[Show abstract][Hide abstract] 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; · 1.10 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
Journal of Neuroscience 06/2014; 34(24):8210-8218. · 6.91 Impact Factor
[Show abstract][Hide abstract] 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;
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: Parkinson´s disease (PD) is characterized by nigro-striatal loss and dopaminergic striatal depletion. The aim of this work is to characterize in-vivo a time-course pattern of functional changes associated with dopaminergic striatal reduction in rat models of PD using Positron Emission Tomography (PET). Forty-four male Sprague-Dawley rats (300-350gr) were used. PET imaging with monoaminergic (11C-(+)-α-dihydrotetrabenazine; 11C-DTBZ) and metabolic (18F-fluorodeoxyglucose; 18F-FDG) radiotracers were performed in a longitudinal study during 6 weeks of the following groups: a) unilaterally lesioned rats by injection of 4µg/4µl (low dose) and 8µg/4µl (high dose) of 6-hydroxydopamine (6-OHDA) in the left median forebrain bundle; and b) bilateral lesion model, in rats receiving intraventricular injection of 100µg/4µl/day of 6-OHDA during 7 days. At the 8th week, the glucose metabolism was also evaluated ex vivo by 18F-FDG autoradiography. Bilaterally lesioned animals were not assessed with metabolic analyses. 11C-DTBZ PET images showed a significant decrease of Striatal Binding (SB) values one week after the lesion (35% SB in the low and 20% SB in the high dose group of unilateral model, and 50% SB in the bilateral model). In the 6th week, no significant differences in these values were found in the unilaterally lesion rats, whereas animals with bilateral lesion showed a higher binding value (65% SB). Remarkably, the metabolic PET study in the unilateral model revealed hypometabolism in ipsilateral somatosensory cortex and hypermetabolism in contralateral entorhinal cortex since the 2nd week onwards. Additionally, the autoradiography analysis showed hypometabolism in bilateral somatosensory cortex and ipsilateral caudate-putamen, motor cortex and thalamus, and also hypermetabolism in the contralateral entorhinal cortex. 11C-DTBZ PET is a sensitive method to ascertain dopaminergic depletion in both the bilateral and, unilateral 6-OHDA rat models. 18F-FDG studies showed a dynamic metabolic pattern that can provide useful in vivo information to monitor brain changes.
15º Congreso Nacional de la Sociedad Española de NeuroCiencia (SENC), Oviedo; 09/2013
[Show abstract][Hide abstract] ABSTRACT: Introduction
To study the localization of the beta activity in the subthalamic nucleus (STN) and of the contacts of the implanted electrodes for chronic stimulation providing the highest benefit (active contacts) in patients with Parkinson’s disease (PD).
We recorded local field potentials in the STN through the surgically implanted electrodes in 30 PD patients during the "off" and "on" dopaminergic states. The position of the contacts of the electrodes was studied using the pre and post-operative MRI where the contacts were referenced to the midpoint of the intercommisural line. The anatomical position of each contact was obtained from a Morel’s based three-dimensional atlas for the STN (divided into functional regions) and the surrounded anatomical areas. Only electrodes programmed in monopolar where selected for the study being the catodes of these electrodes considered as the active contacts. The position of the contact of the electrode where the phase reversal of the recording of the beta activity was obtained was considered as the position where the beta band was generated.
All patients displayed a low beta activity (mean 15.33 Hz) in OFF and a high beta activity (mean 26.22 Hz) in OFF and ON. There were no differences between the topography of the active contacts (X:10.86±1.62; Y:-1.01±1.92; Z:-1.63±1.44) and the position where the generators of the low and high beta activity were recorded: low beta OFF (X:10.45±1.66; Y:-1.45±1.77; Z:-2.19±1.81); high beta OFF (X:10.80±1.56; Y:-1.57±1.77; Z:-2.27±1.35); high beta ON (X:10.81±1.51; Y:-1.53±1.86; Z:-2.44±1.32). Active contacts and oscillatory activity generators in the beta band were located in the rostral portion of the motor region of the STN.
