Using five different medical imaging techniques to study the brain activity of 764 people, including those with Alzheimer’s disease, those on the brink of dementia, and healthy individuals, University researchers have found that the areas of the brain that young, healthy people use when daydreaming are the same areas that fail in people who have Alzheimer’s disease.
On the basis of their data, the researchers are proposing a hypothesis that Alzheimer’s disease may be due to abnormalities in the regions of the brain that operate the “default state.” This is the term used to describe the cognitive state people defer to when musing, daydreaming or thinking to themselves.
Writing in the Aug. 24 issue of the Journal of Neuroscience, the researchers state that “the default activity patterns of the brain may, over many years, augment a metabolic- or activity-dependent cascade that participates in Alzheimer’s disease pathology.”
“The regions of the brain we tend to use in our default state when we are young are very similar to the regions where plaques form in older people with Alzheimer’s disease,” said the study’s lead author, Randy L. Buckner, associate professor of psychology in Arts & Sciences and a Howard Hughes Medical Institute (HHMI) investigator at WUSTL.
“This is quite a remarkable convergence that we did not expect.”
The findings are important because they could help scientists and clinicians identify and understand the beginnings of what is probably a cascade of events that ultimately leads to Alzheimer’s.
The most common form of dementia among older people, Alzheimer’s is characterized outwardly by the erosion of language, thought and memory. Within the brains of people with Alzheimer’s, abnormal clumps of plaque and tangled bundles of fibers form and characterize the physical manifestation of the disease, which may affect as many as 4.5 million Americans.
The disease most frequently manifests itself after age 60, but its causes are unknown.
The availability of powerful imaging techniques and the ability to merge different sets of imaging data through new bioinformatics and statistical methods enabled Buckner and his team to construct a picture of Alzheimer’s from molecular changes to the structural and functional manifestations of the disease.
In the process, the team unexpectedly observed that the regions of the brain that light up when humans slip into comfortable patterns of thought are the same as those that, later in life, exhibit the disabling clumps of plaque characteristic of Alzheimer’s.
That remarkable correlation, Buckner said, suggests that dementia may be a consequence of the everyday function of the brain.
“It may be the normal cognitive function of the brain that leads to Alzheimer’s later in life,” said Buckner, who also holds joint appointments with the Mallinckrodt Institute of Radiology and the Department of Anatomy and Neurobiology in the School of Medicine. “This was not a relationship that we had even considered.
“The hypothesis is that the cascade of events that leads to Alzheimer’s begins at young adulthood.”
Scientists have long known that when the mind is not concentrated on a task — reading, engaging in conversation or solving a math problem, for example — it switches to a default mode, a state of mind where we may muse, daydream or retrieve pleasant memories. When a young person is asked to concentrate on a specific task, they are easily able to shut off the default mode — and the corresponding regions of the brain that run this mode.
With the help of powerful imaging technologies such as positron emission tomography and magnetic resonance imaging, scientists, including Buckner’s HHMI team, have begun to map the activity of the brain in its different states, including the default state. Among the observations they are making is that when a person who has clinical Alzheimer’s disease is asked to concentrate on a specific task, the default mode actually becomes more active — rather than showing less activity, as it would in a young, healthy adult.
The default state, according to Buckner, is characterized by metabolic activity in specific regions of the brain, notably the posterior and cortical regions.
