Detection of individual brain tau deposition in Alzheimer's disease based on latent feature-enhanced generative adversarial network.

OBJECTIVE: The conventional methods for interpreting tau PET imaging in Alzheimer's disease (AD), including visual assessment and semi-quantitative analysis of fixed hallmark regions, are insensitive to detect individual small lesions because of the spatiotemporal neuropathology's heterogeneity. In this study, we proposed a latent feature-enhanced generative adversarial network model for the automatic extraction of individual brain tau deposition regions. METHODS: The latent feature-enhanced generative adversarial network we propose can learn the distribution characteristics of tau PET images of cognitively normal individuals and output the abnormal distribution regions of patients. This model was trained and validated using 1131 tau PET images from multiple centres (with distinct races, i.e., Caucasian and Mongoloid) with different tau PET ligands. The overall quality of synthetic imaging was evaluated using structural similarity (SSIM), peak signal to noise ratio (PSNR), and mean square error (MSE). The model was compared to the fixed templates method for diagnosing and predicting AD. RESULTS: The reconstructed images archived good quality, with SSIM = 0.967 ± 0.008, PSNR = 31.377 ± 3.633, and MSE = 0.0011 ± 0.0007 in the independent test set. The model showed higher classification accuracy (AUC = 0.843, 95 % CI = 0.796-0.890) and stronger correlation with clinical scales (r = 0.508, P < 0.0001). The model also achieved superior predictive performance in the survival analysis of cognitive decline, with a higher hazard ratio: 3.662, P < 0.001. INTERPRETATION: The LFGAN4Tau model presents a promising new approach for more accurate detection of individualized tau deposition. Its robustness across tracers and races makes it a potentially reliable diagnostic tool for AD in practice.

Characterization of tau propagation pattern and cascading hypometabolism from functional connectivity in Alzheimer's disease.

Tau pathology and its spatial propagation in Alzheimer's disease (AD) play crucial roles in the neurodegenerative cascade leading to dementia. However, the underlying mechanisms linking tau spreading to glucose metabolism remain elusive. To address this, we aimed to examine the association between pathologic tau aggregation, functional connectivity, and cascading glucose metabolism and further explore the underlying interplay mechanisms. In this prospective cohort study, we enrolled 79 participants with 18F-Florzolotau positron emission tomography (PET), 18F-fluorodeoxyglucose PET, resting-state functional, and anatomical magnetic resonance imaging (MRI) images in the hospital-based Shanghai Memory Study. We employed generalized linear regression and correlation analyses to assess the associations between Florzolotau accumulation, functional connectivity, and glucose metabolism in whole-brain and network-specific manners. Causal mediation analysis was used to evaluate whether functional connectivity mediates the association between pathologic tau and cascading glucose metabolism. We examined 22 normal controls and 57 patients with AD. In the AD group, functional connectivity was associated with Florzolotau covariance (ß = .837, r = 0.472, p < .001) and glucose covariance (ß = 1.01, r = 0.499, p < .001). Brain regions with higher tau accumulation tend to be connected to other regions with high tau accumulation through functional connectivity or metabolic connectivity. Mediation analyses further suggest that functional connectivity partially modulates the influence of tau accumulation on downstream glucose metabolism (mediation proportion: 49.9%). Pathologic tau may affect functionally connected neurons directly, triggering downstream glucose metabolism changes. This study sheds light on the intricate relationship between tau pathology, functional connectivity, and downstream glucose metabolism, providing critical insights into AD pathophysiology and potential therapeutic targets.

Associations between sex, body mass index and the individual microglial response in Alzheimer's disease.

