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Early-phase amyloid PET reproduces metabolic signatures of cognitive decline in Parkinson's disease.Alzheimer's & Dementia (Amsterdam,... 2024Recent work suggests that amyloid beta (Aβ) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and...
INTRODUCTION
Recent work suggests that amyloid beta (Aβ) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD.
METHODS
One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aβ PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion.
RESULTS
Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions.
DISCUSSION
EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment.
HIGHLIGHTS
Images taken at amyloid beta (Aβ) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aβ burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.
PubMed: 38912306
DOI: 10.1002/dad2.12601 -
JCEM Case Reports Jun 2024Pheochromocytomas (PCCs) and/or paragangliomas (PGLs) are a challenge to diagnose during pregnancy because of elusive signs and testing difficulties. We report a...
Pheochromocytomas (PCCs) and/or paragangliomas (PGLs) are a challenge to diagnose during pregnancy because of elusive signs and testing difficulties. We report a 25-year-old woman with no pertinent medical history who presented to the hospital with hypertension, vision loss, and weakness and was initially diagnosed with preeclampsia. Imaging showed hemangioblastomas in the medulla and thoracic spine, pancreatic cysts, and a renal cyst. The endocrinology service was consulted for possible PCCs associated with von Hippel-Lindau disease (VHL). Serum and urine normetanephrine levels were elevated despite the lack of overt PCCs/PGLs seen on magnetic resonance imaging and magnetic resonance angiography. The patient was medically managed with doxazosin and then labetalol. Despite successful resection of the hemangioblastoma in the medulla, the patient suffered respiratory distress requiring tracheostomy and venous-venous extracorporeal membrane oxygenation (V-V ECMO) and fetal demise. After 3 months, the patient was discharged to rehabilitation. Follow-up genetics were heterozygous for VHL and Lynch syndrome. DOTATATE positron emission tomography/computed tomography scan showed a small hepatic focus of a maximum standard uptake value of 12.1. Altogether, this case illustrates the importance of prompt diagnosis and proper management of PCCs/PGLs during pregnancy and incorporating genetic information during surveillance to lower morbidity and mortality.
PubMed: 38911362
DOI: 10.1210/jcemcr/luae097 -
Nature and Science of Sleep 2024Mental stress induced myocardial ischemia (MSIMI) is regarded as the primary cause of the angina with no obstructive coronary artery disease (ANOCA). Obstructive sleep...
PURPOSE
Mental stress induced myocardial ischemia (MSIMI) is regarded as the primary cause of the angina with no obstructive coronary artery disease (ANOCA). Obstructive sleep apnea (OSA) is autonomously linked to obstructive coronary heart disease, hypertension, and sudden cardiac death. Similar to the impact of psychological stress on the cardiovascular system, individuals with OSA experience periodic nocturnal hypoxia, resulting in the activation of systemic inflammation, oxidative stress, endothelial dysfunction, and sympathetic hyperactivity. The contribution of OSA to MSIMI in ANOCA patients is unclear. To explore the prevalence of OSA in ANOCA patients and the correlation between OSA and MSIMI, a prospective cohort of female ANOCA patients was recruited.
PATIENTS AND METHODS
We recruited female patients aged 18 to 75 years old with ANOCA and evaluated MSIMI using positron emission tomography-computed tomography. Subsequently, Level III portable monitors was performed to compare the relationship between OSA and MSIMI.
RESULTS
There is higher REI (7.8 vs 2.6, =0.019), ODI (4.7 vs 9.2, =0.028) and percentage of OSA (67.74% vs 33.33%, =0.004) in MSIMI patients. The patients diagnosed with OSA demonstrated higher myocardial perfusion imaging scores (SSS: 1.5 vs 3, = 0.005, SDS: 1 vs 3, P = 0.007). Adjusted covariates, the risk of developing MSIMI remained 3.6 times higher in OSA patients (β=1.226, OR = 3.408 (1.200-9.681), = 0.021).
CONCLUSION
Patients with MSIMI exhibit a greater prevalence of OSA. Furthermore, the myocardial blood flow perfusion in patients with OSA is reduced during mental stress.
