RESUMEN
Parkinson's disease (PD) and other neurodegenerative parkinsonisms are characterised by loss of striatal dopaminergic neurons. Dopamine functional deficits can be measured in vivo using positron emission tomography (PET) and single-photon emission computed tomography (SPECT) ligands assessing either presynaptic (e.g. dopamine synthesis and storage, transporter density) or postsynaptic terminals (i.e. D2 receptors availability). Nuclear medicine imaging thus helps the clinician to separate degenerative forms of parkinsonism with other neurological conditions, e.g. essential tremor or drug-induced parkinsonism. With the present study, we aimed at summarizing the current evidence about dopaminergic molecular imaging in the diagnostic evaluation of PD, atypical parkinsonian syndromes and dementia with Lewy bodies (DLB), as well as its potential to distinguish these conditions and to estimate disease progression. In fact, PET/SPECT methods are clinically validated and have been increasingly integrated into diagnostic guidelines (e.g. for PD and DLB). In addition, there is novel evidence on the classification properties of extrastriatal signal. Finally, dopamine imaging has an outstanding potential to detect neurodegeneration at the premotor stage, including REM-sleep behavior disorder and olfactory loss. Therefore, inclusion of subjects at an early stage for clinical trials can largely benefit from a validated in vivo biomarker such as presynaptic dopamine pathways PET/SPECT assessment.
Asunto(s)
Enfermedad de Parkinson , Trastornos Parkinsonianos , Humanos , Dopamina/metabolismo , Imágenes Dopaminérgicas , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Proteínas de Transporte de Dopamina a través de la Membrana PlasmáticaRESUMEN
We report the case of a 67-year-old left-handed female patient with disabling medically refractory essential tremor who underwent successful right-sided magnetic resonance-guided focused ultrasound (MRgFUS) of the ventral intermediate nucleus after ipsilateral gamma knife radiosurgery (GKRS) thalamotomy performed 3 years earlier. The GKRS had a partial effect on her postural tremor without side effects, but there was no reduction of her kinetic tremor or improvement in her quality of life (QoL). The patient subsequently underwent a MRgFUS thalamotomy, which induced an immediate and marked reduction in both the postural and kinetic tremor components, with minor complications (left upper lip hypesthesia, dysmetria in her left hand, and slight gait ataxia). The MRgFUS-induced lesion was centered more medially than the GKRS-induced lesion and extended more posteriorly and inferiorly. The MRgFUS-induced lesion interrupted remaining fibers of the dentatorubrothalamic tract (DRTT). The functional improvement 1-year post-MRgFUS was significant due to a marked reduction of the patient's kinetic tremor. The QoL score (Quality of Life in Essential Tremor) improved by 88% and her Clinical Rating Scale for Tremor left hand score by 62%. The side effects persisted but were minor, with no impact on her QoL. The explanation for the superior efficacy of MRgFUS compared to GKRS in our patient could be due to either a poor response to the GKRS or to a better localization of the MRgFUS lesion with a more extensive interruption of DRTT fibers. In conclusion, MRgFUS can be a valuable therapeutic option after unsatisfactory GKRS, especially because MRgFUS has immediate clinical effectiveness, allowing intra-procedural test lesions and possible readjustment of the target if necessary.
