Brain imaging showing loss in serotonin function as Parkinson's disease progresses. Red/yellow areas show that serotonin function reduces before movement symptoms develop. [Neurodegeneration Imaging Group, King's College London.]

Changes to the serotonin system in the brains of Parkinson’s disease patients can be seen in brain scans well before damage to the dopamine system occurs, according to scientists at Kings College London and the University of Athens Medical School. The researchers say their findings indicate that monitoring for serotonergic pathology could potentially help clinicians detect the very earliest stages of Parkinson’s disease in at risk individuals, many years before clinical symptoms develop. The discovery could also help scientists identify new therapeutic strategies.

“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,” commented research lead professor Marios Politis, Lily Safra professor of neurology & neuroimaging at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN). “Our results suggest that early detection of changes in the serotonin system could open doors to the development of new therapies to slow, and ultimately prevent, the progression of Parkinson’s disease.”

Politis and colleagues report their findings in The Lancet Neurology, in a paper titled, “Serotonergic pathology and disease burden in the premotor and motor phase of A53T α-synuclein parkinsonism: a cross-sectional study.”

Parkinson’s disease is the second most common neurodegenerative disorder after Alzheimer’s disease. The disease causes progressively more pronounced movement abnormalities, along with symptoms including speech problems and cognitive abnormalities. The neuropathology of Parkinson’s disease is characterized by the development of α-synuclein (SNCA) aggregates, which are the main components of the telltale Lewy body formations that gradually spread throughout the brain, and affect dopaminergic and non-dopaminergic neurons, including serotonergic neurons, the authors explained. Neuropathological studies have shown that serotonergic neurons are involved at an early stage in sporadic cases of Parkinson’s disease, and potentially before the dopamine system is affected. However, the researchers continued, “to date, this concept has not been proven, particularly in an in vivo concept.”

Most cases of Parkinson’s disease have no single known cause, but a few cases are linked to gene mutations. Mutations in the SNCA gene, for example, are very rare, but carriers are almost certain to develop Parkinson’s disease during their lifetime. The origins of the SNCA mutation have been tracked to villages in the northern Peloponnese in Greece, and are also found in people who migrated from the region to Italy.

Over the course of two years the researchers identified 14 people with the A53T SNCA gene mutation from Greece and Italy, and took them to London for the study, which involved brain imaging studies and clinical tests. The same tests were carried out on another 65 patients with sporadic (non-genetic) Parkinson’s disease and 25 healthy volunteers.

The researchers used positron emission tomography (PET) brain imaging to look for changes to both the serotonin and dopamine systems in the brains of all the study participants. Initial tests showed that seven of the 14 SNCA mutation carriers already exhibited motor symptoms and in these patients a clinical diagnosis of Parkinson’s disease was confirmed. The other seven SNCA mutation carriers had no motor symptoms, and brain imaging studies showed no changes to the dopaminergic system.

The study results indicated that changes to the serotonin system represented the earliest indicator of Parkinson’s disease, and could be seen in patients before symptomatic movement abnormalities, and also before changes in the dopamine system could be detected in brain images. Serotonin system malfunction was also evident in the brains of the individuals with SNCA mutations who hadn’t been diagnosed with Parkinson’s disease.

‘We found that serotonin function was an excellent marker for how advanced Parkinson’s disease has become,” stated Heather Wilson, PhD, research associate, Neurodegeneration Imaging Group, Kings College London and first author on the reported study. “Crucially, we found detectable changes to the serotonin system among patients who were not yet diagnosed. 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.”

Interestingly, serotonergic damage was also linked with disease burden. “Indeed, our findings indicate that serotonergic pathology in the brainstem, which was present in all A53T SNCA carriers, was associated with total UPDRS [Unified Parkinson’s Disease Rating Scale] scores, which captures the overall burden of the disease including both motor and non-motor symptoms,” the authors wrote.

The team acknowledged that PET scans are expensive and hard to carry out, but they suggest that it may be possible to develop more cost-effective imaging methods for assessing serotonin-related changes in the brain as an aid to early diagnosis and for disease monitoring. “Although PET molecular imaging is expensive and A53T SNCA carriers are rare, our study highlights the potential to extend findings in A53T SNCA carriers to classic forms of idiopathic Parkinson’s disease,” they wrote. “Future work could allow the development of serotonin transporter imaging into an adjunctive tool for screening and monitoring progression for individuals at risk of developing Parkinson’s disease or for patients with Parkinson’s disease, to complement existing molecular imaging tools such as dopaminergic imaging and serve as a sensitive marker of Parkinson’s burden.”

 

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