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1.
Eur J Nucl Med Mol Imaging ; 50(5): 1371-1383, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36513817

RESUMEN

PURPOSE: To examine [18F]RO948 retention in FTD, sampling the underlying protein pathology heterogeneity. METHODS: A total of 61 individuals with FTD (n = 35), matched cases of AD (n = 13) and Aß-negative cognitively unimpaired individuals (n = 13) underwent [18F]RO948PET and MRI. FTD included 21 behavioral variant FTD (bvFTD) cases, 11 symptomatic C9orf72 mutation carriers, one patient with non-genetic bvFTD-ALS, one individual with bvFTD due to a GRN mutation, and one due to a MAPT mutation (R406W). Tracer retention was examined using a region-of-interest and voxel-wise approaches. Two individuals (bvFTD due to C9orf72) underwent postmortem neuropathological examination. Tracer binding was additionally assessed in vitro using [3H]RO948 autoradiography in six separate cases. RESULTS: [18F]RO948 retention across ROIs was clearly lower than in AD and comparable to that in Aß-negative cognitively unimpaired individuals. Only minor loci of tracer retention were seen in bvFTD; these did not overlap with the observed cortical atrophy in the cases, the expected pattern of atrophy, nor the expected or verified protein pathology distribution. Autoradiography analyses showed no specific [3H]RO948 binding. The R406W MAPT mutation carriers were clear exceptions with AD-like retention levels and specific in-vitro binding. CONCLUSION: [18F]RO948 uptake is not significantly increased in the majority of FTD patients, with a clear exception being specific MAPT mutations.


Asunto(s)
Demencia Frontotemporal , Humanos , Demencia Frontotemporal/diagnóstico por imagen , Demencia Frontotemporal/genética , Proteína C9orf72/genética , Proteínas tau/genética , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones , Mutación , Atrofia
2.
Eur J Nucl Med Mol Imaging ; 47(2): 342-354, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31612245

RESUMEN

PURPOSE: [18F]flortaucipir binds to paired helical filament tau and accurately identifies tau in Alzheimer's disease (AD). However, "off-target" binding interferes with the quantification of [18F]flortaucipir in several brain regions. Recently, other tau PET tracers have been developed. Here, we compare [18F]flortaucipir with the novel tau tracer [18F]RO948 head-to-head in vivo. METHODS: We included 18 participants with AD, three with amyloid-ß-positive amnestic mild cognitive impairment, and four healthy controls. All underwent [18F]flortaucipir (80-100 min) and [18F]RO948 (70-90) PET scans within approximately 1 month. Four study participants underwent 0-100-min dynamic scanning. Standardized uptake value ratios (SUVRs) were created using an inferior cerebellar reference region. RESULTS: Neocortical tracer retention was highly comparable using both SUVR and distribution volume ratio-1 values obtained from dynamic scans. However, [18F]RO948 retention was significantly higher in the entorhinal cortex and lower in the basal ganglia, thalamus, and choroid plexus compared with [18F]flortaucipir. Increased off-target binding was observed with age for both tracers. Several cases exhibited strong [18F]RO948 retention in the skull/meninges. This extra-cerebral signal, however, did not affect diagnostic accuracy and remained relatively unchanged when re-examining a subsample after 1 year. Kinetic modeling showed an increase in [18F]flortaucipir SUVR over the scanning interval, compared with a plateau for [18F]RO948. CONCLUSION: [18F]RO948 and [18F]flortaucipir bound comparably in neocortical regions, but [18F]RO948 showed higher retention in the medial temporal lobe and lower intracerebral "off-target" binding. Time-dependent bias of SUVR estimates may prove less of a factor with [18F]RO948, compared with previous tau ligands.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico por imagen , Carbolinas , Humanos , Tomografía de Emisión de Positrones , Proteínas tau
3.
J Labelled Comp Radiopharm ; 63(2): 46-55, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31674045

RESUMEN

The serotonin 7 (5-HT7 ) receptor is suggested to be involved in a broad variety of CNS disorders, but very few in vivo tools exist to study this important target. Molecular imaging with positron emission tomography (PET) would enable an in vivo characterization of the 5-HT7 receptor. However, no clinical PET radiotracer exists for this receptor, and thus we aimed to develop such a tracer. In this study, we present the preclinical evaluation of [11 C]Cimbi-701. Cimbi-701 was synthesized in a one-step procedure starting from SB-269970. Its selectivity profile was determined using an academic screening platform (NIMH Psychoactive Drug Screening Program). Successful radiolabeling of [11 C]Cimbi-701 and subsequent in vivo evaluation was conducted in rats, pigs and baboon. In vivo specificity was investigated by 5-HT7 and σ receptor blocking studies. P-gp efflux transporter dependency was investigated using elacridar. [11 C]Cimbi-701 could successfully be synthesized. Selectivity profiling revealed high affinity for the 5-HT7 (Ki = 18 nM), σ-1 (Ki = 9.2 nM) and σ-2 (Ki = 1.6 nM) receptors. In rats, [11 C]Cimbi-701 acted as a strong P-gp substrate. After P-gp inhibition, rat brain uptake could specifically be blocked by 5-HT7 and σ receptor ligands. In pig, high brain uptake and specific 5-HT7 and σ-receptor binding was found for [11 C]Cimbi-701 without P-gp inhibition. Finally, low brain uptake was found in baboons. Both the specific σ-receptor binding and the low brain uptake of [11 C]Cimbi-701 displayed in baboon discouraged further translation to humans. Instead, we suggest exploration of this structural class as results indicate that selective 5-HT7 receptor imaging might be possible when more selective non-P-gp substrates are identified.


