Getting a Jump on Alzheimer's Disease

The hallmarks of mid-stage Alzheimer's disease are all too readily apparent, including severe memory loss, wandering and getting lost, and inability to perform daily functions like dressing, eating, and bathing without assistance. Unfortunately, by the time the disease has progressed this far, the few treatment strategies available for Alzheimer's are of little help. The fight against Alzheimer's disease, therefore, needs improved methods of diagnosing the disease at its earliest stages, before overt symptoms have appeared.

Today's Testing Challenges
Currently, the primary method of diagnosing Alzheimer's in living patients involves taking detailed patient histories, administering memory and psychological tests, and ruling out other explanations for memory loss, including temporary conditions like depression or vitamin B12 deficiency or permanent ones like stroke. These clinical diagnostic methods, however, are not foolproof.

One obstacle to diagnosis is pinpointing the type of dementia; Alzheimer's disease is only one of many different forms of dementia. Because of this, Alzheimer's disease cannot be diagnosed with complete accuracy until after death, when autopsy reveals the disease's characteristic amyloid plaques and neurofibrillary tangles in a patient's brain. In addition, clinical diagnostic procedures are only helpful after patients have begun displaying significant, abnormal memory loss or personality changes. By then, a patient has likely had Alzheimer's disease for years.

New Tests Under Development
Recognizing the need for earlier and more accurate detection of Alzheimer's disease, scientists are devising new brain imaging technologies and blood, urine, or spinal fluid tests that could improve diagnosis. Dr. John Trojanowski, Professor of Pathology and Laboratory Medicine at the University of Pennsylvania Medical Center, is a member of the National Institute on Aging's Biological Markers Working Group, which is part of the National Institute of Health's Alzheimer's Disease Prevention Initiative.

"We need a way to diagnose Alzheimer's disease in the prodromal, or presymptomatic, phase of Alzheimer's disease, where intervention will have the greatest benefit," he explains. "If using these tests helps a physician make a secure diagnosis in the first year rather than after two years, then that's good for the patient."

The Biological Markers Working Group recently released a discussion of the status of biomarker research in Alzheimer's disease. Biomarkers are substances in a person's biological fluids--blood, urine, or cerebrospinal fluid--that can be measured to indicate whether a person has or is likely to develop Alzheimer's disease.

Amyloid Beta and Tau
Perhaps the most well-researched of these markers are amyloid beta and tau, measured in cerebrospinal fluid. Research has shown that tau, released as neurons degenerate, is higher than normal in the spinal fluids of Alzheimer's patients, whereas beta amyloid is low, presumably because it is trapped in the brain in the form of amyloid plaques.

In April 2003 a study and review of the scientific literature, published in the Journal of the American Medical Association, concluded that by measuring levels of these substances, scientists could distinguish patients with Alzheimer's disease from normal controls with about 90% accuracy. Commercial tests are already available for doctors to measure cerebrospinal amyloid beta and tau levels, but the tests are not likely to gain widespread use--or be covered by insurers--until further, large-scale studies show the benefit of the new diagnostic tool.

Isoprostanes
One significant hurdle to acceptance of an amyloid beta and tau test by patients is that it requires a spinal tap, a potentially frightening and painful procedure. Dr. Trojanowski, Dr. Domenico Pratico and colleagues at the University of Pennsylvania, therefore, have sought another biomarker that not only accurately diagnoses Alzheimer's disease, but can be obtained through blood or even urine: isoprostanes.

Isoprostanes are markers of oxidative damage, caused by substances called free radicals released as a byproduct of oxygen metabolism. Alzheimer's disease is associated with an increased level of oxidative damage in the brain, and persons with Alzheimer's disease have increased levels of isoprostanes in cerebrospinal fluid, blood, and urine. In 2001, Dr. Trojanowski and colleagues authored a paper reporting studies led by Dr. Pratico that showed evidence that heightened oxidative damage is one of the earliest signs of Alzheimer's disease, occurring even before the formation of plaques and tangles. A year later, they demonstrated that persons with mild cognitive impairment--often a precursor to Alzheimer's disease--have increased levels of isoprostanes in their bodily fluids, as compared to normal controls. More recent research led by Dr. Pratico indicates that the isoprostane urine test may also be able to help physicians rule out certain non-Alzheimer's forms of dementia when diagnosing patients.

Advances in Brain Imaging
Just as important as work on biomarkers are new advances in brain imaging technology. "There are three general approaches to using imaging for early detection of Alzheimer's disease," says Dr. Scott Small, Assistant Professor of Neurology at Columbia University. "However, none of them has yet moved from the laboratory into the clinical realm."

