Imaging tau and amyloid-β proteinopathies in Alzheimer disease and
other conditions.Most neurodegenerative conditions are associated
with pathological accumulation of one or more folded or mis- folded
aggregated proteins. Post-mortem examination of the brain was for
many years the only way to con- firm the presence of these
proteinopathies1. However, for patients affected by these
progressive neurodegen- erative conditions, it is imperative to
identify the culprit protein(s) as early as possible so that
appropriate disease- modifying therapy (if available) can be
implemented before irreversible neuronal loss occurs2,3.
Key challenges from a clinical point of view are that a single
disease phenotype can be caused by different aggregated proteins
and that a single aggregated protein can be the underlying cause of
several clinically different diseases. For example, post-mortem
studies of patients with a clinical diagnosis of Alzheimer disease
(AD) do not always find both of the two pathological hallmarks of
the disease — namely, tau intracellular neuro fibrillary tangles
(NFTs) and extracellular amyloid-β (Αβ) plaques4,5 — casting doubt
on the accuracy of the clini- cal diagnosis. Moreover, several
aggregated protein spe- cies are often present in the same
individual, and other aggregated proteins can coexist with tau and
Aβ. For
example, patients with both Lewy bodies ( α-synuclein aggregates in
neurons) and Aβ plaques might have a clinical diagnosis of AD,
dementia with Lewy bodies (DLB), Parkinson disease (PD) or PD
dementia (PDD). In this context, the introduction of in vivo
brain ima- ging of patients with neurodegenerative disorders, in
particular the advent of Aβ imaging, has revolutionized the
diagnosis and management of these diseases. These beneficial
effects are likely to be extended further by the introduction of
selective tau imaging. In the past decade, therefore, many research
and clinical applications of Aβ and tau imaging have been proposed
and implemented (BOX 1). Beyond Aβ and tau, several
proteinopathies associated with neurodegenerative conditions remain
unexplored through imaging. Currently, efforts are focused on
developing selective PET tracers for imaging of α-synuclein6 and
β-secretase 1 (REF. 7). However, these efforts are
outside the scope of this Review and are not discussed
further.
In this Review, we describe the roles of in vivo Aβ and tau
imaging in the diagnosis and differential diagnosis of
neurodegenerative diseases, highlighting the approved and currently
most used tracers. The contributions
1Department of Molecular Imaging and Therapy, Centre for PET,
Austin Health, Heidelberg, Victoria, Australia. 2Department of
Medicine, University of Melbourne, Austin Health, Heidelberg,
Victoria, Australia. 3The Florey Institute of Neuroscience and
Mental Health and University of Melbourne, Parkville, Victoria,
Australia. 4CSIRO, Health and Biosecurity Flagship, The Australian
eHealth Research Centre, Royal Brisbane and Women’s Hospital,
Herston, Queensland, Australia. 5eHealth, CSIRO Health
and Biosecurity, Melbourne, Parkville, Victoria,
Australia.
*e-mail: victorlv@ unimelb.edu.au
Imaging tau and amyloidβ proteinopathies in Alzheimer disease and
other conditions Victor L. Villemagne1,2,3*, Vincent Doré1,4,
Samantha C. Burnham5, Colin L. Masters3 and Christopher
C. Rowe1,2,3
Abstract | Most neurodegenerative disorders are associated with
aggregated protein deposits. In the case of Alzheimer disease (AD),
extracellular amyloidβ (Aβ) aggregates and intracellular tau
neurofibrillary tangles are the two neuropathological hallmarks of
the disease. AβPET imaging has already been approved for clinical
use and is being used in clinical trials of antiAβ therapies both
for patient recruitment and as an outcome measure. These studies
have shown that Aβ accumulation is a protracted process that can
extend for more than 2 decades before the onset of clinical AD.
This Review describes how in vivo brain imaging of Aβ
pathology has revolutionized the evaluation of patients with
clinical AD by providing robust and reproducible statements of
global or regional brain Aβ burden and enabling the monitoring of
disease progression. The role of selective tau imaging is
discussed, focusing on how longitudinal tau and Aβ imaging studies
might reveal the various effects (sequential and/or parallel,
independent and/or synergistic) of these proteins on
progression, cognition and other disease-specific biomarkers of
neurodegeneration. Finally, imaging studies are discussed in the
context of elucidating the respective roles of Aβ and tau in AD and
in advancing our understanding of the relationship and/or interplay
between these two proteinopathies.
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of Aβ and tau imaging to identifying at-risk patients, monitoring
disease progression, disease staging, selec- tion of appropriate
therapy and prognostication are also discussed. Finally, we discuss
the evidence of the rela- tionship between Aβ and tau
proteinopathies from an imaging perspective.
Alzheimer disease AD is the most prevalent neurodegenerative disor-
der and the leading cause of dementia in elderly indi- viduals8. AD
is clinically characterized by progressive memory loss and
cognitive impairment that severely affect patients’ activities of
daily living9,10. The clinical diagnosis of AD is usually preceded
by 3–6 years of amnestic mild cognitive impairment (MCI),
regarded as prodromal AD11–13.
