Jose A Obeso

University Foundation San Pablo CEU, Madrid, Madrid, Spain

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Publications (161)1113.94 Total impact

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    ABSTRACT: OBJECTIVE Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used in patients with Parkinson's disease (PD). However, which target area of this region results in the highest antiparkinsonian efficacy is still a matter of debate. The aim of this study was to develop a more accurate methodology to locate the electrodes and the contacts used for chronic stimulation (active contacts) in the subthalamic region, and to determine the position at which stimulation conveys the greatest clinical benefit. METHODS The study group comprised 40 patients with PD in whom bilateral DBS electrodes had been implanted in the STN. Based on the Morel atlas, the authors created an adaptable 3D atlas that takes into account individual anatomical variability and divides the STN into functional territories. The locations of the electrodes and active contacts were obtained from an accurate volumetric assessment of the artifact using preoperative and postoperative MR images. Active contacts were positioned in the 3D atlas using stereotactic coordinates and a new volumetric method based on an ellipsoid representation created from all voxels that belong to a set of contacts. The antiparkinsonian benefit of the stimulation was evaluated by the reduction in the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) score and in the levodopa equivalent daily dose (LEDD) at 6 months. A homogeneous group classification for contact position and the respective clinical improvement was applied using a hierarchical clustering method. RESULTS Subthalamic stimulation induced a significant reduction of 58.0% ± 16.5% in the UPDRS-III score (p < 0.001) and 64.9% ± 21.0% in the LEDD (p < 0.001). The greatest reductions in the total and contralateral UPDRS-III scores (64% and 76%, respectively) and in the LEDD (73%) were obtained when the active contacts were placed approximately 12 mm lateral to the midline, with no influence of the position being observed in the anteroposterior and dorsoventral axes. In contrast, contacts located about 10 mm from the midline only reduced the global and contralateral UPDRS-III scores by 47% and 41%, respectively, and the LEDD by 33%. Using the ellipsoid method of location, active contacts with the highest benefit were positioned in the rostral and most lateral portion of the STN and at the interface between this subthalamic region, the zona incerta, and the thalamic fasciculus. Contacts placed in the most medial regions of the motor STN area provided the lowest clinical efficacy. CONCLUSIONS The authors report an accurate new methodology to assess the position of electrodes and contacts used for chronic subthalamic stimulation. Using this approach, the highest antiparkinsonian benefit is achieved when active contacts are located within the rostral and the most lateral parts of the motor region of the STN and at the interface of this region and adjacent areas (zona incerta and thalamic fasciculus).
    No preview · Article · Feb 2016 · Journal of Neurosurgery
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    ABSTRACT: Introduction: Mild cognitive impairment (MCI) and visual hallucinations (VH) are common co-morbidities and risk factors for dementia in Parkinson's disease (PD). The relative value of each of them in the progression to dementia is unknown. We investigated cognitive impairment and cerebral hypometabolism in PD-MCI patients with VH (VH-positive) and without (VH-negative). Methods: Twenty-one PD-MCI patients (12 VH-negative, nine VH-positive) and 19 controls were studied using a comprehensive neuropsychological battery and [18F]-Fluorodeoxyglucose positron emission tomography (FDG-PET). The neuropsychological assessment was repeated after 30 months. Regional FDG uptake was analyzed using statistical parametric mapping. Results: VH-positive patients had lower FDG uptake bilaterally in the occipital, and parietal cortex, right temporal lobe and in the left cingulum compared with VH-negative patients. The two groups showed no significant differences in clinical characteristics and cognitive status at baseline. After 30 months of follow-up, three (25%) and four (50%) of the VH-negative and VH-positive patients, respectively, had progressed to dementia. Conclusion: Even in the absence of significant cognitive differences, PD-MCI patients with VH exhibit more severe cerebral hypometabolism and had a higher rate of progression to dementia than VH-negative patients, supporting the importance of VH and cerebral hypometabolism in establishing the risk of dementia in PD-MCI. Hum Brain Mapp, 2015. © 2015 Wiley Periodicals, Inc.
