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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: 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.

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., This work was supported in part by the Universidad del País Vasco/Euskal Herriko Unibertsitatea, the University of Cambridge, PPG 17/51 and GIU 092/19, the Basque government (Saiotek SA-2010/00028, ELEKIN, Engineering and Society and Bioengineering Research Groups, GIC18/136, and ELKARTEK 18/99, 20/81), ‘‘Ministerio de Ciencia e Innovación’’ (SAF201677758R), FEDER funds, DomusVi Foundation (FP18/76), and the government of Gipuzkoa (HELENA, SABRINA, DG18/14-23, DG19/29, DG20/25 projects). This work is also based upon the work from COST Actions CA18106 and CA15225, supported by COST (European Cooperation in Science and Technology).

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.

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.

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.

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 s1-42, 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 s1-42, total tau/α-synuclein, total tau/amyloid s1-42+α-synuclein, and amyloid s1-42/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 s1-42+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.

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].

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-s1-42, total tau, and threonine-181 phosphorylated tau, as well as CSF and plasma levels of cytokines (interleukin-1s, 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-s1-42, 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-s1-42+α-synuclein, and phosphorylated tau/amyloid-s1-42+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-s1-42+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

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.

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.

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 123I-2β-carbomethoxy-3β-(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 123I-2β-carbomethoxy-3β-(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 123I-2β-carbomethoxy-3β-(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. © 2015 International Parkinson and Movement Disorder Society

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.

Objective: The neuropsychological characteristics of patients with Parkinson's Disease (PD) associated with R1441G mutation in the LRRK2 gene (R1441G-PD) are not well known. The aim of this study was to examine the cognitive status and mood of R1441G-PD patients. Methods: Thirty patients with R1441G-PD were compared with thirty idiopathic PD (i-PD) patients who were matched by age, sex, education, disease onset age and duration, using a comprehensive battery of neuropsychological test, and considering the Movement Disorder Society (MDS) criteria for the diagnosis of Mild Cognitive Impairment (PD-MCI) and dementia (PD-Dementia). Results: The mean scores in the depression and anxiety scales were similar in the two groups. Depressive symptoms were detected in 31.8% of R1441G-PD and 25% of i-PD patients and anxiety symptoms were evident in 4.5% and 15%, respectively, but the differences were not significant. The only neuropsychological test on which there was a significantly worse performance in the R1441G-PD group was the Boston naming test but the difference became not significant when Bonferroni's correction was applied. The prevalence of PD-MCI was 30% in both R1441G-PD and i-PD, with no differences in the number and type of domains altered given that executive function, memory and attention were mainly affected. PDDementia was diagnosed in 13.3% (n ¼ 4) of R1441G-PD and 26.7% (n ¼ 8) of i-PD patients (difference was not significant). Conclusion: In conclusion, significant differences were not detected between R1441G-PD and i-PD in cognitive, depression and anxiety scales, or PD-MCI and PD-Dementia prevalence, and the cognitive profile was identical in the two groups.

An inverse relationship between Parkinson's disease (PD) and cancer has been described. However, the association between cancers and genetic forms of PD, in particular the R1441G mutation in the LRRK2 gene, is not well known. The objective of this work was to analyze cancer prevalence in PD patients with R1441G or G2019S mutations in LRRK2, and in idiopathic PD (iPD). A total of 732 patients with PD (70 and 25 carriers of R1441G or G2019S mutations, respectively), and 177 controls, were linked using a population-based cancer registry of the Spanish province of Gipuzkoa. Cancer prevalence was not significantly higher in PD-G2019S carriers (20%) than in PD-R1441G carriers (14.3%), iPD (13.8%), or controls (12.5%). With the exception of a high prevalence of hematological cancers (crude odds ratio of 7.1) in the R1441G group, specific cancer types were not increased in PD mutation carriers. In both the carrier and iPD groups, cancers were diagnosed after the onset of PD. PD patients had a similar prevalence of cancer to control subjects. There was no increased association between G2019S or R1441G mutations and any type of cancer. Although there was a higher prevalence of hematological cancers in the R1441G group, the low number of such cancers overall makes this finding of uncertain significance. There was a slightly higher but not statistically significant prevalence of non-skin cancers in the G2019S group, suggesting that further study to evaluate the association should be undertaken prior to ascribing an increased cancer risk to this population.

