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1.
Exp Neurol ; 322: 113058, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31499061

RESUMO

Evidence indicates that depression is closely related to hyperactivity of the lateral habenula (LHb). However, it is not clear how activation and blockade of AMPA receptors (AMPARs) in the LHb affect depressive-like behaviors, particularly in Parkinson's disease-related depression. In this study, unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta (SNc) in rats induced depressive-like behaviors and led to hyperactivity of LHb neurons compared to SNc sham-lesioned rats. Interestingly, intra-LHb injection of AMPAR agonist (S)-AMPA produced antidepressant-like effects in the two groups of rats and antagonist NBQX induced depressive-like behaviors, although (S)-AMPA excited LHb neurons and NBQX inhibited these neurons. We further found that intra-LHb injection of (S)-AMPA excited dopaminergic neurons in the anterior ventral tegmental area (aVTA) and serotonergic neurons in the dorsal raphe nucleus (DRN), which increased release of DA and 5-HT in the medial prefrontal cortex (mPFC), while NBQX induced the opposite effects. Further, lesioning the GABAergic rostromedial tegmental nucleus did not alter the proportions of the responses of these neurons to AMPAR stimulation. Additionally, lesions of the SNc reduced the level of p-GluR2-S880 in the LHb, which can increase the surface expression of calcium-impermeable GluR2-containing AMPARs (CI-AMPARs). This change in SNc-lesioned rats enhanced effects of (S)-AMPA and NBQX on the behaviors, LHb neuronal firing and release of DA and 5-HT. Collectively, antidepressant-like effects produced by (S)-AMPA attribute to activation of LHb neurons expressing CI-AMPAR, which excites aVTA dopaminergic neurons and DRN serotonergic neurons via the direct projection, thereby increasing release of mPFC DA and 5-HT.


Assuntos
Depressão/metabolismo , Habenula/metabolismo , Transtornos Parkinsonianos/metabolismo , Receptores de AMPA/metabolismo , Animais , Depressão/etiologia , Masculino , Transtornos Parkinsonianos/complicações , Ratos , Ratos Sprague-Dawley
2.
Clin Nucl Med ; 44(12): 987-988, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31524680

RESUMO

A 59-year-old man had developed within a few months walking disorders and rigidity of the left upper limb. I-FP-CIT SPECT/CT was performed in response to the suspicion of atypical parkinsonian syndrome. It showed an anomaly in presynaptic dopaminergic transmission on the right striatum and a voluminous expansive process on CT. MRI revealed an atypical meningioma. The patient had surgery for tumor removal. Later I-FP-CIT SPECT/CT showed normalization of presynaptic dopaminergic transmission on the right striatum.


Assuntos
Erros de Diagnóstico , Neoplasias Meníngeas/complicações , Neoplasias Meníngeas/diagnóstico , Meningioma/complicações , Meningioma/diagnóstico , Transtornos Parkinsonianos/complicações , Humanos , Imagem por Ressonância Magnética , Masculino , Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Pessoa de Meia-Idade , Neostriado/diagnóstico por imagem , Neostriado/metabolismo , Transtornos Parkinsonianos/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos
4.
Neurology ; 93(7): e665-e674, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31289143

