Postural instability in Parkinson’s disease: the adrenergic hypothesis and the locus coeruleus

Abstract

Parkinson’s disease (PD) is traditionally viewed as a mainly hypodopaminergic syndrome, with symptoms resulting predominantly from loss of dopamine-producing neurons in the substantia nigra. However, while most of the cardinal motor features of PD respond well to dopaminergic therapy, many other features of the disease do not. Balance impairment and the associated risk of falling represent one of the most prominent and potentially disabling features that are typically refractory to dopaminergic treatment. Therefore, it is possible that lesions in nondopaminergic systems contribute to the pathophysiology of postural instability in PD. Such nondopaminergic lesions are well recognized, certainly in advanced stages of PD where postural instability and falls dominate the clinical presentation. However, it remains unclear which of the identified nondopaminergic lesions is specifically responsible for postural instability and balance impairment. In this review, we argue that cell loss in the locus coeruleus and a resultant central norepinephrine deficit are intimately involved in the pathophysiology of postural instability in PD. If proven to be correct, this link between defective noradrenergic neurotransmission and postural instability could have important implications for the future development of new symptomatic treatments aimed to correct postural instability and preventing falls. Studies in the next 5 years could test this hypothesis, using a battery of complementary research techniques, including advanced neuroimaging (structural, functional imaging and nuclear), neurochemical studies of cerebrospinal fluid, post-mortem clinicopathological analyses and detailed clinical balance evaluations supplemented by posturography studies.

Keywords::

• dopamine
• locus coeruleus
• nondopaminergic
• norepinephrine
• Parkinson’s disease
• postural instability

Financial & competing interests disclosure

This work was supported by The Netherlands Organisation for Scientific Research VIDI research grant #016.076.352 to Professor BR Bloem. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.