Positron Emission Tomography Measurements Research Articles

Associations Between Glucose Metabolism Measures and Amyloid-β and Tau Load on PET 14 Years Later: Findings From the Framingham Heart Study.

Type 2 diabetes and glucose metabolism have previously been linked to Alzheimer disease (AD). Yet, findings on the relation of glucose metabolism with amyloid-β and tau pathology later in life remain unclear. We included 288 participants (mean age = 43.1 years, SD = 10.7, range 20-70 years) without dementia, from the Framingham Heart Study, who had available measures of glucose metabolism (i.e., one-time fasting plasma glucose and insulin) and positron emission tomography (PET) measures of amyloid-β and/or tau 14 years later. We performed linear regression analyses to test associations of plasma glucose (continuously and categorically; elevated defined as >100 mg/dL), plasma insulin, homeostatic model assessment for insulin resistance (HOMA-IR) with amyloid-β or tau load on PET. When significant, we explored whether age, sex, and APOE ε4 allele carriership (AD genetic risk) modified these associations. Our findings indicated that elevated plasma glucose was associated with greater tau load 14 years later (B [95% CI] = 0.03 [0.01-0.05], P = 0.024 after false discovery rate [FDR] correction) but not amyloid-β. APOE ε4 carriership modified this association (B [95% CI] = -0.08 [-0.12 to -0.03], P = 0.001), indicating that the association was only present in APOE ε4 noncarriers (n = 225). Plasma insulin and HOMA-IR were not associated with amyloid-β or τ load 14 years later after FDR correction. Our findings suggest that glucose metabolism is associated with increased future tau but not amyloid-β load. This provides relevant knowledge for prevention strategies and prognostics to improve health care.

Simultaneous Positron Emission Tomography and Molecular Magnetic Resonance Imaging of Cardiopulmonary Fibrosis in a Mouse Model of Left Ventricular Dysfunction.

Aging-associated left ventricular dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in a left ventricular dysfunction model. Left ventricular dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone mice, a subset of mice that received sham surgery. Three weeks after surgery, mice underwent simultaneous PET-MRI at 4.7 T. Collagen-targeted PET and fibrogenesis magnetic resonance (MR) probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio. Percent signal intensity increase and Δ lung-to-muscle ratio were computed from the pre-/postinjection magnetic resonance images. Elevated allysine in the heart (P=0.02) and lungs (P=0.17) of TAC mice corresponded to an increase in myocardial magnetic resonance imaging percent signal intensity increase (P<0.0001) and Δlung-to-muscle ratio (P<0.0001). Hydroxyproline in the heart (P<0.0001) and lungs (P<0.01) were elevated in TAC mice, which corresponded to an increase in heart (myocardium-to-muscle ratio, P=0.02) and lung (lung-to-muscle ratio, P<0.001) PET measurements. Pressure-volume loop and echocardiography demonstrated adverse left ventricular remodeling, function, and increased right ventricular systolic pressure in TAC mice. Administration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-magnetic resonance imaging signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-magnetic resonance imaging protocol.

Non-invasive mapping of brown adipose tissue activity with magnetic resonance imaging

Thermogenic brown adipose tissue (BAT) has a positive impact on whole-body metabolism. However, in vivo mapping of BAT activity typically relies on techniques involving ionizing radiation, such as [18F]fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) and computed tomography (CT). Here we report a noninvasive metabolic magnetic resonance imaging (MRI) approach based on creatine chemical exchange saturation transfer (Cr-CEST) contrast to assess in vivo BAT activity in rodents and humans. In male rats, a single dose of the β3-adrenoceptor agonist (CL 316,243) or norepinephrine, as well as cold exposure, triggered a robust elevation of the Cr-CEST MRI signal, which was consistent with the [18F]FDG PET and CT data and 1H nuclear magnetic resonance measurements of creatine concentration in BAT. We further show that Cr-CEST MRI detects cold-stimulated BAT activation in humans (both males and females) using a 3T clinical scanner, with data-matching results from [18F]FDG PET and CT measurements. This study establishes Cr-CEST MRI as a promising noninvasive and radiation-free approach for in vivo mapping of BAT activity.

