Standardized Uptake Value Ratio Research Articles

Assessment of [18F]PI-2620 Tau-PET Quantification via Non-Invasive Automatized Image Derived Input Function.

[18F]PI-2620 positron emission tomography (PET) detects misfolded tau in progressive supranuclear palsy (PSP) and Alzheimer's disease (AD). We questioned the feasibility and value of absolute [18F]PI-2620 PET quantification for assessing tau by regional distribution volumes (VT). Here, arterial input functions (AIF) represent the gold standard, but cannot be applied in routine clinical practice, whereas image-derived input functions (IDIF) represent a non-invasive alternative. We aimed to validate IDIF against AIF and we evaluated the potential to discriminate patients with PSP and AD from healthy controls by non-invasive quantification of [18F] PET. In the first part of the study, we validated AIF derived from radial artery whole blood against IDIF by investigating 20 subjects (ten controls and ten patients). IDIF were generated by manual extraction of the carotid artery using the average and the five highest (max5) voxel intensity values and by automated extraction of the carotid artery using the average and the maximum voxel intensity value. In the second part of the study, IDIF quantification using the IDIF with the closest match to the AIF was transferred to group comparison of a large independent cohort of 40 subjects (15 healthy controls, 15 PSP patients and 10 AD patients). We compared VT and VT ratios, both calculated by Logan plots, with distribution volume (DV) ratios using simplified reference tissue modelling and standardized uptake value (SUV) ratios. AIF and IDIF showed highly correlated input curves for all applied IDIF extraction methods (0.78 < r < 0.83, all p < 0.0001; area under the curves (AUC): 0.73 < r ≤ 0.82, all p ≤ 0.0003). Regarding the VT values, correlations were mainly found between those generated by the AIF and by the IDIF methods using the maximum voxel intensity values. Lowest relative differences (RD) were observed by applying the manual method using the five highest voxel intensity values (max5) (AIF vs. IDIF manual, avg: RD = -82%; AIF vs. IDIF automated, avg: RD = -86%; AIF vs. IDIF manual, max5: RD = -6%; AIF vs. IDIF automated, max: RD = -26%). Regional VT values revealed considerable variance at group level, which was strongly reduced upon scaling by the inferior cerebellum. The resulting VT ratio values were adequate to detect group differences between patients with PSP or AD and healthy controls (HC) (PSP target region (globus pallidus): HC vs. PSP vs. AD: 1.18 vs. 1.32 vs. 1.16; AD target region (Braak region I): HC vs. PSP vs. AD: 1.00 vs. 1.00 vs. 1.22). VT ratios and DV ratios outperformed SUV ratios and VT in detecting differences between PSP and healthy controls, whereas all quantification approaches performed similarly in comparing AD and healthy controls. Blood-free IDIF is a promising approach for quantification of [18F]PI-2620 PET, serving as correlating surrogate for invasive continuous arterial blood sampling. Regional [18F]PI-2620 VT show large variance, in contrast to regional [18F]PI-2620 VT ratios scaled with the inferior cerebellum, which are appropriate for discriminating PSP, AD and healthy controls. DV ratios obtained by simplified reference tissue modeling are similarly suitable for this purpose.

Molecular neuroimaging in dominantly inherited versus sporadic early-onset Alzheimer's disease.

Approximately 5% of Alzheimer's disease patients develop symptoms before age 65 (early-onset Alzheimer's disease), with either sporadic (sporadic early-onset Alzheimer's disease) or dominantly inherited (dominantly inherited Alzheimer's disease) presentations. Both sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease are characterized by brain amyloid-β accumulation, tau tangles, hypometabolism and neurodegeneration, but differences in topography and magnitude of these pathological changes are not fully elucidated. In this study, we directly compared patterns of amyloid-β plaque deposition and glucose hypometabolism in sporadic early-onset Alzheimer's disease and dominantly inherited Alzheimer's disease individuals. Our analysis included 134 symptomatic sporadic early-onset Alzheimer's disease amyloid-Positron Emission Tomography (PET)-positive cases from the University of California, San Francisco, Alzheimer's Disease Research Center (mean ± SD age 59.7 ± 5.6 years), 89 symptomatic dominantly inherited Alzheimer's disease cases (age 45.8 ± 9.3 years) and 102 cognitively unimpaired non-mutation carriers from the Dominantly Inherited Alzheimer Network study (age 44.9 ± 9.2). Each group underwent clinical and cognitive examinations, 11C-labelled Pittsburgh Compound B-PET and structural MRI. 18F-Fluorodeoxyglucose-PET was also available for most participants. Positron Emission Tomography scans from both studies were uniformly processed to obtain a standardized uptake value ratio (PIB50-70 cerebellar grey reference and FDG30-60 pons reference) images. Statistical analyses included pairwise global and voxelwise group comparisons and group-independent component analyses. Analyses were performed also adjusting for covariates including age, sex, Mini-Mental State Examination, apolipoprotein ε4 status and average composite cortical of standardized uptake value ratio. Compared with dominantly inherited Alzheimer's disease, sporadic early-onset Alzheimer's disease participants were older at age of onset (mean ± SD, 54.8 ± 8.2 versus 41.9 ± 8.2, Cohen's d = 1.91), with more years of education (16.4 ± 2.8 versus 13.5 ± 3.2, d = 1) and more likely to be apolipoprotein ε4 carriers (54.6% ε4 versus 28.1%, Cramer's V = 0.26), but similar Mini-Mental State Examination (20.6 ± 6.1 versus 21.2 ± 7.4, d = 0.08). Sporadic early-onset Alzheimer's disease had higher global cortical Pittsburgh Compound B-PET binding (mean ± SD standardized uptake value ratio, 1.92 ± 0.29 versus 1.58 ± 0.44, d = 0.96) and greater global cortical 18F-fluorodeoxyglucose-PET hypometabolism (mean ± SD standardized uptake value ratio, 1.32 ± 0.1 versus 1.39 ± 0.19, d = 0.48) compared with dominantly inherited Alzheimer's disease. Fully adjusted comparisons demonstrated relatively higher Pittsburgh Compound B-PET standardized uptake value ratio in the medial occipital, thalami, basal ganglia and medial/dorsal frontal regions in dominantly inherited Alzheimer's disease versus sporadic early-onset Alzheimer's disease. Sporadic early-onset Alzheimer's disease showed relatively greater 18F-fluorodeoxyglucose-PET hypometabolism in Alzheimer's disease signature temporoparietal regions and caudate nuclei, whereas dominantly inherited Alzheimer's disease showed relatively greater hypometabolism in frontal white matter and pericentral regions. Independent component analyses largely replicated these findings by highlighting common and unique Pittsburgh Compound B-PET and 18F-fluorodeoxyglucose-PET binding patterns. In summary, our findings suggest both common and distinct patterns of amyloid and glucose hypometabolism in sporadic and dominantly inherited early-onset Alzheimer's disease.

