DIMENSIONS Spring 2001

SPOTLIGHT ON RESEARCH: NEWEST ADRC RESEARCHERS TACKLE A VARIETY OF ALZHEIMER'S QUESTIONS

by Cheryl Dawes

Dr. Elizabeth Aylward

Clinical symptoms such as problems in memory and judgment are usually the first symptoms detected in a person with Alzheimer's disease (AD). These symptoms are also associated with other forms of dementia. Thorough assessment can rule out other forms of dementia and lead to a diagnosis of probable Alzheimer's.

Diagnoses are accurate most of the time; however, because AD is a disease characterized by major changes in the brain, it can only be definitively diagnosed by examining a patient's brain tissue after death.

To improve accuracy in early diagnosis of AD, the search is on for clinical or biological markers exclusive to the disease, especially at its earliest stages when symptoms of dementia may not be apparent. As part of this search, ADRC researcher Dr. Elizabeth Aylward applies imaging techniques to look for distinctive features of the brain associated with AD. With funding from the National Institute on Aging (NIA), Aylward, professor of radiology, is currently investigating use of a noninvasive brain imaging technique called functional magnetic resonance imaging (fMRI) to develop a diagnostic assessment of the hippo-campus, a brain structure involved in the early stages of AD.

With fMRI, Aylward can identify areas in the brain that become active when a person in the MRI scanner performs a task such as remembering pairs of words. Aylward is studying how the hippocampus is activated in response to a variety of different types of memory tasks. She is working to pinpoint a paradigm that will consistently activate the hippocampal region in adults. Once she and her colleagues have determined a reliable fMRI paradigm, they will begin a study to compare hippo-campal activation in patients with early-stage AD and in normal older adults. Results of this work could lead to a more accurate method for earlier diagnosis and provide researchers a valuable tool for measuring the effectiveness of new treatments designed to prevent or slow the devastating progression of AD.

Dr. David Cook

Funded by the NIA and the VA Merit Review, Dr. David Cook is investigating a complex set of harmful genetic and molecular processes that take place within individual brain cells in AD. Cook, research assistant professor of medicine in the Division of Gerontology and Geriatric Medicine, joined the ADRC in 1999. His research focuses on biochemical processes that occur in neurons-the electrically excitable cells essential for all brain functions. He studies the protein-processing events that cause a build-up of senile plaques, which are the hallmark of AD. These plaques are small, abnormal deposits composed mostly of beta amyloid peptide. As the disease progresses, the plaques litter the brain, causing damage.

Beta amyloid is made when enzymes cut the amyloid precursor protein (APP). To gain insight into the relationship between the processing of APP and AD, Cook is studying neurons derived from an animal model and examining the cascade of biochemical events leading to production of beta amyloid. These studies involve neurons specifically engineered in transgenic mice to express Presenilin genes with the same kinds of mutations that have been linked to early-onset familial AD in humans.

In other studies, Cook is investigating the action of a newly discovered enzyme that is responsible for cutting APP into beta amyloid peptides. This molecule, called BACE, is expressed widely throughout the body. However, the brain expresses it in a form that is different from other tissues in the body. Understanding how BACE is processed should help in understanding how it functions to produce beta amyloid.

Results of Cook's work are likely to provide information for designing new strategies to prevent or slow the destructive changes in the brain caused by the disease.

Dr. Inez Vincent

Damage caused by AD leads to the death of brain cells. The process is complex and the biochemical steps that lead from damage to cell death are not clear. By gaining a better understanding of these steps, ADRC researcher Dr. Inez Vincent hopes to shed light on ways to intervene in the process.

With funding from the NIA, Vincent, research associate professor of pathology, studies the role of proteins that control the cell cycle and the cell death associated with AD. The cell cycle is an ordered set of events that culminates in cell growth and mitosis-the division of a cell into two daughter cells. Results of Vincent's earlier studies support the idea that the proteins responsible for regulating cellular events that lead to mitosis are involved in AD.

In her current research, Vincent is seeking to determine how the normal cell cycle is disrupted to result in deterioration of brain cells instead of cell division. She is investigating the process in cultured human neurons and in mouse models (funded by the NIA and Alzheimer's Association) that display some aspects of AD pathology. Elucidating the cell-cycle events that form the pathway to cell death may provide several points for applying therapeutic strategies to halt the progression of neuron deterioration in AD and other neurodegenerative diseases.


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