In vivo effects of olanzapine on striatal dopamine D2/D3 receptor binding in schizophrenic patients: an iodine-123 iodobenzamide single-photon emission tomography study

Olanzapine is a new atypical antipsychotic agent that belongs to the same chemical class as clozapine. The pharmacological efficacy of olanzapine (in contrast to that of risperidone) has been shown to be comparable to that of clozapine, but olanzapine has the advantage of producing a less pronounced bone marrow depressing effect than clozapine. The specific aims of this study were (a) to assess dopamine D₂/D₃ receptor availability in patients treated with olanzapine by means of iodine-123 iodobenzamide [¹²³I]IBZM single-photon emission tomography (SPET), (b) to compare the results with findings of [¹²³I]IBZM SPET in patients under treatment with risperidone and (c) to correlate the results with the occurrance of extrapyramidal side-effects (EPMS). Brain SPET scans were performed in 20 schizophrenic patients (DSM III R) at 2 h after i.v. administration of 185 MBq [¹²³I]IBZM. Images were acquired using a triple-head gamma camera (Picker Prism 3000 XP). For semiquantitative evaluation of D₂/D₃ receptor binding, transverse slices corrected for attenuation were used to calculate specific uptake values [STR–BKG]/BKG (STR=striatum; BKG=background). The mean daily dose of olanzapine ranged from 0.05 to 0.6 mg/kg body weight. The dopamine D₂/D₃ receptor binding was reduced in all patients treated with olanzapine. Specific IBZM binding [STR–BKG]/BKG ranged from 0.13 to 0.61 (normal controls >0.95). The decreased D₂/D₃ receptor availability revealed an exponential dose-response relationship (r=–0.85, P<0.001). The slope of the curve was similar to that of risperidone and considerably higher than that of clozapine as compared with the results of a previously published study. EPMS were observed in only one patient, presenting with the lowest D₂/D₃ availability. The frequency of EPMS induced by olanzapine (5%) was considerably lower than the frequency under risperidone treatment (40%). Our findings suggest an exponential relationship between the daily dose of olanzapine striatal and decreased D₂/D₃ striatal binding availability. The results are consistent with the findings of in vitro experiments reporting a higher D₂/D₃ receptor affinity and a similar 5HT₂ receptor affinity of olanzapine as compared with clozapine. Thus, the decreased tendency to induce EPMS at therapeutic doses is not due to the limited occupancy of striatal D₂/D₃ receptors in vivo. Patients are protected from EPMS by other intrinsic effects of the drug, i.e. the combination of both D₂/D₃ and 5HT₂ receptor antagonism. Received 6 March 1999 / in revised form 11 April 1999     

Evaluation of gastric motility by Fourier analysis of condensed images

In this study Fourier analysis was applied to condensed images of gastric emptying with the aim of evaluating the amplitude and frequency of gastric contractions as well as gastric emptying in patients with various well-defined disorders. In 15 controls, 65 patients with progressive systemic sclerosis (PSS), 41 patients with diabetes mellitus type I (DM), 12 patients with pyloric stenosis and 9 patients who had undergone gastric surgery, gastric emptying was determined after ingestion of a semi-solid test meal. In addition, condensed images were generated to evaluate the amplitude and frequency of gastric contractions by means of Fourier analysis. In PSS and DM patients, gastric emptying and contraction amplitudes were significantly reduced (P<0.01). Patients with pyloric stenosis displayed regular peristalsis but significantly delayed emptying (P<0.01). Patients who had undergone gastric surgery showed normal or rapid gastric emptying associated with decreased amplitudes (P<0.01). The frequency of gastric contractions in the patient groups was not different from that in controls. This study showed Fourier analysis of condensed images to be a rapid and feasible approach for the evaluation of gastric contractions. Depending on the underlying disorder, gastric emptying and peristalsis showed both corresponding and discrepant findings. Data on gastric contractions provided additional information compared with results obtained by conventional emptying studies. Therefore, both parameters should be routinely assessed to further improve characterisation of gastric dysfunction by scintigraphy.     

