Frequency and phenotypic spectrum of spinocerebellar ataxia 27B and other genetic ataxias in a Spanish cohort of late-onset cerebellar ataxia.

BACKGROUND AND PURPOSE: Dominantly inherited GAA repeat expansions in the fibroblast growth factor 14 (FGF14) gene have recently been shown to cause spinocerebellar ataxia 27B (SCA27B). We aimed to study the frequency and phenotype of SCA27B in a cohort of patients with unsolved late-onset cerebellar ataxia (LOCA). We also assessed the frequency of SCA27B relative to other genetically defined LOCAs. METHODS: We recruited a consecutive series of 107 patients with LOCA, of whom 64 remained genetically undiagnosed. We screened these 64 patients for the FGF14 GAA repeat expansion. We next analysed the frequency of SCA27B relative to other genetically defined forms of LOCA in the cohort of 107 patients. RESULTS: Eighteen of 64 patients (28%) carried an FGF14 (GAA)≥250 expansion. The median (range) age at onset was 62.5 (39-72) years. The most common clinical features included gait ataxia (100%) and mild cerebellar dysarthria (67%). In addition, episodic symptoms and downbeat nystagmus were present in 39% (7/18) and 37% (6/16) of patients, respectively. SCA27B was the most common cause of LOCA in our cohort (17%, 18/107). Among patients with genetically defined LOCA, SCA27B was the main cause of pure ataxia, RFC1-related disease of ataxia with neuropathy, and SPG7 of ataxia with spasticity. CONCLUSION: We showed that SCA27B is the most common cause of LOCA in our cohort. Our results support the use of FGF14 GAA repeat expansion screening as a first-tier genetic test in patients with LOCA.

Endothelial NO synthase 786T/T polymorphism increases hemorrhagic transformation after endovascular thrombectomy.

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 polymorphism, may contribute to individual variability in the occurrence of HT and these results support involvement of this pathway in the pathogenesis of ischemia-reperfusion injury after EVT.

EMD-based data augmentation method applied to handwriting data for the diagnosis of Essential Tremor using LSTM networks.

The increasing capacity of today's technology represents great advances in diagnosing diseases using standard procedures supported by computer science. Deep learning techniques are able to extract the characteristics of temporal signals to study their patterns and diagnose diseases such as essential tremor. However, these techniques require a large amount of data to train the neural network and achieve good results, and the more data the network has, the more accurate the final model implemented. In this work we propose the use of a data augmentation technique to improve the accuracy of a Long short-term memory system in the diagnosis of essential tremor. For this purpose, the multivariate Empirical Mode Decomposition method will be used to decompose the original temporal signals collected from control subjects and patients with essential tremor. The time series obtained from the decomposition, covering different frequency ranges, will be randomly shuffled and combined to generate new artificial samples for each group. Then, both the generated artificial samples and part of the real samples will be used to train the LSTM network, and the remaining original samples will be used to test the model. The experimental results demonstrate the capability of the proposed method, which is compared to a set of 10 different data augmentation methods, and in all cases outperforms all other methods. In the best case, the proposed method increases the accuracy of the classifier from 83.20% to almost 93% when artificial samples are generated, which is a promising result when only small databases are available.

A Set of Reliable Samples for the Study of Biomarkers for the Early Diagnosis of Parkinson's Disease.

Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder, diagnosed according to the clinical criteria that occur in already advanced stages of PD. The definition of biomarkers for the early diagnosis of PD represents a challenge that might improve treatment and avoid complications in this disease. Therefore, we propose a set of reliable samples for the identification of altered metabolites to find potential prognostic biomarkers for early PD. Methods: This case-control study included plasma samples of 12 patients with PD and 21 control subjects, from the Spanish European Prospective Investigation into Cancer and Nutrition (EPIC)-Navarra cohort, part of the EPIC-Spain study. All the case samples were provided by healthy volunteers who were followed-up for 15.9 (±4.1) years and developed PD disease later on, after the sample collection. Liquid chromatography coupled to tandem mass spectrometry was used for the analysis of samples. Results: Out of 40 that were selected and studied due to their involvement in established cases of PD, seven significantly different metabolites between PD cases and healthy control subjects were obtained in this study (benzoic acid, palmitic acid, oleic acid, stearic acid, myo-inositol, sorbitol, and quinolinic acid). These metabolites are related to mitochondrial dysfunction, the oxidative stress, and the mechanisms of energy production. Conclusion: We propose the samples from the EPIC study as reliable and invaluable samples for the search of early biomarkers of PD. Likewise, this study 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.

