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1.
Neurosci Lett ; 770: 136420, 2022 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-34958912

RESUMO

This study aimed to explore the beneficial effects of the antioxidant N-acetylcysteine (NAC) on the degenerated dopamine system. The short- and long-term regulatory mechanisms of NAC on the 6-OHDA hemiparkinsonian rat model were longitudinally investigated by performing positron emission tomography (PET) imaging using the specific dopamine transporter (DAT) radioligand [18F]FE-PE2I. The results demonstrate that after a unilateral dopamine insult NAC has a strong influence on the non-lesioned hemisphere by decreasing the levels of DAT in the striatum early after the lesion. We interpret this early and short-term decrease of DAT in the healthy striatum of NAC-treated animals as a beneficial compensatory effect induced by NAC.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Feminino , Nortropanos/farmacocinética , Oxidopamina/toxicidade , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/etiologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Ratos Sprague-Dawley
2.
Urologiia ; (5): 35-40, 2021 Nov.
Artigo em Russo | MEDLINE | ID: mdl-34743429

RESUMO

BACKGROUND: An overactive bladder and cognitive impairment are two medical and social problems, which have an outmost importance, affecting the quality of life. Both disorders are common in the practice of a urologist, neurologist, internist, and other physicians. Parkinsons disease and multiple sclerosis are the most common neurological diseases, which often manifest by pelvic dysfunction and cognitive dysfunction. The clinician needs to understand the pathogenesis of the underlying disease and the pharmacologic properties of drugs, which can be used both in neurology and urology, as well as in other related specialties. AIM: To evaluate cognitive functions in patients with neurogenic overactive bladder treated with trospium chloride. MATERIALS AND METHODS: A total of 45 patients with neurological disease (28 with Parkinsons disease [group 1] and 17 with multiple sclerosis [group 2]) were included in the study. All patients had symptoms of an overactive bladder. Trospium chloride was administered in an individually adjusted dose for 12 weeks. Cognitive functions were assessed using the international Montreal Cognitive Assessment (MoCA) before and after the therapy. A change of total scores over time was assessed using the paired Wilcoxon test. The level of significance of <0.05 was used (confidence level of 95%). RESULTS: A significant decrease in all studied parameters of an overactive bladder in both groups was seen. The baseline evaluation of the total score on the MoCA scale prior to the start of taking trospium chloride revealed the presence of moderate cognitive impairment (21.3+/-2.9 points) in patients of the group 1. After 12 weeks of therapy, no significant change in cognitive functions was observed (21.7+/-3.1 points; p>0.05). In group 2, moderate cognitive impairment (MoCA 22.5+/-3.7 points) was found at baseline. After taking trospium chloride, no significant changes were noted (MoCA 22.9+/-4.1 points) (p>0.05). No central nervous system side effects were reported in any group. CONCLUSION: Trospium chloride is an effective drug, which does not affect cognitive functions in patients with neurogenic overactive bladder. This drug is safe to use in both Parkinsons disease and multiple sclerosis, considering the low risk of cognitive impairment in polypharmacy.


Assuntos
Nortropanos , Bexiga Urinaria Neurogênica , Bexiga Urinária Hiperativa , Benzilatos , Cognição , Humanos , Qualidade de Vida , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária Hiperativa/tratamento farmacológico
4.
Curr Alzheimer Res ; 18(6): 499-504, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34455969

RESUMO

BACKGROUND: The role of nigrostriatal dopaminergic neurons degeneration is well established in the pathophysiology of Parkinson's disease. However, it is unclear if and how the degeneration of the dopamine pathways affects the manifestation of the neuropsychiatric symptoms (NPS) of Parkinson's Disease (PD). Dopamine transporter (DAT) imaging, a technique to measure the reduction in dopamine transporters is increasingly used as a tool in the diagnosis of PD. METHODS: In this study, we examine if the baseline dopamine transporter density in the striatum measured by the Striatal Binding Ratio (SBR) is associated with the longitudinal onset and/or progression of NPS in PD as measured by part 1 of Movement Disorder Society - Unified Parkinson's Disease Rating Scale, over four years. Data of patients with PD and an abnormal screening present on 123I-ioflupane single-proton emission computed tomography were obtained from Parkinson's Progression Markers Initiative (PPMI) database. Latent Growth Modeling (LGM), a statistical technique that can model the change over time while considering the variability in the rate of change at the individual level, was used to examine the progression of NPS over time. RESULTS: The results indicate the SBR did not correlate with the baseline NPS but did correlate with the rate of change of NPS (p<0.001) over the next four years, even after eliminating age-related variance, which can be a significant confounding factor. CONCLUSION: In conclusion, this study showed gradual worsening in NPS in patients with Parkinson's disease, which inversely correlates with the density of the dopamine transporters as measured by SBR at baseline.


