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Microglial Activation Observed in Early Stage of Isolated REM Sleep Behavior Disorder

Microglial activation in the brains of patients with isolated REM sleep behavior disorder (iRBD), a prodromal phenotype of Parkinson's disease (PD), is associated with a more rapid progression of nigrostriatal dysfunction, according to a report presented during the MDS Virtual Congress 2020, the annual meeting of the International Congress of Parkinson Disease and Movement Disorders.                

The current findings suggest that microglial activation may play a role in earlier stages of PD, the study authors suggested in their abstract.

A collaborative effort between scientists from Aarhus University Hospital in Denmark and the Hospital Clinic de Barcelona, the study aimed to determine if the immune system's microglial activation is protective or if it worsens iRBD.

Previous research by Nicola Pavese, MD, PhD, a professor at Aarhus University, and his colleagues had shown activated microglia in the substantia nigra—evidence of neuroinflammation—on PET scans of patients with iRBD who had no clinical signs of parkinsonism.

For the current study, the team scanned 15 patients with iRBD with 11C-PK11195 to measure microglial activation and 18F-DOPA PET for a baseline measure. Three years later, they returned for another 18F-DOPA PET scan to monitor changes that may have occurred over time.

At baseline, six of the 15 patients had abnormal 11C-PK11195 binding in the substantia nigra and striatum. The 18F-DOPA uptake from baseline to follow-up across the iRBD patients showed a decrease of dopamine uptake in the caudate nuclei and the anterior portion of the putamen bilaterally.

The researchers assessed binding in patient cohorts with and without abnormal 11C-PK11195 separately and observed more widespread and severe changes across the striatal areas in the patients who showed microglial activation at baseline; those who did not have evidence of microglial activation had minimal changes in the left caudate. 

"This (finding) would suggest a detrimental rather than a neuroprotective effect of neuroinflammation even in the early stages of parkinsonism," the scientists said. Neuroinflammation may be a  potential treatment target in the early phases of PD, they suggested.

"The study addresses an exciting and important topic in the field of neurodegenerative diseases, including PD," said Katharina A. Schindlbeck, MD, a scientist and movement disorders expert at the Feinstein Institute for Medical Research, who was not involved with the research.

Several studies support a pathological mechanism of microglial activation in advanced disease stages of PD, but its role in the early stages was less clear. Only recently, the presence of neuroinflammation has been shown in the prodromal phase of the alpha-synucleinopathy-related disease. However, how immune and inflammatory pathways interact with disease progression is still poorly understood, that is, whether increases in microglial activation are associated with more rapid disease progression.

 "These findings encourage the development of drugs targeting neuroinflammation in PD," Dr. Schindlbeck said. "Since neuroinflammatory changes are present early in the disease course, the research supports a potential disease-modifying effect of such therapies."

She added that further studies should investigate whether these imaging modalities are useful to monitor such therapeutic effects. "Multimodal imaging biomarkers could prove useful as secondary outcome measures in clinical trials targeting microglial activation. Given the relatively small sample size of early phase clinical trials, imaging biomarkers may enhance the likelihood of detecting therapeutic effects."

Link Up to Related Information

MDS Abstract 638: Staer K, Iranzo A, Stokholm M, et al. Microglial activation associated with a faster progression of nigrostriatal dysfunction in patients with isolated REM sleep behavior disorder.

Stokholm MG, Iranzo A, Ostergaard K, et al. Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: A case-control study. Lancet Neurol 2017;16(10):789-796.