RESUMO

OBJECTIVE: To investigate the effect of polygenic load on the progression of striatal dopaminergic dysfunction in patients with Parkinson disease (PD). METHODS: Using data from 335 patients with PD in the Parkinson's Progression Markers Initiative (PPMI) database, we investigated the longitudinal association of PD-associated polygenic load with changes in striatal dopaminergic activity as measured by 123I-N-3-fluoropropyl-2-ß-carboxymethoxy-3ß-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT over 4 years. PD-associated polygenic load was estimated by calculating weighted genetic risk scores (GRS) using 1) all available 27 PD-risk single nucleotide polymorphisms (SNPs) in the PPMI database (GRS1) and 2) 23 SNPs with minor allele frequency >0.05 (GRS2). RESULTS: GRS1 and GRS2 were correlated with younger age at onset in patients with PD (GRS1, Spearman ρ = -0.128, p = 0.019; GRS2, Spearman ρ = -0.109, p = 0.047). Although GRS1 did not show an association with changes in striatal 123I-FP-CIT availability, GRS2 was associated with a slower decline of striatal dopaminergic activity (interactions with disease duration in linear mixed model; caudate nucleus, estimate = 0.399, SE = 0.165, p = 0.028; putamen, estimate = 0.396, SE = 0.137, p = 0.016). CONCLUSIONS: Our results suggest that genetic factors for PD risk may have heterogeneous effects on striatal dopaminergic degeneration, and some factors may be associated with a slower decline of dopaminergic activity. Composition of PD progression-specific GRS may be useful in predicting disease progression in patients.


Assuntos
Corpo Estriado/metabolismo , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/metabolismo , Tropanos/metabolismo , Adulto , Idoso , Núcleo Caudado/metabolismo , Progressão da Doença , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/complicações , Doença de Parkinson/genética , Transtornos Parkinsonianos/complicações , Putamen/metabolismo
5.
Pract Neurol ; 19(4): 350-351, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30975708

RESUMO

Both multiple system atrophy and Parkinson's disease may present with parkinsonism and autonomic dysfunction. We describe a patient who initially met the diagnostic criteria for multiple system atrophy and had atypical features for Parkinson's disease including blackouts and pyramidal signs. Ultimately, he was found to have three separate diagnoses rather than a single unifying one.


Assuntos
Insuficiência de Múltiplos Órgãos/diagnóstico por imagem , Atrofia de Múltiplos Sistemas/diagnóstico por imagem , Transtornos Parkinsonianos/diagnóstico por imagem , Idoso , Diagnóstico Diferencial , Humanos , Levodopa/uso terapêutico , Masculino , Insuficiência de Múltiplos Órgãos/complicações , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Atrofia de Múltiplos Sistemas/complicações , Atrofia de Múltiplos Sistemas/tratamento farmacológico , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/tratamento farmacológico
6.
Artigo em Inglês | MEDLINE | ID: mdl-30867978

RESUMO

Background: A re-emergent tremor is suggested to be specific to Parkinson's disease and although a tongue tremor has been reported in levosulpiride-induced parkinsonism (LIP), re-emergence has never been reported. Case Report: A 59-year-old female presented with a 3-month history of bradykinesia, 2-week history of right-leg tremor, and 10-day history of lip and tongue tremor. A review of the medication revealed a 15-month history of levosulpiride consumption. On examination, asymmetric bradykinesia, rigidity, rest tremor of the right leg, and re-emergent tongue tremor were observed. The parkinsonism subsided after levosulpiride was stopped. Discussion: This is the first report of re-emergent tongue tremor in LIP.


Assuntos
Antipsicóticos/efeitos adversos , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/complicações , Língua/fisiopatologia , Tremor/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico por imagem , Tremor/diagnóstico por imagem
7.
J Neurol ; 266(6): 1394-1404, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30859316

RESUMO

Although motor speech disorders represent an early and prominent clinical feature of multiple system atrophy (MSA), the potential usefulness of speech assessment as a diagnostic tool has not yet been explored. This cross-sectional study aimed to provide a comprehensive, objective description of motor speech function in the parkinsonian (MSA-P) and cerebellar (MSA-C) variants of MSA. Speech samples were acquired from 80 participants including 18 MSA-P, 22 MSA-C, 20 Parkinson's disease (PD), and 20 healthy controls. The accurate differential diagnosis of dysarthria subtypes was based on quantitative acoustic analysis of 14 speech dimensions. A mixed type of dysarthria involving hypokinetic, ataxic and spastic components was found in the majority of MSA patients independent of phenotype. MSA-P showed significantly greater speech impairment than PD, and predominantly exhibited harsh voice, imprecise consonants, articulatory decay, monopitch, excess pitch fluctuation and pitch breaks. MSA-C was dominated by prolonged phonemes, audible inspirations and voice stoppages. Inappropriate silences, irregular motion rates and overall slowness of speech were present in both MSA phenotypes. Speech features allowed discrimination between MSA-P and PD as well as between both MSA phenotypes with an area under curve up to 0.86. Hypokinetic, ataxic and spastic dysarthria components in MSA were correlated to the clinical evaluation of rigidity, cerebellar and bulbar/pseudobulbar manifestations, respectively. Distinctive speech alterations reflect underlying pathophysiology in MSA. Objective speech assessment may provide an inexpensive and widely applicable screening instrument for differentiation of MSA and PD from controls and among subtypes of MSA.


