Anxiety symptoms in amnestic mild cognitive impairment are associated with medial temporal atrophy and predict conversion to Alzheimer disease

Abstract

Objective: To test the hypothesis that anxiety in amnestic mild cognitive impairment (aMCI) increases rates of conversion to Alzheimer disease (AD) and to identify potential neural mechanisms underlying such an association.

Methods: Participants (N = 376) with aMCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were studied over a median period of 36 months. A Cox proportional-hazards model was used to assess the association between anxiety severity ratings on the Neuropsychiatric Inventory Questionnaire and AD risk. Other variables were depression, memory loss, and MRI-derived AD-related regions of interest (ROIs), including hippocampal, amygdalar, entorhinal cortical (EC) volumes, and EC thickness, In addition, a linear regression model was used to determine the effect of anxiety in aMCI on rates of atrophy within ROIs.

Results: Anxiety severity increased rate of aMCI conversion to AD, after controlling for depression and cognitive decline. The association between anxiety and AD remained significant even with inclusion of ROI baseline values or atrophy rates as explanatory variables. Further, anxiety status predicted greater rates of decrease in EC volume. An association between anxiety and EC thickness missed significance.

Conclusion: Anxiety symptoms in aMCI predict conversion to AD, over and beyond the effects of depression, memory loss, or atrophy within AD neuroimaging biomarkers. These findings, together with the greater EC atrophy rate predicted by anxiety, are compatible with the hypothesis that anxiety is not a prodromal noncognitive feature of AD but may accelerate decline toward AD through direct or indirect effects on EC.

Keywords: Alzheimer disease; MRI biomarker; amygdala; anxiety; depression; entorhinal cortex; mild cognitive impairment; neuropsychiatric symptoms.

FIGURE

Kaplan-Meier survival curves of progression from aMCI to AD dementia as predicted by NPI-Q anxiety severity (left graph), NPI-Q depression severity (middle graph), and GDS (right graph). Survival indicates absence of progression from aMCI to AD dementia.