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1.
Ageing Res Rev ; 95: 102209, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38286334

RESUMO

Vascular Parkinsonism (VP) is clinical term represents a progressive ischemic changes and subcortical lacunar infarct leading to Parkinsonism mainly in the lower limbs so called lower body Parkinsonism. The VP neuropathology is differed from that of PD neuropathology which rarely associated with basal ganglion lesions. Dopamine transporters are normal in VP but are highly reduced in PD, and dopaminergic agonists had no effective role on VP. The neuropathological mechanisms of VP are related to vascular injury which induces the interruption of the neural connection between basal ganglion and cerebral cortex. Hyperlipidemia and other cardiometabolic risk factors augment VP risk and the related neuropathology. Targeting of these cardiometabolic disorders by lipid-lowering statins may be effective in the management of VP. Therefore, this mini-review aims to clarify the possible role of statins in the management of VP. Statins have neuroprotective effects against different neurodegenerative diseases by anti-inflammatory, antioxidant and antithrombotic effects with enhancement of endothelial function. In conclusion, statins can prevent and treat VP by inhibiting inflammatory and oxidative stress disorders, mitigating of white matter hyperintensities and improving of neuronal signaling pathways. Additional preclinical, clinical trials and prospective studies are warranted in this regard.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Doenças Vasculares , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Transtornos Parkinsonianos/etiologia , Transtornos Parkinsonianos/patologia
2.
Schizophr Res ; 263: 66-81, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37059654

RESUMO

Different types of resistance to passive movement, i.e. hypertonia, were described in schizophrenia spectrum disorders (SSD) long before the introduction of antipsychotics. While these have been rediscovered in antipsychotic-naïve patients and their non-affected relatives, the existence of intrinsic hypertonia vs drug-induced parkinsonism (DIP) in treated SSD remains controversial. This integrative review seeks to develop a commonly accepted framework to specify the putative clinical phenomena, highlight conflicting issues and discuss ways to challenge each hypothesis and model through adversarial collaboration. The authors agreed on a common framework inspired from systems neuroscience. Specification of DIP, locomotor paratonia (LMP) and psychomotor paratonia (PMP) identified points of disagreement. Some viewed parkinsonian rigidity to be sufficient for diagnosing DIP, while others viewed DIP as a syndrome that should include bradykinesia. Sensitivity of DIP to anticholinergic drugs and the nature of LPM and PMP were the most debated issues. It was agreed that treated SSD should be investigated first. Clinical features of the phenomena at issue could be confirmed by torque, EMG and joint angle measures that could help in challenging the selectivity of DIP to anticholinergics. LMP was modeled as the release of the reticular formation from the control of the supplementary motor area (SMA), which could be challenged by the tonic vibration reflex or acoustic startle. PMP was modeled as the release of primary motor cortex from the control of the SMA and may be informed by subclinical echopraxia. If these challenges are not met, this would put new constraints on the models and have clinical and therapeutic implications.


Assuntos
Antipsicóticos , Doença de Parkinson Secundária , Transtornos Psicóticos , Esquizofrenia , Humanos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Antipsicóticos/uso terapêutico , Hipertonia Muscular/etiologia , Hipertonia Muscular/tratamento farmacológico , Transtornos Psicóticos/tratamento farmacológico
3.
Age Ageing ; 52(10)2023 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-37890520