Neuropathologically, AD is typically characterized by widespread
cellular degeneration and diffuse synap- tic and neuronal loss,
accompanied by reactive gliosis and the presence of NFTs and Αβ
plaques4,5. Although age is the strongest risk factor for
sporadic AD, the APΟE*e4 (apolipoprotein E ε4) allele is associated
with an early age of onset of AD and is the most consistent genetic
risk factor associated with this disease. Moreover, homozygous
APΟE*e4 carriers have a higher risk of AD than heterozygous
carriers, suggesting a gene–dosage effect14. Both age and APΟE*e4
carrier status are directly associated with Aβ burden as measured
by PET15–17. Independent of their clinical disease stage, APΟE*e4
carriers present with substantially higher Aβ deposition than
non-carriers15–17. However, although the prevalence of a high Aβ
burden was increased in APΟE*e4 carri- ers18, the rates of Aβ
accumulation did not differ between carriers and non-carriers19.
New AD diagnostic criteria, based on neuroimaging and cerebrospinal
fluid (CSF) biomarkers and not requiring clinical dementia, have
been proposed20,21. These new criteria enable the sepa- ration of
markers of pathology and neurodegeneration from clinical symptoms
that are often late features (and sometimes nonspecific, especially
at early stages) of AD. Furthermore, the use of combinations of
different mark- ers increases both diagnostic specificity and
prognostic accuracy, as is also commonly seen in other medical
fields, such as oncological disease staging.
To date, all available pathological, genetic, biochem- ical and
cellular evidence supports the view that an imbalance between the
production and removal of Αβ leads to its progressive accumulation
in the brain, which is central to the pathogenesis of AD22.
Although still con- troversial, the ‘Aβ-centric’ theory of AD9
postulates that Aβ accumulation in the brain is the precipitating
event in a cascade of effects that lead to neuronal degeneration,
synaptic loss and dementia23.
Amyloid-β imaging Clinical criteria for the appropriate use of Aβ
imaging highlight the need to integrate imaging with a compre-
hensive clinical and cognitive evaluation performed by a clinician
experienced in the evaluation of dementia to ensure that Αβ imaging
has a positive effect on the patient’s management24. These criteria
clearly stipulate the specific circumstances in which Aβ imaging
should be used, such as in patients with persistent or progressive
unexplained cognitive impairment, progressive atypical or unclear
clinical presentations of dementia or demen- tia onset at age
≤65 years24,25. They also outline the cir- cumstances in which
Aβ-PET imaging is inappropriate, such as in patients with probable
AD and a typical age of onset, to determine dementia severity, in
asympto- matic individuals or those with unconfirmed cognitive
impairment, a family history of dementia or presence of the APOE*e4
allele and for nonmedical purposes such as litigation or health
insurance24,25.
Amyloid-β-PET tracers in clinical use. Several com- pounds have
been evaluated as potential Aβ-PET probes (FIG. 1). The
characteristics of Aβ tracers have been com- prehensively reviewed
elsewhere26 and only approved agents are outlined here.
18F-Florbetapir27 (FIG. 1) was the first tracer approved for
the detection of Aβ in vivo and the first 18F-labelled tracer
approved by the FDA since 18F-fluorodeoxyglucose (FDG).
18F-Florbetapir has become the most widely used Aβ tracer. Several
multicentre phase I and phase II studies showed that
18F-florbetapir could discriminate between patients with AD and
age-matched healthy controls. Multicentre studies showed that a
high Aβ burden on 18F-florbetapir-PET was associated with poor
memory performance in clinically healthy elderly individuals28 and
that ~50% of patients with MCI had a high Aβ bur- den on
18F-florbetapir-PET29; these individuals have a substantially
increased risk of cognitive decline over the following
18 months and 36 months30,31. In phase III studies,
18F-florbetapir had a sensitivity of 92% and a specificity of 100%
for the detection of Aβ pathology and no tracer retention in young
control individuals32,33. In a semiquantitative study,
18F-florbetapir retention had >90% sensitivity and specificity
to detect Aβ pathology in the brain34. Two other Αβ tracers,
18F-florbetaben and 18F-flutemetamol (FIG. 1), have also
received FDA and European Medicines Agency approval for
clinical use. 18F-Florbetaben shows high affinity for fibrillary Aβ
in brain homogenates, selectively labelled Aβ plaques and cerebral
amyloid angiopathy in tissue sections from patients with AD35, but
does not bind to Lewy bodies
Key points
• The clinical phenotypes of patients with proteinopathies do not
always enable identification of the underlying cause of the
disorder, especially in early disease
• By contrast, biochemical and imaging biomarkers can identify,
even at presymptomatic stages, the underlying proteinopathy likely
to cause the disease
• Imaging biomarkers of pathology and neuronal injury can also help
to stage these diseases
• Amyloidβ and tau imaging studies can aid in patient selection,
assess target engagement and monitor intervention efficacy in
diseasespecific treatment trials
• Incorporation of biochemical and imaging biomarkers into new
diagnostic criteria for Alzheimer disease offers a rational and
flexible diagnostic approach that does not require the presence of
dementia
• Integration of biochemical and imaging biomarker findings with
cognitive assessment is also expected to improve the predictive
paradigm for Alzheimer disease
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or tau NFTs in post-mortem brain cortex samples from patients with
DLB or frontotemporal lobar degeneration (FTLD) at tracer
concentrations achieved during human PET studies36.
