CLINICAL DIAGNOSIS OF ALZHEIMER'S MAY BE DELAYED

In a study of people with mild cognitive impairment (MCI), those who took the drug donepezil were at reduced risk of progressing to a diagnosis of Alzheimer's disease (AD) during the first year of the trial, but by the end of the 3-year study there was no benefit from the drug. Vitamin E was also tested in the study and was found to have no effect at any time point in the study when compared with placebo.

These findings, from the Memory Impairment Study, are the first to suggest than any agent can delay the clinical diagnosis of AD in people with MCI. The effects of the drug measured in this study "did not provide support for a clear recommendation for the use of donepezil" generally to forestall the diagnosis of AD in people with MCI, the researchers stated in their report, but they did note the potential importance of the findings for some patients. The data, they said, "could prompt a discussion" between clinicians and patients on the possibility of donepezil therapy in certain cases.

The findings were reported in the April 14, 2005, online "The New England Journal of Medicine".

"While the delay in progressing to Alzheimer's disease had a limited effect in this case, it comes at an early stage of memory loss, a critically important time for patients and families hoping that the disease can be held at bay," says Neil Buckholtz, Ph.D., chief of the Dementias of Aging Branch at the NIA.

As part of the study, the researchers examined the effect of donepezil and vitamin E on delaying diagnosis of AD among a subset of people with MCI with apolipoprotein E-4 (APOE-e4), the only known genetic risk factor for late-onset AD. While the overall rate of progression to AD was greater in this group, use of donepezil in the APOE-e4 subset was beneficial for up to 36 months in reducing the risk of an AD diagnosis. The researchers did not recommend APOE-e4 genotyping for people with MCI, suggesting more research
would be needed to understand the mechanism of action of the drug and other factors.

Additional important factors in the study were the success in diagnosing MCI on a reliable basis in a multi-site study and the finding that MCI can be predictive of AD. A condition whose characterization in the medical community is relatively new, MCI is a transitional state that occurs between the cognitive changes of normal aging and the very early stage of AD. The amnestic subtype of MCI, the focus of this research, involves memory
problems not severe enough to be classified as dementia. Previous studies have shown that approximately eight in 10 people who meet criteria for amnestic MCI progress to AD within 6 years of diagnosis and that people with the APOE-e4 gene progress to AD more rapidly.

In this trial, donepezil and the antioxidant vitamin E were each compared to placebo to learn whether either treatment might delay or prevent progression to AD among people with MCI. Participants were randomized to three groups, one taking 2000 International Units daily of vitamin E, the second receiving 10 mg of donepezil daily, and the third on placebo. All participants also took daily multivitamins. The average age of the participants at baseline was 73 years.

Among the 769 study participants enrolled at 69 sites in the U.S. and Canada, 212 developed possible or probable AD within the 3-year study period. The overall rate of progression from MCI to AD for all three treatment groups combined was 16% per year. The study found that the group on donepezil's risk of progression to a diagnosis of AD was reduced by 58 percent one year into the study, 36 percent at 2 years, but there was no risk reduction at the end of the full 3 years of the study.

"These findings give me a great deal of hope," says Petersen. "We have not answered the question of whether donepezil reduces the underlying brain changes in Alzheimer's disease, but now we know that for some people, drug therapy did make a real, clinical difference. I think there will be real opportunities in the future to test other therapies for patients with MCI."

Donepezil, a cholinesterase inhibitor, is currently prescribed for mild to moderate stages of AD to improve memory and other cognitive functions. Cholinesterase inhibitors work by delaying the breakdown of the
neurotransmitter acetylcholine in the brain. Acetylcholine helps communication between the nerve cells and is important for memory.

The report will appear in the June 9, 2005, print version of "The New England Journal of Medicine".

Blood Test for Multiple Sclerosis a Possibility

A simple blood test may one day detect multiple sclerosis before its debilitating symptoms take hold.

Researchers from Wake Forest University Baptist Medical Center have identified three peptides that are present in people with the degenerative nerve disease, but not in people without the condition. The finding could lead to the development of a blood test to spot the disease, which currently requires a round of tests and exams to arrive at a conclusive diagnosis.

Other doctors, however, caution that while the identification of the peptides is a step forward, it is a long way from becoming a clinical tool in the diagnosis of multiple sclerosis (MS).
Finding a distinct pattern of three biomarkers of peptides among the MS patients "suggests the potential for developing a blood test that could allow us to identify the earliest changes that represent MS, and help in its diagnosis," wrote lead researcher Dr. Jagannadha Avasarala, who was affiliated with Wake Forest University Baptist Medical Center at the time of the study. The findings appear in the March 24 issue of the Journal of Molecular Neuroscience.

For the study, researchers compared blood samples from 25 patients who were newly diagnosed with MS to those from 25 people without the disease to see if there were any pattern of proteins and peptides unique to the MS patients.
The MS patients had the most common form of the disease, which is called relapse-remitting and is characterized by attacks that come only periodically. None of them were taking medication and their average age was 29, while the average age of the control group was 28.
The researchers found three peptide biomarkers in all the MS patients that were not present in those without the disease. Proteins are made by genes, and the information locked in the genes is expressed by the proteins. Peptides are the building blocks of proteins.
The findings were made using mass spectrometry, a tool that analyzes proteins with a special software that can recognize protein patterns. Predictive Diagnostics, a California company, developed the technology and funded the research.
"This is an interesting step in the identification of peptides that are unique to MS, but in terms of making a diagnosis, it isn't useful," said Dr. William Sheremata, director of the Multiple Sclerosis Center at the University of Miami School of Medicine.
He said while work with spectrometry is used in many areas of science in identifying compounds in the brain and does represent a new approach to chemistry, using the information to create a simple blood test would require continued research.

Journal of Molecular NeuroscienceJanuary 2005, Volume 25, Issue 1, pps. 119-126