Assuntos
Corpo Estriado/fisiopatologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Dopamina/deficiência , Doença de Parkinson , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/fisiopatologia , Tomografia Computadorizada de Emissão de Fóton Único
5.
Curr Alzheimer Res ; 18(3): 196-207, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34102975

RESUMO

BACKGROUND: Both movement (MD) and cognitive (CD) disorders can occur associated in some neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (AD). OBJECTIVE: We further investigated the usefulness of 123I-Ioflupane SPECT and 18F-FDG PET combined use in patients with these disorders in the early stage. METHODS: We retrospectively enrolled twenty-five consecutive patients with MD and CD clinical symptoms of recent appearance. All patients had undergone neurologic examination, neuropsychological tests, and magnetic resonance imaging. 123I-Ioflupane SPECT was performed in all cases, followed by 18F-FDG PET two weeks later. In the two procedures, both qualitative (QL) and quantitative (QN) image analyses were determined. RESULTS: In patients with both 123I-Ioflupane SPECT and 18F-FDG PET pathologic data, associated dopaminergic and cognitive impairments were confirmed in 56% of cases. Pathologic SPECT with normal PET in 16% of cases could diagnose MD and exclude an associated CD, despite clinical symptoms. On the contrary, normal SPECT with pathologic PET in 28% of cases could exclude basal ganglia damage while confirming CD. QN 123I-Ioflupane SPECT analysis showed better performance than QL since QN correctly characterized two cases of MD with normal QL. Moreover, correct classification of normal metabolism was made only by QN analysis of 18F-FDG PET in four cases, despite suspect areas of hypometabolism at QL. CONCLUSION: The combined use of these imaging procedures proved a reliable diagnostic tool to accurately identify and characterize MD and CD in early stage. QN analysis was effective in supporting QL evaluation, and its routine use is suggested, especially with inconclusive QL.


Assuntos
Transtornos Cognitivos/diagnóstico , Fluordesoxiglucose F18/metabolismo , Transtornos dos Movimentos/diagnóstico , Doenças Neurodegenerativas/metabolismo , Nortropanos/metabolismo , Doença de Alzheimer , Encéfalo/metabolismo , Humanos , Doença de Parkinson , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
6.
AAPS J ; 23(4): 85, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34142242

RESUMO

Food can alter drug absorption and impact safety and efficacy. Besides conducting clinical studies, in vitro approaches such as biorelevant solubility and dissolution testing and in vivo dog studies are typical approaches to estimate a drug's food effect. The use of physiologically based pharmacokinetic models has gained importance and is nowadays a standard tool for food effect predictions at preclinical and clinical stages in the pharmaceutical industry. This manuscript is part of a broader publication from the IQ Consortium's food effect physiologically based pharmacokinetic model (PBPK) modeling working group and complements previous publications by focusing on cases where the food effect was predicted with low confidence. Pazopanib-HCl, trospium-Cl, and ziprasidone-HCl served as model compounds to provide insights into why several food effect predictions failed in the first instance. Furthermore, the manuscript depicts approaches whereby PBPK-based food effect predictions may be improved. These improvements should focus on the PBPK model functionality, especially better reflecting fasted- and fed-state gastric solubility, gastric re-acidification, and complex mechanisms related to gastric emptying of drugs. For improvement of in vitro methodologies, the focus should be on the development of more predictive solubility, supersaturation, and precipitation assays. With regards to the general PBPK modeling methodology, modelers should account for the full solubility profile when modeling ionizable compounds, including common ion effects, and apply a straightforward strategy to account for drug precipitation.