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

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

In vivo whole-cortex marker of excitation-inhibition ratio indexes cortical maturation and cognitive ability in youth

A balanced excitation-inhibition ratio (E/I ratio) is critical for healthy brain function. Normative development of cortex-wide E/I ratio remains unknown. Here, we noninvasively estimate a putative marker of whole-cortex E/I ratio by fitting a large-scale biophysically plausible circuit model to resting-state functional MRI (fMRI) data. We first confirm that our model generates realistic brain dynamics in the Human Connectome Project. Next, we show that the estimated E/I ratio marker is sensitive to the gamma-aminobutyric acid (GABA) agonist benzodiazepine alprazolam during fMRI. Alprazolam-induced E/I changes are spatially consistent with positron emission tomography measurement of benzodiazepine receptor density. We then investigate the relationship between the E/I ratio marker and neurodevelopment. We find that the E/I ratio marker declines heterogeneously across the cerebral cortex during youth, with the greatest reduction occurring in sensorimotor systems relative to association systems. Importantly, among children with the same chronological age, a lower E/I ratio marker (especially in the association cortex) is linked to better cognitive performance. This result is replicated across North American (8.2 to 23.0 y old) and Asian (7.2 to 7.9 y old) cohorts, suggesting that a more mature E/I ratio indexes improved cognition during normative development. Overall, our findings open the door to studying how disrupted E/I trajectories may lead to cognitive dysfunction in psychopathology that emerges during youth.

Testing PET-[11C]ABP688 as a tool to quantify glutamate release in vivo

Abstract The excitatory neurotransmitter glutamate plays a critical role in experience-dependent neuroplasticity, including addiction-related processes. To date, however, it is not possible to measure glutamate release in the living human brain. Positron emission tomography (PET) with [11C]ABP688, a selective allosteric antagonist of metabotropic type 5 glutamate (mGlu5) receptors, could offer an effective strategy. To test this proposition, we conducted a series of studies in rats using microdialysis and [11C]ABP688 microPET imaging, and in humans using PET and magnetic resonance spectroscopy (MRS). Significant calcium-dependent glutamate release was identified in the ventral striatum of awake rats (190.5 ± 34.7%, p &amp;lt; 0.05; n = 7) following administration of a low dose of ethanol (EtOH; 20%, 0.5 g/kg), a pharmacological challenge readily translatable to human research. Simultaneous microdialysis and microPET studies in anesthetized rats yielded concurrent increases in glutamate release (126.9 ± 5.3%, p &amp;lt; 0.001; n = 11) and decreases in striatal [11C]ABP688 binding (6.8 ± 9.6%, p &amp;lt; 0.05). These latter two effects, however, were not significantly correlated (r = 0.25, p = 0.46). In humans, a laboratory stressor yielded significant changes in self-reported mood (ps &amp;lt; 0.041), sympathetic system activations (ps &amp;lt; 0.042), and the MRS index of striatal glutamate reuptake following excitatory neurotransmission, Glx/Cr levels (p = 0.048). These effects, however, were not accompanied by significant changes in [11C]ABP688 BPND (ps &amp;gt; 0.21, n = 9) or correlated with each other (ps &amp;gt; 0.074). Together, these studies document EtOH-induced glutamate release from neurons, EtOH-induced decreases in [11C]ABP688 binding, and stress-induced changes in glutamate turnover, yet fail to provide evidence that the PET [11C]ABP688 method can be exploited to quantify moderate changes in glutamate release. The results underscore the need for highly controlled testing conditions during PET measures of mGlu5 receptors.

Harmonizing florbetapir and PiB PET measurements of cortical Aβ plaque burden using multiple regions-of-interest and machine learning techniques: An alternative to the Centiloid approach.

Machine learning (ML) can optimize amyloid (Aβ) comparability among positron emission tomography (PET) radiotracers. Using multi-regional florbetapir (FBP) measures and ML, we report better Pittsburgh compound-B (PiB)/FBP harmonization of mean-cortical Aβ (mcAβ) than Centiloid. PiB-FBP pairs from 92 subjects in www.oasis-brains.org and 46 in www.gaain.org/centiloid-project were used as the training/testing sets. FreeSurfer-extracted FBP multi-regional Aβ and actual PiB mcAβ in the training set were used to train ML models generating synthetic PiB mcAβ. The correlation coefficient (R) between the synthetic/actual PiB mcAβ in the testing set was assessed. In the testing set, the synthetic/actual PiB mcAβ correlation R=0.985 (R2 =0.970) using artificial neural network was significantly higher (p≤6.6e-4) than the FBP/PiB correlation R=0.927 (R2 =0.860), improving total variance percentage (R2 ) from 86% to 97%. Other ML models such as partial least square, ensemble, and relevance vector regressions also improved R (p=9.677e-05 /0.045/0.0017). ML improved mcAβ comparability. Additional studies are needed for the generalizability to other amyloid tracers, and to tau PET. Highlights Centiloid is a calibration of the amyloid scale, not harmonization. Centiloid unifies the amyloid scale without improving inter-tracer association (R2 ). Machine learning (ML) can harmonize the amyloid scale by improving R2 . ML harmonization maps multi-regional florbetapir SUVRs to PiB mean-cortical SUVR. Artificial neural network ML increases Centiloid R2 from 86% to 97%.

