2 dependent Rab10 Thr73 phosphorylation is significantly elevated in all R1441G LRRKR2 mutation carriers irrespective of disease status. PD manifesting and non-manifesting G2019S mutation carriers as well as idiopathic PD samples did not display elevated Rab10 Thr73 phosphorylation. Furthermore, we analysed brain samples of 10 G2019S and 1 R1441H mutation carriers as well as 10 individuals with idiopathic PD and 10 controls. We find high variability for pRab10Thr73 phosphorylation amongst donors irrespective of genetic and disease state.We conclude that in vivo LRRK2 dependent pRab10Thr73 analysis in human peripheral blood neutrophils is a specific and robust biomarker for LRRK2 kinase activation for individuals with mutations such as R1441G that enhance pRab10Thr73 phosphorylation over 2-fold. We provide the first evidence that the LRRK2 R1441G mutation enhances LRRK2 kinase activity in a primary human cell.

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 13,020male 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 GWASmeta-analyses to identify distinct patterns of genetic risk contributing to disease inmale 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. FUNDING: This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; Project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson’s Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum für Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research (JPND) project under the aegis of JPND -www.jpnd.eu – through Germany, BMBF, funding code 01ED1406 and iMed – the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (http://biowulf.nih.gov), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna (Department of Neurology, Helsinki University Central Hospital), L. Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case–Control Consortium 2 (WTCCC2) from UK patients with Parkinson’s disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from www.wtccc.org.uk. Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson’s UK (grants 8047 and J-0804) and the Medical Research Council (G0700943 and G1100643). Sequencing and genotyping done in McGill University was supported by grants from the Michael J. Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson’s Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson’s Network (http://rpq-qpn.ca/en). We thank the Quebec Parkinson’s Network (http://rpq-qpn.org) and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI – a public-private partnership – is funded by the Michael J. Fox Foundation for Parkinson’s Research and funding partners, the full names of all of the PPMI funding partners can be found at www.ppmi-info.org/ fundingpartners. The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit www.ppmi-info.org. Parkinson’s Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at https://pdbp.ninds.nih.gov/ policy. The PDBP Investigators have not participated in reviewing the data analysis or content of the manuscript

Opercular myoclonic-anarthric status epilepticus (OMASE) is a rare form of epilepsia partialis continua presenting as fluctuating dysarthria, or even anarthria. The condition is caused by an epileptogenic lesion involving the opercular cortex of either hemisphere. Speech impairment is secondary to bilateral epileptic activity affecting the glossopharyngeal muscles. This bilateral nature of the condition is due to the fact that innervation of cranial nerves V, VII, IX, X and XII from the opercular area of the primary motor cortex is bilateral. The aetiology of the condition varies, and includes vascular lesions, tumours, and encephalitis, among other causes. A low threshold for clinical suspicion is necessary in order to ensure the timely initiation of antiepileptic treatment, thereby preventing the condition from becoming drug resistant. We present two cases of OMASE which differ in terms of aetiology, clinical course, and treatment response. [Published with video sequences on www.epilepticdisorders.com].

Essential tremor (ET) in the western world is the most common movement disorder, and 50-70% of essential tremor cases are estimated to be genetic in origin 14. This work on selection of nonlinear biomarkers derived from drawings and handwriting is part of a wider cross-study for the diagnosis of essential tremor led by Biodonostia Institute. These biomarkers include not only classic linear features, but also non-linear: fractal dimension and entropy. The presence of integrated features of other diseases such as stress is also analyzed. In future works, these new biomarkers will be integrated with the ones obtained in the wider study of Biodonostia. Note that the use of these methods provide undoubted benefits towards the development of more sustainable, low-cost, high-quality, and non-invasive technologies. These systems are easily adaptable to the user and environment, and can be very useful in real complex environments with regard to a social and economic point of view.

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.

