Neuronal PET tracers for Alzheimer's disease.

Advancements in brain imaging techniques have emerged as a significant tool in detecting Alzheimer's disease (AD) progression. The complicated cascade of AD progression can be detected using radio imaging, especially with Positron emission tomography (PET). The review focus on recently introduced investigational PET tracers targeting neurofibrillary tau aggregates found typically in AD. Herein, we also address the use of different PET tracers and the clinical implementation of established and newer generation tracers. This review also intends to discuss the importance of several PET radiotracers and challenges in PET imaging.

Radioactive Molecules 2019-2020.

It is with great pleasure that I have accepted the challenge of reviewing and summarizing the articles published in Molecules through 2019 and 2020 on radioactive molecules [...].

The role of physics in radioecology and radiotoxicology.

This article gives an overview of physical concepts important for radioecology and radiotoxicology to help bridge a gap between non-physicists in these scientific disciplines and the intricate language of physics. Relying on description and only as much mathematics as necessary, we discuss concepts ranging from fundamental natural forces to applications of physical modelling in phenomenological studies. We first explain why some atomic nuclei are unstable and therefore transmute. Then we address interactions of ionising radiation with matter, which is the foundation of both radioecology and radiotoxicology. We continue with relevant naturally occurring and anthropogenic radionuclides and their properties, abundance in the environment, and toxicity for the humans and biota. Every radioecological or radiotoxicological assessment should take into account combined effects of the biological and physical half-lives of a radionuclide. We also outline the basic principles of physical modelling commonly used to study health effects of exposure to ionising radiation, as it is applicable to every source of radiation but what changes are statistical weighting factors, which depend on the type of radiation and exposed tissue. Typical exposure doses for stochastic and deterministic health effects are discussed, as well as controversies related to the linear no-threshold hypothesis at very low doses.

Scan MDCs for GPS-Based Gamma Radiation Surveys.

A method for estimating the minimum detectable concentration of a contaminant radionuclide in soil when scanning with gamma radiation detectors (known as the "scan MDC") is described in the Multi-Agency Radiation Survey and Site Investigation Manual (MARSSIM). This paper presents an alternate method for estimating scan MDCs for GPS-based gamma surveys based on detector efficiencies modeled with the probabilistic Monte Carlo N-Particle Extended (MCNPX) Transport simulation code. Results are compared to those provided in MARSSIM. An extensive database of MCNPX-based detection efficiencies has been developed to represent a variety of gamma survey applications and potential scanning configurations (detector size, scan height, size of contaminated soil volume, etc.), and an associated web-based user interface has been developed to provide survey designers and regulators with access to a reasonably wide range of calculated scan MDC values for survey planning purposes.

The use of the EVITA algorithm for clinical assessment of novel agents used in prostate cancer, metastatic melanoma, and systemic lupus erythematosus.

PURPOSE: Existing health technology assessment methods can be time-consuming and complicated to use in practice. EValuation of pharmaceutical Innovations with regard to Therapeutic Advantage (EVITA) is a recently developed drug assessment strategy that provides a detailed and clinically relevant evaluation of new agents compared to standard therapies. We therefore sought to use EVITA to evaluate eight novel agents recently introduced to clinical practice or in late-stage trials for the treatment of prostate cancer, metastatic melanoma, or systemic lupus erythematosus (SLE). METHODS: Eight agents (abiraterone, enzalutamide, sipuleucel-T, Prostvac, radium 223, ipilimumab, vemurafenib, and belimumab) were selected for study using the EVITA algorithm. A comprehensive literature search was performed to find clinical trial data, which were then classified using the EVITA protocol. EVITA was also compared to results from health technology assessments (HTAs) or reimbursement decisions. RESULTS: The EVITA scores for the eight drugs ranged from 5.5 to 9: all the selected agents are therefore classed as 'recommended' and are likely to produce a therapeutic advantage. In particular, vemurafenib is likely to be highly beneficial to patients with metastatic melanoma and radium 223 to patients with metastatic prostate cancer affecting the bone. The EVITA results were generally concordant with HTAs. CONCLUSIONS: All the agents show favourable EVITA scores and are therefore recommended for clinical practice. EVITA is an easy-to-use tool that provides clinical context to the assessment of newly introduced agents and can be easily used by non-specialists.