18F-Florbetaben-PET (FIG. 1) can detect Aβ pathology in a wide
spectrum of neurodegenerative conditions37. Cortical retention of
18F-florbetaben was higher in patients with AD than in age-matched
controls or patients with frontotemporal dementia38. These initial
findings were confirmed in phase II and phase III clin-
ical studies39,40. In a longitudinal study, 18F-florbetaben
retention in patients with MCI was an excellent predictor of
progression to AD41,42. In phase I and phase II studies,
Aβ burden on 18F-flutemetamol-PET43 differentiated between patients
with AD and age-matched healthy controls44,45, and when combined
with measures of brain atrophy improved the prediction of
progression to AD in individuals with MCI46. Aβ burden (as measured
by 18F-flutemetamol-PET) correlates closely with that on
immunohistochemical assessment of brain biopsy tissue47, and this
finding was confirmed in a large phase III study48.
The above Αβ PET tracers possess high affinity and high selectivity
for fibrillar Αβ in plaques and in other Αβ-containing
lesions27,36,43,49,50. On visual assessment of Αβ-PET scans,
cortical tracer retention is usually higher in patients with AD
than in cognitively unimpaired con- trol individuals, particularly
in the frontal, cingulate, pre- cuneus, striatum, parietal and
lateral temporal cortices, whereas occipital, sensorimotor and
mesial temporal cor- tices show much less tracer retention
(FIG. 2). Quantitative and visual assessments of Αβ-PET scans
taken at differ- ent stages of AD progression reveal a consistent
pattern of tracer retention that replicates the sequence of Αβ
deposi- tion found in post-mortem studies of patients with spor-
adic AD51: Αβ is initially deposited in the cingulate gyrus and
precuneus, orbitofrontal cortex and temporal lobe, followed by the
remaining prefrontal and parietal cortices. This pattern of Αβ PET
tracer retention is highly correlated with regional Αβ plaque
density in post- mortem brain or biopsy samples32,52–56 and is
consistently characterized by higher tracer retention (reflecting
higher Aβ concentra- tions) in the frontal cortex than in the hippo
campus57–59. Patterns of Αβ PET tracer retention are somewhat
differ- ent in other conditions characterized by Αβ deposition. For
example, carriers of autosomal mutations associated with familial
AD60–62 and patients with posterior cortical atrophy63,64 or
cerebral amyloid angio pathy65,66 have dif- ferent regional
patterns of tracer retention, reflecting the distribution of Αβ
deposits67,68. Longitudinal studies show that small increases in Αβ
depo sition can be measured using PET, but these increases in Αβ
deposition are pres- ent in those with high and low burdens of Αβ69
and across the whole clinical spectrum from cognitively unimpaired
individuals to patients with AD19,69–77. Αβ accumulation is
observed even in individuals considered to have ‘nor- mal’ Αβ
loads, and in ~7% of such individuals, the Αβ burden increases to
above the threshold of abnormality
within ~2.5 years78.
Differences in the pharmacological and pharma- cokinetic properties
of Aβ tracers impede the compar- ison of results from multicentre
clinical trials, such as IDEAS79 and those conducted by the AMYPAD
group
obtained using different Aβ tracers. Accordingly, all 18F-labelled
Aβ tracers are being cross-calibrated against 11C-Pittsburgh
compound B (PiB) to produce a single common quantitative output
value, called the Centiloid, applicable to all 18F-labelled Aβ
tracers and across all imaging analysis approaches80. 18F-NAV4694
(FIG. 1) and 18F-florbetaben were the first tracers to be
validated using the Centiloid approach81,82.
Differential diagnosis. Aβ imaging can facilitate differ- ential
diagnosis in patients with atypical presentations of dementia63,83.
Patterns of Aβ deposition resembling those in AD are usually
observed in patients with DLB68,84. However, cortical Aβ deposition
— especially cortical Aβ deposition preferentially in posterior
areas of the brain — is a pattern that is not observed in patients
with sporadic AD66 but is prominent in those with cerebral amyloid
angiopathy66. Cortical Aβ deposition is not usually present in
cognitively intact patients with PD85, although vascular and
parenchymal Aβ deposits are frequent in patients with
PDD84,86,87.
FTLD can also be difficult to distinguish clinically from
early-onset AD, especially in the initial stages of the disease88.
However, Aβ deposition is not a pathologi- cal feature of FTLD89,
and these patients (and those with sporadic Creutzfeldt–Jakob
disease) usually have no cor- tical 11C-PiB retention53,68,89–91.
Aβ imaging can, therefore, assist in the differential diagnosis of
FTLD and AD68,89–91. Despite the similar specificities of FDG-PET
and 11C-PiB- PET in the diagnosis of FTLD, Aβ imaging has proved to
be more sensitive than FDG imaging in this setting92. Aβ imaging
also has been used to ascertain the absence of AD pathology in
patients with primary progressive apha- sias (PPAs)90,93,94. TAR
DNA-binding protein 43 (TDP43) pathology is found in 90% of
patients with semantic vari- ant PPA, whereas ~70% of patients
with the progressive
Box 1 | Applications of amyloid-β and tau imaging
• Accurate and early detection of Alzheimer disease pathology:
Early initiation of diseasespecific interventions Differentiation
of neurodegeneration from healthy ageing
• Disease staging and prognostication
• Assessment of spatial and temporal changes in amyloidβ and tau
deposition and their relation to the following factors: Age Disease
progression Genotype Cognitive performance Each other Other disease
biomarkers
• Use in diseasespecific treatment trials: In patient selection
criteria, including floor (and ceiling) target values
Provide proof of target engagement Establish risk of disease
progression Monitor treatment effectiveness Outcome measures
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http://amypad.eu
non-fluent variant PPA present with predominantly tau
pathology95,96. By contrast, the logopenic variant of PPA is
thought to be a language presentation of AD, as these individuals
have Aβ and NFT pathology typical of AD93,94.