Background: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. Objectives: To perform the largest PD genome-wide association study restricted to a single country. Methods: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. Results: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. Conclusions: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain., This research was supported, in part, by the Intramural Research Program of the National Institutes of Health (National Institute on Aging, National Institute of Neurological Disorders and Stroke; project numbers: 1ZIA‐NS003154‐03, Z01‐AG000949‐02, and Z01‐ES101986). In addition, this work was supported by the Department of Defense (award W81XWH‐09‐2‐0128), The Michael J Fox Foundation for Parkinson's Research, and the ISCIII Grants PI 15/0878 (Fondos Feder) to V.A. and PI 15/01013 to J,H. This study was supported by grants from the Spanish Ministry of Economy and Competitiveness (PI14/01823, PI16/01575, PI18/01898, [SAF2006‐10126 (2006‐2009), SAF2010‐22329‐C02‐01 (2010‐2012), and SAF2013‐47939‐R (2013‐2018)]), co‐founded by ISCIII (Subdirección General de Evaluación y Fomento de la Investigación) and by Fondo Europeo de Desarrollo Regional (FEDER), the Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía (CVI‐02526, CTS‐7685), the Consejería de Salud y Bienestar Social de la Junta de Andalucía (PI‐0437‐2012, PI‐0471‐2013), the Sociedad Andaluza de Neurología, the Jacques and Gloria Gossweiler Foundation, the Fundación Alicia Koplowitz, and the Fundación Mutua Madrileña. Pilar Gómez‐Garre was supported by the “Miguel Servet” (from ISCIII16 FEDER) and “Nicolás Monardes” (from Andalusian Ministry of Health) programmes. Silvia Jesús Maestre was supported by the “Juan Rodés” programme, and Daniel Macías‐García was supported by the “Río Hortega” programme (both from ISCIII‐FEDER). Cristina Tejera Parrado was supported by VPPI‐US from the Universidad de Sevilla. This research has been conducted using samples from the HUVR‐IBiS Biobank (Andalusian Public Health System Biobank and ISCIII‐Red de Biobancos PT13/0010/0056). This work was also supported by the grant PSI2014‐57643 from the Junta de Andalucía to the CTS‐438 group and a research award from the Andalusian Society of Neurology.

Among neural disorders related to movement, essential tremor has the highest prevalence, in fact, it is twenty times more common than Parkinson&rsquo, s disease. The drawing of the Archimedes&rsquo, spiral is the gold standard test to distinguish between both pathologies. The aim of this paper is to select non-linear biomarkers based on the analysis of digital drawings. It belongs to a larger cross study for early diagnosis of essential tremor that also includes genetic information. The proposed automatic analysis system consists in a hybrid solution: Machine Learning paradigms and automatic selection of features based on statistical tests using medical criteria. Moreover, the selected biomarkers comprise not only commonly used linear features (static and dynamic), but also other non-linear ones: Shannon entropy and Fractal Dimension. The results are hopeful, and the developed tool can easily be adapted to users, and taking into account social and economic points of view, it could be very helpful in real complex environments.

Essential tremor (ET) is the most common movement disorder. In fact, its prevalence is about 20 times higher than that of Parkinson's disease. In addition, studies have shown that a high percentage of cases, between 50 and 70%, are estimated to be of genetic origin. The gold standard test for diagnosis, monitoring and to differentiate between both pathologies is based on the drawing of the Archimedes' spiral. Our major challenge is to develop the simplest system able to correctly classify Archimedes' spirals, therefore we will exclusively use the information of the x and y coordinates. This is the minimum information provided by any digitizing device. We explore the use of features from drawings related to the Discrete Cosine Transform as part of a wider cross-study for the diagnosis of essential tremor held at Biodonostia. We compare the performance of these features against other classic and already analyzed ones. We outperform previous results using a very simple system and a reduced set of features. Because the system is simple, it will be possible to implement it in a portable device (microcontroller), which will receive the x and y coordinates and will issue the classification result. This can be done in real time, and therefore without needing any extra job from the medical team. In future works these new drawing-biomarkers will be integrated with the ones obtained in the previous Biodonostia study. Undoubtedly, the use of this technology and user-friendly tools based on indirect measures could provide remarkable social and economic benefits. We thank the Ministry of Business and Knowledge of the Government of Catalonia that partially supported this study through the Industrial Doctorates Plan to IA-E. We also thank the grant of Domus Vi Foundation "Kms para recordar," the programs of Basque Government, ETORTEK and IT115-16, the Gipuzkoa Goverment, Red Guipuzcoana de Ciencia, Tecnologia e Innovacion, and the Ministry of Science and Innovation for the TEC2016-77791-C04-R grant, which partially supported the study. Finally we would like to thank reviewers for their detailed and helpful comments to the manuscript.

