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Background Peptide receptor radionuclide therapy (PRRT) is one of the most promising therapeutic strategies in neuroendocrine neoplasms (NENs). Nevertheless, its role in certain tumor sites remains unclear. This study sought to elucidate the efficacy and safety of [177Lu]Lu-DOTATATE in NENs with different locations and evaluate the effect of the tumor origin, bearing in mind other prognostic variables. Advanced NENs overexpressing somatostatin receptors (SSTRs) on functional imaging, of any grade or location, treated at 24 centers were enrolled. The protocol consisted of four cycles of 177Lu-DOTATATE 7.4 GBq iv every 8 weeks (NCT04949282). Results The sample comprised 522 subjects with pancreatic (35%), midgut (28%), bronchopulmonary (11%), pheochromocytoma/ paraganglioma (PPGL) (6%), other gastroenteropancreatic (GEP) (11%), and other non-gastroenteropancreatic (NGEP) (9%) NENs. The best RECIST 1.1 responses were complete response, 0.7%; partial response, 33.2%; stable disease, 52.1%; and tumor progression, 14%, with activity conditioned by the tumor subtype, but with benefit in all strata. Median progression-free survival (PFS) was 31.3 months (95% CI, 25.7–not reached [NR]) in midgut, 30.6 months (14.4-NR) in PPGL, 24.3 months (18.0-NR) in other GEP, 20.5 months (11.8-NR) in other NGEP, 19.8 months (16.8–28.1) in pancreatic, and 17.6 months (14.4–33.1) in bronchopulmonary NENs. [177Lu]Lu-DOTATATE exhibited scant severe toxicity. Conclusion This study confirms the efficacy and safety of [177Lu]Lu-DOTATATE in a wide range of SSTR-expressing NENs, regardless of location, with clinical benefit and superimposable survival outcomes between pNENs and other GEP and NGEP tumor subtypes different from midgut NENs.

Background and purpose: Although sporadic Creutzfeldt–Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored. Methods: We explored 2-[$^{18}$F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods. Results: The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005 receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90–0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization. Conclusions: The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.

It remains unclear whether the supportive imaging features described in the diagnostic criteria for progressive supranuclear palsy (PSP) are suitable for the full clinical spectrum. The aim of the current study was to define and cross-validate the pattern of glucose metabolism in the brain associated with a diagnosis of different PSP variants. A retrospective multicenter cohort study performed on 73 PSP patients who were referred for a fluorodeoxyglucose positron emission tomography PET scan: PSP-Richardson's syndrome, n = 47; PSP-parkinsonian variant, n = 18; and progressive gait freezing, n = 8. In addition, we included 55 healthy controls and 58 Parkinson's disease (PD) patients. Scans were normalized by global mean activity. We analyzed the regional differences in metabolism between the groups. Moreover, we applied a multivariate analysis to obtain a PSP-related pattern that was cross-validated in independent populations at the individual level. Group analysis showed relative hypometabolism in the midbrain, basal ganglia, thalamus, and frontoinsular cortices and hypermetabolism in the cerebellum and sensorimotor cortices in PSP patients compared with healthy controls and PD patients, the latter with more severe involvement in the basal ganglia and occipital cortices. The PSP-related pattern obtained confirmed the regions described above. At the individual level, the PSP-related pattern showed optimal diagnostic accuracy to distinguish between PSP and healthy controls (sensitivity, 80.4%; specificity, 96.9%)s and between PSP and PD (sensitivity, 80.4%; specificity, 90.7%). Moreover, PSP-Richardson's syndrome and PSP-parkinsonian variant patients showed significantly more PSP-related pattern expression than PD patients and healthy controls. The glucose metabolism assessed by fluorodeoxyglucose PET is a useful and reproducible supportive diagnostic tool for PSP-Richardson's syndrome and PSP-parkinsonian variant. © 2020 International Parkinson and Movement Disorder Society.

