Caloric restriction reduces proteinuria in male rats with established nephropathy.

Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: ad libitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria.

Targeted optical fluorescence imaging: a meta-narrative review and future perspectives.

PURPOSE: The aim of this review is to give an overview of the current status of targeted optical fluorescence imaging in the field of oncology, cardiovascular, infectious and inflammatory diseases to further promote clinical translation. METHODS: A meta-narrative approach was taken to systematically describe the relevant literature. Consecutively, each field was assigned a developmental stage regarding the clinical implementation of optical fluorescence imaging. RESULTS: Optical fluorescence imaging is leaning towards clinical implementation in gastrointestinal and head and neck cancers, closely followed by pulmonary, neuro, breast and gynaecological oncology. In cardiovascular and infectious disease, optical imaging is in a less advanced/proof of concept stage. CONCLUSION: Targeted optical fluorescence imaging is rapidly evolving and expanding into the clinic, especially in the field of oncology. However, the imaging modality still has to overcome some major challenges before it can be part of the standard of care in the clinic, such as the provision of pivotal trial data. Intensive multidisciplinary (pre-)clinical joined forces are essential to overcome the delivery of such compelling phase III registration trial data and subsequent regulatory approval and reimbursement hurdles to advance clinical implementation of targeted optical fluorescence imaging as part of standard practice.

The effects of molar activity on [18F]FDOPA uptake in patients with neuroendocrine tumors.

BACKGROUND: 6-[18F]fluoro-L-3,4-dihydroxyphenyl alanine ([18F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [18F]FDOPA is decarboxylated to [18F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [18F]FDOPA has been developed, [18F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([18F]FDOPA-L). AIMS: This study aimed to investigate whether the difference in molar activity affects the [18F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [18F]FDOPA-H would be equal to or higher than [18F]FDOPA-L. METHODS: We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [18F]FDOPA-H and [18F]FDOPA-L within a time span of 5 years. A total of 98 [18F]FDOPA scans (49 [18F]FDOPA-L and 49 [18F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1-2 lesions) and higher tumor load (3-10 lesions). RESULTS: Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [18F]FDOPA-H compared to [18F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [18F]FDOPA-H group with 3-10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L. CONCLUSION: [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV's, with slight increases in uptake of [18F]FDOPA-H in comparison to [18F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [18F]FDOPA.

Recommendations in Second Opinion Reports of Neurologic Head and Neck Imaging: Frequency, Referring Clinicians' Compliance, and Diagnostic Yield.

BACKGROUND AND PURPOSE: Second opinion reports of neurologic head and neck imaging are requested with increased regularity, and they may contain a recommendation to the clinician. Our aim was to investigate the frequency and determinants of the presence of a recommendation and the adherence by the referring physician to the recommendation in a second opinion neurology head and neck imaging report and the diagnostic yield of these recommendations. MATERIALS AND METHODS: This retrospective study included 994 consecutive second opinion reports of neurology head and neck imaging examinations performed at a tertiary care center. RESULTS: Of the 994 second opinion reports, 12.2% (121/994) contained a recommendation. An oncologic imaging indication was significantly (P = .030) associated with a lower chance of a recommendation in the second opinion report (OR = .67; 95% CI, 0.46-0.96). Clinicians followed 65.7% (88/134) of the recommendations. None of the investigated variables (patient age, sex, hospitalization status, indication for the second opinion report, experience of the radiologist who signed the second opinion report, strength of the recommendation, and whether the recommendation was made due to apparent quality issues of the original examination) were significantly associated with the compliance of the referring physician to this recommendation. The 134 individual recommendations eventually led to the establishment of 52 (38.2%) benign diagnoses and 28 (20.6%) malignant diagnoses, while no definitive diagnosis could be established in 56 (41.2%) cases. CONCLUSIONS: Recommendations are relatively common in second opinion reports of neurology head and neck imaging examinations, though less for oncologic indications. They are mostly followed by requesting physicians, thus affecting patient management. In most cases, they also lead to the establishment of a diagnosis, hence adding value to patient care.

