Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions
Graphical abstract
Introduction
To him who holds in his hands the Great Image (of the invisible Tao), the whole world repairs.
Lao Tzu – Tao Teh King (35. 1.)
Several neurodegenerative conditions are associated with misfolded and aggregated protein(s). At present, as there are no reliable means to identify these abnormal proteins in the living patient, clinicians are unable to identify the underlying pathology responsible for the disease, particularly at the early stages of the disease where the clinical phenotypes overlap. Given that the same misfolded and aggregated protein can be associated with different and distinct phenotypes, and that a particular phenotype can be caused by different misfolded proteins [1, 2•, 3], definitive diagnosis is still reliant upon post-mortem examination. The success of amyloid β-protein (Aβ) imaging with Pittsburgh Compound B (PiB) [4•], as well as fluorinated Aβ radioligands [5•, 6, 7, 8] led to a renewed effort to develop selective tau radiotracers.
Section snippets
The great triad: physiology, pathology and phenotypes
Tau is a phosphoprotein that stabilizes microtubules, critical for the neuron cytoskeleton and for axonal transport. In humans, six tau isoforms have been described [9]. The repeats of the microtubule binding domain have been used to classify the six tau isoforms into two functionally different groups, either those with three (3R) or four repeats (4R), respectively [9].
Some studies propose that Aβ promotes endogenous tau hyperphosphorylation leading to weaker microtubule binding [10] and
The Yin and Yang of tau imaging
Radiotracer design for tau deposits in the brain need to follow the demands of any neuroimaging radiotracer, but adapt and/or constrain them to the particular characteristics of tau deposition. We have enumerated in detail before the additional challenges tau imaging poses compared to Aβ imaging [36, 37, 38]. Briefly, tau aggregates are mostly intracellular, adding the extra barrier of the cell membrane to the blood–brain barrier (BBB) for the tau tracer to cross, before reaching its target.
Currently available tau imaging radiotracers
Based on their ability to bind tau over other misfolded proteins, tau tracers can be classified as selective or non-selective. The prototypical non-selective tau tracer is 18F-FDDNP, which binds to both extracellular Aβ plaques and intracellular NFT [52, 53] and that we have described in detail elsewhere [36, 37, 38]. Several strategies such as structure–activity relationship evaluation, tracer docking simulations, or incorporating bulky hydrophilic groups, that prevent binding to Aβ fibrils
Final tautologies
Selective tau imaging will allow a deeper understanding of tau aggregation and deposition in the human brain, providing insight into causes, diagnosis, and treatment of major tauopathies such as Alzheimer's disease, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal syndrome, and some variants of frontotemporal lobar degeneration.
In only a few years, significant progress has been achieved in the field of tau imaging. But there is still plenty of room for improvement,
Conflict of interest statement
Victor Villemagne has received speaker honoraria from GE Healthcare and Piramal Imaging, and consulting honoraria from Novartis. Nobuyuki Okamura has received research support from Clino Co. Ltd. THK compounds have been licensed to GE Healthcare.
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank Professors Christopher Rowe, Yukitsuda Kudo, Colin Masters, Kazuhiko Yanai, Shozo Furumoto, Drs Ryuichi Harada and Michelle Fodero-Tavoletti, and Louis F Destouches, Mrs Svetlana Pejoska-Bozinovski, Ms Fiona Lamb, and the Brain Research Institute for their assistance with this study. This review was supported in part by NHMRC Project Grant 1044361. VLV is supported by NHMRC Research Fellowship 1046471. The funding sources had no input into the design of this study, the analysis of
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