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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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.
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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.
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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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