Revistas
Revista:
NEUROBIOLOGY OF DISEASE
ISSN:
0969-9961
Año:
2022
Vol.:
167
Págs.:
105669
Dopaminergic denervation in patients with Parkinson's disease is associated with changes in brain metabolism. Cerebral in-vivo mapping of glucose metabolism has been studied in severe stable parkinsonian monkeys, but data on brain metabolic changes in early stages of dopaminergic depletion of this model is lacking. Here, we report cerebral metabolic changes associated with progressive nigrostriatal lesion in the pre-symptomatic and symptomatic stages of the progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of Parkinson's Disease. Monkeys (Macaca fascicularis) received MPTP injections biweekly to induce progressive grades of dopamine depletion. Monkeys were sorted according to motor scale assessments in control, asymptomatic, recovered, mild, and severe parkinsonian groups. Dopaminergic depletion in the striatum and cerebral metabolic patterns across groups were studied in vivo by positron emission tomography (PET) using monoaminergic ([11C]-dihydrotetrabenazine; 11C-DTBZ) and metabolic (2-[18F]-fluoro-2-deoxy-d-glucose; 18F-FDG) radiotracers. 11C-DTBZ-PET analysis showed progressive decrease of binding potential values in the striatum of monkeys throughout MPTP administration and the development of parkinsonian signs. 18F-FDG analysis in asymptomatic and recovered animals showed significant hypometabolism in temporal and parietal areas of the cerebral cortex in association with moderate dopaminergic nigrostriatal depletion. Cortical hypometabolism extended to involve a larger area in mild parkinsonian monkeys, which also exhibited hypermetabolism in the globus pallidum pars interna and cerebellum. In severe parkinsonian monkeys, cortical hypometabolism extended further to lateral-frontal cortices and hypermetabolism also ensued in the thalamus and cerebellum. Unbiased histological quantification of neurons in Brodmann's area 7 in the parietal cortex did not reveal neuron loss in parkinsonian monkeys versus controls. Early dopaminergic nigrostriatal depletion is associated with cortical, mainly temporo-parietal hypometabolism unrelated to neuron loss. These findings, together with recent evidence from Parkinson's Disease patients, suggest that early cortical hypometabolism may be associated and driven by subcortical changes that need to be evaluated appropriately. Altogether, these findings could be relevant when potential disease modifying therapies become available.
Autores:
Dileone, M.; Ammann, C.; Catanzaro, V.; et al.
Revista:
BRAIN STIMULATION
ISSN:
1935-861X
Año:
2022
Vol.:
15
N°:
3
Págs.:
857 - 860
Autores:
Basaia, S.; Agosta, F.; Diez, I.; et al.
Revista:
NEUROIMAGE. CLINICAL
ISSN:
2213-1582
Año:
2022
Vol.:
33
Págs.:
102941
The genetic traits that underlie vulnerability to neuronal damage across specific brain circuits in Parkinson's disease (PD) remain to be elucidated. In this study, we characterized the brain topological intersection between propagating connectivity networks in controls and PD participants and gene expression patterns across the human cortex - such as the SNCA gene. We observed that brain connectivity originated from PD-related pathology epicenters in the brainstem recapitulated the anatomical distribution of alpha-synuclein histopathology in postmortem data. We also discovered that the gene set most related to cortical propagation patterns of PDrelated pathology was primarily involved in microtubule cellular components. Thus, this study sheds light on new avenues for enhancing detection of PD neuronal vulnerability via an evaluation of in vivo connectivity trajectories across the human brain and successful integration of neuroimaging-genetic strategies.
Revista:
BRAIN
ISSN:
0006-8950
Año:
2022
Vol.:
145
N°:
6
Págs.:
2092 - 2107
Synaptic impairment might precede neuronal degeneration in Parkinson's disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic alpha-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53T alpha-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. Sequential window acquisition of all theoretical mass spectra proteomics identified deregulated proteins involved first in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when alpha-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics was followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres was evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolved. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated postsynaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells to delay or prevent the development of Parkinson's disease.
