Impact of Tracer Retention Levels on Visual Analysis of Cerebral [18F]- Florbetaben Pet Images.

BACKGROUND: To compare visual and semi-quantitative analysis of brain [18F]Florbetaben PET images in Mild Cognitive Impairment (MCI) patients and relate this finding to the degree of ß-amyloid burden. METHODS: A sample of 71 amnestic MCI patients (age 74 ± 7.3 years, Mini Mental State Examination 24.2 ± 5.3) underwent cerebral [18F]Florbetaben PET/CT. Images were visually scored as positive or negative independently by three certified readers blinded to clinical and neuropsychological assessment. Amyloid positivity was also assessed by semiquantitative approach by means of a previously published threshold (SUVr ≥ 1.3). Fleiss kappa coefficient was used to compare visual analysis (after consensus among readers) and semi-quantitative analysis. Statistical significance was taken at P<0.05. RESULTS: After the consensus reading, 43/71 (60.6%) patients were considered positive. Cases that were interpreted as visually positive had higher SUVr than visually negative patients (1.48 ± 0.19 vs 1.11 ± 0.09) (P<0.05). Agreement between visual analysis and semi-quantitative analysis was excellent (k=0.86, P<0.05). Disagreement occurred in 7/71 patients (9.9%) (6 false positives and 1 false negative). Agreement between the two analyses was 90.0% (18/20) for SUVr < 1.1, 83% (24/29) for SUVr between 1.1 and 1.5, and 100% (22/22) for SUVr > 1.5 indicating lowest agreement for the group with intermediate amyloid burden. CONCLUSION: Inter-rater agreement of visual analysis of amyloid PET images is high. Agreement between visual analysis and SUVr semi-quantitative analysis decreases in the range of 1.1

The brain cognitive reserve hypothesis: A review with emphasis on the contribution of nuclear medicine neuroimaging techniques.

Neuropathological and clinical evidence indicates that the clinical expression of Alzheimer's disease (AD) occurs as neuropathology exceeds the brain reserve capacity. The brain or cognitive reserve (BCR) hypothesis states that high premorbid intelligence, education, and an active and stimulating lifestyle provide reserve capacity, which acts as a buffer against the cognitive deficits due to accumulating neuropathology. Neuroimaging studies that assessed the BCR hypothesis are critically reviewed with emphasis on study design and statistical analysis. Many studies were performed in the last two decades owing to the increasing availability of positron emission tomography (PET) and PET/computed tomography scanners and to the synthesis of new radiopharmaceuticals, including tracers for amyloid and tau proteins. Studies with different tracers provided complementary consistent results supporting the BCR hypothesis. Many studies were appropriately designed with a measure of reserve, a measure of brain anatomy/function/neuropathology, and a measure of cognitive functions that are necessary. Most of the early studies were performed with PET and [ 18 F]fluorodeoxyglucose, and occasionally with [ 15 O]water, reporting a significant association between higher occupation/education and lower glucose metabolism (blood flow) in associative temporo-parietal cortex in patients with AD and also in patients with MCI, after correcting for the degree in the cognitive impairment. On the contrary, performances on several neuropsychological tests increased with increasing education for participants with elevated [ 11 C]PiB uptake. Studies with the tracers specific for tau protein showed that patients with AD with elevated tau deposits had higher cognitive performances compared with patients with similar levels of tau deposits. BCR in AD is also associated with a preserved cholinergic function. The BCR hypothesis has been validated with methodologically sound study designs and sophisticated neuroimaging techniques using different radiotracers and providing an explanation for neuropathological and clinical observations on patients with AD.

[68Ga]-Dota Peptide PET/CT in Neuroendocrine Tumors: Main Clinical Applications.

