Jose A Obeso

University Foundation San Pablo CEU, Madrid, Madrid, Spain

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Publications (151)1092.13 Total impact

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    Marjan Jahanshahi · Ignacio Obeso · John C Rothwell · José A Obeso ·
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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.
    Nature Reviews Neuroscience 11/2015; DOI:10.1038/nrn4038 · 31.43 Impact Factor
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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.
    Journal of Medical Systems 11/2015; 39(11). DOI:10.1007/s10916-015-0348-6 · 2.21 Impact Factor
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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
    Frontiers in Neuroanatomy 10/2015; 9(125). DOI:10.3389/fnana.2015.00125 · 3.54 Impact Factor
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    Ledia F Hernández · Peter Redgrave · José A Obeso ·

    Frontiers in Neuroanatomy 08/2015; 9:99. DOI:10.3389/fnana.2015.00099 · 3.54 Impact Factor
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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.
    Frontiers in Cellular Neuroscience 07/2015; 9:245. DOI:10.3389/fncel.2015.00245 · 4.29 Impact Factor
  • Jorge Guridi · Jose A Obeso ·

    Journal of Neurosurgery 02/2015; 122(4):1-2. DOI:10.3171/2014.8.JNS141799 · 3.74 Impact Factor
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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.
    Neurobiology of Disease 02/2015; 77. DOI:10.1016/j.nbd.2015.01.007 · 5.08 Impact Factor
  • John C Rothwell · José A Obeso ·

    Brain 02/2015; 138(Pt 2):242-4. DOI:10.1093/brain/awu365 · 9.20 Impact Factor
  • Jose A Obeso ·

    Movement Disorders 02/2015; 30(2):167-8. DOI:10.1002/mds.26155 · 5.68 Impact Factor
  • C. Warren Olanow · Jose A. Obeso ·

    Movement Disorders 12/2014; 29(14). DOI:10.1002/mds.26106 · 5.68 Impact Factor
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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.
    Journal of Parkinson's Disease 09/2014; 4(4). DOI:10.3233/JPD-140398 · 1.91 Impact Factor
  • David G. Standaert · C. Warren Olanow · José A. Obeso ·

    Movement Disorders 09/2014; 29(10). DOI:10.1002/mds.26015 · 5.68 Impact Factor
  • C. Warren Olanow · Jose A. Obeso ·

