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.

Accuracy of myocardial perfusion imaging in detecting multivessel coronary artery disease: A cardiac CZT study.

BACKGROUND: Myocardial perfusion imaging (MPI) performed on traditional single-photon emission computed-tomography cameras has been shown to have a sub-optimal accuracy in detecting multivessel coronary artery disease (CAD). METHODS: Six-hundred and ninety-five patients were submitted to MPI on a novel cadmium-zinc-telluride (CZT) camera and coronary angiography. A coronary stenosis >70% was considered obstructive. In every patient, the summed stress score (SSS) was computed. Moreover, the regional stress scores were also calculated for every coronary territory. RESULTS: Four-hundred and forty-one patients had obstructive CAD in one (28%), two (19%), or three (17%) vessels. At per-patient analysis, the SSS showed a significant accuracy in detecting obstructive CAD (AUC 0.87, P < .001). Specifically, its accuracy was maintained also in patients with double (AUC 0.83; P < .001) or triple-vessels disease (AUC 0.79, P < .001), where CZT was able to correctly identify CAD extent in 64% of patients. On a per-vessel basis, CZT confirmed its high accuracy in detecting obstructive CAD (AUC 0.88, P < .001), independently from the involved coronary vessel. CONCLUSIONS: MPI performed on a CZT camera is highly accurate in detecting obstructive CAD, independently from the coronary artery involved and the overall disease burden.

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

Toward the Discovery and Development of PSMA Targeted Inhibitors for Nuclear Medicine Applications.

BACKGROUND: The rising incidence rate of prostate cancer (PCa) has promoted the development of new diagnostic and therapeutic radiopharmaceuticals during the last decades. Promising improvements have been achieved in clinical practice using prostate specific membrane antigen (PSMA) labeled agents, including specific antibodies and small molecular weight inhibitors. Focusing on molecular docking studies, this review aims to highlight the progress in the design of PSMA targeted agents for a potential use in nuclear medicine. RESULTS: Although the first development of radiopharmaceuticals able to specifically recognize PSMA was exclusively oriented to macromolecule protein structure such as radiolabeled monoclonal antibodies and derivatives, the isolation of the crystal structure of PSMA served as the trigger for the synthesis and the further evaluation of a variety of low molecular weight inhibitors. Among the nuclear imaging probes and radiotherapeutics that have been developed and tested till today, labeled Glutamate-ureido inhibitors are the most prevalent PSMA-targeting agents for nuclear medicine applications. CONCLUSION: PSMA represents for researchers the most attractive target for the detection and treatment of patients affected by PCa using nuclear medicine modalities. [99mTc]MIP-1404 is considered the tracer of choice for SPECT imaging and [68Ga]PSMA-11 is the leading diagnostic for PET imaging by general consensus. [18F]DCFPyL and [18F]PSMA-1007 are clearly the emerging PET PSMA candidates for their great potential for a widespread commercial distribution. After paving the way with new imaging tools, academic and industrial R&Ds are now focusing on the development of PSMA inhibitors labeled with alpha or beta minus emitters for a theragnostic application.

[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.

Sentinel Node Mapping in Melanoma of the Back: SPECT/CT Helps Discriminate "True" and "False" in-Transit Lymph Nodes.

A 32-year-old man with melanoma on the right paramedian region of the lower back underwent lymphoscintigraphy for radioguided sentinel node (SN) biopsy. Planar imaging showed the presence of 2 sites of radioactivity accumulation corresponding to an axillary SN and to an "in-transit" SN, located on the right side of the upper trunk. A further "hot spot" placed on the left paramedian region of the lower back was identified by planar lymphoscintigraphy. This last finding could be mistaken for another "in-transit" SN, but SPECT/CT demonstrated it was actually a nonspecific radiopharmaceutical accumulation at the level of the right renal pelvis.

Metabolic and Hormonal Determinants of Glomerular Filtration Rate and Renal Hemodynamics in Severely Obese Individuals.

OBJECTIVE: Renal function is often compromised in severe obesity. A true measurement of glomerular filtration rate (GFR) is unusual, and how estimation formulae (EstForm) perform in such individuals is unclear. We characterized renal function and hemodynamics in severely obese individuals, assessing the reliability of EstForm. METHODS: We measured GFR (mGFR) by iohexol plasma clearance, renal plasma flow (RPF) by 123I-ortho-iodo-hippurate, basal and stimulated vascular renal indices, endothelium-dependent and -independent vasodilation using flow-mediated dilation (FMD) as well as metabolic and hormonal profile in morbid, otherwise healthy, obese subjects. RESULTS: Compared with mGFR, the better performing EstForm was CKD-EPI (5.3 ml/min/1.73 m2 bias by Bland-Altman analysis). mGFR was directly related with RPF, total and incremental glucose AUC, and inversely with PTH and h8 cortisol. Patients with mGFR below the median shown significantly higher PTH and lower vitamin D3. Basal or dynamic renal resistive index, FMD, pulse wave velocity were not related with mGFR. In an adjusted regression model, renal diameter and plasma flow remained related with mGFR (R2 = 0.67), accounting for 15% and 21% of mGFR variance, respectively. CONCLUSIONS: CKD-EPI formula should be preferred in morbid obesity; glucose increments during oral glucose tolerance test correlate with hyperfiltration; RPF and diameter are independent determinants of mGFR; slightly high PTH values, frequent in obesity, might influence mGFR.

