Cardinal Eve

Researchers Develop New Measure of Brain Health

How old is your brain compared to your chronological age? A new measure of brain health developed by researchers at Rush University Medical Center may offer a novel approach to identifying individuals at risk of memory and thinking problems, according to research results published in Alzheimer's & Dementia: The Journal of the Alzheimer's Association.

Dubbed the “cognitive clock” by the researchers, the tool is a measure of brain health based on cognitive performance. It may be used in the future to predict the likelihood of memory and thinking problems that develop as a person ages.

“Alzheimer’s disease, which is of the most common cause of dementia, and other diseases of the brain accumulate slowly over time as people get older. Age is widely recognized as the main risk factor for Alzheimer’s disease, but it’s a very imperfect predictor, since not everyone develops dementia as they age,” said Patricia Boyle, PhD, professor in Rush Medical College’s Division of Behavioral Sciences neuropsychologist in the Rush Alzheimer's Disease Center, and lead author of the study.

“Our new cognitive clock provides a measure of brain health that tells us more about how well a person’s brain is functioning than chronological age. In this way, the clock can help us detect who is at highest risk of developing cognitive impairment in the coming years.

“For some people, cognition remains fairly stable as they age,” Boyle added. “But, for others, cognition declines slowly over time, and still others show steep declines.”The researchers believed that cognitive performance data, even using a simple cognitive screening test, could be used to distinguish people exhibiting normal cognitive aging from those who are on their way to developing memory and thinking problems that are often coupled with aging.

This thesis led the Rush researchers to look at data they acquired from several long-term studies conducted by the RADC, including the Rush Memory and Aging Project which included people living in the community in greater Chicago; the Religious Orders Study, which included older Catholic clergy from across the United States; and the Chicago Health and Aging Project, a biracial population-based study. 

“We used long-term cognitive testing data from our participants to develop a profile of cognitive aging, what we call the cognitive clock” Boyle said.

“The cognitive clock reflects the general pattern of age-related cognitive decline and allows us to see who is doing better than average and who is doing worse at a given point in time. This helps us identify who might be at high risk of developing memory and thinking problems.”

The cognitive clock was first developed working with data from 1,057 participants from the Memory and Aging Project and the Religious Orders Study, who began without cognitive impairment and underwent yearly cognitive assessments for up to 24 years. The cognitive assessment included the Mini-Mental State Exam, a widely used test of cognitive function among the elderly that measures orientation, attention, memory, language and visual-spatial skills. In addition to the MMSE, detailed evaluations also included a structured medical history, neurologic examinations, and a set of neurocognitive tests.

The researchers examined how cognitive performance changes over time with advancing age using a novel statistical approach to identify the typical profile of cognitive aging. Using this cognitive clock, researchers can estimate an individual’s cognitive age -- their position on the clock — at any given point in time.

Cognitive age is an indicator of brain health. “We found that, on average, cognition remains stable until a cognitive age of around 80 years of age, then declines moderately until 90, then declines more rapidly until death,” Boyle said.

“Further, we found that cognitive age is a much better predictor than chronological age of dementia, mild cognitive impairment and mortality. It also is more strongly associated with other aspects of brain health.”

The researchers then applied the clock to an independent sample of 2,592 participants from the Chicago Health and Aging Project to confirm its accuracy for predicting outcomes such as Alzheimer’s dementia, mild cognitive impairment, and mortality. Again, they found that cognitive age was a better predictor of these outcomes than chronological age.

“Essentially, what we did is use cognitive data collected over many years to create a single, easy-to-understand metric that may be used to predict health outcomes with good accuracy,” Boyle said.

This tool may serve as an aid in aging research moving forward and may offer a new tool to identify at risk individuals.

“It is very difficult to develop a test or biomarker that accurately predicts health outcomes on an individual level. This has been a longstanding challenge in aging research. However, we are hoping that with additional research and validation, we may be able extend the approach applied here to clinical settings,” Boyle said.

Same Difference: Two halves of the hippocampus have different gene activity

A study of gene activity in the brain’s hippocampus, led by UT Southwestern researchers, has identified marked differences between the region’s anterior and posterior portions. The findings, published in Neuron, could shed light on a variety of brain disorders that involve the hippocampus and may eventually help lead to new, targeted treatments.

“These new data reveal molecular-level differences that allow us to view the anterior and posterior hippocampus in a whole new way,” says study leader Genevieve Konopka, Ph.D., associate professor of neuroscience at UTSW.

She and study co-leader Bradley C. Lega, M.D., associate professor of neurological surgery, neurology, and psychiatry, explain that the human hippocampus is typically considered a uniform structure with key roles in memory, spatial navigation, and regulation of emotions. However, some research has suggested that the two ends of the hippocampus – the anterior, which points downward toward the face, and the posterior, which points upward toward the back of the head – take on different jobs.

Scientists have speculated that the anterior hippocampus might be more important for emotion and mood, while the posterior hippocampus might be more important for cognition. However, says Konopka, a Jon Heighten Scholar in Autism Research, researchers had yet to explore whether differences in gene activity exist between these two halves.

For the study, Konopka and Lega, both members of the Peter O’Donnell Jr. Brain Institute, and their colleagues isolated samples of both the anterior and posterior hippocampus from five patients who had the structure removed to treat epilepsy. Seizures often originate from the hippocampus, explains Lega, who performed the surgeries. Although brain abnormalities trigger these seizures, microscopic analysis suggested that the tissues used in this study were anatomically normal.

After removal, the samples underwent single nuclei RNA sequencing (snRNA-seq), which assesses gene activity in individual cells. Although snRNA-seq showed mostly the same types of neurons and support cells reside in both sections of the hippocampus, activity of specific genes in excitatory neurons – those that stimulate other neurons to fire – varied significantly between the anterior and the posterior portions of the hippocampus. When the researchers compared this set of genes to a list of genes associated with psychiatric and neurological disorders, they found significant matches. Genes associated with mood disorders, such as major depressive disorder or bipolar disorder, tended to be more active in the anterior hippocampus; conversely, genes associated with cognitive disorders, such as autism spectrum disorder, tended to be more active in the posterior hippocampus.

Lega notes that the more researchers are able to appreciate these differences, the better they’ll be able to understand disorders in which the hippocampus is involved.

“The idea that the anterior and posterior hippocampus represent two distinct functional structures is not completely new, but it’s been underappreciated in clinical medicine,” he says. “When trying to understand disease processes, we have to keep that in mind.”

The closer you get to the light, the greater your shadow becomes.

But don’t be afraid. And don’t forget …