RESUMO

BACKGROUND: Vietnam-era veterans were exposed to Agent Orange (AO), which is associated with a high prevalence of Parkinson's disease (PD). However, little is known about the development of PD-like symptoms caused by drug-induced parkinsonism (DIP) in such populations. This study aimed to investigate PD incidence and PD risk following exposure to AO or DIP-risk drugs in veterans. METHODS: A retrospective cohort study was conducted using 12 years (2009-2020) of electronic medical records of the Veterans Health Service Medical Center, the largest Veterans Affairs hospital in South Korea (n = 37,246; 100% male; age, 65.57 ± 8.12 years). Exposure to AO or DIP-risk drugs, including antipsychotic, prokinetic, anti-epileptic, dopamine-depleting and anti-anginal agents, was assessed in veterans with PD, operationally defined as having a PD diagnosis and one or more prescriptions for PD treatment. The PD risk was calculated using multiple logistic regression analysis adjusted for age and comorbidities. RESULTS: The rates of DIP-risk drug use and AO exposure were 37.92% and 62.62%, respectively. The PD incidence from 2010 to 2020 was 3.08%; 1.30% with neither exposure, 1.63% with AO exposure, 4.38% with DIP-risk drug use, and 6.33% with both. Combined exposure to AO and DIP-risk drugs increased the PD risk (adjusted odds ratio = 1.68, 95% confidence interval, 1.36-2.08, P < 0.001). CONCLUSIONS: The PD incidence was 1.31 times higher with AO exposure alone and 1.68 times higher with AO exposure and DIP-risk drug use. The results suggest the necessity for careful monitoring and DIP-risk drug prescription in patients with AO exposure.


Assuntos
Doença de Parkinson Secundária , Doença de Parkinson , Veteranos , Humanos , Masculino , Idoso , Feminino , Doença de Parkinson/diagnóstico , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/epidemiologia , Estudos Retrospectivos , Agente Laranja/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/diagnóstico
4.
PLoS One ; 18(10): e0290371, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37874827

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease (NDD) characterized by the loss of dopaminergic neurons in the substantia nigra. Similar to other NDDs, the buildup of toxic protein aggregates in PD leads to progressive neuronal loss, culminating in neurodegeneration. Accumulating evidence indicates that alterations in subcellular organelles, particularly the endoplasmic reticulum (ER), are critically involved in pathological neurodegenerative events in NDDs, including PD. Mutations in the F-box only protein 7 (FBXO7 or PARK15) gene have been found to cause early onset autosomal recessive familiar PD. FBXO7 functions as an adaptor protein in the Skp1-Cullin1-F-box protein (SCF) E3 ubiquitin ligase complex, which promotes substrate ubiquitination. Although FBXO7 is involved in the ubiquitination of various target proteins, little is known about the upstream regulatory mechanism of FBXO7 and/or its modulator(s). Ubiquitin specific protease 7 (USP7) is a deubiquitinating enzyme that regulates the balance between protein synthesis and degradation by removing ubiquitin from target substrates. The role of USP7 in various types of cancer is well-established; however, its role in NDDs has not been elucidated to date. In this study, we identified that USP7 acts as a novel regulator of FBXO7, positively regulating the stability of FBXO7 through Lys48-linked deubiquitination. Moreover, USP7 was found to mitigate ER stress-induced cytotoxicity and apoptosis by preventing the proteasomal degradation of FBXO7. Taken together, our study suggests that the functional relationship between FBXO7 and USP7 may play a crucial role in ER stress-induced apoptosis and the pathogenesis of PD.


Assuntos
Proteínas F-Box , Doenças Neurodegenerativas , Doença de Parkinson Secundária , Doença de Parkinson , Humanos , Peptidase 7 Específica de Ubiquitina/metabolismo , Doença de Parkinson/patologia , Proteínas F-Box/genética , Proteínas F-Box/metabolismo , Ubiquitinação , Proteínas/metabolismo , Apoptose
5.
Sci Rep ; 13(1): 15069, 2023 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-37700061