BACKGROUND AND OBJECTIVES: 18-kDa translocator protein position-emission-tomography (TSPO-PET) imaging emerged for in vivo assessment of neuroinflammation in Alzheimer's disease (AD) research. Sex and obesity effects on TSPO-PET binding have been reported for cognitively normal humans (CN), but such effects have not yet been systematically evaluated in patients with AD. Thus, we aimed to investigate the impact of sex and obesity on the relationship between ß-amyloid-accumulation and microglial activation in AD. METHODS: 49 patients with AD (29 females, all Aß-positive) and 15 Aß-negative CN (8 female) underwent TSPO-PET ([18F]GE-180) and ß-amyloid-PET ([18F]flutemetamol) imaging. In 24 patients with AD (14 females), tau-PET ([18F]PI-2620) was additionally available. The brain was parcellated into 218 cortical regions and standardized-uptake-value-ratios (SUVr, cerebellar reference) were calculated. Per region and tracer, the regional increase of PET SUVr (z-score) was calculated for AD against CN. The regression derived linear effect of regional Aß-PET on TSPO-PET was used to determine the Aß-plaque-dependent microglial response (slope) and the Aß-plaque-independent microglial response (intercept) at the individual patient level. All read-outs were compared between sexes and tested for a moderation effect of sex on associations with body mass index (BMI). RESULTS: In AD, females showed higher mean cortical TSPO-PET z-scores (0.91 ± 0.49; males 0.30 ± 0.75; p = 0.002), while Aß-PET z-scores were similar. The Aß-plaque-independent microglial response was stronger in females with AD (+ 0.37 ± 0.38; males with AD - 0.33 ± 0.87; p = 0.006), pronounced at the prodromal stage. On the contrary, the Aß-plaque-dependent microglial response was not different between sexes. The Aß-plaque-independent microglial response was significantly associated with tau-PET in females (Braak-II regions: r = 0.757, p = 0.003), but not in males. BMI and the Aß-plaque-independent microglial response were significantly associated in females (r = 0.44, p = 0.018) but not in males (BMI*sex interaction: F(3,52) = 3.077, p = 0.005). CONCLUSION: While microglia response to fibrillar Aß is similar between sexes, women with AD show a stronger Aß-plaque-independent microglia response. This sex difference in Aß-independent microglial activation may be associated with tau accumulation. BMI is positively associated with the Aß-plaque-independent microglia response in females with AD but not in males, indicating that sex and obesity need to be considered when studying neuroinflammation in AD.

90Y post-radioembolization clinical assessment with whole-body Biograph Vision Quadra PET/CT: image quality, tumor, liver and lung dosimetry.

PURPOSE: Evaluation of 90Y liver radioembolization post-treatment clinical data using a whole-body Biograph Vision Quadra PET/CT to investigate the potential of protocol optimization in terms of scan time and dosimetry. METHODS: 17 patients with hepatocellular carcinoma with median (IQR) injected activity 2393 (1348-3298) MBq were included. Pre-treatment dosimetry plan was based on 99mTc-MAA SPECT/CT with Simplicit90Y™ and post-treatment validation with Quadra using Simplicit90Y™ and HERMIA independently. Regarding the image analysis, mean and peak SNR, the coefficient of variation (COV) and lesion-to-background ratio (LBR) were evaluated. For the post-treatment dosimetry validation, the mean tumor, whole liver and lung absorbed dose evaluation was performed using Simplicit90Y and HERMES. Images were reconstructed with 20-, 15-, 10-, 5- and 1- min sinograms with 2, 4, 6 and 8 iterations. Wilcoxon signed rank test was used to show statistical significance (p < 0.05). RESULTS: There was no difference of statistical significance between 20- and 5- min reconstructed times for the peak SNR, COV and LBR. In addition, there was no difference of statistical significance between 20- and 1- min reconstructed times for all dosimetry metrics. Lung dosimetry showed consistently lower values than the expected. Tumor absorbed dose based on Simplicit90Y™ was similar to the expected while HERMES consistently underestimated significantly the measured tumor absorbed dose. Finally, there was no difference of statistical significance between expected and measured tumor, whole liver and lung dose for all reconstruction times. CONCLUSION: In this study we evaluated, in terms of image quality and dosimetry, whole-body PET clinical images of patients after having been treated with 90Y microspheres radioembolization for liver cancer. Compared to the 20-min standard scan, the simulated 5-min reconstructed images provided equal image peak SNR and noise behavior, while performing also similarly for post-treatment dosimetry of tumor, whole liver and lung absorbed doses.

Distinct subtypes of spatial brain metabolism patterns in Alzheimer's disease identified by deep learning-based FDG PET clusters.

PURPOSE: Alzheimer's disease (AD) is a heterogeneous disease that presents a broad spectrum of clinicopathologic profiles. To date, objective subtyping of AD independent of disease progression using brain imaging has been required. Our study aimed to extract representations of unique brain metabolism patterns different from disease progression to identify objective subtypes of AD. METHODS: A total of 3620 FDG brain PET images with AD, mild cognitive impairment (MCI), and cognitively normal (CN) were obtained from the ADNI database from 1607 participants at enrollment and follow-up visits. A conditional variational autoencoder model was trained on FDG brain PET images of AD patients with the corresponding condition of AD severity score. The k-means algorithm was applied to generate clusters from the encoded representations. The trained deep learning-based cluster model was also transferred to FDG PET of MCI patients and predicted the prognosis of subtypes for conversion from MCI to AD. Spatial metabolism patterns, clinical and biological characteristics, and conversion rate from MCI to AD were compared across the subtypes. RESULTS: Four distinct subtypes of spatial metabolism patterns in AD with different brain pathologies and clinical profiles were identified: (i) angular, (ii) occipital, (iii) orbitofrontal, and (iv) minimal hypometabolic patterns. The deep learning model was also successfully transferred for subtyping MCI, and significant differences in frequency (P < 0.001) and risk of conversion (log-rank P < 0.0001) from MCI to AD were observed across the subtypes, highest in S2 (35.7%) followed by S1 (23.4%). CONCLUSION: We identified distinct subtypes of AD with different clinicopathologic features. The deep learning-based approach to distinguish AD subtypes on FDG PET could have implications for predicting individual outcomes and provide a clue to understanding the heterogeneous pathophysiology of AD.

