Manual and semi-automated approaches to MIBG myocardial scintigraphy in patients with Parkinson's disease.

Objective: This study investigates the effects of manual and semi-automatic methods for assessing MIBG semi-quantitative indices in a clinical setting. Materials and methods: We included 123I-MIBG scans obtained in 35 patients with idiopathic Parkinson's Disease. Early and late heart-to-mediastinum (H/M) ratios were calculated from 123I-MIBG images using regions of interest (ROIs) placed over the heart and the mediastinum. The ROIs were derived using two approaches: (i) manually drawn and (ii) semi-automatic fixed-size ROIs using anatomical landmarks. Expert, moderate-expert, and not expert raters applied the ROIs procedures and interpreted the 123I-MIBG images. We evaluated the inter and intra-rater agreements in assessing 123I-MIBG H/M ratios. Results: A moderate agreement in the raters' classification of pathological and non-pathological scores emerged regarding early and late H/M ratio values (κ = 0.45 and 0.69 respectively), applying the manual method, while the early and late H/M ratios obtained with the semi-automatic method reached a good agreement among observers (κ = 0.78). Cohen-Kappa values revealed that the semi-automatic method improved the agreement between expert and inexpert raters: the agreement improved from a minimum of 0.29 (fair, for early H/M) and 0.69 (substantial, in late H/M) with the manual method, to 0.90 (perfect, in early H/M) and 0.87 (perfect, in late H/M) with the semi-automatic method. Conclusion: The use of the semi-automatic method improves the agreement among raters in classifying' H/M ratios as pathological or non-pathological, namely for inexpert readers. These results have important implications for semi-quantitative assessment of 123I-MIBG images in clinical routine.

Brain Metabolism and Amyloid Load in Individuals With Subjective Cognitive Decline or Pre-Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE: Multicenter study aiming at investigating the characteristics of cognitive decline, neuropsychiatric symptoms, and brain imaging in individuals with subjective cognitive decline (SCD) and subtle cognitive decline (pre-Mild Cognitive Impairment, pre-MCI). METHODS: Data were obtained from the Network-AD project (NET-2011-02346784). The included subjects underwent baseline cognitive and neurobehavioral evaluation, FDG-PET, and, amyloid-PET. We used Principal Component Analysis (PCA) to identify independent neuropsychological and neuropsychiatric dimensions and their association with brain metabolism. RESULTS: A total of 105 subjects (SCD=49, pre-MCI=56) were included. FDG-PET was normal in 45% of subjects and revealed brain hypometabolism in 55%, with a frontal-like pattern as the most frequent finding (28%). Neuropsychiatric symptoms emerging from the Neuropsychiatric Inventory and the Starkstein Apathy Scale were highly prevalent in the whole sample (78%). An abnormal amyloid load was detected in the 18% of the subjects that underwent amyloid-PET (n=60). PCA resulted in three neuropsychological factors: 1) executive/visuo-motor, correlating with hypometabolism in frontal, occipital cortices and basal ganglia; 2) memory, correlating with hypometabolism in temporo-parietal regions; 3) visuo-spatial/constructional, correlating with hypometabolism in fronto-parietal cortices. Two factors emerged from the neuropsychiatric PCA: 1) affective, correlating with hypometabolism in orbito-frontal, cingulate cortex, insula; 2) hyperactive/psychotic, correlating with hypometabolism in frontal, temporal and parietal regions. DISCUSSION: FDG-PET evidence suggests either normal brain function or different patterns of brain hypometabolism in SCD and pre-MCI subjects. These results indicate that SCD and pre-MCI represent heterogeneous populations. Consistently, different neuropsychological and neuropsychiatric profiles emerged, which correlated with neuronal dysfunction in specific brain regions. Long-term follow-up studies are needed to assess the risk of progression to dementia in these conditions.

Evaluation of a 2D UNet-Based Attenuation Correction Methodology for PET/MR Brain Studies.

