The amyloid cascade hypothesis: an updated critical review.

Results from recent clinical trials of antibodies that target amyloid-ß (Aß) for Alzheimer's disease have created excitement and have been heralded as corroboration of the amyloid cascade hypothesis. However, while Aß may contribute to disease, genetic, clinical, imaging and biochemical data suggest a more complex aetiology. Here we review the history and weaknesses of the amyloid cascade hypothesis in view of the new evidence obtained from clinical trials of anti-amyloid antibodies. These trials indicate that the treatments have either no or uncertain clinical effect on cognition. Despite the importance of amyloid in the definition of Alzheimer's disease, we argue that the data point to Aß playing a minor aetiological role. We also discuss data suggesting that the concerted activity of many pathogenic factors contribute to Alzheimer's disease and propose that evolving multi-factor disease models will better underpin the search for more effective strategies to treat the disease.

Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.

Cisplatin-Resistant CD44+ Lung Cancer Cells Are Sensitive to Auger Electrons.

Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44- populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2'-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44- and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations.

Atherosclerosis Burdens in Diabetes Mellitus: Assessment by PET Imaging.

Arteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated.

Assessment of atherosclerosis in multiple myeloma and smoldering myeloma patients using 18F- sodium fluoride PET/CT.

BACKGROUND: To compare the NaF uptake in the thoracic aorta and whole heart, as an early indicator of atherosclerosis, in multiple myeloma (MM) and smoldering multiple myeloma (SMM) patients with a healthy control (HC) group. METHODS: Forty-four untreated myeloma patients (35 MM and nine SMM) and twenty-six age and gender-matched HC subjects were collected. Each individual's NaF uptake in three parts of the aorta (AA: ascending aorta, AR: aortic arch, DA: descending aorta) and the whole heart was segmented. Average global standardized uptake value means were derived by sum of the product of each slice area divided by the sum of those slice areas. Results were reported as target to background ratio (TBR). RESULTS: There was a significant difference between the NaF uptake in the thoracic aorta of myeloma and HC groups [AA (myeloma = 1.82 ± 0.21, HC = 1.24 ± 0.02), AR (myeloma = 1.71 ± 0.19, HC = 1.28 ± 0.03) and DA (myeloma = 1.96 ± 0.28, HC = 1.38 ± 0.03); P-values < 0.001]. The difference in the whole heart NaF uptake between two groups was also significant (P < 0.001). CONCLUSIONS: We observed a higher uptake of NaF in the thoracic aorta and whole heart of myeloma patients in comparison to the matched control group.

Atherosclerosis imaging with 18F-sodium fluoride PET: state-of-the-art review.

PURPOSE: We examined the literature to elucidate the role of 18F-sodium fluoride (NaF)-PET in atherosclerosis. METHODS: Following a systematic search of PubMed/MEDLINE, Embase, and Cochrane Library included articles underwent subjective quality assessment with categories low, medium, and high. Of 2811 records, 1780 remained after removal of duplicates. Screening by title and abstract left 41 potentially eligible full-text articles, of which 8 (about the aortic valve (n = 1), PET/MRI feasibility (n = 1), aortic aneurysms (n = 1), or quantification methodology (n = 5)) were dismissed, leaving 33 published 2010-2012 (n = 6), 2013-2015 (n = 11), and 2016-2018 (n = 16) for analysis. RESULTS: They focused on coronary (n = 8), carotid (n = 7), and femoral arteries (n = 1), thoracic aorta (n = 1), and infrarenal aorta (n = 1). The remaining 15 studies examined more than one arterial segment. The literature was heterogeneous: few studies were designed to investigate atherosclerosis, 13 were retrospective, 9 applied both FDG and NaF as tracers, 24 NaF only. Subjective quality was low in one, medium in 13, and high in 19 studies. The literature indicates that NaF is a very specific tracer that mimics active arterial wall microcalcification, which is positively associated with cardiovascular risk. Arterial NaF uptake often presents before CT-calcification, tends to decrease with increasing density of CT-calcification, and appears, rather than FDG-avid foci, to progress to CT-calcification. It is mainly surface localized, increases with age with a wide scatter but without an obvious sex difference. NaF-avid microcalcification can occur in fatty streaks, but the degree of progression to CT-calcification is unknown. It remains unknown whether medical therapy influences microcalcification. The literature held no therapeutic or randomized controlled trials. CONCLUSION: The literature was heterogeneous and with few clear cut messages. NaF-PET is a new approach to detect and quantify microcalcification in early-stage atherosclerosis. NaF uptake correlates with cardiovascular risk factors and appears to be a good measure of the body's atherosclerotic burden, potentially suited also for assessment of anti-atherosclerotic therapy.

