The role of the locus coeruleus/norepinephrine system in the pathogenesis of neurodegenerative disorders: An update

Abstract

Purpose of reviewThe aim of this review was to provide an update on current and emerging knowledge of the neuropathological processes affecting the locus coeruleus/norepinephrine (LC/NE) system, their effect on Alzheimer's disease and Parkinson's disease symptomatology, including efforts to translate these notions into therapeutic actions targeting the noradrenergic system.Recent findingsOver the past 2 years, work from multiple groups has contributed to support an early role of locus coeruleus degeneration and/or hyperactivation in the neurodegenerative process, including a trigger of neuroinflammation. Imaging advances are allowing the quantification of locus coeruleus structural features in vivo, which is critical in the early stages of disease. Nonmotor and noncognitive symptoms, often secondary to the involvement of the LC/NE system, are becoming more important in the definition of these diseases and their treatment.SummaryThe diverse symptomatology of Parkinson's disease and Alzheimer's disease, which is not limited to cardinal motor and cognitive abnormalities, strongly suggests a multisystem neurodegenerative process. In this context, it is increasingly clear how the LC/NE system plays a key role in the initiation and maintenance of the neurodegenerative process.

Neurogenic orthostatic hypotension in Parkinson’s disease: is there a role for locus coeruleus magnetic resonance imaging?

“…The nucleus of the solitary tract and rostral ventrolateral medulla have been shown to play an important role in the activation of the baroreflex system, receiving the modulation, among others, of the LC itself through both direct and indirect connections (Bockstaele et al 1989 ; Sun 1995 ; Giorgi et al 2021 ; Samuels and Szabadi 2008 ). Although the LC is among the first brain regions to degenerate in PD (Braak et al 2003 ), few studies examined the structural degeneration of LC in the pathogenesis of PD non-motor symptoms (Malatt and Tagliati 2022 ), likely reflecting previous technical difficulties in visualizing in vivo the LC because of its small size and physiological inter-subject variability (Fernandes et al 2012 ). However, in the last decade, LC-MRI data have been shown to be able to provide a quite reliable surrogate for LC integrity determined histopathologically (Keren et al 2015 ), after the improvement of specific MRI sequences, and the development of standardized analysis protocols.…”

Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration

“…During recent decades, it became more and more evident that LC promotes protective effects during a variety of acute and chronic neurodegenerative disorders [ 11 , 12 , 13 , 14 ]. In particular, NE axons arising from LC (LC-NE) protect against neuronal damage in a variety of degenerative disorders [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. This evidence encompasses acute neurological insults, such as epileptic seizures [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 ], brain ischemia [ 34 , 35 , 36 ], and chronic degenerative disorders.…”

Noradrenergic alterations in Parkinson’s disease: a combined 11C-yohimbine PET/neuromelanin MRI study

“…Among these neurotransmitter networks, the noradrenergic system is probably the least well-known. 5 , 6-8 The direct roles of the noradrenergic system in various cognitive functions are well documented. 9 These include specific functions like vigilance, attention and executive control, as well as more transversal functions like learning, cognitive flexibility and working memory, 8 or even more general roles in adaptive adjustments in gain that serve to optimize performance.…”