Dataset Information

Evaluation of tau deposition using ¹⁸F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.

ABSTRACT:

Background

The ability of ¹⁸F-PI-2620 PET to measure the spatial distribution of tau pathology in Alzheimer's disease (AD) has been demonstrated in previous studies. The objective of this work was to evaluate tau deposition using ¹⁸F-PI-2620 PET in beta-amyloid positive subjects with a diagnosis of mild cognitive impairment (MCI) or mild AD dementia and characterize it with respect to amyloid deposition, cerebrospinal fluid (CSF) assessment, hippocampal volume, and cognition.

Methods

Subjects with a diagnosis of MCI due to AD or mild AD dementia and a visually amyloid-positive ¹⁸F-florbetaben PET scan (n=74, 76 ± 7 years, 38 females) underwent a baseline ¹⁸F-PI-2620 PET, T1-weighted magnetic resonance imaging (MRI), CSF assessment (Aβ42/Aβ40 ratio, p-tau, t-tau) (n=22) and several cognitive tests. A 1-year follow-up ¹⁸F-PI-2620 PET scans and cognitive assessments were done in 15 subjects.

Results

Percentage of visually tau-positive scans increased with amyloid-beta deposition measured in ¹⁸F-florbetaben Centiloids (CL) (7.7% (<36 CL), 80% (>83 CL)). ¹⁸F-PI-2620 standardized uptake value ratio (SUVR) was correlated with increased ¹⁸F-florbetaben CL in several regions of interest. Elevated ¹⁸F-PI-2620 SUVR (fusiform gyrus) was associated to high CSF p-tau and t-tau (p=0.0006 and p=0.01, respectively). Low hippocampal volume was associated with increased tau load at baseline (p=0.006 (mesial temporal); p=0.01 (fusiform gyrus)). Significant increases in tau SUVR were observed after 12 months, particularly in the mesial temporal cortex, fusiform gyrus, and inferior temporal cortex (p=0.04, p=0.047, p=0.02, respectively). However, no statistically significant increase in amyloid-beta load was measured over the observation time. The MMSE (Recall score), ADAS-Cog14 (Word recognition score), and CBB (One-card learning score) showed the strongest association with tau deposition at baseline.

Conclusions

The findings support the hypothesis that ¹⁸F-PI-2620 PET imaging of neuropathologic tau deposits may reflect underlying neurodegeneration in AD with significant correlations with hippocampal volume, CSF biomarkers, and amyloid-beta load. Furthermore, quantifiable increases in ¹⁸F-PI-2620 SUVR over a 12-month period in regions with early tau deposition are consistent with the hypothesis that cortical tau is associated with cognitive impairment. This study supports the utility of ¹⁸F-PI-2620 PET to assess tau deposits in an early AD population. Quantifiable tau load and its corresponding increase in early AD cases could be a relevant target engagement marker in clinical trials of anti-amyloid and anti-tau agents.

Trial registration

Data used in this manuscript belong to a tau PET imaging sub-study of the elenbecestat MissionAD Phase 3 program registered in ClinicalTrials.gov ( NCT02956486 ; NCT03036280 ).