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Temblor Esencial , Radiocirugia , Humanos , Femenino , Anciano , Temblor Esencial/diagnóstico por imagen , Temblor Esencial/cirugía , Calidad de Vida , Temblor/cirugía , Tálamo/diagnóstico por imagen , Tálamo/cirugía , Imagen por Resonancia Magnética , Resultado del TratamientoRESUMEN
Dopaminergic neurons (DA) of the substantia nigra pars compacta (SNpc) selectively and progressively degenerate in Parkinson's disease (PD). Until now, molecular analyses of DA in PD have been limited to genomic or transcriptomic approaches, whereas, to the best of our knowledge, no proteomic or combined multiomic study examining the protein profile of these neurons is currently available. In this exploratory study, we used laser capture microdissection to extract regions from DA in 10 human SNpc obtained at autopsy in PD patients and control subjects. Extracted RNA and proteins were identified by RNA sequencing and nanoliquid chromatography-mass spectrometry, respectively, and the differential expression between PD and control group was assessed. Qualitative analyses confirmed that the microdissection protocol preserves the integrity of our samples and offers access to specific molecular pathways. This multiomic analysis highlighted differential expression of 52 genes and 33 proteins, including molecules of interest already known to be dysregulated in PD, such as LRP2, PNMT, CXCR4, MAOA and CBLN1 genes, or the Aldehyde dehydrogenase 1 protein. On the other hand, despite the same samples were used for both analyses, correlation between RNA and protein expression was low, as exemplified by the CST3 gene encoding for the cystatin C protein. This is the first exploratory study analyzing both gene and protein expression of laser-dissected neuronal parts from SNpc in PD. Data are available via ProteomeXchange with identifier PXD024748 and via GEO with identifier GSE 169755.
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Neuronas Dopaminérgicas , Enfermedad de Parkinson , Familia de Aldehído Deshidrogenasa 1 , Cistatina C , Neuronas Dopaminérgicas/metabolismo , Humanos , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , ARN/metabolismo , Sustancia Negra/metabolismoRESUMEN
To respond to the need of objective screening tools for motor speech disorders (MSD), we present the screening version of a speech assessment protocol (MonPaGe-2.0.s), which is based on semi-automated acoustic and perceptual measures on several speech dimensions in French. We validate the screening tool by testing its sensitivity and specificity and comparing its outcome with external standard assessment tools. The data from 80 patients diagnosed with different types of mild to moderate MSD and 62 healthy test controls were assessed against the normative data obtained on 404 neurotypical speakers, with Deviance Scores computed on seven speech dimensions (voice, speech rate, articulation, prosody, pneumophonatory control, diadochokinetic rate, intelligibility) based on acoustic and perceptual measures. A cut-off of the MonPaGe total deviance score (TotDevS) >2 allowed MSD to be diagnosed with specificity of 95% and an overall sensitivity of 83.8% on all patients pulled, reaching 91% when very mildly impaired patients were excluded. A strong correlation was found between the MonPaGe TotDevS and an external composite perceptual score of MSD provided by six experts. The MonPaGe screening protocol has proven its sensitivity and specificity for diagnosing presence and severity of MSD. Further implementations are needed to complement the characterization of impaired dimensions in order to distinguish subtypes of MSD.
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Acústica , Acústica del Lenguaje , Humanos , Habla , Trastornos del Habla , Inteligibilidad del Habla , Medición de la Producción del HablaRESUMEN
YY1 mutations cause Gabriele-de Vries syndrome, a recently described condition involving cognitive impairment, facial dysmorphism and intrauterine growth restriction. Movement disorders were reported in 5/10 cases of the original series, but no detailed description was provided. Here we present a 21-year-old woman with a mild intellectual deficit, facial dysmorphism and a complex movement disorder including an action tremor, cerebellar ataxia, dystonia, and partial ocular apraxia as the presenting and most striking feature. Whole-exome sequencing revealed a novel heterozygous de novo mutation in YY1 [NM: 003403.4 (YY1): c.907 T > C; p.(Cys303Arg)], classified as pathogenic according to the ACMG guidelines.