Molecular imaging of carotid artery atherosclerosis with PET: a systematic review.

PURPOSE: To conduct a systematic review of articles on PET imaging of carotid atherosclerosis with emphasis on clinical usefulness and comparison with other imaging modalities. METHODS: Research articles reporting carotid artery PET imaging with different radiotracers until 30 November 2018 were systematically searched for in Medline/PubMed, Scopus, Embase, Google Scholar, and Cochrane Library. Duplicates were removed, and editorials, case studies, and investigations on feasibility or reproducibility of PET imaging and of patients with end-stage diseases or immunosuppressive medications were omitted. After quality assessment of included articles using Joanna Briggs Institute checklists, all eligible articles were reviewed. RESULTS: Of 1718 primary hits, 53 studies comprising 4472 patients, aged 47-91 years (78.8% males), were included and grouped under the following headlines: diagnostic performance, risk factors, laboratory findings, imaging modalities, and treatment. 18F-fluorodeoxyglucose (FDG) (49/53) and 18F-sodium fluoride (NaF) (5/53) were the most utilized tracers to visualize carotid wall inflammation and microcalcification, respectively. Higher carotid FDG uptake was demonstrated in patients with than without symptomatic carotid atherosclerosis. Normal carotid arteries presented with the lowest FDG uptake. In symptomatic atherosclerosis, carotid arteries ipsilateral to a cerebrovascular event had higher FDG uptake than the contralateral carotid artery. FDG uptake was significantly associated with age, male gender, and body mass index in healthy individuals, and in addition with arterial hypertension, hypercholesterolemia, and diabetes mellitus in patients. Histological assessment indicated a strong correlation between microcalcification and NaF uptake in symptomatic patients. Histological evidence of calcification correlated inversely with FDG uptake, which was associated with increased macrophage and CD68 count, both accounting for increased local inflammatory response. CONCLUSION: FDG-PET visualizes the inflammatory part of carotid atherosclerosis enabling risk stratification to a certain degree, whereas NaF-PET seems to indicate long-term consequences of ongoing inflammation by demonstrating microcalcification allowing discrimination of atherosclerotic from normal arteries and suggesting clinically significant carotid atherosclerosis.

Glomerular filtration rate: comparison of simultaneous plasma clearance of 99mTc-DTPA and 51Cr-EDTA revisited.

The issue of whether 99mTc-DTPA can replace 51Cr-EDTA for measurement of plasma clearance as a surrogate for glomerular filtration rate (GFR) is of great relevance to daily clinical practice. Prompted by the shortage of 51Cr-EDTA we conducted a head-to-head comparison in patients attending our department for GFR determination. The two tracers (3.7 MBq of 51Cr-EDTA and 8 MBq of 99mTc-DTPA) were administered intravenously immediately after each other, and the standard number of blood samples were drawn. Fifty-four patients were enrolled. In 51 of these, single-sample measurement was performed with the following results: GFREDTA was 84.6 ± 23.3 mL/min, GFRDTPA was 84.2 ± 24.7 mL/min. The mean difference was 0.4 ± 2.8 mL/min, p = 0.32, and results based on the two tracers were highly correlated (r = 0.995). GFRDTPA exceeded GFREDTA at high GFR values (difference < 0 at GFREDTA >91.4 mL/min) and vice versa (difference > 0 at GFREDTA < 91.4 mL/min). However, differences fell within few GFR units that most often will have no clinical consequence. We therefore conclude that 99mTc-DTPA can replace 51Cr-EDTA for single-sample determination of GFR in a clinical setting.

Clinical value of FDG-PET/CT in bacteremia of unknown origin with catalase-negative gram-positive cocci or Staphylococcus aureus.