[Ranking of radionuclides and pathways according to their contribution to the dose burden to the population resulting from NPP releases].

Approaches are described towards estimating the consequences of radioactive contamination of ecosystems by nuclear fuel cycle enterprises with the rationale for the optimal specification level for nuclear power plants (NPP) operating in the normal mode. Calculations are made based on the initial data of the IAEA project, INPRO ENV, dealing with the ranking of radionuclides escaping to the environment from the operating NPPs. Influence of various factors on rankings of radionuclides and pathways of public exposure is demon- strated. An important factor is the controlled radionuclide composition of atmospheric NPP releases. It has been found that variation in the dose coefficients for some radionuclides leads to significant changes not only in the ranking results but also in the estimates of total dose burdens. Invariability is shown of the estimation concerning the greatest contribution of the peroral route to the population dose of irradiation in the situation considered. A conclusion was drawn on the need of taking into consideration uncertainties of different factors when comparing effects on the environment from enterprises of conventional and innovative nuclear fuel cycles.

Performance characteristics of a novel radioactive isotope detection and notification system designed for use in hospitals.

Recently, University of Pittsburgh Medical Center (UPMC) Cancer Centers has installed an Emergency Department Notification System (EDNS) in one of its hospitals. This system, manufactured by Thermo Fisher Scientific (Thermo Fisher Scientific, Inc., 81 Wyman Street, Waltham, MA 02454), was designed to discriminate non-medical radioactive isotopes from medical radioactive isotopes routinely used in nuclear medicine and radiation treatments. It is modular in nature and consists of four NaI(Tl) scintillation detectors, a 512 channels multi-channel analyzer, a system controller, and a database-monitoring server. A series of tests were carried out to evaluate the performance characteristics of this system using a variety of radioactive sources of varying activities. These included measurements of minimum detectable activity, detector response distance to various source activities, detector response to different speeds of a moving radioisotope, and single and multiple radioisotope identification and classification. Measured results show that the system is capable of identifying radioactive sources of nominal activity 0.13 MBq (3.5 µCi) and higher in a relatively short period of time (<11.1 s). The database-monitoring server could send an alarm signal to appropriate personnel when the analysis of the results indicated the presence of a non-medical or threat radioisotope. The present paper reports these results.

Radiation doses and cancer risks in the Marshall Islands associated with exposure to radioactive fallout from Bikini and Enewetak nuclear weapons tests: summary.

