Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer's disease

Abstract

Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from the earliest stages of Alzheimer's disease onwards and has been associated with symptoms of agitation. It is hypothesized that compensatory locus coeruleus-noradrenaline system overactivity and impaired emotion regulation could underlie agitation propensity, but to our knowledge this has not previously been investigated. A better understanding of the neurobiological underpinnings of agitation would help the development of targeted prevention and treatment strategies. Using a sample of individuals with amnestic mild cognitive impairment and probable mild Alzheimer's disease dementia from the German Center for Neurodegenerative Diseases (DZNE)-Longitudinal Cognitive Impairment and Dementia (DELCODE) study cohort (N = 309, aged 67-96 years, 51% female), we assessed cross-sectional relationships between a latent factor representing the functional integrity of an affect-related executive regulation network and agitation point prevalence and severity scores. In a subsample of individuals with locus coeruleus MRI imaging data (N = 37, aged 68-93 years, 49% female), we also investigated preliminary associations between locus coeruleus MRI contrast ratios (a measure of structural integrity, whole or divided into rostral, middle, and caudal thirds) and individual affect-related regulation network factor scores and agitation measures. Regression models controlled for effects of age and clinical disease severity and, for models including resting-state functional MRI connectivity variables, grey matter volume and education years. Agitation point prevalence showed a positive relationship with a latent factor representing the functional integrity (and a negative relationship with a corresponding structural measure) of the affect-related executive regulation network. Locus coeruleus MRI contrast ratios were positively associated with agitation severity (but only for the rostral third, in N = 13) and negatively associated with the functional affect-related executive regulation latent factor scores. Resting-state functional connectivity between a medial prefrontal cortex region and the left amygdala was related to locus coeruleus MRI contrast ratios. These findings implicate the involvement of locus coeruleus integrity and emotion dysregulation in agitation in Alzheimer's disease and support the presence of potential compensatory processes. At the neural level, there may be a dissociation between mechanisms underlying agitation risk per se and symptom severity. Further studies are needed to replicate and extend these findings, incorporating longitudinal designs, measures of autonomic function and non-linear modelling approaches to explore potential causal and context-dependent relationships across Alzheimer's disease stages.

Keywords: Alzheimer; agitation; autonomic; emotion regulation; locus coeruleus.

Graphical abstract

Figure 1

SEM to assess regression of agitation point prevalence on the affect-related executive regulation latent factor (fER). The affect-related executive regulation latent factor (fER) was formed of resting-state functional connectivity measures between mPFC-ACC (mPFC_ACC), mPFC-right amygdala (mPFC_Ramyg), mPFC-left amygdala (mPFC_Lamyg), ACC-left amygdala (ACC_Lamyg), ACC-right amygdala (ACC_Ramyg), and executive function factor scores (EXEC). A corresponding structural latent factor (sER) was formed of grey matter volumes of right and left mPFC (mPFC_R, mPFC_L) and averaged bilateral ACC and amygdala values. The fER and sER measurement models showed a good fit after incorporating covariance paths (double-headed arrows) between the observed variables based on modification indices. In a structural equation model, the regression path (single-headed arrow) between agitation point prevalence and the fER latent factor was controlled for grey matter volume (sER), age, education years (edyears), and clinical disease severity (CDR-SB). A separate model for agitation severity is shown in Supplementary Fig. 1. Only statistically significant standardized covariance/regression estimates are displayed. Squares/rectangles represent observed variables and circles represent latent factors. Number of observations used: N = 304 for the agitation point prevalence SEM and N = 244 for the agitation severity SEM.