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
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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The detection of β-amyloid plaques in an Alzheimer's disease rat model with DDNP-SPIO
2015, Clinical RadiologyCitation Excerpt :Various attempts have previously been reported to facilitate reliable in vivo detection of individual Aβ deposits using specific MRI contrast agents.29,32,34–40 However, ionic gadolinium complexes can leak toxic Gd+3 ions, have low magnetic relaxivities, relatively low sensitivity,29,32,34–41 and need to be further tested due to the high dosage of contrast agent.42 Fluorine-19 MRI probes can detect Aβ plaques in vivo, but it is difficult to translate the information obtained into human clinical medicine.41,43–45
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