Lewy bodies are the hallmark of Parkinson disease and their sophisticated analysis will undoubtedly elucidate the pathogenic process. They have been studied by using different microscopic tools. The authors have used atomic force microscopy (AFM) to study the ultramicrotom cut postmortem brain tissue of Parkinson disease patients. Under the same preparation conditions, they have found aggregated fibrillary nanostructures in Lewy bodies, as well as a loss of connections between neurons located in other parts of the substantia nigra. Although these results are preliminary and descriptive in nature, this paper reports the application of a novel and intriguing technique. Further studies including the study of cortical LB and Lewy neurites will be needed to determine the full potential of AFM in the study of the pathogenesis of cell death in Parkinson disease and other synucleinopathies.

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.

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.

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.

In this paper some of novel and low-cost methodologies are analysed for most common cognitive impairments: Alzheimer disease, Parkinson and Essential Tremor. These methodologies allow us to obtain information from the brain in an indirect form, without needing to do neither invasive nor expensive or long-time tests. We will present handwriting and speech as interesting biomarkers for the early detection and monitoring of cognitive impairments and detail possible fields of application, with real experiments carried-out at the Hospital Donostia (Spain) in several past and current projects.

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 (

It has been proposed that olfactory tests and metaiodobenzylguanidine cardiac scintigraphy may help diagnose idiopathic Parkinson's disease in the premotor phase. However, it is not clear what value these tests have in all patients with Parkinson's disease and, particularly, in those who carry mutations in LRRK2. The objective was to analyze olfactory dysfunction and the changes in cardiac I-metaiodobenzylguanidine uptake in patients with Parkinson's disease carrying the R1441G and G2019S mutations in LRRK2, and in patients with Parkinson's disease with no known mutations. Patients with Parkinson's disease were screened for R1441G and G2019S LRRK2 gene mutations and classified as LRRK2 mutation carriers or noncarriers. A total of 190 patients with Parkinson's disease (44 LRRK2 mutation carriers) were tested for olfactory dysfunction using the Brief Smell Identification Test. Cardiac 123I-metaiodobenzylguanidine scintigraphy was performed on 90 patients with Parkinson's disease (27 LRRK2 mutation carriers). Thirty-six percent of patients with LRRK2 mutations have hyposmia, compared to 75% of noncarrier patients with Parkinson's disease (P < .001). Sixty-six percent of LRRK2 mutation carriers have low early metaiodobenzylguanidine uptake, compared to 86% of noncarriers (P = .048). Similarly, the heart/mediastinum ratio in delayed metaiodobenzylguanidine images appeared to differ between these groups of patients with Parkinson's disease, although these results did not reach statistical significance. The data obtained indicate that olfactory and cardiac impairment is less prevalent when Parkinson's disease is associated with mutations in LRRK2, although the underlying mechanisms for this difference remain unclear. Thus, such screening would be less useful to detect the premotor phase in asymptomatic relatives who carry mutations in LRRK2 than in cases not associated with LRRK2. © 2011 Movement Disorder Society

7.5% (95% CI 5.4–9.7), 5.6 (95% CI 3.7–7.5) and 1.4 (95% CI 0.5– 2.3), and 290,000 (95% CI 208,000–372,000), 214,000 (95% CI 141,000–288,000) and 54,000 (95% CI 20,000–88,000) for dementia, AD and VD, respectively. Conclusions – Dementia prevalence in Spain is comparable to other European populations, while a high number of undiagnosed cases live in the community. The potential impact of Mediterranean diet, hypertension control and decreasing vascular risk factors is discussed.