Deep learning (DL) strategies applied to magnetic resonance (MR) images in positron emission tomography (PET)/MR can provide synthetic attenuation correction (AC) maps, and consequently PET images, more accurate than segmentation or atlas-registration strategies. As first objective, we aim to investigate the best MR image to be used and the best point of the AC pipeline to insert the synthetic map in. Sixteen patients underwent a 18F-fluorodeoxyglucose (FDG) PET/computed tomography (CT) and a PET/MR brain study in the same day. PET/CT images were reconstructed with attenuation maps obtained: (1) from CT (reference), (2) from MR with an atlas-based and a segmentation-based method and (3) with a 2D UNet trained on MR image/attenuation map pairs. As for MR, T1-weighted and Zero Time Echo (ZTE) images were considered; as for attenuation maps, CTs and 511 keV low-resolution attenuation maps were assessed. As second objective, we assessed the ability of DL strategies to provide proper AC maps in presence of cranial anatomy alterations due to surgery. Three 11C-methionine (METH) PET/MR studies were considered. PET images were reconstructed with attenuation maps obtained: (1) from diagnostic coregistered CT (reference), (2) from MR with an atlas-based and a segmentation-based method and (3) with 2D UNets trained on the sixteen FDG anatomically normal patients. Only UNets taking ZTE images in input were considered. FDG and METH PET images were quantitatively evaluated. As for anatomically normal FDG patients, UNet AC models generally provide an uptake estimate with lower bias than atlas-based or segmentation-based methods. The intersubject average bias on images corrected with UNet AC maps is always smaller than 1.5%, except for AC maps generated on too coarse grids. The intersubject bias variability is the lowest (always lower than 2%) for UNet AC maps coming from ZTE images, larger for other methods. UNet models working on MR ZTE images and generating synthetic CT or 511 keV low-resolution attenuation maps therefore provide the best results in terms of both accuracy and variability. As for METH anatomically altered patients, DL properly reconstructs anatomical alterations. Quantitative results on PET images confirm those found on anatomically normal FDG patients.

Brain metabolic signatures across the Alzheimer's disease spectrum.

PURPOSE: Given the challenges posed by the clinical diagnosis of atypical Alzheimer's disease (AD) variants and the limited imaging evidence available in the prodromal phases of atypical AD, we assessed brain hypometabolism patterns at the single-subject level in the AD variants spectrum. Specifically, we tested the accuracy of [18F]FDG-PET brain hypometabolism, as a biomarker of neurodegeneration, in supporting the differential diagnosis of atypical AD variants in individuals with dementia and mild cognitive impairment (MCI). METHODS: We retrospectively collected N = 67 patients with a diagnosis of typical AD and AD variants according to the IWG-2 criteria (22 typical-AD, 15 frontal variant-AD, 14 logopenic variant-AD and 16 posterior variant-AD). Further, we included N = 11 MCI subjects, who subsequently received a clinical diagnosis of atypical AD dementia at follow-up (21 ± 11 months). We assessed brain hypometabolism patterns at group- and single-subject level, using W-score maps, measuring their accuracy in supporting differential diagnosis. In addition, the regional prevalence of cerebral hypometabolism was computed to identify the most vulnerable core regions. RESULTS: W-score maps pointed at distinct, specific patterns of hypometabolism in typical and atypical AD variants, confirmed by the assessment of core hypometabolism regions, showing that each variant was characterized by specific regional vulnerabilities, namely in occipital, left-sided, or frontal brain regions. ROC curves allowed discrimination among AD variants and also non-AD dementia (i.e., dementia with Lewy bodies and behavioral variant of frontotemporal dementia), with high sensitivity and specificity. Notably, we provide preliminary evidence that, even in AD prodromal phases, these specific [18F]FDG-PET patterns are already detectable and predictive of clinical progression to atypical AD variants at follow-up. CONCLUSIONS: The AD variant-specific patterns of brain hypometabolism, highly consistent at single-subject level and already evident in the prodromal stages, represent relevant markers of disease neurodegeneration, with highly supportive diagnostic and prognostic role.

Unfavourable gender effect of high body mass index on brain metabolism and connectivity.

The influence of Body Mass Index (BMI) on neurodegeneration in dementia has yet to be elucidated. We aimed at exploring the effects of BMI levels on cerebral resting-state metabolism and brain connectivity, as crucial measures of synaptic function and activity, in a large group of patients with Alzheimer's Dementia (AD) (n = 206), considering gender. We tested the correlation between BMI levels and brain metabolism, as assessed by 18F-FDG-PET, and the modulation of the resting-state functional networks by BMI. At comparable dementia severity, females with high BMI can withstand a lower degree of brain metabolism dysfunction, as shown by a significant BMI-brain metabolism correlation in the temporal-parietal regions, which are typically vulnerable to AD pathology (R = 0.269, p = 0.009). Of note, high BMI was also associated with reduced connectivity in frontal and limbic brain networks, again only in AD females (p < 0.05 FDR-corrected, k = 100 voxels). This suggests a major vulnerability of neural systems known to be selectively involved in brain compensatory mechanisms in AD females. These findings indicate a strong gender effect of high BMI and obesity in AD, namely reducing the available reserve mechanisms in female patients. This brings to considerations for medical practice and health policy.

Quantifying the robustness of [18F]FDG-PET/CT radiomic features with respect to tumor delineation in head and neck and pancreatic cancer patients.

