Novel Intervention Slows Cognitive Decline in At-Risk Adults

Combining cognitive remediation (CR) with transcranial direct current stimulation (tDCS) was associated with slower cognitive decline for up to 6 years in older adults with major depressive disorder that is in remission (rMDD), mild cognitive impairment (MCI), or both, new research suggests.
The CR intervention included a series of progressively difficult computer-based and facilitator-monitored mental exercises designed to sharpen cognitive function. 
Researchers found that using CR with tDCS slowed decline in executive function and verbal memory more than other cognitive functions. The effect was stronger among people with rMDD vs those with MCI and in those at low genetic risk for Alzheimer’s disease. 
“We have developed a novel intervention, combining two interventions that if used separately have a weak effect but together have substantial and clinically meaningful effect of slowing the progression of cognitive decline,” study author Benoit H. Mulsant, MD, chair of the Department of Psychiatry, University of Toronto, and senior scientist at the Center for Addiction and Mental Health, Toronto, told Medscape Medical News. 
The findings were published online October 30 in JAMA Psychiatry. 
High-Risk Group
Research shows that older adults with MDD or MCI are at high risk for cognitive decline and dementia. Evidence also suggests that depression in early or mid-life significantly increases the risk for dementia in late life, even if the depression has been in remission for decades.
A potential mechanism underlying this increased risk for dementia could be impaired cortical plasticity, or the ability of the brain to compensate for damage.
The PACt-MD trial included 375 older adults with rMDD, MCI, or both (mean age, 72 years; 62% women) at five academic hospitals in Toronto, Canada.
Participants received either CR plus tDCS or sham intervention 5 days per week for 8 weeks (acute phase), followed by 5-day “boosters” every 6 months.
tDCS was administered by trained personnel and involved active stimulation for 30 minutes at the beginning of each CR group session. The intervention targets the prefrontal cortex, a critical region for cognitive compensation in normal cognitive aging.
The sham group received a weakened version of CR, with exercises that did not get progressively more difficult. For the sham stimulation, the current flowed at full intensity for only 54 seconds before and after 30-second ramp-up and ramp-down phases, to create a blinding effect, the authors noted. 
A geriatric psychiatrist followed all participants throughout the study, conducting assessments at baseline, month 2, and yearly for 3-7 years (mean follow-up, 48.3 months). 
Participants’ depressive symptoms were evaluated at baseline and at all follow-ups and underwent neuropsychological testing to assess six cognitive domains: processing speed, working memory, executive functioning, verbal memory, visual memory, and language.
To get a norm for the cognitive tests, researchers recruited a comparator group of 75 subjects similar in age, gender, and years of education, with no neuropsychiatric disorder or cognitive impairment. They completed the same assessments but not the intervention.
Study participants and assessors were blinded to treatment assignment.
Slower Cognitive Decline
Participants in the intervention group had a significantly slower decline in cognitive function compared with those n the sham group (adjusted z score difference [active − sham] at month 60, 0.21; P = .006). This is equivalent to slowing cognitive decline by about 4 years, researchers reported. The intervention also showed a positive effect on executive function and verbal memory. 
“If I can push dementia from 85 to 89 years and you die at 86, in practice, I have prevented you from ever developing dementia,” Mulsant said.
The efficacy of CR plus tDCS in rMDD could be tied to enhanced neuroplasticity, said Mulsant. 
The treatment worked well in people with a history of depression, regardless of MCI status, but was not as effective for people with just MCI, researchers noted. The intervention also did not work as well among people at genetic risk for Alzheimer’s disease.
“We don’t believe we have discovered an intervention to prevent dementia in people who are at high risk for Alzheimer disease, but we have discovered an intervention that could prevent dementia in people who have an history of depression,” said Mulsant. 
These results suggest the pathways to dementia among people with MCI and rMDD are different, he added. 
Because previous research showed either treatment alone demonstrated little efficacy, researchers said the new results indicate that there may be a synergistic effect of combining the two. 
The ideal amount of treatment and optimal age for initiation still need to be determined, said Mulsant. The study did not include a comparator group without rMDD or MCI, so the observed cognitive benefits might be specific to people with these high-risk conditions. Another study limitation is lack ofdiversity in terms of ethnicity, race, and education. 
Promising, Important Findings
Commenting for Medscape Medical News, Badr Ratnakaran, MD, assistant professor and division director of geriatric psychiatry at Carilion Clinic-Virginia Tech Carilion School of Medicine, Roanoke, Virginia, said the results are promising and important because there are so few treatment options for the increasing number of older patients with depression and dementia.
The side-effect profile of the combined treatment is better than that of many pharmacologic treatments, Ratnakaran noted. As more research like this comes out, Ratnakaran predicts that CR and tCDS will become more readily available.
“This is telling us that the field of psychiatry, and also dementia, is progressing beyond your usual pharmacotherapy treatments,” said Ratnakaran, who also is chair of the American Psychiatric Association’s Council on Geriatric Psychiatry. 
The study received support from the Canada Brain Research Fund of Brain Canada, Health Canada, the Chagnon Family, and the Centre for Addiction and Mental Health Discovery Fund. Mulsant reported holding and receiving support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto; being a member of the Center for Addiction and Mental Health Board of Trustees; research support from Brain Canada, Canadian Institutes of Health Research, Center for Addiction and Mental Health Foundation, Patient-Centered Outcomes Research Institute, and National Institutes of Health; and nonfinancial support from Capital Solution Design (software used in this study) and HappyNeuron (software used in this study). Ratnakaran reported no relevant conflicts.
 
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