Matteo Bauckneht

18F-NaF Uptake by Atherosclerotic Plaque on PET/CT Imaging: Inverse Correlation Between Calcification Density and Mineral Metabolic Activity

Several studies have highlighted the role of vascular 18F-NaF uptake as a marker of ongoing calcium deposition. However, accumulation of 18F-NaF is often inconsistent with localization of arterial plaque. Calcification activity and thus 18F-NaF uptake might prevail in the earlier plaque stages. To test this hypothesis, we evaluated 18F-NaF uptake in plaque of 3 different densities, using density as a marker of calcification progression. We also tested whether attenuation-weighted image reconstruction affects 18F-NaF uptake in the different plaque stages. Methods: Sixty-four oncologic patients (14 men and 50 women; mean age, 65.3 ± 8.2 y; range, 26–81 y) underwent 18F-NaF PET/CT. A volume of interest was drawn on each plaque within the infrarenal aorta to assess mean standardized uptake value and attenuation (in Hounsfield units [HU]). Plaque was then categorized as light (<210 HU), medium (211–510 HU), or heavy (>510 HU). Standardized uptake value was normalized for blood 18F-NaF activity to obtain the plaque target-to-background ratio (TBR). During this process, several focal, noncalcified areas of 18F-NaF were identified (hot spots). The TBR of the hot spots was computed after isocontour thresholding. The TBR of a noncalcified control region was also calculated. In 35 patients, the TBR of non–attenuation-corrected images was calculated. Results: The average TBR was highest in light plaque (2.21 ± 0.88), significantly lower in medium plaque (1.59 ± 0.63, P < 0.001), and lower still in heavy plaque (1.14 ± 0.37, P < 0.0001 with respect to both light and medium plaque). The TBR of the control region was not significantly different from that of heavy plaque but was significantly lower than that of light and medium plaque (P < 0.01). Hot spots had the highest absolute TBR (3.89 ± 1.87, P < 0.0001 vs. light plaque). TBRs originating from non–attenuation-corrected images did not significantly differ from those originating from attenuation-corrected images. Conclusion: Our results support the concept that 18F-NaF is a feasible option in imaging molecular calcium deposition in the early stages of plaque formation, when active uptake mechanisms are the main determinants of calcium presence, but that retention of 18F-NaF progressively decreases with increasing calcium deposition in the arterial wall. Our data suggest that non–attenuation-corrected reconstruction does not significantly affect evaluation of plaque of any thickness.

The vulnerable coronary plaque: update on imaging technologies

Several studies have been carried out on vulnerable plaque as the main culprit for ischaemic cardiac events. Historically, the most important diagnostic technique for studying coronary atherosclerotic disease was to determine the residual luminal diameter by angiographic measurement of the stenosis. However, it has become clear that vulnerable plaque rupture as well as thrombosis, rather than stenosis, triggers most acute ischaemic events and that the quantification of risk based merely on severity of the arterial stenosis is not sufficient. In the last decades, substantial progresses have been made on optimisation of techniques detecting the arterial wall morphology, plaque composition and inflammation. To date, the use of a single technique is not recommended to precisely identify the progression of the atherosclerotic process in human beings. In contrast, the integration of data that can be derived from multiple methods might improve our knowledge about plaque destabilisation. The aim of this narrative review is to update evidence on the accuracy of the currently available non-invasive and invasive imaging techniques in identifying components and morphologic characteristics associated with coronary plaque vulnerability.

Predicting the transition from normal aging to Alzheimer's disease: A statistical mechanistic evaluation of FDG-PET data.

The assessment of the degree of order of brain metabolism by means of a statistical mechanistic approach applied to FDG-PET, allowed us to characterize healthy subjects as well as patients with mild cognitive impairment and Alzheimers Disease (AD). The intensity signals from 24 volumes of interest were submitted to principal component analysis (PCA) giving rise to a major first principal component whose eigenvalue was a reliable cumulative index of order. This index linearly decreased from 77 to 44% going from normal aging to AD patients with intermediate conditions between these values (r=0.96, p<0.001). Bootstrap analysis confirmed the statistical significance of the results. The progressive detachment of different brain regions from the first component was assessed, allowing for a purely data driven reconstruction of already known maximally affected areas. We demonstrated for the first time the reliability of a single global index of order in discriminating groups of cognitively impaired patients with different clinical outcome. The second relevant finding was the identification of clusters of regions relevant to AD pathology progressively separating from the first principal component through different stages of cognitive impairment, including patients cognitively impaired but not converted to AD. This paved the way to the quantitative assessment of the functional networking status in individual patients.