A retrospective analysis of the diagnostic performance of 11C-choline PET/CT for detection of hyperfunctioning parathyroid glands after prior negative or discordant imaging in primary hyperparathyroidism.

BACKGROUND: Identifying the correct location of a parathyroid adenoma in patients with primary hyperparathyroidism (pHPT) is crucial as it can guide surgical treatment. This study aimed to determine the diagnostic performance of 11C-choline PET/CT in patients with pHPT as a next in-line scan after primary negative or discordant first-line imaging. METHODS: This was a retrospective single-center cohort study. All patients with pHPT that were scanned utilizing 11C-choline PET/CT, after prior negative or discordant imaging, between 2015 and 2019 and who subsequently underwent parathyroid surgery were included. The results of the 11C-choline PET/CT were evaluated lesion-based, with surgical exploration and histopathological examination as the gold standard. RESULTS: In total, 36 patients were included of which three patients were known to have Multiple Endocrine Neoplasia (MEN) syndrome. In these 36 patients, 40 lesions were identified on 11C-choline PET/CT and 37 parathyroid lesions were surgically removed. In 34/36 (94%) patients a focused parathyroidectomy was performed, in one patient a cervical exploration due to an ectopically identified adenoma, and in one patient a bilateral exploration was performed because of a double adenoma. Overall, per-lesion sensitivity of 11C-choline PET/CT was 97%, the positive predictive value was 95% and the accuracy was 94% for all parathyroid lesions. CONCLUSIONS: In patients with pHPT and prior negative or discordant first-line imaging results, pathological parathyroid glands can be localized by 11C-choline PET/CT with high sensitivity and accuracy.

Prognostic superiority of International Prognostic Index over [18F]FDG PET/CT volumetric parameters in post-transplant lymphoproliferative disorder.

BACKGROUND: Post-transplant lymphoproliferative disorders (PTLDs) are a spectrum of hematological malignancies occurring after solid organ and hematopoietic stem cell transplantation. [18F]FDG PET/CT is routinely performed at PTLD diagnosis, allowing for both staging of the disease and quantification of volumetric parameters, such as whole-body metabolic tumor volume (MTV) and total lesion glycolysis (TLG). In this retrospective study, we aimed to determine the prognostic value of MTV and TLG in PTLD patients, together with other variables of interest, such as the International Prognostic Index (IPI), organ transplant type, EBV tumor status, time after transplant, albumin levels and PTLD morphology. RESULTS: A total of 88 patients were included. The 1-, 3-, 5- year overall survival rates were 67%, 58% and 43% respectively. Multivariable analysis indicated that a high IPI (HR: 1.56, 95% CI: 1.13-2.16) and an EBV-negative tumor (HR: 2.71, 95% CI: 1.38-5.32) were associated with poor overall survival. Patients with a kidney transplant had a longer overall survival than any other organ recipients (HR: 0.38 95% CI: 0.16-0.89). IPI was found to be the best predicting parameter of overall survival in our cohort. Whole-body MTV, TLG, time after transplant, hypoalbuminemia and PTLD morphology were not associated with overall survival. CONCLUSION: [18F]FDG PET/CT whole-body volumetric quantitative parameters were not predictive of overall survival in PTLD. In our cohort, high IPI and an EBV-negative tumor were found to predictors of worse overall survival while kidney transplant patients had a longer overall survival compared to other organ transplant recipients.

Time to Reconsider Routine Percutaneous Biopsy in Spondylodiscitis?

Percutaneous image-guided biopsy currently has a central role in the diagnostic work-up of patients with suspected spondylodiscitis. However, on the basis of recent evidence, the value of routine image-guided biopsy in this disease can be challenged. In this article, we discuss this recent evidence and also share a new diagnostic algorithm for spondylodiscitis that was recently introduced at our institution. Thus, we may move from a rather dogmatic approach in which routine image-guided biopsy is performed in any case to a more individualized use of this procedure.

Semi-Quantitative Characterization of Post-Transplant Lymphoproliferative Disorder Morphological Subtypes with [18F]FDG PET/CT.

