The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer's disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down's syndrome (DS), Parkinson's disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first-(e.g., [ 18 F] THK5317, [ 18 F]THK5351, [ 18 F]AV1451, and [ 11 C]PBB3) and second-generation compounds [namely [ 18 F]MK-6240, [ 18 F] RO-948 (previously referred to as [ 18 F]RO69558948), [ 18 F]PI-2620, [ 18 F]GTP1, [ 18 F]PM-PBB3, and [ 18 F]JNJ64349311 ([ 18 F]JNJ311) and its derivative [ 18 F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.

Biomarkers sensitive to functional impairment, neuronal loss, tau, and amyloid pathology based on MR, PET, and CSF studies are increasingly used to diagnose Alzheimer's disease (AD), but clinical validation is incomplete, hampering reimbursement by payers, widespread clinical implementation, and impacting on health care quality. An expert group convened to develop a strategic research agenda to foster the clinical validation of AD biomarkers. These demonstrated sufficient evidence of analytical validity (phase I of a structured framework adapted from oncology). Research priorities were identified based on incomplete clinical validity (phases II and III), and clinical utility (phases IV and V). Priorities included: definition of the assays; reading procedures and thresholds for normality; performance in detecting early disease; accounting for the effect of covariates; diagnostic algorithms comprising combinations of biomarkers; and developing best practice guidelines for the use of biomarkers in qualified memory clinics in the context of phase IV studies. 5 GlossaryBiomarker. An objective measure of a biological or pathogenic process with the purpose of evaluating disease risk or prognosis, guiding clinical diagnosis or monitoring therapeutic interventions. While the term originally referred to traceable substances produced by or introduced into an organism, it later evolved to any measurable parameter, including those obtained via imaging procedures.Roadmap. Objective-oriented, structured, and efficient action plan. In science and technology also called "strategic research agenda".Alzheimer's disease (AD) dementia. Traditionally and according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria, Alzheimer's disease was defined as a syndrome with progressive cognitive impairment severe enough to impact on daily activities. A diagnosis of Alzheimer's disease could only be made after exclusion of other possible causes. 1 Sixty-five to 80% of cases of patients fulfilling these criteria have Alzheimer's pathology (plaques and tangles), the remainder having a range of other pathologies. In order to increase diagnostic certainty, contemporary criteria for AD dementia incorporate biomarker evidence for different aspects of Alzheimer's pathology, including imaging (magnetic resonance imaging -MRI -measures of atrophy; 18 F-fluorodeoxyglucose-positron emission tomography -FDG-PET -measures of cerebral hypometabolism; amyloid PET measures of fibrillar β-amyloid -A -deposition) and cerebrospinal fluid -CSF (decreased levels of A42, increased levels of tau and phospho-tau). 2,3 Alzheimer's disease process. Recognizing that AD pathology is present many years before symptoms emerge, new criteria classify the disease process on a continuum from asymptomatic to prodromal and finally to dementia stage. 4 Individuals at the asymptomatic stage can only be identified by biomarkers of Alzheimer's pathology. None...

See Schott and Fox (doi: ) for a scientific commentary on this article. The relationships between pathophysiological processes in Alzheimer’s disease remain largely unclear. In a longitudinal, multitracer PET study, Rodriguez-Vieitez et al. reveal that progression of autosomal dominant Alzheimer’s disease is accompanied by prominent early and then declining astrocytosis, increasing amyloid plaque deposition and decreasing glucose metabolism. Astrocyte activation may initiate Alzheimer pathology.

Abnormal aggregation of tau in the brain is a major contributing factor in various neurodegenerative diseases. The role of tau phosphorylation in the pathophysiology of tauopathies remains unclear. Consequently, it is important to be able to accurately and specifically target tau deposits in vivo in the brains of patients. The advances of molecular imaging in the recent years have now led to the recent development of promising tau-specific tracers for positron emission tomography (PET), such as THK5317, THK5351, AV-1451, and PBB3. These tracers are now available for clinical assessment in patients with various tauopathies, including Alzheimer’s disease, as well as in healthy subjects. Exploring the patterns of tau deposition in vivo for different pathologies will allow discrimination between neurodegenerative diseases, including different tauopathies, and monitoring of disease progression. The variety and complexity of the different types of tau deposits in the different diseases, however, has resulted in quite a challenge for the development of tau PET tracers. Extensive work remains in order to fully characterize the binding properties of the tau PET tracers, and to assess their usefulness as an early biomarker of the underlying pathology. In this review, we summarize recent findings on the most promising tau PET tracers to date, discuss what has been learnt from these findings, and offer some suggestions for the next steps that need to be achieved in a near future.