Among the most promising technologies is using magnetic resonance imaging (MRI) to examine brain shrinkage, or atrophy, in Alzheimer's patients. Scientific evidence shows that persons with Alzheimer's disease experience an accelerated rate of brain shrinkage: 2.5% a year, as compared to .4% for normal persons the same age. Work published in the April 2, 2002, issue of the Proceedings of the National Academy of Science by a group of researchers at the Institute of Neurology at the University College London suggests that brain atrophy begins before the onset of symptoms of memory loss in Alzheimer's disease, and that the brain locations showing the most atrophy vary as the disease progresses. This may mean that using MRI to measure brain atrophy will be useful not only as an early detection tool, but also as a means to track disease progression.

Another technology being adapted for Alzheimer's diagnosis is positron emission topography, or PET. Researchers are developing ways to use PET scanning to image the plaques and tangles of Alzheimer's disease in living patients. Scientists have developed several substances, called ligands, that when injected into the body travel into the brain and bind to plaques and tangles. The scientists tag the ligand with a radioactive marker, permitting them to image the radiolabeled plaques and tangles with a PET scan. This technique could not only assist doctors with making certain that memory-impaired patients truly have Alzheimer's rather than another type of dementia, but could also be used during clinical trials to monitor whether treatments designed to attack plaques and tangles are having an effect. The approach may not be the best method for early detection, however, as most scientists agree that brain dysfunction precedes the development of plaques and tangles in Alzheimer's disease.

The third technology, a variant of MRI called functional MRI (fMRI), may allow the earliest diagnosis of Alzheimer's disease. Dr. Small has been refining fMRI technology to differentiate between patients with normal age-related memory loss and those in the earliest stages of Alzheimer's disease. Measuring oxygen levels in the blood in the hippocampus--the brain's memory center--while the brain is at rest, Dr. Small has been able to pinpoint differences in brain activity in different subregions of the hippocampus. In 1999, he found that older adults with mild memory loss have one of two different patterns of dysfunction in the hippocampus. The first matches the pattern seen in patients with confirmed Alzheimer's disease and likely indicates early Alzheimer's; the other pattern seems to be associated with normal aging.

Since then, Dr. Small has been working to demonstrate that fMRI scans of the hippocampus could be a valuable and accurate tool for early identification of Alzheimer's disease. Animal studies in rhesus monkeys--who never get Alzheimer's disease--and transgenic mouse models of Alzheimer's disease--who always develop Alzheimer's symptoms--support Dr. Small's theory.
The rhesus monkeys show a pattern of hippocampal function consistent with normal aging, whereas the Alzheimer's mice show the Alzheimer's-like pattern of hippocampal dysfunction. The next step, says Dr. Small, is to do a long-term study of the technology in humans. "We want to image hundreds, or hopefully thousands, of people to be sure about diagnostic specificity and sensitivity," he says. "We plan to test our hypothesis that anyone over 60 with an Alzheimer's-like pattern in the hippocampus is more likely to develop Alzheimer's disease."

A Complement to Existing Techniques
None of these new imaging techniques or biomarkers is likely to become a stand-alone method of diagnosing Alzheimer's disease. Instead, they will complement existing clinical tests and criteria to help patients obtain earlier and more accurate diagnoses. "Most conditions and diseases are not easily diagnosed with one test or marker," notes Dr. Trojanowski. "I think a combination of imaging and biomarkers will help physicians nail down a diagnosis with much greater accuracy than they can now." And perhaps most important, these new techniques should help patients suffering from Alzheimer's disease obtain treatment sooner, allowing them to prolong their health and sustain their quality of life.

References:

Frank RA, Galasko D, Hampel H, Hardy J, de Leon MJ, Mehta PD, Rogers J, Siemers E, Trojanowski JQ; National Institute on Aging Biological Markers Working Group. Biological markers for therapeutic trials in Alzheimer's disease. Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer's disease. Neurobiol Aging 2003; 24: 521-36.

Pratico D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ. Increase of brain oxidative stress in mild cognitive impairment: a possible predictor of Alzheimer disease. Arch Neurol 2002; 59: 972-6.

Pratico D, Uryu K, Leight S, Trojanowski JQ, Lee VM. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J Neurosc. 2001; 21: 4183-7.

Scahill RI, Schott JM, Stevens JM, Rossor MN, Fox NC. Mapping the evolution of regional atrophy in Alzheimer's disease: unbiased analysis of fluid-registered serial MRI. Proc Natl Acad Sci USA 2002; 99: 4703-7.

Small SA, Perera GM, DeLaPaz R, Mayeux R, Stern Y. Differential regional dysfunction of the hippocampal formation among elderly with memory decline and Alzheimer's disease. Ann Neurol 1999; 45: 466-72.

Reviewed: September 3, 2003
Published: September 5, 2003