Standardized Uptake Value Ratio Research Articles

18F‐Florzolotau PET Imaging Unveils Tau Pathology in Dementia with Lewy Bodies

AbstractBackgroundDementia with Lewy bodies (DLB) commonly exhibits a complex neuropathology, sharing characteristics with Alzheimer's disease (AD), including tau aggregates. However, studies using the 18F‐AV‐1451 tau tracer have shown inconsistent findings regarding both the extent and topographical distribution of tau pathology in DLB.ObjectivesOur aim was to elucidate the topographical patterns of tau deposition in DLB and to investigate the in vivo pathological distinction between DLB and AD in virtue of the 18F‐Florzolotau positron emission tomography (PET) imaging.MethodsThis cross‐sectional study enrolled patients with DLB (n = 24), AD (n = 43), and cognitively healthy controls (n = 18). Clinical assessments and 18F‐Florzolotau PET imaging were performed. 18F‐Florzolotau binding was quantitatively assessed on PET images using standardized uptake value ratios and voxel‐wise analysis.Results18F‐Florzolotau PET imaging revealed widespread tau deposition across various cortical regions in DLB, uncovering heterogeneous topographical patterns. Among patients, 54.17% showed patterns similar to AD, whereas 16.67% exhibited distinct patterns. Compared to AD, DLB exhibited a unique in vivo neuropathological profile, characterized by a lower tau protein burden, heterogeneous topographical distributions, and a specific role of the medial temporal lobe in tau pathology.Conclusions18F‐Florzolotau PET imaging elucidated tau pathology patterns in DLB, providing valuable insights for future in vivo pathological differentiation and potential disease‐modifying therapies. © 2024 International Parkinson and Movement Disorder Society.

MRI-free processing of tau PET images for early detection

Abstract Tau positron emission tomography (PET) imaging in Alzheimer’s Disease (AD) is becoming increasingly common to assess in vivo tau burden. MR images are often acquired to assist with processing of PET data, including for region-of-interest definitions in native space and for normalization to template space. However, in the real-world setting, corresponding MRIs may not be available and PET processing may require MRI-free pipelines. This is particularly important and challenging as the field moves towards early detection among clinically unimpaired (CU) individuals where changes in tau PET signal are expected to be subtle. We used two independent [18F]Flortaucipir tau PET datasets to evaluate whether MRI-free PET processing can detect subtle tau PET uptake differences in Amyloid+ (A+) CU individuals (preclinical AD) versus A-. Standardized Uptake Value Ratios (SUVRs) from MRI-free compared to MRI-based methods were evaluated using linear regression and linear mixed-effects regression models. Effect size differences between A+/- CU groups in MRI-free processed cross-sectional and longitudinal tau PET SUVRs were compared to differences quantified through MRI-based processing. Regional MRI-free SUVRs were highly correlated with MRI-based SUVRs within CU individuals (average ICC = 0.90 for ADNI CU and 0.81 for A4 CU). MRI-free and MRI-based pipelines resulted in similar estimates of cross-sectional and longitudinal differences between A- and A+ CU, even in early focal regions within the medial temporal lobe.

Extracerebral Normalization of 18F-FDG PET Imaging Combined with Behavioral CRS-R Scores Predict Recovery from Disorders of Consciousness.

Identifying patients likely to regain consciousness early on is a challenge. The assessment of consciousness levels and the prediction of wakefulness probabilities are facilitated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET). This study aimed to develop a prognostic model for predicting 1-year postinjury outcomes in prolonged disorders of consciousness (DoC) using 18F-FDG PET alongside clinical behavioral scores. Eighty-seven patients with prolonged DoC newly diagnosed with behavioral Coma Recovery Scale-Revised (CRS-R) scores and 18F-FDG PET/computed tomography (18F-FDG PET/CT) scans were included. PET images were normalized by the cerebellum and extracerebral tissue, respectively. Images were divided into training and independent test sets at a ratio of 5:1. Image-based classification was conducted using the DenseNet121 network, whereas tabular-based deep learning was employed to train depth features extracted from imaging models and behavioral CRS-R scores. The performance of the models was assessed and compared using the McNemar test. Among the 87 patients with DoC who received routine treatments, 52 patients showed recovery of consciousness, whereas 35 did not. The classification of the standardized uptake value ratio by extracerebral tissue model demonstrated a higher specificity and lower sensitivity in predicting consciousness recovery than the classification of the standardized uptake value ratio by cerebellum model. With area under the curve values of 0.751 ± 0.093 and 0.412 ± 0.104 on the test sets, respectively, the difference is not statistically significant (P = 0.73). The combination of standardized uptake value ratio by extracerebral tissue and computed tomography depth features with behavioral CRS-R scores yielded the highest classification accuracy, with area under the curve values of 0.950 ± 0.027 and 0.933 ± 0.015 on the training and test sets, respectively, outperforming any individual mode. In this preliminary study, a multimodal prognostic model based on 18F-FDG PET extracerebral normalization and behavioral CRS-R scores facilitated the prediction of recovery in DoC.