SUBMITTER: Bullich S

PROVIDER: S-EPMC9327167 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeCharacteristic features of amyloid-PET (A), tau-PET (T), and FDG-PET (N) can serve for the A/T/N classification of neurodegenerative diseases. Recent studies showed that the early, perfusion-weighted phases of amyloid- or tau-PET recordings serve to detect cerebrometabolic deficits equally to FDG-PET, therefore providing a surrogate of neuronal injury. As such, two channels of diagnostic information can be obtained in the setting of a single PET scan. However, there has hitherto been no comparison of early-phase amyloid- and tau-PET as surrogates for deficits in perfusion/metabolism. Therefore, we undertook to compare [18F]flutemetamol-amyloid-PET and [18F]PI-2620 tau-PET as "one-stop shop" dual purpose tracers for the detection of neurodegenerative disease.MethodsWe obtained early-phase PET recordings with [18F]PI-2620 (0.5-2.5 min p.i.) and [18F]flutemetamol (0-10 min p.i.) in 64 patients with suspected neurodegenerative disease. We contrasted global mean normalized images (SUVr) in the patients with a normal cohort of 15 volunteers without evidence of increased pathology to β-amyloid- and tau-PET examinations. Regional group differences of tracer uptake (z-scores) of 246 Brainnetome volumes of interest were calculated for both tracers, and the correlations of the z-scores were evaluated using Pearson's correlation coefficient. Lobar compartments, regions with significant neuronal injury (z-scores < - 3), and patients with different neurodegenerative disease entities (e.g., Alzheimer's disease or 4R-tauopathies) served for subgroup analysis. Additionally, we used partial regression to correlate regional perfusion alterations with clinical scores in cognition tests.ResultsThe z-scores of perfusion-weighted images of both tracers showed high correlations across the brain, especially in the frontal and parietal lobes, which were the brain regions with pronounced perfusion deficit in the patient group (R = 0.83 ± 0.08; range, 0.61-0.95). Z-scores of individual patients correlated well by region (R = 0.57 ± 0.15; range, 0.16-0.90), notably when significant perfusion deficits were present (R = 0.66 ± 0.15; range, 0.28-0.90).ConclusionThe early perfusion phases of [18F]PI-2620 tau- and [18F]flutemetamol-amyloid-PET are roughly equivalent indices of perfusion defect indicative of regional and lobar neuronal injury in patients with various neurodegenerative diseases. As such, either tracer may serve for two diagnostic channels by assessment of amyloid/tau status and neuronal activity.

Project description:PurposeSecond-generation tau radiotracers for use with positron emission tomography (PET) have been developed for visualization of tau deposits in vivo. For several β-amyloid and first-generation tau-PET radiotracers, it has been shown that early-phase images can be used as a surrogate of neuronal injury. Therefore, we investigated the performance of early acquisitions of the novel tau-PET radiotracer [18F]PI-2620 as a potential substitute for [18F]fluorodeoxyglucose ([18F]FDG).MethodsTwenty-six subjects were referred with suspected tauopathies or overlapping parkinsonian syndromes (Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, multi-system atrophy, Parkinson's disease, multi-system atrophy, Parkinson's disease, frontotemporal dementia) and received a dynamic [18F]PI-2620 tau-PET (0-60 min p.i.) and static [18F]FDG-PET (30-50 min p.i.). Regional standardized uptake value ratios of early-phase images (single frame SUVr) and the blood flow estimate (R1) of [18F]PI-2620-PET were correlated with corresponding quantification of [18F]FDG-PET (global mean/cerebellar normalization). Reduced tracer uptake in cortical target regions was also interpreted visually using 3-dimensional stereotactic surface projections by three more and three less experienced readers. Spearman rank correlation coefficients were calculated between early-phase [18F]PI-2620 tau-PET and [18F]FDG-PET images for all cortical regions and frequencies of disagreement between images were compared for both more and less experienced readers.ResultsHighest agreement with [18F]FDG-PET quantification was reached for [18F]PI-2620-PET acquisition from 0.5 to 2.5 min p.i. for global mean (lowest R = 0.69) and cerebellar scaling (lowest R = 0.63). Correlation coefficients (summed 0.5-2.5 min SUVr & R1) displayed strong agreement in all cortical target regions for global mean (RSUVr 0.76, RR1 = 0.77) and cerebellar normalization (RSUVr 0.68, RR1 = 0.68). Visual interpretation revealed high regional correlations between early-phase tau-PET and [18F]FDG-PET. There were no relevant differences between more and less experienced readers.ConclusionEarly-phase imaging of [18F]PI-2620 can serve as a surrogate biomarker for neuronal injury. Dynamic imaging or a dual time-point protocol for tau-PET imaging could supersede additional [18F]FDG-PET imaging by indexing both the distribution of tau and the extent of neuronal injury.

