18F-FDG PET can effectively rule out conversion to dementia and the presence of CSF biomarker of neurodegeneration: a real-world data analysis.

BACKGROUND: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology. METHODS: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535-62.) data from the National Alzheimer Bank (NAB), and (Davis M, O`Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777-88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels. RESULTS: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers. CONCLUSION: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term. TRIAL REGISTRATION: Clinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered.

177Lu-labeled somatostatin receptor targeted radionuclide therapy dosimetry in meningioma: a systematic review.

INTRODUCTION: Few therapeutic options are currently available for refractory meningiomas. Encouraging results have been reported for 177Lu-labeled somatostatin receptor-targeted radiopeptide therapy (SSTR-RT). The current therapeutic scheme is based on the fixed doses that are recommended for neuroendocrine tumor treatment. However, in personalized medicine, tumor dosimetry can be determined from repeat 177Lu scintigraphy. The aim of this review was to report on the methods used for calculating the tumor absorbed dose (AD) in meningioma patients treated with 177Lu-SSTR-RT and their values. EVIDENCE ACQUISITION: The search was performed in Medline, Embase and the Cochrane Library until March 1st, 2024 to retrieve papers related to the topic. The following terms were used for searching: (meningioma) AND ((sstr) OR (receptors somatostatin) OR (somatostatin) OR (octreotide)) AND ((PRRT) OR (radionuclide therapy) OR (dotatate) OR (dotatoc) OR (177Lu-DOTATOC) OR (177Lu-DOTATATE) OR (radiopeptide)). EVIDENCE SYNTHESIS: Seven articles (including 46 patients and 108 cycles of treatment) reporting on tumor AD during 177Lu-SSTR-RT were included in the analysis. The methods of acquisition, reconstruction parameters and postimage processing to determine tumor AD were very heterogeneous among the studies. The meningioma AD associated with the agonist 177Lu-SSTR-RT reported in the majority of studies ranged from 0.1-1.5 Gy/GBq, which was lower than that reported for neuroendocrine tumors (1.3-22.9 Gy/GBq). CONCLUSIONS: The tumor AD that was reported during treatment with 177Lu-SSTR-RT in refractory meningioma patients is generally low. Harmonization of the methodology for dosimetry calculations is needed to compare the different reported values and optimize treatment at the individual level.

Metabolic brain connectivity reorganization in Alzheimer's disease patients: a systematic review.

INTRODUCTION: Metabolic connectivity has been studied in various neurodegenerative diseases, particularly Alzheimer's disease (AD), but there is a wealth of accumulated evidence and sometimes conflicting results, depending on the methodology applied. Therefore, the aim of this systematic review was to summarize the results obtained regarding metabolic brain connectivity using [18F]-FDG-PET in AD patients compared to cognitively normal subjects. EVIDENCE ACQUISITION: A systematic and exhaustive search of data available in the literature was carried out by querying the PubMed and Web of Science databases. Studies had to meet the following criteria: 1) a metabolic connectivity study with [18F]-FDG-PET in AD patients; 2) the inclusion of a control group of healthy subjects or cognitively normal controls; and 3) use of seed-based, independent/principal component analyses or methods derived from graph theory. This systematic review followed the PRISMA method. EVIDENCE SYNTHESIS: A total of 49 full-text publications were included, involving 3589 AD patients, 3272 prodromal AD patients and 3898 cognitively normal subjects. These results show that AD patients have a reorganization of metabolic connectivity on a global scale, with a decrease in or even the loss of networks seen in the healthy brain and an increase in more local, less efficient connectivity. This reorganization affects not only areas commonly affected in AD but also remote regions known to be usually spared in this pathology. CONCLUSIONS: Changes in metabolic connectivity in AD patients do not simply constitute a decrease in global connectivity but rather more complex local and global changes ultimately affecting all brain regions.

Joint EANM/EANO/RANO/SNMMI practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor ligands: version 1.0.

