Dedicated neck 18 F-FDG PET/CT: An additional tool for risk assessment in thyroid nodules at ultrasound intermediate risk.

BACKGROUND: Several ultrasound (US) risk stratification systems have been proposed for the assessment of thyroid nodules, and their performance was shown as good. However, the rate of nodules assessed at intermediate risk is not negligible and whether they should be submitted or not to further examination is still under debate. The present study aimed to evaluate the reliability of 18 F-FDG PET/CT in stratifying the risk of malignancy in these lesions. METHODS: Two institutions participated to this retrospective study in which a dedicated 18 F-FDG PET/CT was proposed to patients having a thyroid nodule with US assessment of EU-TIRADS 4 or 5. 18 F-FDG PET/CT did not influence the diagnostic and therapeutic decision. Histology was the gold standard for all patients. RESULTS: Ninety-three patients were included for the study with 48 EU-TIRADS 4 and 45 EU-TIRADS 5 nodules. Of these, 26 underwent thyroidectomy following FNAC suspicious for or consistent with malignancy, 38 for inconclusive cytology, 27 because of large goitre and 2 for high-risk lesion at US. At histology, 35 carcinomas and 58 benign lesions were found. Cancer prevalence was 16.7% in EU-TIRADS 4 and 60% in EU-TIRADS 5. Overall, 18 F-FDG PET/CT was positive in 33/35 cancers (94.5% sensitivity) and negative in 31/58 benign lesions (53.4% specificity). When considering only EU-TIRADS 4, 18 F-FDG PET/CT was positive in 7/8 cancers and negative in 20/40 benign lesions; among these, there were 36 cases with FNAC indication according to dimensional cut-off (ie >1.5 cm), and 18 F-FDG PET/CT showed 85.7% sensitivity and 41.4% specificity. CONCLUSIONS: 18 F-FDG PET/CT may have a role in stratifying the cancer risk of thyroid nodules with an intermediate ultrasound assessment. More specifically, thyroid lesions classified as EU-TIRADS 4 and with no 18 F-FDG uptake could be ruled out from further examination, similar to other anamnestic and clinical suspicious factors of patients. Further prospective and cost-effectiveness studies are needed.

Could short thyroid hormone withdrawal be an effective strategy for radioiodine remnant ablation in differentiated thyroid cancer patients?

PURPOSE: Current guidelines recommend thyroid hormone withdrawal (THW) of 3-4 weeks before radioiodine remnant ablation (RRA) of differentiated thyroid carcinoma (DTC). We aimed to evaluate (1) the reliability of a shorter THW (i.e., 14 days) to achieve adequate TSH levels (i.e., 30 mU/l), (2) the association between length of THW and response to therapy, and (3) the potential association between pre-ablation TSH levels and patients' outcome. METHODS: After thyroidectomy, all patients started LT4 therapy, which was subsequently discontinued in order to perform RRA. Patients were broken down into two groups according to the length of THW: group A, 2 weeks of THW, and group B, 3-4 weeks of THW. We used clinical, biochemical, and imaging data to evaluate patients' outcome. By means of univariate and multivariate analysis, including main DTC prognostic factors, we assessed the impact of THW length and TSH levels on patients' outcome. RESULTS: We evaluated 222 patients, 85 of whom were treated with RRA after a THW period of 2 weeks (group A). All other 137 patients underwent RRA after 3-4 weeks THW (group B). At the time of RRA all patients presented TSH levels ≥30 mU/l. After a median follow-up time of 3.4 years, we found 183 patients (82%) with excellent response to treatment and 39 patients (18%) showing incomplete response. Kaplan-Meier response to therapy curves showed that ablation-Tg, tumor size, and lymph node status were significantly associated with prognosis; no associations were found between THW length, TSH levels, and prognosis. Multivariate Cox model showed that only ablation-Tg was significantly associated with treatment response. CONCLUSIONS: Prior to RRA, a short 2-week THW is an effective method to stimulate TSH levels. No difference in terms of incomplete response to treatment was observed between DTC patients prepared for RRA with a short THW and those with the long THW.

Prognostic value of ¹8F-DOPA PET/CT at the time of recurrence in patients affected by neuroblastoma.

