Tau as a diagnostic instrument in clinical trials to predict amyloid in Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is characterized by the presence of both amyloid and tau pathology. In vivo diagnosis can be made with amyloid and tau positron emission tomography (PET) imaging. Emergent evidence supports that amyloid and tau accumulation are associated and that amyloid accumulation may precede that of tau. This report further investigates the relationship between amyloid and tau to assess whether elevated cortical tau can predict elevated amyloid in participants with early symptomatic AD. METHODS: Florbetapir F18 and flortaucipir F18 uptake were evaluated from baseline PET scans collected in three multi-center studies with cognitively impaired participants, including A05 (N = 306; NCT02016560), TB (N = 310; TRAILBLAZER-ALZ; NCT03367403), and TB2 (N = 1165; TRAILBLAZER-ALZ 2; NCT04437511). Images were assessed using visual and quantitative approaches to establish amyloid (A+) and tau (T+) positivity, as well as a combination method (tauVQ) to establish T+. Associations between global amyloid and tau were evaluated with positive and negative predictive values (PPV, NPV) and likelihood ratios (LR+, LR-). Predictive values within subgroups according to ethnicity, race, cognitive score, age, and sex were also evaluated. The relationship between regional tau (four target and two reference regions were tested) and global amyloid was investigated in A05 participant scans using receiver-operating characteristic (ROC) curves. RESULTS: PPV for amyloid positivity was ≥93% for all three trials using various A+ and T+ definitions, including visual, quantitative, and combination methods. Population characteristics did not have an impact on A+ predictability. Regional analyses (early tau (Eτ) volume of interest (VOI), temporal, parietal, frontal) revealed significant area under the ROC curve in Eτ VOI compared to frontal region, regardless of reference region and consistent among visual and quantitative A+ definitions (p < 0.001). DISCUSSION: These findings suggest that a positive tau PET scan is associated (≥93%) with amyloid positivity in individuals with early symptomatic AD, with the potential benefits of reducing clinical trial and health care expenses, radiation exposure, and participant time. Highlights: Positron emission tomography (PET) evaluates candidates for Alzheimer's disease (AD) research. A positive tau PET scan is associated (≥93%) with amyloid positivity.A positive amyloid PET is not necessarily associated with tau positivity.Tau PET could be the sole diagnostic tool to confirm candidates for AD trials.

Early tau detection in flortaucipir images: validation in autopsy-confirmed data and implications for disease progression.