We have performed a complete screening of the Parkin gene (PRKN2) and looked for p.Gly2019Ser (G2019S) and p.Arg1441Gly (R1441G) LRRK2/dardarin gene mutations in twenty seven patients with Parkinson’s disease (PD) with an age at onset younger than 50 years (EOPD), living in Gipuzkoa (Basque Country, Spain). Thirteen of them (48%) were PRKN2 mutation carriers. The c.255256DelA mutation was the most frequent, followed by a deletion involving exons 3 and 4. A deletion involving exons 3 and 12 of the PRKN2 gene and R1441G LRRK2 mutation was found together in one PD patient. Four out of fourteen PRKN2 negative patients carried the p.G2019S mutation. Both PRKN2 mutation carriers and non-carriers presented frequently with family history (10 PRKN2 mutation carriers and 8 PRKN2 non-carriers); in fact, five patients without a known gene mutation had a first degree relative affected, suggesting another monogenic disease. PRKN2 carriers presented with a younger age at onset (36.7 vs. 41.7) and more benign disease progression. Indeed, those PD patients younger than forty who initially presented with unilateral tremor became shortly bilateral. Relatively, symmetric parkinsonism and slow disease progression carried more frequently PRKN2 mutations than patients with unilateral akinetic rigid parkinsonism and age at * Corresponding author.

Objective:Despite the enormous advancements made in deciphering the genetic architecture of Parkinson disease (PD), the majority of PD is idiopathic, with single gene mutations explaining only a small proportion of the cases.Methods:In this study, we clinically evaluated 2 unrelated Spanish families diagnosed with PD, in which known PD genes were previously excluded, and performed whole-exome sequencing analyses in affected individuals for disease gene identification.Results:Patients were diagnosed with typical PD without relevant distinctive symptoms. Two different novel mutations were identified in the CSMD1 gene. The CSMD1 gene, which encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing CNS, was previously shown to be associated with the risk of PD in a genome-wide association study.Conclusions:We conclude that the CSMD1 mutations identified in this study might be responsible for the PD phenotype observed in our examined patients. This, along with previous reported studies, may suggest the complement pathway as an important therapeutic target for PD and other neurodegenerative diseases.

Familial cortical myoclonic tremor and epilepsy is a phenotypically and genetically heterogeneous autosomal dominant disorder characterized by the presence of cortical myoclonic tremor and epilepsy that is often accompanied by additional neurological features. Despite the numerous familial studies performed and the number of loci identified, there is no gene associated with this syndrome. It is expected that through the application of novel genomic technologies, such as whole exome sequencing and whole genome sequencing, a substantial number of novel genes will come to light in the coming years. In this study, we describe the identification of two disease-segregating mutations in a large family featuring cortical myoclonic tremor with epilepsy and parkinsonism. Due to the previous association of ACMSD deficiency with the development of epileptic seizures, we concluded that the identified nonsense mutation in the ACMSD gene, which encodes for a critical enzyme of the kynurenine pathway of the tryptophan metabolism, is the disease-segregating mutation most likely to be responsible for the phenotype described in our family. This finding not only reveals the identification of the first gene associated with familial cortical myoclonic tremor and epilepsy but also discloses the kynurenine pathway as a potential therapeutic target for the treatment of this devastating syndrome.ACMSD is mutated in a family with cortical myoclonus, epilepsy, and parkinsonism. ACMSD mutation contributes to the development of FCMTE QA accumulation is likely to play an important role in the pathogenesis of FCMTE. The kynurenine pathway as a potential drug target for the treatment of epilepsy.

