RESUMEN
INTRODUCTION: Parkinson's disease (PD) presents with a progressive decline in manual dexterity, attributed to dysfunction in the basal ganglia-thalamus-cortex loop, influenced by dopaminergic deficits in the striatum. Recent research suggests that the motor cortex may play a pivotal role in mediating the relationship between striatal dopamine depletion and motor function in PD. Understanding this connection is crucial for comprehending the origins of manual dexterity impairments in PD. Therefore, our study aimed to explore how motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD. MATERIALS AND METHODS: We enrolled 26 mildly affected PD patients in their off-medication phase to undergo [18F]FDOPA PET/CT scans for evaluating striatal dopaminergic function. EEG recordings were conducted during bimanual anti-phase finger tapping tasks to evaluate motor cortex activity, specifically focusing on Event-Related Desynchronization in the beta band. Manual dexterity was assessed using the Purdue Pegboard Test. Regression-based mediation analysis was conducted to examine whether motor cortex activation mediates the association between striatal dopamine depletion and manual dexterity in PD. RESULTS: Mediation analysis revealed a significant direct effect of putamen dopamine depletion on manual dexterity for the affected hand and assembly tasks (performed with two hands), with motor cortex activity mediating this association. In contrast, while caudate nucleus dopamine depletion showed a significant direct effect on manual dexterity, motor cortex mediation on this association was not observed. CONCLUSION: Our study confirms the association between striatum dopamine depletion and impaired manual dexterity in PD, with motor cortex activity mediating this relationship.
Asunto(s)
Dopamina , Corteza Motora , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Anciano , Corteza Motora/fisiopatología , Corteza Motora/diagnóstico por imagen , Corteza Motora/metabolismo , Dopamina/metabolismo , Destreza Motora/fisiología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/fisiopatología , Tomografía Computarizada por Tomografía de Emisión de Positrones , Electroencefalografía , Dihidroxifenilalanina/análogos & derivadosRESUMEN
Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.
Asunto(s)
Cuerpo Estriado , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Dopamina , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón Único , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Dopamina/metabolismo , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/metabolismo , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Cuerpo Estriado/fisiopatología , Estudios de Cohortes , Dihidroxifenilalanina/análogos & derivados , Conectoma , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/metabolismo , Red Nerviosa/fisiopatologíaRESUMEN
The success of polymerase chain reaction (PCR) depends on the quality of deoxyribonucleic acid (DNA) templates. This study developed a cost-effective and eco-friendly DNA extraction system utilizing poly(3,4-dihydroxyphenylalanine)-modified cellulose paper (polyDOPA@paper). PolyDOPA@paper was prepared by oxidatively self-polymerizing DOPA under weak alkaline conditions and utilizing the adhesive property of polyDOPA on different materials. Compared to the uncoated cellulose paper, polyDOPA coating significantly enhances DNA adsorption owing to its abundant amino, carboxyl, and hydroxyl moieties. The DNA extraction mechanism using polyDOPA@paper was discussed. The maximum adsorption capacity of polyDOPA@paper for DNA was 20.7 µg cm-2. Moreover, an automated extraction system was designed and fabricated using 3D printing technology. The device simplifies the operation and ensures the reproducibility and consistency of the results. More importantly, it eliminates the need for specialized training of operators. The feasibility of the polyDOPA@paper-based automated extraction system was evaluated by quantitatively detecting Escherichia coli in spiked milk samples via a real-time PCR. The detection limit was 102 cfu mL-1. The results suggest that the system would have significant potential in detecting pathogens.
