Psychiatric Symptoms Speed Conversion to Dementia

Megan Brooks

February 29, 2016

Neuropsychiatric symptoms (NPS) are associated with more rapid progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD), two new studies confirm.

The first study, led by Sarah Forrester, a doctoral candidate at Johns Hopkins University, in Baltimore, Maryland, pinpoints clusters of NPS associated with faster progression. The second study, led by R. Scott Mackin, PhD, University of California, San Francisco, suggests that chronic depressive symptoms are associated with structural brain changes that may contribute to more rapid conversion.

"Clinically," Forrester told Medscape Medical News, "our study gives clinicians an idea of who to keep an eye on in practice. We can definitively say which patients may deserve greater attention than others, and those in the higher-risk groups may be candidates for preventive measures, such as improvement in general medical health."

The studies are published in the February issue of the American Journal of Geriatric Psychiatry.

Predicting the Future

In the first study, Forrester and colleagues explored the association between NPS and progression to dementia in 540 patients with incident MCI from the Alzheimer's Disease Cooperative Study (ADCS). The patients were followed for a period of 2 years. At each visit, participants were assessed with the Neuropsychiatric Inventory Questionnaire.

The researchers used latent class analysis to classify MCI individuals into distinct subgroups on the basis of the presence or absence of different NPS. They identified three clusters of NPS: a severe cluster, marked by high rates of agitation (84%), anxiety (52%), apathy (51%), nighttime behaviors (48%), and disinhibition (44%); an affective cluster, characterized by high rates of depression (41%), anxiety (31%), irritability (32%), and nighttime behaviors (35%); and an asymptomatic cluster, labeled as such because all symptoms were endorsed by fewer than 5% of patients. The prevalence of each class was 7%, 37% and 56%, respectively.

During follow-up, 121 (22%) patients were judged to have progressed to dementia, 419 (78%) remained with MCI, and 167 (31%) reverted to normal cognition. The rate of progression from MCI to dementia was highest in the severe group, intermediate for the affective group, and lowest for the asymptomatic group, the researchers report.

Compared with the asymptomatic class, the severe class had more than twice the risk for progression to dementia (hazard ratio [HR], 2.69; 95% confidence interval [CI], 1.12 - 2.70); the affective class had more than 1.5 times the risk for progression to dementia (HR, 1.79; 95% CI, 1.12 - 2.70).

"Classifying patients based on their symptom profiles might allow a better understanding of how the addition of certain symptoms may change the risk of dementia diagnosis and shorten time to diagnosis," Forrester and colleagues note in their article.

Apathy and depression were common in both the affective and severe classes. "These symptoms may prove to be part of NPS clusters that are most predictive of progression," they write.

"Our results," they conclude, "have implications for early detection and treatment of dementia in those with NPS. Because patients with more NPS and specific NPS are more likely to progress to dementia diagnosis, preventing NPS earlier in life may be an avenue for prevention of MCI and dementia."

Brain Atrophy

In the second study, Dr Mackin and colleagues examined the role of chronic depressive symptoms in the risk for progression to dementia.

They used data from the Alzheimer's Disease Neuroimaging Initiative to characterize the relationship of chronic depressive symptoms, regional brain atrophy, and progression to AD in 94 individuals with MCI, 32 of whom had chronic depressive symptoms.

The investigators found that chronic depressive symptoms were associated with accelerated cortical atrophy in the frontal lobe and anterior cingulate, regions known to be affected by AD.

During median follow-up of 3 years, 38 participants (42.7%) progressed to AD. Incident AD was more common in those with than in those without chronic depressive symptoms (62.1% vs 33.3%). For patients with chronic depressive symptoms, the time to conversion to AD was 60% shorter than for those without depressive symptoms (P = .008).

The researchers note that the association between chronic depressive symptoms and incident AD was independent of cortical atrophy rates in the temporal regions but not of cortical atrophy rates in frontal regions. Taken together, the findings suggest that chronic depressive symptoms are associated with structural brain changes that may contribute to more rapid conversion to dementia in MCI, they conclude.

Causal Relationship "Likely"

Howard Aizenstein, MD, PhD, coauthor of an accompanying editorial, said that together, the two studies provide support for fully addressing affective symptoms in patients with MCI. Dr Aizenstein is professor of psychiatry and associate professor of bioengineering at the University of Pittsburgh, in Pennsylvania.

"Even without the link to dementia risk, full treatment of the affective symptoms would be recommended — but the accumulating evidence that this also may lower dementia risk provides additional information for patients in considering mental health treatment options," Dr Aizenstein told Medscape Medical News.

"These two studies support the association of affective symptoms with increased dementia risk. Neither study confirms causation; thus, we don't know if the affective symptoms potentiate the progression to AD. It could be that the underlying neurodegenerative changes lead to both the affective symptoms and dementia.

"However, it seems likely that there is a causal relationship, as there are multiple pathways in which affective symptoms can worsen cognition and function and thus hasten progression to AD. Thus, alleviating the affective symptoms may lower the dementia risk," he said.

The study authors and Dr. Aizenstein report no relevant financial relationships.

Am J Geriatr Psychiatry. 2016;24:105-106,117-125,126-135. Forrester et al, abstract; Mackin et al, abstract; Editorial

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