In PET studies, ~25–35% of elderly individuals with normal
performance on cognitive tests have high levels of cortical 11C-PiB
retention, predominantly in the posterior cingulate, precuneus and
prefrontal regions17,97–99. These findings are in perfect agreement
with post-mortem reports showing that ~25% of non-demented
individu- als aged ≥75 years have Aβ plaques100–102, probably
rep- resenting preclinical AD103. Furthermore, the prevalence of
high 11C-PiB retention has increased each decade at the same rate
as the increase in prevalence of plaques in non-demented
individuals in post-mortem studies17. The detection of Aβ pathology
in asymptomatic individuals before the development of AD is of
crucial importance because it is precisely this group who could
benefit the most from therapies aimed at reducing or eliminating Αβ
from the brain before irreversible synaptic or neuronal loss
occurs. On this basis, some secondary prevention
trials of Aβ-targeted therapies in otherwise cognitively unimpaired
people have already started2,3.
People with MCI comprise a heterogeneous group with a wide spectrum
of underlying pathologies11,13. In ~40–60% of patients with
carefully characterized MCI, the criteria for AD are usually met
within the subsequent 3–4 years11. Αβ imaging is useful for
discriminating between individuals with MCI who do and do not have
AD pathology. Approximately 50–70% of individuals with MCI have
high levels of cortical 11C-PiB retention104,105, and this group is
now classed as having either MCI due to AD106 or prodromal AD107.
The lack of a strong correlation between Aβ deposition and measures
of cognition, synap- tic activity and neurodegeneration in patients
with AD, in addition to the evidence of Αβ deposition in a high
per- centage of patients with MCI and asymptomatic healthy
controls, collectively suggest that Αβ deposition is an early and
necessary (although by itself, not sufficient) cause of cognitive
decline in AD98,108,109. However, other down- stream mechanisms,
probably triggered by Αβ (such as NFT formation, synaptic failure
and eventually neuronal loss) are also involved.
Figure 1 | Chemical structures of the most widely used Aβ tracers
and tau tracers. Among the amyloidβ (Aβ) tracers, 18Fflorbetapir,
18Fflutemetamol and 18Fflorbetaben have already been approved for
clinical use by both the FDA and European Medicines Agency. The
firstgeneration tau tracers were plagued by problems that limit
their utility: 18FTHK5351 was shown to bind predominantly to amine
oxidase [flavincontaining] B (also known as monoamine
oxidase B (MAO-B)), 18Fflortaucipir shows ‘offtarget’ binding
to the choroid plexus, midbrain and basal ganglia and 11CPBB3 shows
a limited dynamic range as well as offtarget binding to the
longitudinal sinus and basal ganglia. The second-generation
tau tracers seem to be much less afflicted by these issues, and
some of the new tracers, such as 18FMK6240, show no offtarget
binding. PiB, Pittsburgh compound B.
Nature Reviews | Microbiology
11C-PiB H N
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Correlation with markers of neuronal injury. The association
between fluid and imaging biomarkers of Aβ deposition or
neurodegeneration and brain Aβ bur- den, as measured by PET, has
been comprehensively assessed110–113. A high PET Aβ burden is
associated with regional cerebral atrophy on MRI114–117 and
correlates with the incidence of cerebral atrophy116,118. Moreover,
the relationship between Aβ deposition and cortical atrophy seems
to be sequential: Aβ deposition precedes synaptic dysfunction and
neuronal loss115,119,120, which become manifest as structural
changes116. Several reports have shown that healthy individuals
with a high Aβ bur- den show a substantially increased rate of
atrophy in the temporal and posterior cingulate cortices compared
with those having a low Aβ burden121–124.
Several studies have reported a strong inverse corre- lation
between the severity of Aβ deposition in the brain as assessed by
PET and Aβ1–42 levels in CSF125–133, but no such association was
observed between brain 11C-PiB retention and CSF levels of total
tau or phosphorylated tau134,135. High brain retention of 11C-PiB
and low CSF levels of Aβ1–42 have both been observed in cognitively
unimpaired individuals, in whom these findings prob- ably reflect
the fact that Aβ deposition begins years before manifestation of
the AD phenotype68,97,125,127,130,136. Some PET studies have found
no association between FDG uptake and 11C-PiB retention in the
brains of patients with AD137, whereas others found that these
measures are inversely correlated in temporal and parietal
cortices138. No correlation has been shown between Aβ deposition
and glucose hypometabolism in the frontal lobe67,139.
Both biochemical and imaging biomarkers have been proposed to be
included in new diagnostic criteria for AD20,21,140, MCI106 and
preclinical AD141. For example, the US National Institute on
Ageing–Alzheimer Association (NIA-AA) criteria for preclinical
AD141 classify individu- als into one of three stages on the basis
of two categories of neurodegeneration markers: those specific for
Aβ and those reflecting neuronal injury (namely, elevated total tau
levels in CSF, AD-like glucose hypometabolism on FDG-PET and/or
brain atrophy as measured by struc- tural MRI). Stage 1 is
characterized by isolated brain amyloidosis, stage 2 by amyloidosis
plus neurodegener- ation and stage 3 by amyloidosis and
neurodegeneration accompanied by subtle cognitive deficits141.