PubMed: 38911317
DOI: 10.2147/NSS.S445219 -
Diagnostic Pathology Jun 2024Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These...
BACKGROUND
Follicular lymphoma (FL) is characterized by t(14;18)(q32;q21) involving the IGH and BCL2 genes. However, 10-15% of FLs lack the BCL2 rearrangement. These BCL2-rearrangement-negative FLs are clinically, pathologically, and genetically heterogeneous. The biological behavior and histological transformation of such FLs are not adequately characterized. Here, we report the first case of t(14;18)-negative FL that rapidly progressed to plasmablastic lymphoma (PBL).
CASE PRESENTATION
A previously healthy 51-year-old man presented with leg swelling. Computed tomography (CT) showed enlarged lymph nodes (LNs) throughout the body, including both inguinal areas. Needle biopsy of an inguinal LN suggested low-grade B-cell non-Hodgkin lymphoma. Excisional biopsy of a neck LN showed proliferation of centrocytic and centroblastic cells with follicular and diffuse growth patterns. Immunohistochemical analysis showed that the cells were positive for CD20, BCL6, CD10, and CD23. BCL2 staining was negative in the follicles and weak to moderately positive in the interfollicular areas. BCL2 fluorescence in situ hybridization result was negative. Targeted next-generation sequencing (NGS) revealed mutations in the TNFRSF14, CREBBP, STAT6, BCL6, CD79B, CD79A, and KLHL6 genes, without evidence of BCL2 or BCL6 rearrangement. The pathologic and genetic features were consistent with t(14;18)-negative FL. Two months after one cycle of bendamustine and rituximab chemotherapy, the patient developed left flank pain. Positron emission tomography/CT showed new development of a large hypermetabolic mass in the retroperitoneum. Needle biopsy of the retroperitoneal mass demonstrated diffuse proliferation of large plasmablastic cells, which were negative for the B-cell markers, BCL2, BCL6, and CD10; they were positive for MUM-1, CD138, CD38, and C-MYC. The pathologic findings were consistent with PBL. The clonal relationship between the initial FL and subsequent PBL was analyzed via targeted NGS. The tumors shared the same CREBBP, STAT6, BCL6, and CD79B mutations, strongly suggesting that the PBL had transformed from a FL clone. The PBL also harbored BRAF V600E mutation and IGH::MYC fusion in addition to IGH::IRF4 fusion.
CONCLUSIONS
We propose that transformation or divergent clonal evolution of FL into PBL can occur when relevant genetic mutations are present. This study broadens the spectrum of histological transformation of t(14;18)-negative FL and emphasizes its biological and clinical heterogeneity.
Topics: Humans; Lymphoma, Follicular; Male; Middle Aged; Plasmablastic Lymphoma; Translocation, Genetic; Chromosomes, Human, Pair 14; Chromosomes, Human, Pair 18; Biomarkers, Tumor; Cell Transformation, Neoplastic; Lymph Nodes
PubMed: 38909266
DOI: 10.1186/s13000-024-01512-2 -
BMJ Open Jun 2024Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity... (Randomized Controlled Trial)
Randomized Controlled Trial
Protocol for a double-blind placebo-controlled randomised controlled trial assessing the impact of oral semaglutide in amyloid positivity (ISAP) in community dwelling UK adults.
INTRODUCTION
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently marketed for type 2 diabetes and obesity, may offer novel mechanisms to delay or prevent neurotoxicity associated with Alzheimer's disease (AD). The impact of semaglutide in amyloid positivity (ISAP) trial is investigating whether the GLP-1 RA semaglutide reduces accumulation in the brain of cortical tau protein and neuroinflammation in individuals with preclinical/prodromal AD.