Asunto(s)
Celulosa , Dihidroxifenilalanina , Límite de Detección , Leche , Papel , Polímeros , Celulosa/química , Celulosa/análogos & derivados , Adsorción , Dihidroxifenilalanina/química , Dihidroxifenilalanina/aislamiento & purificación , Dihidroxifenilalanina/análogos & derivados , Polímeros/química , Leche/química , Escherichia coli , Animales , Reproducibilidad de los Resultados , ADN/aislamiento & purificación , ADN/química , Impresión Tridimensional , Reacción en Cadena en Tiempo Real de la Polimerasa , ADN Bacteriano/aislamiento & purificación , ADN Bacteriano/análisisRESUMEN
Objective: Correct diagnosis and prognostic evaluation of medullary thyroid cancer (MTC) are crucial to treat patients. The purpose of this study was to evaluate the diagnostic and prognostic value of [18F]F-DOPA PET/CT in patients with MTC. Methods: We reviewed MTC patients who underwent [18F]F-DOPA PET/CT from June 2008 to November 2023. Clinical characteristics, follow-up data, and the following [18F]F-DOPA PET/CT parameters were recorded: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume (MTV), and SUVmean of multiple organs. The diagnostic value of PET/CT for the detection of tumor lesions was calculated. Serum basal calcitonin (bCt) and stimulated calcitonin (sCt) were determined. Receiver operating characteristics, Kaplan-Meier, and Cox regression analyses were performed. Results: In total, 109 patients (50 women, 59 men; average age, 55 ± 14 years) were included in the analysis. The patient-related sensitivity, specificity, and accuracy of [18F]F-DOPA PET/CT were 95%, 93%, and 94%, respectively. The lesion-related sensitivity, specificity, and accuracy were 65%, 99%, and 72%, respectively. The optimal cutoff values of bCt, sCt, and CEA to obtain positive [18F]F-DOPA PET/CT results were 64 pg/mL, 1808 pg/mL, and 4 µg/L, respectively. Patients with negative [18F]F-DOPA PET/CT had longer overall survival than patients with positive [18F]F-DOPA PET/CT results (P = 0.017). Significant positive correlations were found between bCt, sCt, and CEA with SUVmax, SUVmean, and MTV of [18F]F-DOPA PET/CT (P < 0.001). [18F]F-DOPA PET/CT results and MTV may be useful for the evaluation of the prognosis of patients with recurrent MTC, while age and MTV were independent prognostic factors in patients with primary MTC. For all patients, SUVmean of the left kidney, liver, aorta, and pancreas might be used to independently predict OS. Conclusion: [18F]F-DOPA PET/CT had great value for diagnosis and prognostic assessment in patients with MTC. The DOPA PET/CT parameter SUVmean and MTV showed significant association with OS.
Asunto(s)
Carcinoma Neuroendocrino , Dihidroxifenilalanina , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Tiroides , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Femenino , Masculino , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/diagnóstico , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/mortalidad , Persona de Mediana Edad , Pronóstico , Adulto , Anciano , Carcinoma Neuroendocrino/diagnóstico por imagen , Carcinoma Neuroendocrino/mortalidad , Carcinoma Neuroendocrino/diagnóstico , Carcinoma Neuroendocrino/patología , Dihidroxifenilalanina/análogos & derivados , Estudios Retrospectivos , Radiofármacos , Sensibilidad y EspecificidadRESUMEN
ABSTRACT: A 41-year-old woman presented with 2 months history of right submandibular swelling. Biopsy revealed neuroblastoma (NB). Patient was referred for staging PET/CT scan. We compared the findings of 18 F-DOPA PET/CT and 18 F-FDG PET/CT scans. Both imaging modalities were positive in the patient; however, tumor delineation was superior with 18 F-FDG PET/CT. Tumor uptake of FDG was significantly higher than tumor uptake of DOPA. Follow-up FDG PET/CT scan postsurgery showed local recurrent NB and their metastases avidly concentrate FDG. We present a very rare case of adult NB of the neck better imaged with FDG instead of DOPA PET/CT.
Asunto(s)
Dihidroxifenilalanina , Fluorodesoxiglucosa F18 , Neuroblastoma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Femenino , Adulto , Dihidroxifenilalanina/análogos & derivados , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/patología , Tomografía Computarizada por Rayos X , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias de Cabeza y Cuello/patologíaRESUMEN
Ceria (CeO2) nanoparticles with haloperoxidase (HPO)-like activity have gained attention as a biologically benign antifoulant. 3,4-Dihydroxy-l-phenylalanine (DOPA), a main composition in mussel foot proteins, plays a crucial role in the biofouling process. However, the impact on the HPO-like activity and antifouling performance of CeO2 nanoparticles when DOPA molecules adsorb on them remains unexplored. This interesting question warrants investigation, particularly considering that it may occur in an actual marine environment. Herein, the interaction between DOPA and CeO2 is explored. Despite the higher Ce3+ fractions and the lower band gap energies due to the electron transfer from DOPA to the CeO2 surface, DOPA still had a slightly negative effect on the HPO-like activity of CeO2 since they decreased the exposed Ce3+ sites. The DOPA-CeO2 nanocomposites with HPO-like activities could kill bacteria and trigger quorum-sensing signaling quenching, achieving a biofilm inhibition performance. Amazingly, 0.1% DOPA-CeO2 nanocomposite exhibited higher antibacterial activity and better biofilm suppression activities due to its HPO-like activity and positive zeta potential. The remarkable results demonstrated that DOPA, as a participant in the biofouling process, could enhance the antibacterial activity and antifouling performance of CeO2 nanoparticles at an appropriate concentration.