Revista:
MOVEMENT DISORDERS CLINICAL PRACTICE
ISSN:
2330-1619
Año:
2021
Vol.:
8
N°:
5
Págs.:
701 - 708
Background During magnetic resonance-guided focused ultrasound for essential or parkinsonian tremor, adverse events (headache, nausea/vomiting, or anxiety) may alter the outcome of the procedure despite being mostly transient and mild. Objectives Our aim was to analyze the relationship between demographic, procedural, and anesthetic characteristics with magnetic resonance/ultrasound-related events. Methods This was a retrospective study at the Clinica Universidad de Navarra of patients undergoing thalamotomy with magnetic resonance-guided focused ultrasound between September 2018 and October 2019. The anesthesia protocol included headache and nausea/vomiting prophylaxis and rescue therapy. Dexmedetomidine was used for anxiolysis in some patients after thorough multidisciplinary assessment. Results A total of 123 patients were included. Headache was directly related to skull density ratio (P < 0.001) and skull thickness (P = 0.02). Patients with a skull density ratio less than 0.48 had 3 times the odds of experiencing moderate or severe headache (odds ratio [OR], 3.08; 95% confidence interval [CI], 1.21-7.82) and had a higher odds of aborting sonication due to pain. Sex was associated with increased nausea (P = 0.007). Women had 4 times the odds of nausea than men (OR, 4.4; 95% CI, 1.61-12.11). Dexmedetomidine did not reduce headache or nausea incidence. Patients who received dexmedetomidine had a higher number (P = 0.01) and total minutes of sonication (P = 0.01). Conclusions Patients with lower skull density ratios and higher skull thicknesses could benefit from an aggressive analgesic prophylaxis. Women are more likely to experience nausea. Dexmedetomidine did not reduce headache and nausea, but increased the number and duration of sonications. Its exact effect on tremor is still unclear.
Autores:
Esteban-Peñalba, T.; Paz-Alonso, P. M.; Navalpotro-Gómez, I.; et al.
Revista:
NEUROIMAGE. CLINICAL
ISSN:
2213-1582
Año:
2021
Vol.:
32
Págs.:
102822
Impulse control disorder is a prevalent side-effect of Parkinson's disease (PD) medication, with a strong negative impact on the quality of life of those affected. Although impulsivity has classically been associated with response inhibition deficits, previous evidence from PD patients with impulse control disorder (ICD) has not revealed behavioral dysfunction in response inhibition. In this study, 18 PD patients with ICD, 17 PD patients without this complication, and 15 healthy controls performed a version of the conditional Stop Signal Task during functional magnetic resonance imaging. Whole-brain contrasts, regions of interest, and functional connectivity analyses were conducted. Our aim was to investigate the neural underpinnings of two aspects of response inhibition: proactive inhibition, inhibition that has been prepared beforehand, and restrained inhibition, inhibition of an invalid inhibitory tendency. We observed that, in respect to the other two groups, PD patients with ICD exhibited hyperactivation of the stopping network bilaterally while performing proactive inhibition. When engaged in restrained inhibition, they showed hyperactivation of the left inferior frontal gyrus, an area linked to action monitoring. Restrained inhibition also resulted in changes to the functional co-activation between inhibitory regions and left inferior parietal cortex and right supramarginal gyrus. Our findings indicate that PD patients with ICD completed the inhibition task correctly, showing altered engagement of inhibitory and attentional areas. During proactive inhibition they showed bilateral hyperactivation of two inhibitory regions, while during restrained inhibition they showed additional involvement of attentional areas responsible for alerting and orienting.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2021
Vol.:
36
N°:
4
Págs.:
796 - 799
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2021
Vol.:
36
N°:
1
Págs.:
83
Autores:
Meles, S. K.; Renken, R. J.; Pagani, M.; et al.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2020
Vol.:
47
N°:
2
Págs.:
437 - 450
Rationale In Parkinson's disease (PD), spatial covariance analysis of F-18-FDG PET data has consistently revealed a characteristic PD-related brain pattern (PDRP). By quantifying PDRP expression on a scan-by-scan basis, this technique allows objective assessment of disease activity in individual subjects. We provide a further validation of the PDRP by applying spatial covariance analysis to PD cohorts from the Netherlands (NL), Italy (IT), and Spain (SP). Methods The PDRPNL was previously identified (17 controls, 19 PD) and its expression was determined in 19 healthy controls and 20 PD patients from the Netherlands. The PDRPIT was identified in 20 controls and 20 "de-novo" PD patients from an Italian cohort. A further 24 controls and 18 "de-novo" Italian patients were used for validation. The PDRPSP was identified in 19 controls and 19 PD patients from a Spanish cohort with late-stage PD. Thirty Spanish PD patients were used for validation. Patterns of the three centers were visually compared and then cross-validated. Furthermore, PDRP expression was determined in 8 patients with multiple system atrophy. Results A PDRP could be identified in each cohort. Each PDRP was characterized by relative hypermetabolism in the thalamus, putamen/pallidum, pons, cerebellum, and motor cortex. These changes co-varied with variable degrees of hypometabolism in posterior parietal, occipital, and frontal cortices. Frontal hypometabolism was less pronounced in "de-novo" PD subjects (Italian cohort). Occipital hypometabolism was more pronounced in late-stage PD subjects (Spanish cohort). PDRPIT, PDRPNL, and PDRPSP were significantly expressed in PD patients compared with controls in validation cohorts from the same center (P < 0.0001), and maintained significance on cross-validation (P < 0.005). PDRP expression was absent in MSA. Conclusion The PDRP is a reproducible disease characteristic across PD populations and scanning platforms globally. Further study is needed to identify the topography of specific PD subtypes, and to identify and correct for center-specific effects.
