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1.
Nat Commun ; 12(1): 5185, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34465771

RESUMO

Parkinson's disease (PD) is characterised by the emergence of beta frequency oscillatory synchronisation across the cortico-basal-ganglia circuit. The relationship between the anatomy of this circuit and oscillatory synchronisation within it remains unclear. We address this by combining recordings from human subthalamic nucleus (STN) and internal globus pallidus (GPi) with magnetoencephalography, tractography and computational modelling. Coherence between supplementary motor area and STN within the high (21-30 Hz) but not low (13-21 Hz) beta frequency range correlated with 'hyperdirect pathway' fibre densities between these structures. Furthermore, supplementary motor area activity drove STN activity selectively at high beta frequencies suggesting that high beta frequencies propagate from the cortex to the basal ganglia via the hyperdirect pathway. Computational modelling revealed that exaggerated high beta hyperdirect pathway activity can provoke the generation of widespread pathological synchrony at lower beta frequencies. These findings suggest a spectral signature and a pathophysiological role for the hyperdirect pathway in PD.


Assuntos
Vias Neurais , Doença de Parkinson/fisiopatologia , Estudos de Coortes , Globo Pálido/química , Globo Pálido/fisiopatologia , Humanos , Magnetoencefalografia , Córtex Motor/química , Córtex Motor/fisiopatologia , Núcleo Subtalâmico/química , Núcleo Subtalâmico/fisiopatologia
2.
Neurology ; 97(10): e1031-e1040, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34404743

RESUMO

OBJECTIVE: This study aimed to quantify the trajectory and magnitude of change of the key clinical features and corresponding symptom domains of dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD), including global cognition, parkinsonism, recurrent visual hallucinations, cognitive fluctuations, and sleep disturbance. METHODS: One hundred sixteen patients with Lewy body dementia (DLB = 72, PDD = 44) underwent assessment at baseline and 3 and 6 months as part of a prospective multicenter randomized controlled trial. Linear mixed models were constructed for core outcome measures using the Mini-Mental State Examination (MMSE), motor section of the Unified Parkinson's Disease Rating Scale (UPDRS-III), Dementia Cognitive Fluctuations Scale (DCFS), and Neuropsychiatric Inventory (NPI). RESULTS: Within the time frame of our study (6 months), we were able to identify a significant cognitive decline of 1.3 points on the MMSE (p = 0.002) and significant worsening of motor parkinsonism with an increase in UPDRS-III score of 3.2 points (p = 0.018). Fluctuation severity also increased using the DCFS with a 6-month change in score of 1.3 points (p = 0.001). Uniquely, a signal for increased severity of sleep symptoms of 1.2 points (NPI-sleep) was also detectable (p = 0.04). Significant changes in neuropsychiatric symptoms were not detected. There was no difference in rates of change of scores between DLB and PDD. DISCUSSION: Clinically significant rates of change in core clinical features can be detected and quantified in Lewy body dementia over a relatively short period (6 months) using common clinical instruments and thus may be useful as clinical endpoints for therapeutic trials of disease-modifying and symptomatic agents.


Assuntos
Progressão da Doença , Doença por Corpos de Lewy , Idoso , Idoso de 80 Anos ou mais , Disfunção Cognitiva/fisiopatologia , Feminino , Humanos , Doença por Corpos de Lewy/fisiopatologia , Estudos Longitudinais , Masculino , Doença de Parkinson/fisiopatologia
3.
Am J Phys Med Rehabil ; 100(9): 837-839, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34415886

RESUMO

ABSTRACT: Coronavirus disease 2019 might have an impact on patients with Parkinson disease because of the neuroinvasive potential. Herein, we report the case of a patient with Parkinson disease who developed severe and prolonged oropharyngeal dysphagia after a coronavirus disease 2019 infection. A 73-yr-old male patient with Parkinson disease was diagnosed with coronavirus disease 2019 and admitted to a tertiary care hospital. Before hospitalization, he was assessed at Hoehn and Yahr stage 4 and showed no symptoms of dysphagia. After admission, the patient gradually recovered; however, he was fed through a nasogastric tube. A videofluoroscopic swallowing study revealed a severe oropharyngeal dysphagia with a severely delayed oral phase. Therefore, he underwent percutaneous gastrostomy tube insertion. After discharge, although he received swallowing therapy for 4 mos, he still had severe dysphagia, which made him dependent on enteral feeding. We speculate that the impact of coronavirus disease 2019 on dopaminergic and nondopaminergic mechanisms could lead to the development of dysphagia in this patient. The present case suggests that clinicians must have a high index of suspicion without dismissing the possibility of dysphagia and subsequent aspiration pneumonia in coronavirus disease 2019 patients with Parkinson disease.