Objective A differential diagnosis of thyrotoxicosis is crucial as the treatment of the main causes of this condition can vary significantly. Recently published diagnostic guidelines on thyrotoxicosis embrace the presence of thyrotropin receptor (TSH-R) antibodies (TRAb) as the primary and most important diagnostic step. The application of diagnostic algorithms to aid in the treatment of hyperthyroidism supports using thyroid radionuclide scintigraphy (TRSt) in baffling clinical scenarios, when TRAb are absent or when third-generation TRAb are not available. First-generation TRAb measurement may have limitations. Consequently, patients with thyrotoxicosis and first-generation TRAb results may be misdiagnosed and consequently improperly treated. Our purpose was to compare first-generation TRAb values to TRSt in the differential diagnosis of hyperthyroidism. Methods We conducted a retrospective study of 201 untreated outpatients with overt or subclinical hyperthyroidism on whom first-generation TRAb and TRSt had been performed at the time of diagnosis. Histological specimens were analysed in patients who had previously undergone thyroid surgery at our centre. SPSS 20.0 was used in statistical analysis. Results Seventy-three out of 201 (36.3%) patients had positive TRAb. A diffuse uptake was present in 83.5% (61/73), whereas 13.7% (10/73) had a heterogeneous uptake and 2.7% (2/73) had an absent uptake. Thirty out of 91 (33%) patients with diffuse uptake were negative for positive TRAb and were diagnosed with Graves' disease. Analysis of 37 histological specimens indicated that TRSt had greater accuracy (81% vs 75.7%) and specificity (79.2% vs 57.1%) when compared to TRAb in the differential diagnosis of thyrotoxicosis. However, TRSt sensitivity was inferior to TRAb (84.6% vs 92.3%). Conclusions Our study endorses that initial differential diagnosis of thyrotoxicosis should not be based solely on first-generation TRAb as this approach may leave nearly 20% of the patients misdiagnosed and, consequently, improperly treated. Our results underscore that thyroid scintigraphy should also be performed when only first-generation TRAb assays are available during the initial differential diagnosis of thyrotoxicosis.

We aim to present and critically evaluate the use of FDG-PET in the differential diagnosis between dementing conditions including Alzheimer disease (AD), frontotemporal dementia (FTD) and its variants, vascular dementia (VaD) and pseudodepressive dementia. This review is based on the available consensus recommendations for the use of FDG-PET and current clinical diagnostic criteria. In addition, we updated these reviews with relevant publications in the field after conducting a literature search during the last 5 years through predefined keyword strings relating to the specific terms related to the diseases covered in this review and a common part (‘FDG-PET’). Neurodegenerative disease are complex groups of several forms of dementia and their clinical diagnostic criteria are progressively incorporating imaging biomarkers as a supporting tool. The role of FDG-PET is currently increasing as part of the clinical practice supporting the clinical diagnosis of AD (at both mild cognitive impairment—MCI—and early dementia stages), FTD and its variants, as well as VaD and pseudodepressive dementia. The pattern of AD is well defined and its negative predicted value may help the differential diagnosis when comorbidities like vascular disease or depression are present. However, the formal evidence supporting the use of FDG-PET is reasonable for MCI due to AD, and the differential diagnosis between FTD and AD, but lacking for the remaining clinical uses. Interestingly, the evidence provided during the last years reinforces these recommendations and gives additional clues about the usefulness of semiquantitative methods in addition to visual reading. The large experience accumulated using FDG-PET for the differential diagnosis of the main conditions with dementia has been translated into more formal evidence to support its clinical use. Although FDG-PET form currently part of the clinical practice in many countries, there is still a lack of studies using standardized analysis that confirm specific patterns at individual level.

Resumen Un inicio temprano de la inmunoterapia es fundamental para mejorar el pronostico de los pacientes con encefalitis aguda de origen autoinmune (EAI). Se ha propuesto un nuevo abordaje clinico para el diagnostico temprano basado en aspectos clinicos y pruebas complementarias, pero estas pueden tener una sensibilidad limitada principalmente en las primeras semanas. Mientras que las formas mas comunes de EAI (anti-LGI-1 y anti-NMDAR), muestran frecuentemente patrones de PET con 18Fluor-fluordeoxiglucosa (PET-FDG) consistentes, las anti-Caspr2 son menos frecuentes y los patrones de PET-FDG no estan establecidos. En nuestra experiencia la PET-FDG en la EAI anti-Caspr2 presenta un hipermetabolismo temporal medial y un deficit difuso cortical, incluso con pruebas complementarias negativas. No obstante, es necesaria la estandarizacion del analisis de las imagenes PET mediante metodos basados en voxeles con comparacion con bases de datos de normalidad para definir con claridad las areas de metabolismo alterado que pueden pasar desapercibidas al analisis visual.