INTRODUCTION: Bacteremia is associated with high mortality, especially when the site of infection is unknown. While conventional imaging usually focus on specific body parts, FDG-PET/CT visualizes hypermetabolic foci throughout the body. PURPOSE: To investigate the ability of FDG/PET-CT to detect the site of infection and its clinical impact in bacteremia of unknown origin with catalase-negative Gram-positive cocci (excluding pneumococci and enterococci) or Staphylococcus aureus (BUOCSA). METHODS: We retrospectively identified 157 patients with 165 episodes of BUOCSA, who subsequently underwent FDG-PET/CT. Data were collected from medical records. Decision regarding important sites of infection in patients with bacteremia was based on the entire patient course and served as reference diagnosis for comparison with FDG-PET/CT findings. FDG-PET/CT was considered to have high clinical impact if it correctly revealed site(s) of infection in areas not assessed by other imaging modalities or if other imaging modalities were negative/equivocal in these areas, or if it established a new clinically relevant diagnosis, and/or led to change in antimicrobial treatment. RESULTS: FDG-PET/CT detected sites of infection in 56.4% of cases and had high clinical impact in 47.3%. It was the first imaging modality to identify sites of infection in 41.1% bacteremia cases, led to change of antimicrobial therapy in 14.7%, and established a new diagnosis unrelated to bacteremia in 9.8%. Detection rate and clinical impact were not significantly influenced by duration of antimicrobial treatment preceding FDG-PET/CT, days from suspicion of bacteremia to FDG-PET/CT-scan, type of bacteremia, or cancer. CONCLUSION: FDG-PET/CT appears clinically useful in BUOCSA. Prospective studies are warranted for confirmation.

Association between age, uptake of 18F-fluorodeoxyglucose and of 18F-sodium fluoride, as cardiovascular risk factors in the abdominal aorta.

OBJECTIVE: We aimed to assess the feasibility of quantifying fluorine-18-fluorodexoglucose (18F-FDG) and 18F-sodium fluoride (18F-NaF) uptake in abdominal aorta and examine their association with age and cardiovascular risk factors. SUBJECTS AND METHODS: Our study comprised 123 subjects (48±14 years of age, 62 men) including 78 healthy volunteers and 45 patients with chest pain syndrome, who originally enrolled in the CAMONA study in Odense, Denmark (NCT01724749). All subjects underwent 18F-FDG positron emission tomography/computed tomography (PET/CT) and 18F-NaF PET/CT on separate days, 180min and 90min after administration of tracers, respectively. The global tracer uptake value (GTUV) in the abdominal aorta was determined as sum of the product of each slice area and its corresponding average standardized uptake value (SUV mean), divided by the sum of those slice areas. In addition, for each subject, the 10 years Framingham risk score (FRS) was calculated. The correlations between 18F-NaF and 18F-FDG GTUV with age and 10 years FRS were assessed in all, healthy and patient subjects. RESULTS: There was a significant, positive correlation between subjects' age and 18F-NaF GTUV (r=0.35, P<0.001), but not 18F-FDG GTUV (r=0.06, P=0.53). Also, there was a significant, positive correlation between 10 years FRS and 18F-NaF GTUV (r=0.30, P<0.001), but not 18F-FDG GTUV (r=0.01, P=0.95). Individual differences in 18F-FDG and 118F-NaF uptake were large in both healthy subjects and patients. CONCLUSION: In this study, the global uptake of 18F-NaF in abdominal aorta was positively associated with age and 10 years FRS in all subjects, healthy and patient groups, whereas the global uptake of 18F-FDG was not.

Abass Alavi: A giant in Nuclear Medicine turns 80 and is still going strong!