Exploration of neuroanatomical characteristics to differentiate prodromal Alzheimer’s disease from cognitively unimpaired amyloid-positive individuals

Differentiating clinical stages based solely on positive findings from amyloid PET is challenging. We aimed to investigate the neuroanatomical characteristics at the whole-brain level that differentiate prodromal Alzheimer’s disease (AD) from cognitively unimpaired amyloid-positive individuals (CU A+) in relation to amyloid deposition and regional atrophy. We included 45 CU A+ participants and 135 participants with amyloid-positive prodromal AD matched 1:3 by age, sex, and education. All participants underwent 18F-florbetaben positron emission tomography and 3D structural T1-weighted magnetic resonance imaging. We compared the standardized uptake value ratios (SUVRs) and volumes in 80 regions of interest (ROIs) between CU A+ and prodromal AD groups using independent t-tests, and employed the least absolute selection and shrinkage operator (LASSO) logistic regression model to identify ROIs associated with prodromal AD in relation to amyloid deposition, regional atrophy, and their interaction. After applying False Discovery Rate correction at < 0.1, there were no differences in global and regional SUVR between CU A+ and prodromal AD groups. Regional volume differences between the two groups were observed in the amygdala, hippocampus, entorhinal cortex, insula, parahippocampal gyrus, and inferior temporal and parietal cortices. LASSO logistic regression model showed significant associations between prodromal AD and atrophy in the entorhinal cortex, inferior parietal cortex, both amygdalae, and left hippocampus. The mean SUVR in the right superior parietal cortex (beta coefficient = 0.0172) and its interaction with the regional volume (0.0672) were also selected in the LASSO model. The mean SUVR in the right superior parietal cortex was associated with an increased likelihood of prodromal AD (Odds ratio [OR] 1.602, p = 0.014), particularly in participants with lower regional volume (OR 3.389, p < 0.001). Only regional volume differences, not amyloid deposition, were observed between CU A+ and prodromal AD. The reduced volume in the superior parietal cortex may play a significant role in the progression to prodromal AD through its interaction with amyloid deposition in that region.

Abstract PS05-02: PET Imaging of PARP Expression as a Biomarker of Response to Chemotherapy in Breast Cancer: A Nonrandomized Clinical Trial