BACKGROUND: Sense of Coherence (SOC) is defined as a tendency to perceive life experiences as comprehensible, manageable and meaningful. The construct is split in three major domains: Comprehensibility, Manageability, and Meaningfulness. SOC has been associated with successful coping strategies in the face of illness and traumatic events and is a predictor of self-reported and objective health in a variety of contexts. In the present study we aim to evaluate the association of SOC with disability and dependence in Spanish elders. METHODS: A total of 377 participants aged 75 years or over from nine locations across Spain participated in the study (Mean age: 80.9 years; 65.3% women). SOC levels were considered independent variables in two ordinal logistic models on disability and dependence, respectively. Disability was established with the World health Organization-Disability Assessment Schedule 2.0 (36-item version), while dependence was measured with the Extended Katz Index on personal and instrumental activities of daily living. The models included personal (sex, age, social contacts, availability of an intimate confidant), environmental (municipality size, access to social resources) and health-related covariates (morbidity). RESULTS: High Meaningfulness was a strong protective factor against both disability (Odds Ratio [OR] = 0.50; 95% Confidence Interval [CI] = 0.29-0.87) and dependence (OR = 0.33; 95% CI = 0.19-0.58) while moderate and high Comprehensibility was protective for disability (OR = 0.40; 95% CI = 0.22-0.70 and OR = 0.39; 95%CI = 0.21-0.74), but not for dependence. Easy access to social and health resources was also highly protective against both disability and dependence. CONCLUSIONS: Our results are consistent with the view that high levels of SOC are protective against disability and dependence in the elderly. Elderly individuals with limited access to social and health resources and with low SOC may be a group at risk for dependence and disability in Spain. This project was partially funded by a research contract in support of the project “Epidemiological Study of Dementia in Spain” signed by the Pfizer Foundation and Carlos III Institute of Health. The funding agency had no influence in the scientific process including study design, data collection, data analysis, interpretation of results, and writing of the manuscript. Sí

BACKGROUND: The Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS‐UPDRS) is a newly developed tool to assess Parkinson's disease (PD). Changes in scores on the scale over the course of PD, including increasing disease duration and Hoehn and Yahr (HY) stages, have not been described. The objectives of this study were to analyze MDS‐UPDRS scores on Parts I through IV and their differences based on HY stage and disease duration in a large cohort of patients with PD. METHODS: For this cross‐sectional study, demographic data and MDS‐UPDRS scores were collected, including HY stage. Subscores on MDS‐UPDRS Parts I through IV were analyzed using 1‐way analyses of variance for each HY stage and in 5‐year increments of disease duration. Part III (motor assessment) scores were analyzed separately for on and off states. RESULTS: The mean age of the 3206 patients was 65.8 ± 10.6 years, 53.3% were men, the mean disease duration was 11.5 ± 4.6 years, and the median HY stage was 2 (range, 0–5); 2156 patients were examined in an on state and 987 were examined in an off state. Scores for all MDS‐UPDRS parts increased significantly through HY stages 1 through 5, with an average increase of 3.8, 7.7, 14.6, and 2.0 points consecutively for parts I through IV, respectively. For the 5‐year increments of disease duration, MDS‐UPDRS subscores increased by an average of 1.6, 3.3, 4.2, and 1.4 points consecutively for parts I through IV, respectively. This increase was significant only during the first 15 years of disease for all 4 parts, including part III scores evaluated in both on and off states. CONCLUSIONS: MDS‐UPDRS scores for all 4 parts increase significantly with every HY stage and also with 5‐year increments of disease duration in the first 15 years of the disease.

Dystonias are a clinically and genetically heterogeneous group of movement disorders characterized by involuntary, sustained muscular contractions affecting one or more sites of the body, and abnormal postures. In this study, we describe an autosomal recessive family that presents with a progressive and early-onset form of generalized dystonia. The nuclear family consists of two healthy parents and two affected daughters. To elucidate the genetic causes underlying disease, whole-exome sequencing analysis was performed in one affected sibling, followed by validation, biochemical analyses and MRI brain imaging. A homozygous, disease-segregating mutation (p.Val400Met) was identified in the glutaryl-CoA dehydrogenase (GCDH) gene at chromosome 19p13. The mutation, in an amino acid that is highly conserved among species, was absent in large number of neurologically normal individuals. Biochemical analyses demonstrated increased 3-hydroxy glutaric acid present in urine samples from both patients. MRI imaging revealed a T2 and flair hyperintense signal in lenticular nuclei with bilateral and symmetrical distribution. We conclude that both GCDH activity and GCDH mutation analysis should be considered in the differential diagnosis of progressive forms of early-onset generalized dystonia and that mitochondrial fatty acid metabolism is one important pathway in the development of dystonia. As lysine restriction and L: -carnitine supplementation are important treatments for GCDH deficiency, identification of this deficiency in patients with progressive forms of early-onset generalized dystonia has potential treatment implications.

