PET Biomarkers Research Articles

Clinical correlates of dopamine transporter availability in cross-sectional and longitudinal studies with [18F]FE-PE2I PET: independent validation with new insights.

[18F]FE-PE2I PET is a promising alternative to single positron emission computed tomography-based dopamine transporter (DAT) imaging in Parkinson's disease. While the excellent discriminative power of [18F]FE-PE2I PET has been established, so far only one study has reported meaningful associations between motor severity scores and DAT availability. In this study, we use high-resolution (∼3 mm isotropic) PET to provide an independent validation for the clinical correlates of [18F]FE-PE2I imaging in separate cross-sectional (28 participants with Parkinson's disease, Hoehn-Yahr: 2 and 14 healthy individuals) and longitudinal (initial results from 6 participants with Parkinson's disease with 2-year follow-up) cohorts. In the cross-sectional cohort, DAT availability in the putamen and substantia nigra of patients with Parkinson's disease showed a significant negative association with total motor severity (r = -0.59, P = 0.002 for putamen; r = -0.46, P = 0.018 for substantia nigra), but not tremor severity. To our knowledge, this is the first observed association between motor severity in Parkinson's disease and DAT availability in the substantia nigra. The associations with motor severity in most nigrostriatal regions improved if tremor scores were excluded from motor scores. Further, we found significant asymmetry in DAT availability in the putamen (∼28% lower DAT availability within the more-affected side of the putamen), and DAT-based asymmetry index for the putamen was correlated with asymmetry in motor severity (r = -0.60, P = 0.001). In the longitudinal study, [18F]FE-PE2I PET detected significant annual percentage reduction of DAT availability at the individual level in the putamen (9.7 ± 2.6%), caudate (10.5 ± 3.8%) and ventral striatum (5.5 ± 2.7%), but not the substantia nigra. Longitudinal per cent reduction in DAT availability within the putamen was strongly associated with increase in motor severity (r = 0.91, P = 0.011) at follow-up, demonstrating the high sensitivity of [18F]FE-PE2I PET in tracking longitudinal changes. These results provide further evidence for the utility of [18F]FE-PE2I as an important in vivo PET biomarker in future clinical trials of Parkinson's disease.

Accuracy and longitudinal consistency of PET/MR attenuation correction in amyloid PET imaging amid software and hardware upgrades.

Integrated PET/MR allows the simultaneous acquisition of PET biomarkers and structural and functional MRI to study Alzheimer disease (AD). Attenuation correction (AC), crucial for PET quantification, can be performed using a deep learning approach, DL-Dixon, based on standard Dixon images. Longitudinal amyloid PET imaging, which provides important information about disease progression or treatment responses in AD, is usually acquired over several years. Hardware and software upgrades often occur during a multiple-year study period, resulting in data variability. This study aims to harmonize PET/MR DL-Dixon AC amid software and head coil updates and evaluate its accuracy and longitudinal consistency. Tri-modality PET/MR and CT images were obtained from 329 participants, with a subset of 38 undergoing tri-modality scans twice within approximately three years. Transfer learning was employed to fine-tune DL-Dixon models on images from two scanner software versions (VB20P and VE11P) and two head coils (16-channel and 32-channel coils). The accuracy and longitudinal consistency of the DL-Dixon AC were evaluated. Power analyses were performed to estimate the sample size needed to detect various levels of longitudinal changes in the PET standardized uptake value ratio (SUVR). The DL-Dixon method demonstrated high accuracy across all data, irrespective of scanner software versions and head coils. More than 95.6% of brain voxels showed less than 10% PET relative absolute error in all participants. The median [interquartile range] PET mean relative absolute error was 1.10% [0.93%, 1.26%], 1.24% [1.03%, 1.54%], 0.99% [0.86%, 1.13%] in the cortical summary region, and 1.04% [0.83%, 1.36%], 1.08% [0.84%, 1.34%], 1.05% [0.72%, 1.32%] in cerebellum using the DL-Dixon models for the VB20P-16-channel-coil, VE11P-16-channel-coil and VE11P-32-channel-coil data, respectively. The within-subject coefficient of variation and intra-class correlation coefficient of PET SUVR in the cortical regions were comparable between the DL-Dixon and CT AC. Power analysis indicated that similar numbers of participants would be needed to detect the same level of PET changes using DL-Dixon and CT AC. DL-Dixon exhibited excellent accuracy and longitudinal consistency across the two software versions and head coils, demonstrating its robustness for longitudinal PET/MR neuroimaging studies in AD. AC = attenuation correction; AD = Alzheimer disease; HU = Hounsfield unit; ICC = intraclass correlation coefficient; MAE = mean absolute error; MRAE = mean relative absolute error; pCT = pseudo-CT; PiB = Pittsburgh Compound B; SD = standard deviation; SUVR = standardized uptake value ratio; wCV = within-subject coefficient of variation.