Abstract Introduction: Poly–(adenosine diphosphate–ribose) polymerase (PARP) proteins are involved in double-stranded break repair, mediated through homologous recombination (HR) and non-homologous end joining (NHEJ). The majority of PARP activity in this context is attributed to PARP-1 (85-90%). PARP-1 binding to damaged DNA, catalytic activity, and subsequent release to allow access for other DNA repair proteins are necessary for efficient DNA repair. The critical function of PARP-1 in these processes makes this protein a unique potential biomarker of DNA repair capability. [18F]FluorThanatrace ([18F]FTT) is an 18F-labeled PARP inhibitor analog that binds to the same site as approved PARPi drugs. We hypothesized that the biologically relevant form of PARP in untreated breast cancer might provide an indication of functional tumor DNA repair capabilities and therefore predict chemotherapy response. Thus, this study aimed to determine whether a non-invasive quantitative measure of in vivo PARP expression correlated with response to chemotherapy in breast cancer. Methods: A single-arm prospective trial enriched for subjects with triple negative breast cancer (TNBC) was conducted at the University of Pennsylvania from May 2017 to March 2022 (NCT03083288 and NCT03846167). Inclusion criteria were primary breast cancer with tumor diameter of at least 1 cm on conventional imaging and willingness to undergo an [18F]FTT-PET scan prior to neoadjuvant chemotherapy. Participants provided written informed consent. [18F]FTT uptake in breast cancer was measured pre-therapy and tested for association with pathologic complete response (pCR). Subjects were scanned on an Ingenuity TF PET/CT (Philips Healthcare) following injection of [18F]FTT using a 20-minute static acquisition. Peak 1 cm3 average uptake (SUVpeak) were recorded from a spherical region-of-interest (ROI) covering the primary malignancy, guided by CT and prior imaging studies. All SUVs were partial volume corrected and normalized using muscle (NM). A Mann-Whitney test was used to determine if [18F]FTT uptake differed by pCR. Receiver operating characteristic (ROC) curves were constructed to test the performance of [18F]FTT uptake in predicting pCR. Statistical analyses utilized STATA v15.1 with significance based on a two-sided alpha level of ≤0.05. Participants: Twenty-six women with stage I-III breast cancer met inclusion criteria with age range of 29-74 years and self-reported race as Asian (1, 4%), Black (9, 37%) or White (16, 60%). One subject had bilateral tumors (ER+ stage IIA and HER2+ stage I) that were evaluated separately (27 total tumors). Breast tumors were pathologically confirmed and included 6 (22%) ER+/HER2-, 5 (19%) HER2+, and 16 (59%) TNBC. Germline sequencing was available for 21 participants. Results: Mean tumor diameter ranged from 15 to 91 mm (median 30 mm). A considerable range of [18F]FTT uptake was seen across subjects (SUVpeak/NM 0.66-6.5). [18F]FTT uptake was independent of subtype (ER+, HER2+, TN) (P=0.35), stage (P=0.39), and between mutations in genes associated with homologous recombination deficiency (i.e., BRCA1/2, PALB2) and wild-type (P=0.73). In the TNBC cohort, pre-treatment [18F]FTT uptake was higher in subjects who went on to have a pCR (n=16, P=0.05), while a trend toward higher uptake was seen when including all tumor types (n=27, P=0.11). ROC analysis of the value of [18F]FTT uptake for predicting pCR revealed an AUC of 0.79 and showed that a threshold SUV ratio &amp;lt; 2.47 predicted pCR in TNBC patients with a 100% specificity and 64% sensitivity. Conclusions: These early clinical results suggest a relationship between [18F]FTT uptake, a measure of PARP expression, and chemotherapy sensitivity in TNBC, warranting future studies to elucidate underlying mechanistic processes and potential clinical implications. Citation Format: Sarah Gitto, Anthony Young, Ira Bleiweiss, Amy Clark, Elizabeth McDonald. PET Imaging of PARP Expression as a Biomarker of Response to Chemotherapy in Breast Cancer: A Nonrandomized Clinical Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-02.

Microglia Density and Its Association With Disease Duration, Severity, and Orexin Levels in Patients With Narcolepsy Type 1.

Narcolepsy type 1 (NT1) is due to the loss of hypothalamic neurons that produce orexin (ORX), by a suspected immune-mediated process. Rare postmortem studies are available and failed to detect any inflammation in the hypothalamic region, but these brains were collected years after the first symptoms. In vivo studies close to disease onset are lacking. We aimed to explore microglia density in the hypothalamus and thalamus in NT1 compared with controls using [18F]DPA-714 PET and to study in NT1 the relationships between microglia density in the hypothalamus and in other regions of interest (ROIs) with disease duration, severity, and ORX levels. Patients with NT1 and controls underwent a standardized clinical evaluation and [18F]DPA-714 PET imaging using a radiolabeled ligand specific to the 18 kDa translocator protein (TSPO). TSPO genotyping determined receptor affinity. Images were processed on peripheral module interface using standard uptake value (SUV) on ROIs: hypothalamus, thalamus, frontal area, cerebellum, and the whole brain. SUV ratios (SUVr) were calculated by normalizing SUV with cerebellum uptake. A total of 41 patients with NT1 (21 adults, 20 children, 10 with recent disease onset <1 year) and 35 controls were included, with no significant difference between groups for [18F]DPA-714 binding (SUV/SUVr) in the hypothalamus and thalamus. Unexpectedly, significantly lower SUVr in the whole brain was found in NT1 compared with controls (0.97 ± 0.06 vs 1.08 ± 0.22, p = 0.04). The same finding between NT1 and controls in the whole brain was observed in those with high or mixed TSPO affinity (p = 0.03 and p = 0.04). Similar trend was observed in the frontal area in NT1 (0.96 ± 0.09 vs 1.09 ± 0.25, p = 0.05). In NT1, no association was found between SUVr in different ROIs and age, disease duration, severity, or ORX levels. We found no evidence of in vivo increased microglia density in NT1 compared with controls, even close to disease onset, and even unexpectedly a decrease in the whole brain of these patients. These findings do not support the presence of neuroinflammation in the destruction process of ORX neurons. ClinicalTrials.org NCT03754348.

Association of Basal Forebrain Volume with Amyloid, Tau, and Cognition in Alzheimer's Disease.

Degeneration of cholinergic basal forebrain (BF) neurons characterizes Alzheimer's disease (AD). However, what role the BF plays in the dynamics of AD pathophysiology has not been investigated precisely. To investigate the baseline and longitudinal roles of BF along with core neuropathologies in AD. In this retrospective cohort study, we enrolled 113 subjects (38 amyloid [Aβ]-negative cognitively unimpaired, 6 Aβ-positive cognitively unimpaired, 39 with prodromal AD, and 30 with AD dementia) who performed brain MRI for BF volume and cortical thickness, 18F-florbetaben PET for Aβ, 18F-flortaucipir PET for tau, and detailed cognitive testing longitudinally. We investigated the baseline and longitudinal association of BF volume with Aβ and tau standardized uptake value ratio and cognition. Cross-sectionally, lower BF volume was not independently associated with higher cortical Aβ, but it was associated with tau burden. Tau burden in the orbitofrontal, insular, lateral temporal, inferior temporo-occipital, and anterior cingulate cortices were associated with progressive BF atrophy. Lower BF volume was associated with faster Aβ accumulation, mainly in the prefrontal, anterior temporal, cingulate, and medial occipital cortices. BF volume was associated with progressive decline in language and memory functions regardless of baseline Aβ and tau burden. Tau deposition affected progressive BF atrophy, which in turn accelerated amyloid deposition, leading to a vicious cycle. Also, lower baseline BF volume independently predicted deterioration in cognitive function.

