Early-phase 18F-Flortaucipir Tau-PET as a Proxy for Brain Metabolism in Alzheimer’s Disease

Background

Alzheimer’s Disease (AD) is a common neurodegenerative disorder characterized by extracellular β-amyloid (Aβ) deposition, intracellular pathological tau protein accumulation, and neurodegeneration. These pathological changes begin accumulating in the brain 10 to 20 years before the onset of clinical symptoms. Positron emission tomography (PET) imaging can evaluate protein deposition and neuronal damage in vivo, playing a critical role in the early diagnosis of AD. 18F-fluorodeoxyglucose (18F-FDG) PET is a well-established technique for studying neurodegeneration by detecting glucose metabolism alterations that indicate characteristic metabolic patterns for AD, frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB).

In recent years, dual-phase amyloid-PET and dual-phase tau-PET techniques have emerged as tools for simultaneously evaluating amyloid deposition and neurodegeneration. Early-phase PET images capture perfusion information closely linked to glucose metabolism, making them a potential surrogate biomarker for neurodegeneration. However, limited research exists on early-phase tau-PET, especially using the FDA-approved 18F-Flortaucipir tau tracer. This study aims to evaluate the association between early-phase 18F-Flortaucipir PET, 18F-FDG PET, and early-phase amyloid-PET, as well as their diagnostic value for AD.

Source

This paper was authored by a research team from multiple institutions, including the Geneva University Neurocenter, Geneva University Hospitals, Eli Lilly and Company (USA), and the Nuclear Medicine Unit at San Raffaele Hospital (Italy). The first author is Cecilia Boccalini, and the corresponding author is Valentina Garibotto. The article was accepted by the European Journal of Nuclear Medicine and Molecular Imaging on December 29, 2024, and officially published in 2025.

Study Process and Results

Participants and Data Collection

The study involved 58 participants from the Geneva Memory Center, classified as cognitively unimpaired (CU), mild cognitive impairment (MCI), or dementia patients. All participants underwent dual-phase 18F-Flortaucipir PET (early-phase referred to as eTau) and 18F-FDG PET scans within one year. Additionally, 36 participants underwent dual-phase amyloid-PET (early-phase referred to as eAmy). The study included 43 18F-FDG PET images and 33 eTau images from amyloid-negative healthy controls (HCs) as references.

Data Processing and Analysis

The data were normalized using Statistical Parametric Mapping (SPM) software. Standardized uptake value ratios (SUVR) were extracted from Automated Anatomic Labeling (AAL) regions and AD-specific meta-regions of interest (meta-ROIs). Visual ratings and single-subject voxel-based analyses assessed the metabolic and perfusion patterns in the 18F-FDG PET, eTau, and eAmy images. Receiver operating characteristic (ROC) analyses compared the diagnostic performance of eTau, 18F-FDG PET, and eAmy SUVRs in distinguishing A+/T+ from A-/T- subjects.

Key Findings

1. Strong Correlation between eTau and 18F-FDG SUVR: eTau SUVR showed a strong correlation with 18F-FDG SUVR at the group level (r = 0.839, p < 0.001) and in both T+ (r = 0.855, p < 0.001) and T- (r = 0.834, p < 0.001) subgroups. Similarly, eTau SUVR exhibited strong correlations with eAmy SUVR (r > 0.87, p < 0.001).

2. Individual-Level Metabolic and Perfusion Patterns: Visual ratings confirmed disease-specific metabolic and perfusion patterns. 18F-FDG PET identified distinct neurodegenerative patterns, including temporoparietal hypometabolism (AD-like pattern, n = 22), frontotemporal hypometabolism (FTD-like pattern, n = 4), and temporoparietal and occipital hypometabolism (DLB-like pattern, n = 2). eTau images showed good concordance with 18F-FDG PET in classification (κ = 0.58, p < 0.001).

3. Diagnostic Performance: eTau SUVR in AD meta-ROI achieved an area under the curve (AUC) of 0.604 for distinguishing A+/T+ from A-/T-, slightly lower than 18F-FDG SUVR (AUC = 0.748). The DeLong test confirmed that 18F-FDG PET performed better than eTau (p = 0.04), but there was no significant difference between eTau and eAmy.

Conclusions and Implications

The study demonstrated that early-phase 18F-Flortaucipir PET provides perfusion information closely linked to brain regional glucose metabolism and shows strong consistency with eAmy. Although eTau is slightly less accurate than 18F-FDG PET in diagnosing neurodegeneration, it offers significant clinical value as a dual-purpose tool for evaluating tau pathology and neurodegeneration. The dual-phase tau-PET protocol enables simultaneous assessment of tau pathology and neurodegeneration with a single tracer injection, reducing costs, patient burden, and radiation exposure.

Highlights of the Study

1. First Systematic Evaluation of eTau: This study is the first to systematically evaluate the diagnostic value of FDA-approved 18F-Flortaucipir in early-phase PET, filling a research gap.
2. Potential of Dual-phase Tau-PET: The study confirms the potential of dual-phase tau-PET for assessing tau pathology and neurodegeneration, offering new tools for the early diagnosis of AD.
3. Individual-Level Analysis: Using visual ratings and voxel-based analyses, the study provides detailed descriptions of metabolic and perfusion patterns across different neurodegenerative diseases, yielding valuable clinical insights.

Additional Insights

The study also found high consistency between eTau and eAmy when evaluating neurodegeneration, particularly in dementia patients. Moreover, white matter lesions were associated with better concordance between eTau and eAmy scans, suggesting that cerebrovascular pathology may influence their results similarly.

This research provides compelling evidence for the application of early-phase 18F-Flortaucipir PET in AD diagnosis and sets a foundation for future studies.