Evaluation of response to immune checkpoint inhibitors: Is there a role for positron emission tomography?

Strategies targeting intracellular negative regulators such as immune checkpoint inhibitors (ICPIs) have demonstrated significant antitumor activity across a wide range of solid tumors. In the clinical practice, the radiological effect of immunotherapeutic agents has raised several more relevant and complex challenges for the determination of their imaging-based response at single patient level. Accordingly, it has been suggested that the conventional Response Evaluation Criteria in Solid Tumors assessment alone, based on dimensional evaluation provided by computed tomography (CT), tends to underestimate the benefit of ICPIs at least in a subset of patients, supporting the need of immune-related response criteria. Different from CT, very few data are available for the evaluation of immunotherapy by means of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET). Moreover, since the antineoplastic activity of ICPIs is highly related to the activation of T cells against cancer cells, FDG accumulation might cause false-positive findings. Yet, discrimination between benign and malignant processes represents a huge challenge for FDG-PET in this clinical setting. Consequently, it might be of high interest to test the complex and variegated response to ICPIs by means of PET and thus it is worthwhile to ask if a similar introduction of immune-related PET-based criteria could be proposed in the future. Finally, PET might offer a new insight into the biology and pathophysiology of ICPIs thanks to a growing number of non-invasive immune-diagnostic approaches based on non-FDG tracers.

Progressive disgregation of brain networking from normal aging to Alzheimer’s Disease. Independent Component Analysis on FDG-PET data

Brain connectivity has been assessed in several neurodegenerative disorders investigating the mutual correlations between predetermined regions or nodes. Selective breakdown of brain networks during progression from normal aging to Alzheimer disease dementia (AD) has also been observed. Methods: We implemented independent-component analysis of 18F-FDG PET data in 5 groups of subjects with cognitive states ranging from normal aging to AD—including mild cognitive impairment (MCI) not converting or converting to AD—to disclose the spatial distribution of the independent components in each cognitive state and their accuracy in discriminating the groups. Results: We could identify spatially distinct independent components in each group, with generation of local circuits increasing proportionally to the severity of the disease. AD-specific independent components first appeared in the late-MCI stage and could discriminate converting MCI and AD from nonconverting MCI with an accuracy of 83.5%. Progressive disintegration of the intrinsic networks from normal aging to MCI to AD was inversely proportional to the conversion time. Conclusion: Independent-component analysis of 18F-FDG PET data showed a gradual disruption of functional brain connectivity with progression of cognitive decline in AD. This information might be useful as a prognostic aid for individual patients and as a surrogate biomarker in intervention trials.

Doxorubicin effect on myocardial metabolism as a prerequisite for subsequent development of cardiac toxicity: A translational18F-FDG PET/CT observation

The present translational study aimed to verify whether serial 18F-FDG PET/CT predicts doxorubicin cardiotoxicity. Methods: Fifteen athymic mice were treated intravenously with saline (n = 5) or with 5 or 7.5 mg of doxorubicin per kilogram (n = 5 each) and underwent dynamic small-animal PET beforehand and afterward to estimate left ventricular (LV) metabolic rate of glucose (MRGlu). Thereafter, we retrospectively identified 69 patients who had been successfully treated with a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine for Hodgkin disease (HD) and had undergone 4 consecutive 18F-FDG PET/CT scans. Volumes of interest were drawn on LV myocardium to quantify mean SUV. All patients were subsequently interviewed by telephone (median follow-up, 30 mo); 36 of them agreed to undergo electrocardiography and transthoracic echocardiography. Results: In mice, LV MRGlu was 17.9 ± 4.4 nmol × min−1 × g−1 at baseline. Doxorubicin selectively and dose-dependently increased this value in the standard-dose (27.9 ± 9 nmol × min−1 × g−1, P < 0.05 vs. controls) and high-dose subgroups (37.2 ± 7.8 nmol × min−1 × g−1, P < 0.01 vs. controls, P < 0.05 vs. standard-dose). In HD patients, LV SUV showed a progressive increase during doxorubicin treatment that persisted at follow-up. New-onset cardiac abnormalities appeared in 11 of 36 patients (31%). In these subjects, pretherapy LV SUV was markedly lower with respect to the remaining patients (1.53 ± 0.9 vs. 3.34 ± 2.54, respectively, P < 0.01). Multivariate analysis confirmed the predictive value of baseline LV SUV for subsequent cardiac abnormalities. Conclusion: Doxorubicin dose-dependently increases LV MRGlu, particularly in the presence of low baseline 18F-FDG uptake. These results imply that low myocardial 18F-FDG uptake before the initiation of doxorubicin chemotherapy in HD patients may predict the development of chemotherapy-induced cardiotoxicity, suggesting that prospective clinical trials are warranted to test this hypothesis.