About 70% of healthy elderly individuals did not fit into any of
these three categories142. Accordingly, two additional categories
were proposed142: Stage 0 represents the 43% of healthy elderly
individuals without evidence of either amyloidosis or
neurodegeneration, whereas another 23% were classed as having
‘suspected non-AD pathophysiology’ (SNAP) — defined as the presence
of AD-like neurodegeneration without amyloidosis142. The
overwhelming majority of studies have shown that, unlike patients
with amyloidosis or those on the AD pathway, people classified as
having SNAP did not show declines in brain volume or cognitive
performance over time and had clinical trajectories indis-
tinguishable from those of elderly people without evidence of
amyloidosis or neurodegeneration, suggesting that the SNAP group
had a different (non-AD) pathophysiological mechanism underlying
their neurodegeneration143–146.
Selective tau imaging Tau imaging is the newest addition to the
arsenal of tools for the non-invasive assessment of neuro-
degenerative proteinopathies. The characteristics of tau
pathophysiology are highly idiosyncratic: tau has an intracellular
location, and its six different isoforms can be combined in several
ways and are subject to mul- tiple post- translational
modifications, which in turn lead to heterogeneous ultrastructural
conformations
Figure 2 | Aβ-PET scans obtained using different tracers. Surface
projection images from five patients with Alzheimer disease (AD),
obtained with different amyloidβ (Aβ)PET radiotracers:
11CPittsburgh compound B (PiB), 18Fflorbetapir, 18Fflorbetaben,
18Fflutemetamol and 18FNAV4694. Images show typical patterns of
tracer retention associated with AD, with the highest retention
in the frontal, temporal and posterior cingulate cortices
reflecting the location of Aβ deposits in the brain. Three
of these AβPET tracers, florbetapir, flutemetamol and
florbetaben, are approved for clinical use by the FDA
and European Medicines Agency. Images generated through
CapAIBL (https://capaiblmilxcloud.csiro.au) Commonwealth Scientific
and Industrial Research Organisation (CSIRO) Biomedical Imaging
Group. SUVR, standardized uptake value ratio.
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of the aggregates. Moreover, although the majority of patients with
AD have both high Aβ levels and high tau levels147–149, tau is
present in much lower concentrations than Aβ in colocalizing tau
and Aβ deposits in patients with AD (reviewed in depth
elsewhere150). Nonetheless, the past few years have seen a
tremendous amount of progress, with several of the first-generation
tau- selective PET tracers (namely, 18F-flortaucipir, 18F-THK5351,
18F-THK5317 and 11C-PBB3) being extensively applied in research
studies and novel second-generation tau tracers (namely,
18F-RO69558948, 18F-MK6240, 18F-PI2620 and 18F-PM-PBB3) being
developed and undergoing proof-of-concept studies151–158.
FIG. 3 shows PET scans obtained with some of these tau tracers
(18F-flortaucipir, 18F-THK5351 and 18F-MK6240).
Value of tau imaging. Tau imaging studies show not only that tau
tracer retention reflects the known distribution of aggregated tau
in the brain seen in post- mortem studies51,159 but also that tau
deposition is closely related to other markers of neuronal injury,
such as FDG reten- tion or cortical grey matter
atrophy160–162.Given the close relationship between tau deposition,
impaired cogni- tion and neuronal injury, the ability of tau
imaging to assess the density, extension and regional distribution
of tau deposits in the brain could be useful to predict progression
of AD and/or for disease staging. In con- trast to Aβ imaging
studies, which found that the total amount of Aβ deposition in the
brain is more relevant than the regional Aβ distribution as an
early driver of cognitive decline, post-mortem studies and early
tau
imaging data indicate that the topographical distri- bution of tau
deposits in the brain163,164 might be more important than total tau
levels. Tau imaging might also be more tightly associated than Aβ
imaging with neuro- degeneration and cognitive decline: increasing
levels of cortical tau deposition in individuals with Aβ pathology
were associated with increasing impairment in several
cognitive domains149,165,166.
Most of the research and clinical applications of tau imaging are
identical to those of Aβ imaging (BOX 1). However, some
potential neuroimaging applications, including disease staging,
tracking progression and use as a surrogate marker of cognitive
status, are more amenable to tau imaging than to Aβ imaging.
Several groups that are using tau imaging to evaluate patients with
AD and non-AD tauopathies147,149,167 have found robust differ-
ences in tracer retention between cognitively unimpaired elderly
individuals, patients with AD147,149,154,168–170 (FIG. 3) and
patients with atypical AD presentations. Importantly, the clinical
phenotype of patients with atypical AD closely matched their tau
burden as assessed with 18F-flortaucipir regional retention, but
not their Aβ burden as assessed by 11C-PiB retention148,171,172.
Furthermore, 18F-flortaucipir retention, especially in the temporal
lobe, also correlated with CSF tau levels166,173.
Interestingly, most studies show that high tau levels in mesial and
temporal regions are not necessarily found alongside high Aβ
levels; however, high tau levels in neo- cortical regions are
associated with high Aβ levels, sug- gesting that (detectable)
cortical Aβ deposition precedes (detectable) cortical tau
deposition.