FDG PET and PET/CT: EANM procedure guidelines for tumour PET imaging: version 1.0

The aim of this guideline is to provide a minimum standard for the acquisition and interpretation of PET and PET/CT scans with [18F]-fluorodeoxyglucose (FDG). This guideline will therefore address general information about [18F]-fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) and is provided to help the physician and physicist to assist to carrying out, interpret, and document quantitative FDG PET/CT examinations, but will concentrate on the optimisation of diagnostic quality and quantitative information.     

Ribavirin revisited in the era of direct‐acting antiviral therapy for hepatitis C virus infection

Over the past two decades, ribavirin has been an integral component of treatment for hepatitis C virus (HCV) infection, where it has been shown to improve the efficacy of (pegylated) interferon. However, because of treatment‐limiting side effects and its additive toxicity with interferon, the search for interferon‐ and ribavirin‐free regimens has been underway. The recent approvals of all‐oral direct acting antivirals (DAAs) have revolutionized the HCV therapeutic landscape, and initially it was expected that the role of ribavirin with DAA regimens would be eliminated. On the contrary, what we have witnessed is that ribavirin retains an important role in the optimal treatment of some subgroups of patients, particularly those that historically have been considered the most difficult to cure. Fortunately, it has also been recognized that the safety profile of ribavirin is improved when co‐administered with all‐oral DAA combinations in the absence of interferon. Despite the antiviral mechanism of action of ribavirin being poorly understood, we now have a range of novel insights into the potential role of ribavirin in all‐oral DAA HCV treatment and greater insight into the antiviral mechanism by which it continues to provide clinical benefit for defined patient groups.     

Long-term assessment of striatal dopamine transporters in parkinsonian patients with intrastriatal embryonic mesencephalic grafts

Purpose Single-photon emission computed tomography (SPECT) of striatal dopamine transporters (DAT) has been used to demonstrate presynaptic dopaminergic dysfunction and to monitor the progression of Parkinson’s disease. In parkinsonian patients who were implanted with embryonic mesencephalic tissue in the striatum, positron emission tomography (PET) has shown an increase in striatal [¹⁸F]dopa uptake as an indicator of graft survival and striatal reinnervation. The aim of this study was to investigate two patients who had undergone bilateral intrastriatal transplantation of human embryonic mesencephalic tissue using SPECT and the ¹²³I-labelled DAT ligand N-(3-iodopropen-2-yl)-2β-carbomethoxy-3β-(4-chlorophenyl) tropane (IPT). Methods Two patients were subjected to [¹²³I]IPT SPECT according to a standardised protocol prospectively and repeatedly up to 8 years after transplantation. Results From baseline to year 3 after transplantation, mean striatal DAT availability increased by a mean of 61% (93% and 29% in patients 1 and 2, respectively). It then remained relatively stable up to 8 years in patient 2, but increased further by another 77% of baseline values in patient 1. Clinically, both patients experienced a moderate improvement in motor performance but developed moderate (patient 2) to severe (patient 1) off-medication dyskinesias. Conclusion Our data indicate that DAT imaging using IPT and SPECT can be used to demonstrate graft survival following dopaminergic tissue implantation. Because SPECT with DAT ligands is widely available in the routine clinical setting, this methodology may be a useful alternative to [¹⁸F]dopa PET for repeated scanning of grafted parkinsonian patients. The relevance of the long-term increase in DAT binding for the development of off-medication dyskinesias remains to be elucidated further. An editorial commentary on this paper is available at     

Implementation of the European multicentre database of healthy controls for [<Superscript>123</Superscript>I]FP-CIT SPECT increases diagnostic accuracy in patients with clinically uncertain parkinsonian syndromes

Purpose

Even though [¹²³I]FP-CIT SPECT provides high accuracy in detecting nigrostriatal cell loss in neurodegenerative parkinsonian syndromes (PS), some patients with an inconclusive diagnosis remain. We investigated whether the diagnostic accuracy in patients with clinically uncertain PS with previously inconclusive findings can be improved by the use of iterative reconstruction algorithms and an improved semiquantitative evaluation which additionally implemented a correction algorithm for patient age and gamma camera dependency (EARL-BRASS; Hermes Medical Solutions, Sweden).

