Elsevier

The Lancet Neurology

Volume 10, Issue 7, July 2011, Pages 667-670
The Lancet Neurology

Rapid Review
Clinical amyloid imaging in Alzheimer's disease

https://doi.org/10.1016/S1474-4422(11)70123-5Get rights and content

Summary

Background

The hypothesis that amyloid deposition is the leading cause of Alzheimer's disease (AD) is supported by findings in transgenic animal models and forms the basis of clinical trials of anti-amyloid agents. According to this theory, amyloid deposition causes severe damage to neurons many years before onset of dementia via a cascade of several downstream effects. This hypothesis has, however, not yet been directly tested in human beings because of the very limited possibility of diagnosing amyloid deposition in vivo, which until recently required either brain biopsy or PET imaging with an on-site cyclotron and radiochemistry laboratory. Moreover, a clinical diagnosis of AD requires that patients have dementia, at which stage any effective treatment aimed at reducing amyloid deposition will probably be too late.

Recent developments

The amyloid imaging tracers flutemetamol, florbetapir, and florbetaben labelled with 18F have been developed for PET; they can be produced commercially at central cyclotron sites and subsequently delivered to clinical PET scanning facilities. These tracers are currently undergoing formal clinical trials to establish whether they can be used to accurately image fibrillary amyloid and to distinguish patients with AD from normal controls and those with other diseases that cause dementia. They might also be used as biomarkers to predict development of AD before onset of dementia and to assess the effect of anti-amyloid therapy. Negative amyloid scans indicate absence of AD with a high level of accuracy, but healthy elderly volunteers might have positive amyloid scans, so their predictive value in isolation is less clear. Close association of in-vivo amyloid imaging results with post-mortem histopathological findings was shown with florbetapir in a phase 3 study.

Where next?

Therapeutic studies of anti-amyloid agents that include amyloid tracers as biomarkers are expected to be useful for drug development and to clarify the relation between amyloid removal and clinical effects. Once the 18F tracers become available for diagnostic use, large-scale longitudinal studies will be needed to clarify their prognostic and diagnostic power in relation to age, risk factors, and AD subtypes. Ultimately, these tracers will hopefully clarify the pathophysiological role of amyloid in AD and contribute to development of new treatments.

Introduction

In the next few decades, extraordinary efforts will be spent on the prevention and treatment of dementia, because this illness will affect about 63 million people by 2030, and 114 million by 2050 worldwide.1 One treatment strategy will probably involve anti-amyloid agents: appropriate animal models exist that could lead to the generation of effective compounds. For such agents to be effective, they would need to be given early in the disease course before degeneration has become too advanced. Although early clinical phenotypes, such as mild cognitive impairment (MCI),2 have been explored, only some patients actually progress to dementia; therefore, additional markers of prognosis and underlying pathology are needed to identify patients early in the disease course.3 Furthermore, in clinical trials, response to anti-amyloid agents will probably be very slow and clinical outcome might also be subject to factors unrelated to amyloid deposition, making trials involving patients with MCI extremely time consuming and costly; therefore, early, direct in-vivo measurements of the treatment target might be desirable so that further clinical testing of anti-amyloid drugs that do not affect their target mechanism could be halted. Among possible markers of early Alzheimer's disease (AD), the Pittsburgh compound B (PiB) seems to be a sensitive and specific marker of amyloid-β deposition.4 This ability to image amyloid-β deposition has stimulated the development of several other potential amyloid-β ligands in the hope of advancing early diagnosis and treatment of AD. In this Rapid Review, we discuss the current state of research into PET amyloid imaging tracers.

Section snippets

Pittsburgh compound B

Most amyloid imaging in human beings is currently done in research studies with the 11C-labelled PET tracer PiB.5 However, the very short physical half-life (20 min) of 11C requires that a cyclotron be available on-site for production of the isotope, which prevents widespread clinical use. PiB binds to insoluble fibrillary amyloid β with high affinity, but not to amorphous amyloid plaques and neurofibrillary tangles. Non-specific (ie, non-displaceable) binding is seen mainly in white matter.

