DIMENSIONS Spring 2009

Change is Coming to the ADRC

by Kirsten Rohde

The University of Washington Alzheimer’s Disease Research Center (UW ADRC) is evolving and growing in new and exciting directions. In this interview, our director, Murray Raskind, MD, and associate director, Elaine Peskind, MD, discuss our past accomplishments and new ADRC initiatives.

What has been the focus of research in the ADRC thus far?
Since the ADRC was founded in 1985, our research has addressed both the basic causes of the behavioral and cognitive symptoms of Alzheimer’s disease (AD) and the development of more effective treatments for AD. We have conducted clinical trials that aim to improve or eliminate symptoms and to slow or halt the progression of the disease.

A principal focus that will continue into the future has been the genetics of AD. We have analyzed DNA (genetic material) of families in whom AD occurred over multiple generations and early life (before the age of 60). This enabled us to discover several genetic variations or mutations that cause family members to develop AD. The UW ADRC took a national lead in these studies, and our work was instrumental in identifying two of the three uncommon but very important mutations that cause AD in these families. We also pioneered efforts to find genes that cause frontotemporal dementia, a type of dementia that is related to AD. We continue to search for genetic variations that increase the risk for developing the more common late onset AD as major participants in multisite genetic studies.

What are the new directions for research in the UW ADRC?
As better treatments for AD become available, it is important that we be able to diagnose AD early and accurately. We have begun a program to address this problem using “biomarkers”.

What are biomarkers?
Our research center has focused on identifying brain chemical changes in cerebrospinal fluid (CSF), the fluid that surrounds the brain. Because a barrier prevents most brain chemicals from “crossing” from brain into blood, measurements in CSF obtained by lumbar puncture are the only way to detect changes in brain chemicals that signal the presence of the early stages of AD.

These biomarkers allow us to identify individuals who are at risk of developing AD symptoms, and may help identify individuals even before they show signs of memory loss or other cognitive problems. Biomarkers are also valuable for determining whether a new investigational medication is effective. Currently, the only way to diagnose AD is by a clinical assessment of a patient, and the only way to confirm that diagnosis is to conduct a brain autopsy after the patient has died. We don’t yet have a test in living persons that will definitively say whether someone has AD. However, our CSF biomarker studies are demonstrating differences between people with very early AD who will eventually develop the full-blown disease and people who will not develop AD later in life.

The UW ADRC has led a collaboration with four other ADRCs to create the nation’s largest research bank of spinal fluid. This fluid is collected from volunteers with AD, with mild memory loss, and with no memory loss who participate in a procedure called a lumbar puncture. Studying the spinal fluid allows us to determine whether chemical abnormalities in people with AD can be detected at a very early stage, that is, whether these abnormalities might be biomarkers for the disease before there is any clinical indication that a person is suffering from AD.

When researchers perform before-and-after lumbar punctures in drug studies, what are they looking for?
Pharmaceutical researchers design drugs to change the amount of a biomarker linked to AD (e.g., beta amyloid and tau). Before treatment and after treatment lumbar punctures can be done to see if the biomarker level changes with treatment. We have used this method to study beta amyloid, a substance that makes up the plaque in the brains of people with AD. Other researchers use this method to study other AD-related chemicals. As new discoveries are made, samples that are stored in the bank can be tested to determine the levels of these newly discovered biomarkers in the samples. Brain imaging is done with the same principle in mind—to see whether treatment slows down brain changes.

What other research areas are receiving more attention in the UW ADRC?
We are focusing on the development of improved medication therapy for the aggressiveness, resistance to necessary care, irritability, and restlessness that commonly accompany the advancement of dementia. This disruptive behavior is upsetting to both dementia patients and their caregivers, and is the most common cause of nursing home placement.

Many medications are used to treat disruptive agitation, but few have been demonstrated to work well. The medications that currently show some success often have unacceptable side effects and even slightly increase risk of death. We have discovered a drug, prazosin, that is both effective and well-tolerated for treating disruptive agitation in AD patients. Larger studies of this inexpensive generic drug are now underway. The use of prazosin grew out of UW ADRC studies in AD autopsy brain specimens that showed excessive activity of the excitatory brain chemical norepinephrine. Prazosin is an inexpensive generic medication that safely normalizes the effects of norepinephrine in the brain.

We participate in the testing of new therapeutic agents for the treatment of the memory loss and other cognitive deficits of AD. These clinical trials of investigational drugs include studies that enhance the effects of insulin in AD brain.

What can we expect in terms of research funding in the next years?
Research funds are becoming increasingly scarce. The current state of the economy suggests that this shortfall will continue for some time. UW ADRC investigators continue to compete successfully for funding from government grants. However, contributions from private donors will play an increasingly important role in the fight against AD.

The UW ADRC is fortunate to receive generous and ongoing support from two outstanding organizations: the UW Friends of Alzheimer’s Research (“the Friends”) and the Western and Central Washington Chapter of the Alzheimer’s Association (“the Alzheimer’s Association”). The Friends formed in 1980 from a group of relatives and concerned citizens whose family members or acquaintances were involved in early AD studies at the UW. Over the years they have provided funding for pilot projects in AD research by promising junior investigators, crucial equipment necessary for AD genetic studies, and (most recently) an endowed chair now occupied by Dr. Peskind. Our outstanding local chapter of the national Alzheimer’s Association has provided major funding for mature research projects by established UW AD researchers. The Alzheimer’s Association also is the major force in western and central Washington supporting caregiver support groups, educational programs for professional providers as well as lay caregivers, and referrals for families attempting to cope with AD. The UW ADRC continues to collaborate with the Alzheimer’s Association in education and research.

What is the current direction for clinical trials?
Our center is a major participant in nationwide cooperative studies of promising new therapeutic medications for Alzheimer’s disease. These studies are sponsored both by the National Institute of Aging and by the pharmaceutical industry. The direction of clinical trials has evolved from trying to improve symptoms of memory loss and other cognitive deficits to now trying to modify the disease process by slowing down or even stopping the progression of AD.

What kinds of studies can volunteers expect to see in the next year or two and who can participate?
In our clinical trials of investigational medications, we usually need participants in the early to middle stages of AD who have a caregiver available to assist in study participation and are in reasonably good health. In our studies of disruptive agitation in AD, we are seeking participants who can have more advanced AD and who are experiencing behavioral problems. In our biomarker studies, we are seeking participants in middle and later life who do not have memory problems, participants who have mild memory problems, and participants with AD. Of note, we have also begun programs to study biomarkers in other diseases such as Parkinson disease.

We believe that our emphasis on biological studies will help us better understand the earliest stages of AD. Because of our long history of performing lumbar punctures with little, if any, discomfort and our successful use of spinal fluid measurements to pinpoint brain chemical imbalances in AD, we are well-suited for this transition. This is a maturation of a research theme that we began early in the development of the ADRC. A second goal is to address the very challenging problem of finding effective, safe treatments for the disruptive agitation that complicates the later stages of AD and places such a large burden on caregivers, patients and the community. Finally, we will continue to conduct clinical trials of investigational drugs showing promise to slow or even halt the progression of Alzheimer’s disease.

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