Anxiety, Amyloid Combo a 'Double Whammy' for Cognition

Pauline Anderson

February 13, 2015

Anxiety may contribute to the negative impact of amyloid-beta (Aβ) on cognitive function, new research suggests.

A new study showed that healthy older adults with elevated levels of Aβ and symptoms of anxiety had a greater decrease in various cognitive functions, including verbal memory and language, over time than their counterparts without anxiety symptoms.

Having both high anxiety and an elevated Aβ level is akin to having a "double whammy" in terms of the impact on cognition, lead author Robert H. Pietrzak, PhD, Clinical Neurosciences Division, Department of Veterans Affairs, West Haven, Connecticut, and assistant professor of psychiatry, Yale University, told Medscape Medical News.

The results suggest that reducing anxiety in patients with elevated Aβ may delay or slow decline in various cognitive domains.

The good news, said Dr Pietrzak, is that anxiety can be effectively treated.

The study was published online January 28 in JAMA Psychiatry.

Large Effect Size

The study included 333 older adults ranging in age from 60 to 89 years who underwent Aβ neuroimaging as part of the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

About half of the participants had subjective memory complaints, with a mean Memory Complaint Questionnaire score of 25.3.

About a third (32.7%) of patients were APOE ε4 carriers, and about a quarter (25.2%) were Aβ positive.

The mean Hospital Anxiety and Depression Scale anxiety score of patients was 4.2, and the mean depression score was 2.6. But 13.5% and 4.2% scored 8 or higher on the anxiety and depression subscales, respectively.

At baseline and at 18, 36, and 54 months, researchers carried out neuropsychological assessments. They computed a global cognition score by averaging scores across various cognitive domains.

Researchers plotted slopes of decline over time in various cognitive measures as a function of baseline Aβ level and anxiety symptoms.

They found that a positive Aβ status was associated with a significant decline in various cognitive functions and that elevated anxiety moderated these associations.

Compared with the Aβ-positive, low-anxiety group, slopes were significantly more pronounced in the Aβ-positive, high-anxiety group, with Cohen of values of 0.78 (95% confidence interval [CI], 0.33 - 1.23) for global cognition, 0.54 (95% CI, 0.10 - 0.98) for verbal memory, 0.51 (95% CI, 0.07 - 0.96) for language, and 0.39 (95% CI, 0.05 - 0.83) for executive function.

"We observed an overall effect size that was large ― there was almost a full standard deviation greater decline in the group that was Aβ positive and had high anxiety compared to the folks who were Aβ positive and low anxiety," said Dr Pietrzak.

Potential Mechanisms

The particularly pronounced effects on verbal memory and language function that the study uncovered are in line with neuropathologic models of Alzheimer's disease (AD), in which increased amyloid levels are typically seen in temporal regions of the brain that control those cognitive operations, said Dr Pietrzak.

"With increased amyloid accumulation in the brain, you're not firing on all cylinders. So you have limited bandwidth to begin with, and now you're adding onto that an additional layer of anxiety" that is primarily verbally mediated.

The impact of anxiety symptoms on Aβ-related decline in cognitive function was independent of several risk factors, including advanced age, educational level, IQ, APOE status, subjective memory complaints, vascular risk factors, and depressive symptoms.

"The effects persisted above and beyond the effect of those potentially confounding and really well-established risk factors for cognitive decline," said Dr Pietrzak.

He noted that most study patients had subclinical levels of anxiety and suggested that it might be appropriate to have a lower cutoff on conventional anxiety scales.

"A cut score of 5 or 6 might be indicative of clinically meaningful impairment in an older person."

The study showed no significant effect of depressive symptoms in predicting and moderating the effect of Aβ on cognition. This, said Dr Pietrzak, could be because efforts were made to screen out older persons with clinically meaningful depression.

According to the authors, anxiety may exert its damaging effects by diverting prefrontally mediated attentional resources to fear- and threat-related information, which may negatively affect encoding and retention of verbal information and other prefrontally mediated cognitive processes, such as executive function.

As well, elevated anxiety may increase endogenous levels of glucocorticoids ― stress hormones that can damage brain regions, including the hippocampus ― that are implicated in memory and language ability.

Early Days

The link between anxiety and increased hippocampal activation suggests that treating anxiety may reduce hippocampal hyperactivity, which in turn might mitigate memory decline in prodromal AD.

Research shows that selective serotonin reuptake inhibitors (SSRIs) promote hippocampal neurogenesis and possibly improve memory and global cognition in patients with mild cognitive impairment and AD. There is also evidence that SSRIs may directly influence Aβ levels.

"One potential hypothesis to test based on the results of the current study is that, at appropriate doses, treatment with selective serotonin reuptake inhibitors or other anxiolytic medications may improve memory and related aspects of cognitive function in Aβ positive individuals at risk for AD," the authors note.

It might be that use of such drugs, in addition to psychotherapy, is the way to go, although "it's relatively early days," said Dr Pietrzak.

A limitation of the study was that it may not reflect the general population, because it needed to include enough persons with well-known risk factors for cognitive decline ― for example, APOE ε4 carriers.

Also, the study did not investigate tau or other biological factors that contribute to, and interact with, psychological symptoms to increase cognitive decline.

"Like all research, these are bricks in the structure, or small flames in the cave of ignorance," said Dr Pietrzak. "There is a lot of work to be done."

Makes Sense

Commenting on the findings for Medscape Medical News, James A. Hendrix, PhD, director, Global Science Initiatives, Alzheimer's Association, said the research comes from a group whose work on imaging in this field is among the "most important" anywhere.

"It's an excellent paper and a really interesting hypothesis."

But although it is still a hypothesis at this point, it is consistent with existing literature on the association between cognitive decline and anxiety, said Dr Hendrix.

It makes sense, too, in that what is bad for the heart is generally also bad for the brain. Anxiety is linked to stress, which in turn is linked to heart disease.

The study, said Dr Hendrix, also "opens up other ideas" to look at risk factors beyond anxiety ― possibly lifestyle habits ― in patients with elevated Aβ.

"As amyloid imaging becomes more common, we can start to look at these other risk factors associated with amyloid-positive individuals."

But this will require more studies at a time when research in this field is "way underfunded," said Dr Hendrix. AD is among the top 10 causes of death in the United States, but federal funding for this disease lags behind that for cancer, HIV/AIDS, and heart disease, he said.

Dr Pietrzak reported working as a scientific consultant of Cogstate Ltd, which provided some of the cognitive tests used in the study.

JAMA Psychiatry. Published online January 28, 2015. Abstract

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