Assuntos
Doenças Cerebelares/fisiopatologia , Disartria/diagnóstico , Disartria/fisiopatologia , Atrofia de Múltiplos Sistemas/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Idoso , Doenças Cerebelares/complicações , Estudos de Coortes , Estudos Transversais , Disartria/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Atrofia de Múltiplos Sistemas/complicações , Transtornos Parkinsonianos/complicações , Acústica da Fala
8.
Psychogeriatrics ; 19(4): 345-354, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30784148

RESUMO

BACKGROUND: We performed a questionnaire survey of medical doctors engaged in the management of dementia to identify the actual status of treatment for dementia with Lewy bodies (DLB) in Japan. METHODS: Among participating medical doctors, we selected neurologists (Group N) and psychiatrists (Group P) because these physicians are usually involved in the management of DLB patients. The two groups were compared based on their diagnosis and treatment of DLB and in particular, parkinsonism. RESULTS: Neurological examinations and biomarker tests were less frequently performed by Group P than Group N. Antipsychotics and other psychotropics excluding anti-dementia drugs were significantly more frequently administered by Group P than Group N. The proportion of physicians who selected L-dopa as a first-line therapy for parkinsonism was significantly higher in Group N than in Group P. Despite these between-group differences, the following findings were common to the two groups: there was a discrepancy between the symptom that patients expressed the greatest desire to treat, and the awareness of physicians regarding the treatment of these symptoms; the initial agent was L-dopa; and physicians exercised caution against the occurrence of hallucinations, delusions, and other adverse drug reactions. CONCLUSIONS: The results of the present survey offer valuable insight for the formulation of future DLB therapeutic strategies.


Assuntos
Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Transtornos Parkinsonianos/diagnóstico , Transtornos Parkinsonianos/tratamento farmacológico , Médicos/estatística & dados numéricos , Psicotrópicos/uso terapêutico , Adulto , Antipsicóticos/uso terapêutico , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/tratamento farmacológico , Transtornos Neurológicos da Marcha/etiologia , Humanos , Hipocinesia/diagnóstico , Hipocinesia/tratamento farmacológico , Hipocinesia/etiologia , Doença por Corpos de Lewy/complicações , Doença por Corpos de Lewy/diagnóstico , Doença por Corpos de Lewy/tratamento farmacológico , Pessoa de Meia-Idade , Rigidez Muscular/diagnóstico , Rigidez Muscular/tratamento farmacológico , Rigidez Muscular/etiologia , Neurologistas/estatística & dados numéricos , Transtornos Parkinsonianos/complicações , Equilíbrio Postural/efeitos dos fármacos , Psiquiatria/estatística & dados numéricos , Tremor/diagnóstico , Tremor/tratamento farmacológico , Tremor/etiologia
9.
Exp Neurol ; 315: 72-81, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30772369

