Brain Activity In Youth May Presage Alzheimer's Pathology

On the basis of their data, theresearchers are proposing a new hypothesis that suggests thatAlzheimer's disease may be due to abnormalities in the regions of thebrain that operate the “default state.” This is the term used todescribe the cognitive state people defer to when musing, daydreaming,or thinking to themselves.

Writing in the August 24, 2005, issueof the Journal of Neuroscience, the researchers state that “the defaultactivity patterns of the brain may, over many years, augment ametabolic- or activity-dependent cascade that participates inAlzheimer's disease pathology.”

“The regions of the brain we tendto use in our default state when we are young are very similar to theregions where plaques form in older people with Alzheimer's disease,”said the lead author of the study, Randy L. Buckner, a Howard HughesMedical Institute (HHMI) investigator at Washington University in St.Louis. “This is quite a remarkable convergence that we did not expect,”Buckner adds.

The new findings are important because they couldhelp scientists and clinicians identify and understand the beginningsof what is probably a cascade of events that ultimately leads toAlzheimer'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'sdisease, abnormal clumps of plaque and tangled bundles of fibers formand characterize the physical manifestation of the disease, which mayaffect as many as 4.5 million Americans. The causes of the disease areunknown.

The availability of powerful imaging techniques and theability to merge different sets of imaging data through newbioinformatics and statistical methods enabled Buckner and his team toconstruct a picture of Alzheimer's from molecular changes to thestructural and functional manifestations of the disease. In theprocess, the team unexpectedly observed that the regions of the brainthat light up when we slip into comfortable patterns of thought are thesame as those that, later in life, exhibit the disabling clumps ofplaque characteristic of Alzheimer's, a disease that most frequentlymanifests itself after age 60.

That remarkable correlation, said Buckner, suggests that dementia may be a consequence of the everyday function of the brain.

“Itmay be the normal cognitive function of the brain that leads toAlzheimer's later in life,” said Buckner. “This was not a relationshipthat we had even considered. The hypothesis is that the cascade ofevents that leads to Alzheimer's begins at young adulthood.”

Scientistshave long known that when the mind is not concentrated on a task —reading, engaging in conversation or solving a math problem, forexample — it switches to a default mode, a state of mind where we maymuse, daydream or retrieve pleasant memories. When a young person isasked to concentrate on a specific task, they are easily able to shutoff the default mode — and the corresponding regions of the brain thatrun this mode. With the help of powerful imaging technologies such aspositron emission tomography (PET) and magnetic resonance imaging(MRI), scientists, including Buckner's HHMI team, have begun to map theactivity of the brain in its different states, including the defaultstate. Among the observations they are making is that when a person whohas clinical Alzheimer's disease is asked to concentrate on a specifictask, the default mode actually becomes more active — rather thanshowing less activity, as it would in a young, healthy adult.

Thedefault state, according to Buckner, is characterized by metabolicactivity in specific regions of the brain, notably the posterior andcortical regions. “These regions were active in the default states inyoung adults and also showed amyloid (plaque) deposition in olderadults with Alzheimer's disease,” the researchers write in the newJournal of Neuroscience paper.

“The key insight is that brainactivity and metabolism are not uniform across the brain,” Bucknersaid. “When we looked at people on the cusp of dementia, we saw a lossof brain tissue in the regions we predicted it would occur,” based onour observations of metabolism.

Insight from the new study mayhelp explain why the memory systems of the human brain are vulnerable.“We appear to use memory systems often in our default states. This mayhelp us to plan and solve problems. Maybe it helps us be creative. Butit may also have metabolic consequences,” Buckner explained.

Thenewfound correlation may also have future clinical implications asAlzheimer's is typically diagnosed when it is too late to intervene. Todevelop and administer effective treatments, clinicians will need tofigure out ways to detect the disease in its earliest stages, saidWilliam Klunk, associate professor of psychiatry at the University ofPittsburgh and a co-author of the Journal of Neuroscience paper.

“Youhave to get to this pathology before it has its biggest effect, beforeit has done its damage,” said Klunk, who has developed techniques forimaging the amyloid plaques in Alzheimer's patients.

The findingsreported in the new study, he said, suggest that there is now thepotential to begin to trace the patterns of the disease and developmethods to detect it before the clinical symptoms set in.

Buckneremphasized that the notion of a causative relationship between everydaymetabolic functions of the brain and Alzheimer's remains a hypothesis.However, new studies may help “show if amyloid (plaque) deposition isreally dependent on metabolism. Can we find a biologically plausiblereason for how metabolism causes Alzheimer's disease?”

Moreover,looking to see if the phenomenon varies or is the same among manyindividuals will be required to firm up the link between brainmetabolism in early life and Alzheimer's pathology later in life.Understanding variation may also help us to explain why some people areat high risk for Alzheimer's disease.

“We are very interested inexploring these new observations to understand who is at risk and whois protected from Alzheimer's,” said Buckner.

In addition toBuckner and Klunk, authors of the Journal of Neuroscience articleinclude Abraham Z. Snyder, Benjamin J. Shannon, Gina LaRossa, RimmonSachs, Anthony F. Fotenos, Yvette I. Sheline, John C. Morris and MarkA. Mintun, all of Washington University; and Chester Mathis of theUniversity of Pittsburgh.