BACKGROUND: There is an increasing interest in utilizing tau PET to identify patients early in Alzheimer's disease (AD). In this work, a temporal lobe composite (Eτ) volume of interest (VOI) was evaluated in a longitudinal flortaucipir cohort and compared to a previously described global neocortical VOI. In a separate autopsy-confirmed study, the sensitivity of the Eτ VOI for identifying intermediate (B2) neurofibrillary tangle (NFT) pathology was evaluated. METHODS: A total of 427 subjects received flortaucipir, florbetapir, MRI, and cognitive evaluation at baseline and 18 months. In a separate autopsy study, 67 subjects received ante-mortem flortaucipir scans, and neuropathological findings were recorded according to NIA-AA recommendations by two experts. Two VOIs: Eτ comprising FreeSurfer volumes (bilateral entorhinal cortex, fusiform, parahippocampal, and inferior temporal gyri) transformed to MNI space and a previously published global AD signature-weighted neocortical VOI (ADsignature) (Devous et al., J Nucl Med 59:937-43, 2018), were used to calculate SUVr relative to a white matter reference region (PERSI) (Southekal et al., J Nucl Med Off Publ Soc Nucl Med 59:944-51, 2018). SUVr cutoffs for positivity were determined based on a cohort of young, cognitively normal subjects. Subjects were grouped based on positivity on both VOIs (Eτ+/ADsignature+; Eτ+/ADsignature-; Eτ-/ADsignature-). Groupwise comparisons were performed for baseline SUVr, 18-month changes in SUVr, neurodegeneration, and cognition. For the autopsy study, the sensitivity of Eτ in identifying intermediate Braak pathology (B2) subjects was compared to that of AD signature-weighted neocortical VOI. The average surface maps of subjects in the Eτ+/ADsignature- group and B2 NFT scores were created for visual evaluation of uptake. RESULTS: Sixty-four out of 390 analyzable subjects were identified as Eτ+/ADsignature-: 84% were Aß+, 100% were diagnosed as MCI or AD, and 59% were APOE ε4 carriers. Consistent with the hypothesis that Eτ+/ADsignature- status reflects an early stage of AD, Eτ+/ADsignature- subjects deteriorated significantly faster than Eτ-/ADsignature- subjects, but significantly slower than Eτ+/ADsignature+ subjects, on most measures (i.e., change in ADsignature SUVr, Eτ ROI cortical thickness, and MMSE). The ADsignature VOI was selective for subjects who came to autopsy with a B3 NFT score. In the autopsy study, 12/15 B2 subjects (including 10/11 Braak IV) were Eτ+/ADsignature-. Surface maps showed that flortaucipir uptake was largely captured by the Eτ VOI regions in B2 subjects. CONCLUSION: The Eτ VOI identified subjects with elevated temporal but not global tau (Eτ+/ADsignature-) that were primarily Aß+, APOE ε4 carriers, and diagnosed as MCI or AD. Eτ+/ADsignature- subjects had greater accumulation of tau, greater atrophy, and higher decline on MMSE in 18 months compared to Eτ-/ADsignature- subjects. Finally, the Eτ VOI identified the majority of the intermediate NFT score subjects in an autopsy-confirmed study. As far as we know, this is the first study that presents a visualization of ante-mortem FTP retention patterns that at a group level agree with the neurofibrillary tangle staging scheme proposed by Braak. These findings suggest that the Eτ VOI may be sensitive for detecting impaired subjects early in the course of Alzheimer's disease.

Validating Nonlinear Registration to Improve Subtraction Images for Lesion Detection and Quantification in Multiple Sclerosis.

BACKGROUND AND PURPOSE: To propose and validate nonlinear registration techniques for generating subtraction images because of their ability to reduce artifacts and improve lesion detection and lesion volume quantification. METHODS: Postcontrast T1 -weighted spin echo and T2 -weighted dual echo images were acquired for 20 patients with relapsing-remitting multiple sclerosis (RRMS) on a monthly basis for a year (14 women, average age 33.6 ± 6.9). The T2 -weighted images from the first scan were used as a baseline for each patient. The images from the last scan were registered to the baseline image. Four different registration algorithms used for evaluation included; linear, halfway linear, nonlinear, and nonlinear halfway. Subtraction images were generated after brain extraction, intensity normalization, and Gaussian blurring. Lesion activity changes along with identified artifacts were scored on all four techniques by two independent observers. Additionally, quantitative analysis of the algorithms was performed by estimating the volume changes of simulated lesions and real lesions. For real lesion volume change analysis, five subjects were selected randomly. Subtraction images were generated between all the 11 time points and the baseline image using linear and nonlinear registration for the five subjects. RESULTS: Lesion activity detection resulted in similar performance among the four registration techniques. Lesion volume measurements on subtraction images using nonlinear registration were closer to lesion volume on T2 -weighted images. A statistically significant difference was observed among the four registration techniques while evaluating yin-yang artifacts. Pairwise comparisons showed that nonlinear registration results in the least amount of yin-yang artifacts, which are significantly different. CONCLUSIONS: Nonlinear registration for generation of subtraction images has been demonstrated to be a promising new technique as it shows improvement in lesion activity change detection. This approach decreases the number of artifacts in subtraction images. With improved lesion volume estimates and reduced artifacts, nonlinear registration may lead to discarding less subject data and an improvement in the statistical power of subtraction imaging studies.