Early immunotherapy is of paramount importance for a positive outcome in patients suffering acute encephalitis of autoimmune origin (AIE). A new approach for early diagnosis based on clinical presentation and complementary tests has been proposed, but not all these tests show positive findings in the first weeks. While common forms of AIE (anti-LGI-1 and anti-NMDAR antibodies) exhibit consistent 18Fluor-fluorodeoxiglucose (FDG-PET) patterns in many cases, the anti-Caspr2 form of AIE is infrequent and FDG-PET patterns have not been well characterized. In our experience, FDG-PET in anti-Caspr2 limbic encephalitis shows medial temporal hypermetabolism and diffuse cortical hypometabolism, even in the absence of findings in these tests. However, it is necessary to standardize PET image analysis by means of visual and voxel-based methods compared to normal databases to define the areas of pathological metabolism that may go unnoticed when using visual analysis exclusively.

BackgroundTo facilitate population screening and clinical trials of disease-modifying therapies for Alzheimer’s disease, supportive biomarker information is necessary. This study was aimed to investigate the association of plasma amyloid-beta (Aβ) levels with the presence of pathological accumulation of Aβ in the brain measured by amyloid-PET. Both plasma Aβ42/40 ratio alone or combined with an FDG-PET-based biomarker of neurodegeneration were assessed as potential AD biomarkers.MethodsWe included 39 cognitively normal subjects and 20 patients with mild cognitive impairment from the AB255 Study who had undergone PiB-PET scans. Total Aβ40 and Aβ42 levels in plasma (TP42/40) were quantified using ABtest kits. Subjects were dichotomized as Aβ-PET positive or negative, and the ability of TP42/40 to detect Aβ-PET positivity was assessed by logistic regression and receiver operating characteristic analyses. Combination of plasma Aβ biomarkers and FDG-PET was further assessed as an improvement for brain amyloidosis detection and diagnosis classification.ResultsEighteen (30.5%) subjects were Aβ-PET positive. TP42/40 ratio alone identified Aβ-PET status with an area under the curve (AUC) of 0.881 (95% confidence interval [CI] = 0.779–0.982). Discriminating performance of TP42/40 to detect Aβ-PET-positive subjects yielded sensitivity and specificity values at Youden’s cutoff of 77.8% and 87.5%, respectively, with a positive predictive value of 0.732 and negative predictive value of 0.900. All these parameters improved after adjusting the model for significant covariates. Applying TP42/40 as the first screening tool in a sequential diagnostic work-up would reduce the number of Aβ-PET scans by 64%. Combination of both FDG-PET scores and plasma Aβ biomarkers was found to be the most accurate Aβ-PET predictor, with an AUC of 0.965 (95% CI = 0.913–0.100).ConclusionsPlasma TP42/40 ratio showed a relevant and significant potential as a screening tool to identify brain Aβ positivity in preclinical and prodromal stages of Alzheimer’s disease.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and18F-fluorodeoxyglucose (18F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and18F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.

Purpose This joint practice guideline or procedure standard was developed collaboratively by the European Association of Nuclear Medicine (EANM) and the Society of Nuclear Medicine and Molecular Imaging (SNMMI). The goal of this guideline is to assist nuclear medicine practitioners in recommending, performing, interpreting, and reporting the results of dopaminergic imaging in parkinsonian syndromes. Methods Currently nuclear medicine investigations can assess both presynaptic and postsynaptic function of dopaminergic synapses. To date both EANM and SNMMI have published procedural guidelines for dopamine transporter imaging with single photon emission computed tomography (SPECT) (in 2009 and 2011, respectively). An EANM guideline for D2 SPECT imaging is also available (2009). Since the publication of these previous guidelines, new lines of evidence have been made available on semiquantification, harmonization, comparison with normal datasets, and longitudinal analyses of dopamine transporter imaging with SPECT. Similarly, details on acquisition protocols and simplified quantification methods are now available for dopamine transporter imaging with PET, including recently developed fluorinated tracers. Finally, [18F]fluorodopa PET is now used in some centers for the differential diagnosis of parkinsonism, although procedural guidelines aiming to define standard procedures for [18F]fluorodopa imaging in this setting are still lacking. Conclusion All these emerging issues are addressed in the present procedural guidelines for dopaminergic imaging in parkinsonian syndromes.

