Alzheimer pathology in the human ascending reticular activating system: Early and severe

Abstract

AbstractBackgroundThe ascending reticular activating system (ARAS) is a collection of interconnected brain nuclei that regulates wakefulness, alertness and modulate behaviors. The critical components of ARAS degenerates early during Alzheimer’s disease progression in association with abnormal tau build‐up. Despite accumulating evidence, the role of AD‐related ARAS degeneration in promoting neuropsychiatric symptoms remains underappreciated. This talk will provide the state‐of‐the‐art in the knowledge of arousal system dysfunction in AD based on human studies as a framework for understanding the neuroanatomical changes underlying arousal dysfunction in AD.MethodWe reviewed authorial studies and results from other groups focusing on the isodendritic core of the reticular formation and other neuromodulatory nuclei associated with arousal in the context of AD pathology. Emphasis was given to quantitative studies, clinicopathological correlations and studies focusing on pre‐cognitive change, early AD stages.ResultMultiple nuclei of the ARAS, including the noradrenergic locus coeruleus, show consistent and early changes associated to AD‐type neuropathology build‐up, especially but not restricted to tau protein. These neuropathological changes lead to dysregulation of the respective neurotransmitter systems (both up‐ and downregulation) besides progressive neuronal dysfunction and death.ConclusionThe arousal neuromodulatory systems show early vulnerability to AD‐type changes. further understanding of the mechanisms leading to this vulnerability remains an unmet need and realizing this vision may point to strategies to treat neuropsychological symptoms in AD.