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Villar del Ala, Spain

Iranzo A.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | Iranzo A.,CIBER ISCIII | Gelpi E.,Neurological Tissue Bank | Tolosa E.,Institute dinvestigacions Biomediques August Pi i Sunyer IDIBAPS | And 7 more authors.
Movement Disorders | Year: 2014

Background: Current evidence suggests that there is a prodromal stage in Parkinson disease characterized by a variety of nonmotor symptoms. Methods and Results: A 69-year-old man presented to our sleep center with isolated rapid eye movement sleep behavior disorder. During a 10-year follow-up period, longitudinal clinical and laboratory assessments indicated the development of hyposmia, depression, mild cognitive impairment, and constipation. Parkinsonism was absent, but dopamine transporter imaging showed subclinical substantia nigra damage. Postmortem examination demonstrated neuronal loss and Lewy body pathology in the peripheral autonomic nervous system (eg, cardiac and myenteric plexus), olfactory bulb, medulla, pons, substantia nigra pars compacta (estimated cell loss, 20%-30%), nucleus basalis of Meynert, and amygdala, sparing the neocortex. Conclusions: Our observations indicate that nonmotor symptoms plus widespread peripheral and central nervous system pathological changes occur before parkinsonism and dementia onset in diseases associated with Lewy pathology. The current diagnostic criteria for Parkinson's disease miss these patients, who present only with nonmotor symptoms. © 2014 International Parkinson and Movement Disorder Society.

Fernandez-Irigoyen J.,Clinical Neuroproteomics Group | Zelaya M.V.,Neurological Tissue Bank | Tunon T.,Navarra Hospital Complex | Santamaria E.,Clinical Neuroproteomics Group
Molecular Brain | Year: 2014

Background: The basal ganglia (BG) are a complex network of subcortical nuclei involved in the coordination and integration of the motor activity. Although these independent anatomical structures are functionally related, the proteome present in each isolated nucleus remains largely unexplored. In order to analyse the BG proteome in a large-scale format, we used a multi-dimensional fractionation approach which combines isolation of anatomically-defined nuclei, and protein/peptide chromatographic fractionation strategies coupled to mass spectrometry. Results: Using this workflow, we have obtained a proteomic expression profile across striatum and globus pallidus structures among which 1681 proteins were located in caudate nucleus (CN), 1329 in putamen, 1419 in medial globus pallidus (GPi), and 1480 in lateral globus pallidus (GPe), establishing a BG reference proteome to a depth of 2979 unique proteins. Protein interactome mapping highlighted significant clustering of common proteins in striatal and pallidal structures, contributing to oxidative phosphorylation, protein degradation and neurotrophin signalling pathways. In silico analyses emphasized specific pathways represented in striatal and pallidal structures highlighting 5-hydroxytryptamine degradation, synaptic vesicle trafficking, and dopamine, metabotropic glutamate and muscarinic acetylcholine receptor pathways. Additional bioinformatic analyses also revealed that: i) nearly 4% of identified proteins have been previously associated to neurodegenerative syndromes, ii) 11% of protein set tends to localize to synaptic terminal, and iii) 20% of identified proteins were also localized in cerebrospinal fluid (CSF). Conclusions: Overall, the anatomo-proteomic profiling of BG complements the anatomical atlas of the human brain transcriptome, increasing our knowledge about the molecular basis of the BG and the etiology of the movement disorders.

Fernandez-Irigoyen J.,Clinical Neuroproteomics Group | Labarga A.,Bioinformatics Unit | Zabaleta A.,CIC Biomagune | de Morentin X.M.,Clinical Neuroproteomics Group | And 3 more authors.
Proteomics - Clinical Applications | Year: 2015

The human brain is exceedingly complex, constituted by billions of neurons and trillions of synaptic connections that, in turn, define ∼900 neuroanatomical subdivisions in the adult brain (Hawrylycz et al. An anatomically comprehensive atlas of the human brain transcriptome. Nature 2012, 489, 391-399). The human brain transcriptome has revealed specific regional transcriptional signatures that are regulated in a spatiotemporal manner, increasing the complexity of the structural and molecular organization of this organ (Kang et al. Spatio-temporal transcriptome of the human brain. Nature 2011, 478, 483-489). During the last decade, neuroproteomics has emerged as a powerful approach to profile neural proteomes using shotgun-based MS, providing complementary information about protein content and function at a global level. Here, we revise recent proteome profiling studies performed in human brain, with special emphasis on proteome mapping of anatomical macrostructures, specific subcellular compartments, and cerebrospinal fluid. Moreover, we have performed an integrative functional analysis of the protein compilation derived from these large-scale human brain proteomic studies in order to obtain a comprehensive view of human brain biology. Finally, we also discuss the potential contribution of our meta-analysis to the Chromosome-centric Human Proteome Project initiative. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antonell A.,Institute dInvestigacio Biomedica August Pi i Sunyer IDIBAPS | Gelpi E.,Neurological Tissue Bank | Sanchez-Valle R.,Institute dInvestigacio Biomedica August Pi i Sunyer IDIBAPS | Martinez R.,Hospital Mare de Deu de la Merce | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2012

AβPP locus duplications have been recently identified in early-onset Alzheimer's disease. We describe a patient who initiated memory problems and behavioral disturbances at 57 years, with a progressive cognitive decline, who died at the age of 68 years with dementia. Neuropathological examination revealed a temporobasal hemorrhage, extensive Alzheimer-type pathology, and severe cerebral amyloid angiopathy. We observed a chromosomal 21 region duplication spanning 0.59 Mb, which comprised JAM2, ATP5J, GABPA, and AβPP genes. We propose a replication based mutational mechanism (single Fork-Stalling and Template-Switching) or a recombination based one (non-homologous end-joining repair) for the AβPP locus duplication in this case. © 2012 - IOS Press and the authors. All rights reserved.

Iranzo A.,Neurology Service | Iranzo A.,CIBER ISCIII | Fernandez-Arcos A.,Neurology Service | Tolosa E.,Neurology Service | And 13 more authors.
PLoS ONE | Year: 2014

Objective: To estimate the risk for developing a defined neurodegenerative syndrome in a large cohort of idiopathic REM sleep behavior disorder (IRBD) patients with long follow-up. Methods: Using the Kaplan-Meier method, we estimated the disease-free survival rate from defined neurodegenerative syndromes in all the consecutive IRBD patients diagnosed and followed-up in our tertiary referal sleep center between November 1991 and July 2013. Results: The cohort comprises 174 patients with a median age at diagnosis of IRBD of 69 years and a median follow-up of four years. The risk of a defined neurodegenerative syndrome from the time of IRBD diagnosis was 33.1% at five years, 75.7% at ten years, and 90.9% at 14 years. The median conversion time was 7.5 years. Emerging diagnoses (37.4%) were dementia with Lewy bodies (DLB) in 29 subjects, Parkinson disease (PD) in 22, multiple system atrophy (MSA) in two, and mild cognitive impairment (MCI) in 12. In six cases, in whom postmortem was performed, neuropathological examination disclosed neuronal loss and widespread Lewy-type pathology in the brain in each case. Conclusions: In a large IRBD cohort diagnosed in a tertiary referal sleep center, prolonged follow-up indicated that the majority of patients are eventually diagnosed with the synucleinopathies PD, DLB and less frequently MSA. IRBD represented the prodromal period of these conditions. Our findings in IRBD have important implications in clinical practice, in the investigation of the early pathological events occurring in the synucleinopathies, and for the design of interventions with potential disease-modifying agents. © 2014 Iranzo et al.

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