Autores:
van Veen, R. (Autor de correspondencia); Gurvits, V.; Kogan, R. V.; et al.
Revista:
COMPUTER METHODS AND PROGRAMS IN BIOMEDICINE
ISSN:
0169-2607
Año:
2020
Vol.:
197
Págs.:
105708
Background and objective: Neurodegenerative diseases like Parkinson's disease often take several years before they can be diagnosed reliably based on clinical grounds. Imaging techniques such as MRI are used to detect anatomical (structural) pathological changes. However, these kinds of changes are usually seen only late in the development. The measurement of functional brain activity by means of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can provide useful information, but its interpretation is more difficult. The scaled sub-profile model principal component analysis (SSM/PCA) was shown to provide more useful information than other statistical techniques. Our objective is to improve the performance further by combining SSM/PCA and prototype-based generalized matrix learning vector quantization (GMLVQ).
Methods: We apply a combination of SSM/PCA and GMLVQ as a classifier. In order to demonstrate the combination's validity, we analyze FDG-PET data of Parkinson's disease (PD) patients collected at three different neuroimaging centers in Europe. We determine the diagnostic performance by performing a ten times repeated ten fold cross validation. Additionally, discriminant visualizations of the data are included. The prototypes and relevance of GMLVQ are transformed back to the original voxel space by exploiting the linearity of SSM/PCA. The resulting prototypes and relevance profiles have then been assessed by three neurologists.
Results: One important finding is that discriminative visualization can help to identify disease-related properties as well as differences which are due to center-specific factors. Secondly, the neurologist assessed the interpretability of the method and confirmed that prototypes are similar to known activity profiles of PD patients.
Conclusion: We have shown that the presented combination of SSM/PCA and GMLVQ can provide useful means to assess and better understand characteristic differences in FDG-PET data from PD patients and HCs. Based on the assessments by medical experts and the results of our computational analysis we conclude that the first steps towards a diagnostic support system have been taken successfully.
Keywords: Parkinson¿s disease (PD); Scaled sub-profile scaling model principal component analysis (SSM/PCA); [(18)F]Fluorodeoxyglucose positron emission tomography (FDG-PET); generalized matrix learning vector quantization (GMLVQ).
Autores:
Navalpotro-Gómez, I.; Kim, J. ; Paz-Alonso, P. M.; et al.
Revista:
PARKINSONISM AND RELATED DISORDERS
ISSN:
1353-8020
Año:
2020
Vol.:
70
Págs.:
74 - 81
Background: Dynamic functional network analysis may add relevant information about the temporal nature of the neurocognitive alterations in PD patients with impulse control disorders (PD-ICD). Our aim was to investigate changes in dynamic functional network connectivity (dFNC) in PD-ICD patients, and topological properties of such networks. Methods: Resting state fMRI was performed on 16 PD PD-ICD patients, 20 PD patients without ICD and 17 healthy controls, whose demographic, clinical and behavioral scores were assessed. We conducted a group spatial independent component analysis, sliding window and graph-theory analyses. Results: PD-ICD patients, in contrast to PD-noICD and HC subjects, were engaged across time in a brain configuration pattern characterized by a lack of between-network connections at the expense of strong within-network connections (State III) in temporal, frontoinsular and cingulate cortices, all key nodes of the salience network. Moreover, this increased maintenance of State III in PD-ICD patients was positively correlated with the severity of impulsivity and novelty seeking as measured by specific scales. While in State III, these patients also exhibited increased local efficiency in all the aforementioned areas. Conclusions: Our findings show for the first time that PD-ICD patients have a dynamic functional engagement of local connectivity involving the limbic circuit, leading to the inefficient modulation in emotional processing and reward-related decision-making. These results provide new insights into the pathophysiology of ICD in PD padents and indicate that the dFC study of fMRI could be a useful biomarker to identify patients at risk to develop ICD.
Autores:
Pagonabarraga, J. (Autor de correspondencia); Arbelo, J. M.; Grandas, F. ; et al.
Revista:
BRAIN SCIENCES
ISSN:
2076-3425
Año:
2020
Vol.:
10
N°:
5
Págs.:
313
Autores:
Paz-Alonso, P. M. (Autor de correspondencia); Navalpotro-Gomez, I. ; Boddy, P.; et al.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2020
Vol.:
35
N°:
2
Págs.:
316 - 325
BACKGROUND:
Impulse control disorders related to alterations in the mesocorticolimbic dopamine network occur in Parkinson's disease (PD). Our objective was to investigate the functional neural substrates of reward processing and inhibitory control in these patients.