Expression of regional brain amyloid-β deposition with [18F]Flutemetamol in Centiloid scale -a multi-site study.

The Centiloid project helps calibrate the quantitative amyloid-β (Aβ) load into a unified Centiloid (CL) scale that allows data comparison across multi-site. How the smaller regional amyloid converted into CL has not been attempted. We first aimed to express regional Aβ deposition in CL using [18F]Flutemetamol and evaluate regional Aβ deposition in CL with that in standardized uptake value ratio (SUVr). Second, we aimed to determine the presence or absence of focal Aβ deposition by measuring regional CL in equivocal cases showing negative global CL. Following the Centiloid project pipeline, Level-1 replication, Level-2 calibration, and quality control were completed to generate corresponding Centiloid conversion equations to convert SUVr into Centiloid at regional levels. In equivocal cases, the regional CL was compared with visual inspection to evaluate regional Aβ positivity. 14 out of 16 regional conversions from [18F]Flutemetamol SUVr to Centiloid successfully passed the quality control, showing good reliability and relative variance, especially precuneus/posterior cingulate and prefrontal regions with good stability for Centiloid scaling. The absence of focal Aβ deposition could be detected by measuring regional CL, showing a high agreement rate with visual inspection. The regional Aβ positivity in the bilateral anterior cingulate cortex was most prevalent in equivocal cases. The expression of regional brain Aβ deposition in CL with [18F]Flutemetamol has been attempted in this study. Equivocal cases had focal Aβ deposition that can be detected by measuring regional CL.

Relationship between neuroimaging and cognition in frontotemporal dementia: An FDG-PET and structural MRI study.

Frontotemporal dementia (FTD) is a clinically and pathologically heterogeneous neurodegenerative condition with a prevalence comparable to Alzheimer's disease for patients under 65 years of age. Limited studies have examined the association between cognition and neuroimaging in FTD using different imaging modalities. We examined the association of cognition using Montreal Cognitive Assessment (MoCA) with both gray matter (GM) volume and glucose metabolism using magnetic resonance imaging and fluorodeoxyglucose (FDG)-PET in 21 patients diagnosed with FTD. Standardized uptake value ratio (SUVR) using the brainstem as a reference region was the primary outcome measure for FDG-PET. Partial volume correction was applied to PET data to account for disease-related atrophy. Significant positive associations were found between whole-cortex GM volume and MoCA scores (r = 0.46, p =.04). The association between whole-cortex FDG SUVR and MoCA scores was not significant (r = 0.37, p =.09). GM volumes of the frontal cortex (r = 0.54, p =.01), caudate (r = 0.62, p<.01), and insula (r = 0.57, p<.01) were also significantly correlated with MoCA, as were SUVR values of the insula (r = 0.51, p =.02), thalamus (r = 0.48, p =.03), and posterior cingulate cortex (PCC) (r = 0.47, p =.03). Whole-cortex atrophy is associated with cognitive dysfunction, and this association is larger than for whole-cortex hypometabolism as measured with FDG-PET. At the regional level, focal atrophy and/or hypometabolism in the frontal cortex, insula, PCC, thalamus, and caudate seem to be important for the decline of cognitive function in FTD. Furthermore, these results highlight how functional and structural changes may not overlap and might contribute to cognitive dysfunction in FTD in different ways.

Characterizing brain tau and cognitive decline along the amyloid timeline in Alzheimer's disease.

Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90 min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.

Development and Preclinical Evaluation of a Copper-64-Labeled Antibody Targeting Glycine-Alanine Dipeptides for PET Imaging of C9orf72-Associated Amyotrophic Lateral Sclerosis/Frontotemporal Dementia.

Aggregating poly(glycine-alanine) (poly-GA) is derived from the unconventional translation of the pathogenic intronic hexanucleotide repeat expansion in the C9orf72 gene, which is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Poly-GA accumulates predominantly in neuronal cytoplasmic inclusions unique to C9orf72 ALS/FTD patients. Poly-GA is, therefore, a promising target for PET/CT imaging of FTD/ALS to monitor disease progression and therapeutic interventions. A novel 64Cu-labeled anti-GA antibody (mAb1A12) targeting the poly-GA protein was developed and evaluated in a transgenic mouse model. It was obtained with high radiochemical purity (RCP), radiochemical yield (RCY), and specific activity, and showed high stability in vitro and ex vivo and specifically bound to poly-GA. The affinity of NODAGA-mAb1A12 for poly-GA was not affected by this modification. [64Cu]Cu-NODAGA-mAb1A12 was injected into transgenic mice expressing GFP-(GA)175 in excitatory neurons driven by Camk2a-Cre and in control littermates. PET/CT imaging was performed at 2, 20, and 40 h post-injection (p.i.) and revealed a higher accumulation in the cortex in transgenic mice than in wild-type mice, as reflected by higher standardized uptake value ratios (SUVR) using the cerebellum as the reference region. The organs were isolated for biodistribution and ex vivo autoradiography. Autoradiography revealed a higher cortex-to-cerebellum ratio in the transgenic mice than in the controls. Results from autoradiography were validated by immunohistochemistry and poly-GA immunoassays. Moreover, we confirmed antibody uptake in the CNS in a pharmacokinetic study of the perfused tissues. In summary, [64Cu]Cu-NODAGA-mAb1A12 demonstrated favorable in vitro characteristics and an increased relative binding in poly-GA transgenic mice compared to wild-type mice in vivo. Our results with this first-in-class radiotracer suggested that targeting poly-GA is a promising approach for PET/CT imaging in FTD/ALS.

