Elsevier

The Lancet Neurology

Volume 7, Issue 2, February 2008, Pages 129-135
The Lancet Neurology

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Imaging of amyloid β in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism

https://doi.org/10.1016/S1474-4422(08)70001-2Get rights and content

Summary

Background

Amyloid-β (Aβ) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Aβ imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Aβ-specific ligands. 18F-BAY94-9172 is an Aβ ligand that, due to the half-life of 18F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD.

Methods

15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. 18F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD.

Findings

18F-BAY94-9172 binding matched the reported post-mortem distribution of Aβ plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90–120 min after injection, higher neocortical SUVR was observed in AD patients (2·0 [SD 0·3]) than in healthy controls (1·3 [SD 0·2]; p<0·0001) or FTLD patients (1·2 [SD 0·2]; p=0·009). Visual interpretation was 100% sensitive and 90% specific for detection of AD.

Interpretation

18F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Aβ imaging into clinical practice.

Introduction

Amyloid-β (Aβ) imaging with PET allows assessment in vivo of Aβ deposition in the brain, providing an important new tool for the assessment of the causes, diagnosis, and future treatment of dementias, in which Aβ may play a part. Studies with 11C-labelled Pittsburgh compound B (2-[4′-(methylamino)phenyl]-6-hydrobenzothiazole; PIB), the most specific and widely used PET Aβ ligand, indicate that Aβ imaging may allow earlier diagnosis of Alzheimer's disease (AD) and accurate differential diagnosis of the dementias.1, 2, 3, 4, 5 11C-PIB studies show robust cortical binding in almost all AD patients,2, 6, 7 and correlate well with a reduction in CSF Aβ42.8 Binding also correlates with the rate of cerebral atrophy as measured by MRI,9 and with episodic memory impairment in apparently normal elderly individuals and in patients with mild cognitive impairment.10 Increased 11C-PIB binding may also be predictive of conversion of mild cognitive impairment to AD.11 Furthermore, comparison of the diagnostic use of Aβ imaging versus 18F-fluorodeoxyglucose PET indicates greater accuracy for distinguishing patients with mild AD from elderly controls.12

Subsequent to recent advances in imaging and CSF analysis, Dubois and colleagues13 proposed that the research criteria for the diagnosis of probable AD should be revised to allow earlier diagnosis and therapeutic intervention. The authors of this position statement argue that dementia is not required for the diagnosis of AD if there is a clear history of progressive cognitive decline, objective evidence from psychometric tests of episodic memory impairment, and characteristic abnormalities in the CSF or in neuroimaging studies. The latter includes the imaging of Aβ with appropriate PET tracers. Thus, as the criteria for the diagnosis of AD evolve, Aβ imaging is likely to have an increasingly important role in clinical practice, provided it is accessible and affordable.

Unfortunately, the 20 min radioactive decay half-life of 11C limits the use of 11C-PIB to centres with an on-site cyclotron and 11C radiochemistry expertise. Consequently, access to 11C-PIB PET is restricted and the high cost of studies is prohibitive for routine clinical use. To overcome these limitations, a tracer for imaging Aβ that can be labelled with 18F is required. The 110 min radioactive decay half-life of 18F allows centralised production and regional distribution as currently practised worldwide in the supply of 18F-fluorodeoxyglucose for clinical use.

Barrio and colleagues14 have developed an 18F-labelled tracer that shows binding to both Aβ plaques and neurofibrillary tangles in vitro,15 and report separation of patients with AD from healthy controls with PET imaging.16 However, the analysis required a 2 h continuous scan and only showed 9% higher cortical uptake in AD. By comparison, 11C-PIB shows a 70% increase in cortical binding in AD,2, 7 and 11C-PIB images can be accurately read without quantification and acquired with less than 30 min of PET camera time.12 An 18F tracer with characteristics similar to those of 11C-PIB is needed. Structural and pharmacological evidence supports the claim that a stilbene derivative should have similar specificity to a thioflavin derivative (ie, PIB) for Aβ aggregates.17, 18 Thus, 18F-BAY94-9172 or trans-4-(N-methyl-amino)-4′-{2-[2-(2-[18F]fluoro-ethoxy)-ethoxy]-ethoxy}-stilbene (also known as 18F-AV1/ZK), which shares common structural features to PIB (figure 1), has been developed. 18F-BAY94-9172 and 11C-PIB are small planar molecules with extended aromatic systems and alkyl-amino substitution. They compete pharmacologically for the same binding site on amyloid aggregates with similar affinity, and in human brain sections they show the same pattern of labelling of Aβ plaques.17, 18 Furthermore, another stilbene, 11C-SB13 (11C-4-N-methylamino-4′-hydroxystilbene), has shown the same regional brain distribution pattern as 11C-PIB when studied in the same population of AD patient and age-matched healthy controls.19

18F-BAY94-9172 has been shown to bind avidly to neuritic and diffuse Aβ plaques and to cerebral amyloid angiopathy in vitro; it does not show appreciable labelling of tangles, Pick bodies, Lewy bodies, or glial cytoplasmic inclusions. In brain homogenates from patients with AD, BAY94-9172 was found to bind with high affinity (Ki=6·7±0·3 nM), and in AD tissue sections, 18F-BAY94-9172 selectively labelled Aβ plaques.17 At tracer concentrations, BAY94-9172 did not show binding to post-mortem cortex from patients with frontotemporal dementia, or in post-mortem brain tissue from a variety of neurodegenerative diseases, including tauopathies and α-synucleinopathies. Images of 18F-BAY94-9172 binding to brain slices from patients with AD, frontotemporal lobar degeneration, and normal brain obtained with PhosphorImager plates are shown in webfigure 1. After injection into Tg2576 transgenic mice, ex-vivo brain sections showed localisation of 18F-BAY94-9172 in regions with Aβ plaques as confirmed by thioflavin binding.18 In normal mice, 18F-BAY94-9172 rapidly entered the brain with 8·14% injected dose per gram and washed out to 2·14% injected dose per gram within 2 h.

Preclinical toxicity studies in several animal species showed a good safety profile with no observable effects at 100 times the expected human mass dose. On the basis of these studies, we deemed 18F-BAY94-9172 to be a suitable agent for human studies.

Section snippets

Participants

15 healthy elderly controls, 15 patients who met the NINDS-ADRDA criteria for probable AD and the DSM-IV criteria for dementia of Alzheimer's type, and five patients who met the consensus criteria for frontotemporal lobar degeneration (FTLD) were enrolled in the study. Patients with AD and FTLD were recruited from the Austin Health Memory Disorders Clinic (Heidelberg, Victoria, Australia) if they met the inclusion and exclusion criteria and were willing to participate in the study. Healthy

Results

15 healthy controls (eight men and seven women; age 68·8±6·0 years; MMSE 29·5±1·0; CDR 0·0), 15 patients with probable AD (10 men and five women; age 69·5±10·0 years; MMSE 23·3±4·0; CDR 1·0), and five patients with FTLD (three men and two women; age 67·4±9·0 years; MMSE 24·6±2·0; CDR 1·0) were recruited and studied between September, 2006, and September, 2007. All recruited individuals completed the study and are included in the analysis. Three of the FTLD patients met criteria for

Discussion

18F-BAY94-9172 binding matched the reported histopathological distribution of neuritic plaques in AD, corresponding closely to stage C of Braak's Aβ deposition categories.22, 23 The cortical binding of 18F-BAY94-9172 provided robust separation of individuals with AD from healthy elderly controls and patients with FTLD. This separation was achieved either with visual image interpretation or a simple semiquantitative measure, the ratio of binding in neocortex to cerebellar grey matter expressed

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