RESUMO

Parkinson's disease (PD) is a neurodegenerative disorder that causes progressive dysfunction of dopaminergic and non-dopaminergic neurons, generating motor and nonmotor signs and symptoms. Pain is reported as the most bothersome nonmotor symptom in PD; however, pain remains overlooked and poorly understood. In this study, we evaluated the nociceptive behavior and the descending analgesia circuitry in a rat model of PD. Three independent experiments were performed to investigate: i) thermal nociceptive behavior; ii) mechanical nociceptive behavior and dopaminergic repositioning; and iii) modulation of the pain control circuitry. The rat model of PD, induced by unilateral striatal 6-hydroxydopamine (6-OHDA), did not interfere with thermal nociceptive responses; however, the mechanical nociceptive threshold was decreased bilaterally compared to that of naive or striatal saline-injected rats. This response was reversed by apomorphine or levodopa treatment. Striatal 6-OHDA induced motor impairments and reduced dopaminergic neuron immunolabeling as well as the pattern of neuronal activation (c-Fos) in the substantia nigra ipsilateral (IPL) to the lesion. In the midbrain periaqueductal gray (PAG), 6-OHDA-induced lesion increased IPL and decreased contralateral PAG GABAergic labeling compared to control. In the dorsal horn of the spinal cord, lesioned rats showed bilateral inhibition of enkephalin and µ-opioid receptor labeling. Taken together, we demonstrated that the unilateral 6-OHDA-induced PD model induces bilateral mechanical hypernociception, which is reversed by dopamine restoration, changes in the PAG circuitry, and inhibition of spinal opioidergic regulation, probably due to impaired descending analgesic control. A better understanding of pain mechanisms in PD patients is critical for developing better therapeutic strategies to improve their quality of life.


Assuntos
Corpo Estriado/fisiopatologia , Nociceptividade , Dor/etiologia , Transtornos Parkinsonianos/complicações , Substância Negra/fisiopatologia , Animais , Apomorfina/farmacologia , Comportamento Animal , Agonistas de Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Temperatura Alta , Hidroxidopaminas , Masculino , Rede Nervosa/efeitos dos fármacos , Dor/psicologia , Limiar da Dor , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/fisiopatologia , Estimulação Física , Ratos , Ratos Wistar
10.
Neurotox Res ; 35(4): 918-930, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30796691

RESUMO

The cause of progressive degeneration in Parkinson's disease is not clear, although, in the last years, different studies have suggested that both brain and peripheral inflammation could play a key role in the progression of this disorder. In our study, we aimed to analyze the effect of an acute inflammation confined to the colon on dopaminergic neuronal death and glial response in mice intoxicated with MPTP. The results obtained show a very significant decrease of dopaminergic neurons in the SNpc as well as a significant decrease of dopaminergic fibers in the striatum of the MPTP+DSS-treated group compared with the control animals. In addition, there was a significant exacerbation of microglial and astrocytes activation in MPTP+DSS animals compared with the control group. This data suggests that a specific gastrointestinal injury, which induces a systemic inflammatory response, is able to exacerbate cell death mechanisms of the remaining dopaminergic neurons and then contributes to the persistent progression of the disease. These results leave open new lines of research on the role of exclusive colonic inflammation and the progression of nigrostriatal dopaminergic degeneration.


Assuntos
Morte Celular , Colite/metabolismo , Corpo Estriado/metabolismo , Neurônios Dopaminérgicos/metabolismo , Transtornos Parkinsonianos/metabolismo , Parte Compacta da Substância Negra/metabolismo , Animais , Astrócitos/metabolismo , Colite/complicações , Colite/patologia , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Transtornos Parkinsonianos/complicações , Teste de Desempenho do Rota-Rod
11.
Mov Disord ; 34(2): 264-273, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30633810