PURPOSE: To provide practice guideline/procedure standards for diagnostics and therapy (theranostics) of meningiomas using radiolabeled somatostatin receptor (SSTR) ligands. METHODS: This joint practice guideline/procedure standard was collaboratively developed by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the PET task force of the Response Assessment in Neurooncology Working Group (PET/RANO). RESULTS: Positron emission tomography (PET) using somatostatin receptor (SSTR) ligands can detect meningioma tissue with high sensitivity and specificity and may provide clinically relevant information beyond that obtained from structural magnetic resonance imaging (MRI) or computed tomography (CT) imaging alone. SSTR-directed PET imaging can be particularly useful for differential diagnosis, delineation of meningioma extent, detection of osseous involvement, and the differentiation between posttherapeutic scar tissue and tumour recurrence. Moreover, SSTR-peptide receptor radionuclide therapy (PRRT) is an emerging investigational treatment approach for meningioma. CONCLUSION: These practice guidelines will define procedure standards for the application of PET imaging in patients with meningiomas and related SSTR-targeted PRRTs in routine practice and clinical trials and will help to harmonize data acquisition and interpretation across centers, facilitate comparability of studies, and to collect larger databases. The current document provides additional information to the evidence-based recommendations from the PET/RANO Working Group regarding the utilization of PET imaging in meningiomas Galldiks (Neuro Oncol. 2017;19(12):1576-87). The information provided should be considered in the context of local conditions and regulations.

Amino-acid PET as a prognostic tool after post Stupp protocol temozolomide therapy in high-grade glioma patients.

PURPOSE: This study aimed to evaluate the prognostic performance of amino-acid PET in high-grade gliomas (HGG) patients at the time of temozolomide (TMZ) treatment discontinuation, after the Stupp protocol. METHODS: The analysis included consecutive HGG patients with dynamic [18F]FDOPA PET imaging within 3 months of the end of TMZ therapy, post-Stupp protocol. Static and dynamic PET parameters, responses to RANO criteria for MRI and clinical and histo-molecular factors were correlated to progression-free (PFS). RESULTS: Thirty-two patients (59.4 [54.0;67.6] years old, 13 (41%) women) were included. Static PET parameters peak tumor-to-background ratio and metabolic tumor volume (respective thresholds of 1.9 and 1.5 mL) showed the best 84% accuracies for predicting PFS at 6 months (p = 0.02). These static PET parameters were also independent predictor of PFS in multivariate analysis (p ≤ 0.05). CONCLUSION: In HGG patients having undergone a Stupp protocol, the absence of significant PET uptake after TMZ constitutes a favorable prognostic factor.

The role of [18 F]FDOPA PET as an adjunct to conventional MRI in the diagnosis of aggressive glial lesions.

BACKGROUND: Amino acid PET is recommended for the initial diagnosis of brain lesions, but its value for identifying aggressive lesions remains to be established. The current study therefore evaluates the added-value of dynamic [18 F]FDOPA PET as an adjunct to conventional MRI for determining the aggressiveness of presumed glial lesions at diagnosis. METHODS: Consecutive patients, with a minimal 1 year-follow-up, underwent contrast-enhanced MRI (CE MRI) and dynamic [18 F]FDOPA PET to characterize their suspected glial lesion. Lesions were classified semi-automatically by their CE MRI (MRI-/+), and PET parameters (static tumor-to-background ratio, TBR; dynamic time-to-peak ratio, TTPratio). Diagnostic accuracies of MRI and PET parameters for the differentiation of tumor aggressiveness were evaluated by chi-square test or receiver operating characteristic analyses. Aggressive lesions were either defined as lesions with dismal molecular characteristics based on the WHO 2021 classification of brain tumors or with compatible clinico-radiological profiles. Time-to-treatment failure (TTF) and overall survival (OS) were evaluated. RESULTS: Of the 109 patients included, 46 had aggressive lesions (45 confirmed by histo-molecular analyses). CE MRI identified aggressive lesions with an accuracy of 73%. TBRmax (threshold of 3.2), and TTPratio (threshold of 5.4 min) respectively identified aggressive lesions with an accuracy of 83% and 76% and were independent of CE MRI and clinical factors in the multivariate analysis. Among the MRI-lesions, 11/56 (20%) were aggressive and respectively 55% and 50% of these aggressive lesions showed high TBRmax and short TTPratio in PET. High TBRmax and short TTPratio in PET were significantly associated to poorer survivals (p ≤ 0.009). CONCLUSION: Dynamic [18 F]FDOPA PET provides a similar diagnostic accuracy as contrast enhancement in MRI to identify the aggressiveness of suspected glial lesions at diagnosis. Both methods, however, are complementary and [18 F]FDOPA PET may be a useful additional tool in equivocal cases.