The impact of apathy on health-related quality of life (HRQOL) in recently diagnosed Parkinson's disease (PD) has not been systematically investigated. The objective of this cross-sectional survey (ANIMO study) was to examine the contribution of apathy to HRQOL in a Spanish sample of recently diagnosed PD patients. PD patients, diagnosed within 2 years of inclusion, were recruited at 102 outpatient clinics in 82 communities throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale and HRQOL with the EuroQol-5D questionnaire. A mean EuroQol-5D index score of 0.89 obtained from population references in Spain was used as the cutoff for this study. The relationship between apathy and the dichotomized EuroQol-5D index score (

Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy. To further assess pathogenicity, site-directed mutagenesis, mouse and human brain expression analyses, and patch clamp techniques were performed. A disease-segregating mutation (p.Gly1537Ser) in the SCN4A gene was identified. Posterior functional analyses demonstrated that more rapid kinetics at near-threshold potentials altered ion selectivity and facilitated the conductance of both potassium and ammonium ions, which could contribute to tremor and increase susceptibility to epilepsy, respectively. In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies.

*These authors contributed equally to this work. Essential tremor (ET) is the most prevalent movement disorder affecting millions of people in the United States. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In this study, whole exome sequencing and subsequent approaches were performed in a family with an autosomal dominant form of early-onset ET. Functional analyses including mutagenesis, cell culture, gene expression, enzyme-linked immunosorbent, and apoptosis assays were also performed. A disease-segregating mutation (p.Gly171Ala), absent in normal population, was identified in the SORT1 gene. The p.Gly171Ala mutation was shown not only to impair the expression of its encoding protein sortilin but also the mRNA levels of its binding partner p75 neurotrophin receptor that is known to be implicated in brain injury, neuronal apoptosis, and neurotransmission.

We identified 14 door-to-door prevalence surveys on dementia, parkinsonism or stroke in Spanish populations fulfilling specific criteria and combined selected age- and sex-specific data using logistic regression and taking Pamplona as a reference. The prevalence of dementia and of Alzheimer’s disease varied significantly with space. However, the largest variation was seen for vascular dementia: odds ratio (OR) and 95% confidence interval (CI) for Gerona were 6.42 (3.23–12.3) in women and 2.30 (1.10–4.79) in men. Stroke was particularly frequent among Arevalo’s women, with OR 2.10 and 95% CI 1.26–3.49. The prevalence of Parkinson’s disease was twofold higher in Cantalejo. Although differences in methodology make the interpretation of results problematic, the prevalence of stroke and vascular dementia in Spain seems to vary spatially, indicating a space for prevention.

Objective: Little is known about apathy in the early stages of Parkinson’s disease (PD). We determined the clinical correlates of apathy in a large representative sample of patients recently diagnosed with PD (ANIMO study). Methods: PD patients, diagnosed within 2 years of inclusion, were recruited in 102 outpatient clinics situated in 82 populations throughout Spain. Apathy was quantified using the Lille Apathy Rating Scale (LARS). Clinical comparisons and correlations were performed using nonparametric tests. Regression analyses were used to test the association of clinical variables with apathy. Results: We recruited 557 PD patients (60.3% men) with a mean age of 68.8 ± 9.7 years, and UPDRS motor score of 21.1 ± 10.8. Apathy only was diagnosed in 186 (33.4%), and apathy and depression in 215 patients (38.6%). Patients with higher comorbidity (OR = 1.10, 95% CI 1.01–1.20, p = 0.001), motor impairment (OR = 1.07, 95% CI 1.03–1.10, p < 0.0001), and lower education (OR = 2.16, 95% CI 1.21–3.85, p = 0.009) had higher odds of having apathy, in contrast to patients living in a rural environment (OR = 0.35, 95% CI 0.32–0.85, p = 0.01), and left predominant PD motor laterality (OR = 0.34, 95% CI 0.13–0.88, p = 0.01). LARS scores were significantly correlated with UPDRS motor scores (rs = 0.44, p < 0.001), predominantly with axial score (rs = 0.43, p < 0.001). Conclusions: In PD, apathy is a very common and disabling nonmotor symptom separable from depression. Patients living in a rural environment, with lower comorbidity and motor impairment, higher education background, and left predominant PD motor laterality are at lower risk of suffering from apathy.

