Elsevier

Current Opinion in Neurobiology

Volume 36, February 2016, Pages 43-51
Current Opinion in Neurobiology

Tau imaging in the study of ageing, Alzheimer's disease, and other neurodegenerative conditions

https://doi.org/10.1016/j.conb.2015.09.002Get rights and content

Highlights

  • A deeper insight into tau deposition in primary and secondary tauopathies.

  • Cross-sectional and longitudinal assessment of the patterns of tau deposition.

  • A better understanding of the role tau plays in ageing and neurodegeneration.

  • Earlier and accurate diagnosis, as well as prognosis of disease progression.

  • To be used as a surrogate marker for disease-specific therapeutic trials.

In vivo tau imaging allows a deeper understanding of tau deposition in the brain, providing insights into the causes, diagnosis and treatment of primary and secondary tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. The cross-sectional and longitudinal assessment of the temporal and spatial patterns of tau deposition in the brain will allow a better understanding of the role tau plays in ageing as well as its relationship with cognition, genotype, and neurodegeneration. It is likely that selective tau imaging could be used as a diagnostic and prognostic biomarker of disease progression, as well as a surrogate marker for monitoring of efficacy and patient recruitment for disease-specific therapeutic trials.

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

References (87)

  • M. Laruelle et al.

    Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography

    Mol Imaging Biol

    (2003)
  • V.W. Pike

    PET radiotracers: crossing the blood–brain barrier and surviving metabolism

    Trends Pharmacol Sci

    (2009)
  • V.L. Villemagne et al.

    Aβ Imaging: feasible, pertinent, and vital to progress in Alzheimer's disease

    Eur J Nucl Med Mol Imaging

    (2012)
  • A. Taghavi et al.

    N’-benzylidene-benzohydrazides as novel and selective tau-PHF ligands

    J Alzheimers Dis

    (2011)
  • H. Watanabe et al.

    Synthesis and biological evaluation of novel oxindole derivatives for imaging neurofibrillary tangles in Alzheimer's disease

    Bioorg Med Chem Lett

    (2012)
  • K. Matsumura et al.

    Synthesis and biological evaluation of novel styryl benzimidazole derivatives as probes for imaging of neurofibrillary tangles in Alzheimer's disease

    Bioorg Med Chem

    (2013)
  • N.S. Honson et al.

    Potent inhibition of tau fibrillization with a multivalent ligand

    Biochem Biophys Res Commun

    (2007)
  • X.M. Shao et al.

    Evaluation of [11C]N-methyl lansoprazole as a radiopharmaceutical for PET imaging of tau neurofibrillary tangles

    ACS Med Chem Lett

    (2012)
  • H. Hashimoto et al.

    Radiosynthesis, photoisomerization, biodistribution, and metabolite analysis of 11C-PBB3 as a clinically useful PET probe for imaging of tau pathology

    J Nucl Med

    (2014)
  • C.F. Xia et al.

    [(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease

    Alzheimers Dement

    (2013)
  • M. Vieira et al.

    Transthyretin: a multifaceted protein

    Biomol Concepts

    (2014)
  • V.L. Villemagne et al.

    In vivo evaluation of a novel tau imaging tracer for Alzheimer's disease

    Eur J Nucl Med Mol Imaging

    (2014)
  • V.L. Villemagne et al.

    Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study

    Lancet Neurol

    (2013)
  • A.S. Chen-Plotkin et al.

    TAR DNA-binding protein 43 in neurodegenerative disease

    Nat Rev Neurol

    (2010)
  • G.D. Rabinovici et al.

    Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management

    CNS Drugs

    (2010)
  • H. Seelaar et al.

    Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review

    J Neurol Neurosurg Psychiatry

    (2011)
  • W.E. Klunk et al.

    Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B

    Ann Neurol

    (2004)
  • C.C. Rowe et al.

    Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism

    Lancet Neurol

    (2008)
  • C.C. Rowe et al.

    Head-to-head comparison of 11C-PiB and 18F-AZD4694 (NAV4694) for beta-amyloid imaging in aging and dementia

    J Nucl Med

    (2013)
  • D.F. Wong et al.

    In vivo imaging of amyloid deposition in Alzheimer disease using the radioligand 18F-AV-45 (florbetapir [corrected] F 18)

    J Nucl Med

    (2010)
  • L. Buee et al.

    Tau protein isoforms, phosphorylation and role in neurodegenerative disorders

    Brain Res Brain Res Rev

    (2000)
  • T. Maas et al.

    Interaction of tau with the neural membrane cortex is regulated by phosphorylation at sites that are modified in paired helical filaments

    J Biol Chem

    (2000)
  • X. Li et al.

    Novel diffusion barrier for axonal retention of Tau in neurons and its failure in neurodegeneration

    Embo J

    (2011)
  • H. Zempel et al.

    Amyloid-beta oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin

    EMBO J

    (2013)
  • H. Zempel et al.

    Abeta oligomers cause localized Ca(2+) elevation, missorting of endogenous Tau into dendrites, Tau phosphorylation, and destruction of microtubules and spines

    J Neurosci

    (2010)
  • H. Braak et al.

    Evolution of neuronal changes in the course of Alzheimer's disease

    J Neural Transm Suppl

    (1998)
  • A. Delacourte et al.

    The biochemical pathway of neurofibrillary degeneration in aging and Alzheimer's disease

    Neurology

    (1999)
  • H. Braak et al.

    Frequency of stages of Alzheimer-related lesions in different age categories

    Neurobiol Aging

    (1997)
  • A. Serrano-Pozo et al.

    Neuropathological alterations in Alzheimer disease

    Cold Spring Harb Perspect Med

    (2011)
  • J.L. Guo et al.

    Seeding of normal Tau by pathological Tau conformers drives pathogenesis of Alzheimer-like tangles

    J Biol Chem

    (2011)
  • N. Mohorko et al.

    Tau protein and human tauopathies: an overview

    Zdrav Vestn

    (2008)
  • A.C. McKee et al.

    Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury

    J Neuropathol Exp Neurol

    (2009)
  • P.V. Arriagada et al.

    Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease

    Neurology

    (1992)
  • Cited by (56)

    • Butyrylcholinesterase as a biomarker in Alzheimer’s disease

      2020, Diagnosis and Management in Dementia: The Neuroscience of Dementia, Volume 1
    • AD molecular: Imaging tau aggregates with positron emissions tomography

      2019, Progress in Molecular Biology and Translational Science
    • Neuropathologic, genetic, and longitudinal cognitive profiles in primary age-related tauopathy (PART) and Alzheimer's disease

      2019, Alzheimer's and Dementia
      Citation Excerpt :

      These similarities include association with normal cognition or mild cognitive impairment, neurodegeneration of mesial temporal lobe structures, absence of Aβ deposits, and underrepresentation of APOE ε4 allele relative to AD. Tau PET scanning [46] in conjunction with other imaging, for example, amyloid and vascular imaging, should allow for further delineation of the overlap of PART as a subset of suspected non-Alzheimer's pathophysiology. Tau lesions of the medial temporal lobe are not limited to older individuals but have also been reported in the entorhinal cortex and hippocampus before 30 years of age [42].

    View all citing articles on Scopus
    View full text