Little was written in the stars above the city of Tabriz in Iran on March 15, 1938 indicating that a newborn citizen would immigrate to America and become a master of modern mo-lecular imaging with a sharp focus on 18F-FDG PET to the benefit of millions of people around the world. Nonetheless, that's what happened. A gifted boy who lost his farther early and grew up with his uneducated mother and two siblings in humble circumstances to become a premium student, nationally no. 1 in mathematics while in school, and later a medical doctor before he decided in 1966 to seek his fortune in the US. Here he started education in internal medicine, hematology and oncology, albeit found this unsatisfactory due to tradition and rote learning. He turned to radiology and nuclear medicine in a search for new knowledge and better methods to benefit patients and society, an attitude he had been taught from early childhood. The very same attitude has been the beacon for Alavi's activities throughout his professional life, instead of money, power and social status. He married into a highly academic environment. His wife, Jane Bradley Alavi, was a specialist in hematology and oncology and is still his life partner. They never had children, so their many students and the numerous medical doctors, physicists and other academics they coached became their family. While Jane Alavi retired some years ago, Abass Alavi continued his professional career and has no plans of retirement when he turns 80 on March 15, 2018 after 46 years in nuclear medicine at the University of Pennsylvania and with an admirable network of pupils and colleagues across all five continents. On the contrary, Alavi has probably never been busier, his scientific work goes on, his multinational scientific "family" steadily increases all over the world as does the appli-cation of PET in the shape of PET/CT or PET/MRI. Alavi's contributions to the scientific literature has more than doubled within the last decade making him one of the most cited researchers at the University of Pennsylvania with a production of more than 1,200 articles, a similar number of published abstracts and close to 58,000 citations according to Google Scholar, of which about 20,000 since 2012 when he was 74. This is just part of an amazing story. Having turned to nuclear medicine in 1971, Alavi entered into one of the World's most ingenious and productive medical research en-vironments comprising collaboration of experts in nuclear medicine (David Kuhl) and neurology (Martin Reivich) at Penn, and in physiology and pharmacology (Louis Sokoloff) at the NIH, all of whom contributed significantly to the development of PET. Focus was on cerebral research with beta-emitting 14C-labeled deoxyglucose for mapping regional cerebral glucose metabolism by means of autoradiography. Alavi became a junior member of this collaboration in which the idea of labeling deoxyglucose with a gamma-emitting isotope arose to allow in vivo examination of the normal and diseased human brain. They contacted Alfred Wolf at Brookhaven National Laboratory who had an interest in synthesizing positron-emitting compounds. He suggested labeling instead with 18F-FDG and in 1975 Wolf's group including Tatsuo Ido and Joanna Fowler succeeded in synthesizing 18F-FDG. In the meantime, investigators at Penn had developed high energy collimators for the Mark IV scanner to allow imaging with 18F-FDG, so in August 1976, two normal volunteers were the first to receive a dose of 18F-FDG for tomographic brain imaging showing concentration of 18F-FDG in the gray matter while in one volunteer a "whole-body" scan from the top of the scull to mid-thigh was also obtained. A year before, investigators at Washington University, i.e., Michel Ter-Pogossian in collaboration with Michael Phelps, Edward Hoffmann, and Nizar Mullani had developed what they termed a positron-emission transaxial tomograph for nuclear imaging, i.e. a machine which was the starting point of today's PET scanners. Alavi understood from the beginning the potential of PET and in particular 18F-FDG PET even if PET images at that time were blurry and difficult to interpret, a circum-stance which for a quarter of a century brought the method in poor standing in the minds of many. Alavi started as a brain researcher, but training in internal medicine, hematology, radiology and nuclear medicine broadened his scope and over the years there are few diseases and clinical specialties in which Alavi has not provided results obtained with molecular imaging. He was a pioneer in using iodine-123 in thyroid cancer, MIBG in pheochromocytoma, radiolabeled white blood cells in infection, and 99mTc for the detection of gastrointestinal bleeds, and together with his wife 18F-FDG PET for the demonstration of recurrent brain tumors. Thus, Alavi has contributed often very successfully by promoting new ideas and their implementation to achieve improved ways of examining a variety of medical disorders. Alavi has been accused of seeing 18F-FDG as the only useful PET tracer. In a way this is true. FDG became the dominant tracer and has remained so for over 40 years now. In his 2008 SNM