NIMG-80. IMPACT OF KETOGENIC DIET ON MOLECULAR METABOLIC IMAGING WITH [18F]FDG AND [18F]DASA-23 POSITRON EMISSION TOMOGRAPHY IN A PATIENT WITH GLIOBLASTOMA

Abstract The standard-of-care for neuroimaging in patients with glioblastoma is contrast-enhanced MRI, which does not provide tumor metabolism information. Although [18F]FDG PET is used to image tumor metabolism in many solid organ cancers, it has limited benefit in atients with brain tumors due to the high level of glucose uptake in normal brain cells. [18F]DASA-23 is a novel PET radiotracer that assesses the levels of pyruvate kinase M2 (PKM2), a protein highly expressed in cancer cells, which undergo aberrant glycolysis. Despite [18F]DASA-23 having a higher tumor-to-background ratio (TBR) of standardized uptake values (SUVs) in the brain compared to [18F]FDG, both may be susceptible to altered carbohydrate metabolism in the setting of a ketogenic diet (KD). We report the case of a patient with glioblastoma on a KD, whose [18F]FDG and [18F]DASA-23 PET brain scans were limited in identifying disease progression (PD). Background was defined as the white matter contralateral to the tumor, at the level of the centrum semiovale, for TBR of SUVmax. A 39-year-old man was diagnosed with right temporal glioblastoma after previous diagnoses of grade 2 gliofibrillary oligodendroglioma (age 20) and grade 3 anaplastic oligodendroglioma (age 22). He began a KD after the glioblastoma diagnosis. 21 months later, TBR on [18F]DASA-23 PET was 1.38. One month later, surveillance brain MRI showed PD. Ten days later, TBR on [18F]FDG PET was 1.03. The patient died 15 months later. Despite MRI-based PD, the TBR of each radiotracer was not markedly elevated, although the [18F]DASA-23 TBR 1-month pre-PD was 34% greater than the [18F]FDG PET TBR 10-days post-PD. This may suggest a limitation of metabolic imaging by PET in the setting of a KD, and provide an opportunity to develop novel PET radiotracers that are not susceptible to the patient’s diet.

Evaluation of ComBat Harmonization for Reducing Across-Tracer Differences in Regional Amyloid PET Analyses.

Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [18F]-florbetapir (FBP) and [11C]-Pittsburgh compound-B (PiB). One hundred thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within 90 days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified. In the head-to-head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP-to-PiB proportions. ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses.

SV2A PET shows hippocampal synaptic loss in cognitively unimpaired APOE ε4/ε4 homozygotes.

