Elsevier

The Lancet Neurology

Volume 14, Issue 1, January 2015, Pages 114-124
The Lancet Neurology

Review
Tau imaging: early progress and future directions

https://doi.org/10.1016/S1474-4422(14)70252-2Get rights and content

Summary

Use of selective in-vivo tau imaging will enable improved understanding of tau aggregation in the brain, facilitating research into causes, diagnosis, and treatment of major tauopathies such as Alzheimer's disease, progressive supranuclear palsy, corticobasal syndrome, chronic traumatic encephalopathy, and some variants of frontotemporal lobar degeneration. Neuropathological studies of Alzheimer's disease show a strong association between tau deposits, decreased cognitive function, and neurodegenerative changes. Selective tau imaging will allow the in-vivo exploration of such associations and measure the global and regional changes in tau deposits over time. Such imaging studies will comprise non-invasive assessment of the spatial and temporal pattern of tau deposition over time, providing insight into the role tau plays in ageing and helping to establish the relation between cognition, genotype, neurodegeneration, and other biomarkers. Once validated, selective tau imaging might be useful as a diagnostic, prognostic, and progression biomarker, and a surrogate marker for the monitoring of efficacy and patient recruitment for anti-tau therapeutic trials.

Introduction

Selective tau imaging will allow improved 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.

The success of amyloid β (Aβ) imaging with Pittsburgh compound B (PiB) and fluorinated alternatives has spurred efforts worldwide to develop selective tau PET tracers. These efforts have translated into promising candidates now in clinical studies. Tau imaging has several potential applications. Longitudinal imaging studies can recapitulate the pathological studies of Braak and Braak,1 confirm the various stages of tau deposition, and assist in the early and differential diagnosis of Alzheimer's disease and non-Alzheimer's disease tauopathies. Tau PET tracers are likely to be used as surrogate markers of cognition to predict cognitive decline and disease progression. Selective tau PET tracers will enable the in-vivo assessment of regional tau burden and its relation to Aβ deposition in patients with Alzheimer's disease;2, 3, 4 the combination of tau and Aβ imaging will improve the specificity of diagnosis and enable early detection of pathology in individuals at risk of Alzheimer's dementia. Use of tau PET imaging will help to elucidate the underlying pathology in cognitively unimpaired individuals that present with Alzheimer's disease-like neurodegeneration in the absence of Aβ deposition.5, 6, 7

Post-mortem studies show that tau deposition is highly associated with cognitive impairment8, 9, 10, 11 and tau deregulation is a key mediator of neurodegeneration.12 These findings led to the exploration of several strategies for the treatment of tauopathies.13, 14 Therapeutic interventions have a better chance of success if administered before the occurrence of irreversible neuronal damage. Early detection of the underlying pathological process is crucial for therapeutic trials aimed at modulation of tau aggregation and deposition.15 Tau PET imaging will provide help to clinicians in disease staging and in selecting.individuals most likely to benefit from treatment. As a surrogate outcome measure of the efficacy of anti-tau treatments, tau burden will probably provide a more accurate, stable, and reliable statement about the therapeutic response than tests of cognition.

In this Review we describe the available tau PET tracers and give our views on the characteristics of tau deposition and the requirements of neuroimaging tracer design, with a focus on the achievements in clinical research and some of the unaddressed issues associated with the use of these tracers.

Section snippets

Tau physiology, pathology, and phenotypes

Several neurodegenerative diseases are associated with misfolded and aggregated protein(s). At present, the means to identify these abnormal proteins in vivo is unreliable, and clinicians are unable to identify the underlying pathology associated with the disease, especially in the early stages when many clinical phenotypes overlap. Because the same misfolded and aggregated protein can manifest as different and distinct clinical phenotypes, and a particular phenotype can be caused by different

Issues pertinent to tau imaging

Two inter-related and interdependent issues define key aspects of tau imaging. One relates to the characteristics of tau deposition and the other to the requirements of tau PET tracer design.

Tau imaging ligands

Efforts worldwide have focused on the design of tau PET tracers with the aim of repeating the success of Aβ imaging with PiB.66 Several strategies to achieve selectivity in tau imaging have been proposed.39, 40

Unresolved issues

The development, assessment, and validation of new tau PET tracers is not straightforward owing to the characteristics of tau aggregation and the requirements of tracer design. A thorough preclinical assessment of tracers, such as that used in the assessment of PBB3,92 is needed to characterise the binding affinity and kinetic profiles of novel tau PET tracers. Despite thorough preclinical studies, prediction of the selectivity of tracers, their kinetics, and potential for reversible or

Conclusions and future directions

In-vivo imaging of tau pathology will reveal progressive tau deposition and facilitate research into the causes, neurobiology, diagnosis, and treatment of major neurodegenerative disorders in which tau has a role. Tau imaging will help to disentangle the association between Aβ and tau (figure 6); to understand whether tau accumulation is part of normal ageing or whether it represents a pathological process; and to establish how tau accumulation relates to Aβ accumulation, cognitive decline,

Search strategy and selection criteria

We searched PubMed with search terms including “tau deposition”, “tauopathies”, “Alzheimer's disease”, “tau imaging”, “amyloid imaging”, “neuroimaging radiotracers”, and “neurodegeneration”. We also searched the reference lists of relevant articles. Abstracts and reports from meetings were included only when they related directly to previously published work. Articles published in English between Nov, 1983 and Dec, 2014, and one article from 1970 were included.