18F-labelled tracers

Three 18F-labelled tracers are being investigated in clinical trials; they have been developed as proprietary tracers for commercial distribution, which is possible because of the 110 min physical half-life of 18F. Flutemetamol (GE-067) is the 3′-fluoro-derivative of PiB, whereas florbetaben (BAY-94-9172, AV-1) and florbetapir (AV-45) are stilbene and styrylpyridine derivatives, which exhibit high-affinity binding for fibrillary amyloid similar to PiB (table);20, 21, 22, 23, 24, 25, 26 they

Conclusions and future directions

The data discussed here suggest that all three 18F-labelled amyloid ligands undergoing clinical trials could be used to detect fibrillary amyloid in patients with AD with high sensitivity. Lipophilic plasma metabolites, which have been reported for two tracers, could increase non-specific background activity and thus reduce the contrast between normal cortex and amyloid. Higher non-specific uptake in white matter does not seem to interfere substantially with visual image interpretation, because

Search strategy and selection criteria

A PubMed search of reports, published before April, 2011, for this Rapid Review was done using the key words “positron” and “amyloid”, and specific searches were also done for the tracer names “flutemetamol”, “florbetapir”, “florbetaben”, “AV-45”, “AV-1”, “GE-067”, “BAY-94-9172”, and “FDDNP”. All clinically relevant papers relating to compounds currently in formal clinical trials were included, and other citations were selected only if essential for this Rapid Review. Only articles

References (47)

  • MS Albert et al.

    The diagnosis of mild cognitive impairment due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease

    Alzheimers Dement

    (2011)
  • D Neary et al.

    Frontotemporal dementia

    Lancet Neurol

    (2005)
  • A Wimo et al.

    The magnitude of dementia occurrence in the world

    Alzheimer Dis Assoc Disord

    (2003)
  • E Arnaiz et al.

    Mild cognitive impairment: a cross-national comparison

    J Neurol Neurosurg Psychiatry

    (2004)
  • JA Lonie et al.

    Predicting outcome in mild cognitive impairment: 4-year follow-up study

    Br J Psychiatry

    (2010)
  • H Quigley et al.

    PET imaging of brain amyloid in dementia: a review

    Int J Geriatr Psychiatry

    (2010)
  • WE Klunk et al.

    Imaging brain amyloid in Alzheimer's disease with Pittsburgh Compound-B

    Ann Neurol

    (2004)
  • GD Rabinovici et al.

    Amyloid imaging in aging and dementia: testing the amyloid hypothesis in vivo

    Behav Neurol

    (2009)
  • JC Morris et al.

    Pittsburgh Compound B imaging and prediction of progression from cognitive normality to symptomatic Alzheimer disease

    Arch Neurol

    (2009)
  • EM Reiman et al.

    Fibrillar amyloid-beta burden in cognitively normal people at 3 levels of genetic risk for Alzheimer's disease

    Proc Natl Acad Sci USA

    (2009)
  • J Koivunen et al.

    PET amyloid ligand C-11-PIB uptake and cerebrospinal fluid beta-amyloid in mild cognitive impairment

    Dement Geriatr Cogn Disord

    (2008)
  • N Tolboom et al.

    Relationship of cerebrospinal fluid markers to 11C-PiB and 18F-FDDNP binding

    J Nucl Med

    (2009)
  • AM Fagan et al.

    Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans

    Ann Neurol

    (2006)
  • Cited by (186)

    • Alzheimer's disease amyloid-β pathology in the lens of the eye

      2022, Experimental Eye Research
      Citation Excerpt :

      Various techniques have been developed to measure Aβ brain pathology and functional sequelae, including positron emission tomography (Shoghi-Jadid et al., 2002; Klunk et al., 2004; Nordberg, 2004; Mintun et al., 2006; Small et al., 2006; Rowe et al., 2007; Michael et al., 2017; Canu et al., 2018; Fantoni et al., 2018; Camarda et al., 2020), single photon-emission computed tomography (Kung et al., 2004; Wang et al., 2004; Alagille et al., 2011; Okumura et al., 2018), multiphoton imaging (Bacskai et al., 2001, 2003; Kwan et al., 2009) and magnetic resonance imaging (Benveniste et al., 1999; Poduslo et al., 2002; Sperling, 2007, 2011; Chhatwal and Sperling, 2012). Several of these techniques utilize systemically-administered radioactive tracers to detect Aβ in the brain (Herholz and Ebmeier, 2011; Johnson et al., 2013). Parallel research has targeted development of fluid bioassays to measure Aβ in cerebrospinal fluid and blood (Frank et al., 2003; Shaw et al., 2007; Janelidze et al., 2018; Ashton et al., 2020; Bernath et al., 2020; Fyfe, 2020; Soldan et al., 2020).

    • Thirty years post-injury: Impact of traumatic brain injury on later Alzheimer’s disease

      2022, Diagnosis and Treatment of Traumatic Brain Injury: The Neuroscience of Traumatic Brain Injury
    View all citing articles on Scopus
    View full text