We investigated hippocampal synaptic density using synaptic vesicle 2A positron emission tomography (PET), and its association with amyloid beta (Aβ) and cognitive performance in healthy apolipoprotein E (APOE) ε4 carriers. Synaptic density was assessed in 46 individuals (APOE ε4/ε4 n=14; APOE ε3/ε4 n=16; APOE ε3/ε3 n=16) with [11C]UCB-J-PET standardized uptake value ratios (SUVRs), by using the centrum semiovale as a reference region. Differences in hippocampal [11C]UCB-J SUVRs were analyzed with analysis of variance (ANOVA) and linear models. Associations among [11C]UCB-J SUVR, Aβ, hippocampal volume, and cognitive variables were analyzed with Spearman correlation. Hippocampal synaptic density was different among the APOE groups (PANOVA=0.016): APOE ε4/ε4 carriers had lower [11C]UCB-J SUVRs compared to APOE ε3/ε3 (p=0.013). Hippocampal synaptic density did not correlate with Consortium to Establish a Registry for Alzheimer's Disease (CERAD) total score (rho=-0.052, p=0.74), Alzheimer's Prevention Initiative Preclinical Cognitive Composite (APCC) score (rho=0.17, p=0.28), or [11C]PiB uptake (rho=-0.10, p=0.50). Hippocampal synaptic loss emerges early in the AD continuum and is measurable in vivo in cognitively unimpaired high-risk individuals. Synaptic density was studied in vivo in healthy older adults using [11C]UCB-J positron emission tomography. Apolipoprotein E (APOE) ε4/ε4 carriers had lower hippocampal synaptic density compared to APOE ε3/ε3. Synaptic density was not associated with cognitive performance in this population. Hippocampal synaptic alterations occur before clinical symptoms in APOE ε4/ε4 carriers.

Tracer-Separator: A Deep Learning Model for Brain PET Dual-Tracer (18F-FDG and Amyloid) Separation.

Multiplexed PET imaging revolutionized clinical decision-making by simultaneously capturing various radiotracer data in a single scan, enhancing diagnostic accuracy and patient comfort. Through a transformer-based deep learning, this study underscores the potential of advanced imaging techniques to streamline diagnosis and improve patient outcomes. The research cohort consisted of 120 patients spanning from cognitively unimpaired individuals to those with mild cognitive impairment, dementia, and other mental disorders. Patients underwent various imaging assessments, including 3D T1-weighted MRI, amyloid PET scans using either 18F-florbetapir (FBP) or 18F-flutemetamol (FMM), and 18F-FDG PET. Summed images of FMM/FBP and FDG were used as proxy for simultaneous scanning of 2 different tracers. A SwinUNETR model, a convolution-free transformer architecture, was trained for image translation. The model was trained using mean square error loss function and 5-fold cross-validation. Visual evaluation involved assessing image similarity and amyloid status, comparing synthesized images with actual ones. Statistical analysis was conducted to determine the significance of differences. Visual inspection of synthesized images revealed remarkable similarity to reference images across various clinical statuses. The mean centiloid bias for dementia, mild cognitive impairment, and healthy control subjects and for FBP tracers is 15.70 ± 29.78, 0.35 ± 33.68, and 6.52 ± 25.19, respectively, whereas for FMM, it is -6.85 ± 25.02, 4.23 ± 23.78, and 5.71 ± 21.72, respectively. Clinical evaluation by 2 readers further confirmed the model's efficiency, with 97 FBP/FMM and 63 FDG synthesized images (from 120 subjects) found similar to ground truth diagnoses (rank 3), whereas 3 FBP/FMM and 15 FDG synthesized images were considered nonsimilar (rank 1). Promising sensitivity, specificity, and accuracy were achieved in amyloid status assessment based on synthesized images, with an average sensitivity of 95 ± 2.5, specificity of 72.5 ± 12.5, and accuracy of 87.5 ± 2.5. Error distribution analyses provided valuable insights into error levels across brain regions, with most falling between -0.1 and +0.2 SUV ratio. Correlation analyses demonstrated strong associations between actual and synthesized images, particularly for FMM images (FBP: Y = 0.72X + 20.95, R2 = 0.54; FMM: Y = 0.65X + 22.77, R2 = 0.77). This study demonstrated the potential of a novel convolution-free transformer architecture, SwinUNETR, for synthesizing realistic FDG and FBP/FMM images from summation scans mimicking simultaneous dual-tracer imaging.