FDG imaging with long-axial field-of-view PET/CT in patients with high blood glucose-a matched pair analysis.

PURPOSE: High blood glucose (hBG) in patients undergoing [18F]FDG PET/CT scans often results in rescheduling the examination, which may lead to clinical delay for the patient and decrease productivity for the department. The aim of this study was to evaluate whether long-axial field-of-view (LAFOV) PET/CT can minimize the effect of altered bio-distribution in hBG patients and is able to provide diagnostic image quality in hBG situations. MATERIALS AND METHODS: Oncologic patients with elevated blood glucose (≥ 8.0 mmol/l) and normal blood glucose (< 8.0 mmol/l, nBG) levels were matched for tumor entity, gender, age, and BMI. hBG patients were further subdivided into two groups (BG 8-11 mmol/l and BG > 11 mmol/l). Tracer uptake in the liver, muscle, and tumor was evaluated. Furthermore, image quality was compared between long acquisitions (ultra-high sensitivity mode, 360 s) on a LAFOV PET/CT and routine acquisitions equivalent to a short-axial field-of-view scanner (simulated (sSAFOV), obtained with high sensitivity mode, 120 s). Tumor-to-background ratio (TBR) and contrast-to-noise ratio (CNR) were used as the main image quality criteria. RESULTS: Thirty-one hBG patients met the inclusion criteria and were matched with 31 nBG patients. Overall, liver uptake was significantly higher in hBG patients (SUVmean, 3.07 ± 0.41 vs. 2.37 ± 0.33; p = 0.03), and brain uptake was significantly lower (SUVmax, 7.58 ± 0.74 vs. 13.38 ± 3.94; p < 0.001), whereas muscle (shoulder/gluteal) uptake showed no statistically significant difference. Tumor uptake was lower in hBG patients, resulting in a significantly lower TBR in the hBG cohort (3.48 ± 0.74 vs. 5.29 ± 1.48, p < 0.001). CNR was higher in nBG compared to hBG patients (12.17 ± 4.86 vs. 23.31 ± 12.22, p < 0.001). However, subgroup analysis of nBG 8-11 mmol/l on sSAFOV PET/CT compared to hBG (> 11 mmol/l) patients examined with LAFOV PET/CT showed no statistical significant difference in CNR (19.84 ± 8.40 vs. 17.79 ± 9.3, p = 0.08). CONCLUSION: While elevated blood glucose (> 11 mmol) negatively affected TBR and CNR in our cohort, the images from a LAFOV PET-scanner had comparable CNR to PET-images acquired from nBG patients using sSAFOV PET/CT. Therefore, we argue that oncologic patients with increased blood sugar levels might be imaged safely with LAFOV PET/CT when rescheduling is not feasible.

The clinical acceptability of short versus long duration acquisitions for head and neck cancer using long-axial field-of-view PET/CT: a retrospective evaluation.

PURPOSE: To evaluate the utility of long duration (10 min) acquisitions compared to standard 4 min scans in the evaluation of head and neck cancer (HNC) using a long-axial field-of-view (LAFOV) system in 2-[18F]FDG PET/CT. METHODS: HNC patients undergoing LAFOV PET/CT were included retrospectively according to a predefined sample size calculation. For each acquisition, FDG avid lymph nodes (LN) which were highly probable or equivocal for malignancy were identified by two board certified nuclear medicine physicians in consensus. The aim of this study was to establish the clinical acceptability of short-duration (4 min, C40%) acquisitions compared to full-count (10 min, C100%) in terms of the detection of LN metastases in HNC. Secondary endpoints were the positive predictive value for LN status (PPV) and comparison of SUVmax at C40% and C100%. Histology reports or confirmatory imaging were the reference standard. RESULTS: A total of 1218 records were screened and target recruitment was met with n = 64 HNC patients undergoing LAFOV. Median age was 65 years (IQR: 59-73). At C40%, a total of 387 lesions were detected (highly probable LN n = 274 and equivocal n = 113. The total number of lesions detected at C100% acquisition was 439, of them 291 (66%) highly probable LN and 148 (34%) equivocal. Detection rate between the two acquisitions did not demonstrate any significant differences (Pearson's Chi-Square test, p = 0.792). Sensitivity, specificity, PPV, NPV and accuracy for C40% were 83%, 44%, 55%, 76% and 36%, whilst for C100% were 85%, 56%, 55%, 85% and 43%, respectively. The improved accuracy reached borderline significance (p = 0.057). At the ROC analysis, lower SUVmax was identified for C100% (3.5) compared to C40% (4.5). CONCLUSION: In terms of LN detection, C40% acquisitions showed no significant difference compared to the C100% acquisitions. There was some improvement for lesions detection at C100%, with a small increment in accuracy reaching borderline significance, suggestive that the higher sensitivity afforded by LAFOV might translate to improved clinical performance in some patients.