PURPOSE: To investigate the robustness of PET radiomic features (RF) against tumour delineation uncertainty in two clinically relevant situations. METHODS: Twenty-five head-and-neck (HN) and 25 pancreatic cancer patients previously treated with 18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT)-based planning optimization were considered. Seven FDG-based contours were delineated for tumour (T) and positive lymph nodes (N, for HN patients only) following manual (2 observers), semi-automatic (based on SUV maximum gradient: PET_Edge) and automatic (40%, 50%, 60%, 70% SUV_max thresholds) methods. Seventy-three RF (14 of first order and 59 of higher order) were extracted using the CGITA software (v.1.4). The impact of delineation on volume agreement and RF was assessed by DICE and Intra-class Correlation Coefficients (ICC). RESULTS: A large disagreement between manual and SUV_max method was found for thresholds  ≥50%. Inter-observer variability showed median DICE values between 0.81 (HN-T) and 0.73 (pancreas). Volumes defined by PET_Edge were better consistent with the manual ones compared to SUV40%. Regarding RF, 19%/19%/47% of the features showed ICC < 0.80 between observers for HN-N/HN-T/pancreas, mostly in the Voxel-alignment matrix and in the intensity-size zone matrix families. RFs with ICC < 0.80 against manual delineation (taking the worst value) increased to 44%/36%/61% for PET_Edge and to 69%/53%/75% for SUV40%. CONCLUSIONS: About 80%/50% of 72 RF were consistent between observers for HN/pancreas patients. PET_edge was sufficiently robust against manual delineation while SUV40% showed a worse performance. This result suggests the possibility to replace manual with semi-automatic delineation of HN and pancreas tumours in studies including PET radiomic analyses.

FDG-PET and CSF biomarker accuracy in prediction of conversion to different dementias in a large multicentre MCI cohort.

Background/aims: In this multicentre study in clinical settings, we assessed the accuracy of optimized procedures for FDG-PET brain metabolism and CSF classifications in predicting or excluding the conversion to Alzheimer's disease (AD) dementia and non-AD dementias. Methods: We included 80 MCI subjects with neurological and neuropsychological assessments, FDG-PET scan and CSF measures at entry, all with clinical follow-up. FDG-PET data were analysed with a validated voxel-based SPM method. Resulting single-subject SPM maps were classified by five imaging experts according to the disease-specific patterns, as "typical-AD", "atypical-AD" (i.e. posterior cortical atrophy, asymmetric logopenic AD variant, frontal-AD variant), "non-AD" (i.e. behavioural variant FTD, corticobasal degeneration, semantic variant FTD; dementia with Lewy bodies) or "negative" patterns. To perform the statistical analyses, the individual patterns were grouped either as "AD dementia vs. non-AD dementia (all diseases)" or as "FTD vs. non-FTD (all diseases)". Aß42, total and phosphorylated Tau CSF-levels were classified dichotomously, and using the Erlangen Score algorithm. Multivariate logistic models tested the prognostic accuracy of FDG-PET-SPM and CSF dichotomous classifications. Accuracy of Erlangen score and Erlangen Score aided by FDG-PET SPM classification was evaluated. Results: The multivariate logistic model identified FDG-PET "AD" SPM classification (Expß = 19.35, 95% C.I. 4.8-77.8, p < 0.001) and CSF Aß42 (Expß = 6.5, 95% C.I. 1.64-25.43, p < 0.05) as the best predictors of conversion from MCI to AD dementia. The "FTD" SPM pattern significantly predicted conversion to FTD dementias at follow-up (Expß = 14, 95% C.I. 3.1-63, p < 0.001). Overall, FDG-PET-SPM classification was the most accurate biomarker, able to correctly differentiate either the MCI subjects who converted to AD or FTD dementias, and those who remained stable or reverted to normal cognition (Expß = 17.9, 95% C.I. 4.55-70.46, p < 0.001). Conclusions: Our results support the relevant role of FDG-PET-SPM classification in predicting progression to different dementia conditions in prodromal MCI phase, and in the exclusion of progression, outperforming CSF biomarkers.

FDG-PET/CT Predicts Outcome in Oropharingeal Carcinoma Patients Undergoing Intensity Modulated Radiation Therapy with Dose Escalation to FDG-avid Tumour Volumes.

