March 26, 1999

New lab set to probe mysteries of dementia, Alzheimer’s disease

New lab set to probe mysteries of dementia, Alzheimer's disease


Dr. Richard Margolin

The elderly make up the fastest growing segment of the nation's population. One out of seven Americans is age 65 or older, and in 40 years that number will swell to one out of four.

Currently, about 7 percent of these seniors – and nearly half of Americans age 85 years and older – have Alzheimer's disease. Care of these patients costs the country $100 billion today and will cost much more in the future.

"In coming years, we won't be able to build nursing homes fast enough to take care of people who need supervision if we don't have an effective intervention for AD," said Dr. Richard A. Margolin, associate professor of Psychiatry.

Vanderbilt is taking a leading role in investigating dementia, especially Alzheimer's disease, the most common cause of dementia in the United States. Margolin and fellow collaborators are studying a range of important unsolved problems in Alzheimer's disease, including risk factors, fundamental mechanisms, and possible improvements in diagnosis and treatment.

The new Laboratory of Geriatric Neuroscience, which Margolin directs, has three areas of focus: clinical trials, brain imaging and a cognitive electrophysiology unit to look at working memory in aging and mild dementia. It also has important collaborations with other Vanderbilt Alzheimer's disease researchers and is a satellite of the University of Kentucky's Alzheimer's disease Research Center, the nearest NIH-funded Alzheimer's disease Center. This status has helped Vanderbilt be part of the worldwide effort to understand the disease and has elevated Vanderbilt to a select group of Universities leading the battle.

"The lab will emphasize potentially unique studies of new diagnostic methods for AD, as well as treatment trials aimed at reversing the memory failure it causes or slowing its progression," Margolin said. "We also hope to learn how to deal more effectively with the behavioral complications of the disease. And we have a special interest in a newly appreciated variant of AD called Lewy Body dementia."

Besides Margolin the laboratory's faculty team includes Lynn Nielsen-Bohlman, Ph.D., a cognitive neuroscientist; Lynne McFarland, M.S.N., M.Ed.; and others in the geriatric psychiatry division which Margolin founded and directed for 11 years. There are also two trained research nurses.

Vanderbilt has had active dementia research for the past decade. But now the effort is more focused.

"The lab's overall plan is to help leverage the great opportunities for biomedical investigations of memory and dementing diseases at Vanderbilt," Margolin said. "With active investigators in several departments, we really have the potential to make important and unique contributions here. My goal is to see that that happens."

The laboratory's clinical trials program will soon move into new space on the first floor of the Village at Vanderbilt.

"We have carried out studies for almost 10 years in space basically designed for clinical care of non-elderly adults," Margolin said. "It is gratifying to acquire dedicated research space. Our work has included participation in the pivotal studies of at least a dozen possible treatments."

Many of the studies are done under the umbrella of the Alzheimer's disease Cooperative Study (ADCS), an NIH-funded consortium of 34 leading AD clinical trials academic sites.

The trials target three areas where drugs are being actively tested: improving cognition, especially short-term memory; slowing disease progression; and quieting behavioral complications of Alzheimer's disease.

There are more than 100 drugs in some stage of development for Alzheimer's, but only two cognitive enhancers in one class have made it to the market. VUMC was involved in the development of both – tacrine and donepezil. Both drugs are acetylcholinesterase inhibitors, so they boost levels of acetylcholine, the neurotransmitter that is central to short-term memory, the kind of memory lost in Alzheimer's disease.

The progression of Alzheimer's disease is also a key area of clinical trials efforts. VUMC was involved in an ADCS study that showed that Vitamin E slowed progression by about eight months.

"That may not sound like a lot, but when the cost of a nursing home is $35,000 a year and vitamin E is very inexpensive, it's a fairly significant intervention," Margolin said.

People who develop Alzheimer's disease first show mild symptoms of memory and thinking difficulties as they age.

"You don't just wake up one day with Alzheimer's. There's a progression from normal to a condition we call mild cognitive impairment," Margolin said. "This is a key area of investigation, and the ADCS plans a study of it. "It's intuitive if not proven that the earliest possible intervention would be the most effective intervention."

Another trial recently performed at VUMC looked at the inflammatory hypothesis in Alzheimer's disease. The study examined the possible value of prednisone. With continuing interest in this idea the next step may be testing of non-steroidal anti-inflammatory drugs, including the new COX-2 inhibitors just marketed for arthritis.

"This line of research arose from the observation that people taking anti-inflammatory drugs for other medical conditions like arthritis seem to have a lower prevalence of AD than the general population," Margolin said.

Margolin's program is also continuing to study behavioral problems in Alzheimer's patients, including sleep disturbances.

"If the patient isn't sleeping, the caregiver isn't sleeping. And if the caregiver isn't sleeping, the patient is on a slippery slope toward nursing home placement," Margolin said.

Since medications prescribed for sleep disturbances aren't always well tolerated by patients with Alzheimer's disease, VUMC is participating in an ADCS project to test the natural substance melatonin as a sleep aid.

"This is an exciting study scientifically and also because it evaluates a substance which is widely available without a prescription," Margolin said. "It's gratifying to be able to impact the public's medication use practices directly."

Lynn Nielsen-Bohlman, Ph.D., research assistant professor of Psychiatry, heads the laboratory's cognitive electrophysiology unit. Nielsen-Bohlman, trained in the use of an electroencephalography method called event related potentials, was recruited to Vanderbilt from the University of California, San Francisco in 1997.

She and Margolin will use a newly installed state-of-the-art event related potentials system to study working memory in aging and dementia.

"Dr. Nielsen-Bohlman has received a pilot grant from the University of Kentucky ADRC to initiate her studies, and we also plan to use the powerful emerging technique of functional magnetic resonance imaging too," Margolin said.

"One of the most distressing things about Alzheimer's disease is that we have drugs which look promising but we don't know who will benefit from them," Margolin said. "For example, only about 30% of people with AD benefit from donepezil, and we don't know which 30%. It costs hundreds of millions of dollars to get one effective drug on the market. So it's clear that it would be tremendously helpful to have a method of predicting response, both from a drug development perspective and a clinical perspective. We think that brain imaging, together with biomarkers, will help us do this."

Margolin stressed that intramural collaboration is a key part of the lab's philosophy. Margolin and his lab are working with Dr. Thomas J. Montine, assistant professor of Pathology, in studying a promising biomarker of Alzheimer's disease.

The study looks at spinal fluid and blood levels of substances that reflect oxidative damage to Central Nervous System lipids. These levels may both confirm the diagnosis of Alzheimer's disease as well as indicate its progression.

In another collaboration, Margolin is working with Jonathan L. Haines, Ph.D., associate professor of Molecular Physiology and Biophysics and co-director of the Institute on Genetics and Developmental Pharmacology, to examine candidate genes and environmental risk factors that may interact to produce Alzheimer's disease.

"Given all these exciting possibilities for creative and innovative Alzheimer's research at Vanderbilt, I'm really excited about our prospects for rapid progress," Margolin stressed. "It's going to be a lot of fun as we build a unique program here, and I hope we can one day be a real AD Center in our own right."