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

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 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 modeling approaches to explore potential causal and context-dependent relationships across Alzheimer’s disease stages

Blood biomarkers confirm subjective cognitive decline (SCD) as a distinct molecular and clinical stage within the NIA-AA framework of Alzheimer´s disease

Subjective cognitive decline (SCD) is proposed as an indicator of transitional disease stage 2 in the Alzheimer's disease (AD) continuum. However, molecular and particularly longitudinal fluid biomarker data for this stage are still limited. This study aimed to determine whether blood-based biomarkers in amyloid-positive individuals with SCD (A + SCD) support the notion of stage 2 as a distinct stage between stages 1 and 3 of AD and to identify those at high risk for clinical progression. In a prospective multicenter study (DELCODE) involving 457 participants across the AD continuum, we analyzed plasma phospho-tau 181 (p181) and neurofilament light chain (NfL) and assessed their association with longitudinal cognition, hippocampal atrophy, and AD clinical stage transition. The results showed that baseline plasma p181 levels were elevated and increased more rapidly in A + SCD individuals compared to amyloid-positive cognitively unimpaired (A + CU) individuals (stage 1). NfL levels rose across A + CU, A + SCD, and amyloid-positive mild cognitive impairment (A + MCI, stage 3). In A + SCD, but not in A + CU, higher p181 levels predicted cognitive decline (PACC5) and transition to MCI. In conclusion, plasma p181 provides molecular biomarker evidence supporting A + SCD as a pre-dementia AD stage (stage 2) distinct from A + CU (stage 1) and helps identify individuals at risk for cognitive decline early in the AD continuum