"Currently, there are no effective treatments for Alzheimer's disease, but we do have options for treating vascular disease. So, being able to determine that there is a vascular component to a patient's dementia would make a big difference in planning for treatment," said Norbert Schuff, PhD, a researcher in the Magnetic Resonance Unit at the San Francisco VA Medical Center and a UCSF associate professor of radiology.
The findings of the current study, appearing in the August 12 issue of Neurology, also promise to help speed up the development of new drug therapies for AD. "If we can tell the difference between people with Alzheimer's and those with vascular dementia, we can select the appropriate candidates for clinical trials of new drugs," said Schuff, who is lead author of the current study.
Alzheimer's disease, which affects 4 million Americans over the age of 65, is the most common cause of age-related dementia. It is characterized by progressive decline of cognitive functions. The second leading cause of dementia in the United States is the disruption of blood flow to the brain, known as vascular dementia. It affects between 2 and 3 percent of the U.S. population over the age of 65 years, or about 1 million people. Just as poor circulation in the heart leads to heart attacks, restricted blood flow in the brain can lead to strokes of varying severity.
Schuff and his colleagues studied the brains of 43 elderly patients who had been diagnosed with AD and 13 patients who had suffered small strokes below the surface of the brain, and diagnosed with what is called subcortical ischemic vascular dementia, or SIVD. They compared these subjects to 52 cognitively normal elderly subjects.
The researchers used MRI to create three-dimensional images of the patients' brains in order to look for differences in structure. They also used magnetic resonance spectroscopy to look at the chemical signature of different brain regions. In particular, they looked for a by-product of particular brain cells, called neurons, that make up the wiring of the brain. Active neurons carry electrical signals between different regions of the brain and produce a chemical called N-acetylaspartate, or NAA, which is not produced by other types of brain cells. The amount of NAA in a given region of the brain indicates the level of healthy neurons in that region. A reduction in NAA suggests either neuronal loss or dysfunction.
Researchers found that patients with SIVD had less of the NAA chemical in the region of the brain involved in short-term memory and decision making, called the frontal cortex, when compared to both patients with AD and control subjects. The brains of those with SIVD also had less NAA in the area of the brain involved in language and spatial orientation, called the parietal cortex, when compared to patients with AD and controls. But, SIVD patients had virtually no NAA losses in another brain region involved in memory, called the medial temporal lobe, where patients with AD had substantial NAA deficits.
Accuracy in separating cases of SIVD from AD was improved from 79 percent to 89 percent when researchers added measures taken by MR spectroscopy to measurements taken by conventional MRI.
In patients with SIVD, Schuff and his colleagues also found that lower levels of NAA in outer parts of the brain, called the cortex, were associated with severity of strokes in the layers below the cortex, called white matter. This observation agreed with preliminary findings by other researchers suggesting that SIVD is the result of disconnections between the outer and inner portions of the brain.
This finding suggests that, in patients with SIVD, there may only be neuronal dysfunction rather than neuronal loss, offering hope for recovery of neuronal function in these areas through drug treatment and other forms of therapy, Schuff said. However, there is still the possibility that neuronal loss in SIVD is due to processes indirectly related to stroke that also result in lower NAA. More study in this area will be necessary, Schuff said.
In fact, replication of the current study is also needed, Schuff said. "These patients were very carefully selected. We need to see if this method for distinguishing vascular dementia from Alzheimer's can be done in a clinical setting where many other factors may contribute dysfunction in the brain," he said.
Additional authors include Michael W. Weiner, MD, director of the Magnetic Resonance Unit (MRU) at the SFVAMC and UCSF professor of radiology, medicine, psychiatry and neurology; Antao Du, MD, and Diane L. Amend, PhD, both researchers of SFVAMC's MRU; David Norman, MD, UCSF professor of radiology; Joel H. Kramer, PsyD, UCSF clinical associate professor of psychiatry; Bruce L. Miller, MD, UCSF professor of neurology; Kristine Yaffe, MD, SFVAMC chief of geriatric psychiatry and UCSF associate professor of neurology, psychiatry and epidemiology and biostatistics; Bruce R. Reed, MD, UC Davis associate professor of psychiatry; Joseph O'Neill, PhD, UC Los Angeles assistant professor of radiology; William J. Jagust, MD, UC Davis professor and chair of neurology; Helena C. Chui, MD, University of Southern California professor of neurology; and Andres A. Capizzano, MD, of the MRI Unit of Fernandez Hospital, Bueonos Aires, Argentina.
This study was funded by grants from the Department of Veterans Affairs and a grant to the Northern California Institute for Research and Education from the National Institutes of Health.