Positron emission computed tomography targeting urokinase plasminogen activator receptor (uPAR) in cancer: a systematic review.

INTRODUCTION: To provide an overview of the available literature data on clinical applications of positron emission tomography (PET) targeting the urokinase-type plasminogen activator receptor in oncology. METHODS: A literature search was conducted in PubMed, Web of Science and Scopus databases up to June 2023. The results were presented according to the PRISMA guidelines. The quality of the studies was assessed using the Critical Appraisal Skill Program checklist. RESULTS: Seven papers were selected for final analysis, involving 266 patients with solid tumors who underwent PET with uPAR-ligands. Thematic areas identified include feasibility studies (n = 2) on the safety, pharmacokinetics, and dosimetry of uPAR-targeting radiopharmaceuticals; uPAR-directed imaging in head and neck cancer (n = 2); uPAR PET in prostate cancer (n = 2); and the investigation of uPAR in neuroendocrine neoplasms (n = 1). Six of the seven studies used the radiopharmaceutical [68Ga]Ga-NOTA-AE105 while one study used [64Cu]Cu-DOTA-AE105. The studies showed protocol homogeneity, with static PET imaging at 20 minutes. The quality assessment revealed limitations such as small cohorts and the fact that all studies were performed by a single research group. CONCLUSIONS: uPAR-PET appears to be a promising imaging tool in well-selected oncological settings, but it needs to be validated by multicentre collaboration.

Functional Imaging in Musculoskeletal Disorders in Menopause.

Menopause-related musculoskeletal (MSK) disorders include osteoporosis, osteoarthritis (OA), sarcopenia and sarco-obesity. This review focuses on the applications of nuclear medicine for the functional imaging of the aforementioned clinical conditions. Bone Scan (BS) with 99mTc-labeled phosphonates, alone or in combination with MRI, can identify "fresh" vertebral collapse due to age-associated osteoporosis and provides quantitative parameters characterized by a good correlation with radiological indices in patients with OA. 18F-NaF PET, particularly when performed by dynamic scan, has given encouraging results for measuring bone turnover in osteoporosis and allows the evaluation of subchondral bone metabolic activity in OA. FDG PET can help discriminate between pathological and nonpathological vertebral fractures, especially by applying appropriate SUV-based thresholds. In OA, it can effectively image inflamed joints and support appropriate clinical management. Preliminary evidences suggest a possible application of FDG in sarco-obesity for the detection and quantification of visceral adipose tissue (VAT). Further studies are needed to better define the role of nuclear medicine in menopause-related MSK disease, especially as regards the possible impact of new radiopharmaceuticals (ie, FAPI and RGD peptides) and recent technological advances (eg, total-body PET/CT scanners).

Sleep Dysregulation Is Associated with 18F-FDG PET and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease.

Background: Sleep impairment has been commonly reported in Alzheimer's disease (AD) patients. The association between sleep dysregulation and AD biomarkers has been separately explored in mild cognitive impairment (MCI) and AD patients. Objective: The present study investigated cerebrospinal-fluid (CSF) and 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) biomarkers in MCI and AD patients in order to explore their association with sleep parameters measured with polysomnography (PSG). Methods: MCI and AD patients underwent PSG, 18F-FDG-PET, and CSF analysis for detecting and correlating these biomarkers with sleep architecture. Results: Thirty-five patients were included in the study (9 MCI and 26 AD patients). 18F-FDG uptake in left Brodmann area 31 (owing to the posterior cingulate cortex) correlated negatively with REM sleep latency (p = 0.013) and positively with REM sleep (p = 0.033). 18F-FDG uptake in the hippocampus was negatively associated with sleep onset latency (p = 0.041). Higher CSF orexin levels were associated with higher sleep onset latency (p = 0.042), Non-REM stage 1 of sleep (p = 0.031), wake after sleep onset (p = 0.028), and lower sleep efficiency (p = 0.045). CSF levels of Aß42 correlated negatively with the wake bouts index (p = 0.002). CSF total-tau and phosphorylated tau levels correlated positively with total sleep time (p = 0.045) and time in bed (p = 0.031), respectively. Conclusion: Sleep impairment, namely sleep fragmentation, REM sleep dysregulation, and difficulty in initiating sleep correlates with AD biomarkers, suggesting an effect of sleep on the pathological processes in different AD stages. Targeting sleep for counteracting the AD pathological processes represents a timely need for clinicians and researchers.

Radiological findings in Erdheim Chester disease: A very rare multisistemic disease.