PURPOSE: The aim of this study was to investigate the relationship between (123)I-metaiodobenzylguanidine (MIBG) scan semi-quantification and a new (18)F-DOPA positron emission tomography (PET)/CT score in patients with suspected or documented neuroblastoma (NB) relapse and to assess the association between these two parameters and progression-free survival (PFS)/overall survival (OS). METHODS: We analysed 24 NB patients who had undergone (123)I-MIBG and (18)F-DOPA PET/CT scans at the time of suspected relapse, after applying a proper scoring system for each scan. In time-to-event analyses, the score distributions were regarded as continuous and were categorized in tertiles and medians. We used Kaplan-Meier curves and Cox proportional hazard models for PFS and OS in order to estimate the independent prognostic impact of (123)I-MIBG and (18)F-DOPA PET/CT scans. RESULTS: The (123)I-MIBG and (18)F-DOPA scores were highly and positively correlated (Spearman's rho = 0.8, p < 0.001). Over a median follow-up of 14 months (range 6-82), 12 cases of disease progression and 6 deaths occurred. Multivariate Cox models showed a higher risk of disease progression [hazard ratio (HR) 17.0, 95% confidence interval (CI) 2.7-109] in NB patients with (123)I-MIBG score > 3 (3rd tertile) and an even higher risk (HR:37.2, 95% CI 2.4-574) in those with (18)F-DOPA whole-body metabolic burden (WBMB) >7.5 (median), after adjustment for all main clinical/pathological factors considered. Kaplan-Meier analyses showed a significant association with OS (log-rank p = 0.01 and p = 0.03 for (123)I-MIBG and (18)F-DOPA WBMB, respectively). CONCLUSION: Our results confirm the good agreement between (18)F-DOPA PET/CT and (123)I-MIBG scan in patients affected by NB relapse. In time-to-event analyses, (123)I-MIBG scan and (18)F-DOPA PET/CT scores were independently and significantly associated with disease progression.

¹8F-FDG uptake as a prognostic variable in primary differentiated thyroid cancer incidentally detected by PET/CT: a multicentre study.

PURPOSE: Our aim was to investigate the association between (18)F-fluorodeoxyglucose (FDG) uptake and event-free survival in patients in whom a differentiated thyroid cancer (DTC) was detected by (18)F-FDG positron emission tomography (PET)/CT. METHODS: Among 884 focal (18)F-FDG PET thyroid incidentalomas referred to our 4 Nuclear Medicine Departments, we investigated 54 patients in whom a DTC was confirmed and a clinical follow-up was available. The ratio between maximum standardized uptake value (SUVmax) of DTC and SUVmean of the liver (SUV ratio) was recorded for each scan. All patients underwent total thyroidectomy and (131)I remnant ablation. After a median follow-up of 39 months we assessed the outcome. The association between disease persistence/progression, (18)F-FDG uptake and other risk factors (T, N, M and histological subtype) was evaluated through univariate and multivariate analyses. RESULTS: Of the 54 patients, 39 achieved complete remission. The remaining 15 showed persistence/progression of disease. High (18)F-FDG uptake, i.e. SUV ratio ≥3, showed a low positive predictive value (48 %). Low (18)F-FDG uptake (SUV ratio < 3) displayed a high negative predictive value (93 %). The median of SUV ratios in T1-T2 (2.2), in M0 (2.7) and in non-virulent subtypes (2.7) were significantly lower (p < 0.03) than in T3-T4 (5.0), M1 (7.3) and virulent subtypes (6.0). Kaplan-Maier analysis showed a significant association between high (18)F-FDG uptake and disease persistence/progression (p = 0.001). When we adjusted risk estimates by using a multivariate Cox model, only T (p = 0.05) remained independently associated with disease persistence/progression. CONCLUSION: An intense (18)F-FDG uptake of the primary DTC is associated with persistence/progression of disease. However, when all other prognostic factors have been taken into account, (18)F-FDG uptake does not add further prognostic information.

1,25-Dihydroxy vitamin D and coronary microvascular function.