Sensitivity of unconstrained quantitative magnetization transfer MRI to Amyloid burden in preclinical Alzheimer’s disease

Abstract Magnetization transfer MRI is sensitive to semi-solid macromolecules, including amyloid beta, and has previously been used to discriminate Alzheimer’s disease (AD) patients from controls. Here, we fit an unconstrained 2-pool quantitative MT (qMT) model, i.e., without constraints on the longitudinal relaxation rate R1S of semi-solids, and investigate the sensitivity of the estimated parameters to amyloid accumulation in preclinical participants. We scanned 15 cognitively normal volunteers, of which 9 were amyloid positive by [18F]Florbetaben PET. A 12 min hybrid-state qMT scan with an effective resolution of 1.24 mm isotropic and whole-brain coverage was acquired to estimate the unconstrained 2-pool qMT parameters. Group comparisons and correlations with Florbetaben PET standardized uptake value ratios were analyzed at the lobar level. We find that the exchange rate and semi-solid pool’s R1S were sensitive to the amyloid concentration, while morphometric measures of cortical thickness derived from structural MRI were not. Changes in the exchange rate are consistent with previous reports in clinical AD, while changes in R1S have not been reported previously as its value is typically constrained in the literature. Our results demonstrate that qMT MRI may be a promising surrogate marker of amyloid beta without the need for contrast agents or radiotracers.

The Association Between Constipation and Positron Emission Tomography and Blood-Based Biomarkers in Older Cognitively Unimpaired Adults with Higher Amyloid-β Burden.

Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden. Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18F-florbetapir PET and 18F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers. Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with lessTau burden evaluated by 18F-MK6240 PET Braak stages. Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development.

High-resolution motion compensation for brain PET imaging using real-time electromagnetic motion tracking.

Substantial improvements in spatial resolution in brain positron emission tomography (PET) scanners have greatly reduced partial volume effect, making head movement the main source of image blur. To achieve high-resolution PET neuroimaging, precise real-time estimation of both head position and orientation is essential for accurate motion compensation. A high-resolution electromagnetic motion tracking (EMMT) system with an event-by-event motion correction is developed for PET-CTscanners. EMMT is comprised of a source, an array of sensors, and a readout electronic unit (REU). The source acts as a transmitter and emits an EM dipole field. It is placed in close proximity to the sensor array and detects changes in EM flux density due to sensor movement. The REU digitizes signals from each sensor and captures precise rotational and translational movements in real time. Tracked motion in the EMMT coordinate system is synchronized with the PET list-mode data and transformed into the scanner coordinate system by locating paired positions in both systems. The optimal rigid motion is estimated using singular value decomposition. The rigid motion and depth-of-interaction (DOI) parallax effect are corrected by event-by-event rebinning of mispositioned lines-of-response (LORs). We integrated the EMMT with our recently developed ultra-high resolution Prism-PET prototype brain scanner and a commercial Siemens Biograph mCT PET-CT scanner. We assessed the imaging performance of the Prism-PET/EMMT system using multi-frame motion of point sources and phantoms. The mCT/EMMT system was validated using a set of point sources attached to both a mannequin head and a human volunteer, for simulating multiframe and continuous motions, respectively. Additionally, a human subject for [18F]MK6240 PET imaging wasincluded. The tracking accuracy of the Prism-PET/EMMT system was quantified as a root-mean-square (RMS) error of 0.49 for 100 axial rotations, and an RMS error of 0.15 mm for 100 mm translations.The percent difference (%diff) in average full width at half maximum (FWHM) of point source between motion-corrected and static images, within a motion range of and 10 mm from the center of the scanner's field-of-view (FOV), was 3.9%. The measured recovery coefficients of the 2.5-mm diameter sphere in the activity-filled partial volume correction phantom were 23.9%, 70.8%, and 74.0% for the phantom with multi-frame motion, with motion and motion compensation, and without motion, respectively. In the mCT/EMMT system, the %diff in average FWHM of point sources between motion-corrected and static images, within a motion range of and 10 mm from the center of the FOV, was 14%. Applying motion correction to the [18F]MK6240 PET imaging reduced the motion-induced spill-in artifact in the lateral ventricle region, lowering its standardized uptake value ratio (SUVR) from 0.70 to 0.34. The proposed EMMT system is a cost-effective, high frame-rate, and none-line-of-sight alternative to infrared camera-based tracking systems and is capable of achieving high rotational and translational tracking accuracies for mitigating motion-induced blur in high-resolution brain dedicated PETscanners.

Prognostic Value and Clinical Implication of Lymph Node-to-Primary Tumor SUV Ratio in Node-Positive Hypopharyngeal Squamous Cell Carcinoma Treated With Radiotherapy With or Without Chemotherapy.