RESUMO

BACKGROUND: Pantothenate kinase-associated neurodegeneration is a rare autosomal-recessive disorder, characterized by progressive neurodegeneration associated with brain iron accumulation. DBS has been trialed to treat related movement disorders, particularly dystonia. The objective of this study was to determine the outcome and safety of DBS for pantothenate kinase-associated neurodegeneration. METHODS: We performed a meta-analysis using independent participant data (n = 99) from 38 articles. Primary outcome was change in movement and disability scores of the Burke-Fahn-Marsden Dystonia Rating Scale 1 year postoperatively. Secondary outcomes were response rate and complications. RESULTS: Patients with classic-type (n = 58) and atypical-type (n = 15) pantothenate kinase-associated neurodegeneration were operated on at a median age of 11 and 31 years, respectively (P < 0.001). GPi was primarily targeted (n = 87). Mean dystonia movement score improved 1 year following GPi-DBS (-26%; 95% confidence interval, -37% to -15%), particularly in atypical versus classic cases (-45% vs -16%; P < 0.001). At least 30% improvement was observed in 34% of classic versus 73% of atypical cases (P = 0.04). Higher preoperative score and atypical type predicted larger improvement. GPi-DBS improved dystonia disability score in atypical (-31%; 95% confidence interval, -49% to -13%) but not classic (-5%; 95% confidence interval, -17% to 8%) cases. Prevalence of surgical infections (6%) and hardware failure (7%) was similar to other dystonia etiologies. Two patients died within 3 months. There was insufficient data to describe outcome > 1 year following GPi-DBS or with other DBS targets. Overall, small sample sizes limited generalizability. CONCLUSIONS: This meta-analysis provides level 4 evidence that GPi-DBS for pantothenate kinase-associated neurodegeneration may improve dystonia movement scores in classic type and atypical type and disability scores in atypical type 1 year postoperatively. © 2019 International Parkinson and Movement Disorder Society.


Assuntos
Estimulação Encefálica Profunda , Distonia/terapia , Neurodegeneração Associada a Pantotenato-Quinase/terapia , Transtornos Parkinsonianos/terapia , Adolescente , Adulto , Encéfalo/cirurgia , Criança , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/terapia , Distonia/fisiopatologia , Distúrbios Distônicos/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurodegeneração Associada a Pantotenato-Quinase/complicações , Neurodegeneração Associada a Pantotenato-Quinase/fisiopatologia , Transtornos Parkinsonianos/complicações , Resultado do Tratamento , Adulto Jovem
12.
J Neurol ; 266(2): 426-430, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30536108

RESUMO

Gait festination is one of the most characteristic gait disturbances in patients with Parkinson's disease or atypical parkinsonism. Although festination is common and disabling, it has received little attention in the literature, and different definitions exist. Here, we argue that there are actually two phenotypes of festination. The first phenotype entails a primary locomotion disturbance, due to the so-called sequence effect: a progressive shortening of step length, accompanied by a compensatory increase in cadence. This phenotype strongly relates to freezing of gait with alternating trembling of the leg. The second phenotype results from a postural control problem (forward leaning of the trunk) combined with a balance control deficit (inappropriately small balance-correcting steps). In this viewpoint, we elaborate on the possible pathophysiological substrate of these two phenotypes of festination and discuss their management in daily clinical practice.


Assuntos
Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Equilíbrio Postural/fisiologia , Transtornos Neurológicos da Marcha/classificação , Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/terapia , Humanos , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/terapia , Fenótipo
13.
Neurobiol Aging ; 75: 126-135, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30572183

RESUMO

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/ΔFosB expression, in rats with mild parkinsonism induced by viral-mediated substantia nigra overexpression of human A53T mutated α-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/ΔFosB 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.


Assuntos
Transtornos Disruptivos, de Controle do Impulso e da Conduta/fisiopatologia , Comportamento Impulsivo/efeitos dos fármacos , Doença de Parkinson/fisiopatologia , Pramipexol/farmacologia , Animais , Corpo Estriado/metabolismo , Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Doença de Parkinson/metabolismo , Transtornos Parkinsonianos/complicações , Ratos , Substância Negra/metabolismo , Substância Negra/fisiopatologia
14.
Conf Proc IEEE Eng Med Biol Soc ; 2019: 3290-3296, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31946586