METHODS:
Eighteen PD patients with impulse control disorders, 17 without this complication, and 18 healthy controls performed a version of the Iowa Gambling Task during functional magnetic resonance scanning under 3 conditions: positive, negative, and mixed feedback. Whole-brain contrasts, regions of interest, time courses, functional connectivity analyses, and brain-behavior associations were examined.
RESULTS:
PD patients with impulse control disorders exhibited hyperactivation in subcortical and cortical regions typically associated with reward processing and inhibitory control compared with their PD and healthy control counterparts. Time-course analyses revealed that only PD patients with impulse control disorders exhibited stronger signal intensity during the initial versus final periods of the negative-feedback condition in bilateral insula, and right ventral striatum. Interestingly, hyperactivation of all the examined right-lateralized frontostriatal areas during negative feedback was positively associated with impulse control disorder severity. Importantly, positive associations between impulse control disorder severity and regional activations in the right insula and right inferior frontal gyrus, but not the right subthalamic nucleus, were mediated by functional connectivity with the right ventral striatum.
CONCLUSIONS:
During a reward-based task, PD patients with impulse control disorders showed hyperactivation in a right-lateralized network of regions including the subthalamic nucleus that was strongly associated with impulse control disorder severity. In these patients, the right ventral striatum in particular played a critical role in modulating the functional dynamics of right-lateralized inhibitory-control frontal regions when facing penalties. © 2019 International Parkinson and Movement Disorder Society.
Revista:
PSYCHOPHARMACOLOGY
ISSN:
0033-3158
Año:
2020
Vol.:
237
N°:
8
Págs.:
2419 - 2431
Rationale Impulse control disorders (ICD) and other impulsive-compulsive behaviours are frequently found in Parkinson's disease (PD) patients treated with dopaminergic agonists. To date, there are no available animal models to investigate their pathophysiology and determine whether they can be elicited by varying doses of dopaminergic drugs. In addition, there is some controversy regarding the predispositional pattern of striatal dopaminergic depletion. Objectives To study the effect of two doses of pramipexole (PPX) on motor impulsivity, delay intolerance and compulsive-like behaviour. Methods Male rats with mild dopaminergic denervation in the dorsolateral striatum (bilateral injections of 6-hydroxidopamine (6-OHDA)) treated with two doses of PPX (0.25 mg/kg and 3 mg/kg) and tested in the variable delay-to-signal paradigm. Results Partial (50%) dopaminergic depletion did not induce significant changes in motor impulsivity or delay intolerance. However, 0.25 mg/kg of PPX increased motor impulsivity, while 3 mg/kg of PPX increased both motor impulsivity and delay intolerance. These effects were independent of the drug's antiparkinsonian effects. Importantly, impulsivity scores before and after dopaminergic lesion were positively associated with the impulsivity observed after administering 3 mg/kg of PPX. No compulsive-like behaviour was induced by PPX administration. Conclusions We described a rat model, with a moderate dorsolateral dopaminergic lesion resembling that suffered by patients with early PD, that develops different types of impulsivity in a dose-dependent manner dissociated from motor benefits when treated with PPX. This model recapitulates key features of abnormal impulsivity in PD and may be useful for deepening our understanding of the pathophysiology of ICD.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2020
Vol.:
47
N°:
11
Págs.:
2602 - 2612
Autores:
Navalpotro-Gomez, I.; Dacosta-Aguayo, R.; Molinet-Dronda, F.; et al.
Revista:
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
ISSN:
1619-7070
Año:
2019
Vol.:
46
N°:
10
Págs.:
2065 - 2076
PurposePrevious studies in patients with Parkinson's disease (PD) and impulse control disorders (ICDs) have produced heterogeneous results regarding striatal dopamine transporter (DaT) binding and activity in the mesocorticolimbic network. Our aim here was to study the relationship between striatal DaT availability and cortical metabolism, as well as motor, behavioural and cognitive features of PD patients with ICD.MethodsIn a group of PD patients with ICD (PD-ICD, n=16) and 16 matched PD patients without ICD (PD-noICD, n=16), DaT single-photon emission computed tomography (SPECT) imaging (DaTSCAN) was used to study DaT availability in predefined striatal volumes of interest (VOIs): putamen, caudate nucleus and ventral striatum (VS). In addition, the specific association of striatal DaT binding with cortical limbic and associative metabolic activity was evaluated by F-18-fluorodeoxyglucose (FDG) positron emission tomography (PET) in PD-ICD patients and investigated using statistical parametric mapping (SPM8). Finally, associations between DaT availability and motor, behavioural and cognitive features were assessed.ResultsPD-ICD patients had a significantly lower DaT density in the VS than PD-noICD patients, which was inversely associated with ICD severity. Lower DaT availability in the VS was associated with lower FDG uptake in several cortical areas belonging to the limbic and associative circuits, and in other regions involved in reward and inhibition processes (p<0.0001 uncorrected; k>50 voxels). No significant results were observed using a higher conservative threshold (p<0.05; FDR corrected). PD-ICD patients also displayed impairment in interference and attentional Stroop Task execution, and more anxiety, all associated with reduced DaT availability in the VS and caudate nucleus.ConclusionsICDs in PD patients are related to reduced DaT binding in the VS, which accounts for dysfunction in a complex cortico-subcortical network that involves areas of the mesolimbic and mesocortical systems, being associated with reward evaluation, salience attribution and inhibitory control processes.