Internal dosimetry study of [82Rb]Cl using a long axial field-of-view PET/CT.

PURPOSE: Long axial field-of-view (LAFOV) positron emission tomography (PET) systems allow to image all major organs with one bed position, which is particularly useful for acquiring whole-body dynamic data using short-lived radioisotopes like 82Rb. METHODS: We determined the absorbed dose in target organs of three subjects (29, 40, and 57 years old) using two different methods, i.e., MIRD and voxel dosimetry. The subjects were injected with 407.0 to 419.61 MBq of [82Rb]Cl and were scanned dynamically for 7 min with a LAFOV PET/CT scanner. RESULTS: Using the MIRD formalism and voxel dosimetry, the absorbed dose ranged from 1.84 to 2.78 µGy/MBq (1.57 to 3.92 µGy/MBq for voxel dosimetry) for the heart wall, 2.76 to 5.73 µGy/MBq (3.22 to 5.37 µGy/MBq for voxel dosimetry) for the kidneys, and 0.94 to 1.88 µGy/MBq (0.98 to 1.92 µGy/MBq for voxel dosimetry) for the lungs. The total body effective dose lied between 0.50 and 0.76 µSv/MBq. CONCLUSION: Our study suggests that the radiation dose associated with [82Rb]Cl PET/CT can be assessed by means of dynamic LAFOV PET and that it is lower compared to literature values.

Sedation-free pediatric [18F]FDG imaging on totalbody PET/CT with the assistance of artificial intelligence.

PURPOSE: While sedation is routinely used in pediatric PET examinations to preserve diagnostic quality, it may result in side effects and may affect the radiotracer's biodistribution. This study aims to investigate the feasibility of sedation-free pediatric PET imaging using ultra-fast total-body (TB) PET scanners and deep learning (DL)-based attenuation and scatter correction (ASC). METHODS: This retrospective study included TB PET (uExplorer) imaging of 35 sedated pediatric patients under four years old to determine the minimum effective scanning time. A DL-based ASC method was applied to enhance PET quantification. Both quantitative and qualitative assessments were conducted to evaluate the image quality of ultra-fast DL-ASC PET. Five non-sedated pediatric patients were subsequently used to validate the proposed approach. RESULTS: Comparisons between standard 300-second and ultra-fast 15-second imaging, CT-ASC and DL-ASC ultra-fast 15-second images, as well as DL-ASC ultra-fast 15-second images in non-sedated and sedated patients, showed no significant differences in qualitative scoring, lesion detectability, and quantitative Standard Uptake Value (SUV) (P = ns). CONCLUSIONS: This study demonstrates that pediatric PET imaging can be effectively performed without sedation by combining ultra-fast imaging techniques with a DL-based ASC. This advancement in sedation-free ultra-fast PET imaging holds potential for broader clinical adoption.

Long-axial field-of-view PET/CT for the assessment of inflammation in calcified coronary artery plaques with [68 Ga]Ga-DOTA-TOC.