Sleep and physical activity measures are associated with resting-state network segregation in non-demented older adults

Greater physical activity and better sleep are associated with reduced risk of cognitive decline and dementia among older adults, but little is known about their combined associations with measures of brain function and neuropathology. This study investigated potential independent and interactive cross-sectional relationships between actigraphy-estimated total volume of physical activity (TVPA) and sleep patterns [i.e., total sleep time (TST), sleep efficiency (SE)] with resting-state functional magnetic resonance imaging (rs-fMRI) measures of large scale network connectivity and positron emission tomography (PET) measures of amyloid-β. Participants were 135 non-demented older adults from the BIOCARD study (116 cognitively normal and 19 with mild cognitive impairment; mean age = 70.0 years). Using multiple linear regression analyses, we assessed the association between TVPA, TST, and SE with connectivity within the default-mode, salience, and fronto-parietal control networks, and with network modularity, a measure of network segregation. Higher TVPA and SE were independently associated with greater network modularity, although the positive relationship of SE with modularity was only present in amyloid-negative individuals. Additionally, higher TVPA was associated with greater connectivity within the default-mode network, while greater SE was related to greater connectivity within the salience network. In contrast, longer TST was associated with lower network modularity, particularly among amyloid-positive individuals, suggesting a relationship between longer sleep duration and greater network disorganization. Physical activity and sleep measures were not associated with amyloid positivity. These data suggest that greater physical activity levels and more efficient sleep may promote more segregated and potentially resilient functional networks and increase functional connectivity within specific large-scale networks and that the relationship between sleep and functional networks connectivity may depend on amyloid status.

Effects of the active amyloid beta immunotherapy CAD106 on PET measurements of amyloid plaque deposition in cognitively unimpaired APOE ε4 homozygotes.

Alzheimer's Prevention Initiative Generation Study 1 evaluated amyloid beta (Aβ) active immunotherapy (vaccine) CAD106 and BACE-1 inhibitor umibecestat in cognitively unimpaired 60- to 75-year-old participants at genetic risk for Alzheimer's disease (AD). The study was reduced in size and terminated early. Results from the CAD106 cohort are presented. Sixty-five apolipoprotein E ε4 homozygotes with/without amyloid deposition received intramuscular CAD106 450μg (n=42) or placebo (n=23) at baseline; Weeks 1, 7, 13; and quarterly; 51 of them had follow-up Aβ positron emission tomography (PET) scans at 18 to 24 months. CAD106 induced measurable serum Aβ immunoglobulin G titers in 41/42 participants, slower rates of Aβ plaque accumulation (mean [standard deviation] annualized change from baseline in amyloid PET Centiloid: -0.91[5.65] for CAD106 versus 8.36 [6.68] for placebo; P<0.001), and three amyloid-related imaging abnormality cases (one symptomatic). Despite early termination, these findings support the potential value of conducting larger prevention trials of Aβ active immunotherapies in individuals at risk for AD. This was the first amyloid-lowering prevention trial in persons at genetic risk of late-onset Alzheimer's disease (AD). Active immunotherapy targeting amyloid (CAD106) was tested in this prevention trial. CAD106 significantly slowed down amyloid plaque deposition in apolipoprotein E homozygotes. CAD106 was generally safe and well tolerated, with only three amyloid-related imaging abnormality cases (one symptomatic). Such an approach deserves further evaluation in larger AD prevention trials.

Flortaucipir tau PET findings from former professional and college American football players in the DIAGNOSE CTE research project.

Tau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project. We compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same-age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES). Significantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p<0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups. Additional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.

Positron Emission Tomography Molecular Imaging of the Major Neurodegenerative Disorders: Overview and Pictorial Essay, from a Nuclear Medicine Center's Perspective.