Assuntos
COVID-19/complicações , Transtornos de Deglutição/virologia , Doença de Parkinson/complicações , SARS-CoV-2 , Idoso , COVID-19/fisiopatologia , COVID-19/virologia , Deglutição , Transtornos de Deglutição/fisiopatologia , Humanos , Masculino , Doença de Parkinson/fisiopatologia , Doença de Parkinson/virologia
5.
Int J Mol Sci ; 22(14)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34298977

RESUMO

For decades, lipids were confined to the field of structural biology and energetics as they were considered only structural constituents of cellular membranes and efficient sources of energy production. However, with advances in our understanding in lipidomics and improvements in the technological approaches, astounding discoveries have been made in exploring the role of lipids as signaling molecules, termed bioactive lipids. Among these bioactive lipids, sphingolipids have emerged as distinctive mediators of various cellular processes, ranging from cell growth and proliferation to cellular apoptosis, executing immune responses to regulating inflammation. Recent studies have made it clear that sphingolipids, their metabolic intermediates (ceramide, sphingosine-1-phosphate, and N-acetyl sphingosine), and enzyme systems (cyclooxygenases, sphingosine kinases, and sphingomyelinase) harbor diverse yet interconnected signaling pathways in the central nervous system (CNS), orchestrate CNS physiological processes, and participate in a plethora of neuroinflammatory and neurodegenerative disorders. Considering the unequivocal importance of sphingolipids in CNS, we review the recent discoveries detailing the major enzymes involved in sphingolipid metabolism (particularly sphingosine kinase 1), novel metabolic intermediates (N-acetyl sphingosine), and their complex interactions in CNS physiology, disruption of their functionality in neurodegenerative disorders, and therapeutic strategies targeting sphingolipids for improved drug approaches.


Assuntos
Sistema Nervoso Central/fisiopatologia , Inflamação/fisiopatologia , Lipídeos de Membrana/fisiologia , Modelos Biológicos , Degeneração Neural/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Esfingolipídeos/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Ceramidas/fisiologia , Eicosanoides/fisiologia , Previsões , Homeostase , Humanos , Inflamação/patologia , Lipoxigenase/fisiologia , Lisofosfolipídeos/fisiologia , Degeneração Neural/patologia , Doenças Neurodegenerativas/patologia , Neuroglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Prostaglandina-Endoperóxido Sintases/fisiologia , Esfingosina/análogos & derivados , Esfingosina/fisiologia
6.
Biochemistry (Mosc) ; 86(6): 627-640, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225587

RESUMO

DJ-1, also known as Parkinson's disease protein 7, is a multifunctional protein ubiquitously expressed in cells and tissues. Interacting with proteins of various intracellular compartments, DJ-1 plays an important role in maintaining different cellular functions. Mutant DJ-1 forms containing amino acid substitutions (especially L166P), typical of Parkinson's disease, are characterized by impaired dimerization, stability, and folding. DJ-1 exhibits several types of catalytic activity; however, in the enzyme classification it exists as protein deglycase (EC 3.5.1.124). Apparently, in different cell compartments DJ-1 exhibits catalytic and non-catalytic functions, and their ratio still remains unknown. Oxidative stress promotes dissociation of cytoplasmic DJ-1 dimers into monomers, which are translocated to the nucleus, where this protein acts as a coactivator of various signaling pathways, preventing cell death. In mitochondria, DJ-1 is found in the synthasome, where it interacts with the ß ATP synthase subunit. Downregulation of the DJ-1 gene under conditions of experimental PD increases sensitivity of the cells to neurotoxins, and introduction of the recombinant DJ-1 protein attenuates manifestation of this pathology. The thirteen-membered fragment of the DJ-1 amino acid sequence attached to the heptapeptide of the TAT protein penetrating into the cells exhibited neuroprotective properties in various PD models both in cell cultures and after administration to animals. Low molecular weight DJ-1 ligands also demonstrate therapeutic potential, providing neuroprotective effects seen during their incubation with cells and administration to animals.