Highlight Lecture, Henry N. Wagner, Jr. called FDG the "tracer molecule of the 20thth century". According to a recent forecast of the Global Nuclear Medicine Radioisotopes Market, the global 18F-FDG market is expected to grow from an estimated $1.233 billion in 2014 to $2.148 billion in 2019 and the vast majority of this growth is due to a continued increase in the use of 18F-FDG, indicating that this tracer may remain the tracer molecule of at least the first half of the 21st century. The world calls for more specific tracers than 18F-FDG, and like others Dr. Alavi has constantly been looking for these, but with time, it became apparent that our body holds few organ or disease specific targets, so that the concept of very specific disease-characterizing tracers is not as rosy as previously assumed. Thus, in cancer, genetic profiling has demonstrated that tumors are genetically often a mixture of cellular clones and that these are not necessarily also present in local, regional or remote metastases, meaning that ultra-specific PET tracers for cancer diagnosis and staging may be more a utopian vision than a realistic future possibility. This, together with inborn limitations of the PET technique has made Abass Alavi more prudent and hesitant toward reports of highly promising new PET tracers and an advocate of timely carefulness when using our limited financial resources. Teaching and education of talented young individuals is one of Alavi's main academic missions. Thus, with Gerald Mandell, MD, he established the Alavi-Mandell Award, presented for the first time at the SNM meeting in 1999 to a candidate selected from among all those in a given year who were trainees at the time their names appeared as first authors of papers in JNM. Together with his wife Jane, Alavi established the Bradley-Alavi Student Fellowship which was presented for the first time in 2001 and is given to the top students selected by the SNMMI Education and Research Foundation. Alavi himself is a recipient of multiple awards, including the Georg Charles de Hevesy Nuclear Pioneer Award (2004), the Benedict Cassen Prize for Research in Nuclear Medicine (2012), the Honorary Citizenship of his native town Tabriz (2015) and the Gold Medal of the National Institute for Medical Research Development, Tehran (2015). In addition, he has received the Honorary PhD Degree in Molecular Biology of the University of Shiraz (2007), and the Honorary Doctoral Degrees of the University of Bologna (2007), the University of the Sciences in Philadelphia (2008), the Medical University of Gdansk (2016), and the University of Southern Denmark (2016). Since January 2011, Alavi has been a frequent guest in the city of Odense, Denmark. Its University Hospital holds one of the biggest departments of nuclear medicine and PET in Northern Europe. From being behind, Denmark has become the country in the world with the highest relative number of PET/CT scanners and PET scans, i.e., an estimated 0.7 and 1000, respectively, per 100 000 inhabitants in 2017. At 17 consecutive interdisciplinary Abass Alavi Meetings in Odense, he has been inspirer and initiator of multi-disciplinary scientific projects that have resulted in more than 100 publications and as many scientific presentations. Abass Alavi personifies the polymath, a species rarely found today. He discusses and produces science in as diverse areas as brain, cardiovascular, and musculoskeletal diseases, inflammation, cancer and many more disorders that plague humanity, and he has a clear eye to make results clinically useful. Had the Noble Prize been awarded not only for single inventions but also for the cumulated contribution of an outstanding researcher to patients who suffer and mankind as a whole, Dr. Abass Alavi would be on top of the candidate list. What may such an experienced birthday-person foretell about the future? He would probably say that the gamma camera and SPET will be entirely substituted by PET, that skeletal metastases are bone marrow and not bone metastases and that all indirect methodologies for imaging of skeletal metastases, including bone scintigraphy and CT, will be replaced by PET imaging with 18F-FDG or more cancer specific tracers. Also that motion and partial volume correction will be satisfactorily dealt with to allow calculation of a global disease score representing the total burden of disease in the body, whether caused by cancer, atherosclerosis or other severe disorders, and that, thus, PET will take its lead position as the diagnostic imaging modality of the 21st century. It is hard to say how many of these predictions will come true while Dr. Alavi is still going strong. What is certain is that very few persons, if any, has contributed so significantly to the development and clinical implementation of PET imaging worldwide as have this 80 year old giant in modern nuclear and molecular medicine! Abass Alavi currently holds appointments as Professor and Director of Research Education in the Department of Radiology, Perelman School of Medicine, of the University of Pennsylvania and as Honorary Fellow of the International Society of Medical Olympicus Association in Greece.