PURPOSE: The active form of vitamin D (1,25(OH)(2)D) contributes to blood flow regulation in skeletal muscle. The aim of the present study was to determine whether this hormone also modulates coronary physiology, and thus whether abnormalities in its bioavailability contribute to excess cardiovascular risk in patients with disorders of mineral metabolism. METHODS: As a clinical model of the wide variability in 1,25(OH)(2)D bioavailability, we studied 23 patients (62 ± 8 years) with suspected primary hyperparathyroidism referred for myocardial perfusion imaging because of atypical chest pain and at least one cardiovascular risk factor. Dipyridamole and baseline myocardial blood flow indexes were assessed on G-SPECT imaging of (99m)Tc-tetrofosmin, with normalization of the myocardial count rate to the corresponding first-transit counts in the pulmonary artery. Coronary flow reserve (CFR) was defined as the ratio between dipyridamole and baseline myocardial blood flow indexes. In all patients, parathyroid hormone, 25-hydroxy vitamin D (25(OH)D) and 1,25(OH)(2)D serum levels were determined. RESULTS: Primary hyperparathyroidism was eventually diagnosed in 15 of the 23 patients. The mean 25(OH)D concentration was relatively low (21 ± 10 ng/mL) while the concentrations of 1,25(OH)(2)D varied widely but within the normal range (mean 95 ± 61 pmol/L). No patient showed reversible perfusion defects on G-SPECT. CFR was not correlated with either the serum concentration of 25(OH)D nor that of parathyroid hormone, but was strictly correlated with the serum level of 1,25(OH)(2)D (R = 0.8, p < 0.01). Moreover, patients with a 1,25(OH)(2)D concentration below the median value (86 pmol/L) had markedly lower CFR than the other patients (1.48 ± 0.40 vs. 2.51 ± 0.63, respectively; p < 0.001). CONCLUSION: Bioavailable 1,25(OH)(2)D modulates coronary microvascular function. This effect might contribute to the high cardiovascular risk of conditions characterized by chronic reduction in bioavailability of this hormone.

Automatic semi-quantification of [123I]FP-CIT SPECT scans in healthy volunteers using BasGan version 2: results from the ENC-DAT database.

PURPOSE: The aim of this study was to assess striatal dopamine transporter (DAT) availability in a large group of normal subjects. METHODS: The study included 122 healthy subjects, aged 18-83 years, recruited in the multicentre 'ENC-DAT' study (promoted by the European Association of Nuclear Medicine). Brain single photon emission computed tomography (SPECT) was acquired by means of dual-head cameras 3 h after [(123)I]FP-CIT administration. Specific to nondisplaceable binding ratios (SBRs) in the basal ganglia were computed using the 'BasGan' software, allowing automatic value extraction with partial volume effect correction. Multicentre camera inhomogeneity was taken into account by calibrating values on basal ganglia phantom data. SBR in each caudate nucleus (C) and putamen (P) were the dependent variables in a repeated measures general linear model analysis; age, gender, handedness and body mass index (BMI) were the independent variables. RESULTS: SBR values in C and P were significantly associated with age (mean rate decrease with age: 0.0306 per year, or 0.57 % of the general mean; p < 0.0001) and gender (women had higher values; p = 0.015), while no significant effect was found for handedness and BMI. A significant interaction was found between age and region (p < 0.0001) as the age-related decline was 0.028 for left C, 0.026 for right C and 0.034 for both P. P/C ratio analysis confirmed that age-related SBR decrease was stronger in P than in C (p < 0.0001). No significant effect was found for season or time of the day when the scan was acquired by analysing the residual of SBR values in C and P, after subtraction of age and gender effects. CONCLUSION: This study confirms the dependency of DAT on ageing and highlights the gender differences in a large sample of healthy subjects, while it does not support the dependency of DAT on BMI, handedness, circadian rhythm or season.

A Disseminated Mycobacterium Abscessus Infection in a Patient Affected by Pulmonary Graft versus Host Disease: Case Report with a Revision of Literature.

Mycobacterium abscessus complex, hereinafter Mab, is a taxonomic group of rapidly growing, nontuberculous mycobacteria (NTM). Despite major advances in understanding virulence, pathogenicity and mechanism of antibiotic resistance, Mab remains a significant cause of pulmonary and extra-pulmonary disease. Herein, we describe a disseminated, macrolide-resistant, Mab subspecies abscessus infection occurring in a severely immune-compromised 34-year-old allotransplanted female patient affected by pulmonary chronic graft versus host disease (cGVHD). The infection was characterized by hematogenous spread, and besides lungs, it involved skin, and soft tissues, resulting in a highly debilitating, painful, and finally fatal disease. Our case describes the severe impact of Mab infections in the setting of allogeneic hematopoietic stem cells transplant (alloHSCT) and related complications. It also highlights the unmet need of preventive and surveillance measures together with the urgency of developing effective vaccines and drugs against emerging NTM. The scarce literature regarding Mab infections in alloHSCT patients is also reviewed.

Role of 18F-Choline Positron Emission Tomography/Computed Tomography to Detect Structural Relapse in High-Risk Differentiated Thyroid Cancer Patients.