PURPOSE: Inflamed, prone-to-rupture coronary plaques are an important cause of myocardial infarction and their early identification is crucial. Atherosclerotic plaques are characterized by overexpression of the type-2 somatostatin receptor (SST2) in activated macrophages. SST2 ligand imaging (e.g. with [68 Ga]Ga-DOTA-TOC) has shown promise in detecting and quantifying the inflammatory activity within atherosclerotic plaques. However, the sensitivity of standard axial field of view (SAFOV) PET scanners may be suboptimal for imaging coronary arteries. Long-axial field of view (LAFOV) PET/CT scanners may help overcome this limitation. We aim to assess the ability of [68 Ga]Ga-DOTA-TOC LAFOV-PET/CT in detecting calcified, SST2 overexpressing coronary artery plaques. METHODS: In this retrospective study, 108 oncological patients underwent [68 Ga]Ga-DOTA-TOC PET/CT on a LAFOV system. [68 Ga]Ga-DOTA-TOC uptake and calcifications in the coronary arteries were evaluated visually and semi-quantitatively. Data on patients' cardiac risk factors and coronary artery calcium score were also collected. Patients were followed up for 21.5 ± 3.4 months. RESULTS: A total of 66 patients (61.1%) presented with calcified coronary artery plaques. Of these, 32 patients had increased [68 Ga]Ga-DOTA-TOC uptake in at least one coronary vessel (TBR: 1.65 ± 0.53). Patients with single-vessel calcifications showed statistically significantly lower uptake (SUVmax 1.10 ± 0.28) compared to patients with two- (SUVmax 1.31 ± 0.29, p < 0.01) or three-vessel calcifications (SUVmax 1.24 ± 0.33, p < 0.01). There was a correlation between coronary artery calcium score (CACS) and [68 Ga]Ga-DOTA-TOC uptake, especially in the LAD (p = 0.02). Stroke and all-cause death occurred more frequently in patients with increased [68 Ga]Ga-DOTA-TOC uptake (15.63% vs. 0%; p:0.001 and 21.88% vs. 6.58%; p: 0.04, respectively) during the follow-up period. CONCLUSION: [68 Ga]Ga-DOTA-TOC as a marker for the macrophage activity can reveal unknown cases of inflamed calcified coronary artery plaques using a LAFOV PET system. [68 Ga]Ga-DOTA-TOC uptake increased with the degree of calcification and correlated with higher risk of stroke and all-cause death. [68 Ga]Ga-DOTA-TOC LAFOV PET/CT may be useful to assess patients' cardiovascular risk.

Efficient characterization of multiple binding sites of small molecule imaging ligands on amyloid-beta, tau and alpha-synuclein.

PURPOSE: There is an unmet need for compounds to detect fibrillar forms of alpha-synuclein (αSyn) and 4-repeat tau, which are critical in many neurodegenerative diseases. Here, we aim to develop an efficient surface plasmon resonance (SPR)-based assay to facilitate the characterization of small molecules that can bind these fibrils. METHODS: SPR measurements were conducted to characterize the binding properties of fluorescent ligands/compounds toward recombinant amyloid-beta (Aß)42, K18-tau, full-length 2N4R-tau and αSyn fibrils. In silico modeling was performed to examine the binding pockets of ligands on αSyn fibrils. Immunofluorescence staining of postmortem brain tissue slices from Parkinson's disease patients and mouse models was performed with fluorescence ligands and specific antibodies. RESULTS: We optimized the protocol for the immobilization of Aß42, K18-tau, full-length 2N4R-tau and αSyn fibrils in a controlled aggregation state on SPR-sensor chips and for assessing their binding to ligands. The SPR results from the analysis of binding kinetics suggested the presence of at least two binding sites for all fibrils, including luminescent conjugated oligothiophenes, benzothiazole derivatives, nonfluorescent methylene blue and lansoprazole. In silico modeling studies for αSyn (6H6B) revealed four binding sites with a preference for one site on the surface. Immunofluorescence staining validated the detection of pS129-αSyn positivity in the brains of Parkinson's disease patients and αSyn preformed-fibril injected mice, 6E10-positive Aß in arcAß mice, and AT-8/AT-100-positivity in pR5 mice. CONCLUSION: SPR measurements of small molecules binding to Aß42, K18/full-length 2N4R-tau and αSyn fibrils suggested the existence of multiple binding sites. This approach may provide efficient characterization of compounds for neurodegenerative disease-relevant proteinopathies.

Individual cerebellar metabolic connectome in patients with MTLE and NTLE associated with surgical prognosis.

PURPOSE: This study aimed to comprehensively explore the different metabolic connectivity topological changes in MTLE and NTLE, as well as their association with surgical outcomes. METHODS: This study enrolled a cohort of patients with intractable MTLE and NTLE. Each individual's metabolic connectome, as determined by Kullback-Leibler divergence similarity estimation for the [18F]FDG PET image, was employed to conduct a comprehensive analysis of the cerebral metabolic network. Alterations in network connectivity were assessed by extracting and evaluating the strength of edge and weighted connectivity. By utilizing these two connectivity strength metrics with the cerebellum, we explored the network properties of connectivity and its association with prognosis in surgical patients. RESULTS: Both MTLE and NTLE patients exhibited substantial alterations in the connectivity of the metabolic network at the edge and nodal levels (p < 0.01, FDR corrected). The key disparity between MTLE and NTLE was observed in the cerebellum. In MTLE, there was a predominance of increased connectivity strength in the cerebellum. Whereas, a decrease in cerebellar connectivity was identified in NTLE. It was found that in MTLE, higher edge connectivity and weighted connectivity strength in the contralateral cerebellar hemisphere correlated with improved surgical outcomes. Conversely, in NTLE, a higher edge metabolic connectivity strength in the ipsilateral cerebellar hemisphere suggested a worse surgical prognosis. CONCLUSION: The cerebellum exhibits distinct topological characteristics in the metabolic networks between MTLE and NTLE. The hyper- or hypo-metabolic connectivity in the cerebellum may be a prognostic biomarker of surgical prognosis, which might aid in therapeutic decision-making for TLE individuals.