Nature Reviews | Neurology
HC AD HC AD HC AD
18F-AV1451 18F-THK5351 18F-MK6240 3.0 4.0 3.5
Figure 3 | Tau imaging. Representative sagittal (top row),
transaxial (centre row) and coronal (bottom row) PET images
obtained from healthy elderly control individuals (HC) and patients
with Alzheimer disease (AD) with different tau radiotracers:
18Fflortaucipir (left), 18FTHK5351 (centre) and 18FMK6240 (right).
The patients with AD show marked tracer retention in mesial
temporal, temporoparietal and posterior cingulate cortical regions,
sometimes extending to the frontal cortex. AD patients undergoing
18FTHK5351PET show marked tracer retention in the striatum, even
higher than in cortical regions. Although cortical tracer retention
is absent in all HCs, individuals who underwent 18FTHK5351PET and
18F-flortaucipir-PET show differing degrees of ‘off-target’ tracer
retention in the striatum. Off-target striatal retention is not
present in 18FMK6240PET scans.
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Moreover, the association between tau levels and age strengthens in
the presence of Aβ deposition149. In the early 1970s, post-mortem
studies174 revealed the presence of tau deposits in the mesial
temporal cortex in elderly individuals both with and without
dementia. Similar findings were reported in subsequent
studies103,164 and interpreted as meaning that hippocampal
tauopathy in humans is age-related but not age-dependent, and inde-
pendent of AD but amplified by Aβ pathology159. Amidst some
controversy, the hippocampal tauopathy noted in this almost
50-year-old observation has been rebranded as primary age-related
tauopathy (PART)175–178. This age-related accumulation of tau in
the mesial temporal cortex might drive mild (and Aβ-independent)
memory deficits and hippocampal atrophy178–180. However, high tau
levels in the mesial temporal cortex and high dif- fuse cortical Aβ
levels can both be present in cognitively unimpaired elderly
individuals, suggesting that these two features are not sufficient
to cause substantial cognitive impairment. Instead, such impairment
only becomes manifest once tau deposits spread to cortical
polymodal and unimodal association areas of the brain181. Selective
tau imaging, in combination with Aβ imaging, will help to elucidate
whether Aβ accelerates and/or triggers the spread of tau deposits
outside the mesial temporal cor- tex and to clarify whether this
initial dissemination into cortical association areas manifests as
the insidious and incipient development of MCI103,159. Post-mortem
data suggest that further spreading of tauopathy into the remaining
cortical areas is usually observed in individu- als with severe
cognitive deterioration and dementia103,159. This neuropathological
sequence of events will need to be verified in vivo and is a
crucial issue to be addressed in combined Aβ and tau imaging
studies.
The majority of tau imaging studies have focused on the assessment
of patients with AD, but tau imaging is potentially useful in the
assessment of other Aβ-related neurodegenerative conditions (such
as DLB182) and non-AD tauopathies, such as progressive supranuclear
palsy (PSP) and corticobasal syndrome (CBS), disorders that might
initially present as either aphasia or parkin- sonism. The tracers
used in these imaging studies showed little or no binding to 4R
aggregated tau in vitro, although at a group level the
regional distribution of tau deposits is pathognomonic for these
conditions and can aid in their differential diagnosis183,184. As
we mentioned previously, Aβ deposition is not a pathological
feature of FTLD89. The spectrum of FTLD includes distinct disease
subtypes dis- tinguished by the proteins responsible for forming
intran- euronal inclusions: ubiquitylated, hyperphos phory lated
and proteolysed TDP43 causes FTLD-TDP43; hyper- phosphorylated tau
causes FTLD-tau; and fused in sar- coma (FUS) is mainly associated
with the behavioural variant of FTLD185–188. FTLD-TDP43 accounts
for ~60% of all patients with FTLD and the remainder mainly have
FTLD-tau. Only a few patients with FTLD have
FUS pathology96.
Limitations of tau imaging. About 15–20% of patients with high Aβ
levels in the brain and diagnosed as having probable AD will have
subthreshold cortical tau tracer
retention. One possible interpretation of this observa- tion is
overdiagnosis; high Aβ levels in the brain and an amnestic
presentation certainly indicate that these patients are on the AD
pathway, but the patient might not have dementia, a stage usually
associated with wide- spread cortical tau deposits. Alternatively,
the presence of high Aβ levels in the brain despite apparently low
cortical tau levels could reflect one or more of the fol- lowing
mechanisms (and their potential interactions): the limitations of
the currently available tau tracers with regard to binding
affinity, isoform selectivity, tracer kinetics and/or metabolism,
and so on; differences in the conformation of tau aggregates that
might affect tracer binding, as has also been shown with Aβ
tracers; low concentrations of tau binding sites, especially during
the early stages of cortical tau deposition; tau concen- trations
below the threshold of detectability of current PET scanners (this
threshold depends on the regional density of binding sites; thus, a
low binding site den- sity compounded with partial volume effects
in small or atrophic brain areas might not yield accurate
statements of levels of tau deposition in the brain); or an
artefact derived from the thresholds used to define high and low
tau levels (although this postulate does not account for the
individuals who have almost no detectable tau tracer retention).
Longitudinal studies of the cognitive trajectories of these
patients are required to elucidate the implications of these
phenomena.