Brain positron emission tomography imaging with 18Fluorine-fluorodeoxyglucose (FDG-PET) has demonstrated utility in suspected autoimmune encephalitis. Visual and/or assisted image reading is not well established to evaluate hypometabolism/hypermetabolism. We retrospectively evaluated patients with autoimmune encephalitis between 2003 and 2018. Patients underwent EEG, brain magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) sampling and autoantibodies testing. Individual FDG-PET images were evaluated by standard visual reading and assisted by voxel-based analyses, compared to a normal database. For the latter, three different methods were performed: two based on statistical surface projections (Siemens syngo.via Database Comparison, and 3D-SSP Neurostat) and one based on statistical parametric mapping (SPM12). Hypometabolic and hypermetabolic findings were grouped to identify specific patterns. We found six cases with definite diagnosis of autoimmune encephalitis. Two cases had anti-LGI1, one had anti-NMDA-R and two anti-CASPR2 antibodies, and one was seronegative. 18F-FDG-PET metabolic abnormalities were present in all cases, regardless of the method of analysis. Medial–temporal and extra-limbic hypermetabolism were more clearly depicted by voxel-based analyses. We found autoantibody-specific patterns in line with the literature. Statistical surface projection (SSP) methods (Neurostat and syngo.via Database Comparison) were more sensitive and localized larger hypermetabolic areas. As it may lead to comparable and accurate results, visual analysis of FDG-PET studies for the diagnosis of autoimmune encephalitis benefits from voxel-based analysis, beyond the approach based on MRI, CSF sample and EEG.

Contains fulltext : 229556.pdf (Publisher’s version ) (Closed access) Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and (18)F-fluorodeoxyglucose ((18)F-FDG) PET, which assesses glucose metabolism, provide valuable and complementary information. However, uncertainty remains regarding the optimal timepoint, combination, and an order in which these PET biomarkers should be used in diagnostic evaluations because conclusive evidence is missing. Following an expert panel discussion, we reached an agreement on the specific use of the individual biomarkers, based on available evidence and clinical expertise. We propose a diagnostic algorithm with optimal timepoints for these PET biomarkers, also taking into account evidence from other biomarkers, for early and differential diagnosis of neurodegenerative diseases that can lead to dementia. We propose three main diagnostic pathways with distinct biomarker sequences, in which amyloid-PET and (18)F-FDG-PET are placed at different positions in the order of diagnostic evaluations, depending on clinical presentation. We hope that this algorithm can support diagnostic decision making in specialist clinical settings with access to these biomarkers and might stimulate further research towards optimal diagnostic strategies.

These joint practice guidelines, or procedure standards, were developed collaboratively 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 working group for Response Assessment in Neurooncology with PET (PET-RANO). Brain PET imaging is being increasingly used to supplement MRI in the clinical management of glioma. The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with glioma to achieve a high-quality imaging standard for PET using FDG and the radiolabelled amino acids MET, FET and FDOPA. This will help promote the appropriate use of PET imaging and contribute to evidence-based medicine that may improve the diagnostic impact of this technique in neurooncological practice. The present document replaces a former version of the guidelines published in 2006 (Vander Borght et al. Eur J Nucl Med Mol Imaging. 33:1374-80, 2006), and supplements a recent evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in patients with glioma (Albert et al. Neuro Oncol. 18:1199-208, 2016). The information provided should be taken in the context of local conditions and regulations.