Continuous β-Amyloid CSF/PET Imbalance Model to Capture Alzheimer Disease Heterogeneity.

Discordance between CSF and PET biomarkers of β-amyloid (Aβ) might reflect an imbalance between soluble and aggregated species, possibly reflecting disease heterogeneity. Previous studies generally used binary cutoffs to assess discrepancies in CSF/PET biomarkers, resulting in a loss of information on the extent of discordance. In this study, we (1) jointly modeled Aβ-CSF/PET data to derive a continuous measure of the imbalance between soluble and fibrillar pools of Aβ, (2) investigated factors contributing to this imbalance, and (3) examined associations with cognitive trajectories. Across 822 cognitively unimpaired (n = 261) and cognitively impaired (n = 561) Alzheimer's Disease Neuroimaging Initiative individuals (384 [46.7%] females, mean age 73.0 ± 7.4 years), we fitted baseline CSF-Aβ42 and global Aβ-PET to a hyperbolic regression model, deriving a participant-specific Aβ-aggregation score (standardized residuals); negative values represent more soluble relative to aggregated Aβ and positive values more aggregated relative to soluble Aβ. Using linear models, we investigated whether methodological factors, demographics, CSF biomarkers, and vascular burden contributed to Aβ-aggregation scores. With linear mixed models, we assessed whether Aβ-aggregation scores were predictive of cognitive functioning. Analyses were repeated in an early independent validation cohort of 383 Amyloid Imaging to Prevent Alzheimer's Disease Prognostic and Natural History Study individuals (224 [58.5%] females, mean age 65.2 ± 6.9 years). The imbalance model could be fit (pseudo-R2 = 0.94) in both cohorts, across CSF kits and PET tracers. Although no associations were observed with the main methodological factors, lower Aβ-aggregation scores were associated with larger ventricular volume (β = 0.13, p < 0.001), male sex (β = -0.18, p = 0.019), and homozygous APOE-ε4 carriership (β = -0.56, p < 0.001), whereas higher scores were associated with increased uncorrected CSF p-tau (β = 0.17, p < 0.001) and t-tau (β = 0.16, p < 0.001), better baseline executive functioning (β = 0.12, p < 0.001), and slower global cognitive decline (β = 0.14, p = 0.006). In the validation cohort, we replicated the associations with APOE-ε4, CSF t-tau, and, although modestly, with cognition. We propose a novel continuous model of Aβ CSF/PET biomarker imbalance, accurately describing heterogeneity in soluble vs aggregated Aβ pools in 2 independent cohorts across the full Aβ continuum. Aβ-aggregation scores were consistently associated with genetic and AD-associated CSF biomarkers, possibly reflecting disease heterogeneity beyond methodological influences.

Unraveling Alzheimer's Disease: Investigating Dynamic Functional Connectivity in the Default Mode Network through DCC-GARCH Modeling.

Alzheimer's disease (AD) has a prolonged latent phase. Sensitive biomarkers of amyloid beta ( ), in the absence of clinical symptoms, offer opportunities for early detection and identification of patients at risk. Current biomarkers, such as CSF and PET biomarkers, are effective but face practical limitations due to high cost and limited availability. Recent blood plasma biomarkers, though accessible, still incur high costs and lack physiological significance in the Alzheimer's process. This study explores the potential of brain functional connectivity (FC) alterations associated with AD pathology as a non-invasive avenue for detection. While current stationary FC measurements lack sensitivity at the single-subject level, our investigation focuses on dynamic FC using resting-state functional MRI (rs-fMRI) and introduces the Generalized Auto-Regressive Conditional Heteroscedastic Dynamic Conditional Correlation (DCC-GARCH) model. Our findings demonstrate the superior sensitivity of DCC-GARCH to CSF status, and offer key insights into dynamic functional connectivity analysis in AD.

Early FDG PET imaging and circulating T-cell repertoire biomarkers of response to chemotherapy and PD-1 checkpoint inhibitors in patients with stage IV NSCLC.