    No preview · Article · Dec 2015 · Human Brain Mapping
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    Javier Blesa · Jose L Lanciego · Jose A. Obeso
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    ABSTRACT: Parkinson's disease is a neurodegenerative disorder that affects 1.5% of the global population over 65 years of age. The hallmark feature of this disease is the degeneration of dopamine neurons in the substantia nigra pars compacta and a consequent striatal dopamine deficiency. The pathogenesis of Parkinson's Disease remains unclear. Despite tremendous growth in recent years in our knowledge of the molecular basis of Parkinson's Disease and the molecular pathways of cell death important questions remain regarding why are substantia nigra cells especially vulnerable, which mechanisms underlie progressive cell loss or what do Lewy bodies or alpha-synuclein reveal about disease progression. Understanding the different vulnerability of the dopaminergic neurons from midbrain regions and the mechanisms whereby pathology becomes widespread are primary objectives of basic and clinical research in Parkinson's Disease. This e-Book discusses the etiopathogenesis of Parkinson's Disease, presenting a series of papers that provide up-to-date, state-of-the-art information on molecular and cellular mechanisms involved in the neurodegeneration process in the disease, the role of activation of functional anatomical organization of the basal ganglia and in particular habitual vs goal directed systems as a factor of neuronal vulnerability, the possibility that Parkinson's Disease coulb be a prion disease and how genetic factors linked to familial and sporadic forms of PD. We hope that this e-Book will stimulate the continuing efforts to understand the cell and physiological mechanisms underlying the origin of Parkinson's Disease.
    Full-text · Book · Dec 2015
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    ABSTRACT: Classically, the basal ganglia have been considered to have a role in producing habitual and goal-directed behaviours. In this article, we review recent evidence that expands this role, indicating that the basal ganglia are also involved in neural and behavioural inhibition in the motor and non-motor domains. We then distinguish between goal-directed and habitual (also known as automatic) inhibition mediated by fronto-striato-subthalamic-pallido-thalamo-cortical networks. We also suggest that imbalance between goal-directed and habitual action and inhibition contributes to some manifestations of Parkinson's disease, Tourette syndrome and obsessive-compulsive disorder. Finally, we propose that basal ganglia surgery improves these disorders by restoring a functional balance between facilitation and inhibition.
    Full-text · Article · Nov 2015 · Nature Reviews Neuroscience
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    ABSTRACT: Parkinson's Disease is characterized by alterations in deep brain structures and pathways involved in movement control. However, the understanding of neuroanatomy and spatial relationships of deep brain structures remains a challenge for medical students. Recent developments in information technology may help provide new instructional material that addresses this problem. This paper aims to develop an interactive and digital tool to enhance the study of the anatomical and functional neurological basis involved in Parkinson's Disease. This tool allows the organization and exploration of complex neuroanatomical contents related with Parkinson's Disease in an attractive and interactive way. Educational implications of this tool are analyzed.
    No preview · Article · Nov 2015 · Journal of Medical Systems
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    Javier Blesa · Jose L Lanciego · Jose A Obeso
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    ABSTRACT: The hallmark of Parkinson Disease (PD) is the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the consequent striatal dopamine (DA) deficiency, although it is well recognized that neurodegeneration in PD goes beyond the SNc. Major advances have occurred in recent years on the molecular and pathophysiological basis of PD, however there remain many questions and unknowns regarding SNc cells vulnerability, and the exact significance of Lewy bodies and alpha-synuclein (α-syn) aggregation process regarding disease onset and progression. This Research Topic discuss the etiopathogenesis of PD, presenting a series of papers that provide up-to-date, state-of-the-art