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive cognitive decline and memory loss, and is the most common form of dementia. Amyloid plaques with neurofibrillary tangles are a neuropathological hallmark of AD that produces synaptic dysfunction and culminates later in neuronal loss. Amyloid PET is a useful, available and non-invasive technique that provides in vivo information about the cortical amyloid burden. In the latest revised criteria for the diagnosis of AD biomarkers were defined and integrated: pathological and diagnostic biomarkers (increased retention on fibrillar amyloid PET or decreased Aβ1-42 and increased T-Tau or P-Tau in CSF) and neurodegeneration or topographical biomarkers (temporoparietal hypometabolism on 18F-FDG PET and temporal atrophy on MRI). Recently specific recommendations have been created as a consensus statement on the appropriate use of the imaging biomarkers, including amyloid PET: early-onset cognitive impairment/dementia, atypical forms of AD, mild cognitive impairment with early age of onset, and to differentiate between AD and other neurodegenerative diseases that occur with dementia. Amyloid PET is also contributing to the development of new therapies for AD, as well as in research studies for the study of other neurodegenerative diseases that occur with dementia where the deposition of Aβ amyloid is involved in its pathogenesis. In this paper, we review some general concepts and study the use of amyloid PET in depth and its relationship with neurodegenerative diseases and other diagnostic techniques.

Early-onset Alzheimer disease (EOAD), which presents in patients younger than 65 years, has frequently been described as having different features from those of late-onset Alzheimer disease (LOAD). This review analyses the most recent studies comparing the clinical presentation and neuropsychological, neuropathological, genetic, and neuroimaging findings of both types in order to determine whether EOAD and LOAD are different entities or distinct forms of the same entity. We observed consistent differences between clinical findings in EOAD and in LOAD.Fundamentally, the onset of EOAD is more likely to be marked by atypical symptoms, and cognitive assessments point to poorer executive and visuospatial functioning and praxis with less marked memory impairment. Alzheimer-type features will be more dense and widespread in neuropathology studies, with structural and functional neuroimaging showing greater and more diffuse atrophy extending to neocortical areas (especially the precuneus). In conclusion, available evidence suggests that EOAD and LOAD are 2 different forms of a single entity. LOAD is likely to be influenced by ageing-related processes. Resumen: La enfermedad de Alzheimer de inicio precoz (EAIP), definida como la que se manifiesta antes de los 65 años de edad, muestra ciertas características diferentes de la enfermedad de Alzheimer de inicio tardío (EAIT). Nuestro objetivo fue analizar los trabajos más actuales que comparan la clínica, la neuropsicología, la patología, la genética y la neuroimagen de la EAIP y la EAIT, para determinar si nos enfrentamos a dos enfermedades distintas o a variantes de una misma entidad. Como resultado, hallamos consistencia en algunas características diferenciales entre los 2 cuadros clínicos. Fundamentalmente, la EAIP comienza con mayor frecuencia con una clínica atípica; la valoración cognitiva muestra mayor afectación de las funciones ejecutiva y visuoespacial y de las praxias, y menor afectación de la memoria; la neuropatología evidencia mayor densidad y una distribución más difusa de la patología tipo Alzheimer; los estudios de neuroimagen estructural y funcional muestran una afectación cortical mayor y más difusa, afectando al neocórtex (especialmente el precuneus). En conclusión, las evidencias actuales hacen pensar que la EAIP y la EAIT son variantes clínicas de una misma entidad, que en el caso de la EAIT se ve influida probablemente por factores asociados al envejecimiento. Keywords: Alzheimer disease, Early-onset, Late-onset, Neuropsychology, Neuropathology, Neuroimaging, Palabras clave: Enfermedad de Alzheimer, Inicio precoz, Inicio tardío, Neuropsicología, Neuropatología, Neuroimagen