Revista:
BRAIN IMAGING AND BEHAVIOR
ISSN:
1931-7557
Año:
2019
Vol.:
13
N°:
1
Págs.:
180 - 188
Mild cognitive impairment (MCI) in Parkinson's disease (PD) is a risk factor for dementia and thus, it is of interest to elucidate if specific patterns of atrophy in PD-MCI patients are associated with a higher risk of developing dementia. We aim to define pattern(s) of regional atrophy in PD-MCI patients who developed dementia during 31months of follow-up using cortical thickness analysis Twenty-three PD-MCI patients and 18 controls underwent brain MRI and completed a neuropsychological examination at baseline, PD-MCI patients were followed after a 31month follow-up in order to assess their progression to dementia. At follow up, 8 PD-MCI patients had converted to dementia (PD-MCI converters) whereas 15 remained as PD-MCI (PD-MCI non-converters). All patients were at least 60years old and suffered PD10years. There were no baseline differences between the two groups of patients in clinical and neuropsychological variables. The cortex of PD-MCI converters was thinner than that of PD-MCI non-converters, bilaterally in the frontal, insula and the left middle temporal areas, also displaying a more widespread pattern of cortical thinning relative to the controls. This study shows that aged and long-term PD patients with MCI who convert to dementia in the short-mid term suffer a thinning of the cortex in several areas (frontal cortex, and middle temporal lobe and insula), even when their cognitive impairment was similar to that of PD-MCI non-converters. Thus, MRI analysis of cortical thickness may represent a useful measure to identify PD-MCI patients at a higher risk of developing dementia.
Revista:
NEUROBIOLOGY OF AGING
ISSN:
0197-4580
Año:
2019
Vol.:
75
Págs.:
126 - 135
Treatment with dopaminergic agonists such as pramipexole (PPX) contributes to the development of impulse control disorders (ICDs) in patients with Parkinson's disease (PD). As such, animal models of abnormal impulse control in PD are needed to better study the pathophysiology of these behaviors. Thus, we investigated impulsivity and related behaviors using the 5-choice serial reaction time task, as well as FosB/Delta FosB expression, in rats with mild parkinsonism induced by viral-mediated substantia nigra overexpression of human A53T mutated alpha-synuclein, and following chronic PPX treatment (0.25 mg/kg/d) for 4 weeks. The bilateral loss of striatal dopamine transporters (64%) increased the premature response rate of these rats, indicating enhanced waiting impulsivity. This behavior persisted in the OFF state after the second week of PPX treatment and it was further exacerbated in the ON state throughout the treatment period. The enhanced rate of premature responses following dopaminergic denervation was positively correlated with the premature response rate following PPX treatment (both in the ON and OFF states). Moreover, the striatal dopaminergic deficit was negatively correlated with the premature response rate at all times (pretreatment, ON and OFF states) and it was positively correlated with the striatal FosB/Delta FosB expression. By contrast, PPX treatment was not associated with changes in compulsivity (perseverative responses rate). This model recapitulates some features of PD with ICD, namely the dopaminergic deficit of early PD and the impulsivity traits provoked by dopaminergic loss in association with PPX treatment, making this model a useful tool to study the pathophysiology of ICDs. (C) 2018 Elsevier Inc. All rights reserved.
Autores:
Delgado-Alvarado, M.; Dacosta-Aguayo, R.; Navalpotro-Gomez, I.; et al.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2018
Vol.:
33
N°:
11
Págs.:
1809 - 1814
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 ss 1-42, total tau, threonine-181 phosphorylated tau, and alpha-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 ss 1-42, total tau/alpha-synuclein, total tau/amyloid ss 1-42+alpha-synuclein, and amyloid ss 1-42/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/alpha-synuclein and total tau/amyloid ss 1-42+alpha-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. (c) 2018 International Parkinson and Movement Disorder Society
Autores:
Dranca, L. ; de Mendarozketa, L. D. R.; Goñi, A.; et al.