RESUMO

18F-FP-CIT is a high-resolution imaging marker of nigrostriatal neuronal integrity, differentiating Parkinsonism with loss of dopaminergic terminals (presynaptic Parkinsonian syndrome [PS]) from Parkinsonism without nigrostriatal degeneration (non-PS). We assessed the diagnostic accuracy of 18F-FP-CIT PET in patients with clinically uncertain PS (CUPS) at the first visit. Among the 272 patients who underwent 18F-FP-CIT PET imaging at the first visit between September 2008 and July 2012, 111 had CUPS (age, 62.6 ± 10.5 y; male:female, 45:66; symptom duration, 13.1 ± 8.8 months). Uncertainty criteria included only one of the three cardinal signs of Parkinsonism, two signs without bradykinesia, or atypical signs. The baseline clinical and 18F-FP-CIT PET imaging diagnostic accuracy was compared with the accuracy of clinical diagnosis after > 2-year follow-up. Nuclear medicine physicians assessed the 18F-FP-CIT PET images visually. Focal dopamine transporter binding deficit in the posterior putamen was considered PS. Bilateral symmetric striatum without focal deficit, suggesting normal 18F-FP-CIT PET, and focal deficits elsewhere in the striatum suggesting vascular Parkinsonism were considered non-PS. Seventy-nine patients had PS, and 32 did not. Baseline clinical diagnosis included PS in 45 patients, non-PS in 24, and inconclusive in 42. Among patients in whom initial clinical diagnosis (PS or non-PS) was possible, the sensitivity, specificity, and accuracy of the baseline clinical and 18F-FP-CIT PET imaging diagnoses were 54.4, 50.0, and 53.2%, and 98.7, 100, and 99.1%, respectively. The respective positive and negative predictive values were 95.6 and 66.7%, and 100 and 97.0%. Among those with initially inconclusive diagnosis, 64.2% were eventually diagnosed with PS while 35.7% were diagnosed with non-PS. The final clinical diagnosis of these patients all matched those made by 18F-FP-CIT PET imaging, except in one patient with scan without evidence of dopaminergic deficit (SWEDD). 18F-FP-CIT PET diagnosis was more accurate than clinical diagnosis, reducing the false-negative and inconclusive clinical diagnosis rates at baseline in patients with CUPS.


Assuntos
Doença de Parkinson Secundária , Transtornos Parkinsonianos , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Incerteza , Transtornos Parkinsonianos/diagnóstico por imagem , Dopamina , Tomografia por Emissão de Pósitrons
6.
PLoS Biol ; 21(8): e3002244, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37535686

RESUMO

Functional analyses of genes linked to heritable forms of Parkinson's disease (PD) have revealed fundamental insights into the biological processes underpinning pathogenic mechanisms. Mutations in PARK15/FBXO7 cause autosomal recessive PD and FBXO7 has been shown to regulate mitochondrial homeostasis. We investigated the extent to which FBXO7 and its Drosophila orthologue, ntc, share functional homology and explored its role in mitophagy in vivo. We show that ntc mutants partially phenocopy Pink1 and parkin mutants and ntc overexpression supresses parkin phenotypes. Furthermore, ntc can modulate basal mitophagy in a Pink1- and parkin-independent manner by promoting the ubiquitination of mitochondrial proteins, a mechanism that is opposed by the deubiquitinase USP30. This basal ubiquitination serves as the substrate for Pink1-mediated phosphorylation that triggers stress-induced mitophagy. We propose that FBXO7/ntc works in equilibrium with USP30 to provide a checkpoint for mitochondrial quality control in basal conditions in vivo and presents a new avenue for therapeutic approaches.


Assuntos
Doença de Parkinson Secundária , Doença de Parkinson , Animais , Fosforilação , Mitofagia/genética , Ubiquitinação , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Doença de Parkinson/metabolismo , Drosophila/metabolismo
7.
Pharmacoepidemiol Drug Saf ; 32(12): 1378-1386, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37491627

RESUMO

BACKGROUND: The disease burden of parkinsonism is extremely costly in the United States. Unlike Parkinson's disease, drug-induced parkinsonism (DIP) is acute and reversible; exploring the causative drug is important to prevent DIP in patients at high-risk of parkinsonism. OBJECTIVE: To examine whether the use of gastrointestinal (GI) prokinetics is associated with an increased risk of parkinsonism. METHODS: We conducted a case-crossover study using nationally representative data. We included patients who were newly diagnosed with parkinsonism (ICD-10 G20, G21.1, G25.1) between January 1, 2007 and December 1, 2015. The first prescription date of G20, G21.1, or G25.1 diagnoses was defined as the index date (0 day). Patients with prior extrapyramidal and movement disorders or brain tumors were excluded. We assessed the exposure within the risk (0-29 days) and control periods (60-89 days), before or on the index date. Conditional logistic regression estimated the adjusted odds ratio (aOR) for parkinsonism. RESULTS: Overall, 2268 and 1674 patients were exposed to GI prokinetics during the risk and control periods, respectively. The use of GI prokinetics significantly increased the occurrence of parkinsonism (aOR = 2.31; 95% Confidence Interval [CI], 2.06-2.59). The use of GI prokinetics was associated with a higher occurrence of parkinsonism in elderly patients (≥65 years old; aOR = 2.69; 95% CI, 2.30-3.14) than in younger patients (aOR = 1.90; 95% CI, 1.59-2.27). CONCLUSIONS: The use of GI prokinetics was significantly associated with higher occurrences of parkinsonism, necessitating close consideration when using GI prokinetics.


