Parkinson’s disease (PD) is typically thought of as a dopamine disorder, based on the hallmark degeneration of nigrostriatal dopamine neurons that occurs in people with the disease. Indeed, most medications for PD are directed at increasing the activity of dopaminergic neurons and receptors. Even pipeline treatments, such as gene therapies, tend to target the dopamine system.
Serotonin may be another neurotransmitter affected in PD that is worthy of consideration. Both postmortem and neuroimaging studies support the possibility that the serotonergic system, and brainstem raphe nuclei that produce this neurotransmitter, are impacted in PD. Tremor and non-motor symptoms of PD in particular might be caused by serotonin disruptions. What is not clear, however, is when changes in serotonin signaling take place. Scientists and clinicians also do not know whether changes in serotonin correspond with specific PD symptoms.
Recent research conducted by scientists in the UK, USA, and Denmark delved further into the possibility that alterations in the serotonergic system are present in people with PD early on in the course of the disease. Led by Zahi Qamhawi of the division of Brain Sciences, Imperial College London, the investigators used single photon emission computed tomography (SPECT) taken from participants in the Parkinson’s Progression Markers Initiative. Their goals were both to examine the serotonin-producing raphe nucleus in these individuals and to see whether raphe serotonin transporter levels corresponded with non-motor symptoms. Such symptoms included tremor, depression, fatigue, and sleep problems.
The study subjects included 345 people with early PD who had not yet taken medication, 185 controls who did not have PD, and 56 individuals with possible PD but no evidence of dopamine declines. In people with early PD, 37 had a tremulous PD, 106 had a pure akinetic-rigid form, and 202 had a mixed form of PD.
The scientists found lower serotonin transporter availability in the brainstem raphe nuclei of people with early PD compared to both the controls and the group of individuals with no dopaminergic deficits. Although the effect was statistically significant, only 13% of those with early PD experienced the reductions, indicating that a subgroup of individuals experience these declines in serotonin signaling.
The tremulous PD subgroup seemed most likely to have problems with serotonin. The availability of the raphe nucleus serotonin transporter correlated with measurements of tremor, and the tremulous PD subgroup had decreased serotonin transporter but less severe striatal dopamine deficits when compared to the akinetic-rigid subgroup.
Non-motor symptoms, including fatigue, depression, excessive daytime sleepiness, or rapid eye movement sleep behavior disorder did not correlate with raphe serotonin transporter levels in people with early PD.
In their report, the researchers state, “We conclude that the raphe nuclei are affected in a subgroup of early drug-naive Parkinson’s disease patients and that reduced raphe serotonin transporter availability is associated with the severity of resting tremor but not non-motor symptoms.”
Based on this work, it appears that targeting serotonin in early PD may be useful specifically in those individuals with tremor. However, serotonin deficits do not seem to be associated with other early PD symptoms. The research could aid in clinical decisions about how to treat different PD subtypes.
• Raphe nucleus serotonin transporter levels correlate with measurements of tremor in early PD.
• People with PD and tremor have less severe striatal dopamine deficits when compared to those with akinetic-rigid PD.
• Decreased serotonin signaling in early PD does not seem to correspond with increased non-motor symptoms.