Nuclear weapons testing conducted at Bikini and Enewetak Atolls during 1946-1958 resulted in exposures of the resident population of the present-day Republic of the Marshall Islands to radioactive fallout. This paper summarizes the results of a thorough and systematic reconstruction of radiation doses to that population, by year, age at exposure, and atoll of residence, and the related cancer risks. Detailed methods and results are presented in a series of companion papers in this volume. From our analysis, we concluded that 20 of the 66 nuclear tests conducted in or near the Marshall Islands resulted in measurable fallout deposition on one or more of the inhabited atolls of the Marshall Islands. In this work, we estimated deposition densities (kBq m(-2)) of all important dose-contributing radionuclides at each of the 32 atolls and separate reef islands of the Marshall Islands. Quantitative deposition estimates were made for 63 radionuclides from each test at each atoll. Those estimates along with reported measurements of exposure rates at various times after fallout were used to estimate radiation absorbed doses to the red bone marrow, thyroid gland, stomach wall, and colon wall of atoll residents from both external and internal exposure. Annual doses were estimated for six age groups ranging from newborns to adults. We found that the total deposition of 137Cs, external dose, internal organ doses, and cancer risks followed the same geographic pattern with the large population of the southern atolls receiving the lowest doses. Permanent residents of the southern atolls who were of adult age at the beginning of the testing period received external doses ranging from 5 to 12 mGy on average; the external doses to adults at the mid-latitude atolls ranged from 22 to 59 mGy on average, while the residents of the northern atolls received external doses in the hundreds to over 1,000 mGy. Internal doses varied significantly by age at exposure, location, and organ. Except for internal doses to the thyroid gland, external exposure was generally the major contributor to organ doses, particularly for red bone marrow and stomach wall. Internal doses to the stomach wall and red bone marrow were similar in magnitude, about 1 mGy to 7 mGy for permanent residents of the southern and mid-latitude atolls. However, adult residents of Utrik and Rongelap Island, which are part of the northern atolls, received much higher internal doses because of intakes of short-lived radionuclides leading to doses from 20 mGy to more than 500 mGy to red bone marrow and stomach wall. In general, internal doses to the colon wall were four to ten times greater than those to the red bone marrow and internal doses to the thyroid gland were 20 to 30 times greater than to the red bone marrow. Adult internal thyroid doses for the Utrik community and for the Rongelap Island community were about 760 mGy and 7,600 mGy, respectively. The highest doses were to the thyroid glands of young children exposed on Rongelap at the time of the Castle Bravo test of 1 March 1954 and were about three times higher than for adults. Internal doses from chronic intakes, related to residual activities of long-lived radionuclides in the environment, were, in general, low in comparison with acute exposure resulting from the intakes of radionuclides immediately or soon after the deposition of fallout. The annual doses and the population sizes at each atoll in each year were used to develop estimates of cancer risks for the permanent residents of all atolls that were inhabited during the testing period as well as for the Marshallese population groups that were relocated prior to the testing or after it had begun. About 170 excess cancers (radiation-related cases) are projected to occur among more than 25,000 Marshallese, half of whom were born before 1948. All but about 65 of those cancers are estimated to have already been expressed. The 170 excess cancers are in comparison to about 10,600 cancers that would spontaneously arise, unrelated to radioactive fallout, among the same cohort of Marshallese people.

Alimentary tract absorption (f1 values) for radionuclides in local and regional fallout from nuclear tests.

This paper presents gastrointestinal absorption fractions (f1 values) for estimating internal doses from local and regional fallout radionuclides due to nuclear tests. The choice of f1 values are based on specific circumstances of weapons test conditions and a review of reported f1 values for elements in different physical and chemical states. Special attention is given to fallout from nuclear tests conducted at the Marshall Islands. We make a distinction between the f1 values for intakes of radioactive materials immediately after deposition (acute intakes) and intakes that occur in the course of months and years after deposition, following incorporation into terrestrial and aquatic foodstuffs (chronic intakes). Multiple f1 values for different circumstances where persons are exposed to radioactive fallout (e.g., local vs. regional fallout and coral vs. continental tests) are presented when supportive information is available. In some cases, our selected f1 values are similar to those adopted by the International Commission on Radiological Protection (ICRP) (e.g., iodine and most actinides). However, f1 values for cesium and strontium derived from urine bioassay data of the Marshallese population are notably lower than the generic f1 values recommended by ICRP, particularly for acute intakes from local fallout (0.4 and 0.05 for Cs and Sr, respectively). The f1 values presented here form the first complete set of values relevant to realistic dose assessments for exposure to local or regional radioactive fallout.

Glutamate agonist LY404,039 for treating schizophrenia has affinity for the dopamine D2(High) receptor.