Computed tomography (CT) and magnetic resonance imaging (MRI) provide key structural information on brain pathophysiology. Positron emission tomography (PET) measures metabolism in the living brain; it plays an important role in molecular neuroimaging and is rapidly expanding its field of application to the study of neurodegenerative diseases. Different PET radiopharmaceuticals allow in vivo characterization and quantization of biological processes at the molecular and cellular levels, from which many neurodegenerative diseases develop. In addition, hybrid imaging tools such as PET/CT and PET/MRI support the utility of PET, enabling the anatomical mapping of functional data. In this overview, we describe the most commonly used PET tracers in the diagnostic work-up of patients with Alzheimer's disease, Parkinson's disease, and other neurodegenerative diseases. We also briefly discuss the pathophysiological processes of tracer uptake in the brain, detailing their specific cellular pathways in clinical cases. This overview is limited to imaging agents already applied in human subjects, with particular emphasis on those tracers used in our department.

What do elevated cerebrospinal fluid p‐tau levels signify in the absence of beta‐amyloid pathology?

AbstractBackgroundThe introduction of the A/T/(N) (β‐amyloid/tau/neurodegeneration) framework has revealed an A‐T+ (β‐amyloid‐negative/tau‐positive) group which has been named suspected non‐Alzheimer’s pathophysiology. Cerebrospinal fluid (CSF) markers are often utilized to divide individuals in the A and T categories, but it is unclear what elevated CSF p‐tau levels signify in the absence of β‐amyloid. We aim to better understand A‐T+ as defined by CSF markers in two independent samples of cognitively unimpaired and impaired individuals by assessing baseline and longitudinal change in CSF, magnetic resonance (MRI), positron emission tomography (PET) and cognition measures.MethodCognitively normal (CN) and Mild Cognitive Impairment subjects from BioFINDER‐1 and 2 were included. A status was based on two CSF measures of β‐amyloid 42/40 (Aβ42/40) where A‐ individuals had to be negative on both measures using previously established cut offs. T status was determined by the 75th, 80th and 85th percentile of A‐ CN subjects for Roche Elecsys p‐tau181 (Table 1). Analyses of covariance and linear mixed models were performed to assess baseline and change differences in CSF (p‐tau181, Aβ42/40 ratio, neurofilament light (NFL)), MRI (hippocampal volume, entorhinal cortex and temporal meta‐region of interest thickness), cognition (modified Preclinical Alzheimer’s Cognitive Composite and delayed recall), and PET measures (entorhinal cortex Tau‐PET and early and global Alzheimer’s Disease composite β‐amyloid‐PET uptake) over 8 years (10 for cognition) for BioFINDER‐1 and 4 years for BioFINDER‐2.ResultIn A‐T+ versus A‐T‐, higher baseline NFL levels were found. No other baseline differences were found except for p‐tau181 and Aβ42/40 ratio by design. A‐T+ did not show significant change compared to A‐T‐ on any measure. Using different cut offs for p‐tau181 did not notably change the results. Comparisons with the A+ groups are shown in Figures 1‐2.ConclusionOur results indicate that A‐T+ as determined by p‐tau181 does not seem to be clinically meaningful as this group shows no decline on any of the biomarkers or cognitive measures over several years. The high NFL levels in the A‐T+ group suggest the presence of a latent factor that affects both NFL and p‐tau levels. Analyses will be repeated with other p‐tau isotopes and assays.

Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease

AbstractBackgroundAlthough positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.MethodWe recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aß deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aß40, Aß42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.ResultAmong 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aß42 were associated with A+T+ after adjusting for age, gender, and education (p&lt;0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aß42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).ConclusionA panel of AD‐RAI, plasma p‐tau, and plasma Aß42 might help with screening and diagnosis of Alzheimer’s disease.

Diagnostic Performance of MRI‐based Alzheimer’s Disease Resemblance Atrophy Index and Plasma‐Based Biomarkers on Alzheimer’s Disease