The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson's disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counseling. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic testing for the R1441G mutation in the LRRK2 gene was performed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differences were found in penetrance.

Background: Mutations in the progranulin gene (PGRN) are a major cause of frontotemporal lobar degeneration with tau-negative and ubiquitin-positive neuronal inclusions. Most previous studies aimed at characterizing the clinical and neuropsychological phenotype of PGRN mutation carriers included patients with different PGRN mutations, assuming that the common proposed pathogenetic mechanism of haploinsufficiency will lead to a comparable phenotype. Methods: We studied 21 patients with a single pathogenic splicing mutation in the PGRN gene (c.709-1G>A) in the same tertiary referral center using homogenous diagnostic criteria and protocols. All patients were of Basque descent. Results: Patients exhibited a variable phenotype both in age at onset and initial symptoms. Behavioral variant frontotemporal dementia (52.4%) and progressive nonfluent aphasia (23.8%) were the most common presenting syndromes. Apathy was the most common behavioral symptom. Patients developed a relatively rapidly progressive dementia with features that led to a secondary diagnosis in 61.9% of cases 2 years after primary diagnosis. Notably, this secondary or tertiary diagnosis was corticobasal syndrome in 47.6% of cases, which confirmed the neuropsychological features of parietal lobe dysfunction seen at the initial assessment in 81.8% of patients. Conclusions: Patients carrying the c.709-1G>A mutation in the PGRN gene showed heterogeneous clinical and neuropsychological features and commonly developed corticobasal syndrome as the disease progressed.

The hospital anxiety and depression scale (HADS) is commonly used to assess mood in Parkinson's disease (PD) patients. Very few studies analyze the scale from the standpoint of item response theory. This article sought to analyze how the HADS fits the Rasch model in PD. The HADS was administered to 387 PD patients. Three sets of Rasch analyses were performed for the HADS total score, and anxiety and depression subscales (HADS-T, -A, and -D, respectively). Although the HADS-T and HADS-A displayed a good fit, with little threshold disordering and no differential item functioning, the HADS-D failed to fit the model. The person separation index, a reliability measure, was 0.87 (HADS-T) and 0.80 (HADS-A). Both HADS-T and HADS-A showed unidimensionality. Our results supported the use of HADS-T as a measure of psychological distress in PD patients. Moreover, the HADS-A was also an adequate anxiety measure. Further research is required to address the use of HADS-D in PD.

Background There is an increasing interest in the clinico-pathological correlation of mutations in progranulin ( PGRN ) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. Methods We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. Results Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and τ/α-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. Conclusions Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.

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.

To assess the prevalence of Parkinson’s disease and parkinsonism in two Spanish populations (Irun and Hondarribia, Bidasoa Region) and to compare the results with those of similar surveys. The survey included 2000 participants aged 65 years or older in a door-to-door, three-phase design. In the screening phase we used the SNES (Sicilian Neuro-Epidemiologic Study) screening questionnaire, which has 100% sensitivity. In phases 2 and 3 we carried out a 3-year follow-up of all cases diagnosed with parkinsonism in phase 2. Progressively stricter diagnostic criteria were chosen in order to minimize the impact of false positives on the final results. The prevalence of Parkinson’s disease (PD) was 1.5 % (95% confidence interval, 0.9 to 2.3) and the prevalence of other types of parkinsonism (OP) was 1.1 % (95% confidence interval 0.6 to 1.9). The overall prevalence by age group was 0.4 % (65–74 years), 4.7% (75–84 years), and 2.9% (≥ 85 years) for Parkinson’s disease and 0.7%, 2%, and 3.9 % for parkinsonism, respectively. The other parkinsonism prevalence was 1.3 % in men and 1.6 % in women. These prevalence rates are similar than those found in studies made in other European countries. The prevalence of both Parkinson’s disease and other types of parkinsonism increased with age, with no significant differences between men and women.