Assuntos
Modelos Animais de Doenças , Mutação de Sentido Incorreto , Doença de Parkinson/metabolismo , Proteína Desglicase DJ-1/metabolismo , Animais , Humanos , Modelos Biológicos , Doença de Parkinson/etiologia , Doença de Parkinson/fisiopatologia , Conformação Proteica , Proteína Desglicase DJ-1/genética , Transdução de Sinais
7.
Biochemistry (Mosc) ; 86(6): 737-745, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34225596

RESUMO

The review summarizes the results of studies on the cellular and molecular mechanisms mediating the impact of stress on the pathogenesis of neurodegenerative brain pathologies (Alzheimer's disease, Parkinson's disease, etc.) and presents current information on the role of stress in the hyperphosphorylation of tau protein, aggregation of beta-amyloid, and hyperactivation of the hypothalamic-pituitary-adrenal axis involved in the hyperproduction of factors that contribute to the pathogenetic role of stress in neurodegeneration. The data on the participation of microglia in the effects of stress on the pathogenesis of neurodegenerative diseases are presented.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Doenças Neurodegenerativas/metabolismo , Estresse Psicológico , Proteínas tau/metabolismo , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Animais , Demência/etiologia , Demência/metabolismo , Demência/fisiopatologia , Humanos , Doenças Neurodegenerativas/etiologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Fosforilação , Agregação Patológica de Proteínas , Processamento de Proteína Pós-Traducional
8.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206170

RESUMO

Pleiotrophin (PTN) is a neurotrophic factor that regulates glial responses in animal models of different types of central nervous system (CNS) injuries. PTN is upregulated in the brain in different pathologies characterized by exacerbated neuroinflammation, including Parkinson's disease. PTN is an endogenous inhibitor of Receptor Protein Tyrosine Phosphatase (RPTP) ß/ζ, which is abundantly expressed in the CNS. Using a specific inhibitor of RPTPß/ζ (MY10), we aimed to assess whether the PTN/RPTPß/ζ axis is involved in neuronal and glial injury induced by the toxin MPP+. Treatment with the RPTPß/ζ inhibitor MY10 alone decreased the viability of both SH-SY5Y neuroblastoma cells and BV2 microglial cultures, suggesting that normal RPTPß/ζ function is involved in neuronal and microglial viability. We observed that PTN partially decreased the cytotoxicity induced by MPP+ in SH-SY5Y cells underpinning the neuroprotective function of PTN. However, MY10 did not seem to modulate the SH-SY5Y cell loss induced by MPP+. Interestingly, we observed that media from SH-SY5Y cells treated with MPP+ and MY10 decreases microglial viability but may elicit a neuroprotective response of microglia by upregulating Ptn expression. The data suggest a neurotrophic role of microglia in response to neuronal injury through upregulation of Ptn levels.


Assuntos
Proteínas de Transporte/metabolismo , Comunicação Celular , Citocinas/metabolismo , Microglia/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/metabolismo , Animais , Humanos , Inflamação/metabolismo , Inflamação/fisiopatologia , Camundongos , Microglia/fisiologia , Modelos Biológicos , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Proteínas Tirosina Fosfatases Classe 5 Semelhantes a Receptores/fisiologia , Transdução de Sinais
9.
Biochemistry (Mosc) ; 86(7): 852-866, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34284712

