Depression, MCI Combo Dramatically Accelerates Brain Aging

Deborah Brauser

August 15, 2014

Older adults with both depression and mild cognitive impairment (MCI) may have brain biomarkers signifying an increased risk for accelerated brain aging, which could then lead to the development of dementia, new research suggests.

Dr. Meryl Butters

The study, which included 80 patients older than 64 years with depression, showed that those who also had MCI vs those with normal cognition had significant differences in the brain activity of 24 proteins involved in the regulation of several pathways, including inflammation, intracellular signaling, and cell survival, as well as a greater risk for cerebrovascular disease.

However, there were no between-group differences found in the amount of beta-amyloid deposition.

"This is the first study that's ever looked at so many different kinds of markers all at once," principal investigator Meryl A. Butters, PhD, associate professor of psychiatry and director of the Geriatric Neuropsychology Research Program at the University of Pittsburgh School of Medicine in Pennsylvania, told Medscape Medical News.

"Better understanding of the neurobiology of cognitive impairment in depression can provide new targets for developing more specific treatments, not only for its prevention and treatment but also for its downstream negative outcomes, including the development of dementia and related disorders," she added in a release.

The study was published online August 5 in Molecular Psychiatry.

242 Proteins Tested

Although the risk of developing dementia doubles in older adults diagnosed with major depression vs those without the disorder, the mechanism is unclear. Most previous studies have examined 1 or 2 biomarkers when investigating this question. However, in the current study, the investigators tested 242 blood-based proteins and also examined structural brain abnormalities.

A total of 80 adults with remitted late-life depression were enrolled; 36 had MCI (67% women; mean age, 73.4 years), and 44 had normal cognitive function (87% women; mean age, 72.4 years).

Whole-blood samples were taken from all participants and tested for the proteins associated with pathways for cancer, cardiovascular disease, metabolic syndrome, psychiatric disorders, and neurodegenerative disorders.

In addition, positron emission tomography using Pittsburgh compound B (PiB-PET) was used to measure brain amyloid-beta (Aβ) deposition, thought to be involved in Alzheimer's disease, and MRI scans were used to measure white matter hyperintensity and whole-brain gray matter atrophy volumes.

Results showed that the participants who had both depression and MCI had significant "differential expression" of 24 proteins used in the regulation of immune-inflammatory activity (including higher levels of CCL13-MCP-4 and CXCL11-interferon-inducible T-cell alpha chemoattractant), cell survival, protein and lipid homeostasis, and intracellular signaling (all, P < .05).

"While people with depression typically have immune-inflammatory abnormalities, those who also had [MCI] had poorer immune-inflammatory control," added Dr. Butters.

This group also had significantly greater white matter hyperintensity volume than the group with normal cognition (0.0201 vs 0.006, respectively; P = .015), signaling cerebrovascular disease.

Driven by Vascular Changes?

However, the 2 groups did not differ significantly in gray matter volume, as shown on the MRI scans, or in Aβ deposition, as shown with PiB-PET.

"No difference in the brain shrinkage was somewhat surprising. But the most surprising thing was that those with MCI did not have more beta-amyloids," said Dr. Butters.

The investigators note that this suggests that MCI in depression may be driven by vascular-related changes.

Using "machine learning analysis," the researchers found that, together, the 3 proteins apolipoprotein AI, interleukin-12, and stem cell factor gave 81.3% accuracy, 75% sensitivity, and 86.4% specificity rates in being able to distinguish the patients with MCI from those without.

"This study represents a significant advance in its attempt to provide an integrated view of abnormalities related to cognitive impairment in [late-life depression] using multiple biomarker modalities," write the investigators.

"Ultimately, if we can understand what happens in the brain when people are depressed and suffer cognitive impairment, we can then develop strategies to slow or perhaps stop the impairment from progressing to dementia," said Dr. Butters.

"There's a huge public health significance to all of this. Dementia takes a huge toll on society. And we can make a huge dent in that if we can better understand these pathways and interrupt them at a younger age before they cause permanent damage," she added.

Another Piece of the Puzzle

"I think this is an interesting study," Heather Snyder, PhD, director of medical and scientific operations at the Alzheimer's Association, told Medscape Medical News.

Dr. Heather Snyder

"We've seen in population studies that late-life depression and changes in memory are somehow linked or occur more commonly within the same individual. But we don't really understand why or how these might fit together," she said.

"This is really one of the first studies that I'm aware of that combines multiple biomarkers, multiple markers of biological change, in looking at changes in memory and late-life depression."

However, she added that it is too early to fully understand how these factors might coexist.

"You can almost think about it in that we have a puzzle that we're trying to put together ― and we're not even sure what the puzzle is going to look like at the end of the day," said Dr. Snyder.

"What this study does is give us some pieces of that puzzle. But we really need more understanding about how late-life depression and cognitive decline might be linked together."

Dr. Snyder added that the Alzheimer's Association encourages anyone who is worried about themselves or a loved one to talk with a healthcare professional, especially because other things could also be happening.

"The study shows that the presence of late-life depression is linked to increases in white matter intensity, which is often used as a measure of looking at vascular changes in the brain. And that is an important consideration for a physician."

She pointed out that because there are still many questions about how all the findings fit together and the study only examined 80 individuals, more research is needed in larger and more diverse populations.

The study authors report no relevant financial relationships.

Mol Psychiatry. Published online August 5, 2014. Abstract

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