8622 Background: Chemotherapy and immune checkpoint inhibitors (chemoICI) for stage IV NSCLC without driver mutations produce variable response patterns and outcomes. Early assessment could establish selective benefit from treatment (de)escalation, consolidation, or adaptation. We evaluated FDG PET imaging and circulating T cell repertoire biomarkers of chemoICI response for clinical decision support. Methods: 35 patients with stage IV NSCLC prospectively enrolled on PET BRIGHT (NCT04151940) from 2019-2023 and received first-line carboplatin-pemetrexed-pembrolizumab. Synchronous FDG PET/CT and peripheral blood draws were performed prior to and after first dose of chemoICI at week 3. Imaging biomarkers included standardized uptake value (SUV) and total lesion glycolysis (TLG) metrics within the primary metabolic tumor volume and across lung lesions. Immunophenotyping included T cell receptor (TCR) sequencing from which TCR diversity metrics were extracted. Spearman correlation of FDG PET and TCR biomarkers with bi-dimensional size reduction after initial chemoICI was estimated. ROC analysis of PET and TCR biomarkers to discriminate chemoICI response status was benchmarked against PD-L1 testing, along with Mann-Whitney testing of groupwise differences. Results: The majority tested negative for PD-L1 (58% TPS&lt;1%). Most patients (63%) had partial response (PR) to initial chemoICI versus 33% with stable disease (SD) and 4% with progressive disease (PD). FDG PET primary tumor peak SUV decreased by a median of 15% [-82%, 63%] at week 3, while TLG decreased by 36% [-55%, 83%]. Higher baseline peak SUV and TLG, along with greater decline after first dose, were correlated with post-chemoICI size reduction (R 0.43-0.64, p=0.001-0.036). PR patients had higher baseline peak SUV (12 vs 6 g/mL, p=0.014) and greater week 3 decline in TLG (39% vs 7%, p=0.032) relative to SD/PD patients. Across lung lesions, PR-patient maximum SUV decreased while SD/PD-patient maximum SUV increased at week 3 (20% vs -19%, p=0.010). FDG PET biomarkers were stronger discriminators of chemoICI response status (AUC 0.75-0.82, p=0.009-0.046) than PD-L1 (AUC 0.60, p=0.42). Higher baseline blood TCR Simpson clonality was positively correlated with size reduction (R 0.70, p=0.004), whereas TCR Pielou evenness was negatively correlated (R -0.68, p=0.006). Higher baseline TCR clonality / lower TCR evenness discriminated chemoICI response status (AUC 0.80-0.84, p=0.028-0.049). TCR diversity changes were uncorrelated with response. Conclusions: FDG PET imaging prior to and after first dose chemoICI, along with baseline circulating T cell repertoire biomarkers, predict future response. Further investigation of these patient- and lesion-level biomarkers to guide personalized (de)escalation, consolidation, or adaptation of regimens for stage IV NSCLC is warranted. Clinical trial information: NCT04151940 .

Towards cascading genetic risk in Alzheimer's disease.

Alzheimer's disease typically progresses in stages, which have been defined by the presence of disease-specific biomarkers: amyloid (A), tau (T) and neurodegeneration (N). This progression of biomarkers has been condensed into the ATN framework, in which each of the biomarkers can be either positive (+) or negative (-). Over the past decades, genome-wide association studies have implicated ∼90 different loci involved with the development of late-onset Alzheimer's disease. Here, we investigate whether genetic risk for Alzheimer's disease contributes equally to the progression in different disease stages or whether it exhibits a stage-dependent effect. Amyloid (A) and tau (T) status was defined using a combination of available PET and CSF biomarkers in the Alzheimer's Disease Neuroimaging Initiative cohort. In 312 participants with biomarker-confirmed A-T- status, we used Cox proportional hazards models to estimate the contribution of APOE and polygenic risk scores (beyond APOE) to convert to A+T- status (65 conversions). Furthermore, we repeated the analysis in 290 participants with A+T- status and investigated the genetic contribution to conversion to A+T+ (45 conversions). Both survival analyses were adjusted for age, sex and years of education. For progression from A-T- to A+T-, APOE-e4 burden showed a significant effect [hazard ratio (HR) = 2.88; 95% confidence interval (CI): 1.70-4.89; P < 0.001], whereas polygenic risk did not (HR = 1.09; 95% CI: 0.84-1.42; P = 0.53). Conversely, for the transition from A+T- to A+T+, the contribution of APOE-e4 burden was reduced (HR = 1.62; 95% CI: 1.05-2.51; P = 0.031), whereas the polygenic risk showed an increased contribution (HR = 1.73; 95% CI: 1.27-2.36; P < 0.001). The marginal APOE effect was driven by e4 homozygotes (HR = 2.58; 95% CI: 1.05-6.35; P = 0.039) as opposed to e4 heterozygotes (HR = 1.74; 95% CI: 0.87-3.49; P = 0.12). The genetic risk for late-onset Alzheimer's disease unfolds in a disease stage-dependent fashion. A better understanding of the interplay between disease stage and genetic risk can lead to a more mechanistic understanding of the transition between ATN stages and a better understanding of the molecular processes leading to Alzheimer's disease, in addition to opening therapeutic windows for targeted interventions.