Asunto(s)
Tomografía de Emisión de Positrones , Receptores de Serotonina 5-HT2/metabolismo , Animales , Técnicas de Química Sintética , Masculino , Radioquímica , Ratas , Porcinos , Distribución Tisular
4.
Bioorg Med Chem Lett ; 29(8): 986-990, 2019 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-30795854

RESUMEN

Pretargeted nuclear imaging based on the ligation between tetrazines and nano-sized targeting agents functionalized with trans-cyclooctene (TCO) has recently been shown to improve both imaging contrast and dosimetry in nuclear imaging of nanomedicines. Herein, we describe the improved radiosynthesis of a 11C-labeled tetrazine ([11C]AE-1) and its preliminary evaluation in both mice and pigs. Pretargeted imaging in mice was carried out using both a new TCO-functionalized polyglutamic acid and a previously reported TCO-functionalized bisphosphonate system as targeting agents. Unfortunately, pretargeted imaging was not successful using these targeting agents in pair with [11C]AE-1. However, brain imaging in pig indicated that the tracer crossed the blood-brain-barrier. Hence, we suggest that this tetrazine scaffold could be used as a starting point for the development of pretargeted brain imaging, which has so far been a challenging task.


Asunto(s)
Radioisótopos de Carbono/química , Tomografía de Emisión de Positrones , Radiofármacos/química , Tetrazoles/química , Animales , Encéfalo/diagnóstico por imagen , Radioisótopos de Carbono/metabolismo , Difosfonatos/química , Marcaje Isotópico , Ratones , Neoplasias/diagnóstico por imagen , Ácido Poliglutámico/química , Radiofármacos/metabolismo , Porcinos , Tetrazoles/metabolismo , Distribución Tisular
5.
Brain ; 140(9): 2286-2294, 2017 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-29050382

RESUMEN

Patients with Alzheimer's disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer's disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer's disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer's disease, 21 with late-onset Alzheimer's disease, three with prodromal early-onset Alzheimer's disease and 13 with prodromal late-onset Alzheimer's disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer's disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer's disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer's disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer's disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer's disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer's disease.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Carbolinas/metabolismo , Síntomas Prodrómicos , Tauopatías/diagnóstico por imagen , Proteínas tau/metabolismo , Edad de Inicio , Anciano , Envejecimiento/metabolismo , Envejecimiento/patología , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/patología , Atrofia/patología , Estudios de Casos y Controles , Corteza Cerebral/metabolismo , Corteza Cerebral/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Tomografía de Emisión de Positrones
6.
JAMA ; 320(11): 1151-1162, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30326496