Asunto(s)
Antibacterianos , Biopelículas , Cerio , Cerio/química , Cerio/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Biopelículas/efectos de los fármacos , Peroxidasas/metabolismo , Peroxidasas/química , Dihidroxifenilalanina/química , Dihidroxifenilalanina/farmacología , Staphylococcus aureus/efectos de los fármacos , Incrustaciones Biológicas/prevención & control , Pruebas de Sensibilidad Microbiana , Escherichia coli/efectos de los fármacos , Nanocompuestos/química , Percepción de Quorum/efectos de los fármacosRESUMEN
In this study, we introduce a practical methodology for the synthesis of PET probes by seamlessly combining flow chemistry with photoredox radiofluorination. The clinical PET tracer 6-[18F]FDOPA was smoothly prepared in a 24.3% non-decay-corrected yield with over 99.0% radiochemical purity (RCP) and enantiomeric excess (ee), notably by a simple cartridge-based purification. The flow chemistry-enhanced photolabeling method supplies an efficient and versatile solution for the synthesis of 6-[18F]FDOPA and for more PET tracer development.
Asunto(s)
Radioisótopos de Flúor , Tomografía de Emisión de Positrones , Radioisótopos de Flúor/química , Estructura Molecular , Radiofármacos/química , Radiofármacos/síntesis química , Oxidación-Reducción , Dihidroxifenilalanina/química , Dihidroxifenilalanina/síntesis química , Dihidroxifenilalanina/análogos & derivados , Procesos Fotoquímicos , HalogenaciónRESUMEN
Mussel foot proteins (Mfps) possess unique binding properties to various surfaces due to the presence of L-3,4-dihydroxyphenylalanine (DOPA). Mytilus edulis foot protein-3 (Mefp-3) is one of several proteins in the byssal adhesive plaque. Its localization at the plaque-substrate interface approved that Mefp-3 plays a key role in adhesion. Therefore, the protein is suitable for the development of innovative bio-based binders. However, recombinant Mfp-3s are mainly purified from inclusion bodies under denaturing conditions. Here, we describe a robust and reproducible protocol for obtaining soluble and tag-free Mefp-3 using the SUMO-fusion technology. Additionally, a microbial tyrosinase from Verrucomicrobium spinosum was used for the in vitro hydroxylation of peptide-bound tyrosines in Mefp-3 for the first time. The highly hydroxylated Mefp-3, confirmed by MALDI-TOF-MS, exhibited excellent adhesive properties comparable to a commercial glue. These results demonstrate a concerted and simplified high yield production process for recombinant soluble and tag-free Mfp3-based proteins with on demand DOPA modification.
Asunto(s)
Dihidroxifenilalanina , Mytilus edulis , Animales , Dihidroxifenilalanina/química , Dihidroxifenilalanina/metabolismo , Mytilus edulis/genética , Mytilus edulis/química , Mytilus edulis/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/aislamiento & purificación , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Verrucomicrobia/genética , Verrucomicrobia/metabolismo , Monofenol Monooxigenasa/genética , Monofenol Monooxigenasa/metabolismo , Monofenol Monooxigenasa/química , Proteínas/genética , Proteínas/química , Proteínas/aislamiento & purificación , Hidroxilación , Escherichia coli/genética , Escherichia coli/metabolismoRESUMEN
BACKGROUND: Neuroblastoma varies widely in risk. Risk indicators in infants with incidental neuroblastoma refine treatment confidence for observation or intervention. The potential of functional imaging, particularly PET/CT, remains to be defined. PROCEDURE: A retrospective review of infants under 18 months diagnosed with incidental neuroblastoma from 2008 to May 2022 in our institute was conducted. Before October 2015, incidental patients were treated similarly to symptomatic cases, undergoing biopsy or surgical excision upon diagnosis (early cohort). Post October 2015 (late cohort), treatment decisions were guided by PET/CT findings, with 18F-DOPA PET/CT confirming diagnosis and staging. For tumors with low 18F-FDG uptake, an expectant observation approach was considered. Patient characteristics, diagnostic methods, image findings at diagnosis, treatment courses, and responses were compared between cohorts. RESULTS: Thirty infants less than 18 months were identified with incidental neuroblastoma and completed PET/CT at diagnosis. The early and late cohorts each comprised 15 patients. In the late cohort, nine out of 15 patients (60%) presented with localized FDG non-avid tumors were offered the option of expectant observation. Of these, seven patients opted for observation, thereby avoiding surgery. Treatment outcomes were comparable between early and late cohorts, except for one mortality of a patient who, despite showing 18F-FDG activity, declined treatment. CONCLUSIONS: This study demonstrates the potential utility of 18F-DOPA and 18F-FDG PET/CT scans in aiding clinical decision-making for infants with localized, incidental neuroblastoma. Given the concerns regarding radiation exposure, such imaging may be valuable for cases with suspected metastasis, initial large tumor size, or growth during follow-up.
