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1.
Hum Mol Genet ; 2020 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-32160287

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modelled human PD using human induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus. Human iPSCs from PD Dupl patients and a control individual were differentiated into mDANs and cortical projection neurons (CPNs). SNCA dosage increase did not influence differentiation efficiency of mDANs and CPNs. However, elevated α-Syn pathology, as revealed by enhanced α-Syn insolubility and phosphorylation, was determined in PD-derived mDANs compared to PD CPNs. PD-derived mDANs exhibited higher levels of reactive oxygen species and protein nitration levels compared to CPNs, which might underlie elevated α-Syn pathology observed in mDANs. Finally, increased neuronal death was observed in PD-derived mDANs compared to PD CPNs and to control mDANs and CPNs. Our results reveal, for the first time, a higher α-Syn pathology, oxidative stress level, and neuronal death rate in human PD mDANs compared to PD CPNs from the same patient. The finding implies the contribution of pathogenic α-Syn, probably induced by oxidative stress, to selective vulnerability of substantia nigra dopaminergic neurons in human PD.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32086225

RESUMO

Mobile gait analysis using wearable inertial measurement units (IMUs) provides valuable insights for the assessment of movement impairments in different neurological and musculoskeletal diseases, for example Parkinson's disease (PD). The increase in data volume due to arising long-term monitoring requires valid, robust and efficient analysis pipelines. In many studies an upstream detection of gait is therefore applied. However, current methods do not provide a robust way to successfully reject non-gait signals. Therefore, we developed a novel algorithm for the detection of gait from continuous inertial data of sensors worn at the feet. The algorithm is focused not only on a high sensitivity but also a high specificity for gait. Sliding windows of IMU signals recorded from the feet of PD patients were processed in the frequency domain. Gait was detected if the frequency spectrum contained specific patterns of harmonic frequencies. The approach was trained and evaluated on 150 clinical measurements containing standardized gait and cyclic movement tests. The detection reached as sensitivity of 0.98 and a specificity of 0.96 for the best sensor configuration (angular rate around the medio-lateral axis). On an independent validation data set including 203 unsupervised, semi-standardized gait tests, the algorithm achieved a sensitivity of 0.97. Our algorithm for the detection of gait from continuous IMU signals works reliably and showed promising results for the application in the context of free-living and non-standardized monitoring scenarios.

3.
Brain Sci ; 9(10)2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31601037

RESUMO

OBJECTIVE: To identify structural white matter alterations in patients with pure hereditary spastic paraplegia (HSP) using high angular resolution diffusion tensor imaging (DTI). METHODS: We examined 37 individuals with high resolution DTI, 20 patients with pure forms of hereditary spastic paraplegia and 17 age and gender matched healthy controls. DTI was performed using a 3 T clinical scanner with whole brain tract-based spatial statistical (TBSS) analysis of the obtained fractional anisotropy (FA) data as well as a region-of-interest (ROI)-based analysis of affected tracts including the cervical spinal cord. We further conducted correlation analyses between DTI data and clinical characteristics. RESULTS: TBSS analysis in HSP patients showed significantly decreased fractional anisotropy of the corpus callosum and the corticospinal tract compared to healthy controls. ROI-based analysis confirmed significantly lower FA in HSP compared to controls in the internal capsule (0.77 vs. 0.80, p = 0.048), the corpus callosum (0.84 vs. 0.87, p = 0.048) and the cervical spinal cord (0.72 vs. 0.79, p = 0.003). FA values of the cervical spinal cord significantly correlated with disease duration. CONCLUSION: DTI metrics of the corticospinal tract from the internal capsule to the cervical spine suggest microstructural damage and axonal degeneration of motor neurons. The CST at the level of the cervical spinal cord is thereby more severely affected than the intracranial part of the CST, suggesting an ascending axonal degeneration of the CST. Since there is a significant correlation with disease duration, FA may serve as a future progression marker for assessment of the disease course in HSP.

4.
Neurocase ; 25(6): 243-250, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31532322

RESUMO

We describe a patient with acute herpes simplex encephalitis with left-hemispheric hippocampal, parahippocampal and insular lesions. Although prototypic language areas were unaffected, the patient suffered from an inability to name objects or animals displayed on pictures. This deficit was transient and gradually disappeared 8 weeks after the initial diagnosis. Our findings are in line with a previous report showing similar deficits in a patient with a comparable lesion pattern and support the hypothesis that left insular lesions can produce severe naming deficits. Using FDG-PET we ruled out that functional deactivation in classical language areas account for the observed naming deficits.