Efficacy of 18F-FDG and 18F-NaF PET/CT imaging: A novel semi-quantitative assessment of the effects of age and obesity on hip joint inflammation and bone degeneration.

OBJECTIVE: Osteoarthritis (OA) is characterized by synovial tissue inflammation and underlying bone degeneration in the joints. Aging and obesity are among the major risk factors. This study evaluated the effects of aging and body mass index (BMI) on hip joint inflammation and bone degeneration using fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and fluorine-18 sodium fluoride (18F-NaF) PET/CT imaging, respectively. SUBJECTS AND METHODS: In this retrospective study, a total of 116 subjects (58 males and 58 females) who had undergone both 18F-FDG and 18F-NaF PET/CT imaging were analyzed. The mean age of these subjects was 48.6±14.5 with an age range of 21-75 years. Fluorine-18-FDG and 18F-NaF PET/CT imaging was conducted 180min and 90min (respectively) after intravenous administration of the appropriate tracer. The hip joint was segmented on fused PET/CT images using OsiriX MD v.9.5 (DICOM viewer and image-analysis program, Pixmeo SARL; Bernex, Switzerland). The region of interest (ROI) for the hip joint was indicated by using a 3D-growing region algorithm with upper/lower Hounsfield Units (HU) followed by a morphological closing algorithm. The metabolic activity for the left and right side of the joint was measured and correlated with age and BMI. RESULTS: Fluorine-18-FDG uptake in the hip was 0.83±0.22 (right side: 0.83±0.23, left side: 0.83±0.22, P=0.82). Fluorine-18-NaF uptake in the hip was 3.20±1.07 (right side: 3.25±1.14, left side: 3.15±1.04, P=0.02). Body mass index positively correlated with both 18F-FDG (r=0.29, P=0.001) and NaF (r=0.26, P=0.005) uptake. No significant correlation was seen between age and either 18F-FDG (r=0.12, P=0.19) or 18F-NaF (r=0.03, P=0.78) uptake. CONCLUSION: Body mass index had a significant impact on 18F-FDG and 18F-NaF uptake, whereas age had no correlation with either tracer uptake. Obesity increases the mechanical forces applied on weight-bearing joints such as the hip. Body mass index was related to increased joint inflammation and bone degeneration. These findings further support the studies explaining the role of adipose tissue in promoting OA.

CT-based tissue segmentation to assess knee joint inflammation and reactive bone formation assessed by 18F-FDG and 18F-NaF PET/CT: Effects of age and BMI.

OBJECTIVE: This study was conducted to determine the role of computed tomography (CT)-based segmentation methodology to semi-quantify the degree of inflammation and reactive bone formation in the knee joints by fluorine-18-fluorodeoxyglucose (18F-FDG) and 18F-sodium fluoride positron emission tomography/CT (18F-NaF PET/CT) imaging, respectively. Furthermore, we assessed the impact of aging and body mass index (BMI) on these biological responses. SUBJECTS AND METHODS: In this retrospective study, we examined a total of 97 subjects who had undergone both 18F-FDG and 18F-NaF PET/CT scanning. The mean age was 49.3±14.9 (21-75) and the mean BMI was 26.7±4.3 (17.7-42.0). Whole joint compartments and osseous compartments were segmented on fused PET/CT images using a 3D-growing algorithm with an adjustable upper/lower Hounsfield Units (HU) thresholds and manual tools. The metabolic activity and volume of each compartment was measured, values from the osseous compartment were subtracted from the whole joint to get the volume and metabolic activity of the soft tissue. The metabolic activity was correlated with age and BMI. RESULTS: Fluorine-18-FDG uptake in the soft tissues surrounding the joint was 0.35±0.07 while 0.19±0.04 in the osseous structures (P<0.0001). Aging positively correlated with 18F-FDG uptake in the soft tissue (r=0.37, P=0.0001). Body mass index positively correlated with 18F-FDG uptake in the soft tissue (r=0.53, P<0.0001), osseous compartment (r=0.58, P<0.0001) and 18F-NaF uptake in the joint (r=0.37, P=0.0001). A positive association was noted between the degree of new bone formation and the inflammatory reaction (P<0.01). CONCLUSION: The PET-based molecular imaging probes along with the CT-based segmentation techniques revealed an association between aging and the inflammatory activity of the soft tissue compartment. Similarly, a positive correlation was noted between BMI and inflammation and reactive bone f ormation of the knee joint compartments.

Normal patterns of regional brain 18F-FDG uptake in normal aging.