The aim of this was to evaluate the prognostic significance of the nodal-to-primary tumor SUVmax ratio (NTR) in patients with node-positive hypopharyngeal squamous cell carcinoma (HPSCC) treated with radiotherapy with or without concurrent chemotherapy. The study aims to enhance prognostic accuracy by incorporating NTR into the American Joint Committee on Cancer (AJCC) staging system. This retrospective study included 191 patients with biopsy-proven node-positive HPSCC treated from 2005 to 2013. NTR was calculated as the ratio of SUVmax of metastatic lymph nodes to the primary tumor's SUVmax. Survival analyses were conducted using Cox regression models and Kaplan-Meier analysis. Receiver operating characteristic analysis compared the prognostic performance of the modified and AJCC staging systems. The median follow-up was 8.27 years, with 135 deaths (70.7%). High NTR (≥0.63) was significantly associated with worse overall survival (OS) and was an independent prognostic factor in multivariable analysis (adjusted hazards ratio [HR] = 1.63, P = 0.007). Median OS for high NTR was 17.4 months, compared with 75.2 months for low NTR. High NTR significantly predicted worse OS within AJCC stage IVA patients (HR = 6.09, P = 0.014). Patients in modified stage IVA (AJCC stage IVA with low NTR) had significantly longer OS than those in modified stage IVB (AJCC stage IVA with high NTR and AJCC stage IVB) (HR = 8.62, P = 0.003). The modified staging system incorporating NTR showed superior prognostic performance compared with the AJCC staging system. NTR is a significant independent prognostic factor for OS in node-positive HPSCC patients. Integrating NTR into the AJCC staging system improves prognostic accuracy.

Application of 18 F-fluorodeoxyglucose PET/computed tomography in the diagnosis of infiltrative subsolid nodules in lung adenocarcinoma.

To investigate the diagnostic value of 18 F-fluorodeoxyglucose(FDG) PET/computed tomography (CT) for infiltrative subsolid nodules at different stages of lung adenocarcinoma and to explore predictive factors for invasive adenocarcinoma, providing compelling evidence for timely intervention. A retrospective analysis was conducted on PET/CT imaging data of 170 subsolid nodules lesions confirmed postoperatively as lung adenocarcinoma or precursor glandular lesions. Lesions were categorized into preinvasive lesions including atypical adenomatous hyperplasia and adenocarcinoma in situ, microinvasive adenocarcinoma, and invasive adenocarcinoma. Compared the differences in imaging features and metabolic parameters among different groups and used a multifactor logistic regression model and receiver operating characteristic curve analysis to identify predictive factors for invasive adenocarcinoma. From preinvasive lesions through microinvasive adenocarcinoma to invasive adenocarcinoma, there was a gradual increase in nodule diameter, nodule area, and proportion of part-solid nodule. Statistical significance ( P < 0.05) was observed in the rates of spiculation and pleural indentation between preinvasive lesions versus microinvasive adenocarcinoma and invasive adenocarcinoma groups. The maximum standardized uptake value and maximum standardized uptake ratio show statistically significant differences ( P < 0.05) between the invasive adenocarcinoma group and the other groups. Logistic regression analysis indicated that nodule composition, nodule diameter, and maximum standardized uptake ratio were predictive factors for invasive adenocarcinoma ( P < 0.05). For part-solid nodules, the longest diameter of the solid component has a high diagnostic value. The imaging features of 18 F-FDG PET/CT contribute to the diagnosis of infiltrative subsolid nodules at different stages of lung adenocarcinoma, providing robust evidence for timely intervention.

Added value of 18Fluorine-fluorodeoxyglucose (18F-FDG) PET/MRI for evaluation of failed back surgery syndrome: comparison with non-contrast MRI.

