A Biomarker to Predict Risk of Progression From Mild Cognitive Impairment to Dementia

A Biomarker to Predict Risk of Progression From Mild Cognitive Impairment to Dementia

Posted: April 25, 2024
A Biomarker to Predict Risk of Progression From Mild Cognitive Impairment to Dementia

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Are people with a history of major depression who suffer from mild cognitive impairment more likely to advance to dementia than those without a history of depression? In some cases, yes, but depression history alone was not predictive, researchers found. Rather, EEG measurements of a brain function called TGC was predictive. A reduction in TGC in the prefrontal cortex may be a useful biomarker of progressive cognitive decline.


When someone develops mild cognitive impairment (MCI), is there a way of predicting whether that individual will go on to develop dementia?New research sheds important new light on the question.

While it can be a source of anxiety, MCI does not seriously impair function, with symptoms that can include forgetting things more frequently, losing one’s train of thought, having difficulty remembering appointments, and challenges in spatial navigation, even in familiar places. All of these are a normal part of the aging process, but in MCI they are more frequent than in the typical aging individual. In contrast, dementia involves far more pronounced cognitive symptoms that impair an individual’s ability to function independently. People with dementia have significant memory loss, confusion, personality changes, and disability.

One question about predicting the risk of transitioning from MCI to dementia has revolved around the impact of co-occurring depression. Some studies have suggested that those with a diagnosis of major depression who also suffer from MCI are more likely to advance to dementia. Other studies have not observed this relationship.

A team of researchers led by 2010 BBRF Young Investigator Tarek K. Rajji, M.D., of the Centre for Addiction and Mental Health (CAMH) in Toronto, Canada, has just reported on the question of whether those with MCI and a history of major depression are at higher risk for progression to dementia than those with MCI alone.

Dr. Rajji and a team that included two BBRF Scientific Council members who are also affiliated with CAMH, Zafris J. Daskalakis, M.D., Ph.D., and Artistotle N. Voineskos, M.D., Ph.D., asked if patients with a history of major depressive disorder but currently in remission (“remitted MDD”) have a greater dementia risk than people with MCI alone.

In the clinical study the team just reported in the journal Translational Psychiatry, patients with MCI and a history of major depression, 85 of whom participated, were designed “MCI + rMDD”; 128 patients with MCI alone formed the comparison group. All had been recruited in a larger and broader trial called PACt-MD which includes a test of preventing cognitive decline with cognitive remediation plus a form of brain stimulation called transcranial direct current stimulation.

In the MCI vs. MCI+rMDD study just reported, the typical participant was about 70 years old. All completed a comprehensive battery of neuropsychological tests. These included tests of verbal memory, visuospatial memory, processing speed, language, working memory, and executive function. Of particular importance to the researchers were EEG (electroencephalogram) brain-wave measurements of a brain function called theta phase-gamma amplitude coupling (TGC) that reflects performance on a specific memory task involving near-term recall. Previous research had suggested that a reduction in TGC in the brain’s prefrontal cortex might be an early marker of serious cognitive impairment.

The objective of the study was to determine which of two methods was better at determining the difference in cognitive function between the two groups of participants. One basis of this determination was clinical diagnosis (i.e., whether they were diagnosed with MCI alone or MCI +rMDD); the other was participants’ EEG-based readouts of TGC. After the TGC test, which focused on the prefrontal cortex, participants were separated into “high TGC” and “low TGC” groups, based on their results relative to a “cutoff” level thought to be a potential biomarker for elevated risk of significant cognitive impairment.

The study demonstrated that differences in overall cognition between all participants in the trial was more clearly seen when the basis of determination was the TGC readout, as opposed to clinical diagnosis alone. Those with “high TGC” had very clearly contrasting cognitive performance compared with those with “low TGC,” irrespective of which diagnosis they had received (i.e., MCI alone or MCI +rMDD).

In fact, the team reported, “cognitive performance did not differ” between the two diagnostic groups—those with MCI alone and those with MCI and a history of major depression. And this indicated a step forward in trying to answer the key question: how can we predict which individuals will progress from MCI to dementia? “This suggests that clinical diagnosis alone might provide little information with respect to [current] cognitive functioning and possible risk for future cognitive decline.”

In turn, this finding, said the team, “underscores the need for a biomarker-based cognitive classification.” They propose that the TGC measurement might be a good candidate. The results of the study support the team’s earlier finding that TGC in the prefrontal region of the brain can serve as an index of overall cortical function. A rationale for this, they propose, is that “frontal lobes are critical in working memory and overall executive functioning.” Executive dysfunction “is common in MCI,” they add, “and can be predictive of those more likely to experience cognitive decline or develop dementia.”

It is possible, the team said, that those with MCI who are at low risk of progression to dementia may, as reflected in the TGC readout, have continuing “functional integrity of the executive control network,” which in turn may “contribute to the retention of executive function in MCI.” Conversely, the evidence so far suggests to the team that individuals with MCI and executive dysfunction have alterations in the structure and function of the brain’s frontal cortex. “Thus, if prefrontal cortex TGC is an index of executive functioning, then those with lower TGC and executive functioning could be at higher risk for future cognitive decline or progression to dementia.” They speculate this could be due to thinning of the cortex or “functional disconnection in the frontal cortex due to degenerative disease or other mechanisms.”

The design of the study did not permit the team to directly offer conclusions about cognitive decline, but only about “cognitive impairment as a possible proxy for cognitive decline.” Prefrontal TGC, in their view, is a “promising marker for identifying individuals at higher risk of cognitive decline.”

In addition to being on BBRF’s Scientific Council, Dr. Daskalakis is a 2008 BBRF Independent Investigator and 2006 and 2004 Young Investigator; Dr. Voineskos is a 2014 BBRF Independent Investigator and 2010 Young Investigator. Also on the team were Daniel M. Blumberger, M.D., a 2010 BBRF Young Investigator; Christopher R. Bowie, Ph.D., a 2013 BBRF Independent Investigator; and Sanjeev Kumar, M.D., a 2014 BBRF Young Investigator.