Background and purpose: The Movement Disorder Society sponsored version of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson’s disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. Methods: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire eight items (PDQ-8). Spearman’s rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. Results: The participants’ age was 66.71 10.32 years (51.5% men). PD duration was 8.52 6.14, and median HY was 2 (range 1–5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from 0.46 (Part IV) to 0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. Conclusions: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

The association between sleep disorders and other non-motor symptoms (NMS) in Parkinson's disease (PD) has been scarcely investigated.To describe the prevalence of insomnia and hypersomnia in PD and analyze their relationship with other NMS.Cross-sectional, multicenter study including 388 PD patients evaluated with Hoehn and Yahr, Clinical Impression of Severity Index for PD, Scales for Outcomes in Parkinson's Disease (SCOPA)-Sleep(S), SCOPA-Cognition, SCOPA-Psychiatric Complications, SCOPA-Autonomic, Hospital Anxiety and Depression Scale, and fatigue and pain visual analogue scales. Spearman correlation coefficients, Mann-Whitney test and multiple linear regression analysis were applied.Mean age (54% male) was 65.9 ± 11.2 years old, with disease duration of 8.1 ± 6.0 years and median HY = 2 (range: 1-5). Mean SCOPA-S nocturnal sleep (NS) was 5.4 ± 4.0 (range: 0-15), daytime sleepiness (DS) was 3.76 ± 3.04 (range: 0-15). Most of the sample declared nocturnal or daytime sleep problems (87.4%). Weak-to-moderate correlations were found between sleep disturbances and other NMS (range: 0.14-0.37). SCOPA-S subscales showed higher scores with the presence of most other NMS such as psychiatric complications and autonomic dysfunctions (p 0.05). Regression models showed that fatigue, depression, urinary, cardiovascular, and thermoregulatory dysfunctions were significant determinants of SCOPA-NS score (variance: 23%); cognitive impairment, urinary, cardiovascular, and pupillomotor disorders influenced SCOPA-DS score (variance: 14%).Insomnia and daytime sleepiness are extremely prevalent in PD. Depression, fatigue, cognitive impairment, cardiovascular, urinary and thermoregulatory dysfunctions may contribute to insomnia/hypersomnia. This is the first clinical study to relate cardiovascular and thermoregulatory dysfunctions with sleep in PD.

Objective: To evaluate the motor experiences of daily living section of the Movement Disorders SocietyUnified Parkinson’s Disease Rating Scale (MDS-UPDRS M-EDL) for assessing disability in PD patients; to determine the association between disability and quality of life; and to identify cut-off score ranges for no, mild, moderate and severe disability with this measure. Methods: International, observational, cross-sectional study of 435 PD patients, assessed with: MDSUPDRS, Hoehn and Yahr staging, Rapid Assessment of Disability Scale, Clinical Impression of Severity Index for PD, Parkinson’s Disease Questionnaire-8 and EQ-5D. Descriptive statistics, Spearman’s rank correlation coefficients, KruskaleWallis test for group comparisons, ordinal logistic regression analysis for setting cut-off values and a step-wise multiple linear regression model were calculated. Results: MDS-UPDRS M-EDL correlated 0.70e0.80 with other disability measures, and � 0.46 to 0.74 with quality of life scales. Scores significantly increased with higher disease duration and severity (p < 0.001). Cut-off values for the M-EDL were: 0e2 points, no disability; 3e16, mild; 17e31, moderate; and 32 points or more, severe. Linear regression analysis identified the MDS-UPDRS nM-EDL section as the main determinant of M-EDL, followed by the rest of MDS-UPDRS sections (explained variance: 59%). Conclusions: MDS-UPDRS M-EDL proved to be useful for assessing disability in PD.