Given increasing research suggesting the utility of positron emission tomography/magnetic resonance imaging (PET/MRI) in identifying the pain generator of low back pain, our study aims to assess its effectiveness in evaluating the source of pain in patients with failed back surgery syndrome (FBSS) by comparing the performance of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) PET/MRI with conventional MRI. We retrospectively analyzed data from patients with FBSS who underwent 18F-FDG PET and MRI of the lumbar vertebrae and lower extremities for undetermined sources of pain. We assessed 1) The diagnostic reliability and efficacy of MRI and 18F-FDG PET/MRI according to correct differential diagnosis, affected level, and affected side of the pain source compared to the findings of selective root or peripheral nerve block or revision lumbar spine surgery; and 2) The association between standardized uptake value (SUV) and standardized uptake value ratio (SUVR) threshold and accuracy of the suspected pathology on 18F-FDG PET/MRI. Among 30 included patients, the diagnostic accuracy of pain source recognition was higher for 18F-FDG PET/MRI than for MRI alone (1.0 vs. 0.4 in spinal disease and 0.8 vs. 0 in lower extremity disease, both p < 0.05). SUVR values of 1.4-1.5 showed the highest accuracy (0.93), higher than the accuracy obtained using the SUV threshold (0.87). 18F-FDG PET/MRI added value to MRI alone in detecting of hypermetabolic activity associated with pain from spinal and non-spinal sources.

Amyloid deposition in adults with drug-resistant temporal lobe epilepsy.

Pathological amyloid-β (Aβ) accumulation and hyperphosphorylated tau proteins have been described in resected temporal lobe specimens of epilepsy patients. We aimed to determine cerebrospinal fluid (CSF) Aβ1-42 and p181-tau levels and cerebral Aβ deposits on positron emission tomography (Aβ PET) and correlate these findings with cognitive performance in adults with drug-resistant temporal lobe epilepsy (TLE). In this cross-sectional study, we enrolled individuals with drug-resistant TLE who were 25-55 years old. Each participant underwent 18F-flutemetamol PET, determination of CSF Aβ1-42, p181-tau, and total tau, and a comprehensive neuropsychological assessment. We evaluated normalized standard uptake value ratios (SUVRs) for different brain regions on Aβ PET. Thirty patients (mean age = 41.9 ± SD 8.1 years, 57% men) were included. The median disease duration was 9.5 (interquartile range = 4-24) years. Twenty-six patients (87%) had a clinically significant cognitive impairment on neuropsychological evaluation, 18 (69%) of the amnesic type. On Aβ PET, high uptake was observed in both mesial temporal regions (ipsilateral: SUVR z-score = .90, 95% confidence interval [CI] = .60-1.20; contralateral: SUVR z-score = .92, 95% CI = .57-1.27; p < .001), which was higher when compared to SUVR z-scores in all the remaining regions (p < .001) and in the ipsilateral anterior cingulate (SUVR z-score = .27, 95% CI = .04-.49, p = .020). No significant deposition was observed in other regions. Seven patients (23%) had low Aβ1-42 levels, and two (7%) had elevated p181-tau levels in CSF. Higher p181-tau levels correlated with poorer verbal fluency (R = -.427, p = .044). Our findings reveal a considerable Aβ deposition in mesial temporal regions and ipsilateral anterior cingulate among adults with drug-resistant TLE. Additionally, abnormal CSF Aβ1-42 levels were observed in a significant proportion of patients, and p181-tau levels were associated with verbal fluency. These results suggest that markers of neuronal damage can be observed in adults with TLE, warranting further investigation.

Cognitive Impact of β-Amyloid Load in the Rapid Eye Movement Sleep Behavior Disorder-Lewy Body Disease Continuum.

Rapid eye movement sleep behavior disorder (RBD) is linked to the diffuse-malignant subtype and higher cognitive burden in Lewy body disease (LBD). This study explores brain β-amyloid deposition and its association with cognitive decline across the RBD-LBD continuum. Patients with isolated RBD (iRBD), Parkinson's disease with probable RBD (PDRBD), and dementia with Lewy bodies with probable RBD (DLBRBD) underwent 18F-florbetaben positron emission tomography, 3T magnetic resonance imaging scans, and comprehensive neuropsychological assessments. Subjects were categorized as cognitively normal (NC), mild cognitive impairment (MCI), or dementia. Global and regional standardized uptake value ratios (SUVR) were estimated in predefined cognitive volumes of interest (VOI) derived from voxel-wise comparison analysis among the cognitive groups, namely the prefrontal, parietal, precentral cortices, lingual gyrus, and supplementary motor area. Generalized linear models assessed the relationship between 18F-florbetaben SUVRs and neuropsychological testing, adjusting for age and sex. Subgroup analysis focused on the polysomnography-confirmed iRBD-continuum subset (n = 41) encompassing phenoconverters and nonconverters in our prospective iRBD cohort. Eighty-six subjects were classified as follows: 14 NC, 54 MCI, and 18 dementia. The proportion of positive β-amyloid scans increased with advanced cognitive stages (P = 0.038). β-Amyloid signals in cognitive VOIs were elevated in subgroups showing impairment in Trail-Making Test B (TMT-B). A linear association between TMT-B z score and global cortical β-amyloid levels was observed in the iRBD-continuum subset (P = 0.013). Cortical β-amyloid accumulates with declines in executive function within the RBD-LBD continuum. TMT-B performance may be a useful marker associating with β-amyloid load, particularly in the iRBD population. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