Evidence of Pericyte Damage in a Cognitively Normal Cohort: Association With CSF and PET Biomarkers of Alzheimer Disease.

Blood-brain barrier (BBB) dysfunction is emerging as an important pathophysiologic factor in Alzheimer disease (AD). Cerebrospinal fluid (CSF) platelet-derived growth factor receptor-β (PDGFRβ) is a biomarker of BBB pericyte injury and has been implicated in cognitive impairment and AD. We aimed to study CSF PDGFRβ protein levels, along with CSF biomarkers of brain amyloidosis and tau pathology in a well-characterized population of cognitively unimpaired individuals and correlated CSF findings with amyloid-PET positivity. We performed an institutional review board (IRB)-approved cross-sectional analysis of a prospectively enrolled cohort of 36 cognitively normal volunteers with available CSF, Pittsburgh compound B PET/CT, Mini-Mental State Exam score, Global Deterioration Scale, and known apolipoprotein E ( APOE ) ε4 status. Thirty-six subjects were included. Mean age was 63.3 years; 31 of 36 were female, 6 of 36 were amyloid-PET-positive and 12 of 36 were APOE ε4 carriers. We found a moderate positive correlation between CSF PDGFRβ and both total Tau (r=0.45, P =0.006) and phosphorylated Tau 181 (r=0.51, P =0.002). CSF PDGFRβ levels were not associated with either the CSF Aβ42 or the amyloid-PET. We demonstrated a moderate positive correlation between PDGFRβ and both total Tau and phosphorylated Tau 181 in cognitively normal individuals. Our data support the hypothesis that BBB dysfunction represents an important early pathophysiologic step in AD, warranting larger prospective studies. ClinicalTrials.gov Identifier: NCT00094939.

Medial temporal lobe gray matter microstructure in preclinical Alzheimer's disease.

Typical MRI measures of neurodegeneration have limited sensitivity in early disease stages. Diffusion MRI (dMRI) microstructural measures may allow for detection in preclinical stages. Participants had dMRI and either beta-amyloid PET or plasma biomarkers of Alzheimer's pathology within 18 months of MRI. Microstructure was measured in portions of the medial temporal lobe (MTL) with high neurofibrillary tangle (NFT) burden based on a previously developed post mortem 3D-map. Regressions examined relationships between microstructure and markers of Alzheimer's pathology in preclinical disease and then across disease stages. There was higher isometric volume fraction in amyloid-positive compared to amyloid-negative cognitively unimpaired individuals in high tangle MTL regions. Similarly, plasma biomarkers and 18F-flortaucipir were associated with microstructural changes in preclinical disease. Additional microstructural effects were seen across disease stages. Combining a post mortem atlas of NFT pathology with microstructural measures allows for detection of neurodegeneration in preclinical Alzheimer's disease. Highlights Typical markers of neurodegeneration are not sensitive in preclinical Alzheimer's. dMRI measured microstructure in regions with high NFT. Microstructural changes occur in medial temporal regions in preclinical disease. Microstructural changes occur in other typical Alzheimer's regions in later stages. Combining post mortem pathology atlases with in vivo MRI is a powerful framework.

Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities in a community-dwelling cohort.

We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N=299), mild cognitive impairment (MCI; N=192), or dementia (DEM; N=65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Plasma biomarkers differed across diagnostic groups (DEM>MCI>CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Plasma biomarkers differ across diagnostic groups (DEM>MCI>CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.

Evaluation of Neurodegenerative Disorders with Amyloid-β, Tau, and Dopaminergic PET Imaging: Interpretation Pitfalls.