Project description:18F-PI-2620 is a PET tracer with high binding affinity for aggregated tau, a key pathologic feature of Alzheimer disease (AD) and other neurodegenerative disorders. Preclinically, 18F-PI-2620 binds to both 3-repeat and 4-repeat tau isoforms. The purpose of this first-in-humans study was to evaluate the ability of 18F-PI-2620 to detect tau pathology in AD patients using PET imaging, as well as to assess the safety and tolerability of this new tau PET tracer. Methods: Participants with a clinical diagnosis of probable AD and healthy controls (HCs) underwent dynamic 18F-PI-2620 PET imaging for 180 min. 18F-PI-2620 binding was assessed visually and quantitatively using distribution volume ratios (DVR) estimated from noninvasive tracer kinetics and SUV ratio (SUVR) measured at different time points after injection, with the cerebellar cortex as the reference region. Time-activity curves and SUVR were assessed in AD and HC subjects, as well as DVR and SUVR correlations and effect size (Cohen's d) over time. Results: 18F-PI-2620 showed peak brain uptake around 5 min after injection and fast washout from nontarget regions. In AD subjects, focal asymmetric uptake was evident in temporal and parietal lobes, precuneus, and posterior cingulate cortex. DVR and SUVR in these regions were significantly higher in AD subjects than in HCs. Very low background signal was observed in HCs. 18F-PI-2620 administration was safe and well tolerated. SUVR time-activity curves in most regions and subjects achieved a secular equilibrium after 40 min after injection. A strong correlation (R 2 > 0.93) was found between noninvasive DVR and SUVR for all imaging windows starting at more than 30 min after injection. Similar effect sizes between AD and HC groups were obtained across the different imaging windows. 18F-PI-2620 uptake in neocortical regions significantly correlated with the degree of cognitive impairment. Conclusion: Initial clinical data obtained in AD and HC subjects demonstrated a high image quality and excellent signal-to-noise ratio of 18F-PI-2620 PET for imaging tau deposition in AD subjects. Noninvasive quantification using DVR and SUVR for 30-min imaging windows between 30 and 90 min after injection-for example, 45-75 min-provides robust and significant discrimination between AD and HC subjects. 18F-PI-2620 uptake in expected regions correlates strongly with neurocognitive performance.

Project description:Tau aggregates represent a key pathologic feature of Alzheimer's disease and other neurodegenerative diseases. Recently, PET probes have been developed for in vivo detection of tau accumulation; however, they are limited because of off-target binding and a reduced ability to detect tau in non-Alzheimer's disease tauopathies. The novel tau PET tracer, [18F]PI-2620, has a high binding affinity and specificity for aggregated tau; therefore, it was hypothesized to have desirable properties for the visualization of tau accumulation in Alzheimer's disease and non-Alzheimer's disease tauopathies. To assess the ability of [18F]PI-2620 to detect regional tau burden in non-Alzheimer's disease tauopathies compared with Alzheimer's disease, patients with progressive supranuclear palsy (n = 3), corticobasal syndrome (n = 2), corticobasal degeneration (n = 1) or Alzheimer's disease (n = 8), and healthy controls (n = 7) were recruited. All participants underwent MRI, amyloid β assessment and [18F]PI-2620 PET (Image acquisition at 60-90 min post-injection). Cortical and subcortical tau accumulations were assessed by calculating standardized uptake value ratios using [18F]PI-2620 PET. For pathologic validation, tau pathology was assessed using tau immunohistochemistry and compared with [18F]PI-2620 retention in an autopsied case of corticobasal degeneration. In Alzheimer's disease, focal retention of [18F]PI-2620 was evident in the temporal and parietal lobes, precuneus, and cingulate cortex. Standardized uptake value ratio analyses revealed that patients with non-Alzheimer's disease tauopathies had elevated [18F]PI-2620 uptake only in the globus pallidus, as compared to patients with Alzheimer's disease, but not healthy controls. A head-to-head comparison of [18F]PI-2620 and [18F]PM-PBB3, another tau PET probe for possibly visualizing the four-repeat tau pathogenesis in non-Alzheimer's disease, revealed different retention patterns in one subject with progressive supranuclear palsy. Imaging-pathology correlation analysis of the autopsied patient with corticobasal degeneration revealed no significant correlation between [18F]PI-2620 retention in vivo. High [18F]PI-2620 uptake at 60-90 min post-injection in the globus pallidus may be a sign of neurodegeneration in four-repeat tauopathy, but not necessarily practical for diagnosis of non-Alzheimer's disease tauopathies. Collectively, this tracer is a promising tool to detect Alzheimer's disease-tau aggregation. However, late acquisition PET images of [18F]PI-2620 may have limited utility for reliable detection of four-repeat tauopathy because of lack of correlation between post-mortem tau pathology and different retention pattern than the non-Alzheimer's disease-detectable tau radiotracer, [18F]PM-PBB3. A recent study reported that [18F]PI-2620 tracer kinetics curves in four-repeat tauopathies peak earlier (within 30 min) than Alzheimer's disease; therefore, further studies are needed to determine appropriate PET acquisition times that depend on the respective interest regions and diseases.

