Background: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection ... more Background: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection of cerebral metabolic alterations in neurological diseases vs. normal aging. We assess age- and sex-related brain metabolic changes in healthy subjects, exploring impact of activity normalization methods. Methods: brain scans of Italian Association of Nuclear Medicine normative database (151 subjects, 67 Males, 84 Females, aged 20–84) were selected. Global mean, white matter, and pons activity were explored as normalization reference. We performed voxel-based and ROI analyses using SPM12 and IBM-SPSS software. Results: SPM proved a negative correlation between age and brain glucose metabolism involving frontal lobes, anterior-cingulate and insular cortices bilaterally. Narrower clusters were detected in lateral parietal lobes, precuneus, temporal pole and medial areas bilaterally. Normalizing on pons activity, we found a more significant negative correlation and no positive one. ROIs ana...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose The purpose of this study is to develop and validate a 3D deep learning model that predic... more Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer’s disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model’s performance to that of multiple expert nuclear medicine physicians’ readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer’s disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model’s performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating chara...
We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfuncti... more We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfunction after SARS-CoV-2 infection. Twenty-two patients underwent whole-body [18F]-FDG PET, including a dedicated brain acquisition at our institution between May and December 2020 following their recovery after SARS-Cov2 infection. Fourteen of these patients presented isolated persistent hyposmia (smell diskettes olfaction test was used). A voxel-wise analysis (using Statistical Parametric Mapping software version 8 (SPM8)) was performed to identify brain regions of relative hypometabolism in patients with hyposmia with respect to controls. Structural connectivity of these regions was assessed (BCB toolkit). Relative hypometabolism was demonstrated in bilateral parahippocampal and fusiform gyri and in left insula in patients with respect to controls. Structural connectivity maps highlighted the involvement of bilateral longitudinal fasciculi. This study provides evidence of cortical hypometa...
In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (... more In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (FDG) uptake in the posterior brain, reproducing Alzheimer disease pattern, hampering the diagnostic accuracy of this widely used tool. This phenomenon might involve either a heterogeneous response of glucose metabolism or a different sensitivity to hyperglycemia-related redox stress. Indeed, previous studies reported a close link between FDG uptake and activation of a specific pentose phosphate pathway (PPP), triggered by hexose-6P-dehydrogenase (H6PD) and contributing to fuel NADPH-dependent antioxidant responses in the endoplasmic reticulum (ER). To clarify this issue, dynamic positron emission tomography was performed in 40 BALB/c mice four weeks after administration of saline (n = 17) or 150 mg/kg streptozotocin (n = 23, STZ). Imaging data were compared with biochemical and histological indexes of glucose metabolism and redox balance. Cortical FDG uptake was homogeneous in controls, ...
Purpose Our aim was to compare a widely distributed commercial tool with an older free software (... more Purpose Our aim was to compare a widely distributed commercial tool with an older free software (i) one another, (ii) with a clinical motor score, (iii) versus reading by experts. Procedures We analyzed consecutive scans from one-hundred and fifty-one outpatients submitted to brain DAT SPECT for a suspected parkinsonism. Images were post-processed using a commercial (Datquant®) and a free (BasGanV2) software. Reading by expert was the gold standard. A subset of patients with pathological or borderline scan was evaluated with the clinical Unified Parkinson’s Disease Rating Scale, motor part (MDS-UPDRS-III). Results SBR, putamen-to-caudate (P/C) ratio, and both P and C asymmetries were highly correlated between the two software with Pearson’s ‘r’ correlation coefficients ranging from .706 to .887. Correlation coefficients with the MDS-UPDRS III score were higher with caudate than with putamen SBR values with both software, and in general higher with BasGanV2 than with Datquant®. Datqu...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose: To assess the clinical utility of FDG-PET for detection of early signs of neurodegenerat... more Purpose: To assess the clinical utility of 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, APOE ε4positive 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.