Antiamyloid therapies for Alzheimer disease recently entered clinical practice, making imaging biomarkers for Alzheimer disease even more relevant to guiding patient management. Amyloid and tau PET are valuable tools that can provide objective evidence of Alzheimer pathophysiology in living patients and will increasingly be used to complement 18F-FDG PET in the diagnostic evaluation of cognitive impairment and dementia. Parkinsonian syndromes, also common causes of dementia, can likewise be evaluated with a PET imaging biomarker,18F-DOPA, allowing invivo assessment of the presynaptic dopaminergic neurons. Understanding the role of these PET biomarkers will help the nuclear medicine physician contribute to the appropriate diagnosis and management of patients with cognitive impairment and dementia. To successfully evaluate brain PET examinations for neurodegenerative diseases, knowledge of the necessary protocol details for obtaining a reliable imaging study, inherent limitations for each PET radiopharmaceutical, and pitfalls in image interpretation is critical. This review will focus on underlying concepts for interpreting PET examinations, important procedural details, and guidance for avoiding potential interpretive pitfalls for amyloid, tau, and dopaminergic PET examinations.

Mapping 18F-FDG Kinetics Together with Patient-Specific Bootstrap Assessment of Uncertainties: An Illustration with Data from a PET/CT Scanner with a Long Axial Field of View.

The purpose of this study was to examine a nonparametric approach to mapping kinetic parameters and their uncertainties with data from the emerging generation of dynamic whole-body PET/CT scanners. Methods: Dynamic PET 18F-FDG data from a set of 24 cancer patients studied on a long-axial-field-of-view PET/CT scanner were considered. Kinetics were mapped using a nonparametric residue mapping (NPRM) technique. Uncertainties were evaluated using an image-based bootstrapping methodology. Kinetics and bootstrap-derived uncertainties are reported for voxels, maximum-intensity projections, and volumes of interest (VOIs) corresponding to several key organs and lesions. Comparisons between NPRM and standard 2-compartment (2C) modeling of VOI kinetics are carefully examined. Results: NPRM-generated kinetic maps were of good quality and well aligned with vascular and metabolic 18F-FDG patterns, reasonable for the range of VOIs considered. On a single 3.2-GHz processor, the specification of the bootstrapping model took 140 min; individual bootstrap replicates required 80 min each. VOI time-course data were much more accurately represented, particularly in the early time course, by NPRM than by 2C modeling constructs, and improvements in fit were statistically highly significant. Although 18F-FDG flux values evaluated by NPRM and 2C modeling were generally similar, significant deviations between vascular blood and distribution volume estimates were found. The bootstrap enables the assessment of quite complex summaries of mapped kinetics. This is illustrated with maximum-intensity maps of kinetics and their uncertainties. Conclusion: NPRM kinetics combined with image-domain bootstrapping is practical with large whole-body dynamic 18F-FDG datasets. The information provided by bootstrapping could support more sophisticated uses of PET biomarkers used in clinical decision-making for the individual patient.

Equivalent uniform aerobic dose in radiotherapy for hypoxic tumors

Objective. Equivalent uniform aerobic dose (EUAD) is proposed for comparison of integrated cell survival in tumors with different distributions of hypoxia and radiation dose. Approach. The EUAD assumes that for any non-uniform distributions of radiation dose and oxygen enhancement ratio (OER) within a tumor, there is a uniform distribution of radiation dose under hypothetical aerobic conditions with OER = 1 that produces equal integrated survival of clonogenic cells. This definition of EUAD has several advantages. First, the EUAD allows one to compare survival of clonogenic cells in tumors with intra-tumor and inter-tumor variation of radio sensitivity due to hypoxia because the cell survival is recomputed under the same benchmark oxygen level (OER = 1). Second, the EUAD for homogeneously oxygenated tumors is equal to the concept of equivalent uniform dose. Main results. We computed the EUAD using radiotherapy dose and the OER derived from the 18F-Fluoromisonidazole PET (18F-FMISO PET) images of hypoxia in patients with glioblastoma, the most common and aggressive type of primary malignant brain tumor. The 18F-FMISO PET images include a distribution of SUV (Standardized Uptake Value); therefore, the SUV is converted to partial oxygen pressure (pO2) and then to the OER. The prognostic value of EUAD in radiotherapy for hypoxic tumors is demonstrated using correlation between EUAD and overall survival (OS) in radiotherapy for glioblastoma. The correction to the EUAD for the absolute hypoxic volume that traceable to the tumor control probability improves the correlation with OS. Significance. While the analysis proposed in this research is based on the 18F-FMISO PET images for glioblastoma, the EUAD is a universal radiobiological concept and is not associated with any specific cancer or any specific PET or MRI biomarker of hypoxia. Therefore, this research can be generalized to other cancers, for example stage III lung cancer, and to other hypoxia biomarkers.