The glutamate agonist LY404,039 has been used to treat schizophrenia. Because all currently used antipsychotics act on dopamine receptors, it was decided to examine whether this glutamate agonist also had an affinity for dopamine D2 receptors in vitro. The present data show that LY404,039 inhibited the binding of [3H]domperidone and [3H]+PHNO by 15.5 +/- 1.5% to the high-affinity state, D2(High), of cloned dopamine D2(Long) receptors and rat striatal tissue with dissociation constants of between 8.2 and 12.6 nM. This high-affinity component of LY404,039 on the binding of [3H]domperidone was inhibited by the presence of guanine nucleotide, indicating an agonist action of the drug at D2(High). LY404,039 also stimulated the incorporation of [35S]GTP-gamma-S into D2(Long) receptors (EC50% = 80 +/- 15 nM) over the same range of concentrations as occurred for the inhibition of [3H]domperidone by LY404,039 at D2(High) (IC50%(High) = 50 +/- 10 nM). A possible clinical antipsychotic action of LY404,039 may depend on the combined stimulation of glutamate receptors and a partial dopamine agonist action that would interfere with neurotransmission at D2(High) receptors.

[The main radionuclides and dose formation in fish of the Chernobyl NPP exclusion zone].

The results of the researches of spices-specificity, accumulation dynamics and distribution of 90Sr, of 137Cs and of transuranic elements in fish of the Chernobyl NPP exclusion zone are analysed. The data of estimations of absorbed doze rate from incorporated radionuclides for pray fish and predatory species are given. For the fish from the lake of the left-bank floodplain of the Pripyat River the increase of 90Sr specific activity is registered which is presumably connected with the dynamics of the physical-chemical forms of the radionuclide in soils and their wash out in water bodies from the catchment basin. Now about 90% of internal dose rate of fish from closed aquatic ecosystems within the Chernobyl NPP exclusion zone is caused by 90Sr incorporation.

Development of a database: DACTARI for a radiotoxic element ranking methodology.

Dosimetric impact studies aim at evaluating potential radiological effects of chronic or acute releases from nuclear facilities. A methodology for ranking radionuclides (RN) in terms of their health-related impact on the human population was first developed at CEA with specific criteria for each RN that could be applied to a variety of situations. It is based, in particular, on applying physico-chemical criteria to the complete RN inventory (present in the release or in the source term) and on applying norms related to radiation protection and chemical toxicology. The initial step consisted in identifying and collecting data necessary to apply the methodology, with reference to a previous database of long-lived radionuclides (LLRN, with half-lives ranging from 30 to 10(14) y) containing 95 radionuclides. The initial results have allowed us to identify missing data and revealed the need to complete the study for both toxic and radiotoxic aspects. This led us to the next step, developing a specific database, DAtabase for Chemical Toxicity and Radiotoxicity Assessment of RadIonuclides (DACTARI), to collect data on chemical toxicity and radiotoxicity, including acute or chronic toxicity, the chemical form of the compounds, the contamination route (ingestion, inhalation), lethal doses, target organs, intestinal and maternal-foetal transfer, drinking water guidelines and the mutagenic and carcinogenic properties.

Treatment margins predict biochemical outcomes after prostate brachytherapy.