Revista:
BMC BIOINFORMATICS
ISSN:
1471-2105
Año:
2018
Vol.:
19
N°:
1
Págs.:
471
BackgroundParkinson's Disease (PD) is a chronic neurodegenerative disease associated with motor problems such as gait impairment. Different systems based on 3D cameras, accelerometers or gyroscopes have been used in related works in order to study gait disturbances in PD. Kinect (?) has also been used to build these kinds of systems, but contradictory results have been reported: some works conclude that Kinect does not provide an accurate method of measuring gait kinematics variables, but others, on the contrary, report good accuracy results.MethodsIn this work, we have built a Kinect-based system that can distinguish between different PD stages, and have performed a clinical study with 30 patients suffering from PD belonging to three groups: early PD patients without axial impairment, more evolved PD patients with higher gait impairment but without Freezing of Gait (FoG), and patients with advanced PD and FoG. Those patients were recorded by two Kinect devices when they were walking in a hospital corridor. The datasets obtained from the Kinect were preprocessed, 115 features identified, some methods were applied to select the relevant features (correlation based feature selection, information gain, and consistency subset evaluation), and different classification methods (decision trees, Bayesian networks, neural networks and K-nearest neighbours classifiers) were evaluated with the goal of finding the most accurate method for PD stage classification.ResultsThe classifier that provided the best results is a particular case of a Bayesian Network classifier (similar to a Naive Bayesian classifier) built from a set of 7 relevant features selected by the correlation-based on feature selection method. The accuracy obtained for that classifier using 10-fold cross validation is 93.40%. The relevant features are related to left shin angles, left humerus angles, frontal and lateral bents, left forearm angles and the number of steps during spin.ConclusionsIn this paper, it is shown that using Kinect is adequate to build a inexpensive and comfortable system that classifies PD into three different stages related to FoG. Compared to the results of previous works, the obtained accuracy (93.40%) can be considered high. The relevant features for the classifier are: a) movement and position of the left arm, b) trunk position for slightly displaced walking sequences, and c) left shin angle, for straight walking sequences. However, we have obtained a better accuracy (96.23%) for a classifier that only uses features extracted from slightly displaced walking steps and spin walking steps. Finally, the obtained set of relevant features may lead to new rehabilitation therapies for PD patients with gait problems.
Revista:
JOURNAL OF NEUROSURGERY
ISSN:
0022-3085
Año:
2016
Vol.:
125
N°:
5
Págs.:
1068 - 1079
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).
Revista:
BRAIN
ISSN:
0006-8950
Año:
2014
Vol.:
137
N°:
PT 8
Págs.:
2356-7
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. (18)F-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 contro
Revista:
NEUROBIOLOGY OF DISEASE
Año:
2014
Vol.:
64
Págs.:
60 - 65
Revista:
PARKINSONISM AND RELATED DISORDERS
ISSN:
1353-8020
Año:
2013
Vol.:
19
N°:
5
Págs.:
543 - 547
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.
Revista:
EXPERIMENTAL NEUROLOGY
ISSN:
0014-4886
Año:
2013
Vol.:
239
Págs.:
1 - 12
Normal actions and behaviors often require inhibition of unwanted and inadequate movements. Motor inhibition has been studied using the stop signal task, in which participants are instructed to respond to a go signal. Sporadically, a stop signal is also delivered after a short interval following the go signal, prompting participants to inhibit their already started response to the go signal. Functional MRI studies using this paradigm have implicated the activation of the subthalamic nucleus in motor inhibition. We directly recorded subthalamic nucleus activity from bilaterally implanted deep brain stimulation electrodes in a group of 10 patients with Parkinson's disease, during performance of the stop signal task. Response inhibition was associated with specific changes in subthalamic activity in three different frequency bands. Response preparation was associated with a decrease in power and cortico-subthalamic coherence in the beta band (12-30 Hz), which was smaller and shorter when the response was successfully inhibited. In the theta band, we observed an increase in frontal cortico-subthalamic coherence related to the presence of the stop signal, which was highest when response inhibition was unsuccessful. Finally, a specific differential pattern of gamma activity was observed in the "on" motor state. Performance of the response was associated with a significant increase in power and cortico-subthalamic coherence, while successful inhibition of the response was associated with a bilateral decrease in subthalamic power and cortico-subthalamic coherence. Importantly, this inhibition-related decrease in gamma activity was absent in the four patients with dopamine-agonist related impulse-control disorders. Our results provide direct support for the involvement of the subthalamic nucleus in response inhibition and suggest that this function may be mediated by a specific reduction in gamma oscillations in the cortico-subthalamic connection.