AbstractBackgroundAlthough positron emission tomography (PET) or cerebrospinal fluid measurements of amyloid and tau burden are available for the detection of Alzheimer’s disease pathology, such methods are invasive and not easily accessible. Recent studies show that Alzheimer’s Disease‐resemblance atrophy index (AD‐RAI), an MRI‐based machine learning‐derived biomarker, and plasma‐based biomarkers can be used as accurate biomarkers for Alzheimer’s disease pathology. We aim to evaluate the diagnostic metrics of AD‐RAI and plasma‐based biomarkers for detecting Alzheimer’s disease.MethodWe recruited 69 subjects from the CU‐SEEDS (The Chinese University of Hong Kong‐Screening for Early AlzhEimer’s DiseaSe) study who were stroke‐free and had different degrees of cognitive impairment: 8 cognitive unimpaired [CU], 26 with subjective cognitive decline [SCD], 21 with mild cognitive impairment [MCI] and 14 with dementia. All subjects underwent 11C‐ PIB and 18F‐T807 PET to measure pathological Aβ deposition (A+) and tau burden (T+). Subjects received structural MRI for deriving AD‐RAI. Plasma levels of Aβ40, Aβ42, total tau (t‐tau), phosphorylated tau at 181 (p‐tau181), and neurofilament light chain (NfL) were measured by Single Molecule Array (SiMoA) assays.ResultAmong 69 subjects (mean [SD] age, 67.7 [6.8] years; 28 men [40.6%]), 25 (36.23%) subjects were confirmed to be A+ and T+. AD‐RAI, plasma p‐tau 181, and plasma Aβ42 were associated with A+T+ after adjusting for age, gender, and education (p&lt;0.01). AD‐RAI individually outperformed all plasma‐based biomarkers (AUC = 0.911; Sensitivity = 0.826; Specificity = 0.905). The combination of AD‐RAI, p‐tau181 and Aβ42 yielded the best diagnostic metrics for detecting A+T+ subjects (AUC = 0.957; Sensitivity = 0.870; Specificity = 0.929).ConclusionA panel of AD‐RAI, plasma p‐tau, and plasma Aβ42 might help with screening and diagnosis of Alzheimer’s disease.

Development of Clinical Trial Simulation Tools for Alzheimer’s Disease through the Critical Path for Alzheimer’s Disease (CPAD) Consortium

AbstractBackgroundOptimized clinical trial design remains a major challenge in drug development for Alzheimer’s Disease AD). To advance our understanding of the underlying pathophysiology of disease and help optimize clinical trial design, CPAD developed a clinical trial simulation (CTS) tool for the pre‐dementia stages of Alzheimer’s disease, using CDR‐SB as the primary endpoint. The tool is based on a disease progression model integrating baseline hippocampal volume, the effect of patient drop‐out and relevant sources of variability. The CTS was enhanced using data from contemporary clinical trials, adding fluid and imaging biomarkers of amyloid (Aβ) and tau pathology. Also included are dropout models, a placebo effect model, as well as drug‐effect models. Positron Emission Tomography (PET) measures of tau deposition, leveraging ongoing collaborative efforts to develop a standardized quantification scale across different tau tracers, will also be incorporated, to develop the first disease progression models utilizing a harmonized tau‐PET scale.MethodData were harmonized and both linear and non‐linear mixed effects models were developed for multiple endpoints, including demographics, time from and to diagnosis, genetic status (APOE4). Monte Carlo simulations were performed to compare the statistical power by sample size in trials with and without enrichment using relevant covariates. A longitudinal mixed‐effects model was fit with longitudinal tau and neurodegeneration outcomes. Cognition and biomarkers were explored in a multivariate model.ResultAs of October 2022, CPAD’s clinical trial repository contains over 7,000 unique participants that have baseline CDR‐SB measurement, 4,000+ participants with baseline Aβ measures (fluid or PET), and 2,000+ participants with baseline measures of amyloid, tau (e.g., cerebrospinal fluid p‐tau and/or tau‐PET), and neurodegeneration (e.g., MRI or neurofilament light). With these data, we modeled longitudinal trajectories of cognitive decline using baseline levels of amyloid, tau, and neurodegeneration. Future work will add models of longitudinal biomarker trajectories.ConclusionThe disease progression models will serve as the basis for a clinical trial simulation tool to facilitate design of contemporary clinical trials based on a quantitative understanding of the biological progression of key pathological features, amyloid and tau deposition, of AD.

Aberrant vascular architecture in the hippocampus correlates with tau burden in mild cognitive impairment and Alzheimer’s disease

Cerebrovascular dysfunction is a significant contributor to Alzheimer’s disease (AD) progression. AD mouse models show altered capillary morphology, density, and diminished blood flow in areas of tau and beta-amyloid accumulation. The purpose of this study was to examine alterations in vascular structure and their contributions to perfusion deficits in the hippocampus in AD and mild cognitive impairment (MCI). Seven individuals with AD and MCI (1 AD/6 MCI), nine cognitively intact older healthy adults, and seven younger healthy adults underwent pseudo-continuous arterial spin labeling (PCASL) and gradient-echo/spin-echo (GESE) dynamic susceptibility contrast (DSC) MRI. Cerebral blood flow (CBF), cerebral blood volume, relative vessel size index (rVSI), and mean vessel density were calculated from model fitting. Lower CBF from PCASL and SE DSC MRI was observed in the hippocampus of AD/MCI group. rVSI in the hippocampus of the AD/MCI group was larger than that of the two healthy groups (FDR-P = 0.02). No difference in vessel density was detected between the groups. We also explored relationship of tau burden from 18F-flortaucipir positron emission tomography and vascular measures from MRI. Tau burden was associated with larger vessel size and lower CBF in the hippocampus. We postulate that larger vessel size may be associated with vascular alterations in AD/MCI.