Assuntos
Interações Alimento-Droga , Modelos Biológicos , Administração Oral , Área Sob a Curva , Benzilatos/administração & dosagem , Benzilatos/farmacocinética , Disponibilidade Biológica , Simulação por Computador , Esvaziamento Gástrico/fisiologia , Voluntários Saudáveis , Humanos , Indazóis/administração & dosagem , Indazóis/farmacocinética , Absorção Intestinal/fisiologia , Nortropanos/administração & dosagem , Nortropanos/farmacocinética , Piperazinas/administração & dosagem , Piperazinas/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/farmacocinética , Solubilidade , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacocinética , Tiazóis/administração & dosagem , Tiazóis/farmacocinética
7.
Cell Commun Signal ; 19(1): 61, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34034759

RESUMO

BACKGROUND: Chronic superphysiological glucose and insulin concentrations are known to trigger several tissue and organ failures, including insulin resistance, oxidative stress and chronic low-grade inflammation. Hence, the screening for molecules that may counteract such conditions is essential in current existing therapeutic strategies, thereby the use of medicinal plant derivatives represents a promising axis in this regard. METHODS: In this study, the effect of a selected traditional medicinal plant, Hyoscyamus albus from which, calystegines have been isolated, was investigated in an experimental model of hyperinsulinemia and hyperglycemia induced on HepG2 cells. The mRNA and protein expression levels of different insulin signaling, gluconeogenic and inflammatory pathway- related molecules were examined. Additionally, cell viability and apoptosis, oxidative stress extent and mitochondrial dysfunctions were assayed using flow cytometric and qRT-PCR techniques. RESULTS: Treatment of IR HepG2 cells with calystegines strongly protected the injured cells from apoptosis, oxidative stress and mitochondrial integrity loss. Interestingly, nortropane alkaloids efficiently regulated the impaired glucose metabolism in IR HepG2 cells, through the stimulation of glucose uptake and the modulation of SIRT1/Foxo1/G6PC/mTOR pathway, which is governing the hepatic gluconeogenesis. Furthermore, the alkaloidal extract restored the defective insulin signaling pathway, mainly by promoting the expression of Insr at the mRNA and protein levels. What is more, treated cells exhibited significant mitigated inflammatory response, as evidenced by the modulation and the regulation of the NF- κB/JNK/TLR4 axis and the downstream proinflammatory cytokines recruitment. CONCLUSION: Overall, the present investigation demonstrates that calystegines from Hyoscyamus albus provide cytoprotection to the HepG2 cells against insulin/glucose induced insulin resistance and apoptosis due to the regulation of SIRT1/Foxo1/G6PC/mTOR and NF-κB/JNK/TLR4 signaling pathways. Video Abstract.


Assuntos
Hyoscyamus/química , Hiperglicemia/tratamento farmacológico , Hiperinsulinismo/tratamento farmacológico , Sistema de Sinalização das MAP Quinases , NF-kappa B/metabolismo , Nortropanos/uso terapêutico , Sirtuína 1/metabolismo , Apoptose/efeitos dos fármacos , Caspases/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Gluconeogênese/efeitos dos fármacos , Glucose/metabolismo , Células Hep G2 , Humanos , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Resistência à Insulina , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Nortropanos/farmacologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Sementes/química , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
8.
Mol Imaging Biol ; 23(5): 733-744, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33851345

