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Diabetes Care Jun 2024The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the...
SGLT2 Inhibitor Dapagliflozin Increases Skeletal Muscle and Brain Fatty Acid Uptake in Individuals With Type 2 Diabetes: A Randomized Double-Blind Placebo-Controlled Positron Emission Tomography Study.
OBJECTIVE
The aim of this study was to investigate the impact of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on tissue fatty acid (FA) uptake in the skeletal muscle, brain, small intestine, and subcutaneous and visceral adipose tissue of individuals with type 2 diabetes by using positron emission tomography (PET).
RESEARCH DESIGN AND METHODS
In a 6-week randomized double-blind placebo-controlled trial, 53 patients with type 2 diabetes treated with metformin received either 10 mg dapagliflozin or placebo daily. Tissue FA uptake was quantified at baseline and end of treatment with PET and the long-chain FA analog radiotracer 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid. Treatment effects were assessed using ANCOVA, and the results are reported as least square means and 95% CIs for the difference between groups.
RESULTS
A total of 38 patients (dapagliflozin n = 21; placebo n = 17) completed the study. After 6 weeks, skeletal muscle FA uptake was increased by dapagliflozin compared with placebo (1.0 [0.07, 2.0] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.032), whereas uptake was not significantly changed in the small intestine or visceral or subcutaneous adipose tissue. Dapagliflozin treatment significantly increased whole-brain FA uptake (0.10 [0.02, 0.17] μmol ⋅ 100 g-1 ⋅ min-1; P = 0.01), an effect observed in both gray and white matter regions.
CONCLUSIONS
Six weeks of treatment with dapagliflozin increases skeletal muscle and brain FA uptake, partly driven by a rise in free FA availability. This finding is in accordance with previous indirect measurements showing enhanced FA metabolism in response to SGLT2 inhibition and extends the notion of a shift toward increased FA use to muscle and brain.
PubMed: 38941156
DOI: 10.2337/dc24-0470 -
Translational Stroke Research Jun 2024The development of fibrosis after injury to the brain or spinal cord limits the regeneration of the central nervous system in adult mammals. However, the extent of...
The development of fibrosis after injury to the brain or spinal cord limits the regeneration of the central nervous system in adult mammals. However, the extent of fibrosis in the injured brain has not been systematically investigated in mammals in vivo. This study aimed to assess whether [F]AlF-FAPI-42-based cerebral positron emission tomography (PET) can be utilized to assess the extent of fibrosis in ischemic regions of the brain in vivo. Sprague-Dawley rats underwent permanent occlusion of the right middle cerebral artery (MCAO). On days 3, 7, 14, and 21 after MCAO, the uptake of [F]AlF-FAPI-42 in the ischemic region of the brain in the MCAO groups surpassed that in the control group (day 0). The specific expression of fibroblast activation protein-α (FAP) in ischemic regions of the brain was also confirmed in immunohistofluorescence experiments in vitro. [F]AlF-FAPI-42 intensity correlated with the density of collagen deposition in the ischemic hemisphere (p < 0.001). [F]AlF-FAPI-42 PET/CT imaging demonstrated a specific uptake of radioactivity in the infarcted area in an ischemic stroke patient. PET imaging by using [F]AlF-FAPI-42 offers a promising non-invasive method for monitoring the progression of cerebral fibrosis caused by ischemic stroke and may facilitate the clinical management of stroke patients. Trial registration: chictr.org.cn ChiCTR2200059004. Registered April 22, 2022.
PubMed: 38940873
DOI: 10.1007/s12975-024-01269-2 -
European Journal of Nuclear Medicine... Jun 2024Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal...
Whole pelvis vs. hemi pelvis elective nodal radiotherapy in patients with PSMA-positive nodal recurrence after radical prostatectomy - a retrospective multi-institutional propensity score analysis.
PURPOSE
Despite growing evidence for bilateral pelvic radiotherapy (whole pelvis RT, WPRT) there is almost no data on unilateral RT (hemi pelvis RT, HPRT) in patients with nodal recurrent prostate cancer after prostatectomy. Nevertheless, in clinical practice HPRT is sometimes used with the intention to reduce side effects compared to WPRT. Prostate-specific membrane antigen positron emission tomography / computed tomography (PSMA-PET/CT) is currently the best imaging modality in this clinical situation. This analysis compares PSMA-PET/CT based WPRT and HPRT.
METHODS
A propensity score matching was performed in a multi-institutional retrospective dataset of 273 patients treated with pelvic RT due to nodal recurrence (214 WPRT, 59 HPRT). In total, 102 patients (51 in each group) were included in the final analysis. Biochemical recurrence-free survival (BRFS) defined as prostate specific antigen (PSA) < post-RT nadir + 0.2ng/ml, metastasis-free survival (MFS) and nodal recurrence-free survival (NRFS) were calculated using the Kaplan-Meier method and compared using the log rank test.