Prognostic biomarkers of Parkinson's disease in the Spanish EPIC cohort: a multiplatform metabolomics approach.

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.

Analysis of Fine Motor Skills in Essential Tremor: Combining Neuroimaging and Handwriting Biomarkers for Early Management.

Essential tremor (ET) is a highly prevalent neurological disorder characterized by action-induced tremors involving the hand, voice, head, and/or face. Importantly, hand tremor is present in nearly all forms of ET, resulting in impaired fine motor skills and diminished quality of life. To advance early diagnostic approaches for ET, automated handwriting tasks and magnetic resonance imaging (MRI) offer an opportunity to develop early essential clinical biomarkers. In this study, we present a novel approach for the early clinical diagnosis and monitoring of ET based on integrating handwriting and neuroimaging analysis. We demonstrate how the analysis of fine motor skills, as measured by an automated Archimedes' spiral task, is correlated with neuroimaging biomarkers for ET. Together, we present a novel modeling approach that can serve as a complementary and promising support tool for the clinical diagnosis of ET and a large range of tremors.

A More Homogeneous Phenotype in Parkinson's Disease Related to R1441G Mutation in the LRRK2 Gene.

Parkinson's disease (PD) is characterized by a great clinical heterogeneity. Nevertheless, the biological drivers of this heterogeneity have not been completely elucidated and are likely to be complex, arising from interactions between genetic, epigenetic, and environmental factors. Despite this heterogeneity, the clinical patterns of monogenic forms of PD have usually maintained a good clinical correlation with each mutation once a sufficient number of patients have been studied. Mutations in LRRK2 are the most commonly known genetic cause of autosomal dominant PD known to date. Furthermore, recent genome-wide association studies have revealed variations in LRRK2 as significant risk factors also for the development of sporadic PD. The LRRK2-R1441G mutation is especially frequent in the population of Basque ascent based on a possible founder effect, being responsible for almost 50% of cases of familial PD in our region, with a high penetrance. Curiously, Lewy bodies, considered the neuropathological hallmark of PD, are absent in a significant subset of LRRK2-PD cases. Indeed, these cases appear to be associated with a less aggressive primarily pure motor phenotype. The aim of our research is to examine the clinical phenotype of R1441G-PD patients, more homogeneous when we compare it with sporadic PD patients or with patients carrying other LRRK2 mutations, and reflect on the value of the observed correlation in the genetic forms of PD. The clinical heterogeneity of PD leads us to think that there may be as many different diseases as the number of people affected. Undoubtedly, genetics constitutes a relevant key player, as it may significantly influence the phenotype, with differences according to the mutation within the same gene, and not only in familial PD but also in sporadic forms. Thus, extending our knowledge regarding genetic forms of PD implies an expansion of knowledge regarding sporadic forms, and this may be relevant due to the future therapeutic implications of all forms of PD.

Ratios of proteins in cerebrospinal fluid in Parkinson's disease cognitive decline: prospective study.

BACKGROUND: There is a need for biomarkers of dementia in PD. OBJECTIVES: To determine if the levels of the main CSF proteins and their ratios are associated with deterioration in cognition and progression to dementia in the short to mid term. METHODS: The Parkinson's Progression Markers Initiative database was used as an exploratory cohort, and a center-based cohort was used as a replication cohort. Amyloid ß1-42, total tau, threonine-181 phosphorylated tau, and α-synuclein in the CSF and the ratios of these proteins were assessed. RESULTS: In the Parkinson's Progression Markers Initiative cohort (n = 281), the total tau/amyloid ß1-42, total tau/α-synuclein, total tau/amyloid ß1-42+α-synuclein, and amyloid ß1-42/total tau ratios were associated with a risk of progression to dementia over a 3-year follow-up. In the replication cohort (n = 40), the total tau/α-synuclein and total tau/amyloid ß1-42+α-synuclein ratios were associated with progression to dementia over a 41-month follow-up. CONCLUSION: Ratios of the main proteins found in PD patient brain inclusions that can be measured in the CSF appear to have value as short- to mid-term predictors of dementia. © 2018 International Parkinson and Movement Disorder Society.