RESUMO

In this paper, viability of low-cost off-the-shelf Piezoelectric ceramic disc elements is explored for an insole-based gait monitoring system, `PI-Sole' (Piezo In-Sole). Piezoelectric elements can sense dynamic changes in pressure in a closed-loop environment with good sensitivity and a wide measurement range. In this paper, method to enable these elements to continuously sense plantar pressure while walking is proposed, making them a very cost-efficient alternative to the widely used Force Sensing Resistors (FSR) and pressure plates for monitoring human gait. However, piezoelectric elements show hysteresis in their force response, inducing a drift in calculated pressure which increases with time. A novel and effective method to perform detrending of the signal is also presented utilizing stride contexts from a 6-DoF Inertial Measurement Unit (IMU) and the same is utilized to perform zero-correction in the pressure data. 3-D trajectories of strides are calculated using the IMU, and parameters like stride length, stride height etc. are further derived. In order to test the validity of our proposed methods, important kinetic parameters like Vertical Ground Reaction Force (VGRF) and Center of Pressure (CoP) are calculated using PI-Sole and compared to the ones calculated using FSR's in multiple prior works. Applicability of PI-Sole is demonstrated further by depicting and analysing characteristic differences between a heel-strike toe-off stance type, and a flat-strike stance type, the latter being one of the primary symptoms in many cases of pathological gait, including Parkinsonian gait. Important artefacts from foot's height profile while walking are analysed for both stance types in context of standard gait events. We report a mean error of 2.8cm in stride length calculation, and a mean accuracy of 94.5% in calculating swing/stance duration of gait cycles.


Assuntos
Análise da Marcha , Marcha , Transtornos Parkinsonianos , Caminhada , Algoritmos , Fenômenos Biomecânicos , , Humanos , Monitorização Fisiológica , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico , Dispositivos Eletrônicos Vestíveis
15.
J Neuroinflammation ; 15(1): 333, 2018 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-30501635

RESUMO

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease, presenting with midbrain dopaminergic neurons degeneration. A number of studies suggest that microglial activation may have a role in PD. It has emerged that inflammation-derived oxidative stress and cytokine-dependent toxicity may contribute to nigrostriatal pathway degeneration and exacerbate the progression of the disease in patients with idiopathic PD. Cell therapies have long been considered a feasible regenerative approach to compensate for the loss of specific cell populations such as the one that occurs in PD. We recently demonstrated that erythropoietin-releasing neural precursors cells (Er-NPCs) administered to MPTP-intoxicated animals survive after transplantation in the recipient's damaged brain, differentiate, and rescue degenerating striatal dopaminergic neurons. Here, we aimed to investigate the potential anti-inflammatory actions of Er-NPCs infused in an MPTP experimental model of PD. METHODS: The degeneration of dopaminergic neurons was caused by MPTP administration in C57BL/6 male mice. 2.5 × 105 GFP-labeled Er-NPCs were administered by stereotaxic injection unilaterally in the left striatum. Functional recovery was assessed by two independent behavioral tests. Neuroinflammation was investigated measuring the mRNAs levels of pro-inflammatory and anti-inflammatory cytokines, and immunohistochemistry studies were performed to evaluate markers of inflammation and the potential rescue of tyrosine hydroxylase (TH) projections in the striatum of recipient mice. RESULTS: Er-NPC administration promoted a rapid anti-inflammatory effect that was already evident 24 h after transplant with a decrease of pro-inflammatory and increase of anti-inflammatory cytokines mRNA expression levels. This effect was maintained until the end of the observational period, 2 weeks post-transplant. Here, we show that Er-NPCs transplant reduces macrophage infiltration, directly counteracting the M1-like pro-inflammatory response of murine-activated microglia, which corresponds to the decrease of CD68 and CD86 markers, and induces M2-like pro-regeneration traits, as indicated by the increase of CD206 and IL-10 expression. Moreover, we also show that this activity is mediated by Er-NPCs-derived erythropoietin (EPO) since the co-injection of cells with anti-EPO antibodies neutralizes the anti-inflammatory effect of the Er-NPCs treatment. CONCLUSION: This study shows the anti-inflammatory actions exerted by Er-NPCs, and we suggest that these cells may represent good candidates for cellular therapy to counteract neuroinflammation in neurodegenerative disorders.


