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.
ReviewTau imaging: early progress and future directions
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
References (104)
- et al.
Frequency of stages of Alzheimer-related lesions in different age categories
Neurobiol Aging
(1997) - et al.
Amyloid β deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer's disease: a prospective cohort study
Lancet Neurol
(2013) - et al.
Challenges in the conduct of disease-modifying trials in AD: practical experience from a phase 2 trial of Tau-aggregation inhibitor therapy
J Nutr Health Aging
(2009) - et al.
Tau protein isoforms, phosphorylation and role in neurodegenerative disorders
Brain Res Brain Res Rev
(2000) - et al.
Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease
J Biol Chem
(2009) - 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) - et al.
Seeding of normal tau by pathological tau conformers drives pathogenesis of Alzheimer-like tangles
J Biol Chem
(2011) - et al.
In vivo tau imaging: obstacles and progress
Alzheimers Dement
(2014) - et al.
Human tau isoforms assemble into ribbon-like fibrils that display polymorphic structure and stability
J Biol Chem
(2010) - et al.
Post-translational modifications of tau protein: implications for Alzheimer's disease
Neurochem Int
(2011)
Tau aggregation is driven by a transition from random coil to beta sheet structure
Biochim Biophys Acta
Characterization of tau fibrillization in vitro
Alzheimers Dement
Tau protein pathology in neurodegenerative diseases
Trends Neurosci
PIB binding in aged primate brain: enrichment of high-affinity sites in humans with Alzheimer's disease
Neurobiol Aging
Levels of normal and abnormally phosphorylated tau in different cellular and regional compartments of Alzheimer disease and control brains
FEBS Lett
Relationships between radiotracer properties and image quality in molecular imaging of the brain with positron emission tomography
Mol Imaging Biol
PET radiotracers: crossing the blood-brain barrier and surviving metabolism
Trends Pharmacol Sci
Selectivity requirements for diagnostic imaging of neurofibrillary lesions in Alzheimer's disease: a simulation study
Neuroimage
Localization of neurofibrillary tangles and β -amyloid plaques in the brains of living patients with Alzheimer disease
Am J Geriatr Psychiatry
PET scanning of brain tau in retired national football league players: preliminary findings
Am J Geriatr Psychiatry
Multitracer PET imaging of amyloid plaques and neurofibrillary tangles in Alzheimer's disease
Neuroimage
[(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease
Alzheimers Dement
First case report: image to autopsy correlation for tau imaging with [18F]-T808 (AV-680)
Alzheimer Dementia
Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls
Neuron
Tracking pathophysiological processes in Alzheimer's disease: an updated hypothetical model of dynamic biomarkers
Lancet Neurol
Biomarker modeling of Alzheimer's disease
Neuron
Linking Abeta and tau in late-onset Alzheimer's disease: a dual pathway hypothesis
Neuron
Tau aggregation in the hippocampal formation: an ageing or a pathological process?
Exp Gerontol
18F-THK523: a novel in vivo tau imaging ligand for Alzheimer's disease
Brain
Early clinical PET imaging results with the novel PHF-tau radioligand [F-18]-T807
J Alzheimers Dis
An operational approach to National Institute on Aging-Alzheimer's Association criteria for preclinical Alzheimer disease
Ann Neurol
Rates of β-amyloid accumulation are independent of hippocampal neurodegeneration
Neurology
Short-term clinical outcomes for stages of NIA-AA preclinical Alzheimer disease
Neurology
Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease
Neurology
Imaging β-amyloid burden in aging and dementia
Neurology
Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature
J Neuropathol Exp Neurol
Neuropathological alterations in Alzheimer disease
Cold Spring Harb Perspect Med
Reducing endogenous tau ameliorates amyloid beta-induced deficits in an Alzheimer's disease mouse model
Science
One hundred years after the discovery of Alzheimer's disease. A turning point for therapy?
J Alzheimers Dis
Microtubule-binding drugs offset tau sequestration by stabilizing microtubules and reversing fast axonal transport deficits in a tauopathy model
Proc Natl Acad Sci USA
TAR DNA-binding protein 43 in neurodegenerative disease
Nat Rev Neurol
Frontotemporal lobar degeneration: epidemiology, pathophysiology, diagnosis and management
CNS Drugs
Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review
J Neurol Neurosurg Psychiatry
Tau protein and human tauopathies: an overview
Zdrav Vestn
Neurodegenerative tauopathies
Annu Rev Neurosci
Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury
J Neuropathol Exp Neurol
Biochemistry of amyloid β-protein and amyloid deposits in Alzheimer disease
Cold Spring Harb Perspect Med
Soluble pool of Aβ amyloid as a determinant of severity of neurodegeneration in Alzheimer's disease
Ann Neurol
Tangles and plaques in nondemented aging and “preclinical” Alzheimer's disease
Ann Neurol
The ART of loss: Aβ imaging in the evaluation of Alzheimer's disease and other dementias
Mol Neurobiol
Cited by (407)
Preclinical Evaluation of Novel PET Probes for Dementia
2023, Seminars in Nuclear MedicineMulticomponent Petasis reaction for the identification of pyrazine based multi-target directed anti-Alzheimer's agents: In-silico design, synthesis, and characterization
2023, European Journal of Medicinal ChemistryMusic Therapy as a Complementary Treatment in Patients with Dementia Associated to Alzheimer's Disease: A Systematic Review
2024, Journal of Alzheimer's DiseaseBiomarkers for Alzheimer's Disease – An Overview
2024, Macromolecular Symposia