OBJECTIVE: Neuroendocrine Neoplasms (NENs) are generally defined as rare and heterogeneous tumors. The gastrointestinal system is the most frequent site of NENs localization, however they can be found in other anatomical regions, such as pancreas, lungs, ovaries, thyroid, pituitary, and adrenal glands. Neuroendocrine neoplasms have significant clinical manifestations depending on the production of active peptide. METHODS: Imaging modalities play a fundamental role in initial diagnosis as well as in staging and treatment monitoring of NENs, in particular they vastly enhance the understanding of the physiopathology and diagnosis of NENs through the use of somatostatin analogue tracers labeled with appropriate radioisotopes. Additionally, the use of somatostatin analogues provides the ability to in-vivo measure the expression of somatostatin receptors on NEN cells, a process that might have important therapeutic implications. RESULTS: A large body of evidences showed improved accuracy of molecular imaging based on PET/CT radiotracer with SST analogues (e.g. [68Ga]-DOTA peptide) for the detection of NEN lesions in comparison to morphological imaging modalities. So far, the role of imaging technologies in assessing treatment response is still under debate. CONCLUSION: This review offers the systems of classification and grading of NENs and summarizes the more useful recommendations based on data recently published for the management of patients with NENs, with special focus on the role of imaging modalities based on SST targeting with PET / CT radiotracers.

Sensitivity of fluorine-18-fluoromethylcholine PET/CT to prostate-specific antigen over different plasma levels: a retrospective study in a cohort of 192 patients with prostate cancer.

PURPOSE: Several factors have been identified that predict positive fluorine-18-fluoromethylcholine (F-FCH) PET/CT result in patients with prostate cancer undergoing PET/CT for biochemical failure. Among these factors, prostate-specific antigen (PSA) is the single factor most consistently associated with the prediction of positive F-FCH PET/CT. In this study, we wished to confirm this finding and expand it in a large series of patients. PATIENTS AND METHODS: We retrospectively analyzed 192 patients with prostate cancer who were recruited from the Nuclear Medicine Department of the Sant'Andrea Hospital of La Spezia, Italy, from March 2013 to March 2018 and who underwent F-FCH PET/CT owing to biochemical failure after radical prostatectomy. RESULTS: Median trigger PSA was 2.57 ng/ml. The overall positive detection rate of F-FCH PET/CT was 60.9%. The percent of positive scans was 30.5% for PSA less than 1 ng/ml, 59.4% (38/64) for PSA between 1 and 5 ng/ml, and 88.4% for PSA greater than 5 ng/ml (P<0.001). On univariate regression analysis, high PSA levels, biochemical failure during antiandrogenic therapy at the time of PET/CT, and older age significantly (P<0.05) predicted positive F-FCH PET/CT result. On multivariate regression analysis, only high PSA levels and biochemical failure during antiandrogenic therapy maintained the statistical significance (P<0.05). However, when the analysis was restricted to patients with PSA less than 1 ng/ml, PSA lost the statistical significance. Receiver operating characteristic analysis revealed an area under the curve of 0.795. The PSA cutoff value that best distinguished PET/CT-positive from PET/CT-negative patients was 2.57 ng/ml. Sensitivity and specificity at this PSA value were 66.7 and 76.0%, respectively. CONCLUSION: This study confirms that PSA robustly predicts positive PET/CT result with radiolabeled choline. Unfortunately, this study also confirms the limited sensitivity of F-FCH PET/CT for PSA less than 1 ng/ml, which currently represents the weakest point of the technique.

Molecular Imaging of Huntington's Disease.

The onset and the clinical progression of Huntington Disease (HD) is influenced by several events prompted by a genetic mutation that affects several organs tissues including different regions of the brain. In the last decades years, Positron Emission Tomography (PET) and Magnetic Resonance Imaging (MRI) helped to deepen the knowledge of neurodegenerative mechanisms that guide to clinical symptoms. Brain imaging with PET represents a tool to investigate the physiopathology occurring in the brain and it has been used to predict the age of onset of the disease and to evaluate the therapeutic efficacy of new drugs. This article reviews the contribution of PET and MRI in the research field on Huntington's disease, focusing in particular on some most relevant achievements that have helped recognize the molecular changes, the clinical symptoms and evolution of the disease. J. Cell. Physiol. 232: 1988-1993, 2017. © 2016 Wiley Periodicals, Inc.