European Journal of Nuclear Medicine and Molecular Imaging
To review literature until November 2015 and reach a consensus on whether automatic semi-quantifi... more To review literature until November 2015 and reach a consensus on whether automatic semi-quantification of brain FDG-PET is useful in the clinical setting for neurodegenerative disorders. Methods: Literature search was conducted in Medline, Embase, and Google scholar. Papers were selected with a lower limit of 30 patients (no limits with autopsy confirmation). Consensus recommendations were developed through a Delphi procedure, based on the expertise of panelists, who were also informed about the availability and quality of evidence, assessed by an independent methodology team. Results: Critical outcomes were available in nine among the 17 papers initially selected. Only three papers performed the direct comparison between visual and automated assessment and quantified the incremental value provided by the latter. Sensitivity between visual and automatic analysis is similar but automatic assessment generally improves specificity, and marginally accuracy. Also, automated assessment increases diagnostic confidence. As expected, performance of visual analysis is reported to depend on expertise of readers. Conclusions: Tools for semi-quantitative evaluation are recommended to assist the nuclear medicine physician in reporting brain FDG-PET pattern in neurodegenerative conditions. However, heterogeneity, complexity and drawbacks of these tools should be known by users to avoid misinterpretation. Head-to-head comparisons and an effort to harmonize procedures are encouraged.
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of..., Dec 1, 2017
European journal of nuclear medicine and molecular imaging, Jul 1, 2018
To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic... more To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. Relative to other neurodegenerative diseases, the clinical use of FDG...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose There are no comprehensive guidelines for the use of FDG PET in the following three clini... more 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.
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
European Journal of Nuclear Medicine and Molecular Imaging
Purpose A joint effort of the European Association of Nuclear Medicine (EANM) and the European Ac... more 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.
Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance... more Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD"; n=81) or "negative" (n=63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ42/P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group x Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p<0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (< 4 Hz) and theta (4-8 Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time x Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to "negative" aMCI patients based on 5 serial recording sessions over 2 years.
European Journal of Nuclear Medicine and Molecular Imaging
The aim of this study was to verify the reliability and generalizability of an automatic tool for... more The aim of this study was to verify the reliability and generalizability of an automatic tool for the detection of Alzheimer-related hypometabolic pattern based on a Support-Vector-Machine (SVM) model analyzing F-fluorodeoxyglucose (FDG) PET data. The SVM model processed metabolic data from anatomical volumes of interest also considering interhemispheric asymmetries. It was trained on a homogeneous dataset from a memory clinic center and tested on an independent multicentric dataset drawn from the Alzheimer&amp;amp;#39;s Disease Neuroimaging Initiative. Subjects were included in the study and classified based on a diagnosis confirmed after an adequate follow-up time. The accuracy of the discrimination between patients with Alzheimer Disease (AD), in either prodromal or dementia stage, and normal aging subjects was 95.8%, after cross-validation, in the training set. The accuracy of the same model in the testing set was 86.5%. The role of the two datasets was then reversed, and the accuracy was 89.8% in the multicentric training set and 88.0% in the monocentric testing set. The classification rate was also evaluated in different subgroups, including non-converter mild cognitive impairment (MCI) patients, subjects with MCI reverted to normal conditions and subjects with non-confirmed memory concern. The percent of pattern detections increased from 77% in early prodromal AD to 91% in AD dementia, while it was about 10% for healthy controls and non-AD patients. The present findings show a good level of reproducibility and generalizability of a model for detecting the hypometabolic pattern in AD and confirm the accuracy of FDG-PET in Alzheimer disease.
We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson'... more We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily do...
The close connection between neuronal activity and glucose consumption accounts for the clinical ... more The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. Thirty six-week-old BALB/c female mice were divided into two groups: "control" group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining "STS" mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose rem...
Journal of Alzheimer's disease : JAD, Jan 20, 2018
It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or mo... more It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative...
Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been ... more Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients...