Feature Importance Analysis and Machine Learning for Alzheimer’s Disease Early Detection: Feature Fusion of the Hippocampus, Entorhinal Cortex, and Standardized Uptake Value Ratio

Introduction: Alzheimer’s disease (AD) is a progressive neurological disorder characterized by mild memory loss and ranks as a leading cause of mortality in the USA, accounting for approximately 120,000 deaths per year. It is also the primary form of dementia. Early detection is critical for timely intervention as the neurodegenerative process often starts 15–20 years before cognitive symptoms manifest. This study focuses on determining feature importance in AD classification using fused texture features from 3D magnetic resonance imaging hippocampal and entorhinal cortex and standardized uptake value ratio (SUVR) derived from positron emission tomography (PET) images. Methods: To achieve this objective, we employed four distinct classifiers (Linear Support Vector Classification, Linear Discriminant Analysis, Logistic Regression, and Logistic Regression Classifier with Stochastic Gradient Descent Learning). These classifiers were used to derive both average and top-ranked importance scores for each feature based on their outputs. Our framework is designed to distinguish between two classes, AD-negative (or mild cognitive impairment stable [MCIs]) and AD-positive (or MCI conversion [MCIc]), using a probabilistic neural network classifier and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The findings from the feature importance highlight the crucial role of the GLCM texture features extracted from the hippocampus and entorhinal cortex, demonstrating their superior performance compared to the volume and SUVR. GLCM texture AD classification achieved approximately 90% sensitivity in identifying MCIc cases while maintaining low false positives (below 30%) when fused with other features. Moreover, the receiver operating characteristic curves validate the GLCMs’ superior performance in distinguishing between MCIs and MCIc. Additionally, fusing different types of features improved classification performance compared to relying solely on any single feature category. Conclusion: Our study emphasizes the pivotal role of GLCM texture features in early Alzheimer’s detection.

Phantom and clinical evaluation of the Bayesian penalised likelihood reconstruction algorithm Q.Clear without PSF correction in amyloid PET images

PurposeBayesian penalised likelihood (BPL) reconstruction, which incorporates point-spread-function (PSF) correction, provides higher signal-to-noise ratios and more accurate quantitation than conventional ordered subset expectation maximization (OSEM) reconstruction. However, applying PSF correction to brain PET imaging is controversial due to Gibbs artefacts that manifest as unpredicted cortical uptake enhancement. The present study aimed to validate whether BPL without PSF would be useful for amyloid PET imaging.MethodsImages were acquired from Hoffman 3D brain and cylindrical phantoms for phantom study and 71 patients administered with [18F]flutemetamol in clinical study using a Discovery MI. All images were reconstructed using OSEM, BPL with PSF correction, and BPL without PSF correction. Count profile, %contrast, recovery coefficients (RCs), and image noise were calculated from the images acquired from the phantoms. Amyloid β deposition in patients was visually assessed by two physicians and quantified based on the standardised uptake value ratio (SUVR).ResultsThe overestimated radioactivity in profile curves was eliminated using BPL without PSF correction. The %contrast and image noise decreased with increasing β values in phantom images. Image quality and RCs were better using BPL with, than without PSF correction or OSEM. An optimal β value of 600 was determined for BPL without PSF correction. Visual evaluation almost agreed perfectly (κ = 0.91–0.97), without depending on reconstruction methods. Composite SUVRs did not significantly differ between reconstruction methods.ConclusionGibbs artefacts disappeared from phantom images using the BPL without PSF correction. Visual and quantitative evaluation of [18F]flutemetamol imaging was independent of the reconstruction method. The BPL without PSF correction could be the standard reconstruction method for amyloid PET imaging, despite being qualitatively inferior to BPL with PSF correction for [18F]flutemetamol amyloid PET imaging.

In vivo translocator protein in females with autism spectrum disorder: a pilot study

Sex-based differences in the prevalence of autism spectrum disorder (ASD) are well-documented, with a male-to-female ratio of approximately 4:1. The clinical presentation of the core symptoms of ASD can also vary between sexes. Previously, positron emission tomography (PET) studies have identified alterations in the in vivo levels of translocator protein (TSPO)—a mitochondrial protein—in primarily or only male adults with ASD, with our group reporting lower TSPO relative to whole brain mean in males with ASD. However, whether in vivo TSPO levels are altered in females with ASD, specifically, is unknown. This is the first pilot study to measure in vivo TSPO in the brain in adult females with ASD using [11C]PBR28 PET-magnetic resonance imaging (MRI). Twelve adult females with ASD and 10 age- and TSPO genotype-matched controls (CON) completed one or two [11C]PBR28 PET–MRI scans. Females with ASD exhibited elevated [11C]PBR28 standardized uptake value ratio (SUVR) in the midcingulate cortex and splenium of the corpus callosum compared to CON. No brain area showed lower [11C]PBR28 SUVR in females with ASD compared to CON. Test-retest over several months showed stable [11C]PBR28 SUVR across time in both groups. Elevated regional [11C]PBR28 SUVR in females with ASD stand in stark contrast to our previous findings of lower regional [11C]PBR28 SUVR in males with ASD. Preliminary evidence of regionally elevated mitochondrial protein TSPO relative to whole brain mean in ASD females may reflect neuroimmuno-metabolic alterations specific to females with ASD.