Sentinel Lymph Node Biopsy in Cutaneous Melanoma: Standard and New Technical Procedures and Clinical Advances. A Systematic Review of the Literature.

Melanoma is an important public health problem, and its incidence is increasing worldwide. The disease status of regional lymph nodes is the most important prognostic factor in early-stage melanoma patients. Sentinel lymph node biopsy (SLNB) was introduced in the early 1990s as a less invasive procedure than complete lymph node dissection to allow histopathologic evaluation of the "sentinel lymph node" (SLN), which is the first node along the lymphatic pathway from a primary tumor. Sentinel lymph node biopsy has minimal complication risks compared with standard complete lymph node dissection. Currently, SLNB is the accepted method for staging patients with clinically node-negative cutaneous melanoma and provides the most powerful prognostic information by evaluating the nodal basin status. The current practice of SLNB consists of the injection of Tc-labeled radiopharmaceutical, preoperative lymphoscintigraphy with the possibility of using the SPECT/CT hybrid imaging, and intraoperative SLN localization using a handheld gamma probe with or without the use of blue dye. Recently, the SLN localization and detection have been enhanced with the use of new tracers and new intraoperative devices, which have demonstrated to be particularly useful in melanomas of the head and neck region and in area of complex anatomy. Despite these important advances in the technology and the increasing experience in SLN mapping, major research centers have reported a false-negative rate higher than 15%. This relatively high false-negative rate, greater than those reported in the initial validation studies, points out the importance for the nuclear medicine community to continuously improve their knowledge on the biological behavior of melanoma and to improve the technical aspects that may allow more precise staging. For the SLNB procedure to be accurate, it is of critical importance that all "true" SLNs are identified and removed for examination. The aim of this article is to provide general information about the SLNB procedure in clinical practice highlighting the importance of standardization and accuracy of SLN identification in the light of the most recent technical innovations.

The Value of Oro-Pharyngo-Esophageal Scintigraphy in the Management of Patients with Aspiration into the Tracheo-bronchial Tree and Consequent Dysphagia.

CONTEXT: Tracheo-bronchial aspiration is the most invalidating condition which can happen to patients affected by dysphagia, especially when caused by central neurologic disorders; the associated pneumonia episodes represent the most frequent cause of death in these patients. Oro-pharyngo-esophageal scintigraphy (OPES) allows both functional imaging and semiquantitative evaluation of the subsequent phases of swallowing. CASE REPORT: We evaluated by means of OPES a woman who had previously undergone high-dose external beam radiation therapy for a nasopharyngeal carcinoma, which determined tissue fibrosis and progressive dysphagia. CONCLUSION: In this patient with dysphagia, OPES was a simple, inexpensive, noninvasive, and reliable technique that allowed to show the presence of bolus aspiration and quantified tracheobronchial aspirate.

Dynamic 3D analysis of myocardial sympathetic innervation: an experimental study using 123I-MIBG and a CZT camera.

UNLABELLED: Data on the in vivo myocardial kinetics of (123)I-metaiodobenzylguanidine ((123)I-MIBG) are scarce and have always been obtained using planar acquisitions. To clarify the normal kinetics of (123)I-MIBG in vivo over time, we designed an experimental protocol using a 3-dimensional (3D) dynamic approach with a cadmium zinc telluride (CZT) camera. METHODS: We studied 6 anesthetized pigs (mean body weight, 37 ± 4 kg). Left ventricular myocardial perfusion and sympathetic innervation were assessed using (99m)Tc-tetrofosmin (26 ± 6 MBq), (123)I-MIBG (54 ± 14 MBq), and a CZT camera. A normal perfusion/function match on gated SPECT was the inclusion criterion. A dynamic acquisition in list mode started simultaneously with the bolus injection of (123)I-MIBG, and data were collected every 5 min for the first 20 min and then at acquisition steps of 30, 60, 90, and 120 min. Each step was reconstructed using dedicate software and reframed (60 s/frame). On the reconstructed transaxial slice that best showed the left ventricular cavity, regions of interest were drawn to obtain myocardial and blood pool activities. Myocardial time-activity curves were generated by interpolating data between contiguous acquisition steps, corrected for radiotracer decay and injected dose, and fitted to a bicompartmental model. Time to myocardial maximum signal intensity (MSI), MSI value, radiotracer retention index (RI, myocardial activity/blood pool integral), and washout rate were calculated. The mediastinal signal was measured and fitted to a linear model. RESULTS: The myocardial MSI of (123)I-MIBG was reached within 5.57 ± 4.23 min (range, 2-12 min). The mean MSI was 0.426% ± 0.092%. Myocardial RI decreased over time and reached point zero at 176 ± 31 min (range, 140-229 min). The ratio between myocardial and mediastinal signal at 15 and 125 min and extrapolated at 176 and 4 h was 5.45% ± 0.61%, 4.33% ± 1.23% (not statistically significant vs. 15 min), 3.95% ± 1.46% (P < 0.03 vs. 125 min), and 3.63% ± 1.64% (P < 0.03 vs. 176 min), respectively. Mean global washout rate at 125 min was 15% ± 14% (range, 0%-34%), and extrapolated data at 176 min and 4 h were 18% ± 18% (range, 0.49%-45%) and 25% ± 23% (range, 1.7%-56.2%; not statistically significant vs. 176 min), respectively. CONCLUSION: 3D dynamic analysis of (123)I-MIBG suggests that myocardial peak uptake is reached more quickly than previously described. Myocardial RI decreases over time and, on average, is null about 3 h after injection. The combination of an early peak and variations in delayed myocardial uptake could result in a wide physiologic range of washout rates. Mediastinal activity appears to be constant over time and significantly lower than previously described in planar studies, resulting in a higher heart-to-mediastinum ratio.