RESUMO

The cerebral dopamine neurotrophic factor (CDNF) together with the mesencephalic astrocyte-derived neurotrophic factor (MANF) form a unique family of neurotrophic factors (NTFs) structurally and functionally different from other proteins with neurotrophic activity. CDNF has no receptors on the cell membrane, is localized mainly in the cavity of endoplasmic reticulum (ER), and its primary function is to regulate ER stress. In addition, CDNF is able to suppress inflammation and apoptosis. Due to its functions, CDNF has demonstrated outstanding protective and restorative properties in various models of neuropathology associated with ER stress, including Parkinson's disease (PD). That is why CDNF already passed clinical trials in patients with PD. However, despite the name, CDNF functions extend far beyond the dopamine system in the brain. In particular, there are data on participation of CDNF in the maturation and maintenance of other neurotransmitter systems, regulation of the processes of neuroplasticity and non-motor behavior. In the present review, we discuss the features of CDNF structure and functions, its protective and regenerative properties.


Assuntos
Fatores de Crescimento Neural/metabolismo , Animais , Apoptose , Estresse do Retículo Endoplasmático , Humanos , Inflamação , Fatores de Crescimento Neural/fisiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Conformação Proteica , Resposta a Proteínas não Dobradas
10.
J Clin Neurosci ; 90: 178-183, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34275546

RESUMO

Glutamate is the major excitatory neurotransmitter in the central nervous system and, as such, many brain regions, including the basal ganglia, are rich in glutamatergic neurons. The importance of the basal ganglia in the control of voluntary movement has long been recognised, with the effect of dysfunction of the region exemplified by the motor symptoms seen in Parkinson's disease (PD). However, the basal ganglia and the associated glutamatergic system also play a role in the modulation of emotion, nociception and cognition, dysregulation of which result in some of the non-motor symptoms of PD (depression/anxiety, pain and cognitive deficits). Thus, while the treatment of PD has traditionally been approached from the perspective of dopaminergic replacement, using agents such as levodopa and dopamine receptor agonists, the glutamatergic system offers a novel treatment target for the disease. Safinamide has been approved in over 20 countries globally for fluctuating PD as add-on therapy to levodopa regimens for the management of 'off' episodes. The drug has both dopaminergic and non-dopaminergic pharmacological effects, the latter including inhibition of abnormal glutamate release. The effect of safinamide on the glutamatergic system might present some advantages over dopamine-based therapies for PD by providing efficacy for motor (levodopa-induced dyskinesia) as well as non-motor (anxiety, mood disorders, pain) symptoms. In this article, we discuss the potential role of glutamatergic inhibition on these symptoms, using illustrative real-world examples of patients we have treated with safinamide.


Assuntos
Alanina/análogos & derivados , Antiparkinsonianos/uso terapêutico , Benzilaminas/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Transmissão Sináptica/efeitos dos fármacos , Idoso , Alanina/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/efeitos dos fármacos , Doença de Parkinson/fisiopatologia
11.
Toxicol Lett ; 350: 1-9, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34182063

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease caused by the lacking of dopaminergic neurons. Many reports have illustrated that rotenone is applied to establish the experimental model of PD, which simulates PD-like symptoms. FBXO22 is a poorly understood protein that may be involved in neurological disorders. However, little is known about FBXO22 in PD. In this study, first, SH-SY5Y cells were treated with rotenone to construct PD model in vitro. It was discovered that the FBXO22 expression was down-regulated following rotenone treatment. Additionally, overexpression of FBXO22 reduced rotenone treatment-mediated cell apoptosis in SH-SY5Y cells. In view of the ubiquitination effect of FBXO22, our study uncovered that FBXO22 bound with and degraded PHLPP1 by ubiquitination. Next, the effects of PHLPP1 on AKT pathway in PD were further explored. It was demonstrated that PHLPP1 inactivated AKT pathway through down-regulating the pAKT/AKT and pmTOR/mTOR levels. Through rescue assays, the results showed that PHLPP1 overexpression partially reversed the reduction of rotenone induced neurotoxicity caused by FBXO22 overexpression. Finally, we found that overexpression of FBXO22 alleviated rotenone-induced PD symptoms in rat model. Moreover, it was discovered that l-dopa treatment could not affect the FBXO22 expression in PD. In conclusion, findings from our work proved that FBXO22 degraded PHLPP1 by ubiquitination to ameliorate rotenone induced neurotoxicity, which attributed to activate AKT pathway. This work suggested that FBXO22 may be an effective biological marker for PD treatment.