Background: The prevalence and predictors of functional status and disability of elderly people have been studied in several European countries including Spain. However, there has been no population-based study incorporating the International Classification of Functioning, Disability and Health (ICF) framework as the basis for assessing disability. The present study reports prevalence rates for mild, moderate, and severe/extreme disability by the domains of activities and participation of the ICF. Methods: Nine populations surveyed in previous prevalence studies contributed probabilistic and geographically defined samples in June 2005. The study sample was composed of 503 subjects aged ≥75 years. We implemented a two-phase screening design using the MMSE and the World Health Organization-Disability Assessment Schedule 2nd edition (WHO-DAS II, 12 items) as cognitive and disability screening tools, respectively. Participants scoring within the positive range of the disability screening were administered the full WHO-DAS II (36 items; score range: 0-100) assessing the following areas: Understanding and communication, Getting along with people, Life activities, Getting around, Participation in society, and Self-care. Each disability area assessed by WHO-DAS II (36 items) was reported according to the ICF severity ranges (No problem, 0-4; Mild disability, 5-24; Moderate disability, 25-49; Severe/Extreme disability, 50-100). Results: The age-adjusted disability prevalence figures were: 39.17 ± 2.18%, 15.31 ± 1.61%, and 10.14 ± 1.35% for mild, moderate, and severe/extreme disability, respectively. Severe and extreme disability prevalence in mobility and life activities was three times higher than the average, and highest among women. Sex variations were minimal, although life activities for women of 85 years and over had more severe/extreme disability as compared to men (OR = 5.15 95% CI 3.19-8.32). Conclusions: Disability is highly prevalent among the Spanish elderly. Sex- and age-specific variations of disability are associated with particular disability domains This project was partially funded by a research contract in support of the project “Epidemiological Study of Dementia in Spain” signed by the Pfizer Foundation and Carlos III Institute of Health SI

Background This study describes the prevalence of dementia and major dementia subtypes in Spanish elderly. Methods We identified screening surveys, both published and unpublished, in Spanish populations, which fulfilled specific quality criteria and targeted prevalence of dementia in populations aged 70 years and above. Surveys covering 13 geographically different populations were selected (prevalence period: 1990-2008). Authors of original surveys provided methodological details of their studies through a systematic questionnaire and also raw age-specific data. Prevalence data were compared using direct adjustment and logistic regression. Results The reanalyzed study population (aged 70 year and above) was composed of Central and North-Eastern Spanish sub-populations obtained from 9 surveys and totaled 12,232 persons and 1,194 cases of dementia (707 of Alzheimer's disease, 238 of vascular dementia). Results showed high variation in age- and sex-specific prevalence across studies. The reanalyzed prevalence of dementia was significantly higher in women; increased with age, particularly for Alzheimer's disease; and displayed a significant geographical variation among men. Prevalence was lowest in surveys reporting participation below 85%, studies referred to urban-mixed populations and populations diagnosed by psychiatrists. Conclusion Prevalence of dementia and Alzheimer's disease in Central and North-Eastern Spain is higher in females, increases with age, and displays considerable geographic variation that may be method-related. People suffering from dementia and Alzheimer's disease in Spain may approach 600,000 and 400,000 respectively. However, existing studies may not be completely appropriate to infer prevalence of dementia and its subtypes in Spain until surveys in Southern Spain are conducted Financial aid was obtained from the Spanish RECSP C03-09, CIEN C03-06 and CIBERNED networks, and from the Pfizer Foundation in particular SI