Methods

We identified 101 patients with inconclusive findings who underwent an [¹²³I]FP-CIT SPECT between 2003 and 2010 as part of the diagnostic process of suspected PS at the University of Munich, and re-evaluated these scans using iterative reconstruction algorithms and the new corrected EARL-BRASS. Clinical follow-up was obtained in 62 out of the 101 patients and constituted the gold standard for the re-evaluation to assess the possible improvement in diagnostic accuracy.

Results

Clinical follow-up confirmed the diagnosis of PS in 11 of the 62 patients. In patients in whom both visual and semiquantitative analysis showed concordant findings (48 patients), a high negative predictive value (93 %), positive predictive value (100 %) and accuracy (94 %) were found, and thus a correct diagnosis was obtained in 45 of the 48 patients. Among the 14 patients with discordant findings, the additional semiquantitative analysis correctly identified all five of nine patients patients without PS by nonpathological semiquantitative findings in visually pathological or inconclusive scans. In contrast, four of the remaining five patients with decreased semiquantitative values but visually normal scans did not show a PS during follow-up.

Conclusion

The age-corrected and camera-corrected mode of evaluation using EARL-BRASS provided a notable improvement in the diagnostic accuracy of [¹²³I]FP-CIT SPECT in PS patients with previously inconclusive findings. The gain in accuracy might be achieved by better discrimination between physiological low striatal [¹²³I]FP-CIT binding due to age-related loss of the dopamine transporter or pathological loss of binding.

     

18F-FDG PET and 99mTc-sestamibi scintimammography for monitoring breast cancer response to neoadjuvant chemotherapy: a comparative study

Presurgical neoadjuvant chemotherapy has shown promise in the treatment of locally advanced breast carcinoma (LABC). Response assessment by clinical examination and mammography is difficult. This study evaluated and compared fluorine-18 fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) and technetium-99m sestamibi scintimammography (SMM) as potential methods for the early assessment of tumour response to neoadjuvant chemotherapy in patients with LABC. Seven patients underwent PET and SMM [planar and single-photon emission tomography (SPET)] before beginning chemotherapy, after the first and second cycles of chemotherapy and after completing chemotherapy prior to surgery. PET and SMM results were evaluated visually and semi-quantitatively by calculating standardised uptake values (SUV) and tumour/lung ratios in the initial and subsequent studies. The findings were correlated with the initial clinical and mammographic findings and the final histopathological diagnoses. There was a highly significant correlation between SUV_mean, SUV_max and the tumour/lung ratio determined with SMM-SPET in the studies performed before and during neoadjuvant chemotherapy. All three patients with complete remission showed decreasing FDG and sestamibi uptake as early as 8 days after therapy. In the presurgical study, increased sestamibi and FDG uptake was no longer evident. Three patients had partial remission with clearly reduced but persisting focal FDG and sestamibi uptake after neoadjuvant therapy. One patient who did not respond to therapy had unchanged intense tracer uptake during chemotherapy that was evident with both techniques. An early decline in glucose metabolism or sestamibi uptake 8 days after beginning therapy did not necessarily predict complete tumour remission in the further course of chemotherapy. On the other hand, increased tracer uptake after the first cycle did not exclude a partial tumour response. After the second chemotherapeutic cycle both techniques were able to distinguish between complete and partial/no response. There was a good correlation between preoperative FDG and sestamibi uptake and the histopathologically determined tumour size. However, small residual invasive tumours in patients with clinically complete remission could not be visualised with either technique. The preliminary data demonstrate that sestamibi SMM is as useful as FDG-PET for the monitoring of tumour response to neoadjuvant chemotherapy.     