information on molecular and cellular mechanisms involved in the neurodegeneration process, neuroimmune pathways, the role of functional and anatomical organization of the basal ganglia as a factor of neuronal vulnerability, the possibility that PD is a prion disease and the cellular response to α-syn aggregation. Understanding the mechanisms underlying vulnerability of dopaminergic midbrain neurons and how pathology becomes widespread are primary objectives of basic and clinical research in PD. Are dopaminergic and other neurons dying by the same pathogenic mechanisms? Do they all die to the same extent or at the same rate? What are the molecular determinants of susceptibility to the disease? To gain insights into these questions, researchers mainly rely in animal models. Blesa and Przedborski (2014) provide a summary of the current knowledge of in vivo models of PD. Whereas PD can be sporadic, genetic or possibly related with toxic/infectious agents, a differential pattern of cell loss among midbrain dopaminergic neurons is observed regardless of disease etiology suggesting that differential dopaminergic neuron vulnerability does not depend on the factor triggering PD " per se " but on intrinsic properties of these specific cell groups. Here, Brichta and Greengard (2014) provides an update review on the molecular basis underlying differential vulnerability of midbrain dopaminergic neurons in PD. For example, for many years many studies have suggested calbindin (CB) as a marker to distinguish between midbrain dopaminergic neurons with different susceptibility to degeneration in PD. Although CB dopaminergic neurons seem to be less prone to MPTP-induced degeneration, Dopeso-Reyes et al. (2014) clearly demonstrated that these neurons are not giving rise to nigro-striatal projections and indeed CB-ir/TH-ir neurons only originate nigro-extrastriatal projections. This data sustain the presence of a potential imbalance between the nigro-striatal and nigroextrastriatal systems in advanced diseases states. Also, Afonso-Oramas et al. (2014) revealed that midbrain dopaminergic axons are in close apposition to striatal vessels and perivascular astrocytes in rats and monkeys. The relative weight of this " vascular component " within the meso-striatal pathway suggests a role in the pathophysiology of PD. Aging is another major risk factor for developing PD. Rodriguez et al. (2014) reviewed similarities between neurodegeneration in PD and aging. The progressive course of aging and PD could be induced by the same multi-factorial etiology, including astrocytic and microglia alterations, anomalous action of different proteins, mitochondrial disturbances, alterations of the mitophagy or the ubiquitin-proteasome system and oxidative stress. Proteins involved in PD such as α-syn, PINK1 or DJ-1, are also involved in aging. All these mechanisms of degeneration are
    Full-text · Article · Oct 2015 · Frontiers in Neuroanatomy
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    Ledia F Hernández · Peter Redgrave · José A Obeso
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    ABSTRACT: [This corrects the article on p. 99 in vol. 9, PMID: 26300740.].
    Preview · Article · Aug 2015 · Frontiers in Neuroanatomy
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    ABSTRACT: Levodopa-induced dyskinesias (LIDs) are major complications in the pharmacological management of Parkinson's disease (PD). Abnormal glutamatergic transmission in the striatum is considered a key factor in the development of LIDs. This work aims at: (i) characterizing N-methyl-D-aspartate (NMDA) receptor GluN2A/GluN2B subunit ratio as a common synaptic trait in rat and primate models of LIDs as well as in dyskinetic PD patients; and (ii) validating the potential therapeutic effect of a cell-permeable peptide (CPP) interfering with GluN2A synaptic localization on the dyskinetic behavior of these experimental models of LIDs. Here we demonstrate an altered ratio of synaptic GluN2A/GluN2B-containing NMDA receptors in the striatum of levodopa-treated dyskinetic rats and monkeys as well as in post-mortem tissue from dyskinetic PD patients. The modulation of synaptic NMDA receptor composition by a cell-permeable peptide interfering with GluN2A subunit interaction with the scaffolding protein postsynaptic density protein 95 (PSD-95) leads to a reduction in the dyskinetic motor behavior in the two animal models of LIDs. Our results indicate that targeting synaptic NMDA receptor subunit composition may represent an intriguing therapeutic approach aimed at ameliorating levodopa motor side effects.
    Full-text · Article · Jul 2015 · Frontiers in Cellular Neuroscience