RESUMEN

Importance: The positron emission tomography (PET) tracer [18F]flortaucipir allows in vivo quantification of paired helical filament tau, a core neuropathological feature of Alzheimer disease (AD), but its diagnostic utility is unclear. Objective: To examine the discriminative accuracy of [18F]flortaucipir for AD vs non-AD neurodegenerative disorders. Design, Setting, and Participants: In this cross-sectional study, 719 participants were recruited from 3 dementia centers in South Korea, Sweden, and the United States between June 2014 and November 2017 (160 cognitively normal controls, 126 patients with mild cognitive impairment [MCI], of whom 65.9% were amyloid-ß [Aß] positive [ie, MCI due to AD], 179 patients with AD dementia, and 254 patients with various non-AD neurodegenerative disorders). Exposures: The index test was the [18F]flortaucipir PET standardized uptake value ratio (SUVR) in 5 predefined regions of interest (ROIs). Cut points for tau positivity were determined using the mean +2 SDs observed in controls and Youden Index for the contrast AD dementia vs controls. Main Outcomes and Measures: The reference standard was the clinical diagnosis determined at the specialized memory centers. In the primary analysis, the discriminative accuracy (ie, sensitivity and specificity) of [18F]flortaucipir was examined for AD dementia vs all non-AD neurodegenerative disorders. In secondary analyses, the area under the curve (AUC) of [18F]flortaucipir SUVR was compared with 3 established magnetic resonance imaging measures (hippocampal volumes and AD signature and whole-brain cortical thickness), and sensitivity and specificity of [18F]flortaucipir in MCI due to AD vs non-AD neurodegenerative disorders were determined. Results: Among 719 participants, the overall mean (SD) age was 68.8 (9.2) years and 48.4% were male. The proportions of patients who were amyloid-ß positive were 26.3%, 65.9%, 100%, and 23.8% among cognitively normal controls, patients with MCI, patients with AD dementia, and patients with non-AD neurodegenerative disorders, respectively. [18F]flortaucipir uptake in the medial-basal and lateral temporal cortex showed 89.9% (95% CI, 84.6%-93.9%) sensitivity and 90.6% (95% CI, 86.3%-93.9%) specificity using the threshold based on controls (SUVR, 1.34), and 96.8% (95% CI, 92.0%-99.1%) sensitivity and 87.9% (95% CI, 81.9%-92.4%) specificity using the Youden Index-derived cutoff (SUVR, 1.27) for distinguishing AD dementia from all non-AD neurodegenerative disorders. The AUCs for all 5 [18F]flortaucipir ROIs were higher (AUC range, 0.92-0.95) compared with the 3 volumetric MRI measures (AUC range, 0.63-0.75; all ROIs P < .001). Diagnostic performance of the 5 [18F]flortaucipir ROIs were lower in MCI due to AD (AUC range, 0.75-0.84). Conclusions and Relevance: Among patients with established diagnoses at a memory disorder clinic, [18F]flortaucipir PET was able to discriminate AD from other neurodegenerative diseases. The accuracy and potential utility of this test in patient care require further research in clinically more representative populations.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Carbolinas/farmacocinética , Corteza Cerebral/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Adulto , Anciano , Anciano de 80 o más Años , Péptidos beta-Amiloides/análisis , Área Bajo la Curva , Corteza Cerebral/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Estudios Transversales , Diagnóstico Diferencial , Femenino , Fluorodesoxiglucosa F18/farmacocinética , Humanos , Masculino , Persona de Mediana Edad , Radiofármacos/farmacocinética , Sensibilidad y Especificidad
7.
Tumour Biol ; 39(4): 1010428317697550, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-28381167

RESUMEN

The tumor microenvironment can act so as to stimulate or reject tumor cells. Among the determining factors are cytokines produced, for example, by infiltrating immune cells, tumor cells, and fibroblasts. External radiotherapy has been shown to be able to activate an immune response against tumor cells with cytokine signaling as an important part of the activation. The aim of this study was to evaluate the cytokines present in the tumor microenvironment and whether the cytokine profile changed during tumor regression induced by radioimmunotherapy with the beta emitter 177Lu. Immunocompetent rats with colon carcinoma tumors were injected with 400 MBq/kg 177Lu-mAb, and the tumors were excised after 1, 2, 3, 4, 6, or 8 days post injection (4 rats/day on days 1-6 and 8 rats on day 8). Tumors from 10 untreated rats were used as control tissue. The tumors were divided into half: one half was prepared for cytokine analysis with a cytokine array kit and the other half was used for histological analysis. A total of 18 of the 29 cytokines evaluated were detected in this tumor model, and the majority of these act in a pro-inflammatory manner or stimulate the infiltration of immune cells. The differences between treated tumors and control tumors were small, thus the cytokine profile in the untreated tumors did not transfer to an anti-inflammatory profile during tumor regression induced by radioimmunotherapy with 177Lu. Histological evaluation demonstrated a heterogeneous pattern of ongoing cell death and the formation of granulation tissue.


Asunto(s)
Neoplasias del Colon/radioterapia , Citocinas/análisis , Radioinmunoterapia , Animales , Biomarcadores de Tumor/análisis , Neoplasias del Colon/inmunología , Neoplasias del Colon/patología , Inmunocompetencia , Ratas , Ratas Endogámicas BN , Microambiente Tumoral
8.
Brain ; 139(Pt 9): 2372-9, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27357347

RESUMEN

Tau positron emission tomography ligands provide the novel possibility to image tau pathology in vivo However, little is known about how in vivo brain uptake of tau positron emission tomography ligands relates to tau aggregates observed post-mortem. We performed tau positron emission tomography imaging with (18)F-AV-1451 in three patients harbouring a p.R406W mutation in the MAPT gene, encoding tau. This mutation results in 3- and 4-repeat tau aggregates similar to those in Alzheimer's disease, and many of the mutation carriers initially suffer from memory impairment and temporal lobe atrophy. Two patients with short disease duration and isolated memory impairment exhibited (18)F-AV-1451 uptake mainly in the hippocampus and adjacent temporal lobe regions, correlating with glucose hypometabolism in corresponding regions. One patient died after 26 years of disease duration with dementia and behavioural deficits. Pre-mortem, there was (18)F-AV-1451 uptake in the temporal and frontal lobes, as well as in the basal ganglia, which strongly correlated with the regional extent and amount of tau pathology in post-mortem brain sections. Amyloid-ß ((18)F-flutemetamol) positron emission tomography scans were negative in all cases, as were stainings of brain sections for amyloid. This provides strong evidence that (18)F-AV-1451 positron emission tomography can be used to accurately quantify in vivo the regional distribution of hyperphosphorylated tau protein.