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Trastornos del Movimiento/genética , Trastornos del Neurodesarrollo/genética , Factor de Transcripción YY1/genética , Niño , Preescolar , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Trastornos del Movimiento/patología , Trastornos del Neurodesarrollo/patología , Fenotipo , Secuenciación del ExomaRESUMEN
BACKGROUND: Neuropathological data and nuclear medicine imaging show extensive serotonergic impairment in Parkinson's disease (PD). We undertook a case-controlled analysis of 123I-FP-CIT SPECT images to measure extrastriatal serotonergic transporters (SERT) in PD using the Parkinson's Progression Markers Initiative (PPMI) cohort. METHODS: We included all PD (n = 154) and Control subjects (n = 62) with available 123I-FP-CIT SPECT imaging and high-resolution T1-weighted MRI for coregistration (PD: mean age 61.6 years, 62% male, disease duration 26 months, MDS-UPDRS III score 22). 123I-FP-CIT SPECT images were processed with PETPVE12 using an exploratory voxel-wise analysis including partial-volume effect correction. Linear regressions were performed in the PD group to assess correlations between region of interest 123I-FP-CIT uptake and clinical motor and non-motor impairment. RESULTS: Compared to Controls, PD exhibited an uptake reduction in bilateral caudate nucleus, putamen, insula, amygdala and right pallidum (family-wise error (FWE)-corrected p < 0.05). While lower putaminal uptake on the contralateral side to clinically more affected side was associated with higher MDS-UPDRS III score (p = 0.022), we found a trend association between higher geriatric depression scale and lower pallidum uptake (p = 0.09). Higher SCOPA-AUT gastrointestinal subscore was associated with lower uptake in mean putamen and caudate nucleus (p = 0.01 to 0.03), whereas urological subscore was inversely correlated with mean caudate nucleus, putamen, and pallidum uptake (p = 0.002 to 0.03). REM sleep behaviour disorder screening questionnaire was associated with lower 123I-FP-CIT binding in caudate nucleus, putamen and pallidum (all p < 0.05). No significant association was found for Montreal Cognitive Assessment (all p > 0.45) or excessive daytime sleepiness (all p > 0.29). CONCLUSIONS: In addition to the well-established striatal deficit, this study provides evidence of a major extrastriatal 123I-FP-CIT impairment, and therefore of an altered serotonergic transmission in early PD.
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Encéfalo/diagnóstico por imagen , Enfermedad de Parkinson/diagnóstico por imagen , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Tomografía Computarizada de Emisión de Fotón Único/métodos , Adulto , Anciano , Encéfalo/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Radioisótopos de Yodo , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/análisis , TropanosRESUMEN
BACKGROUND: Acute dyskinesias elicited by STN-DBS, here referred to as stimulation-induced dyskinesias, predict optimal clinical outcome in PD. However, it remains elusive whether stimulation-induced dyskinesias can guide DBS programming. OBJECTIVES: Here, we characterized stimulation-induced dyskinesias clinically and anatomically. We then tested whether dyskinesia-inducing contacts could be effectively programmed using independent current source technology. METHODS: We characterized stimulation-induced dyskinesias with directional and ring stimulation retrospectively in 20 patients. We then localized dyskinesia-inducing contacts by imaging coregistration and eventually programmed those contacts. RESULTS: We elicited dyskinesias in half of our patients. Dyskinesia-inducing contacts were mainly directional and were all located ventrally within the dorsolateral motor STN. When these dyskinesia-inducing contacts were programmed using independent current source technology, dyskinesia disappeared and robust antibradykinetic effects were obtained. CONCLUSION: We confirm that stimulation-induced dyskinesias are helpful clinical observations, which may guide programming of directional STN-DBS in PD. © 2019 International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda , Discinesias/complicaciones , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/cirugía , Estimulación Encefálica Profunda/métodos , Discinesias/terapia , Femenino , Humanos , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Patients with Parkinson's disease (PD) may benefit from deep brain stimulation (DBS) to improve motor and medication-induced symptoms. Yet mixed evidence regarding the outcome of successful DBS on couple satisfaction has been highlighted in the literature. Thirty patients diagnosed with PD were included in