Brain Serotonin Changes May Be Early Warning Sign of Parkinson’s, Study Suggests

Changes to the serotonin system in the brain occur years before the development of motor symptoms in Parkinson’s — and may be an important early warning signal for the disease, a study suggests.

“Therefore, brain imaging of the serotonin system could become a valuable tool to detect individuals at risk for Parkinson’s disease, monitor their progression and help with the development of new treatments,” Heather Wilson, research associate at King’s College London and the study’s first author, said in a press release.

The study, “Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study,” was published in The Lancet Neurology.

Parkinson’s is characterized by the progressive death of brain cells that are responsible for producing dopamine, which eventually leads to the development of motor symptoms associated with the disease, including involuntary tremors or muscle contraction.

Studies have suggested that, in addition to changes in the dopaminergic system, Parkinson’s progression and symptoms may be associated with impaired signals from another important neurotransmitter, called serotonin. Serotonin transmits messages between nerve cells, and is thought to be active in constricting smooth muscles.

To further explore the role of serotonin in Parkinson’s progression, a team led by researchers from King’s College evaluated non-symptomatic carriers of an alpha-synuclein (SNCA) gene variant. That variant is an extremely rare mutation, but a well-known cause for hereditary Parkinson’s disease.

Individuals with mutations in the alpha-synuclein gene are almost certain to develop Parkinson’s during their lifetime, which makes them invaluable candidates to study the biological events that result in the development of the disease.

The study recruited 14 individuals who were carriers of the A53T variant in the SNCA gene, as well as 25 patients with idiopathic (of unknown cause) Parkinson’s disease, and 25 healthy matched volunteers who had no history of neurological or psychiatric disorders.

All participants were evaluated by positron emission tomography (PET) scans. PET scans use a specific dye that binds to the serotonin transporter, and evaluates serotonin metabolism in the brain. Participants also underwent several clinical assessments to determine motor and non-motor symptoms. They were evaluated for cognitive status, dopamine metabolism, and brain structural changes.

Among individuals who were SNCA mutation carriers, 50% were still asymptomatic —  at the premotor stage of the disease — and had dopaminergic deficits.

Compared with healthy controls, the premotor SNCA carriers showed reduced serotonin signals in several brain areas. SNCA carriers who still had normal dopamine transporters already showed “an average of 34% loss of serotonin transporters in raphe nuclei and 22% loss in the striatum compared with healthy controls,” the researchers said.

As the name indicates, a serotonin transporter is a protein that binds to and transports serotonin to different areas of the brain. Raphe nuclei are a type of brain receptor that decrease the release of serotonin. The striatum is a critical brain region involved in voluntary movement.

“Parkinson’s disease has traditionally been thought of as occurring due to damage in the dopamine system, but we show that changes to the serotonin system come first, occurring many years before patients begin to show symptoms,” said Marios Politis, MD, PhD, professor at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN) and senior author of the study.

Those who were SNCA carriers but had already been diagnosed with Parkinson’s disease showed more extensive deficits in the serotonin system, affecting even more areas of the brain. There was 48% serotonin transporter loss in the raphe nuclei, and 57%  loss in the striatum areas.

Further analysis revealed that low serotonin signals in the brainstem were associated with increased total scores on the Movement Disorder Score-Unified Parkinson’s Disease Rating Scale (MDS-UPSRS) — indicating higher disease burden. This occurred in all SNCA carriers, and in those with idiopathic Parkinson’s.

“Our findings provide evidence that molecular imaging of serotonin transporters could be used to visualize premotor pathology of Parkinson’s disease in vivo [in the body],” the researchers said.

Future studies should focus on implementing serotonin transporter imaging as “an adjunctive tool for screening and monitoring progression” for those at risk for, or who already have Parkinson’s.

“This is one of the first studies to suggest that changes in serotonin signaling may be an early consequence of Parkinson’s,” said Beckie Port, PhD, research manager at Parkinson’s UK. “Picking up on the condition earlier and being able to monitor its progression would aid the discovery of new and better treatments that could slow the loss of brain cells in Parkinson’s.”