Assuntos
Doença de Parkinson Secundária , Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Estados Unidos/epidemiologia , Idoso , Estudos Cross-Over , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/epidemiologia , Estudos de Casos e Controles , Doença de Parkinson/epidemiologia , Doença de Parkinson/etiologia , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/epidemiologia
8.
Parkinsonism Relat Disord ; 113: 105483, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37354829

RESUMO

Gait differentiation in progressive supranuclear palsy (PSP) and vascular parkinsonism (VaP) is sometimes difficult to detect with the naked eye. Here, we compared specific gait parameters, neuro-morphometric indices, and their associations between patients with PSP Richardson's syndrome (PSP-RS) and VaP. A total of 18 PSP-RS and 13 VaP patients were recruited. Spatio-temporal gait parameters (GAITRite®) and neuroanatomical morphometry (FreeSurfer pipeline) were assessed. The groups were compared using unpaired t-tests involving 10000 random permutations after statistically controlling for total UPDRS-III and H&Y scores. Statistically significant differences between the groups were decided at < 5% Benjamini-Hochberg False Discovery Rate (FDR) for multiple-comparison related corrections. Spearman's correlations were performed to assess the significant associations (p < 0.05) between the gait parameters and morphometry indices. Among all the spatio-temporal gait parameters, PSP-RS patients displayed greater stride time, step time, swing time, and stance time variabilities compared to VaP. Morphometric analyses showed that thalamus, and caudate volumes were significantly lower, but cerebellar cortex, hippocampus, amygdala, accumbens, and putamen volumes were higher in PSP-RS than VaP. Moreover, the bilateral insula was significantly thinner in VaP than in PSP-RS. Correlation analyses support the involvement of limbic structures besides cerebellum in postural control during self-paced walking of PSP-RS patients. Our findings underline the importance of examining individual brain regions to understand the association of cortical and subcortical morphometric estimates and gait variability parameters in PSP-RS and VaP. This study suggests the involvement of the limbic system in addition to the classical neural structures for motor control and gait.


Assuntos
Doença de Parkinson Secundária , Transtornos Parkinsonianos , Paralisia Supranuclear Progressiva , Humanos , Paralisia Supranuclear Progressiva/diagnóstico , Transtornos Parkinsonianos/diagnóstico , Encéfalo/diagnóstico por imagem , Doença de Parkinson Secundária/complicações , Marcha
11.
Theranostics ; 13(6): 1809-1822, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37064868

RESUMO

Background: Neuroinflammation is involved in the development of Parkinson's disease (PD). Calhm2 plays an important role in the development of microglial inflammation, but whether Calhm2 is involved in PD and its regulatory mechanisms are unclear. Methods: To study the role of Calhm2 in the development of PD, we utilized conventional Calhm2 knockout mice, microglial Calhm2 knockout mice and neuronal Calhm2 knockout mice, and established the MPTP-induced PD mice model. Moreover, a series of methods including behavioral test, immunohistochemistry, immunofluorescence, real-time polymerase chain reaction, western blot, mass spectrometry analysis and co-immunoprecipitation were utilized to study the regulatory mechanisms. Results: We found that both conventional Calhm2 knockout and microglial Calhm2 knockout significantly reduced dopaminergic neuronal loss, and decreased microglial numbers, thereby improving locomotor performance in PD model mice. Mechanistically, we found that Calhm2 interacted with EFhd2 and regulated downstream STAT3 signaling in microglia. Knockdown of Calhm2 or EFhd2 both inhibited downstream STAT3 signaling and inflammatory cytokine levels in microglia. Conclusion: We demonstrate the important role of Calhm2 in microglial activation and the pathology of PD, thus providing a potential therapeutic target for microglia-mediated neuroinflammation-related diseases.