BACKGROUND: This study aimed to evaluate the role of 18F-choline (18F-FCH) positron emission tomography (PET)/computed tomography (CT) in high-risk differentiated thyroid cancer (DTC) patients with suspected relapse. It also compared 18F-FCH-PET/CT results with those of fludeoxyglucose (18F-FDG)-PET/CT and evaluated the additional diagnostic value and clinical impact of the combined use of these two tracers. Finally, it assessed the association between the clinical, biochemical, and histological parameters and 18F-FCH-PET/CT and 18F-FDG-PET/CT results. METHODS: The study prospectively enrolled high-risk DTC patients treated with thyroidectomy and radioactive iodine therapy and presenting high/increasing thyroglobulin levels under thyrotropin suppression, negative/inconclusive neck ultrasound, and negative 131I whole-body scan. All patients underwent 18F-FDG-PET/CT and 18F-FCH-PET/CT within 30 days of each other. Experienced nuclear medicine physicians examined the images of both procedures, and an integrated analysis of the two PET/CT modalities was also conducted. For each modality, a patient-based analysis (PBA) and lesion-based-analysis (LBA) was performed. On PBA, sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were calculated. On LBA, only sensitivity was calculated. The standard of reference was based on clinical, imaging, and histological data. RESULTS: Twenty-five high-risk DTC patients were included; DTC relapse/persistence was confirmed in 23 patients. On PBA, 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the integrated evaluation of the two imaging modalities showed the following rates: sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 69.6%, 100%, 22.2%, 100%, and 72% versus 56.5%, 100%, 16.7%, 100%, and 60% versus 82.6%, 100%, 33.3%, 100%, and 84%, respectively. When compared with 18F-FDG-PET/CT, the integrated analysis of these two imaging procedures changed the clinical management in 4/23 (17%) patients. On LBA, the sensitivity rates of 18F-FDG-PET/CT, 18F-FCH-PET/CT, and the combined evaluation of the two modalities were 58.7%, 38.1%, and 66.7%, respectively; when only lymph node involvement was considered, the rates were 56.3%, 53.1%, and 68.8%, respectively. Serum thyroglobulin doubling time (Tg-DT) <12 months was significantly associated with positive 18F-FCH-PET/CT. A trend toward a significant association was also found between positive 18F-FDG-PET/CT and both Tg-DT <12 months and DTC aggressive subtypes. CONCLUSION: 18F-FCH-PET/CT may add important information during the follow-up of high-risk DTC patients. 18F-FCH-PET/CT may be considered a useful complementary tool in patients affected by non-aggressive DTC subtypes, with Tg-DT <12 months, high risk of lymph node spreading, and negative or doubtful 18F-FDG-PET/CT.

Comparisons between glucose analogue 2-deoxy-2-((18)F)fluoro-D-glucose and (18)F-sodium fluoride positron emission tomography/computed tomography in breast cancer patients with bone lesions.

AIM: To compare 2-deoxy-2-((18)F)fluoro-D-glucose((18)F-FDG) and (18)F-sodium ((18)F-NaF) positron emission tomography/computed tomography (PET/CT) accuracy in breast cancer patients with clinically/radiologically suspected or known bone metastases. METHODS: A total of 45 consecutive patients with breast cancer and the presence or clinical/biochemical or radiological suspicion of bone metastatic disease underwent (18)F-FDG and (18)F-fluoride PET/CT. Imaging results were compared with histopathology when available, or clinical and radiological follow-up of at least 1 year. For each technique we calculated: Sensitivity (Se), specificity (Sp), overall accuracy, positive and negative predictive values, error rate, and Youden's index. McNemar's χ(2) test was used to test the difference in sensitivity and specificity between the two diagnostic methods. All analyses were computed on a patient basis, and then on a lesion basis, with consideration ofthe density of independent lesions on the co-registered CT (sclerotic, lytic, mixed, no-lesions) and the divergent site of disease (skull, spine, ribs, extremities, pelvis). The impact of adding (18)F-NaF PET/CT to the work-up of patients was also measured in terms of change in their management due to (18)F-NaF PET/CT findings. RESULTS: The two imaging methods of (18)F-FDG and (18)F-fluoride PET/CT were significantly different at the patient-based analysis: Accuracy was 86.7% and 84.4%, respectively (McNemar's χ(2) = 6.23, df = 1, P = 0.01). Overall, 244 bone lesions were detected in our analysis. The overall accuracy of the two methods was significantly different at lesion-based analysis (McNemar's χ(2) = 93.4, df = 1, P < 0.0001). In the lesion density-based and site-based analysis, (18)F-FDG PET/CT provided more accurate results in the detection of CT-negative metastasis (P < 0.002) and vertebral localizations (P < 0.002); (18)F-NaF PET/CT was more accurate in detecting sclerotic (P < 0.005) and rib lesions (P < 0.04). (18)F-NaF PET/CT led to a change of management in 3 of the 45 patients (6.6%) by revealing findings that were not detected at (18)F-FDG PET/CT. CONCLUSION: (18)F-FDG PET/CT is a reliable imaging tool in the detection of bone metastasis in most cases, with a diagnostic accuracy that is slightly, but significantly, superior to that of (18)F-NaF PET/CT in the general population of breast cancer patients. However, the extremely high sensitivity of (18)F-fluoride PET/CT can exploit its diagnostic potential in specific clinical settings (i.e., small CT-evident sclerotic lesions, high clinical suspicious of relapse, and negative (18)F-FDG PET and conventional imaging).