Pre-therapy PET-based voxel-wise dosimetry prediction by characterizing intra-organ heterogeneity in PSMA-directed radiopharmaceutical theranostics.

BACKGROUND AND OBJECTIVE: Treatment planning through the diagnostic dimension of theranostics provides insights into predicting the absorbed dose of RPT, with the potential to individualize radiation doses for enhancing treatment efficacy. However, existing studies focusing on dose prediction from diagnostic data often rely on organ-level estimations, overlooking intra-organ variations. This study aims to characterize the intra-organ theranostic heterogeneity and utilize artificial intelligence techniques to localize them, i.e. to predict voxel-wise absorbed dose map based on pre-therapy PET. METHODS: 23 patients with metastatic castration-resistant prostate cancer treated with [177Lu]Lu-PSMA I&T RPT were retrospectively included. 48 treatment cycles with pre-treatment PET imaging and at least 3 post-therapeutic SPECT/CT imaging were selected. The distribution of PET tracer and RPT dose was compared for kidney, liver and spleen, characterizing intra-organ heterogeneity differences. Pharmacokinetic simulations were performed to enhance the understanding of the correlation. Two strategies were explored for pre-therapy voxel-wise dosimetry prediction: (1) organ-dose guided direct projection; (2) deep learning (DL)-based distribution prediction. Physical metrics, dose volume histogram (DVH) analysis, and identity plots were applied to investigate the predicted absorbed dose map. RESULTS: Inconsistent intra-organ patterns emerged between PET imaging and dose map, with moderate correlations existing in the kidney (r = 0.77), liver (r = 0.5), and spleen (r = 0.58) (P < 0.025). Simulation results indicated the intra-organ pharmacokinetic heterogeneity might explain this inconsistency. The DL-based method achieved a lower average voxel-wise normalized root mean squared error of 0.79 ± 0.27%, regarding to ground-truth dose map, outperforming the organ-dose guided projection (1.11 ± 0.57%) (P < 0.05). DVH analysis demonstrated good prediction accuracy (R2 = 0.92 for kidney). The DL model improved the mean slope of fitting lines in identity plots (199% for liver), when compared to the theoretical optimal results of the organ-dose approach. CONCLUSION: Our results demonstrated the intra-organ heterogeneity of pharmacokinetics may complicate pre-therapy dosimetry prediction. DL has the potential to bridge this gap for pre-therapy prediction of voxel-wise heterogeneous dose map.

Metabolic network alterations as a supportive biomarker in dementia with Lewy bodies with preserved dopamine transmission.

PURPOSE: Metabolic network analysis of FDG-PET utilizes an index of inter-regional correlation of resting state glucose metabolism and has been proven to provide complementary information regarding the disease process in parkinsonian syndromes. The goals of this study were (i) to evaluate pattern similarities of glucose metabolism and network connectivity in dementia with Lewy bodies (DLB) subjects with subthreshold dopaminergic loss compared to advanced disease stages and to (ii) investigate metabolic network alterations of FDG-PET for discrimination of patients with early DLB from other neurodegenerative disorders (Alzheimer's disease, Parkinson's disease, multiple system atrophy) at individual patient level via principal component analysis (PCA). METHODS: FDG-PETs of subjects with probable or possible DLB (n = 22) without significant dopamine deficiency (z-score < 2 in putamen binding loss on DaT-SPECT compared to healthy controls (HC)) were scaled by global-mean, prior to volume-of-interest-based analyses of relative glucose metabolism. Single region metabolic changes and network connectivity changes were compared against HC (n = 23) and against DLB subjects with significant dopamine deficiency (n = 86). PCA was applied to test discrimination of patients with DLB from disease controls (n = 101) at individual patient level. RESULTS: Similar patterns of hypo- (parietal- and occipital cortex) and hypermetabolism (basal ganglia, limbic system, motor cortices) were observed in DLB patients with and without significant dopamine deficiency when compared to HC. Metabolic connectivity alterations correlated between DLB patients with and without significant dopamine deficiency (R2 = 0.597, p < 0.01). A PCA trained by DLB patients with dopamine deficiency and HC discriminated DLB patients without significant dopaminergic loss from other neurodegenerative parkinsonian disorders at individual patient level (area-under-the-curve (AUC): 0.912). CONCLUSION: Disease-specific patterns of altered glucose metabolism and altered metabolic networks are present in DLB subjects without significant dopaminergic loss. Metabolic network alterations in FDG-PET can act as a supporting biomarker in the subgroup of DLB patients without significant dopaminergic loss at symptoms onset.