OBJECTIVE: Normal aging alters the brain function even in the absence of recognizable structural changes, which can be detected using modern in vivo functional imaging modalities such as fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) scan. It is highly important to recognize normal age-dependent changes in order to correctly diagnose pathologic states. The goal of the current study was to evaluate the age-related changes in regional brain 18F-FDG uptake in normal healthy population. SUBJECTS AND METHODS: This study was part of the cardiovascular molecular calcification assessed by 18F-sodium fluoride (NaF) (CAMONA) PET/computed tomography (CT) study. This study was approved by the Danish National Committee on Health Research Ethics registered at ClinicalTrials.gov (NCT01724749). Forty normal healthy subjects were prospectively recruited in group A (22-32 years) and B (56-75 years) and underwent 18F-FDG PET/CT. Static images were obtained 180 minutes following 18F-FDG injection. Supratentorial (including individual measurements for frontal, parieto-occipital and temporal lobes) and cerebellar 18F-FDG uptakes were measured by manual placement of region of interest (ROI) over these regions based on predefined criteria for each and standardized uptake value (SUVmean) values were calculated using OsiriX software. RESULTS: The mean ages of the patients in group A was 26.1±3.4 versus 61±4.4 for group B. There were 10 females in group A and 10 females in group B. Mean SUV of cerebellum was 6.80±1.21 for the young subjects compared to 6.08±0.7 among old subjects (independent t-test, P=0.028). Mean SUV of supratentorial brain was 9.14±1.83 for the young subjects compared to 6.92±072 among old subjects (P<0.001). Mean SUV of frontal (9.72±1.97 vs. 7.03±0.69), temporal (7.37±1.52 vs. 5.65±0.68) and parieto-occipital region (10.7±2.28 vs. 7.41±0.79) was higher among young patients (P<0.001). More interestingly, SUVmean of supratentorial brain was significantly higher among female healthy volunteers in both groups (P= 0.025 and 0.047 for group A and B, respectively). CONCLUSION: In conclusion, these findings confirm a significant age dependent reduction of supratentorial 18F-FDG uptake among healthy individuals. However, cerebellum 18F-FDG uptake reduction was not so redundant. Fluorine-18-FDG uptake of all cerebral lobes including frontal, parieto-occipital and temporal decreases with normal aging in a same fashion. Interestingly, among both young and old female subjects, higher uptake was seen in supratentorial brain.

Effects of age and weight on the metabolic activities of the cervical, thoracic and lumbar spines as measured by fluorine-18 fluorodeoxyglucose-positron emission tomography in healthy males.

OBJECTIVE: This study aimed to explore the age and weight-related metabolic trends in the spines of healthy male subjects using fluorine-18 fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging. SUBJECTS AND METHODS: Forty three healthy male subjects (age 23-75 years, weight 50-145kg) were selected from the CAMONA study. A global assessment methodology was applied to the subjects' 18F-FDG 180 minute scans, where each region of the spine (cervical, thoracic and lumbar) was individually encapsulated in a single region of interest, and standardized uptake value (SUVmean) was calculated per respective region. RESULTS: SUVmean increased significantly with weight in both the thoracic spine (Slope=0.0066, P=0.001) and lumbar spine (Slope=0.0087, P<0.0001), but not the cervical spine. There were no significant correlations between age and SUVmean in all three regions. The cervical spine (average SUVmean=1.84±0.31) illustrated elevated activity when compared to the thoracic (average SUVmean=1.46±0.27, P<0.0001) and lumbar (average SUVmean=1.41±0.28, P<0.0001) spines. CONCLUSION: This study illustrated the ability of 18F-FDG PET to assess metabolic processes in the spine. The data provided evidence of weight dependent metabolic activity, likely related to inflammation. This study offers a methodological precedent that can be applied to studies in populations with back pain.

Pandora's Box: mitochondrial defects in ischaemic heart disease and stroke.

Ischaemic heart disease and stroke are vascular events with serious health consequences worldwide. Recent genetic and epigenetic techniques have revealed many genetic determinants of these vascular events and simplified the approaches to research focused on ischaemic heart disease and stroke. The pathogenetic mechanisms of ischaemic heart disease and stroke are complex, with mitochondrial involvement (partially or entirely) recently gaining substantial support. Not only can mitochondrial reactive oxygen species give rise to ischaemic heart disease and stroke by production of oxidised low-density lipoprotein and induction of apoptosis, but the impact on pericytes contributes directly to the pathogenesis. Over the past two decades, publications implicate the causative role of nuclear genes in the development of ischaemic heart disease and stroke, in contrast to the potential role of mitochondrial DNA (mtDNA) in the pathophysiology of the disorders, which is much less understood, although recent studies do demonstrate that the involvement of mitochondria and mtDNA in the development of ischaemic heart disease and stroke is likely to be larger than originally thought, with the novel discovery of links among mitochondria, mtDNA and vascular events. Here we explore the molecular events and mtDNA alterations in relation to the role of mitochondria in ischaemic heart disease and stroke.