The rostral portion of the motor region of the STN is the region where DBS of the STN provides maximal antiparkinsonian benefit coinciding with the position where the beta activity is generated in the STN.
[Show abstract][Hide abstract] ABSTRACT: Recent findings question our present understanding of Parkinson's disease and suggest that new research criteria for the diagnosis of Parkinson's disease are needed, similar to those recently defined in Alzheimer's disease. However, our ability to redefine Parkinson's disease is hampered by its complexity and heterogeneity in genetics, phenotypes, and underlying molecular mechanisms; the absence of biochemical markers or ability to image Parkinson's disease-specific histopathological changes; the long prodromal period during which non-motor manifestations might precede classic motor manifestations; and uncertainty about the status of disorders diagnosed clinically as Parkinson's disease but without Lewy pathology. Although it is too early to confidently redefine Parkinson's disease, the time has come to establish a research framework that could lead to new diagnostic criteria. We propose the establishment of three tiers encompassing clinical features, pathological findings, and genetics or molecular mechanisms. Specific advances in each tier, bridged by neuroimaging and biochemical data, will eventually lead to a redefinition of Parkinson's disease.
The Lancet Neurology 04/2013; · 23.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: It has been proposed that the subthalamic nucleus (STN) mediates response inhibition and conflict resolution through the fronto-basal ganglia pathways. Our aim was to compare the effects of deep brain stimulation (DBS) of the STN on reactive and proactive inhibition and conflict resolution in Parkinson's disease using a single task. We used the conditional Stop signal reaction time task that provides the Stop signal reaction time (SSRT) as a measure of reactive inhibition, the response delay effect (RDE) as a measure of proactive inhibition and conflict-induced slowing (CIS) as a measure of conflict resolution. DBS of the STN significantly prolonged SSRT relative to stimulation off. However, while the RDE measure of proactive inhibition was not significantly altered by DBS of the STN, relative to healthy controls, RDE was significantly lower with DBS off but not DBS on. DBS of the STN did not alter the mean CIS but produced a significant differential effect on the slowest and fastest RTs on conflict trials, further prolonging the slowest RTs on the conflict trials relative to DBS off and to controls. These results are the first demonstration, using a single task in the same patient sample, that DBS of the STN produces differential effects on reactive and proactive inhibition and on conflict resolution, suggesting that these effects are likely to be mediated through the impact of STN stimulation on different fronto-basal ganglia pathways: hyperdirect, direct and indirect.
Experimental Brain Research 03/2013; · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: Deep brain stimulation of the subthalamic nucleus (STN-DBS) reduces motor fluctuations in Parkinson's disease (PD) but its effect on non-motor fluctuations (NMF) is not well known. In this study we assess the efficacy of STN-DBS on NMF two years after surgery. METHODS: Autonomic, cognitive, psychiatric and sensory NMF in 20 patients were evaluated using a questionnaire designed to assess the frequency and severity of the NMF preoperatively and after two years of follow-up. The UPDRS scale was used for assessing the motor state. RESULTS: Compared with the preoperative situation, STN-DBS at 2 years of follow-up was associated with a significant reduction in the number and severity of autonomic and psychiatric NMF in the "off" state (without medication), and in the severity of sensory NMF, which were not observed in the "on" state (with medication). A cross-sectional analysis at the two-year time-point of the four possible motor conditions (combining medication and stimulation) showed a reduction in the total number of NMF and in the severity of autonomic and sensory NMF after switching on the stimulation in the "on" state. Improvement of the UPDRS-motor score was correlated with a reduction in the severity but not in the frequency of NMF. A worsening of motor function after suppressing stimulation in the "off" state was not paralleled by a worsening of NMF. CONCLUSION: After two years of follow-up, STN-DBS in the "off" medication was associated with a reduction in the frequency and severity of NMF. These results will need to be confirmed in controlled studies.
Parkinsonism & Related Disorders 02/2013; · 3.27 Impact Factor