5.
J Parkinsons Dis ; 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31424420

RESUMO

BACKGROUND: Parkinson's disease (PD) is an age dependent neurodegenerative disorder with increasing prevalence. Digital technologies like computers and smartphones offer mobile telecommunication, diagnostic and monitoring and may connect the patient continuously with his healthcare team, providing disease related information, and support healthcare. Since the use of these technologies in western civilization is age dependent, possession and usage cannot be regarded as given in PD. In contrast to increasing efforts to implement digital technology into PD patient care, little is known about the use of computers, smartphones, and internet-affinity in PD patients. OBJECTIVE: We evaluated the use of digital technologies in different age groups of PD patients. METHODS: We developed a questionnaire adapted to the annual German microcensus on "use of digital communication technologies", allowing a comparison to the general population in Germany. RESULTS: 190 PD patients completed the questionnaire. About 75% of PD patients access disease related information on the internet. Patients across all age groups used computers and the internet as frequent or more frequently compared to the German population. Use of computers, smartphones, and the internet in PD was age dependent. Advanced PD patients with higher motor impairment used smartphones less often, while mobile phone usage was not reduced. CONCLUSION: The adoption of a digital lifestyle is present in the PD population, apart from smartphone usage, which is impaired by motor symptoms. Thus, future healthcare technologies are not hampered by the inability of PD patients to use the necessary tools, however, fine motor-skill requirements have to be acknowledged.

6.
Sensors (Basel) ; 19(14)2019 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-31337067

RESUMO

Mobile gait analysis systems using wearable sensors have the potential to analyze and monitor pathological gait in a finer scale than ever before. A closer look at gait in Parkinson's disease (PD) reveals that turning has its own characteristics and requires its own analysis. The goal of this paper is to present a system with on-shoe wearable sensors in order to analyze the abnormalities of turning in a standardized gait test for PD. We investigated turning abnormalities in a large cohort of 108 PD patients and 42 age-matched controls. We quantified turning through several spatio-temporal parameters. Analysis of turn-derived parameters revealed differences of turn-related gait impairment in relation to different disease stages and motor impairment. Our findings confirm and extend the results from previous studies and show the applicability of our system in turning analysis. Our system can provide insight into the turning in PD and be used as a complement for physicians' gait assessment and to monitor patients in their daily environment.


Assuntos
Algoritmos , Monitorização Fisiológica/instrumentação , Doença de Parkinson/fisiopatologia , Sapatos , Dispositivos Eletrônicos Vestíveis , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Desenho de Equipamento , Feminino , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Monitorização Fisiológica/normas , Reprodutibilidade dos Testes , Análise Espaço-Temporal
8.
J Neurol ; 265(11): 2656-2665, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30196324

RESUMO

Mobile, sensor-based gait analysis in Parkinson's disease (PD) facilitates the objective measurement of gait parameters in cross-sectional studies. Besides becoming outcome measures for clinical studies, the application of gait parameters in personalized clinical decision support is limited. Therefore, the aim of this study was to evaluate whether the individual response of PD patients to dopaminergic treatment may be measured by sensor-based gait analysis. 13 PD patients received apomorphine every 15 min to incrementally increase the bioavailable apomorphine dose. Motor performance (UPDRS III) was assessed 10 min after each apomorphine injection. Gait parameters were obtained after each UPDRS III rating from a 2 × 10 m gait sequence, providing 41.2 ± 9.2 strides per patient and injection. Gait parameters and UPDRS III ratings were compared cross-sectionally after apomorphine titration, and more importantly between consecutive injections for each patient individually. For the individual response, the effect size Cohen's d for gait parameter changes was calculated based on the stride variations of each gait sequence after each injection. Cross-sectionally, apomorphine improved stride speed, length, gait velocity, maximum toe clearance, and toe off angle. Between injections, the effect size for individual changes in stride speed, length, and maximum toe clearance correlated to the motor improvement in each patient. In addition, significant changes of stride length between injections were significantly associated with UPDRS III improvements. We therefore show, that sensor-based gait analysis provides objective gait parameters that support clinical assessment of individual PD patients during dopaminergic treatment. We propose clinically relevant instrumented gait parameters for treatment studies and especially clinical care.