Background Behavioural and psychological symptoms of dementia (BPSD) are non-cognitive symptoms commonly associated to Alzheimer's disease (AD). The characterization of the clinical profile of AD patients might help to better understand disease evolution and to improve diagnosis and treatment. Thus, the aim of the present study is to describe the clinical profile of AD patients, and to correlate the presence of BPSD with the severity of the disease. Methods A cross-sectional, observational and multicenter study was conducted at 115 centres in Spain. Patients suffering from AD with higher and lower BPSD scores (ADAS-Noncog score 26-50 and ≤25, respectively) were included. Demographic and clinical data were collected, and dementia severity was assessed by the Mini Mental State Examination (MMSE) [mild 27-21, moderate 20-11, severe ≤10]. The use of ADAS-Noncog in clinical practice was also explored. Results A total of 1014 patients (463 with higher and 551 with lower BPSD scores) were included (mean age 77 ± 7 years, 65% women). Almost all patients (90%) had BPSD at inclusion, 17% of which reported psychotic outbreaks. The most prevalent symptoms were lack of concentration (56%), tremors (56%), depression (44%), lack of cooperation (36%), and delusions (32%). Patients with higher BPSD scores showed a significantly higher prevalence of psychotic symptoms (delusions, hallucinations, and delirium) and tremors, while emotional symptoms (tearfulness and apathy) predominated in patients with lower BPSD scores. MMSE and ADAS-Noncog scores were negatively associated (p = 0.0284), suggesting a correlation between cognitive impairment and BPSD. Lack of concentration and appetite change significantly correlated with MMSE (p = 0.0472 and p = 0.0346, respectively). Rivastigmine and donepezil were the first choice therapies in mild to moderate dementia. ADAS-Noncog was generally considered better or similar to other scales (82%), and 68% of the investigators were willing to use it in the future. Conclusions Our study shows that patients with AD have a high prevalence of noncognitive symptoms, and that cognitive impairment and BPSD are correlated. Therefore, ADAS-Noncog is a useful evaluation tool.

This paper is an extended version of one paper published in the 4th IEEE International Work Conference on Bioinspired Intelligence, Donostia, Spain, 9–12 June 2015 Biomedical systems produce biosignals that arise from interaction mechanisms. In a general form, those mechanisms occur across multiple scales, both spatial and temporal, and contain linear and non-linear information. In this framework, entropy measures are good candidates in order provide useful evidence about disorder in the system, lack of information in time-series and/or irregularity of the signals. The most common movement disorder is essential tremor (ET), which occurs 20 times more than Parkinson's disease. Interestingly, about 50%-70% of the cases of ET have a genetic origin. One of the most used standard tests for clinical diagnosis of ET is Archimedes' spiral drawing. This work focuses on the selection of non-linear biomarkers from such drawings and handwriting, and it is part of a wider cross study on the diagnosis of essential tremor, where our piece of research presents the selection of entropy features for early ET diagnosis. Classic entropy features are compared with features based on permutation entropy. Automatic analysis system settled on several Machine Learning paradigms is performed, while automatic features selection is implemented by means of ANOVA (analysis of variance) test. The obtained results for early detection are promising and appear applicable to real environments. This work has been partially supported by the University of the Basque Country under project ref. UPV/EHU-58/14, SAIOTEK program and others from the Basque Government, the Spanish Ministerio de Ciencia e Innovacion TEC2012-38630-C04-03, the University of Vic-Central University of Catalonia under the research grant R0904, INNPACTO program from the Spanish Government, and UPV/EHU Summer Courses Foundation.

The aim of this study was to re-analyze door-to-door studies on neurological diseases among the elderly, in which vascular risk factors (VRF) were studied, describing methodological characteristics and prevalence of VRF.The surveys were identified in two phases. They were aimed at ascertaining prevalence of stroke, dementias or Parkinsonisms and, at the time of individual screening, had collected data on at least three of the following VRF: arterial hypertension (AHT), smoking habit, diabetes mellitus and hypercholesterolemia. A questionnaire was drawn up to collect the data reported in each study, and a database was constructed. VRF prevalences were quantified and analyzed using logistic regression.The total of the re-analyzed population was 12,510 persons aged 70 years and over, residents in seven geographic areas during the period 1994-2002. Information available on VRF was essentially self-reported. The prevalence of self-reported AHT was 25.7 % in men and 44.2 % in women, and that of measured AHT was 61 % and 71.9 %, respectively. Populations with arterial pressure obtained by direct measurement registered 138 higher risks (OR: 1.74; 95 % CI: 1.51-2.01, and OR: 1.48; 95% CI: 1.33-1.64). Reported prevalence of diabetes, hypercholesterolemia and smoking habit were 14.3 %, 23.3% and 8.5 %, respectively.There was a high prevalence of VRF among the Spanish elderly population. However, its relationship with dementia, Parkinsonisms and cerebrovascular disease could not be studied due to the poor quality of the VRF data. The differences between measured and self-reported arterial pressure suggest the existence of undetected AHT and wide scope for prevention.