Asunto(s)
Carbolinas , Demencia , Hipocampo , Trastornos de la Memoria , Tomografía de Emisión de Positrones/métodos , Lóbulo Temporal , Proteínas tau/metabolismo , Anciano , Atrofia/patología , Demencia/diagnóstico por imagen , Demencia/metabolismo , Demencia/patología , Femenino , Heterocigoto , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Masculino , Trastornos de la Memoria/diagnóstico por imagen , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Persona de Mediana Edad , Mutación , Lóbulo Temporal/diagnóstico por imagen , Lóbulo Temporal/metabolismo , Lóbulo Temporal/patología , Proteínas tau/genética
9.
JAMA Neurol ; 80(7): 749-756, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37213093

RESUMEN

Importance: It is important to determine the added clinical value for tau positron emission tomography (PET) in the diagnostic workup of patients with cognitive symptoms before widespread implementation in clinical practice. Objective: To prospectively study the added clinical value of PET detecting tau pathology in Alzheimer disease (AD). Design, Setting, and Participants: This prospective cohort study (Swedish BioFINDER-2 study) took place from May 2017 through September 2021. A total of 878 patients with cognitive complaints were referred to secondary memory clinics in southern Sweden and then recruited to the study. In total, 1269 consecutive participants were approached, but 391 did not meet inclusion criteria or did not complete the study. Exposures: Participants underwent a baseline diagnostic workup, including clinical examination, medical history, cognitive testing, blood and cerebrospinal fluid sampling, magnetic resonance imaging of the brain, and a tau PET ([18F]RO948) scan. Main Outcomes and Measures: The primary end points were change in diagnosis and change in AD drug therapy or other drug treatment between the pre- and post-PET visits. A secondary end point was the change in diagnostic certainty between the pre- and post-PET visits. Results: A total of 878 participants with a mean age of 71.0 (SD, 8.5) years (491 male [56%]) were included. The tau PET result led to a change in diagnoses in 66 participants (7.5%) and a change in medication in 48 participants (5.5%). The study team found an association with overall increased diagnostic certainty after tau PET in the whole data set (from 6.9 [SD, 2.3] to 7.4 [SD, 2.4]; P < .001). The certainty was higher in participants with a pre-PET diagnosis of AD (from 7.6 [SD, 1.7] to 8.2 [SD, 2.0]; P < .001) and increased even further in participants with a tau PET positive result supporting an AD diagnosis (from 8.0 [SD, 1.4] to 9.0 [SD, 0.9]; P < .001). The association with tau PET results had the largest effect sizes in participants with pathological amyloid-ß (Aß) status, whereas no significant change in diagnoses was seen in participants with normal Aß status. Conclusions and Relevance: The study team reported a significant change in diagnoses and patient medication when tau PET was added to an already extensive diagnostic workup that included cerebrospinal fluid AD biomarkers. Including tau PET was associated with a significant increase in certainty of underlying etiology. The effect sizes for certainty of etiology and diagnosis were largest in the Aß-positive group and the study team suggests that clinical use of tau PET be limited to populations with biomarkers indicating Aß positivity.


Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Masculino , Anciano , Estudios Prospectivos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Tomografía de Emisión de Positrones/métodos , Biomarcadores , Cognición , Proteínas tau/líquido cefalorraquídeo , Disfunción Cognitiva/diagnóstico
10.
Nat Commun ; 14(1): 6750, 2023 10 27.
Artículo en Inglés | MEDLINE | ID: mdl-37891183

RESUMEN

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson's disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.


Asunto(s)
Atrofia de Múltiples Sistemas , Enfermedad de Parkinson , Humanos , alfa-Sinucleína/metabolismo , Atrofia de Múltiples Sistemas/metabolismo , Enfermedad de Parkinson/metabolismo , Tomografía de Emisión de Positrones
11.
BJU Int ; 110(10): 1501-6, 2012 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22502982

RESUMEN

OBJECTIVE: To investigate how often positron emission tomography/computed tomography (PET/CT) scans, with both (18)F-fluorocholine and (18)F-fluoride as markers, add clinically relevant information for patients with prostate cancer who have high-risk tumours and a normal or inconclusive planar bone scan. PATIENTS AND METHODS: Patients with prostate cancer with prostate specific antigen (PSA) levels between 20 and 99 ng/mL and/or Gleason score 8-10 tumours, planned for treatment with curative intent based on routine staging with a negative or inconclusive bone scan, were further investigated with a (18)F-fluorocholine and a (18)F-fluoride PET/CT. None of the patients received hormonal therapy before the staging procedures were completed. RESULTS: For 50 of the 90 included patients (56%) one or both PET/CT scans indicated metastases. (18)F-fluorocholine PET/CT indicated lymph node metastases and/or bone metastases in 35 patients (39%). (18)F-fluoride PET/CT was suggestive for bone metastases in 37 patients (41%). In 18 patients (20%) the PET/CT scans indicated widespread metastases, leading to a change in therapy intent from curative to non-curative. Of the patients with positive scans, 74% had Gleason score 8-10 tumours. Of the patients with Gleason score 8-10 tumours, 64% had positive scans. CONCLUSIONS: PET/CT scans with (18)F-fluorocholine and (18)F-fluoride commonly detect metastases in patients with high-risk prostate cancer and a negative or inconclusive bone scan. For 20% of the patients the results of the PET/CT scans changed the treatment plan.