Assuntos
Canais de Cálcio , Doença de Parkinson Secundária , Animais , Camundongos , Proteínas de Ligação ao Cálcio , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/patologia , Doenças Neuroinflamatórias , Transdução de Sinais , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/genética , Canais de Cálcio/genética
12.
Parkinsonism Relat Disord ; 109: 105360, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36921515

RESUMO

INTRODUCTION: Reliable diagnosis of vascular parkinsonism (VaP) in the presence of a gait hypokinesia is an issue that is encountered in geriatrics. The EVAMAR-AGEX study was focusing on the phenomenon of recurrent falls in older persons (OP) with this parkinsonian gait. The present study is focusing on the diagnosis of VaP-related parkinsonian gait by developing a diagnostic guidance model adapted to OP. METHODS: Data from baseline and the 2-year follow-up visit were used to carry out univariate analysis and calculation of odds ratios, allowing to identify relevant variables to include in the diagnostic guidance model. To evaluate the model, confusion matrices were created, evaluating true positive, false negative, false positive and true negative incidences, sensitivity and specificity, and negative and positive predictive values. RESULTS: 79 patients included 58% male; average age 81.24 years. VaP diagnosis according to Zijlmans criteria occurred in 28%; neurodegenerative parkinsonian syndromes in 72%. A 4-criteria model was established to facilitate diagnostic: lack of prior hallucinations, lack of movement disorders tremor excluded, no cognitive fluctuations, and ≥75 years of age at diagnosis. In combination of 4/4 criteria, all of them were required to disclose a specificity of 91% in the diagnosis of VaP. In combination of 3/4, in case of negative test, a negative predictive value for VaP diagnosis of 0.97 was obtained. CONCLUSION: The challenge of our tool is both to be able to rule out what is probably not a VaP and to argue what makes a VaP diagnosis probable in OP.


Assuntos
Transtornos dos Movimentos , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Doenças Vasculares , Humanos , Masculino , Idoso , Idoso de 80 Anos ou mais , Feminino , Hipocinesia/diagnóstico , Hipocinesia/etiologia , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico , Tremor/epidemiologia , Marcha , Doença de Parkinson Secundária/diagnóstico , Doença de Parkinson Secundária/etiologia
13.
J Viral Hepat ; 30(6): 544-550, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36872452

RESUMO

Research suggests a possible link between chronic infection with hepatitis C virus (HCV) and the development of Parkinson's Disease (PD) and secondary Parkinsonism (PKM). We investigated the impact of antiviral treatment status (untreated, interferon [IFN] treated, direct-acting antiviral [DAA] treated) and outcome (treatment failure [TF] or sustained virological response [SVR]) on risk of PD/PKM among patients with HCV. Using data from the Chronic Hepatitis Cohort Study (CHeCS), we applied a discrete time-to-event approach with PD/PKM as the outcome. We performed univariate followed by a multivariable modelling that used time-varying covariates, propensity scores to adjust for potential treatment selection bias and death as a competing risk. Among 17,199 confirmed HCV patients, we observed 54 incident cases of PD/PKM during a mean follow-up period of 17 years; 3753 patients died during follow-up. There was no significant association between treatment status/outcome and risk of PD/PKM. Type 2 diabetes tripled risk (hazard ratio [HR] 3.05; 95% CI 1.75-5.32; p < .0001) and presence of cirrhosis doubled risk of PD/PKM (HR 2.13, 95% CI 1.31-3.47). BMI >30 was associated with roughly 50% lower risk of PD/PKM than BMI <25 (HR 0.43; 0.22-0.84; p = .0138). After adjustment for treatment selection bias, we did not observe a significant association between HCV patients' antiviral treatment status/outcome on risk of PD/PKM. Several clinical risk factors-diabetes, cirrhosis and BMI-were associated with PD/PKM.


