The observation, published in the April 12 issue of The Lancet, could lead to the development of a non-invasive test to diagnose and track the development of the devastating brain disorder. Eventually, such a test might be used to measure the effectiveness of new strategies to treat or prevent Alzheimer's symptoms and to diagnose the disease in its earliest stages, when new treatments are likely to be most effective. The researchers are planning further studies to confirm their discoveries.
"The formation of A-beta plaques in the brain and the development of cataracts in the lens are both examples of accumulated protein associated with age-related degenerative damage," says Lee Goldstein, MD, PhD, the paper's lead author and a member of the MGH Genetics and Aging Research Unit. "In addition, people with Down's Syndrome, who develop Alzheimer's at an early age, are also prone to early-onset cataracts. But as far as we know, no one had investigated whether there might be any association between the pathology of Alzheimer's disease and age-related changes in the lens."
Goldstein also is associate director for Basic Research at the Center for Ophthalmic Research of the BWH Department of Surgery, a member of the psychiatry departments at MGH and BWH and the MGH Laboratory for Oxidation Biology, and assistant professor of Psychiatry at Harvard Medical School (HMS).
The researchers examined samples of brain tissue and lenses taken from nine people who had died with Alzheimer's disease and from eight controls who died with other neurodegenerative disorders. They also tested samples of aqueous humor (the fluid within the chamber at the front of the eye) taken from healthy volunteer patients who were having cataracts removed.
A-beta was found in all of the lenses studied in concentrations similar to that found in brain tissue samples. It also was detected in the aqueous humor samples at levels comparable to those typically seen in cerebrospinal fluid. Although differences in tissue concentrations of A-beta between the Alzheimer's and non-Alzheimer's samples have not yet been determined, the researchers found a distinctive pattern of A-beta deposits in the outer, peripheral portion of only the lenses from Alzheimer's patients.
"One of the most exciting aspects of this finding is the fact that these deposits are associated with a type of cataract seen rarely in the general population," says Leo T. Chylack, Jr., MD, Director of the BWH Center for Ophthalmic Research and one of the study's principal investigators. "These cataracts do not block vision and can only be seen when the pupil is dilated widely, so they previously would not have been detected in Alzheimer's patients. If the association of these deposits with Alzheimer's holds up in future studies, it would be very simple to develop a non-invasive test of disease progression." Dr. Chylack is professor and vice-chairman (research) of Ophthalmology at HMS.
The researchers note that while many potential treatments for Alzheimer's are under development, testing and effectively using such therapies would require a way to accurately diagnose and monitor the disease, something that does not currently exist.
"Development, testing and effective implementation of any new anti-Alzheimer's therapy requires a safe and effective means of diagnosing and monitoring disease progress," says Goldstein. "If patients at risk of developing the disease could be identified early and accurately, ideally before cognitive symptoms emerge, therapeutic interventions can be instituted before the onset of irreparable damage to the brain.
"Because the lens does not clear protein deposits in the way that brain tissue does, there is a good possibility that a non-invasive test could be developed to identify these deposits in a sensitive and quantitative manner," he adds. An intensive project to develop such a test is underway.
Chylack and Ashley Bush, MD, Director of the MGH Laboratory for Oxidation Biology are co-senior authors of the Lancet report. Other co-authors are Rudolph Tanzi, PhD, director of the MGH Genetics and Aging Research Unit; Robert Moir, PhD, Xudong Huang, PhD, Jennifer Coccia, Kyle Faget, and Karlotta Fitch of MGH; Julien Muffat, MS, of Ecole Normale Superieure, Chacan, France; Robert Cherny, PhD, Christine Mavros, and Colin Masters, MD, of the University of Melbourne, Australia; and Maria Ericsson of Harvard Medical School.
The research was supported by grants from the Rappaport Foundation, the National Institute on Aging, the Alzheimer's Association, the National Health and Medical Research Council of Australia, and the Massachusetts Lions Eye Research Foundation.
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, transplantation biology and photomedicine.
Brigham and Women's Hospital is a 725-bed teaching affiliate of Harvard Medical School. BWH is committed to excellence in patient care, medical research and the training and education of health care professionals. A leading recipient of research grants from the National Institutes of Health, BWH conducts internationally acclaimed clinical, basic and epidemiological studies.
In 1994, MGH and BWH joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups and nonacute and home health services.
Journal
The Lancet