18F]PI-2620 Tau PET signal across the aging and Alzheimer’s disease clinical spectrum

Abstract [18F]PI-2620 is a second generation tracer that has shown high binding affinity for tau aggregation in Alzheimer’s disease (AD). However, [18F]PI-2620 signal in a large sample spanning the healthy aging and AD clinical spectrum as well as the stability of signal across different acquisition time windows have not yet been examined. Here, amyloid negative (Aβ-) cognitively unimpaired (CU; n=49), amyloid positive (Aβ+) CU (n=37), CU individuals with unknown amyloid status (n=5), mild cognitive impairment (MCI; n=14), dementia due to AD (n=19), and non-AD neurodegenerative disorder (n=54) participants were scanned with [18F]PI-2620 using a 45-75 min and/or 60-90 min acquisition time window. The impact of acquisition time on standardized uptake value ratio (SUVR) magnitude was first quantified with linear mixed models and in participants and regions with high [18F]PI-2620 signal, SUVRs increased linearly up to 0.04 SUVR with each additional 5 min past injection time. We then accounted for differences in acquisition time using a voxelwise correction approach and showed high correlations (all rs&amp;gt;0.986) between SUVRs calculated from 45-75 min data and SUVRs from 60-90 min data that were interpolated to the 45-75 min scale in 15 participants who were scanned across both time windows. Using real and interpolated 45-75 min data, we next examined [18F]PI-2620 signal in Braak regions of interest and an off-target binding region (putamen) in Aβ- and Aβ+ CU, Aβ+ MCI, and Aβ+ AD dementia (n=115) and showed that SUVRs in all Braak regions increased with greater disease severity. Within CU, higher Braak I SUVR was significantly associated with greater CSF pTau-181 (n=35), and higher SUVRs were significantly associated with worse memory and language (n=57). Thus, voxelwise acquisition time corrections can be applied to combine [18F]PI-2620 datasets collected at different post-injection times, and once acquisition time is accounted for, [18F]PI-2620 signal shows the expected increases across the AD spectrum and can be used for detection of early tau elevations.

Image reconstruction parameters and the standardized uptake value ratios in brain amyloid PET.

The present study investigated various image reconstruction protocols for amyloid PET using phantom test criteria published by the Japanese Society of Nuclear Medicine (JSNM) and compared them with the composite standardized uptake value ratio (cSUVR) in clinical imaging. Hoffman 3D phantoms and cylindrical phantoms were collected for 30 min according to the JSNM guidelines. Images were created under various reconstruction protocols by three physical evaluation items in the guidelines and were assessed: gray matter/white matter contrast (%contrast), uniformity (SDuROImean), and image noise [coefficient of variation (CV)]. We compared the cSUVR of images reconstructed under 15 protocols using 18F-flutemetamol and 18F-florbetapir in 15 cases each and the guidelines for physical evaluation of reconstruction parameters. No significant differences were observed in cSUVR between reconstruction protocols that satisfied the guidelines' criteria for %contrast and CV and those that did not; however, the visual impression of images differed. SDuROImean, which evaluated uniformity, met the criteria in all data. Reconstruction protocols should be selected appropriately using guidelines and other information, as cSUVR remains largely the same even if the visual impression of the images differs between different reconstruction protocols. When the relationship between %contrast and CV is expressed in terms of several reconstruction protocols, the graph shows a curved shape, and the optimal protocols for both %contrast and CV are near its center. Since cSUVR is similar to optimal parameters, even under parameters outside this range, multiple parameters need to be considered when selecting image reconstruction protocols for amyloid PET.

