β-Amyloid Plaque Load Correlates with Brain Atrophy in Alzheimer's Disease
Abstract & Commentary
By Gunnar Gouras, MD, Associate Professor of Neurology and Neuroscience, Weill Medical College, Cornell University. Dr. Gouras reports no financial relationship relevant to this field of study.
Synopsis: This study on patients with a diagnosis of mild-to-moderate Alzheimer's disease demonstrated a positive correlation of brain β-amyloid load using 11C-PIB positron emission tomography with the rate of brain atrophy using serial volumetric MRI.
Source: Archer HA, et al. Amyloid Load and Cerebral Atrophy in Alzheimer's Disease: An (11)C-PIB Positron Emission Tomography Study. Ann Neurol. 2006;60:145-147.
Alzheimer's disease (AD) is the leading cause of dementia, and increases in life expectancy are placing an ever greater burden on our health care system. β-amyloid peptides, the principle components of the characteristic amyloid plaques that accumulate in the brain with AD, have been increasingly linked to the pathogenesis of the disease. The relative contribution of β-amyloid in AD has been an area of controversy. Rare autosomal dominant familial forms have been found, with mutations that directly elevate β-amyloid, but the relevance of β-amyloid in the more-typical late onset form of the disease has been less certain. This report on a small number of patients with a diagnosis of mild-to-moderate AD provides important new support for the relationship of β-amyloid accumulation and more typical late-onset AD. Brain atrophy is a well established component of the disease that is thought to occur from the progressive destruction of nerve cells. Archer and colleagues demonstrated a positive correlation between the rate of brain atrophy, assessed by 2 MRI scans taken at a mean interval of 12.8 months apart, to the regional uptake on PET of 11C-PIB, a thioflavin-based radioligand that has been shown to detect amyloid plaques in patients with AD (Klunk WE, et al. Imaging Brain Amyloid in Alzheimer's Disease with Pittsburgh Compound-B. Ann Neurol. 2004;55:306-319).
Commentary
The emergence of a PET imaging method to detect AD pathology in patients has been an exciting development, with implications both for diagnosis and as a non-invasive method to visualize amyloid plaques in vivo in therapeutic clinical trials. The seminal work by Alzheimer a century ago had correlated dementia with the accumulation of plaques and neurofibrillary tangles, composed of paired helical filaments of the microtubule protein, tau. Although AD is diagnosed at autopsy by the pathological presence of a sufficient number of plaques and tangles, plaque load has been a poor correlate of cognitive impairment. Moreover, the abundance of cerebral plaques in some individuals, without a known history of dementia, has led some to doubt whether β-amyloid can be used as a measure of disease progression. At the same time, transgenic mouse models of β-amyloidosis have reproduced many of the pathological and behavioral features of the human disease and, increasingly, reduction of β-amyloid has become a leading target of emerging experimental therapies for AD.
This combined 11C-PIB PET and serial volumetric MRI brain study strengthens the feasibility of amyloid imaging as a measure of disease progression and, secondarily, supports the validity of PET amyloid imaging for therapeutic clinical trials in AD. Amyloid load correlated with rate of brain atrophy, reflecting neurodegeneration. But several weaknesses of this study should be noted. First, only 9 patients with a diagnosis of mild-to-moderate AD were studied, and 2 with mild dementia had normal 11C-PIB uptake; these 2 individuals also had no decline on follow-up cognitive testing and were eventually thought not to have AD. Second, the timing of the PET scan was not optimal, ranging from before the first MRI to after the last MRI, with a mean of 7.6 months from the midpoint between MRI scans. Nevertheless, this is an important study that strengthens both the amyloid cascade hypothesis and PET amyloid imaging as a measure of disease progression in AD.
This study on patients with a diagnosis of mild-to-moderate Alzheimer's disease demonstrated a positive correlation of brain β-amyloid load using 11C-PIB positron emission tomography with the rate of brain atrophy using serial volumetric MRI.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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