Asunto(s)
Colina/análogos & derivados , Fluoruros , Radioisótopos de Flúor , Imagen Multimodal , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/patología , Radiofármacos , Tomografía Computarizada por Rayos X , Anciano , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Humanos , Metástasis Linfática/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/diagnóstico por imagen
12.
Clin Transl Radiat Oncol ; 36: 77-82, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35873652

RESUMEN

Background and purpose: The treatment of biochemical recurrence (BCR) after prostatectomy is challenging as the site of the recurrence is often undetectable. Our aim was to test a personalised treatment concept for BCR based on PSA kinetics during salvage radiotherapy (SRT) combined with prostate-specific membrane antigen positron emission tomography (PSMA-PET). Materials and methods: This phase II trial included 100 patients with BCR. PSMA-PET was performed at baseline. PSA was measured weekly during SRT. Initially, 70 Gy in 35 fractions was prescribed to the prostate bed. Radiotherapy was adapted after 50 Gy. Non-responders (PSA still ≥ 0.15 ng/mL) received sequential lymph node irradiation with a boost to PSMA-PET positive lesions, while responders (PSA < 0.15 ng/mL) continued SRT as planned. PET-findings were only taken into consideration for treatment planning in case of PSA non-response after 50 Gy. Results: Data from 97 patients were eligible for analysis. Thirty-four patients were classified as responders and 63 as non-responders. PSMA-PET was positive in 3 patients (9%) in the responder group and in 22 (35%) in the non-responder group (p = 0.007). The three-year failure-free survival was 94% for responders and 68% for non-responders (median follow-up 38 months). There were no significant differences in physician-reported urinary and bowel toxicity. Patient-reported diarrhoea at end of SRT was more common among non-responders. Conclusion: This new personalised treatment concept with intensified SRT based on PSA response demonstrated a high tumour control rate in both responders and non-responders. These results suggest a clinically significant effect with moderate side effects in a patient group with otherwise poor prognosis. PSMA-PET added limited value. The treatment approach is now being evaluated in a phase III trial.Clinical trial registration numbers: NCT02699424&ISRCTN45905321.

13.
EJNMMI Res ; 12(1): 75, 2022 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-36534192

RESUMEN

BACKGROUND: Somatostatin receptor 68Ga PET imaging is standard for evaluation of a patient's suitability for 177Lu peptide receptor radionuclide therapy of neuroendocrine tumours (NETs). The 68Ga PET serves to ensure sufficient somatostatin receptor expression, commonly evaluated qualitatively. The aim of this study is to investigate the quantitative relationships between uptake in 68Ga PET and absorbed doses in 177Lu therapy. METHOD: Eighteen patients underwent [68Ga]Ga-DOTA-TATE PET imaging within 20 weeks prior to their first cycle of [177Lu]Lu-DOTA-TATE. Absorbed doses for therapy were estimated for tumours, kidney, spleen, and normal liver parenchyma using a hybrid SPECT/CT-planar method. Gallium-68 activity concentrations were retrieved from PET images and also used to calculate SUVs and normalized SUVs, using blood and tissue for normalization. The 68Ga activity concentrations per injected activity, SUVs, and normalized SUVs were compared with 177Lu activity concentrations 1 d post-injection and 177Lu absorbed doses. For tumours, for which there was a variable number per patient, both inter- and intra-patient correlations were analysed. Furthermore, the prediction of 177Lu tumour absorbed doses based on a combination of tumour-specific 68Ga activity concentrations and group-based estimates of the effective half-lives for grade 1 and 2 NETs was explored. RESULTS: For normal organs, only spleen showed a significant correlation between the 68Ga activity concentration and 177Lu absorbed dose (r = 0.6). For tumours, significant, but moderate, correlations were obtained, with respect to both inter-patient (r = 0.7) and intra-patient (r = 0.45) analyses. The correlations to absorbed doses did not improve when using 68Ga SUVs or normalized SUVs. The relationship between activity uptakes for 68Ga PET and 177Lu SPECT was stronger, with correlation coefficients r = 0.8 for both inter- and intra-patient analyses. The 177Lu absorbed dose to tumour could be predicted from the 68Ga activity concentrations with a 95% coverage interval of - 65% to 248%. CONCLUSIONS: On a group level, a high uptake of [68Ga]Ga-DOTA-TATE is associated with high absorbed doses at 177Lu-DOTA-TATE therapy, but the relationship has a limited potential with respect to individual absorbed dose planning. Using SUV or SUV normalized to reference tissues do not improve correlations compared with using activity concentration per injected activity.