Assuntos
Antiparasitários/uso terapêutico , Apomorfina/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Análise da Marcha , Doença de Parkinson/tratamento farmacológico , Idoso , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Medicina de Precisão , Resultado do Tratamento
9.
Cell Stem Cell ; 23(1): 123-131.e6, 2018 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-29979986

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD. Higher Th17 frequencies were found in the blood of PD patients and increased numbers of T lymphocytes were detected in postmortem PD brain tissues. We modeled this finding using autologous co-cultures of activated T lymphocytes and iPSC-derived MBNs of sporadic PD patients and controls. After co-culture with T lymphocytes or the addition of IL-17, PD iPSC-derived MBNs underwent increased neuronal death driven by upregulation of IL-17 receptor (IL-17R) and NFκB activation. Blockage of IL-17 or IL-17R, or the addition of the FDA-approved anti-IL-17 antibody, secukinumab, rescued the neuronal death. Our findings indicate a critical role for IL-17-producing T lymphocytes in sporadic PD.


Assuntos
Morte Celular , Células-Tronco Pluripotentes Induzidas/patologia , Modelos Biológicos , Neurônios/patologia , Doença de Parkinson/patologia , Células Th17/metabolismo , Células Cultivadas , Feminino , Humanos , Masculino
10.
Autophagy ; 14(1): 98-119, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29198173

RESUMO

The autophagy-lysosome pathway (ALP) regulates intracellular homeostasis of the cytosolic protein SNCA/alpha-synuclein and is impaired in synucleinopathies, including Parkinson disease and dementia with Lewy bodies (DLB). Emerging evidence suggests that ALP influences SNCA release, but the underlying cellular mechanisms are not well understood. Several studies identified SNCA in exosome/extracellular vesicle (EV) fractions. EVs are generated in the multivesicular body compartment and either released upon its fusion with the plasma membrane, or cleared via the ALP. We therefore hypothesized that inhibiting ALP clearance 1) enhances SNCA release via EVs by increasing extracellular shuttling of multivesicular body contents, 2) alters EV biochemical profile, and 3) promotes SNCA cell-to-cell transfer. Indeed, ALP inhibition increased the ratio of extra- to intracellular SNCA and upregulated SNCA association with EVs in neuronal cells. Ultrastructural analysis revealed a widespread, fused multivesicular body-autophagosome compartment. Biochemical characterization revealed the presence of autophagosome-related proteins, such as LC3-II and SQSTM1. This distinct "autophagosome-exosome-like" profile was also identified in human cerebrospinal fluid (CSF) EVs. After a single intracortical injection of SNCA-containing EVs derived from CSF into mice, human SNCA colocalized with endosome and neuronal markers. Prominent SNCA immunoreactivity and a higher number of neuronal SNCA inclusions were observed after DLB patient CSF EV injections. In summary, this study provides compelling evidence that a) ALP inhibition increases SNCA in neuronal EVs, b) distinct ALP components are present in EVs, and c) CSF EVs transfer SNCA from cell to cell in vivo. Thus, macroautophagy/autophagy may regulate EV protein composition and consequently progression in synucleinopathies.


Assuntos
Autofagossomos/metabolismo , Autofagia/fisiologia , Exossomos/metabolismo , Lisossomos/metabolismo , Neurônios/metabolismo , alfa-Sinucleína/metabolismo , Animais , Autofagossomos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores/metabolismo , Células Cultivadas , Cloroquina/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/ultraestrutura , Humanos , Doença por Corpos de Lewy/metabolismo , Lisossomos/efeitos dos fármacos , Macrolídeos/farmacologia , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Doença de Parkinson/metabolismo , Transporte Proteico , Ratos Sprague-Dawley
11.
Front Neurol ; 8: 550, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29123499