Asunto(s)
Dihidroxifenilalanina , Fluorodesoxiglucosa F18 , Neuroblastoma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Humanos , Neuroblastoma/diagnóstico por imagen , Neuroblastoma/terapia , Neuroblastoma/patología , Lactante , Masculino , Femenino , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Dihidroxifenilalanina/análogos & derivados , Recién Nacido , Hallazgos Incidentales , Estudios de Factibilidad , Estudios de Seguimiento , Toma de Decisiones Clínicas , PronósticoRESUMEN
Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure (i.e., number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.
Asunto(s)
Dihidroxifenilalanina/análogos & derivados , Indoles , Levodopa , Melaninas , Nanopartículas , Compuestos de Amonio Cuaternario , Compuestos de Amonio Cuaternario/química , Compuestos de Amonio Cuaternario/farmacología , Nanopartículas/química , Melaninas/química , Animales , Ratones , Levodopa/química , Terapia Fototérmica , Humanos , Línea Celular Tumoral , Polímeros/química , Polímeros/síntesis química , Polímeros/farmacologíaRESUMEN
Lotus rhizome is an important aquatic vegetable, but the blackening of lotus rhizome epidermis (LRE) seriously affects its appearance and quality, which makes lotus rhizome products unmarketable. In this study, the effects of polyphenols and iron on the LRE color were studied to explore the possible mechanism of LRE blackening. Results indicated that the measurable total phenols contents in the mud treatment (MT) group were significantly reduced, and the total iron contents were significantly increased compared with the bruised treatment group (p < 0.05). The high-performance liquid chromatography results showed that the main polyphenols in LRE were dopa, gallocatechin, and catechin, as well as a small amount of catechol, epicatechin, proanthocyanidin B2, and proanthocyanidin C1. Moreover, the results of color difference and ultraviolet adsorption spectroscopy showed that there were obviously black or brown-gray of dopa (525 nm), gallocatechin (504.5 nm), and catechin (550 and 504.5 nm) with FeCl2. The simulated system treatment of LRE further confirmed that the chromaticity effect of dopa and iron in bruised LRE was similar to that of the MT group, whereas 1% (w/w) ascorbic acid, 2% (w/w) EDTA-2Na, or 3% (w/w) citric acid could solely prohibit the blackening. This suggested that the dopa in LRE and FeCl2 in mud may mainly combine into [2(DOPA-2H+)+Fe3+]- through non-covalent interaction, which leads to the blackening of bruised LRE under neutral conditions. These results can guide the storage of lotus rhizomes and improve the development of the lotus rhizome industry.