RESUMO

PURPOSE: The dopamine transporter (DAT) is a marker of the occurrence and development of Parkinson's disease (PD) and other diseases with nigrostriatal degeneration. 2ß-Carbomethoxy-3ß-(4-chlorophenyl)-8-(2-[18F]-fluoroethyl)nortropane ([18F]FECNT), an 18F-labelled tropane derivative, was reported to be a useful positron-emitting probe for DAT. However, the rapid formation of brain-penetrating radioactive metabolites is an impediment to the proper quantitation of DAT in PET studies with [18F]FECNT. Deuterium-substituted analogues have presented better in vivo stability to reduce metabolites. This study aimed to synthesize a deuterium-substituted DAT radiotracer, [18F]FECNT-d4, and to make a preliminary investigation of its properties as a DAT tracer in vivo. PROCEDURES: The ligand [18F]FECNT-d4 was obtained by one-step radiolabelling reaction. The lipophilicity was measured by the shake-flask method. Binding properties of [18F]FECNT-d4 were estimated by in vitro binding assay, biodistribution, and microPET imaging in rats. In vivo stability of [18F]FECNT-d4 was estimated by radio-HPLC. RESULTS: [18F]FECNT-d4 was synthesized at an average activity yield of 46 ± 17 % (n = 15) and the molar activity was 67 ± 12 GBq/µmol. The deuterated tracer showed suitable lipophilicity and the ability to penetrate the blood-brain barrier (brain uptake of 1.72 % ID at 5 min). [18F]FECNT-d4 displayed a high binding affinity for DAT comparable to that of [18F]FECNT in rat striatum homogenates. Biodistribution results in normal rats showed that [18F]FECNT-d4 exhibited a higher ratio of the target to non-target (striatum/cerebellum) at 15 min post administration (5.00 ± 0.44 vs 3.84 ± 0.24 for [18F]FECNT-d4 vs [18F]FECNT). MicroPET imaging studies of [18F]FECNT-d4 in normal rats showed that the ligand selectively localized to DAT-rich striatal regions and the accumulation could be blocked with DAT inhibitor. Furthermore, in the unilateral PD model rat, a significant reduction of the signal was found in the lesioned side relative to the unlesioned side. Striatal standardized uptake value of [18F]FECNT-d4 remained ~4.02 in the striatum between 5 and 20 min, whereas that of [18F]FECNT fell rapidly from 4.11 to 2.95. Radio-HPLC analysis of the plasma demonstrated better in vivo stability of [18F]FECNT-d4 than [18F]FECNT. CONCLUSION: The deuterated compound [18F]FECNT-d4 may serve as a promising PET imaging agent to assess DAT-related disorders.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina , Radioisótopos de Flúor , Nortropanos , Tomografia por Emissão de Pósitrons/métodos , Animais , Deutério , Proteínas da Membrana Plasmática de Transporte de Dopamina/análise , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacocinética , Masculino , Nortropanos/química , Nortropanos/farmacocinética , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
9.
Auton Neurosci ; 233: 102813, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33894531

RESUMO

OBJECTIVES: Parkinson's disease (PD) is the most common degenerative cause of movement disorder, and autonomic dysfunction has been recognized in this disorder. PD patients' lower urinary tract (LUT) function is not established. We investigated LUT function in PD by single-photon emission computerized tomography (SPECT) imaging of the dopamine transporter with 123I-ioflupane and clinical-urodynamic observations. PATIENTS AND METHODS: We retrospectively analyzed the cases of 30 patients diagnosed with PD based on published criteria who completed a systematized lower urinary tract symptoms (LUTS) questionnaire and a urodynamics examination irrespective of the presence of LUTS. None of the patients were taking anti-parkinsonian medication during the study. RESULTS: The questionnaire revealed that all 30 patients had LUTS: night-time urinary frequency (in 70%), urinary incontinence (40%), and daytime urinary frequency (80%). A urodynamic study revealed a mean volume at the first sensation at 92.3 ml, bladder capacity at 200.9 ml, and detrusor overactivity in 50%. Sphincter electromyography revealed neurogenic change in 13.6% of those for whom the test was performed. The average SBR showed a significant correlation with bladder capacity (Spearman's correlation coefficient p = 0.0076) and Hoehn Yahr motor stage (Spearman's correlation coefficient p = 0.012). CONCLUSION: Our findings demonstrate that the striatum is relevant to the higher control of storage in micturition function in PD.


Assuntos
Doença de Parkinson , Preparações Farmacêuticas , Humanos , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Cintilografia , Estudos Retrospectivos , Bexiga Urinária/diagnóstico por imagem , Urodinâmica
10.
Molecules ; 26(6)2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33807018

RESUMO

The aminocarbonylation of various alkenyl and (hetero)aryl iodides was carried out using tropane-based amines of biological importance, such as 8-azabicyclo[3.2.1]octan-3-one (nortropinone) and 3α-hydroxy-8-azabicyclo[3.2.1]octane (nortropine) as N-nucleophile. Using iodoalkenes, the two nucleophiles were selectively converted to the corresponding amide in the presence of Pd(OAc)2/2 PPh3 catalysts. In the presence of several iodo(hetero)arenes, the application of the bidentate Xantphos was necessary to produce the target compounds selectively. The new carboxamides of varied structure, formed in palladium-catalyzed aminocarbonylation reactions, were isolated and fully characterized. In this way, a novel synthetic method has been developed for the producing of N-acylnortropane derivatives of biological importance.