METHODS AND ANALYSIS
ISAP is an investigator-led, randomised, double-blind, superiority trial of oral semaglutide compared with placebo. Up to 88 individuals aged ≥55 years with brain amyloid positivity as assessed by positron emission tomography (PET) or cerebrospinal fluid, and no or mild cognitive impairment, will be randomised. People with the low-affinity binding variant of the rs6971 allele of the Translocator Protein 18 kDa (TSPO) gene, which can interfere with interpreting TSPO PET scans (a measure of neuroinflammation), will be excluded.At baseline, participants undergo tau, TSPO PET and MRI scanning, and provide data on physical activity and cognition. Eligible individuals are randomised in a 1:1 ratio to once-daily oral semaglutide or placebo, starting at 3 mg and up-titrating to 14 mg over 8 weeks. They will attend safety visits and provide blood samples to measure AD biomarkers at weeks 4, 8, 26 and 39. All cognitive assessments are repeated at week 26. The last study visit will be at week 52, when all baseline measurements will be repeated. The primary end point is the 1-year change in tau PET signal.
ETHICS AND DISSEMINATION
The study was approved by the West Midlands-Edgbaston Research Ethics Committee (22/WM/0013). The results of the study will be disseminated through scientific presentations and peer-reviewed publications.
TRIAL REGISTRATION NUMBER
ISRCTN71283871.
Topics: Humans; Glucagon-Like Peptides; Double-Blind Method; Alzheimer Disease; Positron-Emission Tomography; United Kingdom; Administration, Oral; Male; Middle Aged; Female; tau Proteins; Aged; Brain; Randomized Controlled Trials as Topic
PubMed: 38908839
DOI: 10.1136/bmjopen-2023-081401 -
Bioorganic Chemistry Jun 2024Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review... (Review)
Review
Bioorthogonal reactions have revolutionized chemical biology by enabling selective chemical transformations within living organisms and cells. This review comprehensively explores bioorthogonal chemistry, emphasizing inverse-electron-demand Diels-Alder (IEDDA) reactions between tetrazines and strained dienophiles and their crucial role in chemical biology and various applications within the human body. This highly reactive and selective reaction finds diverse applications, including cleaving antibody-drug conjugates, prodrugs, proteins, peptide antigens, and enzyme substrates. The versatility extends to hydrogel chemistry, which is crucial for biomedical applications, yet it faces challenges in achieving precise cellularization. In situ activation of cytotoxic compounds from injectable biopolymer belongs to the click-activated protodrugs against cancer (CAPAC) platform, an innovative approach to tumor-targeted prodrug delivery and activation. The CAPAC platform, relying on click chemistry between trans-cyclooctene (TCO) and tetrazine-modified biopolymers, exhibits modularity across diverse tumor characteristics, presenting a promising approach in anticancer therapeutics. The review highlights the importance of bioorthogonal reactions in developing radiopharmaceuticals for positron emission tomography (PET) imaging and theranostics, offering a promising avenue for diverse therapeutic applications.
PubMed: 38905885
DOI: 10.1016/j.bioorg.2024.107573 -
BMC Research Notes Jun 2024The study objective was to investigate the potential of quantitative measures of pulmonary inflammation by [18 F]Fluorodeoxyglucose positron emission... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE AND RESULTS DESCRIPTION
The study objective was to investigate the potential of quantitative measures of pulmonary inflammation by [18 F]Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) as a surrogate marker of inflammation in COPD. Patients treated with anti-inflammatory Liraglutide were compared to placebo and correlated with inflammatory markers. 27 COPD-patients (14 receiving Liraglutide treatment and 13 receiving placebo) underwent 4D-respiratory-gated FDG-PET/CT before and after treatment. Two raters independently segmented the lungs from CT images and measured activity in whole lung, mean standard uptake values (SUVmean) corrected for lean-body-mass in the phase-matched PET images of the whole segmented lung volume, and total lesion glycolysis (TLG; SUVmean multiplied by volume). Inter-rater reliability was analyzed with Bland-Altman analysis and correlation plots. We found no differences in metabolic activity in the lungs between the two groups as a surrogate of pulmonary inflammation, and no changes in inflammation markers. The purpose of the research and brief summary of main findings. The degree of and changes in pulmonary inflammation in chronic obstructive pulmonary disease (COPD) may be difficult to ascertain. Measuring metabolic activity as a surrogate marker of inflammation by FDG-PET/CT may be useful, but data on its use in COPD including reproducibility is still limited, especially with respiration-gated technique, which should improve quantification in the lungs. We assessed several quantitative measures of metabolic activity and correlated them with inflammation markers, and we assessed reproducibility of the methods. We found no differences in metabolic activity between the two groups (before and after 40 weeks treatment with Liraglutide vs. placebo). Bland-Altman analysis showed good agreement between the two raters.