RESUMO

Introduction: Cognitive and gait deficits are common symptoms in Parkinson's disease (PD). Motor-cognitive dual tasks (DTs) are used to explore the interplay between gait and cognition. However, it is unclear if DT gait performance is indicative for cognitive impairment. Therefore, the aim of this study was to investigate if cognitive deficits are reflected by DT costs of spatiotemporal gait parameters. Methods: Cognitive function, single task (ST) and DT gait performance were investigated in 67 PD patients. Cognition was assessed by the Montreal Cognitive Assessment (MoCA) followed by a standardized, sensor-based gait test and the identical gait test while subtracting serial 3's. Cognitive impairment was defined by a MoCA score <26. DT costs in gait parameters [(DT - ST)/ST × 100] were calculated as a measure of DT effect on gait. Correlation analysis was used to evaluate the association between MoCA performance and gait parameters. In a linear regression model, DT gait costs and clinical confounders (age, gender, disease duration, motor impairment, medication, and depression) were correlated to cognitive performance. In a subgroup analysis, we compared matched groups of cognitively impaired and unimpaired PD patients regarding differences in ST, DT, and DT gait costs. Results: Correlation analysis revealed weak correlations between MoCA score and DT costs of gait parameters (r/rSp ≤ 0.3). DT costs of stride length, swing time variability, and maximum toe clearance (|r/rSp| > 0.2) were included in a regression analysis. The parameters only explain 8% of the cognitive variance. In combination with clinical confounders, regression analysis showed that these gait parameters explained 30% of MoCA performance. Group comparison revealed strong DT effects within both groups (large effect sizes), but significant between-group effects in DT gait costs were not observed. Conclusion: These findings suggest that DT gait performance is not indicative for cognitive impairment in PD. DT effects on gait parameters were substantial in cognitively impaired and unimpaired patients, thereby potentially overlaying the effect of cognitive impairment on DT gait costs. Limits of the MoCA in detecting motor-function specific cognitive performance or variable individual response to the DT as influencing factors cannot be excluded. Therefore, DT gait parameters as marker for cognitive performance should be carefully interpreted in the clinical context.

12.
PLoS One ; 12(10): e0183989, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29020012

RESUMO

Distinct gait characteristics like short steps and shuffling gait are prototypical signs commonly observed in Parkinson's disease. Routinely assessed by observation through clinicians, gait is rated as part of categorical clinical scores. There is an increasing need to provide quantitative measurements of gait, e.g. to provide detailed information about disease progression. Recently, we developed a wearable sensor-based gait analysis system as diagnostic tool that objectively assesses gait parameter in Parkinson's disease without the need of having a specialized gait laboratory. This system consists of inertial sensor units attached laterally to both shoes. The computed target of measures are spatiotemporal gait parameters including stride length and time, stance phase time, heel-strike and toe-off angle, toe clearance, and inter-stride variation from gait sequences. To translate this prototype into medical care, we conducted a cross-sectional study including 190 Parkinson's disease patients and 101 age-matched controls and measured gait characteristics during a 4x10 meter walk at the subjects' preferred speed. To determine intraindividual changes in gait, we monitored the gait characteristics of 63 patients longitudinally. Cross-sectional analysis revealed distinct spatiotemporal gait parameter differences reflecting typical Parkinson's disease gait characteristics including short steps, shuffling gait, and postural instability specific for different disease stages and levels of motor impairment. The longitudinal analysis revealed that gait parameters were sensitive to changes by mirroring the progressive nature of Parkinson's disease and corresponded to physician ratings. Taken together, we successfully show that wearable sensor-based gait analysis reaches clinical applicability providing a high biomechanical resolution for gait impairment in Parkinson's disease. These data demonstrate the feasibility and applicability of objective wearable sensor-based gait measurement in Parkinson's disease reaching high technological readiness levels for both, large scale clinical studies and individual patient care.


Assuntos
Marcha , Monitorização Fisiológica/instrumentação , Doença de Parkinson/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Equilíbrio Postural , Fatores de Tempo
13.
BMC Neurol ; 17(1): 194, 2017 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-29073886

RESUMO

BACKGROUND: The loss of the swallow-tail sign of the substantia nigra has been proposed for diagnosis of Parkinson's disease. Aim was to evaluate, if the sign occurs consistently in healthy subjects and if it can be reliably detected with high-resolution 7T susceptibility weighted imaging (SWI). METHODS: Thirteen healthy adults received SWI at 7T. 3 neuroradiologists, who were blinded to patients' diagnosis, independently classified subjects regarding the swallow-tail sign to be present or absent. Accuracy, positive and negative predictive values (PPV and NPV) as well as inter- and intra-rater reliability and internal consistency were analyzed. RESULTS: The sign could be detected in 81% of the cases in consensus reading. Accuracy to detect the sign compared to the consensus was 100, 77 and 96% for the three readers with PPV reader 1/2/3 = 1/0.45/0.83 and NPV = 1/1/1. Inter-rater reliability was excellent (inter-class correlation coefficient = 0.844, alpha = 0.871). Intra-rater reliability was good to excellent (reader 1 R/L = 0.625/0.786; reader 2 = 0.7/0.64; reader 3 = 0.9/1). CONCLUSION: The swallow-tail sign can be reliably detected. However, our data suggest its occurrence is not consistent in healthy subjects. It may be possible that one reason is an individually variable molecular organization of nigrosome 1 so that it does not return a uniform signal in SWI.