Thoracic aorta calcification but not inflammation is associated with increased cardiovascular disease risk: results of the CAMONA study.

PURPOSE: Arterial inflammation and vascular calcification are regarded as early prognostic markers of cardiovascular disease (CVD). In this study we investigated the relationship between CVD risk and arterial inflammation (18F-FDG PET/CT imaging), vascular calcification metabolism (Na18F PET/CT imaging), and vascular calcium burden (CT imaging) of the thoracic aorta in a population at low CVD risk. METHODS: Study participants underwent blood pressure measurements, blood analyses, and 18F-FDG and Na18F PET/CT imaging. In addition, the 10-year risk for development of CVD, based on the Framingham risk score (FRS), was estimated. CVD risk was compared across quartiles of thoracic aorta 18F-FDG uptake, Na18F uptake, and calcium burden on CT. RESULTS: A total of 139 subjects (52 % men, mean age 49 years, age range 21 - 75 years, median FRS 6 %) were evaluated. CVD risk was, on average, 3.7 times higher among subjects with thoracic aorta Na18F uptake in the highest quartile compared with those in the lowest quartile of the distribution (15.5 % vs. 4.2 %; P < 0.001). CVD risk was on average, 3.7 times higher among subjects with a thoracic aorta calcium burden on CT in the highest quartile compared with those in the lowest two quartiles of the distribution (18.0 % vs. 4.9 %; P < 0.001). CVD risk was similar in subjects in all quartiles of thoracic aorta 18F-FDG uptake. CONCLUSION: Our findings indicate that an unfavourable CVD risk profile is associated with marked increases in vascular calcification metabolism and vascular calcium burden of the thoracic aorta, but not with arterial inflammation.

Bone Scan Index predicts outcome in patients with metastatic hormone-sensitive prostate cancer.

OBJECTIVE: To evaluate the Bone Scan Index (BSI) for prediction of castration resistance and prostate cancer-specific survival (PCSS). In this retrospective study, we used novel computer-assisted software for automated detection/quantification of bone metastases by BSI. Patients with prostate cancer are M-staged by whole-body bone scintigraphy (WBS) and categorised as M0 or M1. Within the M1 group, there is a wide range of clinical outcomes. The BSI was introduced a decade ago providing quantification of bone metastases by estimating the percentage of bone involvement. Being too time consuming, it never gained widespread clinical use. PATIENTS AND METHODS: In all, 88 patients with prostate cancer awaiting initiation of androgen-deprivation therapy due to metastases were included. WBS was performed using a two-headed γ-camera. BSI was obtained using the automated platform EXINI bone (EXINI Diagnostics AB, Lund, Sweden). In Cox proportional hazard models, time to castration-resistant prostate cancer (CRPC) and PCSS were modelled as the dependent variables, whereas prostate-specific antigen (PSA) level, Gleason score and BSI were used as explanatory factors. For Kaplan-Meier estimates, BSI groups were dichotomously split into: BSI <1 and BSI ≥1. Discrimination between prognostic models was explored using the concordance index (C-index). RESULTS: The mean (range) age of the patients was 72 (52-92) years, the median (range) PSA level was 73 (4-5 740) ng/mL, the mean (range) Gleason score was 7.7 (2-10), and the mean (range) BSI was 1.0 (0-9.2). During a mean (range) follow-up of 26 (8-49) months, 48 patients became castration resistant and 15 had died; most (13) from prostate cancer. In multivariate analysis including PSA level, Gleason score and BSI, only prediction by BSI was statistically significant. This was true both for time to CRPC (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.22-1.74; C-index increase from 0.49 to 0.69) and for PCSS (HR 1.34, 95% CI 1.07-1.67; C-index increase from 0.76 to 0.95). CONCLUSION: BSI obtained using a novel automated computer-assisted algorithm appears to be a useful predictor of outcome for time to CRPC and PCSS in patients with hormone-sensitive metastatic prostate cancer.