Assuntos
Proteínas F-Box/metabolismo , Proteínas Nucleares/metabolismo , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia , Fosfoproteínas Fosfatases/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Rotenona/toxicidade , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Proteínas F-Box/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Modelos Animais , Neuroblastoma/tratamento farmacológico , Neurotoxinas/toxicidade , Fosfoproteínas Fosfatases/genética , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/genética , Rotenona/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação
12.
Curr Neurovasc Res ; 18(1): 162-168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34082680

RESUMO

BACKGROUND: Robust evidence has described that Parkinson´s disease (PD) is associated with an increased risk for developing epileptic seizures. In fact, an interplay between PD and epilepsy has been of interest for many years. An emerging hypothesis is that inflammation could link both diseases. OBJECTIVE: Bearing in mind the experience of our group in the field of Ca2+/cAMP signalling pathways, this article discussed, beyond inflammation, the role of these signalling pathways in this link between PD and epilepsy. METHODS: Publications involving Ca2+/cAMP signalling pathways, PD, and epilepsy (alone or combined) were collected by searching PubMed and EMBASE. RESULTS: The comprehension of the interplay between PD and epilepsy could improve the drug therapy. In addition, a Ca2+ signalling dyshomeostasis due to Coronavirus disease 2019 (COVID-19), an emerging and rapidly evolving situation, has been reported. CONCLUSION: Thus, this article also debated recent findings about therapeutics involving Ca2+ channel blockers for preventing Ca2+ signalling dyshomeostasis due to COVID-19, including the correlation among COVID-19, epilepsy, and PD.


Assuntos
Sinalização do Cálcio , AMP Cíclico , Epilepsia/complicações , Inflamação/complicações , Doença de Parkinson/complicações , Transdução de Sinais , COVID-19/complicações , Bloqueadores dos Canais de Cálcio/uso terapêutico , Epilepsia/fisiopatologia , Humanos , Inflamação/fisiopatologia , Doença de Parkinson/fisiopatologia
13.
Postgrad Med ; 133(7): 721-727, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34082655

RESUMO

Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but a major treatment challenge is that over time, many patients experience periods of return of PD symptoms intermittently through the day, known as OFF periods. OFF periods typically manifest as a return of motor symptoms but can also involve non-motor symptoms and these periods can disrupt good control despite optimization of the oral levodopa regimen. OFF periods emerge in large measure due to a shortening of the duration of clinical benefit from oral levodopa, thought to be related to a progressive loss of dopamine neurons and their ability to store and release levodopa-derived dopamine over many hours. The problem is further compounded by impaired absorption of oral levodopa due to gastroparesis and other factors limiting its uptake in the small intestine, including competition for uptake by meals and their protein content. On-demand therapies are now available for the treatment of OFF episodes in PD and are administered intermittently, on an as-needed basis, on top of the patient's maintenance medication regimen. To be useful, an on-demand medication should take effect more rapidly and reliably than oral levodopa. Options for on-demand therapy for OFF periods have recently increased with the approval of levodopa inhalation powder and sublingual apomorphine as alternatives to the older option of subcutaneous apomorphine injection, each of which avoids the gastrointestinal tract and its potential for absorption delay. On-demand therapy is now available for patients experiencing episodic or intermittent need for rapid and reliable onset of benefit. On-demand therapy may also provide an alternative to more invasive treatment such as infusion of levodopa/carbidopa intestinal gel and for patients whose OFF episodes are not controlled despite deep brain stimulation.