Assuntos
Imagem por Ressonância Magnética/métodos , Doença de Parkinson/diagnóstico por imagem , Substância Negra/diagnóstico por imagem , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/diagnóstico , Reprodutibilidade dos Testes
14.
Case Rep Neurol ; 9(1): 44-48, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28611642

RESUMO

Amantadine is frequently used in addition to dopaminergic substances like dopamine agonists or L-Dopa in advanced Parkinson disease (PD). However, adverse effects like hallucinations limit its use. PD patients developing severe psychotic symptoms upon treatment with either dopaminergic substances and/or amantadine need to stop intake of any psychotropic substance. Here, we report the case of a 71-year-old PD patient without previously known cognitive impairment. He presented with drug-induced psychotic symptoms due to changes in his therapeutic regimen (increase in COMT inhibitors, newly introduced MAO B inhibitors). Also, amantadine had been part of his long-term medication for more than 2 years. The severity of his psychotic symptoms required a L-Dopa monotherapy. After changing his medication, the patient developed severe delirium that resolved rapidly after i.v. amantadine infusion, suggesting an amantadine withdrawal syndrome. Amantadine withdrawal syndrome is a rare adverse event that may present even in PD patients without cognitive impairment. This case report highlights the need for a gradual withdrawal of amantadine even if acute and severe psychotic symptoms are present. Moreover, this is the first report of a cognitively unimpaired patient developing an amantadine withdrawal syndrome.

15.
Conf Proc IEEE Eng Med Biol Soc ; 2016: 672-675, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-28268417

RESUMO

In this study, we intended to differentiate patients with essential tremor (ET) from tremor dominant Parkinson disease (PD). Accelerometer and electromyographic signals of hand movement from standardized upper extremity movement tests (resting, holding, carrying weight) were extracted from 13 PD and 11 ET patients. The signals were filtered to remove noise and non-tremor high frequency components. A set of statistical features was then extracted from the discrete wavelet transformation of the signals. Principal component analysis was utilized to reduce dimensionality of the feature space. Classification was performed using support vector machines. We evaluated the proposed method using leave one out cross validation and we report overall accuracy of the classification. With this method, it was possible to discriminate 12/13 PD patients from 8/11 patients with ET with an overall accuracy of 83%. In order to individualize this finding for clinical application we generated a posterior probability for the test result of each patient and compared the misclassified patients, or low probability scores to available clinical follow up information for individual cases. This non-standardized post hoc analysis revealed that not only the technical accuracy but also the clinical accuracy limited the overall classification rate. We show that, in addition to the successful isolation of diagnostic features, longitudinal and larger sized validation is needed in order to prove clinical applicability.


Assuntos
Tremor Essencial/diagnóstico , Doença de Parkinson/diagnóstico , Acelerometria , Idoso , Idoso de 80 Anos ou mais , Análise Discriminante , Eletromiografia , Tremor Essencial/classificação , Tremor Essencial/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Análise de Componente Principal , Máquina de Vetores de Suporte , Análise de Ondaletas
16.
Restor Neurol Neurosci ; 32(4): 447-62, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24604006

RESUMO

PURPOSE: Parkinson's disease (PD) is characterized by striatal synaptic deafferentation followed by dopaminergic cell death in the substantia nigra pars compacta. Not only degenerative, but also regenerative, compensatory changes at distant sites of the primary lesion may occur in PD. The aim of the study was to analyze the temporal pattern of axonal and glial responses over a time course of six weeks post-lesioning. METHODS: For this aim, 6-hydroxydopamine (6-OHDA) was injected unilaterally into the medial forebrain bundle and both lesioned and non-lesioned striata were analyzed. RESULTS: We detected increased tyrosine hydroxylase (TH) immunoreactivity within the non-lesioned striatum six weeks after injection indicative either of increased TH expression or compensatory neuritic changes. An increased number of microglial cells was present in both lesioned and unlesioned striata. There was no obvious change in microglial phenotype or in pro-inflammatory cytokine gene expression within the striatum without any apparent switch into a pro-inflammatory phenotype. No changes were observed in the number of mature oligodendrocytes. CONCLUSIONS: This temporal pattern shows, that the non-lesioned striatum undergoes profound changes, involving increased TH expression accompanied by a glial response. A better understanding of this complex interplay of neuronal as well as glial components not only within the lesioned, but also non-lesioned striatum may help to restore local neural circuits in PD.


