Abstract
Noradrenergic dysfunction contributes to cognitive impairment in Alzheimer's Disease (AD) and Parkinson's Disease (PD). Conventional therapeutic strategies seek to enhance cholinergic and dopaminergic neurotransmission in AD and PD, respectively, and few studies have examined noradrenergic dysfunction as a target for medication development. We review the literature of noradrenergic dysfunction in AD and PD with a focus on human imaging studies that implicate the locus coeruleus (LC) circuit. The LC sends noradrenergic projections diffusely throughout the cerebral cortex and plays a critical role in attention, learning, working memory, and cognitive control. The LC undergoes considerable degeneration in both AD and PD. Advances in magnetic resonance imaging have facilitated greater understanding of how structural and functional alteration of the LC may contribute to cognitive decline in AD and PD. We discuss the potential roles of the noradrenergic system in the pathogenesis of AD and PD with an emphasis on postmortem anatomical studies, structural MRI studies, and functional MRI studies, where we highlight changes in LC connectivity with the default mode network (DMN). LC degeneration may accompany deficient capacity in suppressing DMN activity and increasing saliency and task control network activities to meet behavioral challenges. We finish by proposing potential and new directions of research to address noradrenergic dysfunction in AD and PD.
Highlights
The proposition that the LC circuit responds to behavioral tasks is supported by task-based studies demonstrating LC activation to stimulus change
In a study of inhibitory control, atomoxetine improved performance in a stop-signal task in correlation with increased insula activity (Chamberlain et al, 2009). These findings suggest that NE influences insula activity and improves a broad spectrum of cognitive functions, providing a pathway whereby noradrenergic dysfunction may contribute to aberrant salience network (SAN) and default-mode network (DMN) activations in AD
It is manifested in structural brain imaging as atrophic changes in structures connected with the LC and in functional imaging as changes in network activity and connectivity
Summary
Alzheimer’s disease (AD) is a well-known cause of dementia that is associated with the accumulation of intraneuronal neurofibrillary tangles (NFTs; Braak et al, 1994) and extraneuronal neuropil threads (Perry et al, 1991). In comparative studies of disease burden in patients with advanced-stage AD the NbM demonstrated the most significant cell loss followed by the LC and transentorhinal cortex (Arendt et al, 2015). Studies have reported that only about half of postmortem brains in PD demonstrated Lewy body pathology consistent with the Braak staging (Kalaitzakis et al, 2008; Jellinger, 2009; Halliday et al, 2012), challenging the notion that PD progresses in a sequence similar to prion diseases (Surmeier et al, 2017). Whereas degeneration of the SNc is the most classic neuropathological finding in PD, postmortem studies demonstrate Lewy body burden and associated loss of noradrenergic neurons in the LC (Chan-Palay and Asan, 1989; Braak et al, 2006; Szot, 2012).
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