Imaging and In Vivo Quantitation of β-Amyloid: An Exemplary Biomarker for Alzheimer’s Disease?

doi:10.1016/j.biopsych.2005.12.004

Biological Psychiatry

Volume 59, Issue 10, 15 May 2006, Pages 940-947

https://doi.org/10.1016/j.biopsych.2005.12.004 Get rights and content

Alzheimer’s disease (AD) is characterized pathologically by the presence of β-amyloid plaques in the brain. A substantial body of research indicates that the presence of increased β-amyloid peptide (Aβ) is neurotoxic and may initiate the further pathology observed in AD, including neurofibrillary tangles, synaptic loss and dysfunction, and neurodegeneration. The use of brain imaging in patients with or at risk for AD has increased our understanding of the pathophysiology of the disease and may potentially aid in diagnosis. The development of new therapeutics that reduce Aβ in the brain has also indicated a potential use for amyloid imaging in monitoring response to treatment. This review explores the utility of amyloid as a biomarker and the use of positron emission tomography and magnetic resonance imaging in the diagnosis and treatment of AD.

Section snippets

The Argument for Amyloid as an Etiological Factor in AD

While the cause of AD is unknown, the discovery of amyloid plaques and neurofibrillary tangles (NFTs) by Aloise Alzheimer in 1907 generated several hypotheses and guided the development of disease models. The amyloid cascade hypothesis posits that environmental or genetic factors enhance secretion and/or reduce clearance of the β-amyloid peptide (Aβ), resulting in the formation of amyloid plaques (Hardy and Selkoe 2002, Hardy and Higgins 1992). The Aβ peptide is a product of the proteolytic

Drug Development: Focus on Mechanisms Targeted for Amyloid

The current treatments available for AD are symptomatic and only partially effective, e.g., cholinesterase inhibitors and the partial N-methyl-d-aspartate (NMDA) antagonist, memantine. In contrast, drugs that reduce amyloid burden in brain would treat and potentially prevent the associated neuropathology. The β-secretases and γ-secretases are promising drug targets for AD. The cleavage of APP by β-secretase and γ-secretase produces the Aβ₄₀ and Aβ₄₂ peptides; drugs which inhibit β-secretase and

Imaging with PET: Radiopharmaceuticals for Amyloid

Radioligands that bind amyloid plaques are derivatives of histological staining agents that have been used for decades to label amyloid. These agents, like Congo Red and Chrysamine G, have ready access to amyloid plaques in brain sections but would be ineffective as in vivo imaging radioligands. Their high polarity and negative charge prevent them from crossing the blood-brain barrier (BBB) to any significant degree (for an in-depth review of amyloid ligand development, see Mathis et al 2004)

Is Amyloid Imaging a Useful Biomarker or Even Surrogate End Point?

A biomarker is an objectively measured characteristic that reflects either a physiological or pathophysiological process in the human body. For example, plasma cholesterol levels are a biomarker for both normal and pathological processing of this steroid in the body. A biomarker can be used for diagnosis and to study pathophysiology. In contrast, a surrogate end point is a subset of biomarkers that can substitute for the ultimate clinical end point. For example, plasma cholesterol is generally

Alternative Imaging Methods: FDG-PET and MRI

The utility of amyloid imaging in AD should also be assessed relative to currently available neuroimaging methods: PET measurement of regional cerebral glucose metabolism and structural MRI. Positron emission tomography with ¹⁸fluorodeoxyglucose has been utilized for a number of years to assess glucose metabolic rates in AD patients and has been demonstrated to significantly enhance clinical diagnosis. Positron emission tomography studies of cerebral blood flow, glucose metabolism, and oxygen

Discussion

Positron emission tomography radioligand imaging has extraordinary sensitivity compared with MRI methods, which are about 10⁻¹² versus 10⁻⁴ mol, respectively. In addition, PET radioligands can specifically label a single protein, whereas FDG-PET provides more general measures of local neuronal activity. In light of these relative capabilities, PET amyloid imaging would appear to be the best method for diagnosis and use as a surrogate end point in clinical trials of antiamyloid therapies. In

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ReviewImaging and In Vivo Quantitation of β-Amyloid: An Exemplary Biomarker for Alzheimer’s Disease?

Section snippets

The Argument for Amyloid as an Etiological Factor in AD

Drug Development: Focus on Mechanisms Targeted for Amyloid

Imaging with PET: Radiopharmaceuticals for Amyloid

Is Amyloid Imaging a Useful Biomarker or Even Surrogate End Point?

Alternative Imaging Methods: FDG-PET and MRI

Discussion

Neuroscience

Brain Res Brain Res Rev

Neurobiol Aging

Lancet

Trends Pharmacol Sci

Exp Neurol

Neuron

Trends Neurosci

Neurobiol Aging

Neurobiol Aging

J Biol Chem

Am J Pathol

Neurosci Lett

Trends Neurosci

Neuron

Lancet Neurol

Nucl Med Biol

Am J Geriatr Psychiatry

Neurobiol Aging

Neurobiol Aging

Curr Opin Pharmacol

J Neurol Sci

J Biol Chem

Binding characteristics of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for beta-amyloid plaques in Alzheimer’s disease

J Neurosci

Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progressionA randomized controlled trial

JAMA

Mild cognitive impairmentCan FDG-PET predict who is to rapidly convert to Alzheimer’s disease?

Neurology

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families

Science

Reconstitution of gamma-secretase activity

Nat Cell Biol

Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium

JAMA

Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo

Proc Natl Acad Sci U S A

Surrogate end points in clinical trialsAre we being misled?

Ann Intern Med

Effects of Abeta immunization (AN1792) on MRI measures of cerebral volume in Alzheimer disease

Neurology

Clinical and pathological correlates of apolipoprotein E epsilon 4 in Alzheimer’s disease

Ann Neurol

Review
Imaging and In Vivo Quantitation of β-Amyloid: An Exemplary Biomarker for Alzheimer’s Disease?