Assuntos
Encefalite/etiologia , Encefalite/cirurgia , Eritropoetina/uso terapêutico , Células-Tronco Neurais/transplante , Transtornos Parkinsonianos/complicações , Recuperação de Função Fisiológica/fisiologia , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Animais , Técnicas de Cocultura , Corpo Estriado/metabolismo , Corpo Estriado/cirurgia , Citocinas/metabolismo , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Eritropoetina/genética , Eritropoetina/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Força Muscular/efeitos dos fármacos , Força Muscular/fisiologia , Células-Tronco Neurais/fisiologia , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/patologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/genética , Olfato/efeitos dos fármacos , Olfato/fisiologia , Tirosina 3-Mono-Oxigenase/metabolismo
17.
J Neuroinflammation ; 15(1): 328, 2018 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-30477535

RESUMO

BACKGROUND: Neuroprotective strategies are becoming relevant to slow down dopaminergic cell death and inflammatory processes related to the progressive neurodegeneration in Parkinson's disease (PD). Interestingly, among others, physical activity (PA) or anti-oxidant agents (such as N-acetyl-L-cysteine, NAC) are common therapeutic strategies. Therefore, this study aims to analyze if there is a synergistic effect of physical activity along with NAC treatment on dopaminergic degeneration and neuroinflammatory response in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism model after subchronic intoxication. METHODS: To ascertain this possibility, 48 8-week-old male mice (C57BL/6 strain) were used. Twenty four of them were placed individually in cages where voluntary physical activity was automatically monitored during 30 days and were divided into groups: (i) control; (ii) NAC; (iii) MPTP, and (iv) MPTP+NAC. The other 24 mice were divided into the same four groups but without physical activity. RESULTS: The data collected during the treatment period showed that there was an overall increase in the total running distance in all groups under physical activity, including Parkinsonian animals. However, the monitoring data per day showed that the activity routine by MPTP and MPTP+NAC groups was disrupted by alterations in the circardian rhythm because of MPTP intoxication. Results from post-mortem studies in the substantia nigra pars compacta (SNpc) showed significant decrease in the number of TH+ cells in all MPTP groups. Moreover, TH+ expression in the striatum was significantly decreased in all MPTP groups. Thus, PA + NAC treatment do not protect dopaminergic neurons against a subchronic intoxication of MPTP. Regarding glial response, the results obtained from microglial analysis do not show significant increase in the number of Iba-1+ cell in MPTP+NAC and MPTP+PA + NAC. In the striatum, a significant decrease is observed only in the MPTP+NAC group compared with that of the MPTP group. The microglial results are reinforced by those obtained from the analysis of astroglial response, in which a decrease in the expression of GFAP+ cells are observed in MPTP+NAC and MPTP+PA + NAC compared with MPTP groups both in the SNpc and in the striatum. Finally, from the study of the astroglial response by the co-localization of GFAP/S100b, we described some expression patterns observed based on the severity of the damage produced by the MPTP intoxication in the different treated groups. CONCLUSIONS: These results suggest that the combination of physical activity with an anti-oxidant agent does not have a synergistic neuroprotective effect in the nigrostriatal pathway. Our results show a potential positive effect, only due to NAC treatment, on the neuroinflammatory response after subchronic MPTP intoxication. Thus, physical activity is not essential, under these conditions. However, we believe that physical activity, used for therapeutic purposes, has a beneficial long-term effect. In this line, these results open the door to design longer studies to demonstrate its promising effect as neuroprotective strategy.