Erdheim-Chester disease is an uncommon non-Langerhans cell histiocytosis affecting multiple systems. There is limited knowledge on the imaging capabilities of this disease. We present an extremely rare case of Erdheim-Chester illness in a 67-year-old man with multisystem involvement, including the cardiovascular system, skeleton, retroperitoneum (renal and adrenal infiltration) and the neurologic system. The involvement of the various organs was thoroughly assessed using multimodal imaging modalities such as computed tomography, magnetic resonance imaging, positron emission tomography and bone scintigraphy. Erdheim-Chester illness was revealed by a bone biopsy. Especially when there is cardiac and cerebral involvement, Erdheim-Chester illness is a rare condition with a poor prognosis. Knowing the imaging characteristics of Erdheim-Chester disease may be helpful in understanding the radiological results of many organs affected by the disease as described and discussed in the current case report.

PET Criteria by Cancer Type from Imaging Interpretation to Treatment Response Assessment: Beyond FDG PET Score.

BACKGROUND: in recent years, the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) has emerged as a reliable diagnostic tool in a wide variety of pathological conditions. This review aims to collect and review PET criteria developed for interpretation and treatment response assessment in cases of non-[18F]fluorodeoxyglucose ([18F]FDG) imaging in oncology. METHODS: A wide literature search of the PubMed/MEDLINE, Scopus and Google Scholar databases was made to find relevant published articles about non-[18F]FDG PET response criteria. RESULTS: The comprehensive computer literature search revealed 183 articles. On reviewing the titles and abstracts, 149 articles were excluded because the reported data were not within the field of interest. Finally, 34 articles were selected and retrieved in full-text versions. CONCLUSIONS: available criteria are a promising tool for the interpretation of non-FDG PET scans, but also to assess the response to therapy and therefore to predict the prognosis. However, oriented clinical trials are needed to clearly evaluate their impact on patient management.

Functional Correlates of Microglial and Astrocytic Activity in Symptomatic Sporadic Alzheimer's Disease: A CSF/18F-FDG-PET Study.

Glial and microglial cells contribute to brain glucose consumption and could actively participate in shaping patterns of brain hypometabolism. Here, we aimed to investigate the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and markers of microglial and astrocytic activity in a cohort of patients with Alzheimer's Disease (AD). We dosed cerebrospinal fluid (CSF) levels of soluble Triggering Receptor Expressed on Myeloid cells (sTREM2), Glial Fibrillary Acidic Protein (GFAP), a marker of reactive astrogliosis, and ß-S100, a calcium-binding protein associated with a neurotoxic astrocytic profile. No associations were found between sTREM-2 and 18F-FDG uptake. Instead, 18F-FDG uptake was associated negatively with CSF ß-S100 in the left supramarginal gyrus, inferior parietal lobe and middle temporal gyrus (Brodmann Areas (BA) 21 and 40). Increased ß-S100 levels could negatively regulate neuronal activity in the temporo-parietal cortex to prevent damage associated with AD hyperactivity, or rather they could reflect neurotoxic astrocytic activation contributing to AD progression in key strategic areas. We also identified a trend of positive association of 18F-FDG uptake with CSF GFAP in the right fronto-medial and precentral gyri (BA 6, 9 and 11), which has been reported in early AD and could either be persisting as an epiphenomenon tied to disease progression or be specifically aimed at preserving functions in the frontal cortex. Overall, CSF markers of astrogliosis seem to correlate with cortical glucose uptake in symptomatic sporadic AD, highlighting the role of astrocytes in shaping regional hypometabolism and possibly clinical presentation.

Functional Correlates of Striatal Dopamine Transporter Cerebrospinal Fluid Levels in Alzheimer's Disease: A Preliminary 18F-FDG PET/CT Study.

The aim of our study was to investigate regional glucose metabolism with 18F-FDG positron emission tomography/computed tomography in a population of patients with Alzheimer's disease (AD) in relation to cerebrospinal (CSF) levels of striatal dopamine transporter (DAT). All patients underwent lumbar puncture and received a biomarker-based diagnosis of AD. Differences in regional brain glucose metabolism were assessed by Statistical Parametric Mapping version 12 with the use of age, gender, and MMSE as covariates in the analysis. A positive correlation between CSF DAT levels and glucose metabolism at the level of two brain areas involved in the pathophysiological process of Alzheimer's disease, the substantia nigra and the posterior cingulate gyrus, has been highlighted. Results indicate that patients with higher CSF DAT levels have a better metabolic pattern in two key zones, suggesting less advanced disease status in patients with more conserved dopaminergic systems.