a study investigating couple satisfaction (MSS-14), depression (HAD-D) and anxiety (HAD-A) at four measurement times: before DBS and 6, 12, and 18 months post-surgically. Sixteen spouses/partners were included as well. Couple satisfaction from the patient perspective was never associated with depression or anxiety. However, poor marital adjustment (i.e., difference and absolute difference between patients and spouses/partners MSS-14 scores) predicted patients' pre-operative depressive mood. Longitudinal analyses showed that couple satisfaction (n = 9) worsened at 12 months and 18 months compared to pre-DBS scores, F(2.047, 16.378) = 8.723, p = .003, and despite concomitant motor improvement. Growth curve analyses showed that couple satisfaction worsening occurred between 6 and 12 months post-operatively (b = 2.938, p < .001). Thus, couple satisfaction did not increase along with motor improvement and deteriorated after the adjustment period following DBS.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Estimulación Encefálica Profunda/psicología , Matrimonio/psicología , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/terapia , Satisfacción del Paciente/estadística & datos numéricos , Satisfacción Personal , Femenino , Estudios de Seguimiento , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: We investigated the acute effect of short pulse widths on the therapeutic window in subthalamic nucleus deep brain stimulation in Parkinson's disease. METHODS: We assessed 10 PD patients with STN-DBS at a 60-µs pulse width. We randomly and double-blindedly applied 10- to 50-µs pulse widths. The principal outcome was the therapeutic window (difference between the amplitude thresholds for visible muscle contraction and for best rigidity control). The secondary outcome was the charge per pulse (which reflects the efficiency of the stimulation) needed to control rigidity. Two-way analysis of variance and pairwise t tests were applied. RESULTS: The therapeutic window widened when the pulse width shortened (r = -0.45; P < 0.001), and charge per pulse was reduced (P < 0.05). CONCLUSIONS: This randomized, double-blind study showed that shorter pulse widths widen the therapeutic window of STN-DBS in PD without increasing the electrical charge required to obtain the same acute clinical benefit. © 2017 International Parkinson and Movement Disorder Society.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Enfermedad de Parkinson/terapia , Núcleo Subtalámico/fisiología , Biofisica , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Resultado del TratamientoRESUMEN
Unlike most basal ganglia disorders, which usually progress slowly and relentlessly, a number of movement disorders may develop as acute or subacute conditions. Their occurrence commonly prompts patients to rush into the emergency room. A proper diagnosis is not always straightforward and requires a detailed analysis of the movement disorder phenomenology and a thorough medication screening, as many of these acute situations may be iatrogenic and drug-related. An accurate identification of the problem may enable an effective management and an appropriate therapy. This article is an overview of three distinct movement disorder emergencies, namely acute dystonia, acute chorea, and acute complications that can be observed in Parkinson's disease. Each topic is illustrated with a case report.
Contrairement à la plupart des affections des ganglions de la base, qui évoluent généralement sur un mode lentement progressif, certains mouvements anormaux peuvent se développer sur un mode aigu ou subaigu, amenant les patients à consulter en urgence. Le diagnostic est souvent délicat. Il repose sur une analyse détaillée de la phénoménologie et une anamnèse médicamenteuse fouillée, dans la mesure où ces situations sont volontiers iatrogènes. Une identification correcte du problème permet souvent une thérapeutique efficace. Le présent article propose une mise au point de trois problématiques de ce type, à savoir la dystonie aiguë, la chorée aiguë et les complications aiguës que l'on peut observer dans la maladie de Parkinson. Chaque sujet est illustré par un cas clinique.
RESUMEN
Advanced Parkinson's disease (PD) is characterized by severe motor and non-motor complications that negatively impact on patients' autonomy and health-related quality of life. In early disease, the therapeutic strategy consists of gradual increase in dopaminergic treatment and levodopa dose fragmentation. In more advanced stages, this approach becomes insufficient and three therapeutic options can be considered: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, and continuous levodopa/carbidopa intestinal gel infusion.