Assuntos
Lateralidade Funcional , Regulação da Expressão Gênica/efeitos dos fármacos , Neuroglia/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Tirosina 3-Mono-Oxigenase/metabolismo , Adrenérgicos/toxicidade , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Corpo Estriado/patologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Lateralidade Funcional/efeitos dos fármacos , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Proteínas dos Microfilamentos/metabolismo , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Oxidopamina/toxicidade , Doença de Parkinson/etiologia , Parte Compacta da Substância Negra/efeitos dos fármacos , Ratos , Ratos Wistar , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/genética
17.
Neurobiol Dis ; 59: 38-51, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23867236

RESUMO

In Parkinson's disease (PD) patients, alpha-synuclein (α-syn) pathology advances in form of Lewy bodies and Lewy neurites throughout the brain. Clinically, PD is defined by motor symptoms that are predominantly attributed to the dopaminergic cell loss in the substantia nigra. However, motor deficits are frequently preceded by smell deficiency or neuropsychological symptoms, including increased anxiety and cognitive dysfunction. Accumulating evidence indicates that aggregation of α-syn impairs synaptic function and neurogenic capacity that may be associated with deficits in memory, learning and mood. Whether and how α-syn accumulation contributes to neuropathological events defining these earliest signs of PD is presently poorly understood. We used a tetracycline-suppressive (tet-off) transgenic mouse model that restricts overexpression of human A30P α-syn to neurons owing to usage of the neuron-specific CaMKIIα promoter. Abnormal accumulation of A30P correlated with a decreased survival of newly generated neurons in the hippocampus and olfactory bulb. Furthermore, when A30P α-syn expression was suppressed, we observed reduction of the human protein in neuronal soma. However, residual dox resistant A30P α-syn was detected in glial cells within the hippocampal neurogenic niche, concomitant with the failure to fully restore hippocampal neurogenesis. This finding is indicative to a potential spread of pathology from neuron to glia. In addition, mice expressing A30P α-syn show increased anxiety-related behavior that was reversed after dox treatment. This implies that glial A30P α-synucleinopathy within the dentate gyrus is part of a process leading to impaired hippocampal neuroplasticity, which is, however, not a sole critical event for circuits implicated in anxiety-related behavior.


Assuntos
Alanina/genética , Ansiedade , Neurogênese/genética , Neuroglia/patologia , Prolina/genética , alfa-Sinucleína/genética , Animais , Ansiedade/genética , Ansiedade/patologia , Ansiedade/fisiopatologia , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Contagem de Células , Modelos Animais de Doenças , Doxiciclina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuropeptídeos/metabolismo , Bulbo Olfatório/metabolismo , Bulbo Olfatório/patologia
18.
PLoS One ; 8(2): e56956, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23431395

RESUMO

Motor impairments are the prerequisite for the diagnosis in Parkinson's disease (PD). The cardinal symptoms (bradykinesia, rigor, tremor, and postural instability) are used for disease staging and assessment of progression. They serve as primary outcome measures for clinical studies aiming at symptomatic and disease modifying interventions. One major caveat of clinical scores such as the Unified Parkinson Disease Rating Scale (UPDRS) or Hoehn&Yahr (H&Y) staging is its rater and time-of-assessment dependency. Thus, we aimed to objectively and automatically classify specific stages and motor signs in PD using a mobile, biosensor based Embedded Gait Analysis using Intelligent Technology (eGaIT). eGaIT consist of accelerometers and gyroscopes attached to shoes that record motion signals during standardized gait and leg function. From sensor signals 694 features were calculated and pattern recognition algorithms were applied to classify PD, H&Y stages, and motor signs correlating to the UPDRS-III motor score in a training cohort of 50 PD patients and 42 age matched controls. Classification results were confirmed in a second independent validation cohort (42 patients, 39 controls). eGaIT was able to successfully distinguish PD patients from controls with an overall classification rate of 81%. Classification accuracy increased with higher levels of motor impairment (91% for more severely affected patients) or more advanced stages of PD (91% for H&Y III patients compared to controls), supporting the PD-specific type of analysis by eGaIT. In addition, eGaIT was able to classify different H&Y stages, or different levels of motor impairment (UPDRS-III). In conclusion, eGaIT as an unbiased, mobile, and automated assessment tool is able to identify PD patients and characterize their motor impairment. It may serve as a complementary mean for the daily clinical workup and support therapeutic decisions throughout the course of the disease.