Two cases of opercular myoclonic-anarthric status epilepticus.

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].

Discrete Cosine Transform for the Analysis of Essential Tremor.

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.

Automatic Analysis of Archimedes' Spiral for Characterization of Genetic Essential Tremor Based on Shannon's Entropy and Fractal Dimension.

Among neural disorders related to movement, essential tremor has the highest prevalence; in fact, it is twenty times more common than Parkinson's disease. The drawing of the Archimedes' 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.

Whole-exome sequencing associates novel CSMD1 gene mutations with familial Parkinson disease.

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.

Tau/α-synuclein ratio and inflammatory proteins in Parkinson's disease: An exploratory study.

BACKGROUND: No CSF or plasma biomarker has been validated for diagnosis or progression of PD. OBJECTIVES: To assess whether the CSF and plasma levels of proteins associated with PD neuropathological inclusions and with neuroinflammation might have value in the diagnosis of PD or in relation to disease severity. METHODS: CSF levels of α-synuclein, amyloid-ß1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1ß, interleukin-2, interleukin, interferon-γ, and tumor necrosis factor α) were studied in 40 PD patients and 40 healthy controls. Plasma levels of cytokines were measured in 51 patients and 26 aditional controls. We also explored the Parkinson's Progression Markers Initiative data set as a replication cohort. RESULTS: CSF levels of α-synuclein, amyloid-ß1-42, and tumor necrosis factor α were lower in patients than in controls, and the total tau/α-synuclein, phosphorylated tau/α-synuclein, total tau/amyloid-ß1-42+α-synuclein, and phosphorylated tau/amyloid-ß1-42+α-synuclein ratios were higher in patients. The best area under the curve value was obtained for the phosphorylated tau/α-synuclein ratio alone (0.86) and also when this was combined with tumor necrosis factor α in CSF (0.91; sensitivity 92.9%, specificity 75% for a cut-off value of ≤ 0.71). Phosphorylated tau/α-synuclein and phosphorylated tau/amyloid-ß1-42+α-synuclein were higher in patients than in controls of the Parkinson's Progression Markers Initiative database. Plasma cytokines did not differ between groups, although interleukin-6 levels were positively correlated with UPDRS-I, -II, and -III scores. CONCLUSIONS: The CSF phosphorylated tau/α-synuclein ratio alone, and in combination with tumor necrosis factor α and plasma interleukin-6 levels, might serve as biomarkers to diagnose PD and monitor its severity. © 2017 International Parkinson and Movement Disorder Society.

Nontraditional Lipid Variables Predict Recurrent Brain Ischemia in Embolic Stroke of Undetermined Source.

OBJECTIVE: The aims of this study are, first, to calculate the risk of brain ischemia recurrence and embolic source diagnosis in the follow-up of patients with ESUS (embolic stroke of undetermined source) and, second, to identify the predictors of these events including cardiologic, laboratory, and clinical factors. METHODS: A retrospective observational cohort study of stroke patients admitted to the stroke unit in a single tertiary hospital from 2012 to 2014 was performed. Patients fulfilling ESUS criteria were identified and followed by medical history review until March 2016. Statistical analysis comprised Kaplan-Meier analysis and Cox proportional hazards multivariate analysis including clinical characteristics, cardiologic data, and blood test results. RESULTS: One hundred and thirteen patients, 8.3% of the overall stroke patients, filled ESUS criteria and they were younger, had less vascular risk factors, and suffered milder strokes than the remainder of stroke patients. Median follow-up of ESUS was 25.6 months. Risk of brain ischemia recurrence was 8.4, 10.8, and 15% at 12, 24, and 36 months, respectively, and was associated to age (HR 1.07, P = .027) and to a higher total cholesterol (TC)/high-density lipoprotein (HDL)-cholesterol (HR = 1.38, P = .002) and low-density lipoprotein (LDL)-cholesterol/HDL-cholesterol ratios (HR = 1.48, P = .001). The risk of major embolic source diagnosis was 6.7, 7.8, 13.6% at 12, 24, and 36 months, and was associated to female sex (HR = 6.05, P = .021). CONCLUSIONS: Brain ischemia recurrence increases with age and increased values of nontraditional lipid variables, TCHDLr and LDLHDLr, in ESUS patients, and women are more frequently diagnosed with a major embolic source in the follow-up.