Background and purpose Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I – Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). Methods To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland–Altman plot. Results As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (rS > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (rS = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60–64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland–Altman plot; LCCC

The Movement Disorder Society-UPDRS (MDS-UPDRS) was published in 2008, showing satisfactory clinimetric results and has been proposed as the official benchmark scale for Parkinson's disease. The present study, based on the official MDS-UPDRS Spanish version, performed the first independent testing of the scale and adds information on its clinimetric properties. The cross-culturally adapted MDS-UPDRS Spanish version showed a comparative fit index ≥ 0.90 for each part (I-IV) relative to the English-language version and was accepted as the Official MDS-UPDRS Spanish version. Data from this scale, applied with other assessments to Spanish-speaking Parkinson's disease patients in five countries, were analyzed for an independent and complementary clinimetric evaluation. In total, 435 patients were included. Missing data were negligible and moderate floor effect (30 %) was found for Part IV. Cronbach's α index ranged between 0.79 and 0.93 and only five items did not reach the 0.30 threshold value of item-total correlation. Test-retest reliability was adequate with only two sub-scores of the item 3.17, Rest tremor amplitude, reaching κ values lower than 0.60. The intraclass correlation coefficient was higher than 0.85 for the total score of each part. Correlation of the MDS-UPDRS parts with other measures for related constructs was high (≥ 0.60) and the standard error of measurement lower than one-third baseline standard deviation for all subscales. Results confirm those of the original study and add information on scale reliability, construct validity, and precision. The MDS-UPDRS Spanish version shows satisfactory clinimetric characteristics.

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.

Sleep is affected in a large number of patients with Parkinson disease. The mechanisms by which this occurs and the different types of sleep disorders that a patient with Parkinson disease may suffer (insufficient or fragmented sleep, persistent excessive daytime sleepiness, sudden onset of sleep episodes, obstructive sleep apnea (OSA), rapid eye movement sleep behavior disorder, and restless legs syndrome) will be reviewed in this study, as well as their relationship with the dopaminergic system. Finally, the most effective treatments will be proposed.

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

To determine the most significant clinical predictors that influence driving ability in Parkinson disease (PD).National-multi-centre, cross-sectional study covering PD outpatients. Clinical assessment was based on the following questionnaires: cognition (SCOPA-Cog); motor impairment and disabilities (SCOPA motor); depression/anxiety; sleep (SCOPA-Sleep); psychosis and severity/global impairment (HY and CISI-PD). Driving status data was obtained using a standardized questionnaire. Comparisons between drivers and ex-drivers were calculated using chi(2) and Student t-tests as appropriate. Multi-variate logistic regression analysis was performed to identify independent driving ability clinical predictors.Compared with the drivers, the ex-drivers were older (p = 0.00005), had longer disease duration (p = 0.03), had more overall cognitive dysfunction (p = 0.004) and had greater motor impairment, as measured by the CISI (p = 0.02), HY stage (p = 0.034) and by the SCOPA-motor scale (p = 0.002) and difficulty in activities of daily life (p = 0.002). In the regression model analysis, aging and ADL impairment were the principal clinical predictors that differentiated drivers from ex-drivers.Although overall driving impairment in PD is associated with advancing disease severity, driving ability seems to be more strongly influenced by age and ADL impairment. Multi-disciplinary teams are required to assess driving ability in patients with PD and develop rehabilitation measures for safer driving.

The Hospital Anxiety and Depression Scale (HADS) has been used in Parkinson's disease (PD) but information about its psychometric properties in this context is limited. The aim of this study is to assess the psychometric properties of the HADS in PD. In an observational, cross-sectional analysis, HADS data quality, acceptability, scaling assumptions, internal consistency, construct validity, and precision were explored. From a sample of 387 PD patients, 22% and 14% scored > or =11 points (definite case) on the HADS anxiety and depression subscales, respectively. Cronbach's alpha was 0.81 and 0.83 for these subscales. Factor analysis revealed two factors (49.8% of the variance) representing anxiety and depression. The HADS closely correlated with health-related quality of life (HRQL) measures and displayed satisfactory discriminative validity for patients grouped by severity level, disease duration, HRQL status, and treatment. The SEM was 1.84 for HADS-Anxiety and 1.72 for HADS-Depression. The HADS is an acceptable, consistent, valid, precise, and potentially responsive scale for use in PD.

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