RESULTS
Median follow-up was 29 months. After propensity matching, both groups were mostly well balanced. However, in the WPRT group there were still significantly more patients with additional local recurrences and biochemical persistence after prostatectomy. There were no significant differences between both groups in BRFS (p = .97), MFS (p = .43) and NRFS (p = .43). After two years, BRFS, MFS and NRFS were 61%, 86% and 88% in the WPRT group and 57%, 90% and 82% in the HPRT group, respectively. Application of a boost to lymph node metastases, a higher RT dose to the lymphatic pathways (> 50 Gy EQD2) and concomitant androgen deprivation therapy (ADT) were significantly associated with longer BRFS in uni- and multivariate analysis.
CONCLUSIONS
Overall, this analysis presents the outcome of HPRT in nodal recurrent prostate cancer patients and shows that it can result in a similar oncologic outcome compared to WPRT. Nevertheless, patients in the WPRT may have been at a higher risk for progression due to some persistent imbalances between the groups. Therefore, further research should prospectively evaluate which subgroups of patients are suitable for HPRT and if HPRT leads to a clinically significant reduction in toxicity.
PubMed: 38940843
DOI: 10.1007/s00259-024-06802-x -
European Journal of Nuclear Medicine... Jun 2024The radionuclide pair cerium-134/lanthanum-134 (Ce/La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (Ac)....
PURPOSE
The radionuclide pair cerium-134/lanthanum-134 (Ce/La) was recently proposed as a suitable diagnostic counterpart for the therapeutic alpha-emitter actinium-225 (Ac). The unique properties of Ce offer perspectives for developing innovative in vivo investigations that are not possible with Ac. In this work, Ac- and Ce-labelled tracers were directly compared using internalizing and slow-internalizing cancer models to evaluate their in vivo comparability, progeny meandering, and potential as a matched theranostic pair for clinical translation. Despite being an excellent chemical match, Ce/La has limitations to the setting of quantitative positron emission tomography imaging.
METHODS
The precursor PSMA-617 and a macropa-based tetrazine-conjugate (mcp-PEG-Tz) were radiolabelled with Ac or Ce and compared in vitro and in vivo using standard (radio)chemical methods. Employing biodistribution studies and positron emission tomography (PET) imaging in athymic nude mice, the radiolabelled PSMA-617 tracers were evaluated in a PC3/PIP (PC3 engineered to express a high level of prostate-specific membrane antigen) prostate cancer mouse model. The Ac and Ce-labelled mcp-PEG-Tz were investigated in a BxPC-3 pancreatic tumour model harnessing the pretargeting strategy based on a trans-cyclooctene-modified 5B1 monoclonal antibody.
RESULTS
In vitro and in vivo studies with both Ac and Ce-labelled tracers led to comparable results, confirming the matching pharmacokinetics of this theranostic pair. However, PET imaging of the Ce-labelled precursors indicated that quantification is highly dependent on tracer internalization due to the redistribution of Ce's PET-compatible daughter La. Consequently, radiotracers based on internalizing vectors like PSMA-617 are suited for this theranostic pair, while slow-internalizing Ac-labelled tracers are not quantitatively represented by Ce PET imaging.
CONCLUSION
When employing slow-internalizing vectors, Ce might not be an ideal match for Ac due to the underestimation of tumour uptake caused by the in vivo redistribution of La. However, this same characteristic makes it possible to estimate the redistribution of Ac's progeny noninvasively. In future studies, this unique PET in vivo generator will further be harnessed to study tracer internalization, trafficking of receptors, and the progression of the tumour microenvironment.
PubMed: 38940841
DOI: 10.1007/s00259-024-06811-w -
Alzheimer's & Dementia : the Journal of... Jun 2024This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured...
BACKGROUND
This study investigated the potential of phosphorylated plasma Tau217 ratio (pTau217R) and plasma amyloid beta (Aβ) 42/Aβ40 in predicting brain amyloid levels measured by positron emission tomography (PET) Centiloid (CL) for Alzheimer's disease (AD) staging and screening.
METHODS
Quantification of plasma pTau217R and Aβ42/Aβ40 employed immunoprecipitation-mass spectrometry. CL prediction models were developed on a cohort of 904 cognitively unimpaired, preclinical and early AD subjects and validated on two independent cohorts.
RESULTS
Models integrating pTau217R outperformed Aβ42/Aβ40 alone, predicting amyloid levels up to 89.1 CL. High area under the receiver operating characteristic curve (AUROC) values (89.3% to 94.7%) were observed across a broad CL range (15 to 90). Utilizing pTau217R-based models for low amyloid levels reduced PET scans by 70.5% to 78.6%.