A protective personal factor against disability and dependence in the elderly: an ordinal regression analysis with nine geographically-defined samples from Spain.

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.

Genetic Mutation Analysis of Parkinson's Disease Patients Using Multigene Next-Generation Sequencing Panels.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting millions of people. Genome-wide association studies (GWAS) have found >25 genetic risk factors and at least 15 loci directly associated with PD. Recent advances in new next-generation DNA sequencing technologies, such as the semiconductor-based Ion Torrent platform, make multigene sequencing cheaper, faster, and more reliable. OBJECTIVES: Our objective was to test the power of this next-generation sequencing technology to analyze large samples by screening the majority of the most relevant PD-related genes known for single and compound mutations. METHODS: To archive a rapid, robust, and cost-effective genetic analysis of a PD cohort, we designed a multiplex, polymerase chain reaction (PCR)-based primer panel to amplify and sequence coding exons of 15 PD-associated genes (SNCA, LRRK2, PARK2, PINK1, PARK7, GIGYF2, ATP13A2, UCHL1, PLA2G6, FBXO7, EIF4G1, VPS35, ACMSD, APOE, and GBA). We conducted parallel sequencing using the Ion Torrent Personal Genome Machine(®) system to detect mutations in 92 blood DNA samples from PD patients. RESULTS: After bioinformatics analysis and filtering, 95.13 % coverage of the targeted region was obtained at >40-fold mean coverage. The results revealed 44 previously documented variants in these 15 genes, with five revealed as pathogenic. We also discovered six novel variants, five of which had an in silico prediction of being pathogenic. CONCLUSIONS: Benchtop next-generation sequencing is a powerful method for genetic screening for PD. Our results indicated that it yielded a high frequency of discovery (66 %; n = 92) of variants in carriers from an enriched Spanish PD sample.

DAT imaging and clinical biomarkers in relatives at genetic risk for LRRK2 R1441G Parkinson's disease.

BACKGROUND: The objective of this study was to study motor and nonmotor symptoms and striatal dopaminergic denervation, as well as the relationship between them, in a cohort of asymptomatic relatives of patients with Parkinson's disease (PD) with the R1441G-leucine-rich repeat kinase 2 mutation. METHODS: Asymptomatic relatives of patients with PD and this mutation were tested for the presence of the mutation and evaluated for striatal, putamenal, and caudate dopaminergic transporters using (123)I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane single-photon emission computed tomography binding ratios. Clinical and neuropsychological evaluations including timed motor tests, a smell identification test, and global cognition, attention, executive, visuospatial, and memory functions as well as depression, constipation, and rapid eye movement sleep behavior disorder were also assessed. RESULTS: Twenty-seven carriers and 19 noncarriers were studied. Compared with noncarriers, mutation carriers had significantly lower (123)I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropan mean striatal (P = 0.03), mean putamenal (P = 0.01), and lowest putamenal (P = 0.01) binding ratios. Multiple linear regression analysis showed that the carrier status and the execution of timed tests significantly predicted striatal (123)I-2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)-nortropane binding. The proportion of variation accounted for by the regression model of these variables was 69% for the putamen and 53% for the caudate nucleus. CONCLUSIONS: Asymptomatic carriers of the R1441G-leucine-rich repeat kinase 2 mutation have evidence of dopaminergic nigrostriatal denervation, mainly in the putamen, which is associated with a decline in the execution of complex motor tests. These tests could be early indicators of the ongoing dopaminergic deficit in this group at risk of PD.

SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy.

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.

Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study.

BACKGROUND/AIMS: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. RESULTS: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. CONCLUSIONS: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.