Assuntos
Marcha , Doença de Parkinson/diagnóstico , Idoso , Estudos de Casos e Controles , Reações Falso-Negativas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Reconhecimento Automatizado de Padrão , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Tremor
19.
Cell Mol Life Sci ; 70(3): 459-73, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22766974

RESUMO

Parkinson's disease (PD), the second most common neurodegenerative disorder, affects 1-2 % of humans aged 60 years and older. The diagnosis of PD is based on motor symptoms such as bradykinesia, rigidity, tremor, and postural instability associated with the striatal dopaminergic deficit that is linked to neurodegenerative processes in the substantia nigra (SN). In the past, cellular replacement strategies have been evaluated for their potential to alleviate these symptoms. Adult neurogenesis, the generation of new neurons within two proliferative niches in the adult brain, is being intensively studied as one potential mode for cell-based therapies. The subventricular zone provides new neurons for the olfactory bulb functionally contributing to olfaction. The subgranular zone of the hippocampus produces new granule neurons for the dentate gyrus, required for memory formation and proper processing of anxiety provoking stimuli. Recent years have revealed that PD is associated with non-motor symptoms such as hyposmia, anhedonia, lack of novelty seeking behavior, depression, and anxiety that are not directly associated with neurodegenerative processes in the SN. This broad spectrum of non-motor symptoms may partly rely on proper olfactorial processing and hippocampal function. Therefore, it is conceivable that some non-motor deficits in PD are related to defective adult neurogenesis. Accordingly, in animal models and postmortem studies of PD, adult neurogenesis is severely affected, although the exact mechanisms and effects of these changes are not yet fully understood or are under debate due to conflicting results. Here, we review the current concepts related to the dynamic interplay between endogenous cellular plasticity and PD-associated pathology.


Assuntos
Neurogênese , Doença de Parkinson/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/química , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/metabolismo , Animais , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/metabolismo , Humanos , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Doença de Parkinson/patologia , alfa-Sinucleína/metabolismo
20.
Eur J Neurosci ; 29(5): 879-90, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19291219

RESUMO

In familial and sporadic forms of Parkinson's disease (PD), alpha-synuclein pathology is present in the brain stem nuclei and olfactory bulb (OB) long before Lewy bodies are detected in the substantia nigra. The OB is an active region of adult neurogenesis, where newly generated neurons physiologically integrate. While accumulation of wild-type alpha-synuclein is one of the pathogenic hallmarks of non-genetic forms of PD, the A30P alpha-synuclein mutation results in an earlier disease onset and a severe clinical phenotype. Here, we study the regulation of adult neurogenesis in the subventricular zone (SVZ)/OB system in a tetracycline-suppressive (tet-off) transgenic model of synucleinopathies, expressing human mutant A30P alpha-synuclein under the control of the calcium/calmodulin-dependent protein kinase II alpha (CaMK) promoter. In A30P transgenic mice alpha-synuclein was abundant at the site of integration in the glomerular cell layer of the OB. Without changes in proliferation in the SVZ, significantly fewer newly generated neurons were observed in the OB granule cell and glomerular layers of A30P transgenic mice than in controls, most probably due to increased cell death. By tetracycline-dependent abrogation of A30P alpha-synuclein expression, OB neurogenesis and programmed cell death was restored to control levels. Our results indicate that, using A30P conditional (tet-off) mice, A30P alpha-synuclein has a negative impact on olfactory neurogenesis and suppression of A30P alpha-synuclein enhances survival of newly generated neurons. This finding suggests that interfering with alpha-synuclein pathology can rescue newly generated neurons, possibly leading to new targets for therapeutic interventions in synucleinopathies.


Assuntos
Alanina/genética , Mutação/genética , Neurogênese/genética , Bulbo Olfatório/citologia , Prolina/genética , alfa-Sinucleína/genética , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Morte Celular/genética , Proliferação de Células , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Neurônios/fisiologia , Neuropeptídeos/metabolismo , Bulbo Olfatório/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , alfa-Sinucleína/metabolismo
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