14.
JAMA Neurol ; 79(2): 149-158, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-34928318

RESUMEN

Importance: There is currently no consensus as to which biomarkers best predict longitudinal tau accumulation at different clinical stages of Alzheimer disease (AD). Objective: To describe longitudinal [18F]RO948 tau positron emission tomography (PET) findings across the clinical continuum of AD and determine which biomarker combinations showed the strongest associations with longitudinal tau PET and best optimized clinical trial enrichment. Design, Setting, and Participants: This longitudinal cohort study consecutively enrolled amyloid-ß (Aß)-negative cognitively unimpaired (CU) participants, Aß-positive CU individuals, Aß-positive individuals with mild cognitive impairment (MCI), and individuals with AD dementia between September 2017 and November 2020 from the Swedish BioFINDER-2 (discovery cohort) and BioFINDER-1 (validation cohort) studies. Exposures: Baseline plasma and cerebrospinal fluid Aß42/Aß40, tau phosphorylated at threonine-217 (p-tau217), p-tau181 and neurofilament light, magnetic resonance imaging, amyloid PET ([18F]flutemetamol), and tau PET ([18F]RO948 in the BioFINDER-2 study; [18F]flortaucipir in the BioFINDER-1 study). Main Outcomes and Measures: Baseline tau PET standardized uptake value ratio (SUVR) and annual percent change in tau PET SUVR across regions of interest derived using a data-driven approach combining clustering and event-based modeling. Regression models were used to examine associations between individual biomarkers and longitudinal tau PET and to identify which combinations best predicted longitudinal tau PET. These combinations were then entered in a power analysis to examine how their use as an enrichment strategy would affect sample size in a simulated clinical trial. Results: Of 343 participants, the mean (SD) age was 72.56 (7.24) years, and 157 (51.1%) were female. The clustering/event-based modeling-based approach identified 5 regions of interest (stages). In Aß-positive CU individuals, the largest annual increase in tau PET SUVR was seen in stage I (entorhinal cortex, hippocampus, and amygdala; 4.04% [95% CI, 2.67%-5.32%]). In Aß-positive individuals with MCI and with AD dementia, the greatest increases were seen in stages II (temporal cortical regions; 4.45% [95% CI, 3.41%-5.49%]) and IV (certain frontal regions; 5.22% [95% CI, 3.95%-6.49%]), respectively. In Aß-negative CU individuals and those with MCI, modest change was seen in stage I (1.38% [95% CI, 0.78%-1.99%] and 1.80% [95% CI, 0.76%-2.84%], respectively). When looking at individual predictors and longitudinal tau PET in the stages that showed most change, plasma p-tau217 (R2 = 0.27, P < .005), tau PET (stage I baseline SUVR; R2 = 0.13, P < .05) and amyloid PET (R2 = 0.10, P < .05) were significantly associated with longitudinal tau PET in stage I in Aß-positive CU individuals. In Aß-positive individuals with MCI, plasma p-tau217 (R2 = 0.24, P < .005) and tau PET (stage II baseline SUVR; R2 = 0.44, P < .001) were significantly associated with longitudinal tau PET in stage II. Findings were replicated in BioFINDER-1 using longitudinal [18F]flortaucipir. For the power analysis component, plasma p-tau217 with tau PET resulted in sample size reductions of 43% (95% CI, 34%-46%; P < .005) in Aß-positive CU individuals and of 68% (95% CI, 61%-73%; P < .001) in Aß-positive individuals with MCI. Conclusions and Relevance: In trials using tau PET as the outcome, plasma p-tau217 with tau PET may prove optimal for enrichment in preclinical and prodromal AD. However, plasma p-tau217 was most important in preclinical AD, while tau PET was more important in prodromal AD.


Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Proteínas tau , Anciano , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores , Encéfalo/diagnóstico por imagen , Carbolinas , Estudios de Cohortes , Femenino , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Síntomas Prodrómicos , Radiofármacos , Reproducibilidad de los Resultados , Proteínas tau/líquido cefalorraquídeo
15.
Nat Med ; 28(11): 2381-2387, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36357681

RESUMEN

A major unanswered question in the dementia field is whether cognitively unimpaired individuals who harbor both Alzheimer's disease neuropathological hallmarks (that is, amyloid-ß plaques and tau neurofibrillary tangles) can preserve their cognition over time or are destined to decline. In this large multicenter amyloid and tau positron emission tomography (PET) study (n = 1,325), we examined the risk for future progression to mild cognitive impairment and the rate of cognitive decline over time among cognitively unimpaired individuals who were amyloid PET-positive (A+) and tau PET-positive (T+) in the medial temporal lobe (A+TMTL+) and/or in the temporal neocortex (A+TNEO-T+) and compared them with A+T- and A-T- groups. Cox proportional-hazards models showed a substantially increased risk for progression to mild cognitive impairment in the A+TNEO-T+ (hazard ratio (HR) = 19.2, 95% confidence interval (CI) = 10.9-33.7), A+TMTL+ (HR = 14.6, 95% CI = 8.1-26.4) and A+T- (HR = 2.4, 95% CI = 1.4-4.3) groups versus the A-T- (reference) group. Both A+TMTL+ (HR = 6.0, 95% CI = 3.4-10.6) and A+TNEO-T+ (HR = 7.9, 95% CI = 4.7-13.5) groups also showed faster clinical progression to mild cognitive impairment than the A+T- group. Linear mixed-effect models indicated that the A+TNEO-T+ (ß = -0.056 ± 0.005, T = -11.55, P < 0.001), A+TMTL+ (ß = -0.024 ± 0.005, T = -4.72, P < 0.001) and A+T- (ß = -0.008 ± 0.002, T = -3.46, P < 0.001) groups showed significantly faster longitudinal global cognitive decline compared to the A-T- (reference) group (all P < 0.001). Both A+TNEO-T+ (P < 0.001) and A+TMTL+ (P = 0.002) groups also progressed faster than the A+T- group. In summary, evidence of advanced Alzheimer's disease pathological changes provided by a combination of abnormal amyloid and tau PET examinations is strongly associated with short-term (that is, 3-5 years) cognitive decline in cognitively unimpaired individuals and is therefore of high clinical relevance.


