The role of the ascending retucular activating system in cognitive fluctuations in dementia wih lewybodies

Abstract

Background Cognitive fluctuations occur in 80-90% of patients with dementia with Lewy bodies (DLB) and have a profound negative impact on the patient’s quality of life. However, cognitive fluctuations are the least well characterised of the core clinical features. The ascending reticular activating system (ARAS) has an important role in arousal and awareness, therefore, has been implicated in the aetiology of cognitive fluctuations in DLB. Methods Post-mortem tissue from components of the ARAS, locus coeruleus, pedunculopontine nucleus, raphe and medial prefrontal cortex (mPFC), was obtained from DLB cases with a clinical history of cognitive fluctuations and compared to cognitively normal control, mixed Alzheimer’s disease (AD)/DLB cases with cognitive fluctuations, and mixed AD/DLB and AD without cognitive fluctuations. Pathological burden of protein aggregates and neurotransmitter markers were quantified in individual cases. Immunoblots were performed on isolated synaptosomes from mPFC tissue to examine ARAS projection integrity. Influence of pathological and biochemical markers on the presence and severity of cognitive fluctuations were determined Key findings Neurodegenerative pathology was observed in all regions examined, with no specific pattern or level of pathological burden associated with the presence or absence of cognitive fluctuations. Alterations to the serotonergic system in DLB may relate to the severity of cognitive fluctuations. Synaptosomal isolation may preferentially select for intact, functional, synapses as neurotransmitter marker levels analysed did not differ from controls Conclusions This study identified that the severity of protein aggregates in the ARAS was not associated with the presence or absence of cognitive fluctuations. The results may indicate that DLB patients have a pathologically compromised arousal system, but that this likely acts in concert with other mechanisms to elicit cognitive fluctuations. As cognitive fluctuations are transient, one may speculate that static protein aggregates are unlikely to underlie a clinical feature defined by variable clinical presence.