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.
ReviewPET imaging of amyloid in Alzheimer's disease
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
References (80)
- et al.
Auguste D and Alzheimer's disease
Lancet
(1997) - et al.
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein
Biochem Biophys Res Commun
(1984) - et al.
Image analysis of beta-amyloid load in Alzheimer's disease and relation to dementia severity
Lancet
(1995) - et al.
Deficits in cerebral glucose metabolism demonstrated by positron emission tomography in individuals at risk of familial Alzheimer's disease
Neurosci Lett
(1995) - et al.
Imaging the pathology of Alzheimer's disease: amyloid-imaging with positron emission tomography
- et al.
Localization of neurofibrillary tangles and beta-amyloid plaques in the brains of living patients with Alzheimer disease
Am J Geriatr Psychiatry
(2002) - et al.
Molecular targeting of Alzheimer's amyloid plaques for contrast-enhanced magnetic resonance imaging
Neurobiol Dis
(2002) - et al.
A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain
Bioorg Med Chem Lett
(2002) - et al.
Development of small molecule probes for the beta-amyloid protein of Alzheimer's disease
Neurobiol Aging
(1994) - et al.
Chrysamine-G binding to Alzheimer and control brain: autopsy study of a new amyloid probe
Neurobiol Aging
(1995)
Visualization of fibrillar amyloid deposits in living, transgenic Caenorhabditis elegans animals using the sensitive amyloid dye, X-34
Neurobiol Aging
Uncharged thioflavin-T derivatives bind to amyloid-beta protein with high affinity and readily enter the brain
Life Sci
Dimethylamino-fluorenes: ligands for detecting beta-amyloid plaques in the brain
Nucl Med Biol
Iodinated tracers for imaging amyloid plaques in the brain
Mol Imaging Biol
11C-labeled stilbene derivatives as Abeta-aggregate-specific PET imaging agents for Alzheimer's disease
Nucl Med Biol
In vivo labeling of amyloid with BF-108
Neurosci Res
2-Dialkylamino-6-acylmalononitrile substituted naphthalenes (DDNP analogs): novel diagnostic and therapeutic tools in Alzheimer's disease
Mol Imaging Biol
The magnitude of dementia occurrence in the world
Alzheimer Dis Assoc Disord
Uber einen eigenartigen schweren Erkrankungsprozess der Hirnrinde
Neurologisches Centralblatt
Neuroreceptor changes in Alzheimer disease
Cerebrovasc Brain Metab Rev
The cholinergic hypothesis—ten years on
Br Med Bull
Amyloid plaque core protein in Alzheimer disease and Down syndrome
Proc Natl Acad Sci USA
David Oppenheimer memorial lecture 1995: some neuropathological aspects of Alzheimer's disease and its relevance to other disciplines
Neuropathol Appl Neurobiol
Neuropathological stageing of Alzheimer-related changes
Acta Neuropathol
Phases of A beta-deposition in the human brain and its relevance for the development of AD
Neurology
Evolution of neuronal changes in the course of Alzheimer's disease
J Neural Transm Suppl
Alzheimer's disease: the amyloid cascade hypothesis
Science
The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics
Science
A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid
Nat Genet
Abundance of the longer A beta 42 in neocortical and cerebrovascular amyloid beta deposits in Swedish familial Alzheimer's disease and Down's syndrome
Neuro report
Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production
Nature
Predominant deposition of amyloid-beta 42(43) in plaques in cases of Alzheimer's disease and hereditary cerebral hemorrhage associated with mutations in the amyloid precursor protein gene
Am J Pathol
Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline
JAMA
Correlation between Aβx-40-, Aβx-42-, and Aβx-43-containing amyloid plaques and cognitive decline
Arch Neurol
Deciphering the genesis and fate of amyloid beta-protein yields novel therapies for Alzheimer disease
J Clin Invest
Assessing the onset of structural change in familial Alzheimer's disease
Ann Neurol
Longitudinal positron emission tomographic studies in families with chromosome 14 and 21 encoded Alzheimer's disease
A follow-up study of the family with the Swedish APP 670/671 Alzheimer's disease mutation
Dement Geriatr Cogn Disord
Cerebral metabolic and cognitive decline in persons at genetic risk for Alzheimer's disease
Proc Natl Acad Sci USA
Declining brain activity in cognitively normal apolipoprotein E epsilon 4 heterozygotes: a foundation for using positron emission tomography to efficiently test treatments to prevent Alzheimer's disease
Proc Natl Acad Sci USA
Cited by (394)
Brain structural indicators of β-amyloid neuropathology
2024, Neurobiology of AgingAdvances in X-ray neuroimaging: Bridging scales from molecular to organ architectures
2024, TrAC - Trends in Analytical ChemistryPreparation and quality control of a new porphyrin complex labeled with <sup>45</sup>Ti for PET imaging
2023, Applied Radiation and Isotopes