Asunto(s)
Catequina , Color , Hierro , Lotus , Polifenoles , Rizoma , Rizoma/química , Polifenoles/farmacología , Polifenoles/análisis , Hierro/análisis , Catequina/farmacología , Catequina/análisis , Lotus/química , Cromatografía Líquida de Alta Presión , Epidermis de la Planta/química , Proantocianidinas/farmacología , Proantocianidinas/análisis , Catecoles/farmacología , Dihidroxifenilalanina/química , BiflavonoidesRESUMEN
BACKGROUND: Amino acid PET is recommended for the initial diagnosis of brain lesions, but its value for identifying aggressive lesions remains to be established. The current study therefore evaluates the added-value of dynamic [18 F]FDOPA PET as an adjunct to conventional MRI for determining the aggressiveness of presumed glial lesions at diagnosis. METHODS: Consecutive patients, with a minimal 1 year-follow-up, underwent contrast-enhanced MRI (CE MRI) and dynamic [18 F]FDOPA PET to characterize their suspected glial lesion. Lesions were classified semi-automatically by their CE MRI (MRI-/+), and PET parameters (static tumor-to-background ratio, TBR; dynamic time-to-peak ratio, TTPratio). Diagnostic accuracies of MRI and PET parameters for the differentiation of tumor aggressiveness were evaluated by chi-square test or receiver operating characteristic analyses. Aggressive lesions were either defined as lesions with dismal molecular characteristics based on the WHO 2021 classification of brain tumors or with compatible clinico-radiological profiles. Time-to-treatment failure (TTF) and overall survival (OS) were evaluated. RESULTS: Of the 109 patients included, 46 had aggressive lesions (45 confirmed by histo-molecular analyses). CE MRI identified aggressive lesions with an accuracy of 73%. TBRmax (threshold of 3.2), and TTPratio (threshold of 5.4 min) respectively identified aggressive lesions with an accuracy of 83% and 76% and were independent of CE MRI and clinical factors in the multivariate analysis. Among the MRI-lesions, 11/56 (20%) were aggressive and respectively 55% and 50% of these aggressive lesions showed high TBRmax and short TTPratio in PET. High TBRmax and short TTPratio in PET were significantly associated to poorer survivals (p ≤ 0.009). CONCLUSION: Dynamic [18 F]FDOPA PET provides a similar diagnostic accuracy as contrast enhancement in MRI to identify the aggressiveness of suspected glial lesions at diagnosis. Both methods, however, are complementary and [18 F]FDOPA PET may be a useful additional tool in equivocal cases.
Asunto(s)
Neoplasias Encefálicas , Dihidroxifenilalanina , Glioma , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Dihidroxifenilalanina/análogos & derivados , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Neoplasias Encefálicas/diagnóstico por imagen , Adulto , Glioma/diagnóstico por imagen , Glioma/patología , Anciano , Adulto JovenRESUMEN
PURPOSE: Functional PET (fPET) is a novel technique for studying dynamic changes in brain metabolism and neurotransmitter signaling. Accurate quantification of fPET relies on measuring the arterial input function (AIF), traditionally achieved through invasive arterial blood sampling. While non-invasive image-derived input functions (IDIF) offer an alternative, they suffer from limited spatial resolution and field of view. To overcome these issues, we developed and validated a scan protocol for brain fPET utilizing cardiac IDIF, aiming to mitigate known IDIF limitations. METHODS: Twenty healthy individuals underwent fPET/MR scans using [18F]FDG or 6-[18F]FDOPA, utilizing bed motion shuttling to capture cardiac IDIF and brain task-induced changes. Arterial and venous blood sampling was used to validate IDIFs. Participants performed a monetary incentive delay task. IDIFs from various blood pools and composites estimated from a linear fit over all IDIF blood pools (3VOI) and further supplemented with venous blood samples (3VOIVB) were compared to the AIF. Quantitative task-specific images from both tracers were compared to assess the performance of each input function to the gold standard. RESULTS: For both radiotracer cohorts, moderate to high agreement (r: 0.60-0.89) between IDIFs and AIF for both radiotracer cohorts was observed, with further improvement (r: 0.87-0.93) for composite IDIFs (3VOI and 3VOIVB). Both methods showed equivalent quantitative values and high agreement (r: 0.975-0.998) with AIF-derived measurements. CONCLUSION: Our proposed protocol enables accurate non-invasive estimation of the input function with full quantification of task-specific changes, addressing the limitations of IDIF for brain imaging by sampling larger blood pools over the thorax. These advancements increase applicability to any PET scanner and clinical research setting by reducing experimental complexity and increasing patient comfort.