    Movement Disorders 08/2014; 29(9). DOI:10.1002/mds.26002 · 5.68 Impact Factor
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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.
    Brain 07/2014; DOI:10.1093/brain/awu159 · 9.20 Impact Factor
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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.
    The Lancet 06/2014; 384(9942). DOI:10.1016/S0140-6736(13)62418-6 · 45.22 Impact Factor
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    ABSTRACT: The cause of degeneration of nigrostriatal dopamine (DA) neurons in idiopathic Parkinson's disease (PD) is still unknown. Intraneuro-nally, DA is largely confined to synaptic vesicles where it is protected from metabolic breakdown. In the cytoplasm, however, free DA can give rise to formation of cytotoxic free radicals. Normally, the concentration of cytoplasmic DA is kept at a minimum by continuous pumping activity of the vesicular monoamine transporter (VMAT)2. Defects in handling of cytosolic DA by VMAT2 increase levels of DA-generated oxy radicals ultimately resulting in degeneration of DAergic neurons. Here, we isolated for the first time, DA storage vesicles from the striatum of six autopsied brains of PD patients and four controls and measured several indices of vesicular DA storage mechanisms. We found that (1) vesicular uptake of DA and binding of the VMAT2-selective label [ 3 H]dihydrotetrabenazine were profoundly reduced in PD by 87–90% and 71– 80%, respectively; (2) after correcting for DA nerve terminal loss, DA uptake per VMAT2 transport site was significantly reduced in PD caudate and putamen by 53 and 55%, respectively; (3) the VMAT2 transport defect appeared specific for PD as it was not present in Macaca fascicularis (7 MPTP and 8 controls) with similar degree of MPTP-induced nigrostriatal neurodegeneration; and (4) DA efflux studies and measurements of acidification in the vesicular preparations suggest that the DA storage impairment was localized at the VMAT2 protein itself. We propose that this VMAT2 defect may be an early abnormality promoting mechanisms leading to nigrostriatal DA neuron death in PD.
    The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 06/2014; 34(24):8210-8218. DOI:10.1523/JNEUROSCI.5456-13.2014 · 6.34 Impact Factor
  • Susanne A Schneider · Jose A Obeso ·
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    ABSTRACT: Parkinson's diseaseParkinson's disease (PD) is, after Alzheimer's disease, the second most common neurodegenerative disorder with an approximate prevalence of 0.5-1 % among persons 65-69 years of age, rising to 1-3 % among persons 80 years of age and older. Pathologically, PD is characterized by the loss of neurons in the substantia nigra pars compacta (SNpc), and by the presence of eosinophilic protein deposits (Lewy bodiesLewy bodies ) in this region, in other aminergic nuclei and in cortical and limbic structures. Moreover, it has now been shown that pathologypathology also involves the peripheral nervous system. Braak and colleagues suggested a thread of pathology starting from the vagal nerve to progress to the brainstem, and eventually to limbic and neocortical brain regions. This progression of pathology may account for the clinical evolution of PD toward a composite symptomatology. However, this hypothesis has been criticized by others. In this chapter, we review the clinical features of PD (motormotor and nonmotornonmotor ) and their pathological correlatespathological correlates .
    Current Topics in Behavioral Neurosciences 05/2014; 22. DOI:10.1007/7854_2014_317
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    ABSTRACT: The aim of our study was to investigate two inter-related hypotheses about the role of the subthalamic nucleus. First that the subthalamic nucleus plays a role in adjusting response thresholds and speed-accuracy trade-offs and second that it is involved in reactive and proactive inhibition and conflict resolution. These were addressed by comparing the performance of 10 patients with Parkinson's disease treated with right subthalamotomy and 12 patients with left subthalamotomy, to 14 unoperated patients with Parkinson's disease and 23 age-matched healthy control participants on a conditional stop signal task and applying the drift diffusion model. Unilateral subthalamotomy significantly improved Parkinson's disease motor signs. Patients with right subthalamotomy had significantly faster Go reaction times with their contra-lesional hand than the unoperated patients and did not differ from the control participants, indicating their speed of response initiation was 'normalized'. However, operated patients made significantly more discrimination errors than unoperated patients and controls, suggesting that subthalamotomy influenced speed-accuracy trade-offs. This was confirmed by the drift diffusion model, revealing that while the unoperated patients had significantly lower drift rate and higher response thresholds than the control participants, the response thresholds for the operated groups did not differ from the controls and the patients with right subthalamotomy had a significantly higher drift rate than unoperated patients and similar to that of controls. The drift diffusion model further established that unlike the control participants, operated patients failed to show context-dependent strategic modulation of response thresholds. The patients with right subthalamotomy could not engage in late phase, fast inhibition of the response and showed minimal proactive inhibition when tested with the contra-lesional hand. These results provide strong evidence that the subthalamic nucleus is involved in response inhibition, in modulating the rate of information accumulation and the response threshold and influencing the balance between speed and accuracy of performance. Accordingly, the subthalamic nucleus can be considered a key component of the cerebral inhibitory network.
    Brain 03/2014; 137(5). DOI:10.1093/brain/awu058 · 9.20 Impact Factor
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    ABSTRACT: Objective: Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. Methods: Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. Results: In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. Interpretation: α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.
    Annals of Neurology 03/2014; 75(3). DOI:10.1002/ana.24066 · 9.98 Impact Factor
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    C Warren Olanow · Jose A Obeso ·

    Movement Disorders 01/2014; 29(1):1-2. DOI:10.1002/mds.25812 · 5.68 Impact Factor

Publication Stats

6k Citations
1,092.13 Total Impact Points


  • 2015
    • University Foundation San Pablo CEU
      Madrid, Madrid, Spain
  • 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
  • 1989-2015
    • Universidad de Pamplona
      Памплона, Norte de Santander, Colombia
  • 2014
    • Hospital Sanitas CIMA
      Barcino, Catalonia, Spain
  • 1992-2014
    • Clínica Universidad de Navarra
      Madrid, Madrid, Spain
  • 2011-2013
    • 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
  • 2006
    • Mount Sinai School of Medicine
      • Department of Neurology
      Manhattan, NY, United States
  • 2003
    • Emory University
      Atlanta, Georgia, United States
  • 1997
    • Oregon Health and Science University
      • Department of Neurology
      Portland, Oregon, United States