Evaluation of Tau Imaging in Staging Alzheimer Disease and Revealing Interactions Between β-Amyloid and Tauopathy

Abstract

Importance: In vivo tau imaging may become a diagnostic marker for Alzheimer disease (AD) and provides insights into the pathophysiology of AD.

Objective: To evaluate the usefulness of [18F]-AV-1451 positron emission tomography (PET) imaging to stage AD and assess the associations among β-amyloid (Aβ), tau, and volume loss.

Design, setting, and participants: An imaging study conducted at Knight Alzheimer Disease Research Center at Washington University in St Louis, Missouri. A total of 59 participants who were cognitively normal (CN) (Clinical Dementia Rating [CDR] score, 0) or had AD dementia (CDR score, >0) were included.

Main outcomes and measures: Standardized uptake value ratio (SUVR) of [18F]-AV-1451 in the hippocampus and a priori-defined AD cortical signature regions, cerebrospinal fluid Aβ42, hippocampal volume, and AD signature cortical thickness.

Results: Of the 59 participants, 38 (64%) were male; mean (SD) age was 74 (6) years. The [18F]-AV-1451 SUVR in the hippocampus and AD cortical signature regions distinguished AD from CN participants (area under the receiver operating characteristic curve range [95% CI], 0.89 [0.73-1.00] to 0.98 [0.92-1.00]). An [18F]-AV-1451 SUVR cutoff value of 1.19 (sensitivity, 100%; specificity, 86%) from AD cortical signature regions best separated cerebrospinal fluid Aβ42-positive (Aβ+) AD from cerebrospinal fluid Aβ42-negative (Aβ-) CN participants. This same cutoff also divided Aβ+ CN participants into low vs high tau groups. Moreover, the presence of Aβ+ was associated with an elevated [18F]-AV-1451 SUVR in AD cortical signature regions (Aβ+ participants: mean [SD], 1.3 [0.3]; Aβ- participants: 1.1 [0.1]; F = 4.3, P = .04) but not in the hippocampus. The presence of Aβ+ alone was not related to hippocampal volume or AD signature cortical thickness. An elevated [18F]-AV-1451 SUVR was associated with volumetric loss in both the hippocampus and AD cortical signature regions. The observed [18F]-AV-1451 SUVR volumetric association was modified by Aβ status in the hippocampus but not in AD cortical signature regions. An inverse association between hippocampal [18F]-AV-1451 SUVR and volume was seen in Aβ+ participants (R2 = 0.55; P < .001) but not Aβ- (R2 = 0; P = .97) participants.

Conclusions and relevance: Use of [18F]-AV-1451 has a potential for staging of the preclinical and clinical phases of AD. β-Amyloid interacts with hippocampal and cortical tauopathy to affect neurodegeneration. In the absence of Aβ, hippocampal tau deposition may be insufficient for the neurodegenerative process that leads to AD.

Figure 1. Regional and Vertexwise Associations Between [¹⁸F]-AV-1451 Binding and Cortical Thickness

Pearson correlation between [¹⁸F]-AV-1451 binding and cortical thickness was assessed for each region of interest that composed the Alzheimer disease (AD) cortical signature (A) and each vertex across the cortical mantle (B). The regional correlation coefficients are showed with a bar graph in an order that is consistent with the hypothetical sequence of neurofibrillary tangles spreading. The color-coded anatomic location of AD cortical signature regions is labeled in the bar graph accordingly. The significance of vertexwise correlation was thresholded at P < .05, corrected for multiple comparisons at the cluster level. Both AD cortical signature regions and vertexwise correlation are displayed on the semi-inflated cortical surface of the FreeSurfer average brain, with light gray regions representing gyri and dark gray regions representing sulci.

Figure 2. Regional [¹⁸F]-AV-1451 Binding, Volumetric Measurement, and Cerebrospinal Fluid (CSF) Phosphorylated Tau₁₈₁ (ptau₁₈₁) Accordingto β-Amyloid (Aβ) Status and Clinical Diagnosis

Hippocampal [¹⁸F]-AV-1451 binding (ie, standardized uptake value ratio [SUVR]) or volume (adjusted with intracranial volume) (A), Alzheimer disease (AD) signature [¹⁸F]-AV-1451 SUVR or cortical thickness (B), and CSF ptau₁₈₁ (C) are presented with individual data points and boxplot showing the range, median, and interquartile range. The dashed line, corresponds to an SUVR of 1.19 derived from the AD cortical signature composite for [¹⁸F]-AV-1451 and represents a cutoff that best separated CSF Aβ42-positive (Aβ+) AD from CSF Aβ42-negative (Aβ−) cognitively normal (CN) participants. TheAβ level was measured by CSF assay of Aβ42. Cutoffs for Aβ status (ie, CSF Aβ+ vs Aβ−) were determined from an independent cohort. Group difference in each measurement was compared using a t test. ^a P < .05 in comparison between Aβ+ AD vs Aβ− CN. ^b P < .05 in comparison between Aβ+ AD vs Aβ+ CN. ^c P < .05 in comparison between Aβ+ CN vs Aβ− CN.

Figure 3. Associations Among β-Amyloid (Aβ) Status, [¹⁸F]-AV-1451 Binding, and Volumetric Measurement

[¹⁸F]-AV-1451 binding (standardized uptake value ratio [SUVR]) is plotted against volumetric measurement for the hippocampus (A) and Alzheimer disease (AD) cortical signature regions (B). Linear fitting is presented for the entire cohort (N = 59, black line) and separately for Aβ positive (Aβ+) (n = 20, green line) vs Aβ negative (Aβ−) group (n = 22, blue line). With Aβ status, the slope of linear fitting was significantly different in the hippocampus (P = .01) but not AD cortical signature regions (P > .05) after adjusting for age and Clinical Dementia Rating (CDR) status (CDR 0 vs CDR >0). Aβ+ or Aβ− indicates positive or negative for Aβ biomarker, respectively.