Derivation and Validation of a Phenoconversion-Related Pattern in Idiopathic Rapid Eye Movement Behavior Disorder.

BACKGROUND: Idiopathic rapid eye movement sleep behavior disorder (iRBD) represents the prodromal stage of α-synucleinopathies. Reliable biomarkers are needed to predict phenoconversion. OBJECTIVE: The aim was to derive and validate a brain glucose metabolism pattern related to phenoconversion in iRBD (iRBDconvRP) using spatial covariance analysis (Scaled Subprofile Model and Principal Component Analysis [SSM-PCA]). METHODS: Seventy-six consecutive iRBD patients (70 ± 6 years, 15 women) were enrolled in two centers and prospectively evaluated to assess phenoconversion (30 converters, 73 ± 6 years, 14 Parkinson's disease and 16 dementia with Lewy bodies, follow-up time: 21 ± 14 months; 46 nonconverters, 69 ± 6 years, follow-up time: 33 ± 19 months). All patients underwent [18 F]FDG-PET (18 F-fluorodeoxyglucose positron emitting tomography) to investigate brain glucose metabolism at baseline. SSM-PCA was applied to obtain the iRBDconvRP; nonconverter patients were considered as the reference group. Survival analysis and Cox regression were applied to explore prediction power. RESULTS: First, we derived and validated two distinct center-specific iRBDconvRP that were comparable and significantly able to predict phenoconversion. Then, SSM-PCA was applied to the whole set, identifying the iRBDconvRP. The iRBDconvRP included positive voxel weights in cerebellum; brainstem; anterior cingulate cortex; lentiform nucleus; and middle, mesial temporal, and postcentral areas. Negative voxel weights were found in posterior cingulate, precuneus, middle frontal gyrus, and parietal areas. Receiver operating characteristic analysis showed an area under the curve of 0.85 (sensitivity: 87%, specificity: 72%), discriminating converters from nonconverters. The iRBDconvRP significantly predicted phenoconversion (hazard ratio: 7.42, 95% confidence interval: 2.6-21.4). CONCLUSIONS: We derived and validated an iRBDconvRP to efficiently discriminate converter from nonconverter iRBD patients. [18 F]FDG-PET pattern analysis has potential as a phenoconversion biomarker in iRBD patients. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Neuropsychiatric, neuropsychological, and neuroimaging features in isolated REM sleep behavior disorder: The importance of MCI.

BACKGROUND: Mild cognitive impairment (MCI) is frequently diagnosed in patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), although the extent of MCI-associated neuropathology has not yet been quantified. The present study compared the differences in neuropsychiatric, neuropsychological, and neuroimaging markers of neurodegeneration in MCI-iRBD and iRBD patients with normal cognition. METHODS: Sixty-one patients with iRBD were included in the study: 30 patients were included in the MCI subgroup (RBD-MCI) and 31 in the normal cognition subgroup (RBD-NC). Both groups underwent neuropsychiatric and neuropsychological assessments to evaluate psychopathological symptoms and neuropsychological functions. Brain [18F]FDG PET and 123I-FP-CIT-SPECT were performed to evaluate brain glucose metabolism and nigrostriatal dopaminergic function in convenient subgroups of patients, respectively. RESULTS: Neuropsychological measures generally confirmed overall cognitive decline in patients with iRBD-MCI. Immediate long-term verbal memory and visuospatial functions, as well as attentional-executive impairment were evident in the MCI group compared to the NC group. Neuroimaging results indicated reduced brain glucose uptake in the bilateral posterior cingulate cortex and more evident nigrostriatal deafferentation in the RBD-MCI group. There were no differences in psychopathological symptoms between the two groups. CONCLUSIONS: This study confirmed that iRBD patients with MCI had a more impaired cognitive status that those with NC. Moreover, the MCI subgroup presented reduced cerebral glucose consumption in brain areas critical for cognition, and a more severe deafferentation of the nigro-striatal regions, highlighting the importance of identifying iRBD patients with MCI for urgent neuroprotective trials.

18F-FDG PET, cognitive functioning, and CSF biomarkers in patients with obstructive sleep apnoea before and after continuous positive airway pressure treatment.