Asunto(s)
Enfermedad de Alzheimer , Amiloidosis , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Encéfalo/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismo , Placa Amiloide , Biomarcadores
16.
Microvasc Res ; 82(3): 339-45, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21906604

RESUMEN

A key feature of sepsis is hypovolemia due to increased microvascular permeability. It has been suggested that the negative charge of albumin and of the endothelial glycocalyx is important for maintenance of the normally low permeability for albumin. Here we tested the hypothesis that charge effects contribute to the increased permeability in sepsis. Transcapillary escape rate (TER) and initial distribution volume for (125)I-labeled bovine serum albumin (BSA, isoelectric point pH 4.6) and for (131)I-labeled charge modified BSA (cBSA, average isoelectric point, pH 7.1) was measured 3h after sepsis was induced by cecal ligation and incision (CLI) (n=11) and in control animals (n=12). The importance of charge for permeability in sepsis was estimated by comparing the ratio between TER for cBSA and TER for BSA during control conditions to that after CLI. Plasma concentration of the glycocalyx component glycosaminoglycans (GAGs) was measured in separate control and CLI animals. The initial distribution volume for BSA and cBSA in control animals was 38 ± 3 ml/kg and 47 ± 4 mL/kg and decreased by 17% and 19%, respectively, following CLI. TER for BSA increased from 16.7 ± 4.1% in the controls to 20.1 ± 1.9% following CLI. Corresponding values for cBSA were 26.7 ± 5.6% and 29.8 ± 3.5%, respectively. The ratio between TER for cBSA and TER for BSA was 1.62 ± 0.1 in the control group and 1.49 ± 0.1 following CLI (p<0.05). Plasma GAG concentrations were higher in CLI animals than in the control group. We conclude that CLI induce hypovolemia secondary to increased microvascular permeability. Negative charge contributes to the normally low permeability of albumin and the importance of charge is decreased in early experimental sepsis. The observed charge effects are associated with CLI-induced breakdown of the glycocalyx.


Asunto(s)
Permeabilidad Capilar , Hipovolemia/etiología , Microvasos/metabolismo , Sepsis/sangre , Albúmina Sérica Bovina/metabolismo , Animales , Volumen Sanguíneo , Modelos Animales de Enfermedad , Glicocálix/metabolismo , Glicosaminoglicanos/sangre , Hipovolemia/sangre , Hipovolemia/fisiopatología , Punto Isoeléctrico , Microvasos/fisiopatología , Ratas , Ratas Sprague-Dawley , Sepsis/complicaciones , Sepsis/fisiopatología , Albúmina Sérica Bovina/química , Factores de Tiempo
17.
Pharmaceuticals (Basel) ; 14(7)2021 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-34206688

RESUMEN

In the struggle to understand and accurately diagnose Parkinson's disease, radiopharmaceuticals and medical imaging techniques have played a major role. By being able to image and quantify the dopamine transporter density, noninvasive diagnostic imaging has become the gold standard. In the shift from the first generation of SPECT tracers, the fluorine-18-labeled tracer [18F]FE-PE2I has emerged as the agent of choice for many physicians. However, implementing suitable synthesis for the production of [18F]FE-PE2I has proved more challenging than expected. Through a thorough analysis of the relevant factors affecting the final radiochemical yield, we were able to implement high-yielding fully automated GMP-compliant synthesis of [18F]FE-PE2I on a Synthera®+ platform. By reaching RCYs up to 62%, it allowed us to isolate 25 GBq of the formulated product, and an optimized formulation resulted in the shelf life of 6 h, satisfying the increased demand for this radiopharmaceutical.