Association of β-Amyloid, Microglial Activation, Cortical Thickness, and Metabolism in Older Adults Without Dementia.

Plasma β-amyloid42 (Aβ42)/Aβ40 levels have shown promise in identifying Aβ-PET positive individuals. This study explored the concordance and discordance of plasma Aβ42/Aβ40 positivity (Plasma±) with CSF Aβ42/Aβ40 positivity (CSF±) and Aβ-PET positivity (PET±) in older adults without dementia. Associations of Aβ deposition, cortical thickness, glucose metabolism, and microglial activation were also investigated. We selected participants without dementia who had concurrent plasma Aβ42/Aβ40 and Aβ-PET scans from the Alzheimer's Disease Neuroimaging Initiative cohort. Participants were categorized into Plasma±/PET± based on thresholds of composite 18F-florbetapir (FBP) standardized uptake value ratio (SUVR) ≥1.11 and plasma Aβ42/Aβ40 ≤0.1218. Aβ-PET-negative individuals were further divided into Plasma±/CSF± (CSF Aβ42/Aβ40 ≤0.138), and the concordance and discordance of Aβ42/Aβ40 in the plasma and CSF were investigated. Baseline and slopes of regional FBP SUVR were compared among Plasma±/PET± groups, and associations of regional FBP SUVR, FDG SUVR, cortical thickness, and CSF soluble Triggering Receptor Expressed on Myeloid Cell 2 (sTREM2) levels were analyzed. One hundred eighty participants (mean age 72.7 years, 51.4% female, 96 cognitively unimpaired, and 84 with mild cognitive impairment) were included. We found that the proportion of Plasma+/PET- individuals was 6.14 times higher (odds ratio (OR) = 6.143, 95% confidence interval (CI) 2.740-16.185, p < 0.001) than that of Plasma-/PET+ individuals, and Plasma+/CSF- individuals showed 8.5 times larger percentage (OR = 8.5, 95% CI: 3.031-32.974, p < 0.001) than Plasma-/CSF+ individuals in Aβ-PET-negative individuals. Besides, Plasma+/PET- individuals exhibited faster (p < 0.05) Aβ accumulation predominantly in bilateral banks of superior temporal sulcus (BANKSSTS) and supramarginal, and superior parietal cortices compared with Plasma-/PET- individuals, despite no difference in baseline FBP SUVRs. In Plasma+/PET+ individuals, higher CSF sTREM2 levels correlated with slower BANKSSTS Aβ accumulation (standardized β (βstd) = -0.418, 95% CI -0.681 to -0.154, p = 0.002). Conversely, thicker cortical thickness and higher glucose metabolism in supramarginal and superior parietal cortices were associated with faster (p < 0.05) CSF sTREM2 increase in Plasma+/PET- individuals rather than in Plasma+/PET+ individuals. These findings suggest that plasma Aβ42/Aβ40 abnormalities may predate CSF Aβ42/Aβ40 and Aβ-PET abnormalities. Higher sTREM2-related microglial activation is linked to thicker cortical thickness and higher metabolism in early amyloidosis stages but tends to mitigate Aβ accumulation primarily at relatively advanced stages.

Abstract LB419: Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging

Abstract Introduction: While 5-10 years of aromatase inhibitor (AI) treatment clearly improves survival rates of postmenopausal women with hormone-sensitive breast cancer, up to 85% of AI users report aromatase inhibitor associated musculoskeletal syndrome (AIMSS, including arthralgias, myalgias, and muscle stiffness). The biological mechanisms underlying AIMSS are not well understood, but accumulating preclinical and clinical evidence implicate an important role for neuroinflammation in the development and maintenance of other types of chronic musculoskeletal pain (e.g., low back pain, fibromyalgia etc.). The purpose of this pilot study was to investigate the role of neuroinflammation in breast cancer patients with AIMSS. Methods: This cross-sectional case control study used Siemens 3 T integrated positron emission tomography-magnetic resonance imaging (PET/MRI) with the radioligand [11C]PBR28, which binds to the neuroinflammation marker 18kDa translocator protein (TSPO), to assess neuroinflammation in two cohorts (chronic AIMSS, no-AIMSS) of breast cancer patients undergoing AI therapy, and age-, sex- and TSPO genotype-matched healthy controls. Static [11C]PBR28 PET images were reconstructed from 60-90 minutes post-injection. Standardized uptake value (SUV) maps were obtained voxel-wise by normalizing radioactivity by injected dose/body weight. SUV maps were normalized to whole brain to obtain SUV ratio (SUVR) maps. SUVR images spatially normalized to MNI template and then spatially smoothed (FWHM=8mm). Results: Two breast cancer patients (1 AIMSS, 1 no-AIMSS) and 2 matched healthy controls were included in this analysis. Compared to their individual matched healthy controls, both breast cancer patients showed increased [11C]PBR28 signal uptake in the thalamus/midbrain and pons. This elevated signal was more prominent in the breast cancer patient with AIMSS. Conclusions: These preliminary findings suggest an elevated signal of neuroinflammation in the thalamus and brainstem in AI-treatment and AIMSS, aligning with existing literature emphasizing their pivotal role in chronic pain pathology. While it is imperative to acknowledge the limitation of a small sample size, these promising findings suggest a potential role of neuroinflammation for the first time in AIMSS. Future focused Region of Interest (ROI) analysis in thalamus and brainstem with a larger sample size may confirm. Citation Format: Yehui Zhu, Natalie Swanson, Jennifer Murphy, Minhae Kim, Ann Partridge, Robert Edwards, Kristin Schreiber, Marco Loggia. Neuroinflammation and aromatase inhibitor associated musculoskeletal syndrome (AIMSS) in breast cancer: Initial insights from [11C]PBR28 PET/MR imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB419.