Project description:18F-PI-2620 is a next-generation tau PET tracer that has demonstrated ability to image the spatial distribution of suspected tau pathology. The objective of this study was to assess the tracer biodistribution, dosimetry, and quantitative methods of 18F-PI-2620 in the human brain. Full kinetic modeling to quantify tau load was investigated. Noninvasive kinetic modeling and semiquantitative methods were evaluated against the full tracer kinetics. Finally, the reproducibility of PET measurements from test and retest scans was assessed. Methods: Three healthy controls (HCs) and 4 Alzheimer disease (AD) subjects underwent 2 dynamic PET scans, including arterial sampling. Distribution volume ratio (DVR) was estimated using full tracer kinetics (reversible 2-tissue-compartment [2TC] model and Logan graphical analysis [LGA]) and noninvasive kinetic models (noninvasive LGA [NI-LGA] and the multilinear reference tissue model [MRTM2]). SUV ratio (SUVR) was determined at different imaging windows after injection. The correlation between DVR and SUVR, effect size (Cohen's d), and test-retest variability (TRV) were evaluated. Additionally, 6 HCs received 1 tracer administration and underwent whole-body PET for dosimetry calculation. Organ doses and the whole-body effective dose were calculated using OLINDA 2.0. Results: A strong correlation was found across different kinetic models (R 2 > 0.97) and between DVR(2TC) and SUVR between 30 and 90 min, with an R 2 of more than 0.95. Secular equilibrium was reached at around 40 min after injection in most regions and subjects. TRV and effect size for SUVR across different regions were similar at 30-60 min (TRV, 3.8%; Cohen's d, 3.80), 45-75 min (TRV, 4.3%; Cohen's d, 3.77) and 60-90 min (TRV, 4.9%; Cohen's d, 3.73) and increased at later time points. Elimination was via the hepatobiliary and urinary systems. The whole-body effective dose was 33.3 ± 2.1 μSv/MBq for an adult female and 33.1 ± 1.4 μSv/MBq for an adult male, with a 1.5-h urinary bladder voiding interval. Conclusion: 18F-PI-2620 exhibits fast kinetics, suitable dosimetry, and low TRV. DVR measured using the 2TC model with arterial sampling correlated strongly with DVR measured by NI-LGA, MRTM2, and SUVR. SUVR can be used for 18F-PI-2620 PET quantification of tau deposits, avoiding arterial blood sampling. Static 18F-PI-2620 PET scans between 45 and 75 min after injection provide excellent quantification accuracy, a large effect size, and low TRV.

Dataset Information

Evaluation of tau deposition using ¹⁸F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.

Background

Methods

Results

Conclusions

Trial registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Evaluation of tau deposition using 18F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.

Background

Methods

Results

Conclusions

Trial registration

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Evaluation of tau deposition using ¹⁸F-PI-2620 PET in MCI and early AD subjects-a MissionAD tau sub-study.