La maladie de Parkinson (MP) avancée est caractérisée par la présence de complications motrices et non motrices qui ont un impact significatif sur l'autonomie et la qualité de vie des patients. La stratégie thérapeutique consiste à fractionner le traitement dopaminergique, à recourir aux formes à libération prolongée, et aux inhibiteurs des enzymes de dégradation de la dopamine. Lorsque ces mesures sont insuffisantes, trois options thérapeutiques plus invasives peuvent être envisagées : la stimulation cérébrale profonde, la perfusion sous-cutanée continue d'apomorphine et l'administration intrajéjunale de gel de lévodopa/carbidopa. L'objectif de cet article est de décrire les indications, bénéfices et effets secondaires potentiels de ces traitements dits « complexes ¼.
RESUMEN
PURPOSE: To assess correlations between the degree of dopaminergic depletion measured using single-photon emission computed tomography (SPECT) and different clinical parameters of disease progression in Parkinson's disease (PD). METHODS: This retrospective study included 970 consecutive patients undergoing (123)I-ioflupane SPECT scans in our institution between 2003 and 2013, from which we selected a study population of 411 patients according to their clinical diagnosis: 301 patients with PD (69.4 ± 11.0 years, of age, 163 men) and 110 patients with nondegenerative conditions included as controls (72.7 ± 8.0 years of age, 55 men). Comprehensive and operator-independent data analysis included spatial normalization into standard space, estimation of the mean uptake values in the striatum (caudate nucleus + putamen) and voxel-wise correlation between SPECT signal intensity and disease stage as well as disease duration in order to investigate the spatiotemporal pattern of the dopaminergic nigrostriatal degeneration. To compensate for potential interactions between disease stage and disease duration, one parameter was used as nonexplanatory coregressor for the other. RESULTS: Increasing disease stage was associated with an exponential decrease in (123)I-ioflupane uptake (R(2) = 0.1501) particularly in the head of the ipsilateral caudate nucleus (p < 0.0001), whereas increasing disease duration was associated with a linear decrease in (123)I-ioflupane uptake (p < 0.0001; R(2) = 0.1532) particularly in the contralateral anterior putamen (p < 0.0001). CONCLUSION: We observed two distinct spatiotemporal patterns of posterior to anterior dopaminergic depletion associated with disease stage and disease duration in patients with PD. The developed operator-independent reference database of 411 (123)I-ioflupane SPECT scans can be used for clinical and research applications.
Asunto(s)
Enfermedad de Parkinson/diagnóstico por imagen , Tomografía Computarizada de Emisión de Fotón Único , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Cuerpo Estriado/diagnóstico por imagen , Progresión de la Enfermedad , Dopamina/química , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Radioisótopos de Yodo/química , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Nortropanos/química , Enfermedad de Parkinson/fisiopatología , Estudios RetrospectivosRESUMEN
BACKGROUND: Gait and akinesia deterioration in PD patients during the immediate postoperative period of DBS has been directly related to stimulation in the subthalamic region. The underlying mechanisms remain poorly understood. The aim of the present study was to clinically and anatomically describe this side effect. METHODS: PD patients presenting with a worsening of gait and/or akinesia following STN-DBS, that was reversible on stimulation arrest were included. The evaluation included (1) a Stand Walk Sit Test during a monopolar survey of each electrode in the on-drug condition; (2) a 5-condition test with the following conditions: off-drug/off-DBS, off-drug/on-best-compromise-DBS, on-drug/off-DBS, on-drug/on-best-compromise-DBS, and on-drug/on-worsening-DBS, which utilized the contact inducing the most prominent gait deterioration. The following scales were performed: UPDRSIII subscores, Stand Walk Sit Test, and dyskinesia and freezing of gait scales. Localization of contacts was performed using a coregistration method. RESULTS: Twelve of 17 patients underwent the complete evaluation. Stimulation of the most proximal contacts significantly slowed down the Stand Walk Sit Test. The on-drug/on-worsening-DBS condition compared with the on-drug/off-DBS condition worsened akinesia (P = 0.02), Stand Walk Sit Test (P = 0.001), freezing of gait (P = 0.02), and improved dyskinesias (P = 0.003). Compared with the off-drug/off-DBS condition, the on-drug/on-worsening-DBS condition improved rigidity (P = 0.007) and tremor (P = 0.007). Worsening contact sites were predominantly dorsal and anterior to the STN in the anterior zona incerta and Forel fields H2. CONCLUSIONS: A paradoxical deterioration of gait and akinesia is a rare side effect following STN-DBS. We propose that this may be related to misplaced contacts, and we discuss the pathophysiology and strategies to identify and manage this complication. © 2016 International Parkinson and Movement Disorder Society.