Purpose: There are no comprehensive guidelines for the use of FDG PET in the following three clinical scenarios: (1) diagnostic work-up of patients with idiopathic Parkinson’s disease (PD) at risk of future cognitive decline, (2) discriminating idiopathic PD from progressive supranuclear palsy, and (3) identifying the underlying neuropathology in corticobasal syndrome. Methods: We therefore performed three literature searches and evaluated the selected studies for quality of design, risk of bias, inconsistency, imprecision, indirectness and effect size. Critical outcomes were the sensitivity, specificity, accuracy, positive/negative predictive value, area under the receiving operating characteristic curve, and positive/negative likelihood ratio of FDG PET in detecting the target condition. Using the Delphi method, a panel of seven experts voted for or against the use of FDG PET based on published evidence and expert opinion. Results: Of 91 studies selected from the three literature searches, only four included an adequate quantitative assessment of the performance of FDG PET. The majority of studies lacked robust methodology due to lack of critical outcomes, inadequate gold standard and no head-to-head comparison with an appropriate reference standard. The panel recommended the use of FDG PET for all three clinical scenarios based on nonquantitative evidence of clinical utility. Conclusion: Despite widespread use of FDG PET in clinical practice and extensive research, there is still very limited good quality evidence for the use of FDG PET. However, in the opinion of the majority of the panellists, FDG PET is a clinically useful imaging biomarker for idiopathic PD and atypical parkinsonism associated with dementia.

Purpose: We aim to report the quality of accuracy studies investigating the utility of [18F]fluorodeoxyglucose (FDG)-PET in supporting the diagnosis of prodromal Alzheimer’s Disease (AD), frontotemporal lobar degeneration (FTLD) and prodromal dementia with Lewy bodies (DLB) in mild cognitive impairment (MCI) subjects, and the corresponding recommendations made by a panel of experts. Methods: Seven panellist, four from the European Association of Nuclear Medicine, and three from the European Academy of Neurology, produced recommendations taking into consideration the incremental value of FDG-PET, as added on clinical-neuropsychological examination, to ascertain the aetiology of MCI (AD, FTLD or DLB). A literature search using harmonized population, intervention, comparison, and outcome (PICO) strings was performed, and an evidence assessment consistent with the European Federation of Neurological Societies guidance was provided. The consensual recommendation was achieved based on Delphi rounds. Results: Fifty-four papers reported the comparison of interest. The selected papers allowed the identification of FDG patterns that characterized MCI due to AD, FTLD and DLB. While clinical outcome studies supporting the diagnosis of MCI due to AD showed varying accuracies (ranging from 58 to 100%) and varying areas under the receiver-operator characteristic curves (0.66 to 0.97), no respective data were identified for MCI due to FTLD or for MCI due to DLB. However, the high negative predictive value of FDG-PET and the existence of different disease-specific patterns of hypometabolism support the consensus recommendations for the clinical use of this imaging technique in MCI subjects. Conclusions: FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD. Although promising also in detecting MCI due to FTLD and MCI due to DLB, more research is needed to ultimately judge the clinical utility of FDG-PET in these entities.

Purpose: A joint effort of the European Association of Nuclear Medicine (EANM) and the European Academy of Neurology (EAN) aims at clinical guidance for the use of FDG-PET in neurodegenerative diseases. This paper addresses the diagnostic utility of FDG-PET over clinical/neuropsychological assessment in the differentiation of the three forms of primary progressive aphasia (PPA). Methods: Seven panelists were appointed by the EANM and EAN and a literature search was performed by using harmonized PICO (Population, Intervention, Comparison, Outcome) question keywords. The studies were screened for eligibility, and data extracted to assess their methodological quality. Critical outcomes were accuracy indices in differentiating different PPA clinical forms. Subsequently Delphi rounds were held with the extracted data and quality assessment to reach a consensus based on both literature and expert opinion. Results: Critical outcomes for this PICO were available in four of the examined papers. The level of formal evidence supporting clinical utility of FDG-PET in differentiating among PPA variants was considered as poor. However, the consensual recommendation was defined on Delphi round I, with six out of seven panelists supporting clinical use. Conclusions: Quantitative evidence demonstrating utility or lack thereof is still missing. Panelists decided consistently to provide interim support for clinical use based on the fact that a typical atrophy or metabolic pattern is needed for PPA according to the diagnostic criteria, and the synaptic failure detected by FDG-PET is an earlier phenomenon than atrophy. Also, a normal FDG-PET points to a non-neurodegenerative cause.