Improved Tau PET SUVR Quantification in 4-Repeat Tau Phenotypes with [18F]PI-2620.

We used a new data-driven methodology to identify a set of reference regions that enhanced the quantification of the SUV ratio of the second-generation tau tracer 2-(2-([18F]fluoro)pyridin-4-yl)-9H-pyrrolo[2,3-b:4,5-c']dipyridine ([18F]PI-2620) in a group of patients clinically diagnosed with 4-repeat tauopathy, specifically progressive supranuclear palsy or cortical basal syndrome. The study found that SUV ratios calculated using the identified reference regions (i.e., fusiform gyrus and crus-cerebellum) were significantly associated with symptom severity and disease duration. This establishes, for the first time to our knowledge, the suitability of [18F]PI-2620 for tracking disease progression in this 4-repeat disease population. This is an important step toward increased clinical utility, such as patient stratification and monitoring in disease-modifying treatment trials. Additionally, the applied methodology successfully optimized reference regions for automated detection of brain imaging tracers. This approach may also hold value for other brain imaging tracers.

Impact of PET Reconstruction on Amyloid-β Quantitation in Cross-Sectional and Longitudinal Analyses.

Amyloid-β (Aβ) accumulation in Alzheimer disease (AD) is typically measured using SUV ratio and the centiloid (CL) scale. The low spatial resolution of PET images is known to degrade quantitative metrics because of the partial-volume effect. This article examines the impact of spatial resolution, as determined by the reconstruction configuration, on the Aβ PET quantitation in both cross-sectional and longitudinal data. Methods: The cross-sectional study involved 89 subjects with 20-min [18F]florbetapir scans generated on an mCT (44 Aβ-negative [Aβ-], 45 Aβ-positive [Aβ+]) using 69 reconstruction configurations, which varied in number of iteration updates, point-spread function, time-of-flight, and postreconstruction smoothing. The subjects were classified as Aβ- or Aβ+ visually. For each reconstruction, Aβ CL was calculated using CapAIBL, and the spatial resolution was calculated as full width at half maximum (FWHM) using the barrel phantom method. The change in CLs and the effect size of the difference in CLs between Aβ- and Aβ+ groups with FWHM were examined. The longitudinal study involved 79 subjects (46 Aβ-, 33 Aβ+) with three 20-min [18F]flutemetamol scans generated on an mCT. The subjects were classified as Aβ- or Aβ+ using a cutoff CL of 20. All scans were reconstructed using low-, medium-, and high-resolution configurations, and Aβ CLs were calculated using CapAIBL. Since linear Aβ accumulation was assumed over a 10-y interval, for each reconstruction configuration, Aβ accumulation rate differences (ARDs) between the second and first periods were calculated for all subjects. Zero ARD was used as a consistency metric. The number of Aβ accumulators was also used to compare the sensitivity of CL across reconstruction configurations. Results: In the cross-sectional study, CLs in both the Aβ- and the Aβ+ groups were impacted by the FWHM of the reconstruction method. Without postreconstruction smoothing, Aβ- CLs increased for a FWHM of 4.5 mm or more, whereas Aβ+ CLs decreased across the FWHM range. High-resolution reconstructions provided the best statistical separation between groups. In the longitudinal study, the median ARD of low-resolution reconstructed data for the Aβ- group was greater than zero whereas the ARDs of higher-resolution reconstructions were not significantly different from zero, indicating more consistent rate estimates in the higher-resolution reconstructions. Higher-resolution reconstructions identified 10 additional Aβ accumulators in the Aβ- group, resulting in a 22% increased group size compared with the low-resolution reconstructions. Higher-resolution reconstructions reduced the average CLs of the negative group by 12 points. Conclusion: High-resolution PET reconstructions, inherently less impacted by partial-volume effect, may improve Aβ PET quantitation in both cross-sectional and longitudinal data. In the cross-sectional analysis, separation of CLs between Aβ- and Aβ+ cohorts increased with spatial resolution. Higher-resolution reconstructions also exhibited both improved consistency and improved sensitivity in measures of Aβ accumulation. These features suggest that higher-resolution reconstructions may be advantageous in early-stage AD therapies.