Assuntos
Antiparkinsonianos/uso terapêutico , Apomorfina/uso terapêutico , Carbidopa/uso terapêutico , Agonistas de Dopamina/uso terapêutico , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/administração & dosagem , Apomorfina/administração & dosagem , Carbidopa/administração & dosagem , Agonistas de Dopamina/administração & dosagem , Vias de Administração de Medicamentos , Combinação de Medicamentos , Humanos , Levodopa/administração & dosagem , Doença de Parkinson/fisiopatologia
14.
Medicine (Baltimore) ; 100(26): e26534, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190190

RESUMO

ABSTRACT: Many previous studies have estimated the rate of dopaminergic denervation in Parkinson disease (PD) via imaging studies. However, they lack the considerations of onset age, disease duration at onset, gender, and dopaminergic denervation due to normal aging. Herein, using a large prospective cohort, we estimated the rate of dopaminergic denervation in PD patients, compared with an age- and gender-matched normal control group.One hundred forty-one normal controls and 301 PD patients were enrolled. Striatal specific binding ratios (SBRs) of I-123 FP-CIT single positron emission tomography images were analyzed according to the age of onset, gender, and the duration of motor symptoms.In the PD group, symptom duration was significantly correlated with caudate SBRs, but with putamen SBRs (P  < .05, R2 = 0.02). Moreover, was significantly inversely related to caudate SBRs, but not with putamen SBRs (P  < .05, R2 = 0.02). Patients of different age onsets did not show any significant correlation between symptom durations and striatal SBRs. In the age-matched group, no significant relationship was observed between symptom duration and percent decrease of caudate SBRs, but there was a significant relationship between symptom duration and percent decrease of the putamen SBRs (P  < .01, R2 = 0.06). There was no significant relationship between the symptom duration and the percent decrease of striatal SBRs in the age- and gender-matched group.The significance and R2 values from the regression analysis between symptom duration, age, and dopaminergic denervation are low. This suggests that, contrary to previous knowledge, there is a relatively weak association between dopaminergic denervation and age or symptom duration.


Assuntos
Corpo Estriado , Diagnóstico por Imagem , Dopamina/metabolismo , Neurônios Dopaminérgicos , Degeneração Neural , Doença de Parkinson , Idade de Início , Biomarcadores/análise , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Diagnóstico por Imagem/classificação , Diagnóstico por Imagem/métodos , Diagnóstico por Imagem/estatística & dados numéricos , Progressão da Doença , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Degeneração Neural/diagnóstico , Degeneração Neural/fisiopatologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/epidemiologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia , Gravidade do Paciente , República da Coreia/epidemiologia , Avaliação de Sintomas/métodos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
15.
Lancet Neurol ; 20(7): 559-572, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34146514

RESUMO

The development of interventions to slow or halt the progression of Parkinson's disease remains a priority for patients and researchers alike. To date, no agents have been shown to have unequivocal evidence of disease-modifying effects in Parkinson's disease. The absence of disease-modifying treatments might relate not only to inadequate approaches for the selection of therapeutic candidates but also to insufficient attention to detail in clinical trial design. Better understanding of Parkinson's disease pathogenesis associated with advances in laboratory models, the use of objective biomarkers of disease progression and target engagement, and a focus on agents known to be safe for human use, alongside the use of precision medicine approaches, should together greatly increase the likelihood for successful identification of disease-modifying treatments for Parkinson's disease.


Assuntos
Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Doença de Parkinson/terapia , Biomarcadores , Progressão da Doença , Humanos , Medicina de Precisão
16.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34066951

RESUMO

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer's disease (AD) and Parkinson's disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.


Assuntos
Doença de Alzheimer/patologia , Doenças de Pequenos Vasos Cerebrais/patologia , Esclerose Múltipla/patologia , Degeneração Neural/patologia , Doença de Parkinson/patologia , Doença de Alzheimer/fisiopatologia , Animais , Biomarcadores/metabolismo , Doenças de Pequenos Vasos Cerebrais/fisiopatologia , Humanos , Esclerose Múltipla/fisiopatologia , Degeneração Neural/fisiopatologia , Doença de Parkinson/fisiopatologia
17.
Int J Mol Sci ; 22(11)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071457

RESUMO

Neurodegenerative diseases (NDs), such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), are disorders characterized by progressive degeneration of the nervous system. Currently, there is no disease-modifying treatments for most NDs. Meanwhile, numerous studies conducted on human and animal models over the past decades have showed that exercises had beneficial effects on NDs. Inter-tissue communication by myokine, a peptide produced and secreted by skeletal muscles during exercise, is thought to be an important underlying mechanism for the advantages. Here, we reviewed studies about the effects of myokines regulated by exercise on NDs and their mechanisms. Myokines could exert beneficial effects on NDs through a variety of regulatory mechanisms, including cell survival, neurogenesis, neuroinflammation, proteostasis, oxidative stress, and protein modification. Studies on exercise-induced myokines are expected to provide a novel strategy for treating NDs, for which there are no adequate treatments nowadays. To date, only a few myokines have been investigated for their effects on NDs and studies on mechanisms involved in them are in their infancy. Therefore, future studies are needed to discover more myokines and test their effects on NDs.