Revista:
PARKINSONISM AND RELATED DISORDERS
ISSN:
1353-8020
Año:
2012
Vol.:
18
N°:
6
Págs.:
765-769
It is important to identify this hardware problem in view of the growing number of patients receiving this therapy. A protocol for patients with loss of stimulation efficacy and electrode impedance increment needs to be created in clinical visits in order to detect the failed stimulation mechanism.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2012
Vol.:
27
N°:
1
Págs.:
146 - 151
Background and objective. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene at chromosome 12q12 are the most common genetic cause of sporadic and familial late-onset Parkinson's disease. Our aim was to identify novel LRRK2 mutations in late-onset Parkinson's disease families.
Design. We analyzed chromosome 12p11.2-q13.1 haplotypes in 14 late-onset Parkinson's disease families without known LRRK2 mutations.
Results. Haplotype analysis identified 12 families in which the affected subjects shared chromosome 12p11.2-q13.1 haplotypes. LRRK2 sequencing revealed a novel co-segregating missense mutation in exon 36 (c.5281A > C; p.S1761R) located within a highly conserved region of the COR [C-terminal of ROC (Ras of complex proteins)] domain wherein it could deregulate LRRK2 kinase activity by modifying ROC-COR dimer stability. p.S1761R was present in a late-onset Parkinson's disease family and in 2 unrelated Parkinson's disease subjects, but not in 2491 healthy controls. LRRK2 p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37-72 years) suggesting age-dependent penetrance. These findings indicate that mutations interfering with LRRK2 ROC-COR domain dimerization lead to typical Parkinson's disease.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2012
Vol.:
27
N°:
9
Págs.:
1176 - 1179
From a neurophysiological viewpoint, patients exhibited oscillatory activity typical of the "on" medication state during diphasic dyskinesias. The minimal presence of gamma activity during diphasic dyskinesias, however, suggests that this "on" state might be incomplete or limited to dopaminergic mechanisms affecting the lower limbs.
Revista:
EUROPEAN JOURNAL OF NEUROLOGY
ISSN:
1351-5101
Año:
2012
Vol.:
19
N°:
8
Págs.:
1100-7
White matter hyperintensities do not influence the cognitive status of patients with PD. Frontal WMHs have a negative impact on semantic fluency. Brain vascular burden may have an effect on cognitive impairment in patients with PD as WMHs increase overtime might increase the risk of conversion to dementia. This finding needs further confirmation in larger prospective studies.
Revista:
NEUROBIOLOGY OF DISEASE
ISSN:
0969-9961
Año:
2012
Vol.:
48
N°:
1
Págs.:
79 - 91
Revista:
CLINICAL IMAGING
ISSN:
0899-7071
Año:
2011
Vol.:
35
N°:
3
Págs.:
236 - 241
The 3-T fMRI shows a higher sensitivity for the motor and somatosensory stimulation and more specific localization in the grey substance. The 3-T fMRI detects additional areas of activation with the motor paradigm.
Revista:
BRAIN
ISSN:
0006-8950
Año:
2011
Vol.:
134
N°:
1
Págs.:
36-49
Behavioural abnormalities such as impulse control disorders may develop when patients with Parkinson's disease receive dopaminergic therapy, although they can be controlled by deep brain stimulation of the subthalamic nucleus. We have recorded local field potentials in the subthalamic nucleus of 28 patients with surgically implanted subthalamic electrodes. According to the predominant clinical features of each patient, their Parkinson's disease was associated with impulse control disorders (n = 10), dyskinesias (n = 9) or no dopaminergic mediated motor or behavioural complications (n = 9). Recordings were obtained during the OFF and ON dopaminergic states and the power spectrum of the subthalamic activity as well as the subthalamocortical coherence were analysed using Fourier transform-based techniques. The position of each electrode contact was determined in the postoperative magnetic resonance image to define the topography of the oscillatory activity recorded in each patient. In the OFF state, the three groups of patients had similar oscillatory activity. By contrast, in the ON state, the patients with impulse control disorders displayed theta-alpha (4-10 Hz) activity (mean peak: 6.71 Hz) that was generated 2-8 mm below the intercommissural line. Similarly, the patients with dyskinesia showed theta-alpha activity that peaked at a higher frequency (mean: 8.38 Hz) and was generated 0-2 mm below the intercommissural line. No such activity was detected in patients that displayed no dopaminergic side effects. Cortico-subthalamic coherence was more frequent in the impulsive patients in the 4-7.5 Hz range in scalp electrodes placed on the frontal regions anterior to the primary motor cortex, while in patients with dyskinesia it was in the 7.5-10 Hz range in the leads overlying the primary motor and supplementary motor area. Thus, dopaminergic side effects in Parkinson's disease are associated with oscillatory activity in the theta-alpha band, but at different frequencies and with different topography for the motor (dyskinesias) and behavioural (abnormal impulsivity) manifestations. These findings suggest that the activity recorded in parkinsonian patients with impulse control disorders stems from the associative-limbic area (ventral subthalamic area), which is coherent with premotor frontal cortical activity. Conversely, in patients with l-dopa-induced dyskinesias such activity is recorded in the motor area (dorsal subthalamic area) and it is coherent with cortical motor activity. Consequently, the subthalamic nucleus appears to be implicated in the motor and behavioural complications associated with dopaminergic drugs in Parkinson's disease, specifically engaging different anatomo-functional territories
Revista:
EUROPEAN JOURNAL OF NEUROLOGY
ISSN:
1351-5101
Año:
2010
Vol.:
17
N°:
2
Págs.:
321 - 325
Revista:
Archives of Neurology (Chicago)
ISSN:
0003-9942
Año:
2010
Vol.:
67
N°:
12
Págs.:
1464 - 1472
Autores:
Bickel, S; Alvarez, I; Macías, R; et al.