Clinical applications of choline PET/CT in brain tumors.

Malignant gliomas and metastatic tumors are the most common forms of brain tumors. From a clinical perspective, neuroimaging plays a significant role, in diagnosis, treatment planning, and follow-up. To date MRI is considered the current clinical gold standard for imaging, however, despite providing superior structural detail it features poor specificity in identifying viable tumors in brain treated with surgery, radiation, or chemotherapy. In the last years functional neuroimaging has become largely widespread thanks to the use of molecular tracers employed in cellular metabolism which has significantly improved the management of patients with brain tumors, especially in the post-treatment phase. Despite the considerable progress of molecular imaging in oncology its use in the diagnosis of brain tumors is still limited by a few wellknown technical problems. Because 18F-FDG, the most common radiotracer used in oncology, is avidly accumulated by normal cortex, the low tumor/background signal ratio makes it difficult to distinguish the tumor from normal surrounding tissues. By contrast, radiotracers with higher specificity for the tumor are labeled with a short half-life isotopes which restricts their use to those centers equipped with a cyclotron and radiopharmacy facility. 11C-choline has been reported as a suitable tracer for neuroimaging application. The recent availability of choline labeled with a long half-life radioisotope as 18F increases the possibility of studying this tracer's potential role in the staging of brain tumors. The present review focuses on the possible clinical applications of PET/CT with choline tracers in malignant brain tumors and brain metastases, with a special focus on malignant gliomas.

SPECT radiopharmaceuticals for dementia.

Over the last decade the interest towards functional neuroimaging has gradually increased, especially in the field of neurodegenerative diseases. At present, diagnosis of dementia is mostly clinical. Numerous modalities of neuroimaging are today available, each of them allowing a different aspect of neurodegeneration to be investigated. Although during the last period many have predicted a forthcoming disappearance of SPECT imaging in favour of the PET imaging, many new radiotracers SPECT, dual-SPECT tracers techniques and receptor targeting designed radiopharmaceuticals are currently at study. Besides, last decade has also assisted to the development of new SPECT imaging systems, most of them integrated with other imaging modalities (MRI, CT, ultrasound techniques), granting improved imaging capabilities. All these improved conditions, especially appealing for the neuroimaging, together with the new radiopharmaceuticals in development may renovate the interest for SPECT clinical applications.

Weighted registration of 123I-FP-CIT SPECT images improves accuracy of binding potential estimates in pathologically low striatal uptake.

To test whether the use of a striatum weighted image may improve registration accuracy and diagnostic outcome in patients with parkinsonian syndromes (PS), weighted images were generated by increasing signal intensity of striatal voxels and used as intermediate dataset for co-registering the brain image onto template. Experimental validation was performed using an anthropomorphic striatal phantom. (123)I-FP-CIT SPECT binding ratios were manually determined in 67 PS subjects and compared to those obtained using unsupervised standard (UWR) and weighted registered (WR) approach. Normalized cost function was used to evaluate the accuracy of phantom and subjects registered images to the template. Reproducibility between unsupervised and manual ratios was assessed by using intra-class correlation coefficient (ICC) and Bland and Altman analysis. Correlation coefficient was used to assess the dependence of semi-quantitative ratios on clinical findings. Weighted method improves accuracy of brain registration onto template as determined by cost function in phantom (0.86 ± 0.06 vs. 0.98 ± 0.02; Student's t-test, P = 0.04) and in subject scans (0.69 ± 0.06 vs. 0.53 ± 0.06; Student's t-test, P < 0.0001). Agreement between manual and unsupervised derived binding ratios as measured by ICC was significantly higher on WR as compared to UWR images (0.91 vs. 0.76). Motor UPDRS score was significantly correlated with manual and unsupervised derived binding potential. In phantom, as well as in subjects studies, correlations were more significant using the WR method (BPm: R(2) = 0.36, P = 0.0001; BPwr: R(2) = 0.368, P = 0.0001; BPuwr: R(2) = 0.300, P = 0.0008). Weighted registration improves accuracy of binding potential estimates and may be a promising approach to enhance the diagnostic outcome of SPECT imaging, correlation with disease severity, and for monitoring disease progression in Parkinsonian syndromes.