Application of PET imaging delta radiomics for predicting progression-free survival in rare high-grade glioma.

This study assesses the feasibility of using a sample-efficient model to investigate radiomics changes over time for predicting progression-free survival in rare diseases. Eighteen high-grade glioma patients underwent two L-3,4-dihydroxy-6-[18F]-fluoro-phenylalanine positron emission tomography (PET) dynamic scans: the first during treatment and the second at temozolomide chemotherapy discontinuation. Radiomics features from static/dynamic parametric images, alongside conventional features, were extracted. After excluding highly correlated features, 16 different models were trained by combining various feature selection methods and time-to-event survival algorithms. Performance was assessed using cross-validation. To evaluate model robustness, an additional dataset including 35 patients with a single PET scan at therapy discontinuation was used. Model performance was compared with a strategy extracting informative features from the set of 35 patients and applying them to the 18 patients with 2 PET scans. Delta-absolute radiomics achieved the highest performance when the pipeline was directly applied to the 18-patient subset (support vector machine (SVM) and recursive feature elimination (RFE): C-index = 0.783 [0.744-0.818]). This result remained consistent when transferring informative features from 35 patients (SVM + RFE: C-index = 0.751 [0.716-0.784], p = 0.06). In addition, it significantly outperformed delta-absolute conventional (C-index = 0.584 [0.548-0.620], p < 0.001) and single-time-point radiomics features (C-index = 0.546 [0.512-0.580], p < 0.001), highlighting the considerable potential of delta radiomics in rare cancer cohorts.

Assessment of a one-week ketogenic diet on brain glycolytic metabolism and on the status epilepticus stage of a lithium-pilocarpine rat model.

The ketogenic diet (KD) has been shown to be effective in refractory epilepsy after long-term administration. However, its interference with short-term brain metabolism and its involvement in the early process leading to epilepsy remain poorly understood. This study aimed to assess the effect of a short-term ketogenic diet on cerebral glucose metabolic changes, before and after status epilepticus (SE) in rats, by using [18F]-FDG PET. Thirty-nine rats were subjected to a one-week KD (KD-rats, n = 24) or to a standard diet (SD-rats, n = 15) before the induction of a status epilepticus (SE) by lithium-pilocarpine administrations. Brain [18F]-FDG PET scans were performed before and 4 h after this induction. Morphological MRIs were acquired and used to spatially normalize the PET images which were then analyzed voxel-wisely using a statistical parametric-based method. Twenty-six rats were analyzed (KD-rats, n = 15; SD-rats, n = 11). The 7 days of the KD were associated with significant increases in the plasma ß-hydroxybutyrate level, but with an unchanged glycemia. The PET images, recorded after the KD and before SE induction, showed an increased metabolism within sites involved in the appetitive behaviors: hypothalamic areas and periaqueductal gray, whereas no area of decreased metabolism was observed. At the 4th hour following the SE induction, large metabolism increases were observed in the KD- and SD-rats in areas known to be involved in the epileptogenesis process late-i.e., the hippocampus, parahippocampic, thalamic and hypothalamic areas, the periaqueductal gray, and the limbic structures (and in the motor cortex for the KD-rats only). However, no statistically significant difference was observed when comparing SD and KD groups at the 4th hour following the SE induction. A one-week ketogenic diet does not prevent the status epilepticus (SE) and associated metabolic brain abnormalities in the lithium-pilocarpine rat model. Further explorations are needed to determine whether a significant prevention could be achieved by more prolonged ketogenic diets and by testing this diet in less severe experimental models, and moreover, to analyze the diet effects on the later and chronic stages leading to epileptogenesis.

EANM practice guidelines for an appropriate use of PET and SPECT for patients with epilepsy.

