DIMENSIONS Winter 2007

Spotlight on Research: ADRC Researchers Identify Biomarkers for Alzheimer's Disease

by Cheryl Dawes

As new treatments for Alzheimer’s disease (AD) are developed, the importance of early diagnosis grows. Diagnosis early in the course of the disease increases the likelihood of success for treatments that might slow disease progression, as well as helping patients and their families make plans for future care. Although AD is the most common cause of dementia, the clinical diagnosis of probable AD remains uncertain until it is confirmed by pathological examination of brain tissue during autopsy.

ADRC researcher Dr. Jing Zhang and his colleagues have taken a major stride on the path toward early and accurate diagnosis of AD and other progressive brain diseases. Using an advanced analytical technique, they have identified proteins in the human body that may serve as “biomarkers” for AD, Parkinson’s disease and dementia with Lewy bodies. A biomarker is a feature or condition in the body that can be objectively measured to indicate disease risk, presence, and progression.

“We’re getting very close to being able to use these biomarkers for the clinical diagnosis of Alzheimer’s and Parkinson’s disease, and dementia with Lewy bodies,” said Zhang, Associate Professor of Pathology at the UW.

Looking for biomarkers in AD is a complex, multi-step process involving ADRC researchers around the country. Pioneering work by Dr. Elaine Peskind of the UW ADRC has perfected the use of lumbar punctures in individuals with AD, a technique in which a thin needle is inserted into the lower back and a small amount of fluid is extracted. This cerebrospinal fluid (CSF) can then be analyzed to identify what chemicals are present.

Zhang and the other researchers conducted a multi-site study to identify specific proteins in cerebrospinal fluid from patients with neurodegenerative diseases and healthy controls. To identify and evaluate these proteins, they used a state-of-the-art technique called iTRAQ, a highly sensitive and specific method that relies on isotopic labeling of protein molecules followed by mass spectrometry analysis. The technique is a major improvement on other biomarker detection techniques, according to Zhang.

The researchers identified and measured more than 1,500 proteins in CSF samples from four groups of study volunteers—10 patients with AD, 10 patients with Parkinson’s disease, 10 patients with dementia with Lewy bodies, and 10 healthy age-matched controls. After identifying the CSF proteins, Zhang and his colleagues determined which of these proteins were potential biomarkers. The researchers then compared distributions of those markers in CSF collected from patients compared to the healthy controls.

The results of this comparison enabled the researchers to determine unique panels of biomarkers that distinguished healthy controls from patients with neurodegenerative disease, and which distinguished between AD, Parkinson’s disease and dementia with Lewy bodies. The researchers then confirmed their results with an alternative method known as Western blot analysis.

“A key to our research was that we compared three different diseases with normal controls, so we knew a particular protein response was related to a specific disease, not just a neurodegenerative disease in general,” explained Zhang.

Although the study results are promising, the disease biomarkers Zhang and his colleagues identified must be tested in a larger group of patients before becoming part of a diagnostic tool used by clinicians. The large number of proteins that the group identified in patients with neurodegenerative diseases will likely be useful in developing methods of clinical diagnosis and monitoring disease progression.

Zhang and his colleagues are now investigating whether the biomarkers they found in CSF, which requires a lumbar puncture to obtain, are present in blood, which can be sampled in a less invasive manner.

The results of the CSF study are published in the Journal of Alzheimer’s Disease, volume 9, August 2006. Other UW researchers who participated in the study included James Leverenz, Elaine Peskind, Cyrus Zabetian, Ali Samii, Catherine Pan, Yan Wang, Jinghua Jin, David Zhu, G. Jane Li, and Thomas Montine. The multi-site study also included researchers from Oregon Health and Science University in Portland; Baylor College of Medicine in Houston; the Fred Hutchinson Cancer Research Center in Seattle; and Applied Biosystems in Framingham, Mass.

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