Oxygen extraction fraction is not uniform in human brain: a positron emission tomography study

The regional differences in cerebral oxygen extraction fraction (OEF) in brain were investigated using positron emission tomography (PET) in detail with consideration of systemic errors in PET measurement estimated by simulation studies. The cerebral blood flow (CBF), cerebral blood volume (CBV), OEF, and cerebral metabolic rate of oxygen (CMRO2) were measured on healthy men by PET with 15O-labeled gases. The OEF values in the pons and the parahippocampal gyrus were significantly smaller than in the other brain regions. The OEF value in the lateral side of the occipital cortex was largest among the cerebral cortical regions. Simulation studies have revealed that errors in OEF caused by regional differences in the distribution volume of 15O-labeled water, as well as errors in OEF caused by a mixture of gray and white matter, must be negligible. The regional differences in OEF in brain must exist which might be related to physiological meanings.Article title: Kindly check and confirm the edit made in the article title.I have checked the article title and it is OK as is.Trial registration: The UMIN clinical trial number: UMIN000033382, https://www.umin.ac.jp/ctr/index.htm

Non-invasive PD-L1 quantification using [18F]DK222-PET imaging in cancer immunotherapy

BackgroundCombination therapies that aim to improve the clinical efficacy to immune checkpoint inhibitors have led to the need for non-invasive and early pharmacodynamic biomarkers. Positron emission tomography (PET) is a...

PET-measured human dopamine synthesis capacity and receptor availability predict trading rewards and time-costs during foraging

Foraging behavior requires weighing costs of time to decide when to leave one reward patch to search for another. Computational and animal studies suggest that striatal dopamine is key to this process; however, the specific role of dopamine in foraging behavior in humans is not well characterized. We use positron emission tomography (PET) imaging to directly measure dopamine synthesis capacity and D1 and D2/3 receptor availability in 57 healthy adults who complete a computerized foraging task. Using voxelwise data and principal component analysis to identify patterns of variation across PET measures, we show that striatal D1 and D2/3 receptor availability and a pattern of mesolimbic and anterior cingulate cortex dopamine function are important for adjusting the threshold for leaving a patch to explore, with specific sensitivity to changes in travel time. These findings suggest a key role for dopamine in trading reward benefits against temporal costs to modulate behavioral adaptions to changes in the reward environment critical for foraging.

Cortical Amyloid Burden Relates to Basal Forebrain Volume in Subjective Cognitive Decline.

Atrophy of cholinergic basal forebrain (BF) nuclei is a frequent finding in magnetic resonance imaging (MRI) volumetry studies that examined patients with prodromal or clinical Alzheimer's disease (AD), but less clear for individuals in earlier stages of the clinical AD continuum. To examine BF volume reductions in subjective cognitive decline (SCD) participants with AD pathologic changes. The present study compared MRI-based BF volume measurements in age- and sex-matched samples of N = 24 amyloid-positive and N = 24 amyloid-negative SCD individuals, based on binary visual ratings of Florbetaben positron emission tomography (PET) measurements. Additionally, we assessed associations of BF volume with cortical amyloid burden, based on semiquantitative Centiloid (CL) analyses. Group differences approached significance for BF total volume (p = 0.061) and the Ch4 subregion (p = 0.059) only, showing the expected relative volume reductions for the amyloid-positive subgroup. There were also significant inverse correlations between BF volumes and CL values, which again were most robust for BF total volume and the Ch4 subregion. The results are consistent with the hypothesis that amyloid-positive SCD individuals, which are considered to represent a transitional stage on the clinical AD continuum, already show incipient alterations of BF integrity. The negative association with a continuous measure of cortical amyloid burden also suggests that this may reflect an incremental process. Yet, further research is needed to evaluate whether BF changes already emerge at "grey zone" levels of amyloid accumulation, before amyloidosis is reliably detected by PET visual readings.