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Estimulación Encefálica Profunda/efectos adversos , Dopaminérgicos/farmacología , Discinesias/etiología , Trastornos Neurológicos de la Marcha/etiología , Levodopa/farmacología , Enfermedad de Parkinson/terapia , Núcleo Subtalámico , Adulto , Anciano , Terapia Combinada , Dopaminérgicos/administración & dosificación , Femenino , Humanos , Levodopa/administración & dosificación , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
Recently awarded by the prestigious Lasker Foundation, high-frequency deep brain stimulation (DBS) has been used for the first time in 1987 in tremor and in 1993 in Parkinson's disease (PD) by the Grenoble group. So far, over 100 000 patients have been operated on worldwide. In PD, DBS induces an almost complete abatement of tremor, motor fluctuations and dyskinesias along with a reduction in levodopa dose. Although its mechanism of action is not fully understood, DBS would inhibit or modulate the expression of abnormal neuronal networks associated with given symptoms. It is therefore expected that DBS will extend to other severe neurological and psychiatric disorders. Furthermore, technological advances of the procedure are ongoing to optimize final outcomes.
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Estimulación Encefálica Profunda/tendencias , Enfermedad de Parkinson/terapia , Estimulación Encefálica Profunda/métodos , Humanos , Trastornos Mentales/terapia , Enfermedades del Sistema Nervioso/terapia , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Movement disorders such as Parkinson's disease (PD), essential tremor (ET) and dystonia can benefit from deep brain stimulation (DBS). DBS is considered when symptoms are disabling despite optimal medical therapy. Contraindications include dementia, uncontrolled psychiatric disease and/or comorbid conditions with potential for evolution. Targets are the subthalamic nucleus for PD, the ventral intermediate nucleus for ET and the globus pallidus internus for dystonia. The beneficial effet of DBS has been well documented for symptom control. Optimal target localization of the electrodes reduces the occurrence of side-effects. Stimulation-induced adverse effects can usually be abolished by turning the stimulation off, changing the active contact or other stimulation parameters.
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Estimulación Encefálica Profunda/métodos , Trastornos del Movimiento/terapia , Enfermedad de Parkinson/terapia , Contraindicaciones , Estimulación Encefálica Profunda/efectos adversos , Distonía/fisiopatología , Distonía/terapia , Temblor Esencial/fisiopatología , Temblor Esencial/terapia , Humanos , Trastornos del Movimiento/fisiopatología , Enfermedad de Parkinson/fisiopatologíaRESUMEN
Parkinson's disease (PD) pathology spreads throughout the brain following a region-specific process predominantly affecting the substantia nigra (SN) pars compacta. SN exhibits a progressive loss of dopaminergic neurons responsible for the major cardinal motor symptoms, along with the occurrence of Lewy bodies in the surviving neurons. To gain new insights into the underlying pathogenic mechanisms in PD, we studied postmortem nigral tissues dissected from pathologically confirmed PD cases (n = 5) and neurologically intact controls (n = 8). Using a high-throughput shotgun proteomic strategy, we simultaneously identified 1795 proteins with concomitant quantitative data. To date, this represents the most extensive catalog of nigral proteins. Of them, 204 proteins displayed significant expression level changes in PD patients versus controls. These were involved in novel or known pathogenic processes including mitochondrial dysfunction, oxidative stress, or cytoskeleton impairment. We further characterized four candidates that might be relevant to PD pathogenesis. We confirmed the differential expression of ferritin-L and seipin by Western blot and demonstrated the neuronal localization of gamma glutamyl hydrolase and nebulette by immunohistochemistry. Our preliminary findings suggest a role for nebulette overexpression in PD neurodegeneration, through mechanisms that may involve cytoskeleton dynamics disruption. All MS data have been deposited in the ProteomeXchange with identifier PXD000427 (http://proteomecentral.proteomexchange.org/dataset/PXD000427).