Background: Post-transplant lymphoproliferative disorder (PTLD) is a complication of organ transplantation classified according to the WHO as nondestructive, polymorphic, monomorphic, and classic Hodgkin Lymphoma subtypes. In this retrospective study, we investigated the potential of semi-quantitative 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET/computed tomography (CT)-based parameters to differentiate between the PTLD morphological subtypes. Methods: 96 patients with histopathologically confirmed PTLD and baseline [18F]FDG PET/CT between 2009 and 2019 were included. Extracted semi-quantitative measurements included: Maximum, peak, and mean standardized uptake value (SUVmax, SUVpeak, and SUVmean). Results: Median SUVs were highest for monomorphic PTLD followed by polymorphic and nondestructive subtypes. The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD (17.8, interquartile range (IQR):16) than in polymorphic subtypes (9.8, IQR:13.4) and nondestructive (4.1, IQR:6.1) (p = 0.04 and p ≤ 0.01, respectively). An SUVpeak ≥ 24.8 was always indicative of a monomorphic PTLD in our dataset. Nevertheless, there was a considerable overlap in SUV across the different morphologies. Conclusion: The median SUVpeak at the biopsy site was significantly higher in monomorphic PTLD than polymorphic and nondestructive subtypes. However, due to significant SUV overlap across the different subtypes, these values may only serve as an indication of PTLD morphology, and SUV-based parameters cannot replace histopathological classification.

Validation of thoracic aortic dimensions on ECG-triggered SSFP as alternative to contrast-enhanced MRA.

OBJECTIVES: Assessment of thoracic aortic dimensions with non-ECG-triggered contrast-enhanced magnetic resonance angiography (CE-MRA) is accompanied with motion artefacts and requires gadolinium. To avoid both motion artefacts and gadolinium administration, we evaluated the similarity and reproducibility of dimensions measured on ECG-triggered, balanced steady-state free precession (SSFP) MRA as alternative to CE-MRA. METHODS: All patients, with varying medical conditions, referred for thoracic aortic examination between September 2016 and March 2018, who underwent non-ECG-triggered CE-MRA and SSFP-MRA (1.5 T) were retrospectively included (n = 30). Aortic dimensions were measured after double-oblique multiplanar reconstruction by two observers at nine landmarks predefined by literature guidelines. Image quality was scored at the sinus of Valsalva, mid-ascending aorta and mid-descending aorta by semi-automatically assessing the vessel sharpness. RESULTS: Aortic dimensions showed high agreement between non-ECG-triggered CE-MRA and SSFP-MRA (r = 0.99, p < 0.05) without overestimation or underestimation of aortic dimensions in SSFP-MRA (mean difference, 0.1 mm; limits of agreement, - 1.9 mm and 1.9 mm). Intra- and inter-observer variabilities were significantly smaller with SSFP-MRA for the sinus of Valsalva and sinotubular junction. Image quality of the sinus of Valsalva was significantly better with SSFP-MRA, as fewer images were of impaired quality (3/30) than in CE-MRA (21/30). Reproducibility of dimensions was significantly better in images scored as good quality compared to impaired quality in both sequences. CONCLUSIONS: Thoracic aortic dimensions measured on SSFP-MRA and non-ECG-triggered CE-MRA were similar. As expected, SSFP-MRA showed better reproducibility close to the aortic root because of lesser motion artefacts, making it a feasible non-contrast imaging alternative. KEY POINTS: • SSFP-MRA provides similar dimensions as non-ECG-triggered CE-MRA. • Intra- and inter-observer reproducibilities improve for the sinus of Valsalva and sinotubular junction with SSFP-MRA. • ECG-triggered SSFP-MRA shows better image quality for landmarks close to the aortic root in the absence of cardiac motion.

Monitoring the Crosstalk Between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 with PET.