INTRODUCTION: Dysregulation of cerebral glucose consumption, alterations in cerebrospinal fluid (CSF) biomarkers, and cognitive impairment have been reported in patients with obstructive sleep apnoea (OSA). On these bases, OSA has been considered a risk factor for Alzheimer's disease (AD). This study aimed to measure cognitive performance, CSF biomarkers, and cerebral glucose consumption in OSA patients and to evaluate the effects of continuous positive airway pressure (CPAP) treatment on these biomarkers over a 12-month period. METHODS: Thirty-four OSA patients and 34 controls underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), cognitive evaluation, and CSF analysis. A subgroup of 12 OSA patients treated with beneficial CPAP and performing the 12-month follow-up was included in the longitudinal analysis, and cognitive evaluation and 18F-FDG PET were repeated. RESULTS: Significantly reduced glucose consumption was observed in the bilateral praecuneus, posterior cingulate cortex, and frontal areas in OSA patients than controls. At baseline, OSA patients also showed lower ß-amyloid42 and higher phosphorylated-tau CSF levels than controls. Increased total tau and phosphorylated tau levels correlated with a reduction in brain glucose consumption in a cluster of different brain areas. In the longitudinal analysis, OSA patients showed an improvement in cognition and a global increase in cerebral 18F-FDG uptake. CONCLUSIONS: Cognitive impairment, reduced cerebral glucose consumption, and alterations in CSF biomarkers were observed in OSA patients, which may reinforce the hypothesis of AD neurodegenerative processes triggered by OSA. Notably, cognition and brain glucose consumption improved after beneficial CPAP treatment. Further studies are needed to evaluate the long-term effects of CPAP treatment on these AD biomarkers.

Nocturnal Hypoxia and Sleep Fragmentation May Drive Neurodegenerative Processes: The Compared Effects of Obstructive Sleep Apnea Syndrome and Periodic Limb Movement Disorder on Alzheimer's Disease Biomarkers.

BACKGROUND: Sleep disorders may cause dysregulation in cerebral glucose metabolism and synaptic functions, as well as alterations in cerebrospinal fluid (CSF) biomarker levels. OBJECTIVE: This study aimed at measuring sleep, CSF Alzheimer's disease (AD) biomarkers, and cerebral glucose consumption in patients with obstructive sleep apnea syndrome (OSAS) and patients with periodic limb movement disorder (PLMD), compared to controls. METHODS: OSAS and PLMD patients underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET), polysomnographic monitoring, and lumbar puncture to quantify CSF levels of amyloid-ß42 (Aß42), total tau, and phosphorylated tau. All patients were compared to controls, who were not affected by sleep or neurodegenerative disorders. RESULTS: Twenty OSAS patients, 12 PLMD patients, and 15 controls were included. Sleep quality and sleep structure were altered in both OSAS and PLMD patients when compared to controls. OSAS and PLMD patients showed lower CSF Aß42 levels than controls. OSAS patients showed a significant increase in glucose uptake in a wide cluster of temporal-frontal areas and cerebellum, as well as a reduced glucose consumption in temporal-parietal regions compared to controls. PLMD patients showed increased brain glucose consumption in the left parahippocampal gyrus and left caudate than controls. CONCLUSION: Sleep dysregulation and nocturnal hypoxia present in OSAS patients, more than sleep fragmentation in PLMD patients, were associated with the alteration in CSF and 18F-FDG PET AD biomarkers, namely reduction of CSF Aß42 levels and cerebral glucose metabolism dysregulation mainly in temporal areas, thus highlighting the possible role of sleep disorders in driving neurodegenerative processes typical of AD pathology.

Tau Biomarkers in Dementia: Positron Emission Tomography Radiopharmaceuticals in Tauopathy Assessment and Future Perspective.

Abnormal accumulation of Tau protein is closely associated with neurodegeneration and cognitive impairment and it is a biomarker of neurodegeneration in the dementia field, especially in Alzheimer's disease (AD); therefore, it is crucial to be able to assess the Tau deposits in vivo. Beyond the fluid biomarkers of tauopathy described in this review in relationship with the brain glucose metabolic patterns, this review aims to focus on tauopathy assessment by using Tau PET imaging. In recent years, several first-generation Tau PET tracers have been developed and applied in the dementia field. Common limitations of first-generation tracers include off-target binding and subcortical white-matter uptake; therefore, several institutions are working on developing second-generation Tau tracers. The increasing knowledge about the distribution of first- and second-generation Tau PET tracers in the brain may support physicians with Tau PET data interpretation, both in the research and in the clinical field, but an updated description of differences in distribution patterns among different Tau tracers, and in different clinical conditions, has not been reported yet. We provide an overview of first- and second-generation tracers used in ongoing clinical trials, also describing the differences and the properties of novel tracers, with a special focus on the distribution patterns of different Tau tracers. We also describe the distribution patterns of Tau tracers in AD, in atypical AD, and further neurodegenerative diseases in the dementia field.