PURPOSE: Due to the theoretical role of treatment margins (TMs) in cancer, we have correlated biochemical outcomes with post-implant TMs in patients treated with brachytherapy for early stage prostate cancer. METHODS: From November 1998 through September 2003, 492 of a planned total of 600 patients with 1997 AJC clinical stage T1c-T2a prostatic carcinoma (Gleason score 5 or 6, PSA 4 to 10 ng/mL) have been randomized to implantation with (125)I (144 Gy, TG-43) versus (103)Pd (125 Gy, NIST-99). This preliminary analysis included only the first 122 analyzable patients, while accrual to the trial finishes. Isotope implantation was performed by standard techniques, using a modified peripheral loading pattern. Axial CT images at 3 mm intervals were acquired within four hours postoperatively for post-implant dosimetry. The contoured images and sources were entered into Varian Variseed system 7.1 (Charlottesville, VA). After completion of standard dosimetric calculations, the 100% prescription dose TMs were measured and tabulated around the prostate periphery at the 0.0, 1.0, 2.0 and 3.0 cm planes, going distal from the bladder-prostate interface. Measurements were limited to the transverse planes. Freedom from biochemical failure was defined as a serum PSA < or = 0.5 ng/mL at last follow-up. Patients were censored at last follow-up if their serum PSA was still decreasing. Patients whose serum PSA nadired at a value >0.5 ng/mL were scored as failures at the time at which their PSA nadired. The follow-up period for non-failing patients ranged from 2.1-5.0 years (median: 3.3 years). RESULTS: The average 100% prescription dose treatment margin (for individual patients) ranged from -5.0 to 8.7 mm, with an overall average of 2.6 mm (+/-3.1). In univariate analysis, the D(90) was the best predictor of biochemical control for (125)I, while the average TM was the best predictor for (103)Pd. Similarly, in multivariate analysis using the D(90), V(100), and average TM as the independent variables and biochemical control as the dependent variable, the D(90) was most closely related to biochemical control for (125)I patients, while average TM was most closely related for (103)Pd patients. In separate analysis of TM by site, the anterior TMs were the best predictors of biochemical outcomes. CONCLUSION: V(100), D(90), and TMs all appear to have a bearing on biochemical freedom from relapse after prostate brachytherapy. Efforts to better identify and test geographic dosimetric parameters are theoretically appealing, and supported by the clinical data summarized here.

Dating the age of a nuclear event by gamma spectrometry.

The age of a nuclear event can be determined by measuring the activity of two fission products. The event studied was a short irradiation, of a small sample of uranium, in a nuclear reactor. Two types of a clock were investigated: non-isobaric and isobaric parent-daughter fission products. Measurements of the source by gamma spectrometry yielded very good agreement between true and measured ages. The accuracy of each clock and the upper and lower age limits of applicability were studied.

Scientific basis for the development of biokinetic models for radionuclide-contaminated wounds.

Radionuclide-contaminated wounds are of radiological concern because the wound provides a portal of entry of the radionuclide to the systemic circulation, and can also be a tissue at risk if sufficient dose is deposited at the wound site. Accordingly, a scientific committee established jointly by the US National Council on Radiation Protection and the International Commission on Radiological Protection has been developing an approach to describing the biokinetics of radionuclides deposited in wounds and calculating dose to the wound site. This paper focuses on the analyses, performed principally using experimental animal data, that have led to the development of a biokinetic model for deposited soluble radionuclides as well as more insoluble forms, such as colloids, particles and fragments. The available data for injected soluble materials have provided a basis for categorising 48 different elements (from Be to Cm and representing all of the chemical groups, except halogens and noble gases) into four distinct retention groups. In general, the data are adequate for developing a mechanistically based biokinetic model, whose application is exemplified for soluble radionuclides.

Infant doses from the transfer of radionuclides in mothers' milk.

Assessments of potential internal exposures of the child following radionuclide intakes by the mother require consideration of transfers during lactation as well as during pregnancy. Current ICRP work on internal dosimetry includes the estimation of radiation doses to newborn infants from radionuclides ingested in mothers' milk. Infant doses will be calculated for maternal intakes by ingestion or inhalation of the radionuclides, radioisotopes of 31 elements, for which fetal dose coefficients have been published. In this paper, modelling approaches are examined, concentrating on models developed for iodine, caesium, polonium, alkaline earth elements and the actinides. Comparisons of model predictions show maximum overall transfer to milk following maternal ingestion during lactation of about 30% of ingested activity for 131I, 20% for 45Ca and 137Cs, 10% for 90Sr, 1% for 210Po and low values of less than 0.01% for 239Pu and 241Am. The corresponding infant doses from milk consumption are estimated in preliminary calculations to be about two to three times the adult dose for 45Ca and 131I, 70-80% of the adult dose for 90Sr, about 40% for 137Cs, 20% for 210Po, and <0.1% for 239Pu and 241Am. Infant doses from radionuclides in breast milk are compared with doses to the offspring resulting from in utero exposures during pregnancy.