DISCUSSION
pTau217R effectively predicts brain amyloid levels, surpassing cerebrospinal fluid Aβ42/Aβ40's range. Combining it with plasma Aβ42/Aβ40 enhances sensitivity for low amyloid detection, reducing unnecessary PET scans and expanding clinical utility.
HIGHLIGHTS
Phosphorylated plasma Tau217 ratio (pTau217R) effectively predicts amyloid-PET Centiloid (CL) across a broad spectrum. Integrating pTau217R with Aβ42/Aβ40 extends the CL prediction upper limit to 89.1 CL. Combined model predicts amyloid status with high accuracy, especially in cognitively unimpaired individuals. This model identifies subjects above or below various CL thresholds with high accuracy. pTau217R-based models significantly reduce PET scans by up to 78.6% for screening out individuals with no/low amyloid.
PubMed: 38940656
DOI: 10.1002/alz.14073 -
Alzheimer's & Dementia : the Journal of... Jun 2024Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for...
INTRODUCTION
Trisomy 21, or Down syndrome (DS), predisposes individuals to early-onset Alzheimer's disease (AD). While monoclonal antibodies (mAbs) targeting amyloid are approved for older AD patients, their efficacy in DS remains unexplored. This study examines amyloid positron emission tomography (PET) positivity (A+), memory function, and clinical status across ages in DS to guide mAb trial designs.
METHODS
Cross-sectional data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) was analyzed. PET amyloid beta in Centiloids classified amyloid status using various cutoffs. Episodic memory was assessed using the modified Cued Recall Test, and clinical status was determined through consensus processes.
RESULTS
Four hundred nine DS adults (mean age = 44.83 years) were evaluated. A+ rates increased with age, with mean amyloid load rising significantly. Memory decline and cognitive impairment are also correlated with age.
DISCUSSION
These findings emphasize the necessity of tailoring mAb trials for DS, considering age-related AD characteristics.
HIGHLIGHTS
There is rapid increase in prevalence of amyloid beta (Aβ) positron emission tomography (PET) positivity in Down syndrome (DS) after the age of 40 years. Aβ PET positivity thresholds have significant impact on prevalence rates in DS. There is a significant lag between Aβ PET positivity and clinical symptom onset in DS.
PubMed: 38940611
DOI: 10.1002/alz.14068 -
Brain : a Journal of Neurology Jun 2024Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma...
Increasing evidence shows that neuroinflammation is a possible modulator of tau spread effects on cognitive impairment in Alzheimer's disease. In this context, plasma levels of the glial fibrillary acidic protein (GFAP) have been suggested to have a robust association with Alzheimer's disease pathophysiology. This study aims to assess the correlation between plasma GFAP and Alzheimer's disease pathology, and their synergistic effect on cognitive performance and decline. A cohort of 122 memory clinic subjects with amyloid and tau positron emission tomography, MRI scans, plasma GFAP, and Mini-Mental State Examination (MMSE) was included in the study. A subsample of 94 subjects had a follow-up MMSE score at least one year after baseline. Regional and voxel-based correlations between Alzheimer's disease biomarkers and plasma GFAP were assessed. Mediation analyses were performed to evaluate the effects of plasma GFAP on the association between amyloid and tau PET, and tau PET and cognitive impairment and decline. GFAP was associated with increased tau PET ligand uptake in the lateral temporal and inferior temporal lobes in a strong left-sided pattern independently of age, gender, education, amyloid, and APOE status (β=0.001, p < 0.01). The annual rate of MMSE change was significantly and independently correlated with both GFAP (β=0.006, p < 0.01) and global tau SUVR (β=4.33, p < 0.01), but not with amyloid burden. Partial mediation effects of GFAP were found on the association between amyloid and tau pathology (13.7%), and between tau pathology and cognitive decline (17.4%), but not on global cognition at baseline. Neuroinflammation measured by circulating GFAP is independently associated with tau Alzheimer's disease pathology and with cognitive decline, suggesting neuroinflammation as a potential target for future disease-modifying trials targeting tau pathology. Peretti et al. show that a circulatory marker of neuroinflammation-glial fibrillary acidic protein-is associated with tau pathology in lateral temporal and frontal regions in patients with Alzheimer's disease, independent of amyloid load. Neuroinflammation appears to modulate the association between amyloid and tau biomarkers.
PubMed: 38940331
DOI: 10.1093/brain/awae211 -
Journal of Extracellular Biology Feb 2024Extracellular vesicles (EVs) have been involved in metabolic syndrome, although their specific role in the development of the pathology is still unknown. To further...