  • No preview · Conference Paper · Jun 2015
  • Jorge Guridi · Jose A Obeso

    No preview · Article · Feb 2015 · Journal of Neurosurgery

  • No preview · Article · Feb 2015 · Neurobiology of Disease
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    ABSTRACT: Carbon-11 labeled dihydrotetrabenazine ((11)C-DTBZ) binds to the vesicular monoamine transporter 2 and has been used to assess nigro-striatal integrity in animal models and patients with Parkinson's disease. Here, we applied (11)C-DTBZ positron emission tomography (PET) to obtain longitudinally in-vivo assessment of striatal dopaminergic loss in the classic unilateral and in a novel bilateral 6-hydroxydopamine (6-OHDA) lesion rat model. Forty-four Sprague-Dawley rats were divided into 3 sub-groups: 1. 6-OHDA-induced unilateral lesion in the medial forebrain bundle, 2. Bilateral lesion by injection of 6-OHDA in the third ventricle, 3. Vehicle injection in either site. (11)C-DTBZ PET studies were investigated in the same animals successively at baseline, 1, 3 and 6weeks after lesion using an anatomically standardized volumes-of-interest approach. Additionally, 12 rats had PET and Magnetic Resonance Imaging to construct a new (11)C-DTBZ PET template. Behavior was characterized by rotational, catalepsy and limb-use asymmetry tests and dopaminergic striatal denervation was validated post-mortem by immunostaining of the dopamine transporter (DAT). (11)C-DTBZ PET showed a significant decrease of striatal binding (SB) values one week after the unilateral lesion. At this point, there was a 60% reduction in SB in the affected hemisphere compared with baseline values in 6-OHDA unilaterally lesioned animals. A 46% symmetric reduction over baseline SB values was found in bilaterally lesioned rats at the first week after lesion. SB values remained constant in unilaterally lesioned rats whereas animals with bilateral lesions showed a modest (22%) increase in binding values at the 3rd and 6th week post-lesion. The degree of striatal dopaminergic denervation was corroborated histologically by DAT immunostaining. Statistical analysis revealed a high correlation between (11)C-DTBZ PET SB and striatal DAT immunostaining values (r=0.95, p<0.001). The data presented here indicate that (11)C-DTBZ PET may be used to ascertain changes occurring in-vivo throughout the evolution of nigro-striatal dopaminergic neurodegeneration, mainly in the unilateral 6-OHDA lesion rat. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Feb 2015 · Neurobiology of Disease
  • John C Rothwell · José A Obeso

    No preview · Article · Feb 2015 · Brain
  • Jose A Obeso

    No preview · Article · Feb 2015 · Movement Disorders
  • C. Warren Olanow · Jose A. Obeso
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    ABSTRACT: DBS of the STN improves quality of life (QoL) and motor function not only in advanced Parkinson's disease (PD), but also in PD with early motor complications, as shown in the recent EARLYSTIM study. In spite of the evidence in favor of STN-DBS, the findings of the EARLYSTIM study have recently been controversially debated. Here, we argue that a placebo or lessebo effect is unlikely to have relevantly contributed to the favorable outcome of STN-DBS in the EARLYSTIM study. The method of quantification of the placebo effect of DBS in a previous publication reveals flaws leading to implausible results, and therefore the placebo effect of DBS remains currently elusive, especially because blinding of PD patients with STN-DBS as a crucial preassumption for assessing a placebo effect is practically impossible. Moreover, we claim that the extent of such a placebo effect is most likely very small. Specific challenges of STN-DBS at an earlier stage of PD and inclusion criteria are the risk of inclusion of patients who later evolve to atypical parkinsonism, the risk of a floor effect for the benefit from DBS, the need for experienced multidisciplinary care including prevention of suicidal behavior, and the need for highly qualified long-term follow-up. The EARLYSTIM study has shown that STN-DBS may be proposed earlier on in the course of PD, as soon as motor complications start to cause relevant disability despite proper medical management. This can lead to a gain of several years of improved QoL. (C) 2014 International Parkinson and Movement Disorder Society
    No preview · Article · Dec 2014 · Movement Disorders
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    ABSTRACT: Background: Dementia and mild cognitive impairment (MCI) are frequent in Parkinson's disease (PD). Deficits in some cognitive tests are considered risk factors for dementia in PD. However, how cognitive deficits progress in aged and long-lasting non-demented PD is not known. Objective: To study the rate and pattern of progression of cognitive deficits in aged and long-lasting non-demented PD. Methods: Forty-nine non-demented patients (23 cognitively normal (PD-CN) and 26 with MCI (PD-MCI)) were studied over 31 months using individual tests and z-scores covering five cognitive domains. All patients were at least 60 year old and have had PD ≥ 10 years. Results: Attention, executive function and memory worsened in 5 PD-CN patients who progressed to MCI (21.7% of the sample) and in 1 patient who became demented (4.3% of the sample). Eleven PD-MCI patients who developed dementia (42.3% of the sample) showed aggravation of visuospatial, executive and attention domains. Multidomain-MCI and poor execution of Stroop-Words, copy of intersecting pentagons and Raven Progressive Matrices tests were associated with conversion to dementia. Conclusions: This pilot study shows that in long-lasting PD 21.7% of PD-CN patients progress to MCI and 42.3% of PD-MCI progress to dementia over a 31 months observation period. The transition from cognitively normal to MCI is featured by attention, executive and memory dysfunction and the evolution from MCI to dementia is marked by the appearance of visuospatial deficits and worsening of attention and executive function. These data are compatible with the concept that cognitive decline in PD follows a distinct dysfunction pattern with progressive anterior to posterior cortical involvement.
    Full-text · Article · Sep 2014 · Journal of Parkinson's Disease
  • David G. Standaert · C. Warren Olanow · José A. Obeso