PURPOSE: Ovarian cancer (OC) leads to poor survival rates mainly due to late stage detection and innate or acquired resistance to chemotherapy. Thus, efforts have been made to exploit the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) to treat OC. However, patients eventually become resistant to these treatments as well. HER2 overexpression contributes to the acquired resistance to ER-targeted treatment. Trastuzumab treatment, on the other hand, can result in increased expression of ER, which, in turn, increases the sensitivity of the tumors towards anti-estrogen therapy. More insight into the crosstalk between ER and HER2 signaling could improve our knowledge about acquired resistance in ovarian cancer. The aim of this study was to evaluate whether PET could be used to detect changes in ER expression induced by HER2-targeted treatment in vivo. PROCEDURES: Male athymic nude mice were subcutaneously (sc) inoculated with 106 SKOV3 human ovarian cancer cells (HER2+/ER+). Two weeks after inoculation, tumor-bearing mice were treated intraperitoneally with either vehicle, the HER2 antibody trastuzumab (20 mg/kg, 2×/week), or the HER2-tyrosine kinase inhibitor lapatinib (40 mg/kg, 5 days/week) for 2 weeks. Thereafter, ER expression in the tumor was assessed by PET imaging with 16α-[18F]-fluoro-17ß-estradiol ([18F]FES). Tumors were excised for ex vivo ER and HER2 measurement with Western blotting and immunohistochemistry. RESULTS: All treatments led to smaller tumors than vehicle-treated tumors. Higher [18F]FES maximum standardize tumor uptake (SUVmax) was observed in animals treated with trastuzumab (+ 29 %, P = 0.002) or lapatinib (+ 20 %, P = 0.096) than in vehicle-treated controls. PET results were in agreement with ex vivo analyses. CONCLUSION: FES-PET imaging can detect changes in ER expression induced by HER2-targeted treatment and therefore can be used to investigate the crosstalk between ER and HER2 in a noninvasive manner.

Ovariectomy-induced depressive-like behavior and brain glucose metabolism changes in female rats are not affected by chronic mild stress.

The increased incidence of depression in women going through peri-menopause suggests that fluctuations in estrogen levels may increase the risk of developing depression. Nonetheless, this psychiatric disorder is likely to be multifactorial and consequently an additional trigger may be needed to induce depression in this population. Stress could be such a trigger. We therefore investigated the effect of ovarian estrogen depletion and chronic mild stress (CMS) on depressive-like behavior and brain metabolism in female rats. Approximately 2 and 9 weeks after estrogen depletion by ovariectomy, behavioral changes were assessed in the open-field test and the forced swim test, and brain metabolism was measured with [18F]FDG PET imaging. A subset of animals was subjected to a 6-weeks CMS protocol starting 17 days after ovariectomy. Short-term estrogen depletion had a significant effect on brain metabolism in subcortical areas, but not on behavior. Differences in depressive-like behavior were only found after prolonged estrogen depletion, leading to an increased immobility time in the forced swim test. Prolonged estrogen depletion also resulted in an increase in glucose metabolism in frontal cortical areas and hippocampus, whereas a decrease glucose metabolism was found in temporal cortical areas, hypothalamus and brainstem. Neither short-term nor prolonged estrogen depletion caused anxiety-like behavior. Changes in body weight, behavior and brain glucose metabolism were not significantly affected by CMS. In conclusion, ovarian estrogen depletion resulted in changes in brain metabolism and depressive-like behavior, but these changes were not enhanced by CMS.

Diagnostic performance of FDG-PET/CT of post-transplant lymphoproliferative disorder and factors affecting diagnostic yield.

