Test–retest repeatability of [18F]Flortaucipir PET in Alzheimer’s disease and cognitively normal individuals

The aim of this study was to investigate the test–retest (TRT) repeatability of various parametric quantification methods for [¹⁸F]Flortaucipir positron emission tomography (PET). We included eight subjects with dementia or mild cognitive impairment due to Alzheimer’s disease and six cognitively normal subjects. All underwent two 130-min dynamic [¹⁸F]Flortaucipir PET scans within 3 ± 1 weeks. Data were analyzed using reference region models receptor parametric mapping (RPM), simplified reference tissue method 2 (SRTM2) and reference logan (RLogan), as well as standardized uptake value ratios (SUVr, time intervals 40–60, 80–100 and 110–130 min post-injection) with cerebellar gray matter as reference region. We obtained distribution volume ratio or SUVr, first for all brain regions and then in three tau-specific regions-of-interest (ROIs). TRT repeatability (%) was defined as |retest–test|/(average (test + retest)) × 100. For all methods and across ROIs, TRT repeatability ranged from (median (IQR)) 0.84% (0.68–2.15) to 6.84% (2.99–11.50). TRT repeatability was good for all reference methods used, although semi-quantitative models (i.e. SUVr) performed marginally worse than quantitative models, for instance TRT repeatability of RPM: 1.98% (0.78–3.58) vs. SUVr_80–100: 3.05% (1.28–5.52), p < 0.001. Furthermore, for SUVr_80–100 and SUVr_110–130, with higher average SUVr, more variation was observed. In conclusion, while TRT repeatability was good for all models used, quantitative methods performed slightly better than semi-quantitative methods.     

Radionuclide evaluation of liver transplants

Orthotopic liver transplantation is now an established technique for treating patients with various forms of end stage liver disease. The number of centers performing the procedure is increasing and, as the number of transplant recipients in the population increases, many institutions performing nuclear medicine studies will be confronted with requests to evaluate these patients. While a variety of radionuclides are proving useful in this evaluation, the 99mTc iminodiacetic acid (IDA) compounds, particularly 99mTc diisopropyl IDA (DISIDA), will probably account for the majority of radionuclide evaluations of these patients because they are well suited to monitor both structural and functional changes of the graft. The primary application of radionuclide studies is focused in the postoperative period, when problems with the vascular and biliary anastomoses, rejection, infections, and bile leaks all produce alterations in radionuclide hepatobiliary studies. Abnormalities such as rejection and infection produce primarily functional, rather than structural changes and are not easily differentiated based upon the kinetics of 99mTc-DISIDA extraction and excretion by the liver, serial imaging and correlation with clinical data is necessary in such situations. Quantitative analyses of kinetic 99mTc IDA (DISIDA) studies and quantitative approaches with other compounds such as 99mTc galactosyl-neoglycoalbumin (NGA) may permit better assessments of relatively subtle changes in liver function in the posttransplant period.     

Molecular characterization of the Clostridium difficile toxin A gene

The gene encoding the toxin A protein of Clostridium difficile (strain VPI 10463) was cloned and sequenced. The coding region of 8,133 base pairs had a mol% G + C of 26.9 and encodes 2,710 amino acids. The deduced polypeptide has a molecular mass of ca. 308 kilodaltons. Nearly a third of the gene, at the 3' end, consists of 38 repeating sequences. The repeating units were grouped into two classes, I and II, on the basis of length and the low levels of DNA sequence similarities between them. There were seven class I repeating units, each containing 90 nucleotides, and 31 class II units, which, with two exceptions, were either 60 or 63 nucleotides in length. On the basis of DNA sequence similarities, the class II repeating units were further segregated into subclasses: 7 class IIA, 13 class IIB, 5 class IIC, and 6 class IID. The dipeptide tyrosine-phenylalanine was found in all 38 repeating units, and other amino acid sequences were unique to a specific class or subclass. This region of the protein has epitopes for the monoclonal antibody PCG-4 and includes the binding region for the Gal alpha 1-3Gal beta 1-4GlcNAc carbohydrate receptor. Located 1,350 base pairs upstream from the toxin A translation start site is the 3' end of the toxin B gene. Between the two toxin genes is a small open reading frame, which encodes a deduced polypeptide of ca. 16 or 19 kilodaltons. The role of this open reading frame is unknown.     