Individual regional associations between Aß-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

ß-amyloid (Aß) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aß-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aß (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aß (AD: ßT = 0.412 ± 0.196 vs. ßA = 0.142 ± 0.123, p < 0.001; AD-CBS: ßT = 0.385 ± 0.176 vs. ßA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (ßT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aß related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases.

A metabolism-functional connectome sparse coupling method to reveal imaging markers for Alzheimer's disease based on simultaneous PET/MRI scans.

Abnormal glucose metabolism and hemodynamic changes in the brain are closely related to cognitive function, providing complementary information from distinct biochemical and physiological processes. However, it remains unclear how to effectively integrate these two modalities across distinct brain regions. In this study, we developed a connectome-based sparse coupling method for hybrid PET/MRI imaging, which could effectively extract imaging markers of Alzheimer's disease (AD) in the early stage. The FDG-PET and resting-state fMRI data of 56 healthy controls (HC), 54 subjective cognitive decline (SCD), and 27 cognitive impairment (CI) participants due to AD were obtained from SILCODE project (NCT03370744). For each participant, the metabolic connectome (MC) was constructed by Kullback-Leibler divergence similarity estimation, and the functional connectome (FC) was constructed by Pearson correlation. Subsequently, we measured the coupling strength between MC and FC at various sparse levels, assessed its stability, and explored the abnormal coupling strength along the AD continuum. Results showed that the sparse MC-FC coupling index was stable in each brain network and consistent across subjects. It was more normally distributed than other traditional indexes and captured more SCD-related brain areas, especially in the limbic and default mode networks. Compared to other traditional indices, this index demonstrated best classification performance. The AUC values reached 0.748 (SCD/HC) and 0.992 (CI/HC). Notably, we found a significant correlation between abnormal coupling strength and neuropsychological scales (p < .05). This study provides a clinically relevant tool for hybrid PET/MRI imaging, allowing for exploring imaging markers in early stage of AD and better understanding the pathophysiology along the AD continuum.

Routine 4D Cardiac CT to Identify Concomitant Transthyretin Amyloid Cardiomyopathy in Older Adults with Severe Aortic Stenosis.

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) often coexists with severe aortic stenosis (AS). Although strain analysis from cardiac MRI and echocardiography was demonstrated to predict coexisting ATTR-CM, comparable data from four-dimensional (4D) cardiac CT are lacking despite wide availability. Purpose To evaluate the diagnostic performance of 4D cardiac CT-derived parameters in identifying ATTR-CM in older adults considered for transcatheter aortic valve implantation (TAVI). Materials and Methods This prospective single-center screening study for ATTR-CM included consecutive patients with severe AS considered for TAVI who underwent 4D cardiac CT between August 2019 and August 2021 approximately 1 day before technetium 99m (99mTc) 3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) scintigraphy. The diagnostic performance of CT-based left ventricular (LV), right ventricular, and left atrial dimensions, ejection fraction (EF), and myocardial strain were evaluated against 99mTc-DPD scintigraphy as the reference standard to identify ATTR-CM. Predictors and an unweighted cardiac CT score were validated with internal bootstrapping. The assignment of variables to the score was based on cutoff values achieving the highest Youden index J. Results Among 263 participants (mean age, 83 years ± 4.6 [SD]; 149 male and 114 female participants), 99mTc-DPD scintigraphy (Perugini grade 2 or 3) confirmed coexisting ATTR-CM in 27 (10.3%). CT-derived LV mass index, LV and LA global longitudinal strain (GLS), and relative apical longitudinal strain each predicted the presence of ATTR-CM with an area under the curve (AUC) of at least 0.70. Implementing these parameters with cutoff values of 81 g/m2 or higher, -14.9% or higher, less than 11.5%, and 1.7 or higher in the CT score, respectively, yielded high diagnostic performance (AUC = 0.89; 95% CI: 0.81, 0.94; P < .001) robust to internal bootstrapping validation (AUC = 0.88; 95% CI: 0.82, 0.94). If two criteria were fulfilled, the sensitivity and specificity in the detection of ATTR-CM were 96.3% (95% CI: 81.0, 99.9) and 58.9% (95% CI: 52.3, 65.2), respectively. Conclusion When compared against 99mTc-DPD scintigraphy as the reference standard, routine 4D cardiac CT in older adults considered for TAVI provided high diagnostic performance in the detection of concomitant ATTR-CM by assessing LV and left atrial GLS, relative apical longitudinal strain, and LV mass index. ClinicalTrials.gov registration no.: NCT04061213 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tavakoli and Onder in this issue.