PURPOSE: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, requiring a timely and accurate diagnosis. In this study, we evaluated the diagnostic performance of FDG-PET/CT in patients with suspected PTLD and examined if lactate dehydrogenase (LDH) levels, Epstein-Barr virus (EBV) load, or timing of FDG-PET/CT relate to detection performance of FDG-PET/CT. METHODS: This retrospective study included 91 consecutive patients with clinical suspicion of PTLD and a total of 97 FDG-PET/CT scans within an 8-year period. Pathology reports and a 2-year follow-up were used as the reference standard. Diagnostic performance of FDG-PET/CT for detection of PTLD as well as logistic regression analysis for factors expected to affect diagnostic yield were assessed. RESULTS: The diagnosis of PTLD was established in 34 patients (35%). Fifty-seven FDG-PET/CT scans (59%) were true negative, 29 (30%) were true positive, 6 (6%) false positive, and 5 (5%) false negative. Sensitivity of FDG-PET/CT for the detection of PTLD was 85%, specificity 90%, positive predictive value 83%, and negative predictive value 92%, with good inter-observer variability (k = 0.78). Of the parameters hypothesized to be associated with a true positive FDG-PET/CT result for the diagnosis of PTLD, only LDH was statistically significant (OR 1.03, p = 0.04). CONCLUSION: FDG-PET/CT has a good diagnostic performance in patients suspected of PTLD, with a good inter-observer agreement. Only LDH levels seemed to influence the detection performance of FDG-PET/CT. EBV-DNA load and timing of FDG-PET/CT after transplantation did not affect FDG-PET/CT diagnostic yield.

Therapy-Induced Changes in CXCR4 Expression in Tumor Xenografts Can Be Monitored Noninvasively with N-[11C]Methyl-AMD3465 PET.

PURPOSE: Chemokine CXCL12 and its receptor CXCR4 are constitutively overexpressed in human cancers. The CXCL12-CXCR4 signaling axis plays an important role in tumor progression and metastasis, but also in treatment-induced recruitment of CXCR4-expressing cytotoxic immune cells. Here, we aimed to demonstrate the feasibility of N-[11C]methyl-AMD3465 positron emission tomography (PET) to monitor changes in CXCR4 density in tumors after single-fraction local radiotherapy or in combination with immunization. PROCEDURE: TC-1 cells expressing human papillomavirus antigens E6 and E7 were inoculated into the C57BL/6 mice subcutaneously. Two weeks after tumor cell inoculation, mice were irradiated with a single-fraction 14-Gy dose of X-ray. One group of irradiated mice was immunized with an alpha-viral vector vaccine, SFVeE6,7, and another group received daily injections of the CXCR4 antagonist AMD3100 (3 mg/kg -intraperitoneal (i.p.)). Seven days after irradiation, all animals underwent N-[11C]methyl-AMD3465 PET. RESULTS: PET imaging showed N-[11C]methyl-AMD3465 uptake in the tumor of single-fraction irradiated mice was nearly 2.5-fold higher than in sham-irradiated tumors (1.07 ± 0.31 %ID/g vs. 0.42 ± 0.05 % ID/g, p < 0.01). The tumor uptake was further increased by 4-fold (1.73 ± 0.17 % ID/g vs 0.42 ± 0.05 % ID/g, p < 0.01) in mice treated with single-fraction radiotherapy in combination with SFVeE6,7 immunization. Administration of AMD3100 caused a 4.5-fold reduction in the tracer uptake in the tumor of irradiated animals (0.24 ± 0.1 % ID/g, p < 0.001), suggesting that tracer uptake is indeed due to CXCR4-mediated chemotaxis. CONCLUSION: This study demonstrates the feasibility of N-[11C]methyl-AMD3465 PET imaging to monitor treatment-induced changes in the density of CXCR4 receptors in tumors and justifies further evaluation of CXCR4 as a potential imaging biomarker for evaluation of anti-tumor therapies.

A light-responsive liposomal agent for MRI contrast enhancement and monitoring of cargo delivery.

Medical magnetic resonance imaging (MRI) produces high-resolution anatomical images of the human body, but has limited capacity to provide useful molecular information. The light-responsive, liposomal MRI contrast agent described herein could be used to provide an intrinsic theranostic aspect to MRI and enable tracking the distribution and cargo release of drug delivery systems upon light-triggered activation.

Performance of advanced imaging modalities at diagnosis and treatment response evaluation of patients with post-transplant lymphoproliferative disorder: A systematic review and meta-analysis.