Revista:
Parkinsonism & Related Disorders
ISSN:
1353-8020
Año:
2010
Vol.:
16
N°:
8
Págs.:
535 - 539
Revista:
THE JOURNAL OF NEUROSCIENCE
ISSN:
1529-2401
Año:
2010
Vol.:
30
N°:
19
Págs.:
6667 - 6677
Revista:
The Lancet Neurology
ISSN:
1474-4422
Año:
2010
Vol.:
9
N°:
6
Págs.:
558 - 559
Autores:
Moro, E; Lozano, AM; Pollack, P; et al.
Revista:
Movement Disorders
ISSN:
0885-3185
Año:
2010
Vol.:
25
N°:
5
Págs.:
578 - 586
We report the 5 to 6 year follow-up of a multicenter study of bilateral subthalamic nucleus (STN) and globus pallidus internus (GPi) deep brain stimulation (DBS) in advanced Parkinson's disease (PD) patients. Thirty-five STN patients and 16 GPi patients were assessed at 5 to 6 years after DBS surgery. Primary outcome measure was the stimulation effect on the motor Unified Parkinson's Disease Rating Scale (UPDRS) assessed with a prospective cross-over double-blind assessment without medications (stimulation was randomly switched on or off). Secondary outcomes were motor UPDRS changes with unblinded assessments in off- and on-medication states with and without stimulation, activities of daily living (ADL), anti-PD medications, and dyskinesias. In double-blind assessment, both STN and GPi DBS were significantly effective in improving the motor UPDRS scores (STN, P < 0.0001, 45.4%; GPi, P = 0.008, 20.0%) compared with off-stimulation, regardless of the sequence of stimulation. In open assessment, both STN- and GPi-DBS significantly improved the off-medication motor UPDRS when compared with before surgery (STN, P < 0.001, 50.5%; GPi, P = 0.002, 35.6%). Dyskinesias and ADL were significantly improved in both groups. Anti-PD medications were significantly reduced only in the STN group. Adverse events were more frequent in the STN group. These results confirm the long-term efficacy of STN and GPi DBS in advanced PD. Although the surgical targets were not randomized, there was a trend to a better outcome of motor signs in the STN-DBS patients and fewer adverse events in the GPi-DBS group.
Revista:
MOVEMENT DISORDERS
ISSN:
0885-3185
Año:
2010
Vol.:
25
N°:
1
Págs.:
130 - 132
Revista:
Neurobiology of Disease
ISSN:
0969-9961
Año:
2010
Vol.:
38
N°:
3
Págs.:
456 - 463
Autores:
Alvarez, M; Macias, R; Pavon, N; et al.
Revista:
Journal of Neurology, Neurosurgery and Psychiatry
ISSN:
0022-3050
Año:
2010
Vol.:
80
N°:
9
Págs.:
979 - 985
BACKGROUND:
Stereotactic thermocoagulative lesions of the subthalamic nucleus (STN) have been shown to induce significant motor improvement in patients with Parkinson's disease (PD).
PATIENTS AND METHODS:
89 patients with PD were treated with unilateral subthalamotomy. 68 patients were available for evaluations after 12 months, 36 at 24 months and 25 at 36 months.
RESULTS:
The Unified Parkinson's Disease Rating Scale (UPDRS) motor scores improved significantly contralaterally to the lesion in the "off" and "on" states throughout the follow-up, except for the "on" state at the last evaluation. Axial features and signs ipsilateral to the lesion progressed steadily throughout the study. Levodopa daily doses were significantly reduced by 45%, 36% and 28% at 12, 24 and 36 months post-surgery. 14 patients (15%) developed postoperative hemichorea-ballism which required pallidotomy in eight. These 14 patients had significantly higher dyskinesia scores (levodopa induced) preoperatively than the entire cohort.
CONCLUSION:
Unilateral subthalamotomy was associated with significant and sustained motor benefit contralateral to the lesio