We explored the presence of both reserve and resilience in late-converter mild cognitive impairme... more We explored the presence of both reserve and resilience in late-converter mild cognitive impairment due to Alzheimer's disease (MCI-AD) and in patients with slowly progressing amyloid-positive MCI by assessing the topography and extent of neurodegeneration with respect to both "aggressive" and typically progressing phenotypes and in the whole group of patients with MCI, grounding the stratification on education level. We analyzed 94 patients with MCI-AD followed until conversion to dementia and 39 patients with MCI who had brain amyloidosis (AMY+ MCI), all with available baseline F-fluorodeoxyglucose positron emission tomography (FDG-PET) results. Using a data-driven approach based on conversion time, patients with MCI-AD were divided into typical AD and late-converter subgroups. Similarly, on the basis of annual rate of Mini Mental State Examination score reduction, AMY+ MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgrou...
Background: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection ... more Background: 18F-fluorodeoxyglucose (18F-FDG) positron-emission-tomography (PET) allows detection of cerebral metabolic alterations in neurological diseases vs. normal aging. We assess age- and sex-related brain metabolic changes in healthy subjects, exploring impact of activity normalization methods. Methods: brain scans of Italian Association of Nuclear Medicine normative database (151 subjects, 67 Males, 84 Females, aged 20–84) were selected. Global mean, white matter, and pons activity were explored as normalization reference. We performed voxel-based and ROI analyses using SPM12 and IBM-SPSS software. Results: SPM proved a negative correlation between age and brain glucose metabolism involving frontal lobes, anterior-cingulate and insular cortices bilaterally. Narrower clusters were detected in lateral parietal lobes, precuneus, temporal pole and medial areas bilaterally. Normalizing on pons activity, we found a more significant negative correlation and no positive one. ROIs ana...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose The purpose of this study is to develop and validate a 3D deep learning model that predic... more Purpose The purpose of this study is to develop and validate a 3D deep learning model that predicts the final clinical diagnosis of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), mild cognitive impairment due to Alzheimer’s disease (MCI-AD), and cognitively normal (CN) using fluorine 18 fluorodeoxyglucose PET (18F-FDG PET) and compare model’s performance to that of multiple expert nuclear medicine physicians’ readers. Materials and methods Retrospective 18F-FDG PET scans for AD, MCI-AD, and CN were collected from Alzheimer’s disease neuroimaging initiative (556 patients from 2005 to 2020), and CN and DLB cases were from European DLB Consortium (201 patients from 2005 to 2018). The introduced 3D convolutional neural network was trained using 90% of the data and externally tested using 10% as well as comparison to human readers on the same independent test set. The model’s performance was analyzed with sensitivity, specificity, precision, F1 score, receiver operating chara...
We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfuncti... more We aimed to evaluate the brain hypometabolic signature of persistent isolated olfactory dysfunction after SARS-CoV-2 infection. Twenty-two patients underwent whole-body [18F]-FDG PET, including a dedicated brain acquisition at our institution between May and December 2020 following their recovery after SARS-Cov2 infection. Fourteen of these patients presented isolated persistent hyposmia (smell diskettes olfaction test was used). A voxel-wise analysis (using Statistical Parametric Mapping software version 8 (SPM8)) was performed to identify brain regions of relative hypometabolism in patients with hyposmia with respect to controls. Structural connectivity of these regions was assessed (BCB toolkit). Relative hypometabolism was demonstrated in bilateral parahippocampal and fusiform gyri and in left insula in patients with respect to controls. Structural connectivity maps highlighted the involvement of bilateral longitudinal fasciculi. This study provides evidence of cortical hypometa...