INTRODUCTION AND AIM: Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after solid organ and hematopoietic stem cell transplantation, associated with significant morbidity and mortality. In this systematic review we evaluated the clinical performance of advanced imaging modalities at diagnosis and treatment response evaluation of PTLD patients after solid organ and hematopoietic stem cell transplantation. METHODS: We have carried out a literature search until December 15, 2017 using PubMed/Medline, Embase, "Web of Science" and Cochrane Library databases concerning the performance of computed tomography (CT), magnetic resonance imaging (MRI) and 18F-flurodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) at diagnosis or treatment response evaluation of PTLD patients. RESULTS: A total of 11 studies were included comprising 368 patients, from which FDG-PET(/CT) was the primary imaging modality investigated. The methodological quality according to QUADAS-2 of the reviewed studies was moderate-poor. Subgroup analysis of imaging results for detection and staging in patients with PTLD indicated that FDG-PET/(CT) identified additional lesions not detected by CT and/or MRI in 27.8%, (95% confidence interval [95%CI]) 17.0%-42.0% (I2 = 51.1%), from which extra-nodal sites in 23.6% (95%CI: 7.9%-52.4%) (I2 = 76.6%). False negative results occurred in 11.5% (95%CI: 4.9%-24.5%) (I2 = 73.4%), predominantly in physiological high background activity regions and in early PTLD lesions. False positive results occurred in 4.8% (95%CI: 2.6%-8.6%) (I2 = 0%) predominantly due to inflammatory conditions. Subgroup analysis of imaging results at treatment response evaluation indicated that FDG-PET(/CT) findings altered or guided treatment in 29.0% (95%CI: 14.0%-50.5%) (I2 = 40.1%). False positive results during treatment response evaluation were reported in 20.0% (95%CI: 10.7%-34.2%) (I2 = 0%), predominantly due to inflammatory conditions. CONCLUSION: FDG-PET(/CT) is currently the most frequently investigated imaging modality in PTLD patients. Available studies report promising results in detection, staging and therapy evaluation but suffer from methodological shortcomings. Concerns remain with regard to occurrence of false negatives due to physiological high background activity and early PTLD lesions as well as false positives due to inflammatory conditions.

Crossed Cerebellar Diaschisis in Alzheimer's Disease.

BACKGROUND: We describe the phenomenon of crossed cerebellar diaschisis (CCD) in four subjects diagnosed with Alzheimer's disease (AD) according to the National Institute on Aging - Alzheimer Association (NIA-AA) criteria, in combination with 18F-FDG PET and 11C-PiB PET imaging. METHODS: 18F-FDG PET showed a pattern of cerebral metabolism with relative decrease most prominent in the frontal-parietal cortex of the left hemisphere and crossed hypometabolism of the right cerebellum. 11C-PiB PET showed symmetrical amyloid accumulation, but a lower relative tracer delivery (a surrogate of relative cerebral blood flow) in the left hemisphere. CCD is the phenomenon of unilateral cerebellar hypometabolism as a remote effect of supratentorial dysfunction of the brain in the contralateral hemisphere. The mechanism implies the involvement of the cortico-ponto-cerebellar fibers. The pathophysiology is thought to have a functional or reversible basis but can also reflect in secondary morphologic change. CCD is a well-recognized phenomenon, since the development of new imaging techniques, although scarcely described in neurodegenerative dementias. RESULTS: To our knowledge this is the first report describing CCD in AD subjects with documentation of both 18F-FDG PET and 11C-PiB PET imaging. CCD in our subjects was explained on a functional basis due to neurodegenerative pathology in the left hemisphere. There was no structural lesion and the symmetric amyloid accumulation did not correspond with the unilateral metabolic impairment. CONCLUSION: This suggests that CCD might be caused by non-amyloid neurodegeneration. The pathophysiological mechanism, clinical relevance and therapeutic implications of CCD and the role of the cerebellum in AD need further investigation.

Altered adenosine 2A and dopamine D2 receptor availability in the 6-hydroxydopamine-treated rats with and without levodopa-induced dyskinesia.