Prediction of Cognitive Progression Due to Alzheimer's Disease in Normal Participants Based on Individual Default Mode Network Metabolic Connectivity Strength

BackgroundPredicting cognitive decline among individuals in the aging population who are already amyloid-β (Aβ) positive or tau positive poses clinical challenges. In Alzheimer's disease research, intra–default mode network (DMN) connections play a pivotal role in diagnosis. In this article, we propose metabolic connectivity within the DMN as a supplementary biomarker to the Aβ, pathological tau, and neurodegeneration framework. MethodsExtracting data from 1292 participants in the Alzheimer’s Disease Neuroimaging Initiative, we collected paired T1-weighted structural magnetic resonance imaging and 18F-labeled-fluorodeoxyglucose positron emission computed tomography scans. Individual metabolic DMN networks were constructed, and metabolic connectivity (MC) strength in the DMN was assessed. In the cognitively unimpaired group, the Cox model identified cognitively unimpaired (MC+), high-risk participants, with Kaplan-Meier survival analyses and hazard ratios revealing the strength of MC’s predictive performance. Spearman correlation analyses explored relationships between MC strength, and Aβ, pathological tau, neurodegeneration biomarkers, and clinical scales. DMN standard uptake value ratio (SUVR) provided comparative insights in the analyses. ResultsBoth MC strength and SUVR exhibited gradual declines with cognitive deterioration, displaying significant intergroup differences. Survival analyses indicated enhanced Aβ and tau prediction with both metrics, with MC strength outperforming SUVR. Combined MC strength and Aβ yielded optimal predictive performance (hazard ratio = 9.29), followed by MC strength and tau (hazard ratio = 8.92). Generally, the strength of MC’s correlations with Aβ, pathological tau, and neurodegeneration biomarkers exceeded SUVR. ConclusionsIndividuals with normal cognition and disrupted DMN metabolic connectivity face an elevated risk of cognitive decline linked to Aβ that precedes metabolic issues.

Arrhythmic manifestations and outcomes of definite and probable cardiac sarcoidosis

BackgroundThe 2014 Heart Rhythm Society consensus statement defines histological (definite) and clinical (probable) diagnostic categories of cardiac sarcoidosis (CS), but few studies have compared their arrhythmic phenotypes and outcomes. ObjectiveThe purpose of this study was to evaluate the electrophysiological/arrhythmic phenotype and outcomes of patients with definite and probable CS. MethodsWe analyzed the arrhythmic/electrophysiological phenotype in a single-center North American cohort of 388 patients (median age 56 years; 39% female, n = 151) diagnosed with definite (n = 58) or probable (n = 330) CS (2000–2022). The primary composite outcome was survival to first ventricular tachycardia/fibrillation (VT/VF) event or sudden cardiac death. Key secondary outcomes were also assessed. ResultsAt index evaluation, in situ cardiac implantable electronic devices and antiarrhythmic drug use were more common in definite CS. At a median follow-up of 3.1 years, the primary outcome occurred in 22 patients with definite CS (38%) and 127 patients with probable CS (38%) (log-rank, P = .55). In multivariable analysis, only a higher ratio of the 18F-fluorodeoxyglucose maximum standardized uptake value of the myocardium to the maximum standardized uptake value of the blood pool (hazard ratio 1.09; 95% confidence interval 1.03–1.15; P = .003, per 1 unit increase) was associated with the primary outcome. During follow-up, patients with definite CS had a higher burden of device-treated VT/VF events (mean 2.86 events per patient-year vs 1.56 events per patient-year) and a higher rate of progression to heart transplant/left ventricular assist device implantation but no difference in all-cause mortality compared with patients with probable CS. ConclusionPatients with definite and probable CS had similarly high risks of first sustained VT/VF/sudden cardiac death and all-cause mortality, though patients with definite CS had a higher overall arrhythmia burden. Both CS diagnostic groups as defined by the 2014 Heart Rhythm Society criteria require an aggressive approach to prevent arrhythmic complications.

Clinical Outcomes and Tau Pathology in Retired Football Players: Associations With Diagnosed and Witnessed Sleep Apnea.

Obstructive sleep apnea (SA) is common in older men and a contributor to negative cognitive, psychiatric, and brain health outcomes. Little is known about SA in those who played contact sports and are at increased risk of neurodegenerative disease(s) and other neuropathologies associated with repetitive head impacts (RHI). In this study, we investigated the frequency of diagnosed and witnessed SA and its contribution to clinical symptoms and tau pathology using PET imaging among male former college and former professional American football players. The sample included 120 former National Football League (NFL) players, 60 former college players, and 60 asymptomatic men without exposure to RHI (i.e., controls). Diagnosed SA was self-reported, and all participants completed the Mayo Sleep Questionnaire (MSQ, informant version), the Epworth Sleepiness Scale (ESS), neuropsychological testing, and tau (flortaucipir) PET imaging. Associations between sleep indices (diagnosed SA, MSQ items, and the ESS) and derived neuropsychological factor scores, self-reported depression (Beck Depression Inventory-II [BDI-II]), informant-reported neurobehavioral dysregulation (Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A] Behavioral Regulation Index [BRI]), and tau PET uptake, were tested. Approximately 36.7% of NFL players had diagnosed SA compared with 30% of the former college football players and 16.7% of the controls. Former NFL players and college football players also had higher ESS scores compared with the controls. Years of football play was not associated with any of the sleep metrics. Among the former NFL players, diagnosed SA was associated with worse Executive Function and Psychomotor Speed factor scores, greater BDI-II scores, and higher flortaucipir PET standard uptake value ratios, independent of age, race, body mass index, and APOE ε4 gene carrier status. Higher ESS scores correlated with higher BDI-II and BRIEF-A BRI scores. Continuous positive airway pressure use mitigated all of the abovementioned associations. Among the former college football players, witnessed apnea and higher ESS scores were associated with higher BRIEF-A BRI and BDI-II scores, respectively. No other associations were observed in this subgroup. Former elite American football players are at risk of SA. Our findings suggest that SA might contribute to cognitive, neuropsychiatric, and tau outcomes in this population. Like all neurodegenerative diseases, this study emphasizes the multifactorial contributions to negative brain health outcomes and the importance of sleep for optimal brain health.