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Interdisciplinary collaboration fosters Alzheimer’s insight Randy L. Buckner, Ph.D., lead author of the potentially paradigm-shifting paper on Alzheimer’s disease in the Aug. 24 issue of the Journal of Neuroscience, credits the breakthrough to the close-knit and creative collaboration of researchers in array of cognitive science specializations at Washington University. Buckner, an associate professor of psychology in Arts & Sciences, also holds joint appointments with the Mallinckrodt Institute of Radiology and the Department of Anatomy and Neurobiology in the School of Medicine. “The work stems from major involvement of the Alzheimer’s Disease Research Center in the Department of Neurology,” Buckner said. “It also relies heavily on novel imaging methods spearheaded by Mark Mintun in radiology and visualized using methods and software developed by David Van Essen in neurobiology.” His School of Medicine collaborators on this study include: • Anthony F. Fotenos, a doctoral student in the Medical Scientist Training Program and the Division of Biology and Biomedical Sciences; • Gina LaRossa, a medical student; • Mintun, M.D., professor of radiology and of psychiatry with the Mallinckrodt Institute of Radiology; • John C. Morris, M.D., the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology, professor of pathology and immunology and of physical therapy, and director of the Alzheimer’s Disease Research Center; • Rimmon Sachs, senior programmer analyst with the Mallinckrodt Institute of Radiology; • Benjamin J. Shannon, a graduate student in the Neuro-science Program of the Division of Biology and Biomedical Sciences; • Yvette I. Sheline, M.D., associate professor of psychiatry, of radiology and of neurology with the Mallinckrodt Institute of Radiology; and • Abraham Z. Snyder, Ph.D., M.D., with the Mallinckrodt Institute of Radiology and the Department of Radiology. “This provocative study reflects the commitment of the Alzheimer Disease Research Center (ADRC) in exploring novel methods to better understand this terrible disease,” Morris said. “The ADRC fosters multidisciplinary neuroimaging studies of healthy aging and Alzheimer’s disease and has benefited from the remarkable talents of investigators such as Drs. Buckner and Mintun, among many others, at Washington Univer-sity and from a very productive collaboration with Drs. (William E.) Klunk and (Chester) Mathis at the University of Pittsburgh. “By shedding new light on how the brain functions, Dr. Buckner’s elegant study brings us closer to identifying the basic causes of Alzheimer’s.” — Gerry Everding |
“These regions were active in the default states in young adults and also showed amyloid (plaque) deposition in older adults with Alzheimer’s disease,” the researchers wrote.
“The key insight is that brain activity and metabolism are not uniform across the brain,” Buckner said. “When we looked at people on the cusp of dementia, we saw a loss of brain tissue in the regions we predicted it would occur,” based on their observations of metabolism.
Insight from the study may help explain why the memory systems of the human brain are vulnerable.
“We appear to use memory systems often in our default states,” Buckner said. “This may help us to plan and solve problems. Maybe it helps us be creative. But it may also have metabolic consequences.”
The newfound correlation may also have future clinical implications, because Alzheimer’s is typically diagnosed when it is too late to intervene. To develop and administer effective treatments, clinicians will need to figure out ways to detect the disease in its earliest stages, said William E. Klunk, M.D., Ph.D., associate professor of psychiatry at the University of Pittsburgh and a co-author of the Journal of Neuroscience paper.
“You have to get to this pathology before it has its biggest effect, before it has done its damage,” said Klunk, who has developed techniques for imaging the amyloid plaques in Alzheimer’s patients.
Klunk said the findings suggest there is now the potential to begin to trace the patterns of the disease and develop methods to detect it before the clinical symptoms set in.
Buckner emphasized that the notion of a causative relationship between everyday metabolic functions of the brain and Alzheimer’s remains a hypothesis. However, new studies may help “show if amyloid (plaque) deposition is really dependent on metabolism. Can we find a biologically plausible reason for how metabolism causes Alzheimer’s disease?”
Moreover, looking to see if the phenomenon varies or is the same among many individuals will be required to firm up the link between brain metabolism in early life and Alzheimer’s pathology later in life.
Understanding variation may also help explain why some people are at high risk for Alzheimer’s.
“We are very interested in exploring these new observations to understand who is at risk and who is protected from Alzheimer’s,” Buckner said.
In addition to Buckner and Klunk, the study authors include Abraham Z. Snyder, Benjamin J. Shannon, Gina LaRossa, Rimmon Sachs, Anthony F. Fotenos, Yvette I. Sheline, John C. Morris and Mark A. Mintun, all of Washington University; and Chester Mathis of the University of Pittsburgh.