Assuntos
Acetilcisteína/uso terapêutico , Encefalite/reabilitação , Neuroprostanos/uso terapêutico , Transtornos Parkinsonianos/complicações , Condicionamento Físico Animal/métodos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Análise de Variância , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Modelos Animais de Doenças , Encefalite/tratamento farmacológico , Encefalite/etiologia , Encefalite/patologia , Proteína Glial Fibrilar Ácida/metabolismo , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas dos Microfilamentos/metabolismo , Microscopia Confocal , Transtornos Parkinsonianos/induzido quimicamente , Condicionamento Físico Animal/fisiologia , Subunidade beta da Proteína Ligante de Cálcio S100/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Mov Disord ; 33(11): 1814-1819, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30398675

RESUMO

BACKGROUND: The genetic bases of PD in sub-Saharan African (SSA) populations remain poorly characterized, and analysis of SSA families with PD might lead to the discovery of novel disease-related genes. OBJECTIVES: To investigate the clinical features and identify the disease-causing gene in a black South African family with 3 members affected by juvenile-onset parkinsonism and intellectual disability. METHODS: Clinical evaluation, neuroimaging studies, whole-exome sequencing, homozygosity mapping, two-point linkage analysis, and Sanger sequencing of candidate variants. RESULT: A homozygous 28-nucleotide frameshift deletion in the PTRHD1 coding region was identified in the 3 affected family members and linked to the disease with genome-wide significant evidence. PTRHD1 was recently nominated as the disease-causing gene in two Iranian families, each containing 2 siblings with similar phenotypes and homozygous missense mutations. CONCLUSION: Together with the previous reports, we provide conclusive evidence that loss-of-function mutations in PTRHD1 cause autosomal-recessive juvenile parkinsonism and intellectual disability. © 2018 International Parkinson and Movement Disorder Society.


Assuntos
Saúde da Família , Deficiência Intelectual/genética , Proteínas de Membrana/genética , Proteínas Mitocondriais/genética , Mutação/genética , Transtornos Parkinsonianos/genética , Adulto , África ao Sul do Saara , Análise Mutacional de DNA , Feminino , Humanos , Deficiência Intelectual/complicações , Masculino , Transtornos Parkinsonianos/complicações
20.
Neurology ; 91(22): e2045-e2056, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30381367

RESUMO

OBJECTIVE: To examine mortality and associated risk factors, including possible effects of mild cognitive impairment, imaging, and CSF abnormalities, in a community-based population with incident parkinsonism and Parkinson disease. METHODS: One hundred eighty-two patients with new-onset, idiopathic parkinsonism were diagnosed from January 2004 through April 2009, in a catchment area of 142,000 inhabitants in Sweden. Patients were comprehensively investigated according to a multimodal research protocol and followed prospectively for up to 13.5 years. A total of 109 patients died. Mortality rates in the general Swedish population were used to calculate standardized mortality ratio and expected survival, and Cox proportional hazard models were used to investigate independent predictors of mortality. RESULTS: The standardized mortality ratio for all patients was 1.84 (95% confidence interval 1.50-2.22, p < 0.001). Patients with atypical parkinsonism (multiple system atrophy or progressive supranuclear palsy) had the highest mortality. In early Parkinson disease, a mild cognitive impairment diagnosis, freezing of gait, hyposmia, reduced dopamine transporter activity in the caudate, and elevated leukocytes in the CSF were significantly associated with shorter survival. CONCLUSION: Although patients presenting with idiopathic parkinsonism have reduced survival, the survival is highly dependent on the type and characteristics of the parkinsonian disorder. Patients with Parkinson disease presenting with normal cognitive function seem to have a largely normal life expectancy. The finding of a subtle CSF leukocytosis in patients with Parkinson disease with short survival may have clinical implications.


Assuntos
Doença de Parkinson/mortalidade , Transtornos Parkinsonianos/mortalidade , Disfunção Cognitiva/etiologia , Humanos , Estudos Longitudinais , Doença de Parkinson/complicações , Transtornos Parkinsonianos/complicações , Fenótipo , Fatores de Risco , Suécia/epidemiologia
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