18.
ACS Pharmacol Transl Sci ; 4(5): 1556-1566, 2021 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-34661074

RESUMEN

Aliphatic nucleophilic substitution (SN2) with [18F]fluoride is the most widely applied method to prepare 18F-labeled positron emission tomography (PET) tracers. Strong basic conditions commonly used during 18F-labeling procedures inherently limit or prohibit labeling of base-sensitive scaffolds. The high basicity stems from the tradition to trap [18F]fluoride on anion exchange cartridges and elute it afterward with basic anions. This sequence is used to facilitate the transfer of [18F]fluoride from an aqueous to an aprotic organic, polar reaction medium, which is beneficial for SN2 reactions. Furthermore, this sequence also removes cationic radioactive contaminations from cyclotron-irradiated [18O]water from which [18F]fluoride is produced. In this study, we developed an efficient elution procedure resulting in low basicity that permits SN2 18F-labeling of base-sensitive scaffolds. Extensive screening of trapping and elution conditions (>1000 experiments) and studying their influence on the radiochemical yield (RCY) allowed us to identify a suitable procedure for this. Using this procedure, four PET tracers and three synthons could be radiolabeled in substantially higher RCYs (up to 2.5-fold) compared to those of previously published procedures, even from lower precursor amounts. Encouraged by these results, we applied our low-basicity method to the radiolabeling of highly base-sensitive tetrazines, which cannot be labeled using state-of-art direct aliphatic 18F-labeling procedures. Labeling succeeded in RCYs of up to 20%. We believe that our findings facilitate PET tracer development by opening the path toward simple and direct SN2 18F fluorination of base-sensitive substrates.

19.
Cancer Biother Radiopharm ; 35(7): 540-548, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32486837

RESUMEN

Thorium-227 (227Th) is a long-lived (T1/2 = 18.7 d) α-emitter that has emerged as candidate for radioimmunotherapy. Imaging of patients treated with thorium-227 conjugates is challenging due to the low activity administered and to photon emissions with low yields. In addition, the radioactive daughter radium-223 (223Ra) have photon emissions in the same energy range as 227Th. The long half-life of 223Ra (T1/2 = 11.4 d) and the possibility of redistribution motivates efforts to separate 227Th and 223Ra. The aim of this study was to investigate the feasibility of imaging of patients treated with 227Th-labeled-monoclonal antibody (mAb) and to determine acquisition and image processing parameters to enable discrimination between 227Th and 223Ra. Imaging was performed with a GE Discovery 670 NM/CT γ-camera. Radionuclide separation with different energy windows (EW) and collimators was studied in images of vials with either 227Th or 223Ra. Phantom acquisitions with clinically relevant activities were performed to assess image quality and the usefulness of background subtraction and spatial filtering. Two patients treated with 227Th-labeled-mAb were imaged. Imaging of vials showed that 223Ra can be distinguished from 227Th using multiple energy windows. Medium- and high-energy collimators showed similar performance of sensitivity and spatial resolution, whereas the low-energy collimator had higher sensitivity but poor resolution due to collimator penetration. Visually, the image quality was improved with background subtraction and spatial filtering. The patient images exhibited the expected image quality and a possibility to separate 227Th and 223Ra. γ-Camera imaging of patients treated with 227Th-mAb is feasible and 223Ra can be distinguished from 227Th. Image quality is substantially improved using background subtraction and a spatial smoothing filter. Acquisition settings recommended for planar images are: high-energy general purpose or medium-energy general purpose collimator, 40 min acquisition time and energy windows: (1) 70-100 keV (227Th and 223Ra); (2) 215-260 keV (227Th); (3) 260-290 keV (223Ra); (4) 350-420 keV (223Ra).


Asunto(s)
Radioinmunoterapia/métodos , Radiofármacos/farmacocinética , Radio (Elemento)/farmacocinética , Torio/farmacocinética , Ensayos Clínicos Fase I como Asunto , Estudios de Factibilidad , Cámaras gamma , Semivida , Humanos , Procesamiento de Imagen Asistido por Computador , Fantasmas de Imagen , Radiometría/métodos , Radiofármacos/administración & dosificación , Radio (Elemento)/administración & dosificación , Espectrometría gamma/instrumentación , Espectrometría gamma/métodos , Torio/administración & dosificación , Distribución Tisular
20.
Neuropharmacology ; 172: 107830, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-31669129

RESUMEN

Since its discovery in 1993, the serotonin receptor subtype 7 (5-HT7) has attracted significant attention as a potential drug target; due to its elucidated roles in conditions such as insomnia, schizophrenia, and more. Therefore, it is unsurprising that there has been relatively early efforts undertaken to develop a positron emission tomography (PET) imaging agent for said receptor system. PET can be clinically used to probe receptor systems in vivo, permitting information such as a drug's occupancy against this system to be investigated. This review focuses on the efforts towards the development of a 5-HT7R selective PET CNS tracer over the last 20 years, critically reflecting on applied strategies and commonly employed chemical frameworks and suggests future considerations that are needed to successfully develop a PET tracer for this clinically relevant target. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'.


Asunto(s)
Sistema Nervioso Central/diagnóstico por imagen , Tomografía de Emisión de Positrones/métodos , Tomografía de Emisión de Positrones/tendencias , Receptores de Serotonina/metabolismo , Animales , Humanos , Imagen Molecular , Serotonina/metabolismo
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