TRIAL REGISTRATION
The study was conducted between February 2018 and March 2020 at the Department of Pulmonary Diseases at Hospital South West Jutland and Lillebaelt Hospital, Denmark, and registered from March 2018 at clinicaltrials.gov with trial registration number NCT03466021.
Topics: Humans; Pulmonary Disease, Chronic Obstructive; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Male; Female; Aged; Middle Aged; Lung; Pneumonia; Liraglutide; Respiration; Radiopharmaceuticals
PubMed: 38902794
DOI: 10.1186/s13104-024-06820-w -
Scientific Reports Jun 202417β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order...
17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain F-fluoroestradiol (F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health.
Topics: Humans; Female; Middle Aged; Cognition; Brain; Aging; Receptors, Estrogen; Positron-Emission Tomography; Adult; Estradiol; Neurosecretory Systems; Menopause
PubMed: 38902275
DOI: 10.1038/s41598-024-62820-7 -
Oncotarget Jun 2024Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST... (Comparative Study)
Comparative Study
Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.
OBJECTIVES
Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST (imPERCIST), shown by [F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and modified RECIST (mRECIST), shown by CT, were compared for response evaluation and prognosis prediction.
RESULTS
imPERCIST indicated nine progressive metabolic disease (PMD), eight stable metabolic disease (SMD), four partial metabolic response (PMR), and five complete metabolic response (CMR) cases. mRECIST showed nine with progressive disease (PD), nine stable disease (SD), seven partial response (PR), and one complete response (CR). Although high concordance was noted (κ = 0.827), imPERCIST correctly judged a greater percentage with CMR (15.4%). Following a median 10.0 months, 15 patients showed progression and eight died from MPM. With both, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients without progression (CMR/PMR/SMD, CR/PR/SD, respectively) as compared to PMD/PD patients (imPERCIST < 0.0001 and = 0.015, respectively; mRECIST < 0.0001 and = 0.015, respectively).
METHODS
Twenty-six patients (23 males, 3 females; median 73.5 years) with histologically proven MPM and no curative surgery received nivolumab plus ipilimumab combination therapy. FDG-PET/CT and diagnostic CT scanning at the baseline, and after 2-4 cycles (2 in three, 3 in 17, 4 in six patients) were performed. Therapeutic response findings evaluated using imPERCIST and mRECIST were compared. PFS and OS analyses were done using log-rank and Cox methods.
CONCLUSION
For unresectable MPM patient examinations, FDG-PET and CT provide accurate findings for evaluating tumor response and also prognosis prediction following first-line nivolumab plus ipilimumab immunotherapy (approximately three cycles).
Topics: Humans; Ipilimumab; Male; Nivolumab; Female; Aged; Fluorodeoxyglucose F18; Positron Emission Tomography Computed Tomography; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Prognosis; Pleural Neoplasms; Mesothelioma, Malignant; Mesothelioma; Lung Neoplasms; Aged, 80 and over; Tomography, X-Ray Computed; Treatment Outcome
PubMed: 38900646
DOI: 10.18632/oncotarget.28594 -
Addiction Biology Jun 2024The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced...
Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.
BACKGROUND
The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far.
METHODS
This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status.
RESULTS
We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability.
CONCLUSIONS
The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.
Topics: Humans; Positron-Emission Tomography; Gyrus Cinguli; Male; Alcoholism; Receptors, Dopamine D2; Adult; Female; Receptors, Dopamine D3; gamma-Aminobutyric Acid; Magnetic Resonance Spectroscopy; Middle Aged; Corpus Striatum; Case-Control Studies; Glutamic Acid; Benzamides
PubMed: 38899357
DOI: 10.1111/adb.13424