Several lines of evidence imply alterations in adenosine signaling in Parkinson's disease (PD). Here, we investigated cerebral changes in adenosine 2A receptor (A2AR) availability in 6-hydroxydopamine (6-OHDA)-lesioned rats with and without levodopa-induced dyskinesia (LID) using positron-emission tomography (PET) with [11C]preladenant. In parallel dopamine type 2 receptor (D2R) imaging with [11C]raclopride PET and behavioral tests for motor and cognitive function were performed. METHODS: Parametric A2AR and D2R binding potential (BPND) images were reconstructed using reference tissue models with midbrain and cerebellum as reference tissue, respectively. All images were anatomically standardized to Paxinos space and analyzed using volume-of-interest (VOI) and voxel-based approaches. The behavioral alternations were assessed with the open field test, Y-maze, novel object recognition test, cylinder test, and abnormal involuntary movement (AIM) score. In total, 28 female Wistar rats were included. RESULTS: On the behavioral level, 6-OHDA-lesioned rats showed asymmetry in forepaw use and deficits in spatial memory and explorative behavior as compared to the sham-operated animals. 15-Days of levodopa (L-DOPA) treatment induced dyskinesia but did not alleviate motor deficits in PD rats. Intranigral 6-OHDA injection significantly increased D2R binding in the lesioned striatum (BPND: 2.69 ± 0.40 6-OHDA vs. 2.31 ± 0.18 sham, + 16.6%; p = 0.03), whereas L-DOPA treatment did not affect the D2R binding in the ipsilateral striatum of the PD rats. In addition, intranigral 6-OHDA injection tended to decrease the A2AR availability in the lesioned striatum. The decrease became significant when data were normalized to the non-affected side (BPND: 4.32 ± 0.41 6-OHDA vs. 4.58 ± 0.89 sham; NS, ratio: 0.94 ± 0.03 6-OHDA vs. 1.00 ± 0.02 sham; - 6.1%; p = 0.01). L-DOPA treatment significantly increased A2AR binding in the affected striatum (BPND: 6.02 ± 0.91 L-DOPA vs. 4.90 ± 0.76 saline; + 23.4%; p = 0.02). In PD rats with LID, positive correlations were found between D2R and A2AR BPND values in the ipsilateral striatum (r = 0.88, ppeak = 8.56.10-4 uncorr), and between AIM score and the D2R BPND in the contralateral striatum (r = 0.98; ppeak = 9.55.10-5 uncorr). CONCLUSION: A2AR availability changed in drug-naïve and in L-DOPA-treated PD rats. The observed correlations of striatal D2R availability with A2AR availability and with AIM score may provide new knowledge on striatal physiology and new possibilities to further unravel the functions of these targets in the pathophysiology of PD.

Noninvasive monitoring of cancer therapy induced activated T cells using [18F]FB-IL-2 PET imaging.

Cancer immunotherapy urgently calls for methods to monitor immune responses at the site of the cancer. Since activated T lymphocytes may serve as a hallmark for anticancer responses, we targeted these cells using the radiotracer N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL-2) for positron emission tomography (PET) imaging. Thus, we noninvasively monitored the effects of local tumor irradiation and/or immunization on tumor-infiltrating and systemic activated lymphocytes in tumor-bearing mice. A 10- and 27-fold higher [18F]FB-IL-2 uptake was observed in tumors of mice receiving tumor irradiation alone or in combination with immunization, respectively. This increased uptake was extended to several non-target tissues. Administration of the CXCR4 antagonist AMD3100 reduced tracer uptake by 2.8-fold, indicating a CXCR4-dependent infiltration of activated T lymphocytes upon cancer treatment. In conclusion, [18F]FB-IL-2 PET can serve as a clinical biomarker to monitor treatment-induced infiltration of activated T lymphocytes and, on that basis, may guide cancer immunotherapies.

Evaluating [11C]PBR28 PET for Monitoring Gut and Brain Inflammation in a Rat Model of Chemically Induced Colitis.