Where Should I Draw the Line: PET-Driven, Data-Driven, or Manufacturer Cut-Off?

The optimal cut-off for Alzheimer's disease (AD) CSF biomarkers remains controversial. To analyze the performance of cut-off points standardized by three methods: one that optimized the agreement between 11C-Pittsburgh compound B PET (a-PET) and CSF biomarkers (Aβ1-42, pTau, tTau, and Aβ1-42/Aβ1-40 ratio) in our population, called PET-driven; an unbiased cut-off using data from a healthy research cohort, called data-driven, and that provided by the manufacturer. We also compare changes in ATN classification. CSF biomarkers measured by the LUMIPULSE G600II platform and qualitative visualization of amyloid positron emission tomography (a-PET) were performed in all the patients. We established a cut-off for each single biomarker and Aβ1-42/Aβ1-40 ratio that optimized their agreement with a-PET using ROC curves. Sensitivity, Specificity, and Overall Percent of Agreement are assessed using a-PET or clinical diagnosis as gold standard for every cut-off. Also, we established a data-driven cut-off from our cognitively unimpaired cohort. We then analyzed changes in ATN classification. One hundred and ten patients were recruited. Sixty-six (60%) were a-PET positive. PET-driven cut-offs were: pTau > 57, tTau > 362.62, Aβ1-42/Aβ1-40 < 0.069. For a single biomarker, pTau showed the highest accuracy (AUC 0.926). New PET-driven cut-offs classified patients similarly to manufacturer cut-offs (only two patients changed). However, 20 patients (18%) changed when data-driven cut-offs were used. We established our sample's best CSF biomarkers cut-offs using a-PET as the gold standard. These cut-offs categorize better symptomatic subjects than data-driven in ATN classification, but they are very similar to the manufacturer's.

The diagnostic and prognostic value of tau-PET in amnestic MCI with different FDG-PET subtypes.

Mild cognitive impairment presenting with an amnestic syndrome (aMCI) and amyloid positivity is considered due to AD. Many subjects, however, can show an overall very slow progression relevant for differential diagnosis, prognosis, and treatment. This study assessed PET biomarkers, includingbrain glucose metabolism, tau, and amyloid load, in a series of comparable aMCI at baseline, clinically evaluated at follow-up. We included 72 aMCI subjects from Geneva Memory Center (N = 31) and ADNI cohorts (N = 41), selected based on available FDG-PET, tau-PET, amyloid-PET, and clinical follow-up (2.3 years ± 1.2). A data-driven algorithm classified brain metabolic patterns into subtypes that were then compared for clinical and PET biomarker measures and cognitive decline. Voxel-wise comparisons were performed both with FDG-PET and tau-PET data. The algorithm classified three metabolic subtypes, namely "Hippocampal-sparing with cortical hypometabolism" (Type1; N = 27), "Hippocampal and cortical hypometabolism" (Type 2; N = 23), and "Medial temporal hypometabolism" (Type 3; N = 22). Amyloid positivity and tau accumulation in the medial temporal and neocortical regions characterized Type 1 and Type 2, whereas Type 3 showed no significant tau pathology, variable amyloid positivity, and stability at follow-up. All tau-positive patients, independently of the FDG-based subtype, showed faster cognitive decline. aMCI subjects can differ in metabolic patterns, tau and amyloid pathology, and clinical progression. Here, we complemented with PET tau biomarker the specific brain hypometabolic patterns at the individual level in the prodromal phase, contributing to the patient's classification. Tau PET is the most accurate biomarker in supporting or excluding the AD diagnosis in aMCI across metabolic subtypes and also predicting the risk of decline.

Clinical Arterial Spin-Labeling MR Imaging to Screen for Typical and Atypical Neurodegenerative Disease in the New Era of Alzheimer Treatment.