    No preview · Article · Sep 2014 · Movement Disorders
  • C. Warren Olanow · Jose A. Obeso

    No preview · Article · Aug 2014 · Movement Disorders
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    ABSTRACT: The pathophysiological process underlying cognitive decline in Parkinson's disease is not well understood. Cerebral atrophy and hypometabolism have been described in patients with Parkinson's disease and dementia or mild cognitive impairment with respect to control subjects. However, the exact relationships between atrophy and hypometabolism are still unclear. To determine the extension and topographical distribution of hypometabolism and atrophy in the different cognitive states of Parkinson's disease, we examined 46 patients with Parkinson's disease (19 female, 27 male; 71.7 ± 5.9 years old; 14.6 ± 4.2 years of disease evolution; modified Hoehn and Yahr mean stage 3.1 ± 0.7). Cognitive status was diagnosed as normal in 14 patients, as mild cognitive impairment in 17 and as dementia in 15 patients. Nineteen normal subjects (eight female, 11 male; 68.1 ± 3.2 years old) were included as controls. 18F-fluorodeoxyglucose positron emission tomography and magnetic resonance imaging scans were obtained, co-registered, corrected for partial volume effect and spatially normalized to the Montreal Neurological Institute space in each subject. Smoothing was applied to the positron emission tomography and magnetic resonance imaging scans to equalize their effective smoothness and resolution (10 mm and 12 mm full-width at half-maximum and Gaussian kernel, respectively). Z-score maps for atrophy and for hypometabolism were obtained by comparing individual images to the data set of control subjects. For each group of patients, a paired Student's t-test was performed to statistically compare the two Z-map modalities (P < 0.05 false discovery rate corrected) using the direct voxel-based comparison technique. In patients with mild cognitive impairment, hypometabolism exceeded atrophy in the angular gyrus, occipital, orbital and anterior frontal lobes. In patients with dementia, the hypometabolic areas observed in the group with mild cognitive impairment were replaced by areas of atrophy, which were surrounded by extensive zones of hypometabolism. Areas where atrophy was more extended than hypometabolism were found in the precentral and supplementary motor areas in both patients with mild cognitive impairment and with dementia, and in the hippocampus and temporal lobe in patients with dementia. These findings suggest that there is a gradient of severity in cortical changes associated with the development of cognitive impairment in Parkinson's disease in which hypometabolism and atrophy represent consecutive stages of the same process in most of the cortical regions affected.
    Full-text · Article · Jul 2014 · Brain
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    ABSTRACT: The basal ganglia were originally thought to be associated purely with motor control. However, dysfunction and pathology of different regions and circuits are now known to give rise to many clinical manifestations beyond the association of basal ganglia dysfunction with movement disorders. Moreover, disorders that were thought to be caused by dysfunction of the basal ganglia only, such as Parkinson's disease and Huntington's disease, have diverse abnormalities distributed not only in the brain but also in the peripheral and autonomic nervous systems; this knowledge poses new questions and challenges. We discuss advances and the unanswered questions, and ways in which progress might be made.
    No preview · Article · Jun 2014 · The Lancet

Publication Stats

6k Citations
1,113.94 Total Impact Points


  • 2015
    • University Foundation San Pablo CEU
      Madrid, Madrid, Spain
  • 2011-2015
    • Instituto de Salud Carlos III
      Madrid, Madrid, Spain
    • Universidad de Extremadura
      Ara Pacis Augustalis, Extremadura, Spain
    • Centre Hospitalier Universitaire de Bordeaux
      • Centre de référence de l’atrophie multi systématisée
      Burdeos, Aquitaine, France
  • 1990-2015
    • Universidad de Navarra
      • • Center for Applied Medical Research (CIMA)
      • • Division of Neurosciences
      • • Department of Neurology and Neurosurgery
      • • Department of Nephrology
      Iruña, Navarre, Spain
  • 2010-2014
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 1989-2009
    • Universidad de Pamplona
      Памплона, Norte de Santander, Colombia
  • 2006
    • Mount Sinai School of Medicine
      • Department of Neurology
      Manhattan, NY, United States
  • 1997
    • Oregon Health and Science University
      • Department of Neurology
      Portland, Oregon, United States