References (104)

  • M von Bergen et al.

    Tau aggregation is driven by a transition from random coil to beta sheet structure

    Biochim Biophys Acta

    (2005)
  • S Xu et al.

    Characterization of tau fibrillization in vitro

    Alzheimers Dement

    (2010)
  • MG Spillantini et al.

    Tau protein pathology in neurodegenerative diseases

    Trends Neurosci

    (1998)
  • RF Rosen et al.

    PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease

    Neurobiol Aging

    (2011)
  • S Khatoon et al.

    Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains

    FEBS Lett

    (1994)
  • 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)
  • VW Pike

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

    Trends Pharmacol Sci

    (2009)
  • KN Schafer et al.

    Selectivity requirements for diagnostic imaging of neurofibrillary lesions in Alzheimer's disease: a simulation study

    Neuroimage

    (2012)
  • K Shoghi-Jadid et al.

    Localization of neurofibrillary tangles and β -amyloid plaques in the brains of living patients with Alzheimer disease

    Am J Geriatr Psychiatry

    (2002)
  • GW Small et al.

    PET scanning of brain tau in retired national football league players: preliminary findings

    Am J Geriatr Psychiatry

    (2013)
  • J Shin et al.

    Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease

    Neuroimage

    (2008)
  • CF Xia et al.

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

    Alzheimers Dement

    (2013)
  • H Kolb et al.

    First case report: image to autopsy correlation for tau imaging with [18F]-T808 (AV-680)

    Alzheimer Dementia

    (2013)
  • M Maruyama et al.

    Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls

    Neuron

    (2013)
  • CR Jack et al.

    Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers

    Lancet Neurol

    (2013)
  • CR Jack et al.

    Biomarker modeling of Alzheimer's disease

    Neuron

    (2013)
  • SA Small et al.

    Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis

    Neuron

    (2008)
  • A Delacourte et al.

    Tau aggregation in the hippocampal formation: an ageing or a pathological process?

    Exp Gerontol

    (2002)
  • MT Fodero-Tavoletti et al.

    18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease

    Brain

    (2011)
  • DT Chien et al.

    Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807

    J Alzheimers Dis

    (2013)
  • CR Jack et al.

    An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease

    Ann Neurol

    (2012)
  • CR Jack et al.

    Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration

    Neurology

    (2014)
  • DS Knopman et al.

    Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease

    Neurology

    (2012)
  • PV Arriagada et al.

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

    Neurology

    (1992)
  • CC Rowe et al.

    Imaging β-amyloid burden in aging and dementia

    Neurology

    (2007)
  • PT Nelson et al.

    Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature

    J Neuropathol Exp Neurol

    (2012)
  • A Serrano-Pozo et al.

    Neuropathological alterations in Alzheimer disease

    Cold Spring Harb Perspect Med

    (2011)
  • ED Roberson et al.

    Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model

    Science

    (2007)
  • E Giacobini et al.

    One hundred years after the discovery of Alzheimer's disease. A turning point for therapy?

    J Alzheimers Dis

    (2007)
  • B Zhang et al.

    Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model

    Proc Natl Acad Sci USA

    (2005)
  • AS Chen-Plotkin et al.

    TAR DNA-binding protein 43 in neurodegenerative disease

    Nat Rev Neurol

    (2010)
  • GD 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)
  • N Mohorko et al.

    Tau protein and human tauopathies: an overview

    Zdrav Vestn

    (2008)
  • VM Lee et al.

    Neurodegenerative tauopathies

    Annu Rev Neurosci

    (2001)
  • AC McKee et al.

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

    J Neuropathol Exp Neurol

    (2009)
  • CL Masters et al.

    Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease

    Cold Spring Harb Perspect Med

    (2012)
  • CA McLean et al.

    Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease

    Ann Neurol

    (1999)
  • JL Price et al.

    Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease

    Ann Neurol

    (1999)
  • VL Villemagne et al.

    The ART of loss: Aβ imaging in the evaluation of Alzheimer's disease and other dementias

    Mol Neurobiol

    (2008)
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