Assuntos
Nortropanos/química , Nortropanos/síntese química , Paládio/química , Catálise , Estrutura Molecular
11.
Clin Neurol Neurosurg ; 202: 106514, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33529967

RESUMO

INTRODUCTION: Fahr's syndrome due to hypoparathyroidism refers to bilateral basal ganglia (BG) calcifications and manifests with movement disorders, seizures, cognitive and behavioral symptoms. CASE PRESENTATION: We report a case of a 74-year-old woman, who presented with parkinsonism due to post-surgical hypoparathyroidism and normal DaT scan, despite extensive calcifications of the BG, periventricular white matter, and cerebellum. METHODS: A comprehensive literature review of all reported cases of Fahr's syndrome due to hypoparathyroidism was conducted in the electronic databases PubMed and Web of science. Moreover, demographic and clinical characteristics of the patients overall were calculated and associated with radiological findings. RESULTS: We reviewed a total of 223 cases with Fahr's syndrome due to hypoparathyroidism (124 female, 99 male). Mean age on presentation was 44.6 ± 17.7 years. Thirty nine percent of patients had idiopathic hypoparathyroidism, 35.4 % acquired and 25.6 % pseudohypoparathyroidism. Almost half of the patients had tetany, seizures or a movement disorder and approximately 40 % neuropsychiatric symptoms. The patients with a movement disorder had a 2.23 likelihood of having neuropsychiatric symptoms as well (OR 2.23, 95 % CI 1.29-3.87). Moreover, there was a statistically significant association between the phenotype severity (i.e. the presence of more than one symptom) and the extent of brain calcifications (χ2 = 32.383, p = 0.009). CONCLUSION: Fahr's syndrome is a rare disorder, which nonetheless manifests with several neurological symptoms. A head CT should be considered for patients with hypoparathyroidism and neurological symptoms. More studies using DaT scan are needed to elucidate the effects of calcifications on the dopaminergic function of the BG.


Assuntos
Doenças dos Gânglios da Base/fisiopatologia , Calcinose/fisiopatologia , Hipoparatireoidismo/metabolismo , Doenças Neurodegenerativas/fisiopatologia , Transtornos Parkinsonianos/fisiopatologia , Complicações Pós-Operatórias/metabolismo , Tireoidectomia , Idoso , Doenças dos Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/etiologia , Calcinose/diagnóstico por imagem , Calcinose/etiologia , Feminino , Humanos , Hipoparatireoidismo/complicações , Imageamento por Ressonância Magnética , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/etiologia , Nortropanos , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/etiologia , Tomografia por Emissão de Pósitrons , Índice de Gravidade de Doença , Tomografia Computadorizada por Raios X
12.
Ann Nucl Med ; 35(4): 504-513, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33630226

RESUMO

OBJECTIVE: Dopamine transporter single-photon emission computed tomography (DAT SPECT) has been widely used to diagnose Parkinson syndrome. Using the standardized uptake value (SUV) of DAT SPECT, we propose "functional dopamine transporter volume (f-DTV)" as a new quantitative index to evaluate the three-dimensional volume of functional dopamine transporters and assess its diagnostic ability in differentiating dopaminergic neurodegenerative diseases (dNDD) from non-dNDD. METHODS: Seventy-nine patients were enrolled (42 dNDD, 37 non-dNDD; 38 men; age 24-88 years). We analyzed seven quantitative indices. The specific binding ratio (SBR) was calculated using a program specialized for DAT SPECT (SBR_Bolt). The SUVmax, SUVpeak, and SUVmean were calculated using a quantification program for bone SPECT. SBR_SUV was calculated by dividing striatal SUVmean by the average of background SUVmean. The cutoff value of the active dopamine transporter level was examined using three methods (threshold of 40% of SUVmax, SUV 2, and SUV 3) to calculate the active dopamine transporter volume (ADV). The f-DTV was calculated by multiplying ADV and SUVmean. We assessed the correlations between SBR_Bolt and SBR_SUV, and compared the mean value of each index between the dNDD and non-dNDD groups. The abilities of SBR_Bolt, SBR_SUV, SUVmax, SUVpeak, SUVmean, ADV, and f-DTV in differentiating dNDD from non-dNDD were determined by the area under the receiver operating curve (AUC) generated by the receiver operating characteristics analysis. RESULTS: The SBR_Bolt and SBR_SUV highly correlated with each other (r = 0.71). The cutoff value of the active dopamine transporter level was determined as SUV 3. All seven quantitative indices showed lower values in the dNDD group than in the non-dNDD group, and the difference between the two groups was statistically significant (p < 0.05). Sensitivity, specificity, and AUC of f-DTV were slightly lower than those of SBR_Bolt (71%, 79%, and 0.81, respectively, for f-DTV, and 81%, 84%, 0.88, respectively, for SBR_Bolt). The difference in AUC between f-DTV and SBR_Bolt was not statistically significant. CONCLUSIONS: This study demonstrates the utility of f-DTV as a novel quantitative index for evaluating the three-dimensional volume of functional dopamine transporters, and that f-DTV has almost the same diagnostic ability to differentiate dNDD from non-dNDD using DAT SPECT.


Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Radioisótopos do Iodo/química , Nortropanos/química , Doença de Parkinson/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Transporte Biológico , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/classificação , Imagens de Fantasmas , Curva ROC , Estudos Retrospectivos
13.
N Engl J Med ; 384(8): 717-726, 2021 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-33626254

RESUMO

BACKGROUND: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown. METHODS: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2. RESULTS: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups. CONCLUSIONS: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.).


Assuntos
Antipsicóticos/uso terapêutico , Benzilatos/uso terapêutico , Antagonistas Colinérgicos/uso terapêutico , Agonistas Muscarínicos/uso terapêutico , Nortropanos/uso terapêutico , Piridinas/uso terapêutico , Esquizofrenia/tratamento farmacológico , Tiadiazóis/uso terapêutico , Administração Oral , Adulto , Antipsicóticos/efeitos adversos , Benzilatos/efeitos adversos , Antagonistas Colinérgicos/efeitos adversos , Método Duplo-Cego , Combinação de Medicamentos , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Pessoa de Meia-Idade , Agonistas Muscarínicos/efeitos adversos , Nortropanos/efeitos adversos , Piridinas/efeitos adversos , Tiadiazóis/efeitos adversos
14.
J Cereb Blood Flow Metab ; 41(6): 1291-1300, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32955955

RESUMO

Quantification of dopamine transporter (DAT) availability with [18F]FE-PE2I PET enables the detection of presynaptic dopamine deficiency and provides a potential progression marker for Parkinson`s disease (PD). Simplified quantification is feasible, but the time window of short acquisition protocols may have a substantial impact on the reliability of striatal binding estimates. Dynamic [18F]FE-PE2I PET data of cross-sectional (33 PD patients, 24 controls), test-retest (9 patients), and longitudinal (12 patients) cohorts were used to assess the variability and reliability of specific binding ratios (SBR) measured during early peak and late pseudo-equilibrium. Receiver operating characteristics area under the curve (PD vs. controls) was high for early (0.996) and late (0.991) SBR. Early SBR provided more favourable effect size, absolute variability, and standard error of measurement than late SBR (caudate: 1.29 vs. 1.23; 6.9% vs. 9.8%; 0.09 vs. 0.20; putamen: 1.75 vs. 1.67; 7.7% vs. 14.0%; 0.08 vs. 0.17). The annual percentage change was comparable for both time windows (-7.2%-8.5%), but decline was significant only for early SBR. Whereas early and late [18F]FE-PE2I PET acquisitions have similar discriminative power to separate PD patients and controls, the early peak equilibrium acquisition can be recommended if [18F]FE-PE2I is used to measure longitudinal changes of DAT availability.


Assuntos
Neuroimagem/métodos , Nortropanos , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Idoso , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes
15.
Clin Toxicol (Phila) ; 59(3): 235-245, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32762574

RESUMO

CONTEXT: Investigate whether 123I-ioflupane SPECT (DaT SPECT) has the potential as a marker of basal ganglia damage in acute methanol poisoning. METHODS: Prospective, single-centre, cohort study of patients with confirmed methanol poisoning was conducted. DaT SPECT was performed twice with semi-quantification using DaTQUANTTM and MRI-based volumetry was calculated. Specific binding ratios (SBR) of striatum, caudate nucleus, and putamen were correlated with laboratory parameters of outcome, volumetric data, and retinal nerve fibres layer (RNFL) thickness measurements. RESULTS: Forty-two patients (mean age 46.3 ± 4.2 years; 8 females), including 15 with MRI-detected putamen lesions (group I) and 27 patients with intact putamen (group II), underwent DaT SPECT. Volumetry was calculated in 35 of the patients assessed. SBR values for the left putamen correlated with putamen volume (r = 0.665; p < 0.001). Decreased bilateral SBR values were determined for the striatum and the putamen, but not for the nucleus caudate, in group I (p < 0.05). Significant correlation was observed between the SBR of the posterior putamen and arterial blood pH (r = 0.574; p < 0.001) and other toxicological parameters of severity of poisoning/outcome including serum lactate, glucose, and creatinine concentrations (p < 0.05). The SBR of the posterior putamen positively correlated with the global RNFL thickness (p < 0.05). ROC analysis demonstrated a significant discriminatory ability of SBR of the posterior putamen with AUC = 0.753 (95%CI 0.604-0.902; p = 0.007). The multivariate regression model demonstrated that arterial blood pH, age, and gender were the most significant factors associated with SBR of the posterior putamen. CONCLUSION: DaT SPECT demonstrates significant potential for the diagnosis of methanol-induced basal ganglia damage.