Purpose: To assess the clinical utility of 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET) for detection of early signs of neurodegeneration in conditions of increased risk for Alzheimer’s disease (AD) as defined by: subjective cognitive decline (SCD), evidence of cerebral amyloid-pathology, apolipoprotein E (APOE) ε4-positive genotype, or autosomal dominant forms of AD (ADAD) in asymptomatic stages. Methods: A comprehensive literature search was conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on three different diagnostic scenarios. Results: The level of empirical study evidence for the use of FDG-PET to detect meaningful early signs of neurodegeneration was considered to be poor for ADAD and lacking for SCD and asymptomatic persons at risk, based on APOE ε4-positive genotype or cerebral amyloid pathology. Consequently, and consistent with current diagnostic criteria, panelists decided not to recommend routine clinical use of FDG-PET in these situations and to currently mainly reserve it for research purposes. Conclusion: Currently, there is limited evidence on which to base recommendations regarding the clinical routine use of FDG-PET to detect diagnostically meaningful early signs of neurodegeneration in asymptomatic subjects with ADAD, with APOE ε4-positive genotype, or with cerebral amyloid pathology, and in subjects with SCD. Future prospective studies are warranted and in part already ongoing, aiming to assess the added value of FDG-PET in this context beyond research applications.

Background: Easily accessible biomarkers are needed for the early identification of individuals at risk of developing Alzheimer’s disease (AD) in large population screening strategies. Objectives: This study evaluated the potential of plasma β-amyloid (Aβ) biomarkers in identifying early stages of AD and predicting cognitive decline over the following two years. Design: Total plasma Aβ42/40 ratio (TP42/40) was determined in 83 cognitively normal individuals (CN) and 145 subjects with amnestic mild cognitive impairment (a-MCI) stratified by an FDG-PET AD-risk pattern. Results: Significant lower TP42/40 ratio was found in a-MCI patients compared to CN. Moreover, a-MCIs with a high-risk FDG-PET pattern for AD showed even lower plasma ratio levels. Low TP42/40 at baseline increased the risk of progression to dementia by 70%. Furthermore, TP42/40 was inversely associated with neocortical amyloid deposition (measured with PiB-PET) and was concordant with the AD biomarker profile in cerebrospinal fluid (CSF). Conclusions: TP42/40 demonstrated value in the identification of individuals suffering a-MCI, in the prediction of progression to dementia, and in the detection of underlying AD pathology revealed by FDG-PET, Amyloid-PET and CSF biomarkers, being, thus, consistently associated with all the well-established indicators of AD.

Resumen Objetivo conocer la situacion de los estudios de neuroimagen de Medicina Nuclear que se realizaron en Espana en el ano 2013 y primer trimestre del 2014, con el fin de definir las actividades del grupo de trabajo de Neuroimagen de la Sociedad Espanola de Medicina Nuclear e Imagen Molecular (SEMNIM). Material y metodos Se diseno un cuestionario de 14 preguntas dividido en 3 partes: caracteristicas de los servicios (equipamiento y profesionales involucrados), tipo de exploraciones e indicaciones clinicas y metodos de evaluacion. El cuestionario se remitio a los 166 servicios de Medicina Nuclear que figuraban en la secretaria de la Sociedad Espanola de Medicina Nuclear e Imagen Molecular. Resultados Respondieron a la encuesta un total de 54 centros distribuidos entre todas las comunidades autonomas. La mayoria de los centros realizaron entre 300 y 800 exploraciones de neuroimagen al ano, representando mas de 25 exploraciones al mes. La media de equipos por servicio era de 3, teniendo la mitad de ellos equipos PET/TC y SPECT/TC. Las exploraciones realizadas con mas frecuencia son la SPECT cerebral con 123 I-FP-CIT, seguida de la SPECT cerebral de perfusion y de la PET con 18 F-FDG, siendo las indicaciones clinicas mas frecuentes los estudios de deterioro cognitivo seguidos por los de trastornos del movimiento. Para la evaluacion de las pruebas la mayoria de los centros utilizaron unicamente la valoracion visual, en la valoracion cuantitativa la cuantificacion por regiones de interes fue la mas utilizada. Conclusiones Los resultados reflejan cual fue la actividad clinica del ano 2013 y primer trimestre del 2014, siendo las indicaciones principales los estudios de deterioro cognitivo y trastorno del movimiento. La variabilidad en la evaluacion de los estudios PET y la colaboracion con los especialistas clinicos que demandan las exploraciones de neuroimagen de Medicina Nuclear son algunos de los retos que debemos afrontar en los proximos anos.