Asunto(s)
Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Masculino , Femenino , Adulto , Encéfalo/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Corazón/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador/métodos , Dihidroxifenilalanina/análogos & derivados , Persona de Mediana EdadRESUMEN
BACKGROUND AND PURPOSE: Fluorine 18-fluoro-L-dopa ([18F]-FDOPA) was approved by the FDA in 2019 and reimbursed by the Centers for Medicare & Medicaid Services in 2022 for use with PET to visualize dopaminergic nerve terminals in the striatum for evaluation of parkinsonism. We sought to determine the optimal image acquisition time for [18F]-FDOPA PET by evaluating rater-estimated FDOPA positivity and image quality across 4 time points. MATERIALS AND METHODS: Brain PET/CT was acquired 90 minutes following injection of 185 megabecquerel (5 mCi) of [18F]-FDOPA. PET was acquired in list mode for 20 minutes, and data were replayed to represent 15-, 10-, and 5-minute acquisitions. By means of MIMneuro, PET/MR imaging or PET/CT was independently graded for FDOPA positivity and image quality by 2 readers, blinded to the clinical report and diagnosis. Expert neuroradiologist clinical reads were used as the criterion standard. RESULTS: Twenty patients were included, average age 65.6 years, 55% women. Image-quality ratings decreased with shorter acquisition times for both readers (reader 1, ρ = 0.23, P = .044; reader 2, ρ = 0.24, P = .036), but there was no association between abnormality confidence scores and acquisition time (reader 1, ρ = -0.13, P = .250; reader 2, ρ = -0.19, P = .100). There was a high degree of consistency in intra- and interrater agreement and agreement with the expert reads when using acquisition times of ≥10 minutes (maximal confidence score consistency [ρ = 0.92] and interrater agreement [κ = 0.90] were observed at 15 minutes), while image quality was consistently rated as low and FDOPA positivity ratings were inconsistent when using a 5-minute acquisition time. CONCLUSIONS: Our study suggests that image-quality ratings were stable after 15 minutes and that between-subject abnormality detection rates were highly consistent between the 2 readers when acquired for at least 10 and up to 20 minutes but were inconsistent at 5 minutes. Shorter [18F]-FDOPA PET acquisition times may help maximize patient comfort while increasing throughput in the clinical setting.
Asunto(s)
Dihidroxifenilalanina , Trastornos Parkinsonianos , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos , Humanos , Femenino , Masculino , Dihidroxifenilalanina/análogos & derivados , Anciano , Trastornos Parkinsonianos/diagnóstico por imagen , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Persona de Mediana Edad , Factores de Tiempo , Encéfalo/diagnóstico por imagenRESUMEN
The aromatic amino acids tryptophan, phenylalanine, and tyrosine are targets for oxidation during food processing. We investigated whether S. cerevisiae can use nonproteinogenic aromatic amino acids as substrates for degradation via the Ehrlich pathway. The metabolic fate of seven amino acids (p-, o-, m-tyrosine, 3,4-dihydroxyphenylalanine (DOPA), 3-nitrotyrosine, 3-chlorotyrosine, and dityrosine) in the presence of S. cerevisiae was assessed. All investigated amino acids except dityrosine were metabolized by yeast. The amino acids 3-nitrotyrosine and o-tyrosine were removed from the medium as fast as p-tyrosine, and m-tyrosine, 3-chlorotyrosine, and DOPA more slowly. In summary, 11 metabolites were identified by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). DOPA, 3-nitrotyrosine, and p-tyrosine were metabolized predominantly to the Ehrlich alcohols, whereas o-tyrosine and m-tyrosine were metabolized predominantly to α-hydroxy acids. Our results indicate that nonproteinogenic aromatic amino acids can be taken up and transaminated by S. cerevisiae quite effectively but that decarboxylation and reduction to Ehrlich alcohols as the final metabolites is hampered by hydroxyl groups in the o- or m-positions of the phenyl ring. The data on amino acid metabolism were substantiated by the analysis of five commercial beer samples, which revealed the presence of hydroxytyrosol (ca. 0.01-0.1 mg/L) in beer for the first time.
