Elsevier

The Lancet Neurology

Volume 3, Issue 9, September 2004, Pages 519-527
The Lancet Neurology

Review
PET imaging of amyloid in Alzheimer's disease

https://doi.org/10.1016/S1474-4422(04)00853-1Get rights and content

Summary

Alzheimer's disease (AD) is the most common form of dementia and is characterised by progressive impairment in cognitive function and behaviour. The pathological features of AD include neuritic plaques composed of amyloid-β peptide (Aβ) fibrils, neurofibrillary tangles of hyper-phosphorylated tau, and neurotransmitter deficits. Increases in the concentration of Aβ in the course of the disease with subtle effects on synaptic efficacy will lead to gradual increase in the load of amyloid plaques and progression in cognitive impairment. Direct imaging of amyloid load in patients with AD in vivo would be very useful for the early diagnosis of AD and the development and assessment of new treatment strategies. Three different strategies are being used to develop compounds suitable for in vivo imaging of amyloid deposits in human brains. Monoclonal antibodies against Aβ and peptide fragments have had limited uptake by the brain when tested in patients with AD. When putrescine-gadolinium-Aβ has been injected into transgenic mice overexpressing amyloid, labelling has been observed with MRI. The small molecular approach for amyloid imaging has so far been most successful. The binding of different derivatives of Congo red and thioflavin has been studied in human autopsy brain tissue and in transgenic mice. Two compounds, fluorine-18-labelled-FDDNP and carbon-11-labelled-PIB, both show more binding in the brains of patients with AD than in those of healthy people. Additional compounds will probably be developed that are suitable not only for PET but also for single photon emission CT (SPECT).

Section snippets

The amyloid hypothesis

The presence of amyloid in a form of dementia (which later became known as AD) was described by Alois Alzheimer.2 The German physician, described the presence of amyloid plaques and neurofibrillary tangles in the brain of a 51-year-old woman named Auguste D who had a history of progressive memory impairment.3 The extracellular plaques and deposits and intracellular neurofibrillary tangles became the hallmark pathological features of AD together with neuronal and synaptic losses and

Early detection of AD

The rapid recent development of non-invasive tools for the imaging of human brains has had a great effect on our ability to investigate and understand brain function. Structural brain imaging, such as MRI as well as functional brain imaging with single photon emission CT (SPECT) and PET have revealed and increased the understanding of early changes in AD. Longitudinal studies in families with AD caused by mutations in the APP and presenilin genes have shown evidence for structural changes22 and

Amyloid imaging

An ideal imaging ligand should fulfil several criteria (panel). In the past 10 years several different strategies have been used to develop compounds suitable for amyloid imaging with different chemical structures and properties (figure 5). The binding properties of the compounds have been studied in vitro by autoradiographic ligand studies with tissue homogenates or thin slices from mice or human brains. Labelled compounds have been injected into mice to study in vivo uptake and binding. Some

Radiolabelled Aβ antibodies and peptide fragments

Antibodies to Aβ have been tested as suitable imaging agents for amyloid. A saturable binding of iodine-125-labelled Aβ1–40 protein to tissue homogenates prepared from AD temporal cortex was observed.48 Antibodies to Aβ1–28 labelled with technetium-99 were developed by Friedland and co-workers.49 The monoclonal antibody 10H3 was identified as a promising amyloid imaging agent.40 When the compound was given to six people with probable AD, SPECT studies revealed an uptake of 99-10H3 solely around

Detection of brain amyloid by MRI

Magnetic resonance microscopy (MRM) produces images with higher spatial resolution than conventional MRI. When MRM was applied in human brain autopsy tissue from five patients with AD and three age-matched control individuals in vitro, neuritic plaques were observed in the hippocampus of patients.58 The plaques were visualised as areas of decreased signal intensity of T2* weighted MRM images. The accelerated T2* relaxation was caused by the presence of metal ions in the plaque. Because imaging

Small molecular methods of amyloid imaging

Several research groups have used the small-molecule approach to the development of substances suitable for amyloid imaging (figure 5). Some of the most promising compounds have been Congo red, thioflavin, stilbene, and FDDNP. The substances differ in binding characteristics and in their brain uptake. Encouraging in vitro and in vivo properties for some of the substances has recently led to promising in vivo imaging of amyloid in patients with AD.37, 38

Amyloid imaging in AD with 18F-FDDNP

The 18F-FDDNP studies by Shoghi-Jadid and co-workers41 were the second attempt in patients with AD to detect in vivo abnormal amyloid deposition in the brain. 18F-FDDNP was given intravenously to nine patients with different degrees of cognitive impairment and seven age-matched controls. The retention of 18F-FDDNP in the temporal, parietal, frontal, and occipital cortical regions of the patients was 10–15% higher than in the pons.41 The highest retention of 18F-FDDNP in the patients was

Amyloid binding in AD with 11C-PIB

The first human study with 11C-PIB in 16 patients with mild AD and nine healthy people has recently been published.39 When 11C-PIB was injected intravenously in a bolus dose we found that the compound rapidly reached the brain and no metabolites of PIB was produced that crossed the blood–brain barrier.39 11C-PIB showed a rapid uptake to brain and a substantial retention in the frontal, temporal, parietal, and occipital cortices and the striatum but low entry into the cerebellum and subcortical

Future prospects

The rapid development of different compounds suitable for the visualising of amyloid during the past 10 years has led to the first promising in vivo studies of the amyloid ligands PIB62 and FDDNP;41 the latter compound also seems to label neurofibrillary tangles in patients with AD. The development of several of the amyloid ligand candidates has failed because of poor passage across the blood-brain barrier or low measurable signal activity. The robust difference in PIB binding between AD tissue

Search strategy and selection criteria

The starting point for this review article was the recent publications of original articles on the development of compounds for the imaging of amyloid in the brains of patients with AD. Additional references for this review were obtained by searches (1988–2004) of PubMed with the terms “amyloid binding”, “brain”, “Alzheimer's disease”, and “imaging”. Only papers published in English were reviewed.

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