OBJECTIVE: To evaluate the predictive value of FDG-PET/CT parameters on outcome of oropharyngeal squamocellular cancer (OSCC) patients undergoing helical tomotherapy (HTT), with dose escalation to FDG-PET/CT positive tumour volumes using the simultaneous integrated boost (SIB) technique. MATERIALS AND METHODS: We analysed 41 patients studied by FDG-PET/CT and treated with radical intent between 2005 and 2014 for OSCC. HTT-SIB was delivered in 30 fractions concomitantly: 69 Gy, as SIB, to the PET-positive volume (biological target volume - BTV-PET), both to the primary tumour (T) and lymph nodes (N), 66 Gy to the T and positive N, 54 Gy to the laterocervical nodes at risk. Selected PET parameters were recovered: maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) obtained with different thresholds (40-50-60% of the SUVmax) for T and N. The correlation between these parameters and the 3-year overall (OS), cancer specific (CSS), disease free (DFS), local relapse free for T and N (LRFS-T and LRFS-N) and distant metastasis free (DMFS) survivals was investigated. RESULTS: The median follow-up was 37 months (range: 3-125). The 3-year OS, CSS, DFS, LRFST, LRFS-N and DMFS were 86%, 88%, 76%, 83%, 88% and 91%, respectively. BTVT+ N>30.9cc and BTV-T>22.4cc were correlated with CSS (p=0.02) and OS (p=0.006) respectively; TLG-T-60>34.6cc was correlated with CSS (p=0.04) and OS (p=0.01). MTV-T-60>4.4cc could predict a higher risk of relapse/death (CSS: p=0.033; hazard ratio (HR) =10.92; OS: p=0.01; HR=16.4; LRFS-T: p=0.02; HR=13.90; LRFS-T+N: p=0.03; HR=6.50). CONCLUSION: PET parameters predicted survival outcomes and may be considered in the future in the implementation of more personalized treatment schedules in patients affected by OSCC undergoing radiotherapy. FDG-PET/CT dose escalated HTT-SIB allowed very promising 3-year disease control rates in OSCC patients.

Simultaneous PET-MRI Studies of the Concordance of Atrophy and Hypometabolism in Syndromic Variants of Alzheimer's Disease and Frontotemporal Dementia: An Extended Case Series.

BACKGROUND: Simultaneous PET-MRI is used to compare patterns of cerebral hypometabolism and atrophy in six different dementia syndromes. OBJECTIVES: The primary objective was to conduct an initial exploratory study regarding the concordance of atrophy and hypometabolism in syndromic variants of Alzheimer's disease (AD) and frontotemporal dementia (FTD). The secondary objective was to determine the effect of image analysis methods on determination of atrophy and hypometabolism. METHOD: PET and MRI data were acquired simultaneously on 24 subjects with six variants of AD and FTD (n = 4 per group). Atrophy was rated visually and also quantified with measures of cortical thickness. Hypometabolism was rated visually and also quantified using atlas- and SPM-based approaches. Concordance was measured using weighted Cohen's kappa. RESULTS: Atrophy-hypometabolism concordance differed markedly between patient groups; kappa scores ranged from 0.13 (nonfluent/agrammatic variant of primary progressive aphasia, nfvPPA) to 0.49 (posterior cortical variant of AD, PCA). Heterogeneity was also observed within groups; the confidence intervals of kappa scores ranging from 0-0.25 for PCA to 0.29-0.61 for nfvPPA. More widespread MRI and PET changes were identified using quantitative methods than on visual rating. CONCLUSION: The marked differences in concordance identified in this initial study may reflect differences in the molecular pathologies underlying AD and FTD syndromic variants but also operational differences in the methods used to diagnose these syndromes. The superior ability of quantitative methodologies to detect changes on PET and MRI, if confirmed on larger cohorts, may favor their usage over qualitative visual inspection in future clinical diagnostic practice.

Validation of an optimized SPM procedure for FDG-PET in dementia diagnosis in a clinical setting.

Diagnostic accuracy in FDG-PET imaging highly depends on the operating procedures. In this clinical study on dementia, we compared the diagnostic accuracy at a single-subject level of a) Clinical Scenarios, b) Standard FDG Images and c) Statistical Parametrical (SPM) Maps generated via a new optimized SPM procedure. We evaluated the added value of FDG-PET, either Standard FDG Images or SPM Maps, to Clinical Scenarios. In 88 patients with neurodegenerative diseases (Alzheimer's Disease-AD, Frontotemporal Lobar Degeneration-FTLD, Dementia with Lewy bodies-DLB and Mild Cognitive Impairment-MCI), 9 neuroimaging experts made a forced diagnostic decision on the basis of the evaluation of the three types of information. There was also the possibility of a decision of normality on the FDG-PET images. The clinical diagnosis confirmed at a long-term follow-up was used as the gold standard. SPM Maps showed higher sensitivity and specificity (96% and 84%), and better diagnostic positive (6.8) and negative (0.05) likelihood ratios compared to Clinical Scenarios and Standard FDG Images. SPM Maps increased diagnostic accuracy for differential diagnosis (AD vs. FTD; beta 1.414, p = 0.019). The AUC of the ROC curve was 0.67 for SPM Maps, 0.57 for Clinical Scenarios and 0.50 for Standard FDG Images. In the MCI group, SPM Maps showed the highest predictive prognostic value (mean LOC = 2.46), by identifying either normal brain metabolism (exclusionary role) or hypometabolic patterns typical of different neurodegenerative conditions.