In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (... more In cognitively normal patients, mild hyperglycemia selectively decreases 18F-Fluorodeoxyglucose (FDG) uptake in the posterior brain, reproducing Alzheimer disease pattern, hampering the diagnostic accuracy of this widely used tool. This phenomenon might involve either a heterogeneous response of glucose metabolism or a different sensitivity to hyperglycemia-related redox stress. Indeed, previous studies reported a close link between FDG uptake and activation of a specific pentose phosphate pathway (PPP), triggered by hexose-6P-dehydrogenase (H6PD) and contributing to fuel NADPH-dependent antioxidant responses in the endoplasmic reticulum (ER). To clarify this issue, dynamic positron emission tomography was performed in 40 BALB/c mice four weeks after administration of saline (n = 17) or 150 mg/kg streptozotocin (n = 23, STZ). Imaging data were compared with biochemical and histological indexes of glucose metabolism and redox balance. Cortical FDG uptake was homogeneous in controls, ...
Purpose Our aim was to compare a widely distributed commercial tool with an older free software (... more Purpose Our aim was to compare a widely distributed commercial tool with an older free software (i) one another, (ii) with a clinical motor score, (iii) versus reading by experts. Procedures We analyzed consecutive scans from one-hundred and fifty-one outpatients submitted to brain DAT SPECT for a suspected parkinsonism. Images were post-processed using a commercial (Datquant®) and a free (BasGanV2) software. Reading by expert was the gold standard. A subset of patients with pathological or borderline scan was evaluated with the clinical Unified Parkinson’s Disease Rating Scale, motor part (MDS-UPDRS-III). Results SBR, putamen-to-caudate (P/C) ratio, and both P and C asymmetries were highly correlated between the two software with Pearson’s ‘r’ correlation coefficients ranging from .706 to .887. Correlation coefficients with the MDS-UPDRS III score were higher with caudate than with putamen SBR values with both software, and in general higher with BasGanV2 than with Datquant®. Datqu...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose: To assess the clinical utility of FDG-PET for detection of early signs of neurodegenerat... more Purpose: To assess the clinical utility of 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, APOE ε4positive 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.
European Journal of Nuclear Medicine and Molecular Imaging
To review literature until November 2015 and reach a consensus on whether automatic semi-quantifi... more To review literature until November 2015 and reach a consensus on whether automatic semi-quantification of brain FDG-PET is useful in the clinical setting for neurodegenerative disorders. Methods: Literature search was conducted in Medline, Embase, and Google scholar. Papers were selected with a lower limit of 30 patients (no limits with autopsy confirmation). Consensus recommendations were developed through a Delphi procedure, based on the expertise of panelists, who were also informed about the availability and quality of evidence, assessed by an independent methodology team. Results: Critical outcomes were available in nine among the 17 papers initially selected. Only three papers performed the direct comparison between visual and automated assessment and quantified the incremental value provided by the latter. Sensitivity between visual and automatic analysis is similar but automatic assessment generally improves specificity, and marginally accuracy. Also, automated assessment increases diagnostic confidence. As expected, performance of visual analysis is reported to depend on expertise of readers. Conclusions: Tools for semi-quantitative evaluation are recommended to assist the nuclear medicine physician in reporting brain FDG-PET pattern in neurodegenerative conditions. However, heterogeneity, complexity and drawbacks of these tools should be known by users to avoid misinterpretation. Head-to-head comparisons and an effort to harmonize procedures are encouraged.
The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of..., Dec 1, 2017
European journal of nuclear medicine and molecular imaging, Jul 1, 2018
To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic... more To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. Relative to other neurodegenerative diseases, the clinical use of FDG...
European Journal of Nuclear Medicine and Molecular Imaging
Purpose There are no comprehensive guidelines for the use of FDG PET in the following three clini... more 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.
If citing, it is advised that you check and use the publisher's definitive version for pagination... more If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections.
European Journal of Nuclear Medicine and Molecular Imaging
Purpose A joint effort of the European Association of Nuclear Medicine (EANM) and the European Ac... more 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.
Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance... more Auditory "oddball" event-related potentials (aoERPs), resting state functional magnetic resonance imaging (rsfMRI) connectivity, and electroencephalographic (rsEEG) rhythms were tested as longitudinal functional biomarkers of prodromal Alzheimer's disease (AD). Data were collected at baseline and four follow-ups at 6, 12, 18, and 24 months in amnesic mild cognitive impairment (aMCI) patients classified in two groups: "positive" (i.e., "prodromal AD"; n=81) or "negative" (n=63) based on a diagnostic marker of AD derived from cerebrospinal samples (Aβ42/P-tau ratio). A linear mixed model design was used to test functional biomarkers for Group, Time, and Group x Time effects adjusted by nuisance covariates (only data until conversion to dementia was used). Functional biomarkers that showed significant Group effects ("positive" versus "negative", p<0.05) regardless of Time were 1) reduced rsfMRI connectivity in both the default mode network (DMN) and the posterior cingulate cortex (PCC), both also giving significant Time effects (connectivity decay regardless of Group); 2) increased rsEEG source activity at delta (< 4 Hz) and theta (4-8 Hz) rhythms and decreased source activity at low-frequency alpha (8-10.5 Hz) rhythms; and 3) reduced parietal and posterior cingulate source activities of aoERPs. Time x Group effects showed differential functional biomarker progression between groups: 1) increased rsfMRI connectivity in the left parietal cortex of the DMN nodes, consistent with compensatory effects and 2) increased limbic source activity at theta rhythms. These findings represent the first longitudinal characterization of functional biomarkers of prodromal AD relative to "negative" aMCI patients based on 5 serial recording sessions over 2 years.
European Journal of Nuclear Medicine and Molecular Imaging
The aim of this study was to verify the reliability and generalizability of an automatic tool for... more The aim of this study was to verify the reliability and generalizability of an automatic tool for the detection of Alzheimer-related hypometabolic pattern based on a Support-Vector-Machine (SVM) model analyzing F-fluorodeoxyglucose (FDG) PET data. The SVM model processed metabolic data from anatomical volumes of interest also considering interhemispheric asymmetries. It was trained on a homogeneous dataset from a memory clinic center and tested on an independent multicentric dataset drawn from the Alzheimer&amp;amp;#39;s Disease Neuroimaging Initiative. Subjects were included in the study and classified based on a diagnosis confirmed after an adequate follow-up time. The accuracy of the discrimination between patients with Alzheimer Disease (AD), in either prodromal or dementia stage, and normal aging subjects was 95.8%, after cross-validation, in the training set. The accuracy of the same model in the testing set was 86.5%. The role of the two datasets was then reversed, and the accuracy was 89.8% in the multicentric training set and 88.0% in the monocentric testing set. The classification rate was also evaluated in different subgroups, including non-converter mild cognitive impairment (MCI) patients, subjects with MCI reverted to normal conditions and subjects with non-confirmed memory concern. The percent of pattern detections increased from 77% in early prodromal AD to 91% in AD dementia, while it was about 10% for healthy controls and non-AD patients. The present findings show a good level of reproducibility and generalizability of a model for detecting the hypometabolic pattern in AD and confirm the accuracy of FDG-PET in Alzheimer disease.
We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson'... more We hypothesized that dopamine neuromodulation might affect cortical excitability in Parkinson's disease (PD) patients set in quiet wakefulness, as revealed by resting state eyes-closed electroencephalographic (rsEEG) rhythms at alpha frequencies (8-12 Hz). Clinical and rsEEG rhythms in PD with dementia (N = 35), PD with mild cognitive impairment (N = 50), PD with normal cognition (N = 35), and normal (N = 50) older adults were available from an international archive. Cortical rsEEG sources were estimated by exact low-resolution brain electromagnetic tomography. Compared with the normal older group, the PD groups showed reduced occipital alpha sources and increased widespread delta (<4 Hz) sources. Widespread frontal and temporal alpha sources exhibited an increase in PD with dementia compared with PD with mild cognitive impairment and PD with normal cognition groups, as function of dopamine depletion severity, typically greater in the former than the latter groups. A daily do...