PurposeThe aim of this study was to explore the cerebral distribution of the tau-specific PET tracer [18F]THK5317 (also known as (S)-[18F]THK5117) retention in different stages of Alzheimer’s disease; and study any associations with markers of hypometabolism and amyloid-beta deposition.MethodsThirty-three individuals were enrolled, including nine patients with Alzheimer’s disease dementia, thirteen with mild cognitive impairment (MCI), two with non-Alzheimer’s disease dementia, and nine healthy controls (five young and four elderly). In a multi-tracer PET design [18F]THK5317, [11C] Pittsburgh compound B ([11C]PIB), and [18F]FDG were used to assess tau pathology, amyloid-beta deposition and cerebral glucose metabolism, respectively. The MCI patients were further divided into MCI [11C]PIB-positive (n = 11) and MCI [11C]PIB-negative (n = 2) groups.ResultsTest-retest variability for [18F]THK5317-PET was very low (1.17–3.81 %), as shown by retesting five patients. The patients with prodromal (MCI [11C]PIB-positive) and dementia-stage Alzheimer’s disease had significantly higher [18F]THK5317 retention than healthy controls (p = 0.002 and p = 0.001, respectively) in areas exceeding limbic regions, and their discrimination from this control group (using the area under the curve) was >98 %. Focal negative correlations between [18F]THK5317 retention and [18F]FDG uptake were observed mainly in the frontal cortex, and focal positive correlations were found between [18F]THK5317 and [11C]PIB retentions isocortically. One patient with corticobasal degeneration syndrome and one with progressive supranuclear palsy showed no [11C]PIB but high [18F]THK5317 retentions with a different regional distribution from that in Alzheimer’s disease patients.ConclusionsThe tau-specific PET tracer [18F]THK5317 images in vivo the expected regional distribution of tau pathology. This distribution contrasts with the different patterns of hypometabolism and amyloid-beta deposition.Electronic supplementary materialThe online version of this article (doi:10.1007/s00259-016-3363-z) contains supplementary material, which is available to authorized users.

Ligands targeting tau for use with positron emission tomography have rapidly been developed during the past several years, enabling the in vivo study of tau pathology in patients with Alzheimer's disease and related non-Alzheimer's disease tauopathies. Several candidate compounds have been developed, showing good in vitro characteristics with respect to their ability to bind tau deposits; off-target binding, however, has also been observed. In this short commentary, we briefly summarize the available in vivo and in vitro evidence pertaining to their off-target binding and discuss the different approaches that are needed for the future development of tau positron emission tomography tracers.

PET and CSF biomarkers of amyloid-β are considered interchangeable in defining ‘amyloid positivity’. However, Leuzy et al. report discordance between these measures in a multicentre memory clinic population. This suggests that in a minority of individuals these metrics may not be interchangeable, and may instead reflect distinct but interrelated processes.

The development of tau-specific positron emission tomography (PET) tracers allows imaging in vivo the regional load of tau pathology in Alzheimer's disease (AD) and other tauopathies. Eighteen patients with baseline investigations enroled in a 17-month follow-up study, including 16 with AD (10 had mild cognitive impairment and a positive amyloid PET scan, that is, prodromal AD, and six had AD dementia) and two with corticobasal syndrome. INTRODUCTIONThe aggregation of abnormally hyperphosphorylated tau protein into paired helical filaments is a key aspect of the pathology of Alzheimer's disease (AD). 1 Both the regional distribution of tau pathology in the brains of patients with AD and the sequential staging of its progression have been extensively described in postmortem studies. 2-5 These studies indicated, for the first time, that an early and relatively long preclinical phase of tau aggregation precedes the symptomatic stages of AD. 6,7 Despite this, the time course of tau pathology propagation, especially in relation to changes in the concomitant clinical and cognitive profiles of the individual patients, remains largely speculative because of the inherent limitations of post-mortem studies.During the past 5 years, the development of tau-specific positron emission tomography (PET) tracers 8 has provided a valuable addition to the neuroimaging arsenal. THK5317 [(S)-THK5117], a well characterised tau-specific tracer, 9-11 showed high retention in patients with AD with a regional pattern matching that of the distribution of tau pathology described by post-mortem studies. 12 Cross-sectionally, high load of tau pathology, as measured with THK5317 PET, was associated with