27 December 2011. In line with a push to test potential Alzheimer’s therapies at earlier stages of disease (see editorial by Sperling et al., 2011, and ARF comments), new research boosts support for the use of magnetic resonance imaging (MRI) to identify seniors at the cusp of cognitive decline. In this study, some apparently healthy individuals with atrophy in a subset of cortical regions had cerebrospinal fluid biomarkers consistent with preclinical AD, and were more likely to develop subtle memory problems over the next three years. Brad Dickerson of Massachusetts General Hospital, Charlestown, and David Wolk, University of Pennsylvania, Philadelphia, reported the findings in the December 21 Neurology online.
Much structural neuroimaging research in AD focuses on the hippocampus and other medial temporal lobe (MTL) areas that are important for memory and degenerate early in the disease. Using MRI to measure thinning in these regions, researchers can separate older adults with AD from those without the disease. However, the methods cannot predict, on an individual basis, who will come down with AD—which is what a preclinical AD biomarker needs to do (see ARF related news story on Sperling et al., 2011, and
Dubois et al., 2010).
Newer MRI strategies survey more of the brain, measuring atrophy not only in the MTL but in other regions as well—for example, those responsible for language and problem solving—which also deteriorate in AD. The current paper extends a line of research that began years ago when Dickerson and colleagues took newly diagnosed AD patients and compared their whole cerebral cortex to a group of healthy people of similar age, gender, and demographics. Using structural MRI, the scientists determined that thinning in a set of nine cortical areas—which they call the “AD signature” (ADsig)—correlated with symptom severity in mild AD patients. They also found slight but quantifiable ADsig loss in cognitively normal people with brain amyloid (Dickerson et al., 2009). Taking the approach into people with mild cognitive impairment (MCI), the scientists found that the thinner the patients' ADsig regions were, the faster they progressed to dementia (Bakkour et al., 2009). And more recently, Dickerson’s team detected shrinkage of these signature brain areas on MRI scans of seniors who were still cognitively normal, and determined that one standard deviation of cortical thinning tripled the risk of subsequent dementia (Dickerson et al., 2011).
That study, which came out in Neurology in April, analyzed two cohorts—one from MGH, the other from Rush University Medical Center in Chicago. Also, as presented at a recent conference, scientists collaborating with Dickerson tested ADsig in presymptomatic carriers of autosomal-dominant AD and found a signal (see ARF related news story).
In the present paper, the scientists applied what they learned from those two samples to examine a third—159 cognitively normal subjects from the Alzheimer’s Disease Neuroimaging Initiative (see ARF ADNI series).
Dickerson and colleagues homed in on normal ADNI participants who fell below the 15th percentile (i.e., one standard deviation or more below mean) for ADsig cortical thickness. “We took that as an indicator of ‘silent AD’ and wanted to see if these people had other biomarkers that look like preclinical AD, and whether, over the next three years, they were more likely to develop subtle memory decline consistent with early AD,” Dickerson said.
Both turned out to be true. Of the 19 subjects deemed “high risk for preclinical AD” based on the 15th percentile ADsig cut-off, 21 percent showed signs of mental decline after three years. They had more errors on the Clinical Dementia Rating-Sum of Boxes test than the other subjects, and a standard deviation drop in at least one of three neuropsychological tests. In comparison, none of those with high cortical thickness (i.e., at least one standard deviation above mean) in the ADsig regions, and only 7 percent of those with average cortical thicknesses (i.e., within one standard deviation of the mean) showed cognitive loss. Furthermore, among “high-risk” participants with available cerebrospinal fluid (CSF) data, 60 percent had CSF Aβ1-42 levels consistent with AD, whereas only 19 percent of those with high cortical thickness and 36 percent of those with average cortical thicknesses had AD-like CSF reads.
The study “adds fuel to an already burning fire, supporting the use of a targeted, focused group of brain regions as indicators of AD,” Bill Jagust of the University of California, Berkeley, wrote in an e-mail to ARF. “I think the main novelty here is the CSF finding—showing that ADsig not only predicts cognitive decline, but also seems to be associated with a major Aβ biomarker.”
In recent years, AD researchers have puzzled over why some seniors can rack up brain amyloid without showing any signs of mental decline. In an accompanying editorial, Susan Resnick of the National Institute on Aging, Baltimore, Maryland, and Philip Scheltens of VU University Medical Center, Amsterdam, The Netherlands, suggest that the ADsig marker could help predict which of these amyloid-positive “normals” will progress toward dementia.
This capability would make ADsig useful in AD clinical trials, where biomarkers need to identify people “whose cognition will change in a meaningful way in some reasonable timeframe,” Dickerson said. “If people have amyloid in their brains but won’t develop symptoms for another five years, they won’t be informative for a drug trial that’s only going to last five years.” Toward that end, Dickerson’s group is trying to figure out how well the ADsig measure can predict the timeframe for symptoms to develop—“within the next two years, within the next four years, instead of saying changes are present or absent,” he told ARF.
How does the ADsig cortical thinning biomarker fare against other structural MRI measures in AD? It was “a little more sensitive and quite a bit more specific” than measures of hippocampal and entorhinal cortex volumes, Dickerson said, citing his earlier findings (Bakkour et al., 2009). ADsig has not been compared with functional MRI measures.—Esther Landhuis.
Dickerson BC, Wolk DA on behalf of the Alzheimer’s Disease Neuroimaging Initiative. MRI cortical thickness biomarker predicts AD-like CSF and cognitive decline in normal adults. Neurology. 21 Dec 2011. Abstract
Resnick SM and Scheltens P. MRI-based biomarkers of preclinical AD. Neurology. 21 Dec 2011. Abstract