Extracellular vesicles (EVs) have been involved in metabolic syndrome, although their specific role in the development of the pathology is still unknown. To further study the role of EVs, we have analysed by Raman tweezers microspectroscopy and mass spectrometry-based lipidomics the small EVs population secreted by fatty (ZF) and lean (ZL) hepatocytes obtained from Zucker rats. We have also explored in vivo and ex vivo biodistribution of these EVs through fluorine-18-radiolabelling using a positron emission tomography imaging. Based on the proportion of proteins to lipids and the types of lipids, our results indicate that within the range of small EVs, primary hepatocytes secrete different subpopulations of particles. These differences were observed in the enrichment of triglyceride species in EVs secreted by ZF hepatocytes. Biodistribution experiments showed accumulation in the brain, heart, lungs, kidney and specially in bladder after intravenous administration. In summary, we show that EVs released by a fatty hepatocytes carry a different lipid signature compared to their lean counterpart. Biodistribution experiment has shown no difference in the distribution of EVs secreted by ZF and ZL hepatocytes but has given us a first view of possible target organs for these particles. Our results might open a door to both pathology studies and therapeutic interventions.
PubMed: 38939902
DOI: 10.1002/jex2.140 -
JACC. Advances May 2024It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent...
BACKGROUND
It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent epicardial vasodilation.
OBJECTIVES
The purpose of this study was to investigate the effect of obesity and severe obesity on flow-mediated epicardial vasomotion with positron emission tomography/computed tomography-determined longitudinal decrease in myocardial blood flow (MBF) from the base-to-apex direction of the left ventricle or gradient.
METHODS
N-ammonia positron emission tomography/computed tomography evaluated global MBF during pharmacologically induced hyperemia and at rest for assessment of coronary microvascular function. In addition, the Δ longitudinal MBF gradient (hyperemia minus rest) was determined. Patients were then grouped according to the body mass index (BMI) into normal weight (NW) (BMI 20.0-24.9 kg/m, n = 27), overweight (OW) (BMI 25.0-29.9 kg/m, n = 29), obesity (OB) (BMI 30.0-39.9 kg/m, n = 53), and severe obesity (morbid obesity: BMI ≥40 kg/m, n = 43).
RESULTS
Compared to NW, left ventricular Δ longitudinal MBF gradient progressively declined in OW and OB (0.04 ± 0.09 mL/g/min vs -0.11 ± 0.14 mL/g/min and -0.15 ± 0.11 mL/g/min; ≤ 0.001, respectively) but not significantly in SOB (-0.01 ± 0.11 mL/g/min, = 0.066). Regadenoson-induced global hyperemic MBF was lower in OB than in NW (1.88 ± 0.40 mL/g/min vs 2.35 ± 0.32 mL/g/min; ≤ 0.001), while comparable between NW and SOB (2.35 ± 0.32 mL/g/min vs 2.26 ± 0.40 mL/g/min; = 0.302). The BMI of the study population was associated with the Δ longitudinal MBF gradient in a U-turn fashion (r = 0.362, standard error of the estimate = 0.124; < 0.001).
CONCLUSIONS
Increased body weight associates with abnormalities in coronary circulatory function that advances from an impairment flow-mediated, epicardial vasodilation in overweight and obesity to coronary microvascular dysfunction in obesity, not observed in severe obesity. The U-turn of flow-mediated epicardial vasomotion outlines obesity and severe obesity to affect epicardial endothelial function differently.
PubMed: 38939628
DOI: 10.1016/j.jacadv.2024.100936 -
Polish Journal of Radiology 2024To evaluate the predictive capability of the apparent diffusion coefficient (ADC) at initial diagnosis in treatment-naive patients with laryngeal squamous cell carcinoma...
PURPOSE
To evaluate the predictive capability of the apparent diffusion coefficient (ADC) at initial diagnosis in treatment-naive patients with laryngeal squamous cell carcinoma (LSCC) for the development of future metastases.
MATERIAL AND METHODS
Magnetic resonance images of patients with pathologically proven non-metastatic, treatmentnaive LSCC were retrospectively evaluated. Follow-up positron emission tomography scans were assessed for the scanning of metastases.
RESULTS
A total of 37 patients (32 males and 5 females) with a mean age of 62.8 ± 8.9 years were enrolled. Mean tumour volume and ADC were 4.8 ± 62 cm and 0.72 ± 0.51 × 10 mm/s, respectively. Six local and 8 distant metastases were detected in a mean follow-up period of 17.5 ± 10.2 months. A significant association between ADC and the presence distant metastases ( = 0.046) and local metastases ( = 0.042) was found. The difference in mean ADC values between future metastatic and non-metastatic initial tumours was significant ( = 0.017).
CONCLUSIONS
Pre-treatment ADC values and volume of the initial tumour might provide early information about the development of future metastases in patients with LSCC in this series.
PubMed: 38938659
DOI: 10.5114/pjr/187675