Apathy in rapid eye movement sleep behaviour disorder is associated with serotonin depletion in the dorsal raphe nucleus.

Thomas R Barber,Kinan Muhammed,Daniel R Mcgowan,Daniel S Drew,Marie Crabbe,Ludovica Griffanti,Clare E Mackay,Michele T Hu,Christine Lo,Johannes C Klein,Kevin M Bradley,Masud Husain

doi:10.1093/brain/awy240

Abstract

Apathy is a common and under-recognized disorder that often emerges in the prodromal phase of Parkinsonian diseases. The mechanism by which this occurs is not known, but recent evidence from patients with established Parkinson's disease suggests that serotonergic dysfunction may play a role. The integrity of the raphe serotonergic system can be assessed alongside dopaminergic basal ganglia imaging using the radioligand 123I-ioflupane, which binds both serotonin and dopamine transporters. To investigate the relative roles of these neurotransmitters in prodromal parkinsonism, we imaged patients with idiopathic rapid eye movement sleep behaviour disorder, the majority of whom will develop a parkinsonian disorder in future. Forty-three patients underwent brain imaging with 123I-ioflupane single photon emission computed tomography and structural MRI. Apathy was quantified using the Lille Apathy Rating Scale. Other clinical parkinsonian features were assessed using standard measures. A negative correlation was observed between apathy severity and serotonergic 123I-ioflupane signal in the dorsal raphe nucleus (r = -0.55, P < 0.001). There was no significant correlation between apathy severity and basal ganglia dopaminergic signal, nor between dorsal raphe signal and other neuropsychiatric scores. This specific association between apathy and raphe 123I-ioflupane signal suggests that the serotonergic system might represent a target for the treatment of apathy.

Highlights

Apathy is a common and debilitating condition characterized by motivational deficits that impair emotional, social and behavioural function (Ang et al, 2017)
Since apathy itself might be a marker of emerging Parkinsonism, we compared a number of other clinical variables according to apathy status to investigate whether apathetic patients had more extensive signs of prodromal disease (Table 1)
To investigate whether the association between apathy and dorsal raphe nucleus (DRN) signal was explained by a general reduction in brain monoamine transporters in apathetic patients, we looked at the relationship between apathy and 123I-ioflupane signal in the median raphe nucleus and a number of dopaminergic regions (Table 2)

Summary

Introduction

Apathy is a common and debilitating condition characterized by motivational deficits that impair emotional, social and behavioural function (Ang et al, 2017). Apathy is a prominent feature of parkinsonian disorders, where it causes a significant burden on patients and caregivers alike (Muhammed and Husain, 2016). The role of dopaminergic projections in motivation and reward has led to much focus on the relationship between dopamine loss and apathy in Parkinson’s disease (Chong, 2018). Whilst it is clear that dopamine does modulate apathy in Parkinson’s disease, its contribution to the underlying aetiology is less certain and may depend upon disease stage (MacDonald et al, 2013). Recent evidence from functional neuroimaging suggests that depletion of serotonin may be an important feature in the development of apathy in early disease (Maillet et al, 2016)

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