Functional Activation of Osteoclast Commitment in Chronic Lymphocytic Leukaemia: A Possible Role for RANK/RANKL Pathway

Skeletal erosion has been found to represent an independent prognostic indicator in patients with advanced stages of chronic lymphocytic leukaemia (CLL). Whether this phenomenon also occurs in early CLL phases and its underlying mechanisms have yet to be fully elucidated. In this study, we prospectively enrolled 36 consecutive treatment-naïve patients to analyse skeletal structure and bone marrow distribution using a computational approach to PET/CT images. This evaluation was combined with the analysis of RANK/RANKL loop activation in the leukemic clone, given recent reports on its role in CLL progression. Bone erosion was particularly evident in long bone shafts, progressively increased from Binet stage A to Binet stage C, and was correlated with both local expansion of metabolically active bone marrow documented by FDG uptake and with the number of RANKL + cells present in the circulating blood. In immune-deficient NOD/Shi-scid, γcnull (NSG) mice, administration of CLL cells caused an appreciable compact bone erosion that was prevented by Denosumab. CLL cell proliferation in vitro correlated with RANK expression and was impaired by Denosumab-mediated disruption of the RANK/RANKL loop. This study suggests an interaction between CLL cells and stromal elements able to simultaneously impair bone structure and increase proliferating potential of leukemic clone.

Amyloid positron emission tomography and cognitive reserve.

Alzheimers disease (AD) is characterized by a non-linear progressive course and several aspects influence the relationship between cerebral amount of AD pathology and the clinical expression of the disease. Brain cognitive reserve (CR) refers to the hypothesized capacity of an adult brain to cope with brain damage in order to minimize symptomatology. CR phenomenon contributed to explain the disjunction between the degree of neurodegeneration and the clinical phenotype of AD. The possibility to track brain amyloidosis (Aβ) in vivo has huge relevance for AD diagnosis and new therapeutic approaches. The clinical repercussions of positron emission tomography (PET)-assessed Aβ load are certainly mediated by CR thus potentially hampering the prognostic meaning of amyloid PET in selected groups of patients. Similarly, amyloid PET and cerebrospinal fluid amyloidosis biomarkers have recently provided new evidence for CR. The present review discusses the concept of CR in the framework of available neuroimaging studies and specifically deals with the reciprocal influences between amyloid PET and CR in AD patients and with the potential consequent interventional strategies for AD.

New Tracers and New Perspectives for Molecular Imaging in Lewy Body Diseases

The term Lewy body diseases (LBDs) refers to a subset of neurodegenerative disorders that share the accumulation of the so-called Lewy bodies (LB) including: Parkinsons disease (PD), dementia with Lewy bodies (DLB), and PD later characterized by the occurrence of dementia (PDD). Moreover, multiple system atrophy (MSA) and idiopatic Rem Sleeping behaviour disorders (RBD) complete the group of synucleinopathies and have also common symptoms with respect to LBDs. The clinical diagnosis of LBDs can be challenging for physicians, particularly in the early stages of disease. Given the growing number of individuals affected by these neurodegenerative disorders, early and accurate diagnosis can lead to improved clinical management of patients. For this reason, information obtained from molecular imaging biomarkers is playing an increasingly important role in this framework. The present narrative review discusses both established milestones and new evidence on the use of molecular imaging tracers already part of the clinical practice as well as available evidence on new molecular imaging approaches in PD, PDD and DLB.

Acute myocardial infarction in pregnancy

Acute myocardial infarction is a rare but potential life-threatening complication of pregnancy. Its incidence is increasing because of the enlargement of the reproductive age. Treatment needs to be urgent because of the very high mortality rate. The aim of this literature review is to provide a better understanding of the available diagnostic modalities and interventional and pharmacological treatment options in the management of pregnant patients with acute myocardial infarction in order to improve the overall care provision and ensure both maternal and fetal well-being.