Objective To determine the status of neuroimaging studies of Nuclear Medicine in Spain during 2013 and first quarter of 2014, in order to define the activities of the neuroimaging group of the Spanish Society of Nuclear Medicine and Molecular Imaging (SEMNIM). Material and methods A questionnaire of 14 questions was designed, divided into 3 parts: characteristics of the departments (equipment and professionals involved); type of scans and clinical indications; and evaluation methods. The questionnaire was sent to 166 Nuclear Medicine departments. Results A total of 54 departments distributed among all regions completed the questionnaire. Most departments performed between 300 and 800 neuroimaging examinations per year, representing more than 25 scans per month. The average pieces of equipment were three; half of the departments had a PET/CT scanner and SPECT/CT equipment. Scans performed more frequently were brain SPECT with 123 I-FP-CIT, followed by brain perfusion SPECT and PET with 18 F-FDG. The most frequent clinical indications were cognitive impairment followed by movement disorders. For evaluation of the images most sites used only visual assessment, and for the quantitative assessment the most used was quantification by region of interest. Conclusions These results reflect the clinical activity of 2013 and first quarter of 2014. The main indications of the studies were cognitive impairment and movement disorders. Variability in the evaluation of the studies is among the challenges that will be faced in the coming years.

Various biomarkers are available to support the diagnosis of neurodegenerative diseases in clinical and research settings. Among the molecular imaging biomarkers, amyloid-PET, which assesses brain amyloid deposition, and

© 2019 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/), Background: amyloid-PET reading has been classically implemented as a binary assessment, although the clinical experience has shown that the number of borderline cases is non negligible not only in epidemiological studies of asymptomatic subjects but also in naturalistic groups of symptomatic patients attending memory clinics. In this work we develop a model to compare and integrate visual reading with two independent semi-quantification methods in order to obtain a tracer-independent multi-parametric evaluation. Methods: We retrospectively enrolled three cohorts of cognitively impaired patients submitted to 18F-florbetaben (53 subjects), 18F-flutemetamol (62 subjects), 18F-florbetapir (60 subjects) PET/CT respectively, in 6 European centres belonging to the EADC. The 175 scans were visually classified as positive/negative following approved criteria and further classified with a 5-step grading as negative, mild negative, borderline, mild positive, positive by 5 independent readers, blind to clinical data. Scan quality was also visually assessed and recorded. Semi-quantification was based on two quantifiers: the standardized uptake value (SUVr) and the ELBA method. We used a sigmoid model to relate the grading with the quantifiers. We measured the readers accord and inconsistencies in the visual assessment as well as the relationship between discrepancies on the grading and semi-quantifications. Conclusion: It is possible to construct a map between different tracers and different quantification methods without resorting to ad-hoc acquired cases. We used a 5-level visual scale which, together with a mathematical model, delivered cut-offs and transition regions on tracers that are (largely) independent from the population. All fluorinated tracers appeared to have the same contrast and discrimination ability with respect to the negative-to-positive grading. We validated the integration of both visual reading and different quantifiers in a more robust framework thus bridging the gap between a binary and a user-independent continuous scale., V.G. was supported by the Swiss National Science Foundation (under grant SNF 320030_169876) and by the Velux Stiftung (project n. 1123). E.P. was supported by Airalzh Onlus – COOP Italia (grant number 138812/Rep n° 2459).

Multiple System Atrophy, Progressive Supranuclear Palsy, and Corticobasal Degeneration are three neurodegenerative disorders characterized by parkinsonism along with involvement of other brain cortical and subcortical regions. The ante mortem diagnosis of these disorders is extremely challenging with up to a quarter of these patients being misdiagnosed, particularly in the early stages of disease. While highly specific and sensitive imaging biomarkers of individual atypical parkinsonisms have not been identified yet, molecular PET and SPECT imaging have improved our knowledge of the physiopathology and neuropathology of these disorders and are often used as supportive criteria for the differential diagnosis of these conditions. This chapter will provide a state-of-the-art overview of the use of PET in atypical parkinsonisms.