Biomarkers for tau pathology

Abstract

The aggregation of fibrils of hyperphosphorylated and C-terminally truncated microtubule-associated tau protein characterizes 80% of all dementia disorders, the most common neurodegenerative disorders. These so-called tauopathies are hitherto not curable and their diagnosis, especially at early disease stages, has traditionally proven difficult. A keystone in the diagnosis of tauopathies was the development of methods to assess levels of tau protein in vivo in cerebrospinal fluid, which has significantly improved our knowledge about these conditions. Tau proteins have also been measured in blood, but the importance of tau-related changes in blood is still unclear. The recent addition of positron emission tomography ligands to visualize, map and quantify tau pathology has further contributed with information about the temporal and spatial characteristics of tau accumulation in the living brain. Together, the measurement of tau with fluid biomarkers and positron emission tomography constitutes the basis for a highly active field of research. This review describes the current state of biomarkers for tau biomarkers derived from neuroimaging and from the analysis of bodily fluids and their roles in the detection, diagnosis and prognosis of tau-associated neurodegenerative disorders, as well as their associations with neuropathological findings, and aims to provide a perspective on how these biomarkers might be employed prospectively in research and clinical settings.

Fig. 1

Chemical structures of current PET ligands binding to PHF tau protein.

Fig. 2

Representative PET scans using different current ligands presumably specific for tau in cognitively healthy elderly individuals (upper rows), patients with early-onset (EOAD, middle rows) and late-onset Alzheimer's disease (LOAD, lower rows). All images were processed in a unified manner including co-registration of PET to its corresponding T1-weighted magnetic resonance imaging (MRI) scan, spatial normalization to Montreal Neurological Institute (MNI) template space and creation of standardized uptake value ratios (SUVR) using an inferior cerebellum reference region (see (Baker et al., 2017b) for methods). Note that this is not a head-to-head comparison but merely a display of sample scans from different representative cases, obtained at various sites using scanners with different spatial resolution, and non-harmonized image reconstruction. FTP images (80–100 min SUVR) were derived from the Berkeley Aging Cohort Study (BACS; University of California, Berkeley/San Francisco, Drs. William Jagust and Gil Rabinovici), [¹⁸F]GTP1 (60–90 min SUVR) images were kindly provided by Genentech (Drs. Robby Weimer and Sandra Sanabria Bohorquez), RO6958948 images (60–90 min SUVR) by Roche (Drs. Gregory Klein and Edilio Borroni) and Drs. Dean Wong and Hiroto Kuwabara from Johns Hopkins University, Baltimore, Maryland, MK6240 images (90–110 min SUVR) by Drs. Pedro Rosa-Neto and Tharick Ali Pascoal at McGill University, Montreal, Canada, and PI2620 scans (60–90 min SUVR) by Drs. André Müller and Santaigo Bullich at Life Molecular Imaging GmbH (former Piramal Imaging). Aβ pos/neg: Amyloid status positive/negative based on Aβ PET scans; MMSE = Mini Mental State Examination.

Fig. 3

Tau tracer uptake patterns resemble ex vivo Braak stages. A. Schematic display of Braak stages in the development of Alzheimer's disease-associated tau pathology based on post mortem data. Reprinted from “Stages of the Pathologic Process in Alzheimer Disease: Age Categories From 1 to 100 Years,” (Braak et al., 2011). Copyright 2011 by Oxford University Press B. Voxel-wise two-sample t-tests on Flortaucipir SUVR images between subjects assigned to contiguous tau-PET based Braak stages. Results are Family-Wise Error (FWE) corrected at voxel level (p_voxel < 0.05, k > 100). Individuals included cognitively normal adults and AD patients. See (Maass et al., 2017) for more information.

Fig. 4

Association between global Aβ and regional tau PET measures in cognitively normal elderly. A. Partial correlation (r-values) of global PiB with regional FTP PET measures in 420 cognitively normal individuals (age 50+) after adjusting for age. Highest correlations were in medial temporal regions, specifically entorhinal cortex (ERC). Reprinted from “Tau-PET uptake: Regional variation in average SUVR and impact of amyloid deposition,” (Vemuri et al., 2017). Copyright 2017 by Elsevier Inc. (on behalf of the Alzheimer's Assocation) B. Mean partial correlation r values for associations between global PiB DVR and FTP SUVR in different ROIs in 46 normal elderly from BACS, demonstrating strongest correlation in temporal lobe. Adapted from “Amyloid and tau PET demonstrate region-specific associations in normal older people,” (Lockhart et al., 2017b). Copyright 2017 by Elsevier.

Fig. 5

Tau PET signal relates to episodic memory performance in cognitively normal elderly. A. Higher Braak I/II FTP SUVR (mean across entorhinal cortex and hippocampus after partial volume correction) relates to worse episodic memory (Z-score of verbal and visual recall) in 83 older adults from BACS. R denotes skipped Pearson correlation coefficient with bootstrapped 95% CI from robust correlations; outliers colored in black. See Maass et al., 2018 for details. B. Higher mean FTP SUVR across amygdala, entorhinal, lateral occipital and inferior temporal cortex relates to worse episodic memory in elderly sample from WashU. Adapted from “AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure,” by Mishra et al., 2017, Neuroimage, 161:171–178. Copyright 2017 by Elsevier C. Voxel-wise regressions of episodic memory on FTP SUVR in subjects from A. (whole brain, p_cluster < 0.05, p_voxel < 0.001, no explicit mask). Significant regions include bilateral entorhinal/parahippocampal cortex, left inferior temporal gyrus and middle temporal gyrus.