Brain metabolic changes in major depressive disorder from pre- to post-treatment with paroxetine

Functional brain imaging studies of subjects with Major Depressive Disorder (MDD) have suggested that decreased dorsolateral (DLPFC) and increased ventrolateral (VLPFC) prefrontal cortical activity mediate the depressed state. Pre- to post-treatment studies indicate that these abnormalities normalize with successful treatment. We performed [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans on 16 outpatients with MDD before and after treatment with paroxetine (target dose = 40 mg/day). Regions of interest (ROIs) for this analysis were drawn by a rater blind to subject identity on the magnetic resonance image of each subject and transferred onto their coregistered PET scans. We hypothesized that DLPFC metabolism would increase, while ventral frontal metabolism [in the VLPFC, the orbitofrontal cortex (OFC), and the inferior frontal gyrus (IFG)] would decrease with successful treatment. Treatment response was defined as a decrease in the Hamilton Depression Rating Scale of > 50% and a Clinical Global Improvement Scale rating of 'much' or 'very much' improved. By these criteria, nine of the subjects were classified as treatment responders. These responders had significantly greater decreases in normalized VLPFC and OFC metabolism than did non-responders. There were no significant effects of treatment response on change in the DLPFC or IFG in this sample. However, there was a positive correlation between change in HAM-D scores and change in normalized IFG and VLPFC metabolism. There were no significant interactions with laterality. On pre-treatment scans, lower metabolism in the left ventral anterior cingulate gyrus was associated with better treatment response. These findings implicate ventral prefrontal-subcortical brain circuitry in the mediation of response to serotonin reuptake inhibitors in MDD.     

Characterization of primitive subpopulations of normal and leukemic cells present in the blood of patients with newly diagnosed as well as established chronic myeloid leukemia

Elevated numbers of primitive Philadelphia chromosome-positive (Ph+) progenitors, including long-term culture-initiating cells (LTC-IC) as well as colony-forming cells (CFC), have been previously described in the blood of patients with chronic myeloid leukemia (CML) in chronic phase with high white blood cell counts. In the present study, which focused primarily on an analysis of circulating progenitors present in such patients at diagnosis, we discovered the frequent and occasionally exclusive presence of circulating normal (Ph-) LTC-IC, often at levels above those seen for LTC-IC in the blood of normal individuals. The presence of detectable numbers of circulating Ph- LTC-IC was independent of the fact that the same peripheral blood samples also contained elevated numbers of predominantly or exclusively Ph+ CFC. Interestingly, both the Ph+ and Ph- LTC-IC in these samples were CD34+CD71- and variably CD38- and Thy-1+, as previously documented for LTC-IC in normal marrow. Thus, neither CD38 nor Thy-1 expression was useful for discriminating between Ph+ and Ph- LTC-IC in mixed populations. Nevertheless, an association of these phenotypes with LTC- IC function did allow highly enriched (> 5% pure) suspensions of either Ph+ or Ph- LTC-IC to be obtained from selected samples of CML blood in which the initial LTC-IC population was either predominantly Ph+ or Ph- , respectively. These findings suggest that the mechanisms causing mobilization of leukemic stem cells in untreated CML patients may affect their normal counterparts. They also indicate a possible new source of autologous cells for the support of intensive therapy of CML patients. Finally, they provide a method for obtaining the most highly purified populations of Ph+ LTC-IC described to date. This method should be useful for further analyses of the molecular activities of these very primitive neoplastic cells.