Assuntos
Carcinoma Hepatocelular , Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Hepatite C , Neoplasias Hepáticas , Doença de Parkinson Secundária , Doença de Parkinson , Humanos , Antivirais/uso terapêutico , Estudos de Coortes , Doença de Parkinson/epidemiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C/tratamento farmacológico , Hepacivirus , Resposta Viral Sustentada , Doença de Parkinson Secundária/induzido quimicamente , Doença de Parkinson Secundária/complicações , Doença de Parkinson Secundária/tratamento farmacológico , Cirrose Hepática/complicações , Neoplasias Hepáticas/tratamento farmacológico , Carcinoma Hepatocelular/tratamento farmacológico
15.
Fundam Clin Pharmacol ; 37(4): 794-806, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-36807936

RESUMO

Parkinson's disease (PD) is a neuromuscular ailment that affects people in their later years and causes both motor and non-motor deficits. Receptor-interacting protein-1 (RIP-1) is a critical participant in necroptotic cell death, possibly through an oxidant-antioxidant imbalance and cytokine cascade activation in PD pathogenesis. The present study examined the role of RIP-1-mediated necroptosis and neuroinflammation in the MPTP-induced PD mouse model, as well as their protection by Necrostatin-1s (an RIP signalling inhibitor), antioxidant DHA and their functional interaction. BALB/c mice were given acute MPTP therapy (4 injections of 15 mg/kg i.p. at 2-h intervals) on day 1. After MPTP intoxication, Necrostatin-1s (Nec-1s; 8 mg/kg/day, i.p.) and DHA (300 mg/kg/day, p.o.) treatments were given once daily for 7 days. The Nec-1s treatment prevented MPTP-induced behavioural, biochemical and neurochemical alterations, and the addition of DHA increases Nec-1s' neuroprotective impact. In addition, Nec-1s and DHA significantly improve the survival of TH-positive dopaminergic neurons and lower expression levels of the inflammatory cytokines, IL-1ß and TNF-α. Furthermore, Nec-1s dramatically reduced RIP-1 expression, whereas DHA had little effect. Our research raises the possibility that neuroinflammatory signalling and acute MPTP-induced necroptosis are both mediated by TNFR1-driven RIP-1 activity. In this study, RIP-1 ablation through Nec-1s and the addition of DHA showed a reduction in the levels of pro-inflammatory and oxidative markers, as well as protection from MPTP-driven dopaminergic degeneration and neurobehavioural changes, suggesting potential therapeutic applications. For a better understanding, additional research about the mechanism(s) behind Nec-1s and DHA is required.


Assuntos
Ácidos Docosa-Hexaenoicos , Fármacos Neuroprotetores , Doença de Parkinson , Proteína Serina-Treonina Quinases de Interação com Receptores , Animais , Humanos , Camundongos , Antioxidantes/farmacologia , Modelos Animais de Doenças , Ácidos Docosa-Hexaenoicos/farmacologia , Neurônios Dopaminérgicos , Camundongos Endogâmicos C57BL , Doenças Neuroinflamatórias , Fármacos Neuroprotetores/farmacologia , Doença de Parkinson/tratamento farmacológico , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Doença de Parkinson Secundária
16.
Int J Mol Sci ; 24(3)2023 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-36769288