A particular issue is the low hippocampal signal observed with some
tau tracers, which is compounded by inconsistent and erratic tracer
binding to the choroid plexus, which lies just above the
hippocampus. Some researchers have asserted that these tracers do
indeed bind to aggregated tau in the choroid plexus189, despite the
lack of corroborative evidence from in vitro autoradio-
graphic studies, which have consistently failed to show tracer
binding in the striatum or choroid plexus190,191. Others have
proposed that these tracers bind to other β-sheet aggregated
proteins, such as trans thyretin, pig- ments such as lipofuscin,
minerals such as iron or the fil- aments constituting Biondi
bodies192–194. The low level of tracer signal observed in the
hippocampus relative to that in the entorhinal cortex might
actually reflect differences in the concentration of paired helical
filament (PHF)- tau in these two regions: the reported
concentration of PHF-tau in the entorhinal cortex is almost double
that observed in the hippocampus195.
Currently available tau tracers have not yet been vali dated
against pathology196 for clinical use, and some reports have
highlighted discrepancies between the preclinical (in vitro)
and clinical (in vivo) binding profiles of tau PET tracers
such as 18F-flortaucipir191,194, as well as some discrepancies
between ante-mortem and post-mortem findings190,197. Notably, these
incon- sistencies do not apply to the 3R or 4R PHF-tau found in AD
but mainly relate to the straight 4R tau filaments found in PSP and
CBS. When PET scans from groups of patients with PSP are compared
with scans from groups of age-matched healthy controls, a distinct
pat- tern of tau tracer retention in the pallidus, midbrain and
dentate nuclei of the cerebellum is evident in the
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PSP group183,184,198. However, post-mortem findings in some of
these patients failed to show any tracer bind- ing to these
structures, despite the typical tau lesions being present190,197.
This apparent discrepancy might be explained by the low binding
affinity of 18F-flortaucipir for 4R tau; thus, in vivo tracer
binding might be strong enough to yield a PET signal but not able
to endure the series of washes required for in vitro
autoradiographic studies. Most first-generation and
second-generation tau tracers do not bind to 3R tau in vitro.
By contrast, in vitro studies show that PI2620, the latest
addition to the expanding spectrum of tau tracers158, binds not
only to PHF-tau and 4R tau but also to 3R tau. Proof- of-concept
studies are underway to ascertain whether PI2620 also binds to 3R
tau in vivo.
Much more problematic are the serious doubts cast over the tau
selectivity of some of these PET tracers. Thus, discrepancies in
tau imaging findings that have been widely interpreted as
‘off-target’ binding might actually result from tracer binding to
an alternative tar- get. For example, after a single 5 mg oral dose
of selegiline — a selective and irreversible inhibitor of amine
oxidase [ flavin-containing] B (also known as monoamine oxi-
dase type B (MAO-B)) — signal reductions of ~35% and ~50% in
the cortical and basal ganglia, respectively, are seen on
18F-THK5351 imaging. These observations sug- gest that a
substantial percentage of the ‘tau’ signal of 18F- THK5351 is due
to MAO-B binding199. If this initial report is confirmed, this
tracer would be unsuitable for selective tau imaging studies.
Fortunately, initial human studies of some second-generation
tracers, such as 18F-RO69558948, have shown reduced off-target
binding155, and two tracers (18F-MK6240 (FIG. 3) and
18F-PI2620) have shown no off-target binding thus far153,158.
Usefulness of proteinopathy biomarkers The neurodegenerative
process associated with pro- teinopathies usually begins decades
before symptoms manifest, impeding their early identification. In
turn, delayed diagnosis precludes starting disease-modifying
medications (if available) during the presymptomatic period, when
they are most likely to achieve a maxi- mal benefit in terms of
preventing neuronal loss200. As a consequence of this unmet need
for accurate and early diagnosis, the diagnostic paradigm is moving
away from the identification of signs and symptoms of neuronal
failure (which represents evidence that cen- tral compensatory
mechanisms have been exhausted and that extensive synaptic and
neuronal damage is already present) and towards the non-invasive
detec- tion of biomarkers140,201,202. Useful biomarkers are those
that identify an increased risk of developing a disease (antecedent
biomarkers), confirm the presence of dis- ease (diagnostic
biomarkers), assess disease evolution (progression biomarkers),
predict future disease course (prognostic biomarkers) and evaluate
or customize therapy ( theranostic biomarkers).
CSF levels of Aβ and tau, structural imaging (MRI and CT) and
molecular imaging (FDG-PET and Aβ-PET) all have the potential to
provide good diag- nostic and prognostic biomarkers for AD,
especially
when used in combination203. The data available to date suggest
that CSF Aβ levels and Aβ-PET provide good antecedent biomarkers in
the preclinical and pro- dromal stages of AD70,204,205. Conversely,
CSF levels of total tau and phosphorylated tau, MRI brain
structural changes and FDG-PET provide excellent biomarkers of
disease progression204. Although Aβ burden does not correlate with
markers of neurodegeneration, disease severity or cognitive
impairment in established AD dementia206,207, Aβ burden is
associated with such mark- ers in the preclinical and prodromal
phases of AD50,104,200. A combination of CSF markers (namely,
levels of Aβ1–42, total tau and phosphorylated tau) has been found
to be highly predictive of disease progression208. Evidence of
glucose hypometabolism on FDG-PET and a long list of MRI measures
of global or regional brain atrophy, as well as white matter
hyperintensities, have also been proposed as predictors of
conversion to AD204,209,210. Aβ burden as assessed by PET is an
excellent predic- tive biomarker208,211: the likelihood of
developing AD is extremely small for a cognitively unimpaired
individual with a low Aβ burden70, whereas the positive predictive
value of a high Aβ burden is >80% in patients with MCI or
prodromal AD211.