Some aspects of the fetal doses given in ICRP Publication 88.

The International Commission on Radiological Protection (ICRP) has recently published dose coefficients (dose per unit intake, Sv Bq(-1)) for the offspring of women exposed to radionuclides during or before pregnancy. These dose estimates include in utero doses to the embryo and fetus and doses delivered postnatally to the newborn child from radionuclides retained at birth. This paper considers the effect on doses of the time of radionuclide intake and examines the proportion of dose delivered in utero and postnatally for different radionuclides. Methods used to calculate doses to the fetal skeleton are compared. For many radionuclides, doses are greatest for intakes early in pregnancy but important exceptions, for which doses are greatest for intakes later in pregnancy, are iodine isotopes and isotopes of the alkaline earth elements, including strontium. While radionuclides such as 131I deliver dose largely in utero, even for intakes late in pregnancy, others such as 239Pu deliver dose largely postnatally, even for intakes early during pregnancy. For alpha emitters deposited in the skeleton, the assumption made is of uniform distribution of the radionuclide and of target cells for leukaemia and bone cancer in utero; that is, the developing bone structure is not considered. However, for beta emitters, the bone structure was considered. Both approaches can be regarded as reasonably conservative, given uncertainties in particular in the location of the target cells and the rapid growth and remodelling of the skeleton at this stage of development.

Database of calculated values of retention and excretion for members of the public following acute intake of radionuclides.

Intakes of radionuclides can be estimated from measurements of radioactivity in the whole body or in specific organs or in excreta by comparing them with predicted retention or excretion data calculated using standard biokinetic models. For occupational exposure monitoring, data are presented by ICRP for 29 radionuclides in Publication 78 (1997) and by the authors for 42 radionuclides as electronic look-up tables in Microsoft Excel. In the present work, values of retention and excretion were computed for selected radionuclides inhaled or ingested by members of the public. Graphs were constructed from the computed results showing the predicted monitoring data as functions of time following acute intakes of radionuclides. A graphical database was assembled on the Web site http//www.nirs.go.jp/RPD/ to provide a tool for the interpretation of bioassay measurements.

Radiotracer-based strategies to image angiogenesis.

Tumour-induced angiogenesis plays an important role in tumour progression. Great efforts are made to develop therapeutic strategies to interfere with this process resulting in the starvation of the tumour. However, strategies to monitor conventional therapies seems to be inappropriate to control these approaches. Thus, there is a keen interest in developing methods supplying information about the corresponding therapeutical effects. Several radiotracer-based approaches focused on different targets in the angiogenic process are currently investigated. One class of tracers is based on matrix metalloproteinases inhibitors. These compounds show promising results in in vitro assays. However, initial data from in vivo studies using murine tumour models could not confirm successful non-invasive monitoring of MMP activity yet. Another strategy uses a radiolabelled single chain fragment against the ED-B domain of fibronectin, an extracellular matrix protein. Promising results demonstrated selective accumulation of the tracer in the tumour vasculature of a murine tumour model. Most of the studies are concentrated on the development of radiolabelled antagonists of the integrin alpha(v)beta(3). This heterodimeric transmembrane glycoprotein is involved in the migration of activated endothelial cells during formation of new vessels. Different compounds have been labelled with (18F), (111)In, (99m)Tc, (90)Y and several iodine isotopes. In in vitro assays most of them revealed high alpha(v)beta(3) affinity and selectivity. Moreover, in different murine tumour models successful non-invasive determination of alpha(v)beta(3) expression has been shown. Some of these approaches indicate that tumour-induced angiogenesis can be monitored in animal studies. Nevertheless, translation of these approaches into clinical settings allowing visualisation of tumour-induced angiogenesis in patients needs still to be demonstrated.