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Enfermedad de Parkinson/patología , Proteoma/análisis , Proteómica/métodos , Sustancia Negra/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/metabolismo , Proteoma/metabolismo , Sustancia Negra/metabolismoRESUMEN
The identification of genetic causes for Mendelian disorders has been based on the collection of multi-incident families, linkage analysis, and sequencing of genes in candidate intervals. This study describes the application of next-generation sequencing technologies to a Swiss kindred presenting with autosomal-dominant, late-onset Parkinson disease (PD). The family has tremor-predominant dopa-responsive parkinsonism with a mean onset of 50.6 ± 7.3 years. Exome analysis suggests that an aspartic-acid-to-asparagine mutation within vacuolar protein sorting 35 (VPS35 c.1858G>A; p.Asp620Asn) is the genetic determinant of disease. VPS35 is a central component of the retromer cargo-recognition complex, is critical for endosome-trans-golgi trafficking and membrane-protein recycling, and is evolutionarily highly conserved. VPS35 c.1858G>A was found in all affected members of the Swiss kindred and in three more families and one patient with sporadic PD, but it was not observed in 3,309 controls. Further sequencing of familial affected probands revealed only one other missense variant, VPS35 c.946C>T; (p.Pro316Ser), in a pedigree with one unaffected and two affected carriers, and thus the pathogenicity of this mutation remains uncertain. Retromer-mediated sorting and transport is best characterized for acid hydrolase receptors. However, the complex has many types of cargo and is involved in a diverse array of biologic pathways from developmental Wnt signaling to lysosome biogenesis. Our study implicates disruption of VPS35 and retromer-mediated trans-membrane protein sorting, rescue, and recycling in the neurodegenerative process leading to PD.
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Mutación , Enfermedad de Parkinson/genética , Proteínas de Transporte Vesicular/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Transporte Biológico , Endosomas/genética , Endosomas/metabolismo , Femenino , Regulación de la Expresión Génica , Variación Genética , Genoma Humano , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Vacuolas/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Red trans-Golgi/metabolismoRESUMEN
In deep brain stimulation (DBS) studies in patients with Parkinson's disease, the Lead-DBS toolbox allows the reconstruction of the location of ß-oscillations in the subthalamic nucleus (STN) using Vercise Cartesia directional electrodes (Boston Scientific). The objective was to compare these probabilistic locations with those of intraoperative monopolar ß-oscillations computed from local field potentials (0.5-3 kHz) recorded by using shielded single wires and an extracranial shielded reference electrode. For each electrode contact, power spectral densities of the ß-band (13-31 Hz) were compared with those of all eight electrode contacts on the directional electrodes. The DBS Intrinsic Template AtLas (DISTAL), electrophysiological, and DBS target atlases of the Lead-DBS toolbox were applied to the reconstructed electrodes from preoperative MRI and postoperative CT. Thirty-six electrodes (20 patients: 7 females, 13 males; both STN electrodes for 16 of 20 patients; one single STN electrode for 4 of 20 patients) were analyzed. Stimulation sites both dorsal and/or lateral to the sensorimotor STN were the most efficient. In 33 out of 36 electrodes, at least one contact was measured with stronger ß-oscillations, including 23 electrodes running through or touching the ventral subpart of the ß-oscillations' probabilistic volume, while 10 did not touch it but were adjacent to this volume; in 3 out of 36 electrodes, no contact was found with ß-oscillations and all 3 were distant from this volume. Monopolar local field potentials confirmed the ventral subpart of the probabilistic ß-oscillations.