Microglial Activation and Connectivity in Alzheimer Disease and Aging.

OBJECTIVE: Alzheimer disease (AD) is characterized by amyloid ß (Aß) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aß and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. METHODS: We included 32 Aß-positive early AD subjects (18 women, 14 men) and 18 Aß-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. RESULTS: We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. INTERPRETATION: Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022;92:768-781.

Combined [68 Ga]Ga-PSMA-11 and low-dose 2-[18F]FDG PET/CT using a long-axial field of view scanner for patients referred for [177Lu]-PSMA-radioligand therapy.

PURPOSE: Performing 2-[18F]FDG PET/CT in addition to a PSMA-ligand PET/CT can assist in the detection of lesions with low PSMA expression and may help in prognostication and identification of patients who likely benefit from PSMA-radioligand therapy (PSMA-RLT). However, the cost and time needed for a separate PET/CT examination might hinder its routine implementation. In this communication, we present our initial experiences with additional low-dose 2-[18F]FDG PET/CT as part of a dual-tracer and same-day imaging protocol which exploits the higher sensitivity exhibited by long-axial field-of-view (LAFOV) and total-body PET/CT systems and demonstrates its feasibility. METHODS: Fourteen patients referred for evaluation for PSMA-RLT received [68 Ga]Ga-PSMA-11 PET/CT at 1 h p.i. with a standard activity of 150 MBq and an additional low-dose 2-[18F]FDG PET/CT with 40 MBq 1 h thereafter using a long-axial field-of-view PET/CT system in a single sitting and as per institutional protocol. Scans were scrutinized by two experienced nuclear medicine physicians for mismatch findings. RESULTS: The combined protocol identified additional lesions with low or absent PSMA-expression but high FDG-avidity in 1/14 (7%) patients. The protocol was easily implemented and well tolerated by all patients. CONCLUSION: Additional low-dose 2-[18F]FDG-PET/CT is feasible as part of a same-day imaging protocol and can help reveal lesions of low PSMA avidity as part of therapy assessment for [177Lu]-PSMA radioligand therapy and demonstrates higher sensitivity compared to [68 Ga]Ga-PSMA-11 PET/CT alone in some patients.

Phantom-based evaluation of yttrium-90 datasets using biograph vision quadra.

PURPOSE: The image quality characteristics of two NEMA phantoms with yttrium-90 (90Y) were evaluated on a long axial field-of-view (AFOV) PET/CT. The purpose was to identify the optimized reconstruction setup for the imaging of patients with hepatocellular carcinoma after 90Y radioembolization. METHODS: Two NEMA phantoms were used, where one had a 1:10 sphere to background activity concentration ratio and the second had cold background. Reconstruction parameters used are as follows: iterations 2 to 8, Gaussian filter 2- to 6-mm full-width-at-half-maximum, reconstruction matrices 440 × 440 and 220 × 220, high sensitivity (HS), and ultra-high sensitivity (UHS) modes. 50-, 40-, 30-, 20-, 10-, and 5-min acquisitions were reconstructed. The measurements included recovery coefficients (RC), signal-to-noise ratio (SNR), background variability, and lung error which measures the residual error in the corrections. Patient data were reconstructed with 20-, 10-, 5-, and 1-min time frames and evaluated in terms of SNR. RESULTS: The RC for the hot phantom was 0.36, 0.45, 0.53, 0.63, 0.68, and 0.84 for the spheres with diameters of 10, 13, 17, 22, 28, and 37 mm, respectively, for UHS 2 iterations, a 220 × 220 matrix, and 50-min acquisition. The RC values did not differ with acquisition times down to 20 min. The SNR was the highest for 2 iterations, measured 11.7, 16.6, 17.6, 19.4, 21.9, and 27.7 while the background variability was the lowest (27.59, 27.08, 27.36, 26.44, 30.11, and 33.51%). The lung error was 18%. For the patient dataset, the SNR was 19%, 20%, 24%, and 31% higher for 2 iterations compared to 4 iterations for 20-, 10-, 5-, and 1-min time frames, respectively. CONCLUSIONS: This study evaluates the NEMA image quality of a long AFOV PET/CT scanner with 90Y. It provides high RC for the smallest sphere compared to other standard AFOV scanners at shorter scan times. The maximum patient SNR was for 2 iterations, 20 min, while 5 min delivers images with acceptable SNR.