January 4, 2012 — Using magnetic resonance imaging (MRI) to measure areas of the brain that are involved in Alzheimer’s disease may be a way of detecting the disease at its earliest preclinical stages, a new study suggests.
Cognitively normal adults for whom regions of the brain’s cortex were found to be smaller than those of their peers when examined with MRI were significantly more likely to develop symptoms of cognitive decline after 3 years, Bradford C. Dickerson, MD, from Harvard Medical School, Boston, and David A. Wolk, MD, from the University of Pennsylvania, Philadelphia, report.
"MRI cortical thickness, as a biomarker, is capable of detecting preclinical Alzheimer’s disease," Dr. Dickerson told Medscape Medical News. "These areas of the brain appear to be atrophic; they are smaller than they should be, and probably have shrunk in these individuals."
Dr. Dickerson and Dr. Wolk are researchers with the Alzheimer’s Disease Neuroimaging Initiative (ADNI), which was started in 2003. One of ADNI’s aims is to find ways of detecting preclinical Alzheimer’s disease at a stage when treatment to slow its progression might be more successful.
"ADNI is a great example of a partnership that involves government agencies from the NIH, private groups, including the Alzheimer’s Association, and pharmaceutical companies to improve the knowledge about this disease and make it public," Dr. Dickerson said.
Their findings were published online December 21, 2011, and will appear in the January 10 issue of Neurology.
ADNI Project
In this study, Dr. Dickerson and his group hypothesized that cognitively normal older adults would be more likely to experience cognitive decline if they harbored an MRI biomarker suggestive of early Alzheimer’s disease neurodegeneration than their peers who did not have this biomarker.
To test their hypothesis, they used MRI scans to measure a set of 9 areas of the brain important for memory, language, problem solving, and other cognitive functions that are affected the earliest in Alzheimer’s disease.
"I call these areas of the brain the 'Alzheimer's disease signature,' " Dr. Dickerson said.
Their analysis included 159 people free of dementia, the average age of whom was 76 years. Nineteen of these patients were classified as having high risk for preclinical Alzheimer's disease, owing to smaller size of the signature in the cortex; 116 were classified as having average risk, and 24 having as having low risk.
The participants also underwent cognitive testing at study entry and over the next 3 years.
The researchers found that 21% of those at high risk experienced cognitive decline during the 3 years of follow-up after the MRI scan, compared with 7% of those at average risk, and none at low risk (P = 0.03).
The investigators also found that participants whose MRI signature was positive on this measure were twice as likely to have abnormal levels of amyloid in their spinal fluid than those whose MRI signature was not. Of the high-risk preclinical Alzheimer's disease, 60% had amyloid in their spinal fluid, compared with 36% of the average-risk group.
Amyloid levels are thought to be the most specific marker of Alzheimer's disease currently available; however, patients must undergo a spinal tap to have these levels measured.
"It is a testimony to how dedicated these individuals are that so many of them are willing to undergo this procedure. Some of them have family members who are affected, others are just altruistic, but it is really impressive what people will volunteer to do in order to help fight this disease," Dr. Dickerson said.
In this study sample of 159 participants, 84 underwent spinal tap.
Still, Dr. Dickerson pointed out that MRI is not available for use in clinical practice to detect preclinical Alzheimer's disease and may never be.
"It's not necessarily something we are going to recommend that people try to obtain in their clinical practice, unless there's a clinical trial that shows it's actually useful. If it turns out that this is an efficient way to screen people in a clinical trial, and it turns out that a drug in a clinical trial works, then that would be a whole different story," he said.
In that case, MRI could be used to screen people who may be at high risk, such as those with family members who are affected, after an initial screening with a challenging 10-word memory test, he suggested. "I don’t see it being a first-line screen because MRI scans, no matter how efficient you try to make them, end up costing about $500."
Preclinical AD
In an accompanying editorial, Susan M. Resnick, PhD, from the National Institute on Aging, and Philip Scheltens, MD, PhD, from the Alzheimer Center at the University Medical Center, Amsterdam, the Netherlands, write that "Dickerson and Wolk provide additional support for the utility of MRI-based biomarkers in identifying cognitively normal individuals at increased risk for cognitive impairment and AD."
They point out that recently published diagnostic criteria for prodromal Alzheimer's disease, mild cognitive impairment associated with Alzheimer's disease, and probable Alzheimer’'s dementia do incorporate some imaging biomarkers. "However, these measures have limited sensitivity and specificity in predicting who will develop AD in individual patients," they write. "The development and validation of new structural neuroimaging biomarkers sensitive to early changes in the disease process will be critical to implementation of new research criteria for preclinical AD."
Although the sample size in the current study was small, with only 14 individuals with complete cognitive follow-up data meeting the criteria for high risk for preclinical AD, and longer follow-up will be required to validate the AD signature against other imaging biomarkers, the ability to identify cognitively normal individuals at higher risk for subsequent cognitive decline is an important step toward implementing and evaluating the new criteria for preclinical Alzheimer's disease, they conclude.
Dr. Dickerson serves on the editorial board of Hippocampus and has financial relationships with Pfizer, the NIH, and the Alzheimer’s Association. Dr. Wolk has financial relationships with GE Healthcare, Pfizer, the NIH, and the PA Department of Health. Dr. Resnick serves as Action Editor for Brain and Cognition; and reports that she has a financial relationship with the NIH/NIA Intramural Research Program, and that her spouse has financial relationships with Amgen, Eli Lilly, Roche, Amgen, Avid Radiopharmaceuticals, Johnson & Johnson, Lundbeck, Synosia Therapeutics, GE Healthcare, and the NIH.Dr. Scheltens reports financial relationships with Danone Research, Wyeth/Elan Corporation, Bristol-Myers Squibb, Genentech, Pfizer, GE Healthcare, Jansen AI, Lundbeck Inc, Nutricia, Avid Radiopharnaceuticals, Eli Lily and Company, Alzheimer Nederland and Stichting VUmc fonds, and that he serves as Book Review Editor for Alzheimer’s Disease and Associated Disorders and on the editorial board of Dementia Geriatric Cognitive Disorders.
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