Epilepsy is one of the most frequent neurological conditions with an estimated prevalence of more than 50 million people worldwide and an annual incidence of two million. Although pharmacotherapy with anti-seizure medication (ASM) is the treatment of choice, ~30% of patients with epilepsy do not respond to ASM and become drug resistant. Focal epilepsy is the most frequent form of epilepsy. In patients with drug-resistant focal epilepsy, epilepsy surgery is a treatment option depending on the localisation of the seizure focus for seizure relief or seizure freedom with consecutive improvement in quality of life. Beside examinations such as scalp video/electroencephalography (EEG) telemetry, structural, and functional magnetic resonance imaging (MRI), which are primary standard tools for the diagnostic work-up and therapy management of epilepsy patients, molecular neuroimaging using different radiopharmaceuticals with single-photon emission computed tomography (SPECT) and positron emission tomography (PET) influences and impacts on therapy decisions. To date, there are no literature-based praxis recommendations for the use of Nuclear Medicine (NM) imaging procedures in epilepsy. The aims of these guidelines are to assist in understanding the role and challenges of radiotracer imaging for epilepsy; to provide practical information for performing different molecular imaging procedures for epilepsy; and to provide an algorithm for selecting the most appropriate imaging procedures in specific clinical situations based on current literature. These guidelines are written and authorized by the European Association of Nuclear Medicine (EANM) to promote optimal epilepsy imaging, especially in the presurgical setting in children, adolescents, and adults with focal epilepsy. They will assist NM healthcare professionals and also specialists such as Neurologists, Neurophysiologists, Neurosurgeons, Psychiatrists, Psychologists, and others involved in epilepsy management in the detection and interpretation of epileptic seizure onset zone (SOZ) for further treatment decision. The information provided should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals and imaging modalities.

PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group.

Response Assessment in Neuro-Oncology (RANO) response criteria have been established and were updated in 2023 for MRI-based response evaluation of diffuse gliomas in clinical trials. In addition, PET-based imaging with amino acid tracers is increasingly considered for disease monitoring in both clinical practice and clinical trials. So far, a standardised framework defining timepoints for baseline and follow-up investigations and response evaluation criteria for PET imaging of diffuse gliomas has not been established. Therefore, in this Policy Review, we propose a set of criteria for response assessment based on amino acid PET imaging in clinical trials enrolling participants with diffuse gliomas as defined in the 2021 WHO classification of tumours of the central nervous system. These proposed PET RANO criteria provide a conceptual framework that facilitates the structured implementation of PET imaging into clinical research and, ultimately, clinical routine. To this end, the PET RANO 1.0 criteria are intended to encourage specific investigations of amino acid PET imaging of gliomas.

Theranostics in Neurooncology: Heading Toward New Horizons.

Therapeutic approaches to brain tumors remain a challenge, with considerable limitations regarding delivery of drugs. There has been renewed and increasing interest in translating the popular theranostic approach well known from prostate and neuroendocrine cancer to neurooncology. Although far from perfect, some of these approaches show encouraging preliminary results, such as for meningioma and leptomeningeal spread of certain pediatric brain tumors. In brain metastases and gliomas, clinical results have failed to impress. Perspectives on these theranostic approaches regarding meningiomas, brain metastases, gliomas, and common pediatric brain tumors will be discussed. For each tumor entity, the general context, an overview of the literature, and future perspectives will be provided. Ongoing studies will be discussed in the supplemental materials. As most theranostic agents are unlikely to cross the blood-brain barrier, the delivery of these agents will be dependent on the successful development and clinical implementation of techniques enhancing permeability and retention. Moreover, the international community should strive toward sufficiently large and randomized studies to generate high-level evidence on theranostic approaches with radioligand therapies for central nervous system tumors.

Ultra-fast whole-body bone tomoscintigraphies achieved with a high-sensitivity 360° CZT camera and a dedicated deep-learning noise reduction algorithm.

This study aimed to determine whether the whole-body bone Single Photon Emission Computed Tomography (SPECT) recording times of around 10 min, routinely provided by a high-sensitivity 360° cadmium and zinc telluride (CZT) camera, can be further reduced by a deep-learning noise reduction (DLNR) algorithm. METHODS: DLNR was applied on whole-body images recorded after the injection of 545 ± 33 MBq of [99mTc]Tc-HDP in 19 patients (14 with bone metastasis) and reconstructed with 100%, 90%, 80%, 70%, 60%, 50%, 40%, and 30% of the original SPECT recording times. RESULTS: Irrespective of recording time, DLNR enhanced the contrast-to-noise ratios and slightly decreased the standardized uptake values of bone lesions. Except in one markedly obese patient, the quality of DLNR processed images remained good-to-excellent down to 60% of the recording time, corresponding to around 6 min SPECT-recording. CONCLUSION: Ultra-fast SPECT recordings of 6 min can be achieved when DLNR is applied on whole-body bone 360° CZT-SPECT.