Assuntos
Citocinas/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Esclerose Amiotrófica Lateral/metabolismo , Esclerose Amiotrófica Lateral/fisiopatologia , Animais , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/fisiopatologia , Doenças Neurodegenerativas/fisiopatologia , Doença de Parkinson/metabolismo , Doença de Parkinson/fisiopatologia
18.
Methods Mol Biol ; 2322: 151-160, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34043201

RESUMO

The use of deep brain stimulation (DBS) as a therapy for neurological disorders, especially Parkinson's disease (PD), is widely applied in the field of functional neurosurgery. Both the subthalamic nucleus and the globus pallidus interna are major targets for PD. Experimental DBS is performed using animal models to evaluate new indications and promote advancements in technology. In this chapter, we reviewed our experience with the concept of experimental DBS, including its development and validation. The following work aimed to establish that experimental DBS in animals is an adequate tool for exploring new indications for DBS and to further refine DBS technology.


Assuntos
Estimulação Encefálica Profunda/métodos , Doença de Parkinson/fisiopatologia , Animais , Modelos Animais de Doenças , Globo Pálido/fisiopatologia , Humanos , Macaca fuscata , Procedimentos Neurocirúrgicos/métodos , Núcleo Subtalâmico/fisiopatologia
19.
Methods Mol Biol ; 2322: 195-206, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34043205

RESUMO

Drosophila melanogaster (Drosophila, fruit fly, or fly) is an important model organism in the studies of molecular genetic analysis and mechanism of Parkinson's disease (PD), benefiting from its powerful genetic tools and massive available genetic mutants. People have generated different fly models to mimic the inherited PDs and most of them have obvious mitochondrial abnormalities. Here, we describe some common approaches to analyze mitochondrial functions and morphological changes in Drosophila PD models.


Assuntos
Drosophila melanogaster/genética , Drosophila melanogaster/fisiologia , Mitocôndrias/genética , Mitocôndrias/fisiologia , Animais , Modelos Animais de Doenças , Proteínas de Drosophila/genética , Testes Genéticos/métodos , Doença de Parkinson/genética , Doença de Parkinson/fisiopatologia
20.
Clin Neurophysiol ; 132(7): 1708-1713, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33958263

RESUMO

OBJECTIVE: Parkinson's disease (PD) is a chronic neurodegenerative disorder with increasing prevalence in the elderly. Especially patients with advanced PD often require complex medication regimens due to fluctuations, that is abrupt transitions from ON to OFF or vice versa. Current gold standard to quantify PD-patients' motor symptoms is the assessment of the Unified Parkinson's Disease Rating Scale (UPDRS), which, however, is cumbersome and may depend upon investigators. This work aimed at developing a mobile, objective and unobtrusive measurement of motor symptoms in PD. METHODS: Data from 45 PD-patients was recorded using surface electromyography (sEMG) electrodes attached to a wristband. The motor paradigm consisted of a tapping task performed with and without dopaminergic medication. Our aim was to predict UPDRS scores from the sEMG characteristics with distinct regression models and machine learning techniques. RESULTS: A random forest regression model outnumbered other regression models resulting in a correlation of 0.739 between true and predicted UPDRS values. CONCLUSIONS: PD-patients' motor affection can be extrapolated from sEMG data during a simple tapping task. In the future, such records could help determine the need for medication changes in telemedicine applications. SIGNIFICANCE: Our findings support the utility of wearables to detect Parkinson's symptoms and could help in developing tailored therapies in the future.


Assuntos
Eletromiografia/métodos , Testes de Estado Mental e Demência , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
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