Asunto(s)
Aminoácidos Aromáticos , Saccharomyces cerevisiae , Saccharomyces cerevisiae/metabolismo , Aminoácidos Aromáticos/metabolismo , Espectrometría de Masas en Tándem , Tirosina/metabolismo , Aminoácidos/metabolismo , Dihidroxifenilalanina/metabolismo , Alcoholes/metabolismoRESUMEN
Dopa and tetrahydrobiopterin (BH4) supplementation are recommended therapies for the dopa-responsive dystonia caused by GTP cyclohydrolase 1 (GCH1, also known as GTPCH) deficits. However, the efficacy and mechanisms of these therapies have not been intensively studied yet. In this study, we tested the efficacy of dopa and BH4 therapies by using a novel GTPCH deficiency mouse model, Gch1KI/KI, which manifested infancy-onset motor deficits and growth retardation similar to the patients. First, dopa supplementation supported Gch1KI/KI mouse survival to adulthood, but residual motor deficits and dwarfism remained. Interestingly, RNAseq analysis indicated that while the genes participating in BH4 biosynthesis and regeneration were significantly increased in the liver, no significant changes were observed in the brain. Second, BH4 supplementation alone restored the growth of Gch1KI/KI pups only in early postnatal developmental stage. High doses of BH4 supplementation indeed restored the total brain BH4 levels, but brain dopamine deficiency remained. While total brain TH levels were relatively increased in the BH4 treated Gch1KI/KI mice, the TH in the striatum were still almost undetectable, suggesting differential BH4 requirements among brain regions. Last, the growth of Gch1KI/KI mice under combined therapy outperformed dopa or BH4 therapy alone. Notably, dopamine was abnormally high in more than half, but not all, of the treated Gch1KI/KI mice, suggesting the existence of variable synergetic effects of dopa and BH4 supplementation. Our results provide not only experimental evidence but also novel mechanistic insights into the efficacy and limitations of dopa and BH4 therapies for GTPCH deficiency.
Asunto(s)
Biopterinas/análogos & derivados , Dihidroxifenilalanina , Dopamina , Fenilcetonurias , Humanos , Ratones , Animales , GTP Ciclohidrolasa/genética , Modelos Animales de EnfermedadRESUMEN
The gene encoding 5'-nucleotidase domain-containing protein 2 (NT5DC2) has been associated with neuropsychiatric disorders related to the abnormality of dopamine activity in the brain. However, its physiological functions remain unclear. In this study, we analyzed the features of NT5DC2 that influence its binding with tyrosine hydroxylase (TH) and its effects on dihydroxyphenylalanine (DOPA) synthesis, using NT5DC2 overexpressed in PC12D cells by the pCMV vector. Western blot analysis revealed that the purified NT5DC2-DYKDDDDK-tag (NT5DC2-tag) protein can bind with the phosphorylated form of recombinant human TH type 1 (rhTH1), apart from the endogenous TH in PC12D cells. Proteomic analysis by mass spectrometry revealed that the purified NT5DC2-tag protein has the potential to bind to 41 proteins with multiple phosphorylation sites in PC12D cells (NT5DC2 binding proteins: positive, 391 sites/41 proteins; and negative, 85 sites/27 proteins). Overexpression of NT5DC2 in PC12D cells decreased DOPA levels in the medium. When the lysate of PC12D cells overexpressing NT5DC2 was incubated at 37 °C, the phosphorylated form of endogenous TH in PC12D cells decreased. This decrease was also detected when phosphorylated rhTH1 was incubated with purified NT5DC2-tag. Overall, our results suggest that NT5DC2 regulates DOPA synthesis by promoting the dephosphorylation of TH, similar to a phosphatase. Therefore, our study provides useful information for understanding various disorders associated with abnormalities in dopamine levels in the brain.
Asunto(s)
Oxigenasas de Función Mixta , Tirosina 3-Monooxigenasa , Humanos , Tirosina 3-Monooxigenasa/genética , Tirosina 3-Monooxigenasa/metabolismo , Fosforilación , Oxigenasas de Función Mixta/metabolismo , Dopamina , Proteínas Portadoras/metabolismo , Proteómica , Dihidroxifenilalanina/metabolismoRESUMEN