The clinical standard of care in the diagnosis of neurodegenerative diseases relies on [18F] FDG-PET/CT or PET MR imaging. Limitations of FDG-PET include cost, the need for IV access, radiation exposure, and availability. Arterial spin-labeling MR imaging has been shown in research settings to be useful as a proxy for FDG-PET in differentiating Alzheimer disease from frontotemporal dementia. However, it is not yet widely used in clinical practice, except in cerebrovascular disease. Here, we present 7 patients, imaged with our routine clinical protocol with diverse presentations of Alzheimer disease and other neurodegenerative diseases, in whom arterial spin-labeling-derived reduced CBF correlated with hypometabolism or amyloid/tau deposition on PET. Our case series illustrates the clinical diagnostic utility of arterial spin-labeling MR imaging as a fast, accessible, and noncontrast screening tool for neurodegenerative disease. Arterial spin-labeling MR imaging can guide patient selection for subsequent PET or fluid biomarker work-up, as well as for possible therapy with antiamyloid monoclonal antibodies.

Bile acid profile associated with CSF and PET biomarkers in Alzheimer’s disease

BackgroundRecent studies have shown that gut microbiota can affect the development of Alzheimer’s disease (AD) through various mechanisms. Bile acids (BAs), which are the final byproducts of cholesterol metabolism created through both the human body and gut microbiome, appear to be influenced by gut microbiota and may impact AD pathological characteristics such as the accumulation of tau and amyloid-β. We aimed to investigate the associations between various serum BAs and CSF biomarkers (including Aβ, total tau, and p-tau). Additionally, we sought to examine the longitudinal changes in brain Aβ and tau through PET imaging in relation to BAs profile.MethodsThe data of 828 subjects including 491 diagnosed with mild cognitive impairment (MCI), 119 patients diagnosed with AD, and 267 cognitively normal (CN) participants were obtained from ADNI. The baseline and longitudinal [18F] florbetapir and [18F] flortaucipir PET standard uptake value ratios (SUVR) measures were obtained to assess the accumulation of tau and Aβ. Moreover, baseline levels of serum BAs and CSF Aβ1–42, tau, and p-tau were used.ResultsAfter FDR correction we observed that five BAs level and relevant calculated ratios were associated with CSF p-tau and tau, three with CSF Aβ1–42. Furthermore, three BAs level and relevant calculated ratios were associated with the tau-PET rate of change, and two with the Aβ rate of change.ConclusionThe findings from our study suggest a correlation between altered profiles of BAs and CSF and imaging biomarkers associated with AD. These results provide supporting evidence for the link between the gut microbiome and the pathological features of AD.

Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology

BackgroundAntibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181, p-tau217 and p-tau231 with established immunoassay techniques.MethodsWe measured p-tau181, p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods. All subjects were clinically evaluated by dementia specialists and had amyloid-PET and tau-PET assessments. Bland–Altman analyses evaluated the agreement between immunoassay and mass spectrometry p-tau181, p-tau217 and p-tau231. P-tau associations with amyloid-PET and tau-PET uptake were also compared. Receiver Operating Characteristic (ROC) analyses compared the performance of mass spectrometry and immunoassays p-tau concentrations to identify amyloid-PET positivity.ResultsMass spectrometry and immunoassays of p-tau217 were highly comparable in terms of diagnostic performance, between-group effect sizes and associations with PET biomarkers. In contrast, p-tau181 and p-tau231 concentrations measured using antibody-free mass spectrometry had lower performance compared with immunoassays.ConclusionsOur results suggest that while similar overall, immunoassay-based p-tau biomarkers are slightly superior to antibody-free mass spectrometry-based p-tau biomarkers. Future work is needed to determine whether the potential to evaluate multiple biomarkers within a single run offsets the slightly lower performance of antibody-free mass spectrometry-based p-tau quantification.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

The significance of the dynamics of PET biomarkers in assessing the response to R-CHOP immunochemotherapy in patients with diffuse large B-cell lymphoma