Given the complexity (and sometimes overlapping characteristics) of
these proteinopathies, and despite advances in their molecular
characterization, any single biomarker is unlikely to be able to
provide the diagnos- tic certainty required for early detection of
neurodegen- erative diseases such as AD, and especially not for the
identification of at-risk individuals before the develop- ment of
clinical symptoms. Therefore, the identification of these patients
demands a multimodal approach that combines biochemical and
neuroimaging markers of pathology and neurodegeneration212. Such
biomarkers have already been incorporated into new diagnostic cri-
teria for the prodromal, preclinical and overt stages of
AD20,21,106,141,213,214. Moreover, in AD-specific treatment
trials215, the use of Aβ and/or tau biomarkers for patient
selection, to confirm target engagement, and as a sur- rogate
outcome measure of treatment efficacy75,216 has enabled the
implementation of shorter-duration trials with smaller sample sizes
than was previously possible. In these trials, structural
biomarkers are also used to detect adverse effects associated with
Aβ removal from the brain, such as amyloid-related imaging
abnormalities (ARIAs)217. At the same time, however, the incorpora-
tion of biomarkers into treatment trials requires their validation,
standardization of their use across sites and the translation of
associated knowledge and technol- ogy from basic research into
clinical settings. All these factors increase the cost of
therapeutic trials218.
Conclusions Clinical diagnosis of sporadic neurodegenerative con-
ditions is challenging, especially in early disease stages when
patients often present with mild and nonspecific symptoms that
could be attributable to any of several diverse and overlapping
proteinopathies. Overall, the accuracy of clinical diagnosis of AD
is ~70–90%, compared with the gold-standard, post-mortem
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neuropathological examination196. Current diagnostic criteria for
AD based on clinical symptoms and struc- tural neuroimaging studies
are sensitive and specific enough to diagnose AD only at middle to
late stages of the disease, as they focus on nonspecific findings
(such as impaired memory, functional decline and brain atrophy)
that develop fairly late in the disease process. By contrast, the
new NIA-AA diagnostic criteria for AD20,21,140, MCI106 and
preclinical AD141 have adopted a more flexible model that does not
require the presence of dementia and instead relies on measurement
of bio- chemical and imaging biomarkers integrated with cog- nitive
assessment. Revised criteria are currently being prepared that will
propose that biomarkers for the assess- ment of elderly individuals
should not only ascertain the presence or absence of Aβ and/or
neurodegeneration but also incorporate tau status (based on tau
imaging findings or CSF levels of phosphorylated tau)214. As the
diagnostic criteria for AD continue to evolve, imaging of Aβ and
tau aggregates is likely to play an increasingly central part as
these techniques become more affordable and available for use in
clinical practice26.
The advent of tau imaging is also expected to improve the accuracy
of disease staging and to deter- mine whether Aβ and/or tau have
independent and/or synergistic effects on cognition, whether such
effects are sequential or parallel and whether (and if so at what
stage of the disease) Aβ and/or tau either become or stop being the
driver of cognitive decline. This know- ledge will have a crucial
role in planning anti-Aβ and/or anti-tau therapeutic trials by
enabling the determina- tion of a personalized optimal window for
therapeutic intervention. On the basis of data accrued from Aβ and
(preliminary) tau imaging studies, a growing consensus is evident
that, to be effective, not only does disease- specific therapy need
to be given early in the course of the disease215, even before
symptoms appear3, but also that downstream mechanisms need to be
addressed to
successfully prevent the development of irreversible syn- aptic and
neuronal damage. However, as has been shown for cancer and AIDS, no
single disease-modifying agent is likely to be effective in
arresting or delaying cogni- tive decline. Therefore, a successful
therapeutic strategy for AD might require combinations of
disease-specific anti-tau (anti-aggregant agents, antibodies and
micro- tubule stabilizers) and anti-Aβ approaches ( β-secretase
inhibitors, antibodies, small-molecule agents and clear-
ance-promoting strategies) with nonspecific agents
(anti-inflammatory drugs and cholinesterases) and lifestyle
interventions (including those focusing on diet, exercise and
sleep) while simultaneously addressing the comorbidities associated
with ageing. Treatment-related adverse effects, such as ARIAs217,
which are inevitably associated with removal of aggregated Aβ from
the brain, will also need to be taken into consideration. Dosages
might need to be adjusted to maximize treatment effectiveness while
minimizing these adverse effects.
In vivo Aβ and tau imaging will also facilitate research into
the pathophysiology of neurodegenerative condi- tions linked to
these aggregated proteins. Longitudinal Aβ and tau imaging studies
can detect changes in the deposition of Aβ and tau over time51 and
will probably be used for both predicting cognitive decline and
moni- toring disease progression. Ultimately, changes in Aβ or tau
burden might yield more stable, reliable and accu- rate statements
about disease progression or therapeutic response than changes in
cognitive measures. Imaging studies could also clarify the complex
interplay between Aβ and tau accumulation and normal ageing: Aβ and
tau imaging will be essential for elucidating the under- lying
pathology in cognitively unimpaired individuals who present with
markers of neurodegeneration in the absence of Aβ deposition142. To
this end, a shift in research focus from why people with AD have
plaques and tangles to why not all people with this pathology have
AD219 would indeed be welcomed.
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