RESUMO

We report the singular case of a 31-year-old woman who developed very serious Fluphenazine-induced parkinsonism over a few days due to a doubly incongruent drug prescription by indication and dosage having been applied to a healthy subject over one week instead of seven months. Unlike gradual drug-induced parkinsonism, our patient experienced acute extrapyramidal syndrome (EPS), reaching significant motor and sphincter disability in just a few days, followed by a gradual incomplete recovery over more than six months. In fact, after drug discontinuation, hypomimia and slight left hemi-somatic rigidity with bradykinesia remained, as well as stable non-progressive memory disturbances. Despite bio-humoral and instrumental investigations and DaTScan were negative, MRI post-analysis evidenced a 6.5% loss in brain volume. Specifically, irreversible cortical and sub-cortical grey matter reduction and cerebrospinal fluid space enlargement with spared white matter were found. Our observations suggest that the sudden availability of Fluphenazine results in a kind of plateau effect of parkinsonism presentation, partially reversible due to the neurotoxic drug effect on the cortical and sub-cortical grey matter, resulting in asymmetric EPS and stable memory loss, respectively. Our report confirms the debated neurotoxicity of first-generation neuroleptics and the postulated theory of differential susceptibility to the cytotoxic stressors on the central nervous system.


Assuntos
Antipsicóticos , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Feminino , Humanos , Adulto , Flufenazina/efeitos adversos , Doença de Parkinson Secundária/induzido quimicamente , Antipsicóticos/efeitos adversos , Amnésia , Transtornos da Memória/induzido quimicamente
17.
Clin Neurol Neurosurg ; 225: 107595, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36709622

RESUMO

OBJECTIVE: The present study aimed to investigate levels and clinical significance of serum SIRT1 in Parkinson's disease (PD) and Vascular parkinsonism (VP). METHODS: This prospective observational research enrolled a total of 165 VP and 159 PD patients who were admitted during March 2018 to December 2021. Blood samples and medical characteristics were also obtained from 160 healthy volunteers. The serum Sirtuin1 (SIRT1) and cytokines levels of all subjects were measured by enzyme-linked immunosorbent assay (ELISA) method. Demographic and clinical data were also collected. Statistical analysis was conducted using SPSS software with P < 0.05 as statistically different. RESULTS: The mean age, the UPDRSIII score of VP patients was significantly higher compared with the PD patients (p<0.05), while the MMSE score of VP patients was significantly lower than the PD patients (p<0.001). The serum SIRT1 levels of the VP patients were remarkably lower than the PD patients or the healthy persons (p<0.05). Pearson's analysis showed that SIRT1 levels were negatively correlated with levels of IL-6, TNF- α and hcy. The UPDRSIII of SIRT1 low levels group was remarkably higher than the SIRT1 high levels group (p=0.048), while the MMSE score was lower than the SIRT1 high levels group (p<0.001). In addition, ROC curves showed that SIRT1 could be a potential diagnostic biomarker of VP. SIRT1 was a risk factor for VP. CONCLUSION: Our present study indicated that SIRT1 associated with disease severity and could discriminate PD from VP.


Assuntos
Doença de Parkinson Secundária , Doença de Parkinson , Doenças Vasculares , Humanos , Estudos Observacionais como Assunto , Doença de Parkinson/diagnóstico , Doença de Parkinson Secundária/diagnóstico , Estudos Prospectivos , Sirtuína 1
18.
Neurol Sci ; 44(4): 1235-1241, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-36547780

RESUMO

BACKGROUND: So far, mutations in genes encoding lysosomal enzymes have been associated with Parkinson's disease (PD). Fabry disease (FD) is an X-linked lysosomal storage disease caused by alpha-galactosidase A (α-GAL) deficiency, leading to deposition of globotriaosylceramide in the nervous system and other organs. We aimed to screen for FD a case series of PD patients from Southern Italy and to review the literature. METHODS: One hundred and forty-four consecutive unrelated PD subjects were enrolled. The α-GAL activity was measured in all men and, in case of pathological values, subsequent determination of globotriaosylsphingosine (lyso-Gb3) and GLA gene sequencing were also performed. All the women underwent GLA gene sequencing. RESULTS: α-GAL levels resulted low in fifteen men, whereas lyso-Gb3 testing showed values within the reference range in all of them. GLA gene variants were not detected in any tested subjects. One pathological study, six case series, and five case reports are currently reported in literature. CONCLUSIONS: The few studies reviewed are heterogeneous, and the results are controversial. An unknown significance variant in GLA gene was detected in PD patients in one large study, whereas decreased α-GAL activity was observed in PD subjects in two other researches, but without confirmation by lyso-Gb3 assessment or genetic analysis. Vascular parkinsonism was associated to FD in five case reports. We found no association between PD and FD in our population. However, it is not possible to draw definitive conclusions due to limited sample size. Furthermore, controls would have been missing in case of a positive finding.