Evaluation of ComBat harmonization for reducing across-tracer differences in regional amyloid PET analyses.

Introduction Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [18F]-florbetapir (FBP) and [11C]-Pittsburgh Compound-B (PiB). Methods One-hundred-thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within ninety days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Variants of ComBat, including longitudinal ComBat and PEACE, were also tested. Intraclass correlation coefficient (ICC) and mean absolute error (MAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified. Results In the head-to-head tracer comparison, ComBat with no covariates was the best at increasing ICC and decreasing MAE of both global summary and regional amyloid PET SUVRs between scan pairs of the same group of subjects. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FBP-to-PiB proportions. Conclusion ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses.

Genome-wide scan of Flortaucipir PET levels finds JARID2 associated with cerebral tau deposition.

Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD. We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses. GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers. We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.

12204 Role Of [18F]FDG-PET/CT In Detection Of Immunotherapy-induced Hypophysitis - A Case-control Study

Abstract Disclosure: A. Fischer: None. J.M. Martinez Gomez: None. J. Mangana: None. R. Dummer: None. Z. Erlic: None. S. Nölting: None. F. Beuschlein: None. A. Maurer: None. M. Messerli: None. M.W. Huellner: None. S. Skawran: None. Adverse events related to immune-checkpoint inhibitor (ICI) therapy frequently affect endocrine organs. Depending on the type of ICI therapy, 0.5% to 10% of patients develop hypophysitis. Diagnosis relies on unspecific clinical symptoms and low serum cortisol level. On MRI, the diagnosis of ICI-induced hypophysitis is supported by enlargement of the pituitary gland and its stalk. However, pituitary MRI is negative in up to 2/3 of patients with hypophysitis on anti-PD-1 monotherapy. A delayed diagnosis increases the risk for life-threatening adrenal crisis. Consequently, there is a need for diagnostic tools that facilitate the early detection of ICI-induced hypophysitis. In this retrospective, single-center case-control-study, we investigated the diagnostic efficacy of [[1]8F]FDG positron emission tomography/computed tomography (FDG-PET/CT) in detecting ICI-induced hypophysitis. Fourteen patients with metastatic melanoma and ICI-induced hypophysitis were compared to a control group of 14 metastatic melanoma patients undergoing ICI treatment without evidence of hypophysitis, matched for age and sex. FDG-PET/CT scans were acquired as part of routine clinical care between 79 days before to 8 days after hypophysitis diagnosis (mean 26+/-29 days before diagnosis) in the case group. In the control group, FDG-PET/CT scans were obtained at a mean of 78+/-31 days after initiating ICI therapy. To mitigate inter-individual differences in standardized uptake value (SUV), the ratio of maximum SUV of the pituitary gland to the mean SUV of the blood pool (SUV-ratio pituitary/bloodpool) was calculated. Hypophysitis was diagnosed at a median of 83 (range: 65 - 98) days after the first ICI treatment; 9/14 (64.3%) patients received ipilimumab/nivolumab. Isolated cortisol deficiency was observed in 6/14 patients (42.9%), while 7/14 (50.0%) patients also displayed secondary hypothyroidism. Visual assessment of the distribution of the SUV-ratio pituitary/bloodpool demonstrated a positive correlation with decreasing proximity to the time of diagnosis. To evaluate diagnostic performance, only patients within 50 days before and 8 days after diagnosis (12/14) were included. The SUV-ratio pituitary/bloodpool was significantly higher in the case group compared to the control group (mean 3.57+/-3.24 vs. 1.69+/-0.41 respectively; p = 0.034). By optimizing the Youden index through area under the receiver operating characteristics curve (AUC) analysis, a sensitivity of 72.7% and a specificity of 90.9% were achieved at a threshold of 2.41 for the SUV-ratio pituitary/bloodpool (AUC = 0.769). In conclusion, our findings indicate that in patients undergoing ICI treatment for metastatic melanoma, an pituitary SUV-ratio pituitary/bloodpool in FDG-PET/CT of approximately 2.5 might indicate impending ICI-induced hypophysitis and should trigger close clinical monitoring. Presentation: 6/3/2024