Heart rate variability and risk of agitation in Alzheimer’s disease: the Atherosclerosis Risk in Communities Study

Abstract

Agitation in Alzheimer’s disease is common and may be related to impaired emotion regulation capacity. Heart rate variability, a proposed index of autonomic and emotion regulation neural network integrity, could be associated with agitation propensity in Alzheimer’s disease. We used the Atherosclerosis Risk in Communities Study cohort data, collected over seven visits spanning over two decades, to investigate whether heart rate variability (change) was associated with agitation risk in individuals clinically diagnosed with dementia due to Alzheimer’s disease. Agitation (absence/presence) at Visit 5, the primary outcome, was based on the Neuropsychiatric Inventory agitation/aggression subscale, or a composite score comprising the total number of agitation/aggression, irritability, disinhibition and aberrant motor behaviour subscales present. Visit 1–5 heart rate variability measures were the log-transformed root mean square of successive differences in R–R intervals and standard deviation of normal-to-normal R–R intervals obtained from resting, supine, standard 12-lead ECGs. To aid interpretability, heart rate variability data were scaled such that model outputs were expressed for each 0.05 log-unit change in heart rate variability (which approximated to the observed difference in heart rate variability with every 5 years of age). Among 456 participants who had dementia, 120 were clinically classified to have dementia solely attributable to Alzheimer’s disease. This group showed a positive relationship between heart rate variability and agitation risk in regression models, which was strongest for measures of (potentially vagally mediated) heart rate variability change over the preceding two decades. Here, a 0.05 log-unit of heart rate variability change was associated with an up to 10-fold increase in the odds of agitation and around a half-unit increase in the composite agitation score. Associations persisted after controlling for participants’ cognitive status, heart rate (change), sociodemographic factors, co-morbidities and medications with autonomic effects. Further confirmatory studies, incorporating measures of emotion regulation, are needed to support heart rate variability indices as potential agitation propensity markers in Alzheimer’s disease and to explore underlying mechanisms as targets for treatment development.

The emotion paradox in the aging body and brain

“…49 In addition, among participants with dementia in the longitudinal Atherosclerosis Risk in Communities study, a positive 0.05 log-unit of HRV change over the preceding two decades was associated with up to a 10-fold increase in the odds of agitation symptoms. 50 These findings of negative relationships between resting HRV and emotion regulation abilities among older people or patients with Alzheimer's disease are inconsistent with theories of how HRV relates to emotion regulation that have been developed based on data from younger adults. 48,[51][52][53][54][55] The current paper outlines a new model that may help address these inconsistencies.…”

“…In contrast, if the main source of noradrenergic hyperactivity is the LC, the vmPFC regulatory response may increase peripheral HRV, while failing to fully downregulate the hyperactive LC. This could explain the surprising finding that patients with dementia who showed increases in HRV in the preceding two decades had a greater risk of showing agitation symptoms 50 -both the increases in HRV and agitation could be downstream effects of LC hyperactivity.…”