Assuntos
Doença de Fabry , Doença de Parkinson Secundária , Doença de Parkinson , Masculino , Humanos , Feminino , Doença de Fabry/complicações , Doença de Fabry/diagnóstico , Doença de Fabry/genética , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , alfa-Galactosidase/genética , Mutação/genética
19.
J Neurol Sci ; 444: 120526, 2023 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-36584558

RESUMO

Secondary parkinsonism induced by exposure to dopamine (DA) receptor antagonists as first and second generation antipsychotics, DA storage depleters, calcium channel blockers, benzamides substituted and other classes of drugs is traditionally believed to be completely reversible in most of patients following withdrawal of the offending drug even though after a variable time delay. The lack of recovery or initial full recovery with subsequent development of progressive parkinsonism has been regarded to result from an underlying subclinical degenerative process like PD unmasked by the inducing drug. These well-recognized clinical outcomes of drug-induced parkinsonism (DIP) have disregarded the existence of another outcome, characterized by permanent non-progressive parkinsonism. This syndrome may fullfil the criteria of tardive parkinsonism, a controversial entity currently referred to as a persistent condition without indication of its long-term course and clinical features. On reviewing the published literature on DIP, we have identified two prospective long-term follow-up of elderly patients in which parkinsonism induced by the calcium channel antagonists cinnarizine and flunarizine became permanent and non-progressive following drug discontinuation in a non-negligible proportion of patients, consistent with the clinical concept of a true tardive syndrome, according to currently accepted criteria. The authors hypothesize that the development of tardive parkinsonism might be due to a neurotoxic effect of the pharmacodynamic proprieties of the calcium channel blockers and their metabolites, exerted on post-synaptic striatal neurons and/or a neurotoxic damage on presynaptic DA neurons in patients without an underlying subclinical degenerative parkinsonism, so accounting for the stable and non-progressive course over time.


Assuntos
Antipsicóticos , Cinarizina , Doença de Parkinson Secundária , Transtornos Parkinsonianos , Humanos , Idoso , Flunarizina/efeitos adversos , Cinarizina/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Estudos Prospectivos , Transtornos Parkinsonianos/induzido quimicamente , Doença de Parkinson Secundária/induzido quimicamente , Antagonistas de Dopamina/efeitos adversos , Antipsicóticos/efeitos adversos , Síndrome
20.
Behav Brain Res ; 439: 114240, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36455673

RESUMO

Parkinson's disease (PD) is a common neurodegenerative disease with the exact etiology still unclear, but gut microbial disorders are thought to be related to the initiation and progression of it. Exercise training has a significant effect on the intestinal flora, so to investigate the promotion effect of exercise training on Parkinson's disease, we performed a rotarod walking training (5 times a week at 25 rpm for 20 min for 8 weeks) on a chronic mouse model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and observed the locomotor function of mice, function of dopaminergic neurons, intestinal mucosal barrier condition, intestinal inflammation and the structure and composition of intestinal flora. The results showed in these PD mice, exercise training improved their motility, increased the dopamine (DA) content in the striatum, along with promoted the gene expression of tyrosine hydroxylase and brain-derived neurotrophic factor in the striatum, which suggests this exercise training might protect striatal dopaminergic neurons from MPTP damage; the results also showed exercise training promoted recovery from ileal pathology, reduced the gene expression of intestinal inflammatory factors, and significantly altered the composition and structure of the intestinal flora in these mice.


Assuntos
Microbioma Gastrointestinal , Doença de Parkinson Secundária , Condicionamento Físico Animal , Animais , Camundongos , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Camundongos Endogâmicos C57BL , Tirosina 3-Mono-Oxigenase/metabolismo , Doença de Parkinson Secundária/microbiologia , Doença de Parkinson Secundária/terapia
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