PURPOSE: To compare the detection ability of 68Ga-labelled DOTA-l-Nal3-octreotide ([68Ga]Ga-DOTA-NOC) and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]DOPA) in patients with phaeochromocytomas and paragangliomas (PPGLs) of different origins and gene mutations, such as germline succinate dehydrogenase complex genes (SDHx). METHODS: Eighty-five patients with histopathologically confirmed PPGLs who underwent both [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT from March 2017 to June 2023 were enrolled in this retrospective study. For comparative analyses, PPGLs were classified as phaeochromocytoma (PCC), sympathetic paraganglioma (sPGL), and head/neck paraganglioma (HNPGL). Detection rates were analyzed on per-patient and per-lesion bases and compared using the Chi-square/Fischer's exact test. RESULTS: Among 85 patients with PPGLs (48 males; 43 years ± 17 [SD]), the patient-based detection rates of [68Ga]Ga-DOTA-NOC and [18F]DOPA PET/CT were 87.1% (74/85) and 89.4% (76/85), respectively (p = 0.634), and the lesion-based detection rates were 80.8% (479/593) and 71.2% (422/593), respectively (p < 0.001). Only one patient with a recurrent PCC presented double-negative imaging, while 66 patients exhibited double-positive imaging. The remaining patients were either [68Ga]Ga-DOTA-NOC-negative/[18F]DOPA-positive (n = 10) or [68Ga]Ga-DOTA-NOC-positive/[18F]DOPA-negative (n = 8). In subgroup analyses, [68Ga]Ga-DOTA-NOC PET/CT detected significantly more metastases of sPGL (91.1%, 236/259) and SDHx-related PPGL (89.6%, 86/96) than [18F]DOPA PET/CT (48.6%[126/259] and 50.0%[48/96], respectively; both p < 0.001). However, [18F]DOPA showed significantly higher detection rates of PCC in both primary/recurrent and metastatic lesions (94.3%[50/53] vs. 62.3%[33/53] and 87.9%[174/198] vs. 69.2%[137/198], respectively; both p < 0.001). Regarding metastases in different organs, [68Ga]Ga-DOTA-NOC PET/CT detected more lesions than [18F]DOPA PET/CT in bone (96.2%[176/183] vs. 66.1%[121/183]; p < 0.001) and lymph nodes (82.0%[73/89] vs. 53.9%[48/89]; p < 0.001) but less lesions in peritoneum (20%[4/20] vs. 100%[20/20]; p < 0.001). CONCLUSION: [68Ga]Ga-DOTA-NOC and [18F]DOPA are complementary in diagnosing PPGL under the appropriate clinical setting. [68Ga]Ga-DOTA-NOC should be considered as the ideal first-line tracer for detecting metastases of sPGL and SDHx-related tumours, whereas [18F]DOPA may be the optimal tracer for evaluating non-SDHx-related PCC, especially in detecting primary lesions and monitoring recurrence.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales , Dihidroxifenilalanina , Compuestos Organometálicos , Paraganglioma , Feocromocitoma , Tomografía Computarizada por Tomografía de Emisión de Positrones , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Feocromocitoma/diagnóstico por imagen , Masculino , Femenino , Persona de Mediana Edad , Dihidroxifenilalanina/análogos & derivados , Adulto , Neoplasias de las Glándulas Suprarrenales/diagnóstico por imagen , Paraganglioma/diagnóstico por imagen , Anciano , Estudios Retrospectivos , Adulto Joven , AdolescenteRESUMEN
ABSTRACT: Although 18F-FDG is the dominant radiotracer for PET imaging of hematological malignancies, radiolabeled amino acids have also been investigated to improve image quality in areas of high 18F-FDG uptake such as the central nervous system. We present a case of a 57-year-old woman who underwent an 18F-FDOPA scan for primary CNS lymphoma, which demonstrated an unexpected false-positive uptake in the right frontal lobe, due to a developmental venous anomaly.
Asunto(s)
Dihidroxifenilalanina/análogos & derivados , Fluorodesoxiglucosa F18 , Linfoma , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Linfoma/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodosRESUMEN
Adding bio-based flame retardants to improve the flame retardancy of polymer materials without sacrificing other properties is a great challenge. Herein, a novel flame-retardant CS-DOPA was prepared from chitosan and 10-hydroxy-9,10-dihydro-9-oza-10-phosphaphenanthrene-10-oxide by acid-base neutralization reaction and fully characterized. The 4 wt% CS-DOPA modified EP showed good flame retardancy in both gaseous and condensed phase. The peak heat release rate, total smoke production, CO production, and smoke production rate of EP composites containing 4 wt% CS-DOPA were reduced by 55 %, 34 %, 45 %, and 46 %, respectively, to pass the UL-94 V-1 rating with a limiting oxygen index of 34.1 %. The CS-DOPA contributes to the formation of the condensed phase of the thermo-oxidation-resistant high-quality char layer with non-flammable other and phosphorus-containing free radicals released in the gas phase. In addition, EP/4CS-DOPA has good water resistance, mechanical properties, and transparency, with tensile and flexural strength improved by 12.7 % and 13.9 %, respectively, and still has high strength even after water treatment. The present work provides a green and facile strategy to use chitosan as a main raw material to manufacture EP materials with high performance.