Yale University researchers can’t tell you where you left your car keys — but they can tell you why you can’t find them.
A
new study published July 27 in the journal Nature shows that the neural
networks in the brains of the middle-aged and elderly have weaker
connections and fire less robustly than in youthful ones. Intriguingly,
note the scientists, the research suggests that this condition is
reversible.
“Age-related
cognitive deficits can have a serious impact on our lives in the
Information Age, as people often need higher cognitive functions to meet
even basic needs, such as paying bills or accessing medical care,” says
Amy Arnsten, professor of neurobiology and psychology and a member of
the Kavli Institute for Neuroscience. “These abilities are critical for
maintaining demanding careers and being able to live independently as we
grow older.”
As
people age, they tend to forget things, are more easily distracted and
have greater difficulty with executive functions. These age-related
deficits have been known for years but the cellular basis for these
common cognitive difficulties has not been understood. The new study
examined for the first time age-related changes in the activity of
neurons in the prefrontal cortex (PFC), the area of the brain that is
responsible for higher cognitive and executive functions.
Networks
of neurons in the prefrontal cortex generate persistent firing to keep
information “in mind” even in the absence of cues from the environment.
This process is called “working memory,” which allows us to recall
information, such as where the car keys were left, even when that
information must be constantly updated. This ability is the basis for
abstract thought and reasoning, and is often called the “Mental Sketch
Pad.” It is also essential for executive functions, such as
multi-tasking, organizing, and inhibiting inappropriate thoughts and
actions.
Arnsten
and her team studied the firing of prefrontal cortical neurons in
young, middle-aged and old animals as they performed a working memory
task. Neurons in the prefrontal cortex of the young animals were able to
maintain firing at a high rate during working memory, while neurons in
older animals showed slower firing rates. However, when the researchers
adjusted the neurochemical environment around the neurons to be more
similar to that of a younger subject, the neuronal firing rates were
restored to more youthful levels.
Arnsten
says that the aging prefrontal cortex appears to accumulate excessive
levels of a signaling molecule called cAMP, which can open ion channels
and weaken prefrontal neuronal firing. Agents that either inhibited cAMP
or blocked cAMP-sensitive ion channels were able to restore more
youthful firing patterns in the aged neurons. One of the compounds that
enhanced neuronal firing was guanfacine, a medication that is already
approved for treating hypertension in adults and prefrontal deficits in
children, suggesting that it may be helpful in the elderly as well, note
the researchers.
Arnsten’s
finding is already moving to the clinical setting. Yale School of
Medicine is enrolling subjects in a clinical trial testing guanfacine’s
ability to improve working memory and executive functions in elderly
subjects who do not have Alzheimer’s disease or other dementias.
Information can be found at http://clinicaltrials.gov/ct2/show/NCT00935493.
Other
Yale authors are lead author Min Wang, Nao J. Gamo, Yang Yang,
Xiao-jing Wang, Mark Laubach, James A. Mazer and Daeyeol Lee.
Disclosure:
Yale University and Arnsten receive royalties from the sale of extended
release guanfacine (Intuniv), which is used for the treatment of
Attention Deficit Hyperactivity Disorder in children and adolescents.
Royalties are not received from the sale of the immediate-release form
of guanfacine, which is the form used in Arnsten’s studies and is the
test compound in Yale’s clinical trial of elderly subjects.