Sentinel lymph node mapping in melanoma: the issue of false-negative findings.

Management of cutaneous melanoma has changed after introduction in the clinical routine of sentinel lymph node biopsy (SLNB) for nodal staging. By defining the nodal basin status, SLNB provides a powerful prognostic information. Nevertheless, some debate still surrounds the accuracy of this procedure in terms of false-negative rate. Several large-scale studies have reported a relatively high false-negative rate (5.6%-21%), correctly defined as the proportion of false-negative results with respect to the total number of "actual" positive lymph nodes. In this review, we identified all the technical aspects that the nuclear medicine physician, the surgeon, and the pathologist should take into account to improve accuracy of the procedure and minimize the false-negative rate. In particular, SPECT/CT imaging detects more SLNs than those found by planar lymphoscintigraphy. Furthermore, the nuclear medicine community should reach a consensus on the radioactive counting rate threshold to better guide the surgeon in identifying the lymph nodes with the highest likelihood of housing metastases ("true biologic SLNs"). Analysis of the harvested SLNs by conventional techniques is also a further potential source for error. More accurate SLN analysis (eg, molecular analysis by reverse transcriptase-polymerase chain reaction) and more extensive SLN sampling identify more positive nodes, thus reducing the false-negative rate.The clinical factors identifying patients at higher-risk local recurrence after a negative SLNB include older age at diagnosis, deeper lesions, histological ulceration, and head-neck anatomic location of the primary lesion.The clinical impact of a false-negative SLNB on the prognosis of melanoma patients remains controversial, because the majority of studies have failed to demonstrate overall statistically significant disadvantage in melanoma-specific survival for false-negative SLNB patients compared with true-positive SLNB patients.When new more effective drugs will be available in the adjuvant setting for stage III melanoma patients, the implication of an accurate staging procedure for the sentinel lymph nodes will be crucial for both patients and clinicians. Standardization and accuracy of SLN identification, removal, and analysis are required.

Role of 18F-DOPA PET/CT in diagnosis and follow-up of adrenal and extra-adrenal paragangliomas.

PURPOSE: The objective of this study was to establish the clinical value of F-DOPA PET/CT in patients with adrenal and extra-adrenal paragangliomas (PGLs). METHODS: Twenty-six consecutive patients with suspected or recurrent PGL underwent MR (and/or CT) and F-DOPA PET/CT. Histopathology confirmation was obtained in 20 cases. Genetic analysis on known susceptibility genes for PGL (VHL, RET, SDHx, TMEM127) was available in 13 patients. RESULTS: Fourteen patients were affected by PGL (8 with head/neck location, 6 with abdominal/thoracic location), whereas 12 showed masses of other origin. Three patients proved to be SDHD, 1 SDHB, 2 SDHC, and 1 TMEM127 mutation carriers. F-DOPA PET/CT showed pathological uptake in 13 of 26 patients. The procedure identified all PGLs except one with bone metastases (previous malignant adrenal PGL). No uptake was found in patients without proven PGL. Thus, in the whole group, F-DOPA PET/CT sensitivity was 92.8%, and specificity was 100% with positive and negative predictive values of 100% and 92.3%, respectively. Total diagnostic accuracy was 96.2%. In the head/neck subgroup, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were 100%. In the abdominal location, sensitivity was 80% and specificity was 100%, and positive and negative predictive values were 100% and 91.7%, respectively. Abdominal diagnostic accuracy was 93.7%. Radiotracer uptake was superimposable in head/neck PGLs versus abdominal PGLs and in mutated versus wild-type patients. CONCLUSIONS: The high diagnostic performance of F-DOPA PET/CT showed this technique to be a useful tool in detecting PGLs, above all those located at the head/neck site, regardless of the genetic pattern.