Association of Biomarkers with Serious Cardiac Adverse Events during Abiraterone Acetate Treatment in Castration Resistant Prostate Cancer.

BACKGROUND: Abiraterone acetate is an effective drug for castration-resistant prostate cancer, but cardiac serious adverse events (SAEs) may occur. We studied their association with N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin T (TnT) during abiraterone therapy. PATIENTS AND METHODS: In a single institution, 17 patients were treated with abiraterone acetate 1 g daily with concomitant prednisone and then switched to dexametasone plus canrenone. Blood samples for PSA, NT-proBNP, and TnT were obtained at baseline and after 1, 3, and 6 months. RESULTS: Five patients (29.4%) experienced G3 to 4 cardiac SAEs after a median of 13 weeks (range, 9-32), including pulmonary edema, heart failure, acute coronary syndrome, sinus bradycardia with syncope, and pulmonary edema. At baseline, 4 weeks, and 3 months, median NT-proBNP and TnT levels were higher in patients with subsequent cardiac SAEs (P= .03 and P= .04 for NT-proBNP and TnT at 3 months, respectively). After switching to dexametasone and introducing canrenone, no additional cardiac SAEs were noted. Overall response rate was 67%. CONCLUSIONS: Our study suggests a higher than expected risk of cardiac SAEs during abiraterone treatment which may well be due to the small sample size and the unrestricted entry criteria. However, baseline and frequent NT-proBNP and TnT monitoring predicted a higher risk for cardiac SAE. Larger studies should confirm our findings.

Papillary thyroid cancer in a struma ovarii: a report of a rare case.

After removal of an ovarian mass in a 43-year-old woman, a struma ovarii was diagnosed. Within this teratoma, a papillary thyroid cancer was found. The tumor was negative for BRAF, NRAS, KRAS, PIK3CA and c-KIT mutations on molecular analysis. Thyroid function and morphology were normal. Thyroidectomy, L-T4 TSH-suppressive therapy and rhTSH-induced radioiodine ablation were performed. So far, the follow-up has been favorable. This is the first case of thyroid cancer in a struma ovarii in which mutations of PIK3CA exons 9 and 20, and c-KIT exons 9, 11 and 13 have been evaluated and the third in which ablation has been performed under rhTSH. The prognosis of patients with thyroid cancer in a struma ovarii is generally poor. In our patient, as in those who undergo ablative radioactive iodine therapy, this was not the case.

Giant cell arteritis: a systematic review of the qualitative and semiquantitative methods to assess vasculitis with 18F-fluorodeoxyglucose positron emission tomography.

Giant cell arteritis (GCA) is the most common vasculitis affecting medium and large vessels. It shows a close clinical association with polymyalgia rheumatica (PMR), a musculoskeletal inflammatory disorder, which is clinically characterized by girdles pain and stiffness. 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) is an effective tool for the diagnosis, grading, and follow-up of patients affected by GCA involving the aorta and its proximal branches, but the lack of a standardized method for the assessment of vascular inflammation remains a critical issue, potentially leading to misclassification. In our systematic review, including 19 original articles for a total of 442 GCA patients (with or without PMR symptoms) and 535 healthy controls, we described the different qualitative, semiquantitative and combined methods that have been proposed throughout the literature for assessing the presence and grading the severity of GCA-related vascular inflammation on 18F-FDG PET scans, focusing on the diagnostic performance and examining their respective advantages and limitations. The majority of the included studies adopted qualitative methods of PET image analysis, which are less sensitive but more specific than semiquantitative ones. Among the semiquantitative approaches, the aortic-to-blood pool uptake ratio of the aortic arch seems to be the most accurate method.