No evidence of chromosome damage in children and adolescents with differentiated thyroid carcinoma after receiving 131I radiometabolic therapy, as evaluated by micronucleus assay and microarray analysis.

PURPOSE: As (131)I therapy, used to achieve ablation of thyroid gland remnant, can cause chromosome damage in cultured peripheral lymphocytes especially, we investigated whether administration of radioiodine may induce early genome damage in peripheral T lymphocytes of adolescents with differentiated thyroid carcinoma (DTC). METHODS: We studied 11 patients, aged 14.8 +/- 3.1 years, who assumed (131)I (range: 1.11-4.44 GBq) to ablate thyroid remnant. A blood sample for micronucleus assay and for evaluating expression of some genes involved in the DNA repair or the apoptosis pathways was obtained from each patient 1 h before (T(0)) and 24 (T(1)) and 48 h (T(2)) post-radioiodine administration. RESULTS: Compared to T(0), we did not find any difference in the number of micronucleated cells at both T(1) and T(2) in any subject. Nine out of 11 patients had altered expression levels in a majority of the DNA repair and apoptosis genes at T(1), which decreased at T(2). CONCLUSIONS: We demonstrated for the first time that peripheral cells of DTC children and adolescents who received (131)I at a mean dosage of 3.50 +/- 0.37 GBq did not show chromosome damage within 48 h from the end of radiometabolic therapy. This may be due to a prompt activation of the cell machinery that maintains the integrity of the genome to prevent harmful double-strand breaks from progressing to chromosome mutations, either by repairing the lesions or by eliminating the most seriously damaged cells via apoptosis.

Comparison between remnant and red-marrow absorbed dose in thyroid cancer patients submitted to 131I ablative therapy after rh-TSH stimulation versus hypothyroidism induced by L-thyroxine withdrawal.

OBJECTIVE: In thyroidectomized patients, increased levels of thyroid stimulating hormone (TSH) are necessary to maximize I uptake. Traditionally, this has been achieved by withdrawing L-thyroxine (L-T4) for 4-6 weeks, inducing hypothyroidism in patients. The availability of a genetically engineered version of the recombinant human TSH (rh-TSH) provides an alternative tool to enhance the TSH serum level without inducing hypothyroidism. In this paper the I remnant and red-marrow doses calculated in differentiated thyroid cancer (DTC) patients pre-treated with rh-TSH are compared to those calculated in patients in hypothyroidism induced by L-T4 withdrawal. METHODS: Forty-six DTC patients, submitted to I ablative therapy, were randomly divided in group A (pre-treated with rh-TSH) and group B (treated after L-T4 withdrawal for 30 days). The red-marrow absorbed dose per unit administered activity and the remnant cumulated activity per unit administered activity were calculated for both groups. RESULTS: The red-marrow dose in 17 rh-TSH treated patients is 0.06+/-0.02 mGy.MBq; that in 14 hypothyroid patients is 0.09+/-0.03 mGy.MBq (two-tailed unpaired t-test P=0.003). The remnant cumulated activity per unit administered activity in 10 rh-TSH treated patients is 0.9+/-0.8 h; that calculated in 21 hypothyroid patients is 1.55+/-1.05 h (two-tailed unpaired t-test P=0.063). This last result is mainly due to the difference between the maximum uptake (U) in rh-TSH (U=0.01+/-0.01) and hypothyroid patients (U=0.03+/-0.02) (two-tailed unpaired t-test P=0.019). CONCLUSION: The rh-TSH pre-treated patients seem to have a lower uptake compared to those in hypothyroidism induced by L-T4 withdrawal. On the other hand their red-marrow absorbed dose seems to be lower.