Effects of medication on dopamine transporter imaging using [123I]I-FP-CIT SPECT in routine practice.

PURPOSE: Dopamine transporter (DAT) imaging is used to support the diagnosis of neurodegenerative parkinsonian disorders. Specific medications have been reported to confound the interpretation of [123I]I-FP-CIT SPECT scans, but there is limited data. The aim of the current study is to identify potential medication effects on the interpretation of [123I]I-FP-CIT SPECT scans in routine practice. MATERIALS AND METHODS: Consecutive patients undergoing a [123I]I-FP-CIT SPECT/CT scan on a 360° CZT camera between September 2019 and December 2022 were included. An exhaustive review of patient medications (antidepressants, antipsychotics, anti-epileptics, anti-parkinsonians, benzodiazepines, lithium, opioids, and stimulants) was performed. Two experienced nuclear physicians, blinded to the medication reports, interpreted the [123I]I-FP-CIT SPECT scans visually and a semi-quantitative analysis was performed using a local normal database. RESULTS: The study included 305 patients (71.0 ± 10.4, 135 women) and 145 (47.5%) visually interpreted normal scans. In normal scans, the striatum/occiput radioligand uptake ratio was decreased by noradrenergic and specific serotonergic antidepressants (NASSAs) (n = 15, z-score of - 0.93) and opioid medication (tramadol, n = 6, z-score of - 0.85) and was associated with a younger age in the multivariate analysis. In the overall population, the striatum/occiput ratio was influenced by NASSAs and associated with consensual visual analysis, age, sex, and anti-parkinsonian medications related to the status of the disease. CONCLUSION: Our study confirms the potential impact of antidepressant (NASSA) and opioid (tramadol) medications on the semi-quantitative analysis of [123I]I-FP-CIT SPECT scans. However, when performing a visual analysis, only NASSAs significantly impacted the interpretation of [123I]I-FP-CIT SPECT scans.

Volume of the proximal half of the thoracic aorta is the most comprehensive FDG-PET/CT indicator of arterial aging throughout adulthood.

INTRODUCTION: 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) and computed tomography (CT) features of the proximal and more elastic half of the thoracic aorta are known to correlate with aorta stiffness in older populations. This prospective study aimed to analyze the changes in these FDG-PET/CT features between young, middle-aged, and older adults, and investigate associations with arterial stiffness and blood pressure (BP). METHODS: Young (< 40 years), middle-aged (40-to-60 years), and older (> 60 years) adults, who underwent an FDG-PET/CT, were prospectively recruited. FDG-PET/CT features of the proximal half of the thoracic aorta were analyzed relative to the age categories, BP and carotid-femoral pulse wave velocity (PWV), a reference indicator of aorta stiffness. RESULTS: We included 79 patients (38 women; 22 young, 19 middle-aged, and 38 older adults). An increase in age category was associated with increases in mean standardized uptake values (SUVs) of blood and aorta and most significantly in aorta SUV heterogeneity, represented by SUV standard deviation (SUV-SD), aorta calcification volume, and the aorta volume indexed to body surface area. However, this indexed aorta volume was the sole variable: (i) exhibiting a stepwise increase from young (median: 25 cm3/m2 [interquartile range: 20-28 cm3/m2]), to middle-aged (41 [30-48] cm3/m2, p < 0.001 vs. Young), and older (62 [44-70] cm3/m2, p < 0.001 vs. middle-age) adults, and (ii) selected in the multivariate predictions of systolic, diastolic, and pulse BP. Indexed aorta volume was also a multivariate predictor of PWV but in association with SUV-SD and hypertension. CONCLUSION: In a population of patients referred to an FDG-PET/CT investigation, the indexed volume of the proximal and more elastic half of the thoracic aorta is the most comprehensive indicator of arterial aging. This imaging parameter exhibits a stepwise increase from young to middle-aged and older adults, is strongly linked to inter-individual changes in both arterial stiffness and BP, and thus, could help assess the early phases of arterial aging. Trial registration ClinicalTrial.gov, NCT03345290. Registered 17 November 2017, https://clinicaltrials.gov/ct2/show/NCT03345290?term=NCT03345290&draw=2&rank=1.