The close connection between neuronal activity and glucose consumption accounts for the clinical ... more The close connection between neuronal activity and glucose consumption accounts for the clinical value of 18F-fluoro-2-deoxyglucose (FDG) imaging in neurodegenerative disorders. Nevertheless, brain metabolic response to starvation (STS) might hamper the diagnostic accuracy of FDG PET/CT when the cognitive impairment results in a severe food deprivation. Thirty six-week-old BALB/c female mice were divided into two groups: "control" group (n = 15) were kept under standard conditions and exposed to fasting for 6 h before the study; the remaining "STS" mice were submitted to 48 h STS (absence of food and free access to water) before imaging. In each group, nine mice were submitted to dynamic micro-PET imaging to estimate brain and skeletal muscle glucose consumption (C- and SM-MRGlu*) by Patlak approach, while six mice were sacrificed for ex vivo determination of the lumped constant, defined as the ratio between CMRGlu* and glucose consumption measured by glucose rem...
Journal of Alzheimer's disease : JAD, Jan 20, 2018
It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or mo... more It is an open issue whether blood biomarkers serve to diagnose Alzheimer's disease (AD) or monitor its progression over time from prodromal stages. Here, we addressed this question starting from data of the European FP7 IMI-PharmaCog/E-ADNI longitudinal study in amnesic mild cognitive impairment (aMCI) patients including biological, clinical, neuropsychological (e.g., ADAS-Cog13), neuroimaging, and electroencephalographic measures. PharmaCog/E-ADNI patients were classified as "positive" (i.e., "prodromal AD" n = 76) or "negative" (n = 52) based on a diagnostic cut-off of Aβ42/P-tau in cerebrospinal fluid as well as APOE ε 4 genotype. Blood was sampled at baseline and at two follow-ups (12 and 18 months), when plasma amyloid peptide 42 and 40 (Aβ42, Aβ40) and apolipoprotein J (clusterin, CLU) were assessed. Linear Mixed Models found no significant differences in plasma molecules between the "positive" (i.e., prodromal AD) and "negative...
Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been ... more Early Alzheimer's disease (AD) detection using cerebrospinal fluid (CSF) biomarkers has been recommended as enrichment strategy for trials involving mild cognitive impairment (MCI) patients. To model a prodromal AD trial for identifying MRI structural biomarkers to improve subject selection and to be used as surrogate outcomes of disease progression. APOE ɛ4 specific CSF Aβ42/P-tau cut-offs were used to identify MCI with prodromal AD (Aβ42/P-tau positive) in the WP5-PharmaCog (E-ADNI) cohort. Linear mixed models were performed 1) with baseline structural biomarker, time, and biomarker×time interaction as factors to predict longitudinal changes in ADAS-cog13, 2) with Aβ42/P-tau status, time, and Aβ42/P-tau status×time interaction as factors to explain the longitudinal changes in MRI measures, and 3) to compute sample size estimation for a trial implemented with the selected biomarkers. Only baseline lateral ventricle volume was able to identify a subgroup of prodromal AD patients...
We explored the presence of both reserve and resilience in late-converter mild cognitive impairme... more We explored the presence of both reserve and resilience in late-converter mild cognitive impairment due to Alzheimer's disease (MCI-AD) and in patients with slowly progressing amyloid-positive MCI by assessing the topography and extent of neurodegeneration with respect to both "aggressive" and typically progressing phenotypes and in the whole group of patients with MCI, grounding the stratification on education level. We analyzed 94 patients with MCI-AD followed until conversion to dementia and 39 patients with MCI who had brain amyloidosis (AMY+ MCI), all with available baseline F-fluorodeoxyglucose positron emission tomography (FDG-PET) results. Using a data-driven approach based on conversion time, patients with MCI-AD were divided into typical AD and late-converter subgroups. Similarly, on the basis of annual rate of Mini Mental State Examination score reduction, AMY+ MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgrou...
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Papers by Flavio Nobili