Assessment of Oxidative, Inflammatory, and Fibrinolytic Biomarkers and DNA Strand Breakage in Hypercholesterolemia

The aim of this study was to assess the levels of oxidative, inflammatory, and fibrinolytic biomarkers as well as DNA strand breakage in hypercholesterolemic subjects. Fasting glucose, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, uric acid, total protein, albumin, apolipoprotein (Apo) A, Apo B, advanced oxidation protein products (AOPP), increased ischemia-modified albumin (IMA), ―SH, NOx, IL-6, and D-dimer levels were assessed, and DNA strand breakage was evaluated using comet assay in 38 patients with hypercholesterolemia and 20 healthy controls. Total cholesterol, triglycerides, LDL cholesterol, Apo A, Apo B, AOPP, IMA, IL-6, and D-dimer concentrations were significantly higher in subjects with hypercholesterolemia. However, NOx and plasma ―SH group concentrations were lower in hypercholesterolemic subjects, while no significant differences were observed with respect to DNA strand breakage between the two groups. Hypercholesterolemia is related to oxidative stress and inflammation. Accordingly, AOPP concentration was higher in subjects with hypercholesterolemia, and we speculate that AOPP can reflect the enhancement of protein oxidation and inflammation.     

Signal changes on MRI and increases in reactive microgliosis, astrogliosis, and iron in the putamen of two patients with multiple system atrophy.

A correlation of clinical, MRI, and neuropathological data is reported in two patients with multiple system atrophy (MSA). On MRI, patient 1 showed striatal atrophy, reduction of T2 relaxation times within most of the putamen, and a band of hyperintense signal changes in the lateral putamen. In patient 2, MRI disclosed only shortening of the T2 signal in the putamen. Immunohistochemistry showed pronounced reactive microgliosis and astrogliosis in the affected brain regions. In patient 1, the area with the most pronounced microgliosis and astrogliosis most likely correlated with the area of hyperintense signal changes on MRI. This area also contained the highest amount of ferric iron, which was increased in the putamen of patient 1 but not patient 2. It is unlikely that the hypointense signal changes in the putamen are due to an increase of iron alone. Reactive microglial and astroglial cells may play a part in the pathogenesis of MSA.     

Clinical testing of an optimized software solution for an automated, observer-independent evaluation of dopamine transporter SPECT studies.

A lack of standardized evaluation procedures for dopamine transporter (DAT) SPECT investigations impairs both intra- and interindividual comparisons as well as multicenter trials-for example, for assessment of disease progression or the response to various drug treatments. Therefore, the aim of this study was to evaluate a novel automated method, which has been specifically developed for a standardized quantification of N-(3-fluoropropyl)-2beta-carbomethoxy-3beta-(4-iodophenyl)nortropane (123I-FP-CIT) SPECT studies. METHODS: DAT binding ratios of 155 (123)I-FP-CIT SPECT studies in 14 control subjects and 141 patients referred to confirm or exclude a presynaptic dopaminergic deficit were determined manually and by a fully automated technique. The latter included coregistration of patient studies to an 123I-FP-CIT mean template of controls with specialized, nonrigid adjustment for variation in striatal location, followed by calculation of specific striatal DAT binding using a standardized 3-dimensional volume-of-interest (VOI) map. The map is based on a MR scan and covers the striatum (S), caudate (C), putamen (P), and an occipital reference region. The semiquantitative ratios of both methods were compared with the visual findings. RESULTS: Excellent linear correlations were observed between manually and automatically determined results (S: r = 0.99; C: r = 0.99; P: r = 0.99; P < 0.001, respectively). Automated evaluations delivered highly reproducible and visually exact coregistrations. Individual variations in striatal anatomy (e.g., atrophy) were considered and VOI positions were corrected before quantification. Both the manual and the automated method showed identical accuracy in supporting the visual diagnoses. CONCLUSION: In a large patient population, excellent agreement was observed between quantitative DAT results using a time-consuming, observer-dependent, conventional manual method and the objective, automated evaluation specifically developed for a standardized evaluation of 123I-FP-CIT SPECT studies. It is suggested that the novel automated technique may substantially facilitate both intra- and interindividual comparisons as well as multicenter trials.