Introduction. In recent years, the prognostic role of baseline values of 18F-FDG PET biomarkers – tumor metabolic volume and tumor glycolysis volume have been actively studied in patients with diffuse large B-cell lymphoma (DLBCL). At the same time, no researchers are studying the dynamics of these biomarkers after treatment and their relationship with the Deauville scale and response to treatment.Objective. Assessment of the significance of changes in PET biomarkers after R-CHOP immunochemotherapy (ICT) and search for their possible relationship with the Deauville scale. Materials and methods. An analysis of immediate clinical results (complete, partial remission, stabilization of the disease) and PET biomarkers was carried out before and after R-CHOP ICT in 46 primary patients with DLBCL. Volumetric PET biomarkers obtained after ICT were correlated with patient response to therapy and Deauville scores. The results were statistically processed using parametric and nonparametric analysis methods using the IBM SPSS Statistics v26.Results. A pronounced direct correlation was found between the increased risk of early progression according to the criteria of the International Prognostic Index (IPI) and the levels of initial biomarkers TMTV (r=0.63, p&lt;0.05) and TTLG (r=0.60, p&lt; 0.05). High baseline levels of TMTV and TTLG (more than 420 cm3 and 3200 g/ml x cm3 , respectively) were significantly associated with a worse immediate response to R-CHOP ICT (total OR – 3.43 and 2.87, respectively, p&lt;0.05).Significant reductions in ΔSUVmax (&gt;70% of baseline), ΔTTLG (&gt;55%) and ΔTMTV (&gt;55%) after treatment were significantly associated with a higher rate of complete clinical response. The rate of complete remission after R-CHOP ICT with a combination of an initially low TMTV and a high average SUVmax was higher (72.7%) compared to the rates for patients with a high TMTV and low SUVmax (10.4%). In multivariate analysis, the combination of a low baseline TMTV and a high mean SUVmax values was an independent prognostic factor. Bivariate regression models were obtained with high multiple correlation coefficients between the combination of IPI risk categories as a binary variable (&lt;3 vs. ≥3) with the Deauville scale (r = 0.812). As well as with the combination of the level of reduction in ΔSUVmax as a binary variable (&lt;70% vs. ≥70%) with the Deauville scale (r=0.785; p&lt; 0.05) compared with the univariate model using only the Deauville scale (r=0.686; p&lt;0.05). Conclusion. For the first time, we have shown the importance of not only the basic indicators of PET biomarkers, but also, more importantly, their dynamics and combination with the Deauville scale in assessing the immediate results of R-CHOP ICT. The use of additional parameters increases the value of the Deauville scale, and the resulting regression equations and models are superior to changes in the threshold values of the Deauville scale and can be used to estimate the likelihood of achieving a complete response to R-CHOP ICT in patients with DLBCL.

Exploring biomarker profiles of the cognitively unimpaired individuals in early tau PET Braak stage

AbstractBackgroundIn this study, we evaluated the association between tau PET and fluid biomarkers and explored biological mechanisms associated with elevated tau in cognitively unimpaired(CU) individuals.MethodSeventy‐nine CU individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted MRI, CSF and plasma biomarkers. Longitudinal changes in cognition were measured using cognition composites(Table1). Participants were categorized into AT stages using CSF biomarkers and pre‐established cut‐offs(Table 1). [18F]RO‐948 SUVR was measured in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference. Regional positivity thresholds per Braak region were calculated as mean+2SD of the A‐T‐ group. [18F]flutemetamol PET scans were quantified in Centiloids(CL). Associations between [18F]RO‐948 SUVRs and AD biomarkers (Figure1) were assessed using Pearson correlations. Receiver Operating Curve(ROC) analyses were conducted to determine the capacity of biomarkers to predict BraakI/II positivity. In those with CL&gt;cut‐off for tau‐PET positivity, differences in non‐core AD fluid biomarkers(Figure2) and longitudinal cognition were sought between tau BraakI/II positive and negative individuals. The mediating effect of non‐core AD biomarkers on the AD pathophysiological cascade were sought. FDR‐corrected p‐values&lt;0.05 were considered significant.ResultNine cases(11.4%) were positive in BraakI/II. Following a hierarchical pattern, four of them were also positive for BraakIII/IV and one for BraakV/VI. Fluid biomarkers presented correlations with tau PET SUVR in all Braak stages (Figure1) and predictive capacity for tau‐PET positivity in BraakI/II(Table2). In individuals with CL&gt;32.53, BraakI/II positives had higher levels of CSF‐GFAP(p&lt;0.01) and CSF‐NFL(p = 0.03), and presented declines in PACC and in visual, attention, and memory composites (Figure1). CSF‐GFAP partially mediated the association between CL and tau‐PET (16%) and between tau‐PET and CSF‐NfL (30%).ConclusionEarly in the AD continuum, [18F]RO‐948 PET conformed to the Braak hierarchical model. CSF and plasma biomarkers showed moderate associations with tau PET SUVR but good capacity to predict tau PET positivity in BraakI/II. Tau‐PET positivity in this region was associated with higher astrogliosis, neurodegeneration and cognitive decline as compared to tau‐PET negatives with similar levels of amyloid deposition. Astrogliosis partially explained the observed associations between amyloid deposition and the presence of tau tangles in medial temporal regions and, even strongly, between the latter and neurodegeneration.