Assuntos
Doenças dos Gânglios da Base/induzido quimicamente , Gânglios da Base/efeitos dos fármacos , Metanol/envenenamento , Adulto , Gânglios da Base/diagnóstico por imagem , Doenças dos Gânglios da Base/diagnóstico por imagem , Feminino , Humanos , Radioisótopos do Iodo , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Nortropanos , Estudos Prospectivos , Putamen/diagnóstico por imagem , Putamen/efeitos dos fármacos , Compostos Radiofarmacêuticos , Tomografia Computadorizada de Emissão de Fóton Único/métodos
16.
Neuroimage ; 224: 117399, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-32971267

RESUMO

In the last two decades, it has been shown that anatomically-guided PET reconstruction can lead to improved bias-noise characteristics in brain PET imaging. However, despite promising results in simulations and first studies, anatomically-guided PET reconstructions are not yet available for use in routine clinical because of several reasons. In light of this, we investigate whether the improvements of anatomically-guided PET reconstruction methods can be achieved entirely in the image domain with a convolutional neural network (CNN). An entirely image-based CNN post-reconstruction approach has the advantage that no access to PET raw data is needed and, moreover, that the prediction times of trained CNNs are extremely fast on state of the art GPUs which will substantially facilitate the evaluation, fine-tuning and application of anatomically-guided PET reconstruction in real-world clinical settings. In this work, we demonstrate that anatomically-guided PET reconstruction using the asymmetric Bowsher prior can be well-approximated by a purely shift-invariant convolutional neural network in image space allowing the generation of anatomically-guided PET images in almost real-time. We show that by applying dedicated data augmentation techniques in the training phase, in which 16 [18F]FDG and 10 [18F]PE2I data sets were used, lead to a CNN that is robust against the used PET tracer, the noise level of the input PET images and the input MRI contrast. A detailed analysis of our CNN in 36 [18F]FDG, 18 [18F]PE2I, and 7 [18F]FET test data sets demonstrates that the image quality of our trained CNN is very close to the one of the target reconstructions in terms of regional mean recovery and regional structural similarity.


Assuntos
Encéfalo/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação , Tomografia por Emissão de Pósitrons , Fluordesoxiglucose F18 , Humanos , Imageamento por Ressonância Magnética , Nortropanos , Compostos Radiofarmacêuticos , Tirosina/análogos & derivados
17.
Neurobiol Aging ; 97: 120-128, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33212336

RESUMO

Striatal dopamine transporter (DAT) uptake assessment through I123-Ioflupane Single-Pphoton Emission Computed Tomography (SPECT) provides valuable information about the dopaminergic denervation occurring in Parkinson's disease (PD). However, little is known about the clinical or biological relevance of extrastriatal DAT uptake in PD. Here, from the Parkinson's Progression Markers Initiative, we studied 623 participants (431 PD and 192 healthy controls) with available SPECT data. Even though striatal denervation was undoubtedly the imaging hallmark of PD, extrastriatal DAT uptake was also reduced in patients with PD. Topographically, widespread frontal but also temporal and posterior cortical regions showed lower DAT uptake in PD patients with respect to healthy controls. Importantly, a longitudinal voxelwise analysis confirmed an active one-year loss of extrastriatal DAT uptake within the PD group. Extrastriatal DAT uptake also correlated with the severity of motor symptoms, cognitive performance, and cerebrospinal fluid α-synuclein levels. In addition, we found an association between the Catechol-O-methyltransferase val158met genotype and extrastriatal DAT uptake. These results highlight the clinical and biological relevance of extrastriatal SPECT-DAT uptake in PD.


