The role of noradrenaline in cognition and cognitive disorders

Abstract

Many aspects of cognition and behaviour are regulated by noradrenergic projections to the forebrain originating from the locus coeruleus, acting through alpha and beta adrenoreceptors. Loss of these projections is common in neurodegenerative diseases and contributes to their cognitive and behavioural deficits. We review the evidence for a noradrenergic modulation of cognition in its contribution to Alzheimer's disease, Parkinson's disease and other cognitive disorders. We discuss the advances in human imaging and computational methods that quantify the locus coeruleus and its function in humans, and highlight the potential for new noradrenergic treatment strategies.

Keywords: cognition; dementia; locus coeruleus; neurodegeneration; noradrenaline.

Figure 1

Neuroanatomical location and projections of the LC. (A) Schematic sagittal view of the brain, illustrating locus coeruleus anatomy, projections, and downstream cognitive dysfunction associated with disturbed LC projections. (B) Coronal and (C) axial views of the locus coeruleus obtained from magnetization transfer weighted sequences at 7 T MRI. Ant = anterior; Post = posterior. Image courtesy of Dr Rong Ye and Dr Claire O’Callaghan.

Figure 2

Noradrenaline synthesis pathway, distribution of pre and postsynaptic adrenoreceptors, and available noradrenergic agonist and antagonists used in animal and human studies. Agonists are depicted by a plus symbol and dark green arrows, whilst antagonists are depicted by the letter ‘X’ and orange arrows. Drugs used in human studies and clinical trials are marked with an asterisk. Noradrenaline synthesis pathway: noradrenaline is synthesized from tyrosine, which is initially converted to l-DOPA through the action of tyrosine hydroxylase (TH); l-DOPA is further converted to dopamine by aromatic l-amino acid decarboxylase (AADC), before finally being converted to noradrenaline through the action of dopamine β-monooxygenase (DA-C; also known as dopamine β-hydroxylase). Noradrenaline is recycled through the norepinephrine transporter (NET) and degraded by monoamine oxidase (MOA), to the principal end product vanillylmandelic acid or a conjugated form of 3-methoxy-4-hydroxyphenylglycol (MHPG). Methylphenidate = mixed noradrenaline and dopamine reuptake inhibitor.

Figure 3

Schematic illustration of the non-linear function of performance versus locus coeruleus activity, analogous to the Yerkes-Dodson model of arousal and comparable to non-linear relationships in dopaminergic and serotonergic systems.