PURPOSE: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon that affects an increasing number of patients. High comorbidity is observed between UC and other diseases in which inflammation may be involved, including brain diseases such as cognitive impairment, mental disorders, anxiety, and depression. To investigate the increased occurrence of these brain diseases in patients with UC, non-invasive methods for monitoring peripheral and central inflammation could be applied. Therefore, the goal of this study is to assess the feasibility of monitoring gut and brain inflammation in a rat model of chemically induced colitis by positron emission tomography (PET) with [11C]PBR28, a tracer targeting the translocator protein (TSPO), which is upregulated when microglia and macrophages are activated. PROCEDURES: Colitis was induced in rats by intra-rectal injection of 2,4,6-trinitrobenzenesulfonic acid (TNBS). Rats with colitis and healthy control animals were subjected to [11C]PBR28 PET of the abdomen followed by ex vivo biodistribution in order to assess whether inflammation in the gut could be detected. Another group of rats with colitis underwent repetitive [11C]PBR28 PET imaging of the brain to investigate the development of neuroinflammation. RESULTS: Eleven days after TNBS injection, ex vivo biodistribution studies demonstrated increased [11C]PBR28 uptake in the inflamed cecum and colon of rats with colitis as compared to healthy controls, whereas PET imaging did not show any difference between groups at any time. Similarly, repetitive PET imaging of the brain did not reveal any neuroinflammation induced by the TNBS administration in the colon. In contrast, significantly increased [11C]PBR28 uptake in cerebellum could be detected in ex vivo biodistribution studies on day 11. CONCLUSION: Inflammation in both the gut and the brain of rats with chemically induced colitis was observed by ex vivo biodistribution. However, these effects could not be detected by [11C]PBR28 PET imaging in our colitis model, which is likely due to spill-over effects and insufficient resolution of the PET camera.

N-[11C]Methyl-AMD3465 PET as a Tool for In Vivo Measurement of Chemokine Receptor 4 (CXCR4) Occupancy by Therapeutic Drugs.

PURPOSE: Chemokine receptor 4 (CXCR4) is overexpressed in many cancers and a potential drug target. We have recently developed the tracer N-[11C]methyl-AMD3465 for imaging of CXCR4 expression by positron emission tomography (PET). We investigated the pharmacokinetics of N-[11C]methyl-AMD3465 in rats bearing a C6 tumor and assessed whether the CXCR4 occupancy by the drug Plerixafor® can be measured with this PET tracer. PROCEDURE: A subcutaneous C6 tumor was grown in Wistar rats. Dynamic N-[11C]methyl-AMD3465 PET scans with arterial blood sampling was performed in control rats and rats pretreated with Plerixafor® (30 mg/kg, s.c). The distribution volume (V T) of the tracer was estimated by compartment modeling with a two-tissue reversible compartment model (2TRCM) and by Logan graphical analysis. The non-displaceable binding potential (BPND) was estimated with the 2TRCM. Next, CXCR4 receptor occupancy of different doses of the drug Plerixafor® (0.5-60 mg/kg) was investigated. RESULTS: The tumor could be clearly visualized by PET in control animals. Pretreatment with 30 mg/kg Plerixafor® significantly reduced tumor uptake (SUV 0.65 ± 0.08 vs. 0.20 ± 0.01, p < 0.05). N-[11C]Methyl-AMD3465 was slowly metabolized in vivo, with 70 ± 7% of the tracer in plasma still being intact after 60 min. The tracer showed reversible in vivo binding to its receptor. Both 2TRCM modeling and Logan graphical analysis could be used to estimate V T. Pre-treatment with 30 mg/kg Plerixafor® resulted in a significant reduction in V T (2TCRM 0.87 ± 0.10 vs. 0.23 ± 0.12, p < 0.05) and BPND (1.85 ± 0.14 vs. 0.87 ± 0.12, p < 0.01). Receptor occupancy by Plerixafor® was dose-dependent with an in vivo ED50 of 12.7 ± 4.0 mg/kg. Logan analysis gave comparable results. CONCLUSION: N-[11C]Methyl-AMD3465 PET can be used to visualize CXCR4 expression and to calculate receptor occupancy. V T determined by Logan graphical analysis is a suitable parameter to assess CXCR4 receptor occupancy. This approach can easily be translated to humans and used for early drug development and optimization of drug dosing schedules.