Assuntos
Corpo Estriado/diagnóstico por imagem , Corpo Estriado/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/metabolismo , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Feminino , Genótipo , Humanos , Radioisótopos do Iodo , Masculino , Pessoa de Meia-Idade , Nortropanos , Doença de Parkinson/genética , Compostos Radiofarmacêuticos , Índice de Gravidade de Doença
18.
Eur J Neurol ; 28(4): 1392-1395, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33175431

RESUMO

BACKGROUND AND PURPOSE: Anti-IgLON5 disease is a rare disorder characterized by a heterogeneous myriad of symptoms that may include sleep disorders, bulbar dysfunction, gait problems, movement disorders, cognitive impairment, oculomotor abnormalities, and nervous system hyperexcitability. Its physiopathology remains unknown, with a combination of both autoimmune and neurodegenerative findings. METHODS: We describe clinical, cerebrospinal fluid (CSF), and ioflupane single-photon emission computed tomography (SPECT) findings of a positive case of anti-IgLON5 disease mimicking probable progressive supranuclear palsy (PSP). We performed a literature review of previous publications reporting on anti-IgLON5 disease and ioflupane SPECT. RESULTS: We report the case of a 66-year-old male who met clinical criteria for probable PSP, in whom ioflupane SPECT showed an alteration of the left presynaptic dopaminergic pathway. However, the presence of atypical neurological symptoms for PSP led to further complementary tests, and IgLON5 antibodies were detected in CSF. According to our literature review, ioflupane SPECT findings have been previously described in only three other patients with anti-IgLON5 disease, with a reduced uptake in the striatum in two of them. CONCLUSIONS: Ioflupane SPECT abnormalities, though scarcely described, are not uncommon in anti-IgLON5 disease. They could be related to nigrostriatal dopaminergic degeneration in the context of the tauopathy component of the disease, but further case descriptions are necessary.


Assuntos
Encefalite , Nortropanos , Paralisia Supranuclear Progressiva , Idoso , Moléculas de Adesão Celular Neuronais , Humanos , Masculino , Paralisia Supranuclear Progressiva/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único
19.
Parkinsonism Relat Disord ; 82: 29-36, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33242662

RESUMO

INTRODUCTION: Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [11C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [18F]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. METHODS: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [18F]-DPA714 and [11C]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. RESULTS: PD patients showed significantly higher [18F]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [11C]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). CONCLUSION: [18F]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients. TRIAL REGISTRATION: Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.


Assuntos
Progressão da Doença , Lobo Frontal/metabolismo , Inflamação , Mesencéfalo/metabolismo , Microglia/metabolismo , Doença de Parkinson/imunologia , Doença de Parkinson/metabolismo , Putamen/metabolismo , Receptores de GABA/metabolismo , Idoso , Feminino , Radioisótopos de Flúor/farmacocinética , Lobo Frontal/diagnóstico por imagem , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Mesencéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Nortropanos/farmacocinética , Doença de Parkinson/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Putamen/diagnóstico por imagem , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Fatores de Tempo
20.
J Nucl Med Technol ; 49(2): 114-119, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33361183

RESUMO

The aim of the current article is to describe how to improve the quality of imaging with 123I-ioflupane SPECT and to serve as a teaching tool on this topic. The radiopharmaceutical 123I-ioflupane is used to visualize the nigrostriatal pathway. Parkinson disease and parkinsonian syndromes are movement disorders that exhibit nigrostriatal degeneration, with a decreased dopamine transporter level in the pathway and thus a decreased 123I-ioflupane distribution. Other nonparkinsonian movement disorders, such as essential tremor, will have intact dopaminergic neurons and exhibit a normal distribution of the radiopharmaceutical throughout the striata. Parkinsonian disorders are usually diagnosed clinically. However, 123I-ioflupane SPECT can be a valuable tool when the clinical features are not sufficiently clear. 123I-ioflupane SPECT image interpretation is not always straightforward. Many pitfalls, including biologic factors, technical factors, medications, and factors such as age, race, ethnicity, and body habitus, can make the interpretation challenging. The technologist and nuclear radiologist must identify the expected imaging findings to avoid the most common mistakes related to artifacts. This article reviews the usual pitfalls and artifacts of 123I-ioflupane SPECT that can compromise an accurate diagnosis and lead to misinterpretation of image findings.


Assuntos
Artefatos , Transtornos Parkinsonianos , Humanos , Radioisótopos do Iodo , Nortropanos , Transtornos Parkinsonianos/diagnóstico por imagem , Melhoria de Qualidade , Tomografia Computadorizada de Emissão de Fóton Único
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