Value of fused 18F-Choline-PET/MRI to evaluate prostate cancer relapse in patients showing biochemical recurrence after EBRT: preliminary results.

PURPOSE: We compared the accuracy of (18)F-Choline-PET/MRI with that of multiparametric MRI (mMRI), (18)F-Choline-PET/CT, (18)F-Fluoride-PET/CT, and contrast-enhanced CT (CeCT) in detecting relapse in patients with suspected relapse of prostate cancer (PC) after external beam radiotherapy (EBRT). We assessed the association between standard uptake value (SUV) and apparent diffusion coefficient (ADC). METHODS: We evaluated 21 patients with biochemical relapse after EBRT. Patients underwent (18)F-Choline-PET/contrast-enhanced (Ce)CT, (18)F-Fluoride-PET/CT, and mMRI. Imaging coregistration of PET and mMRI was performed. RESULTS: (18)F-Choline-PET/MRI was positive in 18/21 patients, with a detection rate (DR) of 86%. DRs of (18)F-Choline-PET/CT, CeCT, and mMRI were 76%, 43%, and 81%, respectively. In terms of DR the only significant difference was between (18)F-Choline-PET/MRI and CeCT. On lesion-based analysis, the accuracy of (18)F-Choline-PET/MRI, (18)F-Choline-PET/CT, CeCT, and mMRI was 99%, 95%, 70%, and 85%, respectively. Accuracy, sensitivity, and NPV of (18)F-Choline-PET/MRI were significantly higher than those of both mMRI and CeCT. On whole-body assessment of bone metastases, the sensitivity of (18)F-Choline-PET/CT and (18)F-Fluoride-PET/CT was significantly higher than that of CeCT. Regarding local and lymph node relapse, we found a significant inverse correlation between ADC and SUV-max. CONCLUSION: (18)F-Choline-PET/MRI is a promising technique in detecting PC relapse.

Metabolic networks underlying cognitive reserve in prodromal Alzheimer disease: a European Alzheimer disease consortium project.

UNLABELLED: This project aimed to investigate the metabolic basis for resilience to neurodegeneration (cognitive reserve) in highly educated patients with prodromal Alzheimer disease (AD). METHODS: Sixty-four patients with amnestic mild cognitive impairment who later converted to AD dementia during follow-up, and 90 controls, underwent brain (18)F-FDG PET. Both groups were divided into a poorly educated subgroup (42 controls and 36 prodromal AD patients) and a highly educated subgroup (48 controls and 28 prodromal AD patients). Brain metabolism was first compared between education-matched groups of patients and controls. Then, metabolism was compared between highly and poorly educated prodromal AD patients in both directions to identify regions of high education-related metabolic depression and compensation. The clusters of significant depression and compensation were further used as volumetric regions of interest (ROIs) in a brain interregional correlation analysis in each prodromal AD subgroup to explore metabolic connectivity. All analyses were performed by means of SPM8 (P < 0.001 uncorrected at peak level, P < 0.05 false discovery rate-corrected at cluster level; age, sex, Mini-Mental State Examination score, and center as nuisance). RESULTS: Highly educated prodromal AD patients showed more severe hypometabolism than poorly educated prodromal AD patients in the left inferior and middle temporal gyri and the left middle occipital gyrus (ROI depression). Conversely, they showed relative hypermetabolism in the right inferior, middle, and superior frontal gyri (ROI compensation). The sites of compensation, mainly corresponding to the right dorsolateral prefrontal cortex (DLFC), showed wide metabolic correlations with several cortical areas in both hemispheres (frontotemporal cortex, parahippocampal gyrus, and precuneus) in highly educated prodromal AD patients but not in poorly educated prodromal AD patients. To provide evidence on whether these metabolic correlations represent preservation of the physiologic networks of highly educated control subjects (neural reserve) or rather the recruitment of alternative networks (neural compensation), or a combination of the two, we performed metabolic connectivity analysis of the DLFC in highly educated controls as well. The correlation sites of right DLFC partly overlapped those of highly educated prodromal AD patients but were less extended. CONCLUSION: The present findings suggest that highly educated prodromal AD patients can cope better with the disease thanks to neural reserve but also to the recruitment of compensatory neural networks in which the right DLFC plays a key role.