Unveiling the role of olfactory circuits in cognitive impairment of Parkinson’s disease

Cognitive impairment, a prevalent non-motor symptom of Parkinson's disease (PD), significantly impacts patient quality of life. However, its underlying mechanisms remain elusive. Intriguingly, olfactory impairment emerges as one of the earliest and most consistent indicators of PD, preceding its motor symptoms. This early-stage dysfunction is linked to the aggregation and misfolding of α-synuclein in the olfactory bulb (OB). Despite this, how the olfactory system contributes to the cognitive decline observed in PD has remained largely unexplored.

Recently, the researchers identified two distinct subpopulations of mitral/tufted (M/T) cells within the OB that project to the anterior piriform cortex (aPC) and entorhinal cortex (EC). These neural circuits mediate cognitive memory processes through specific-frequency neural coherence. Their discovery not only offers a potential biomarker for cognitive function assessment in PD, but also highlights a candidate therapeutic target for mitigating cognitive decline.

The study was published in Research, the first Science Partner Journal recently launched by the American Association for the Advancement of Science (AAAS) in collaboration with the China Association for Science and Technology (CAST). Han is a professor of Cardiovascular Pharmacology in Key Laboratory of Cardiovascular & Cerebrovascular Medicine, Drug Target and Drug Discovery Center, School of Pharmacy, Nanjing Medical University.

“A clearer understanding of olfactory circuit perturbations not only deepens our grasp of cognitive dysfunction in PD but also lays the groundwork for identifying predictors and solutions for this debilitating condition.” said Feng Han, who led this project.

The team elucidated how olfactory circuit perturbations impair cognitive function in PD. Using clinical functional magnetic resonance imaging (fMRI), and demonstrated that OB-PC and OB-EC neural coherences are significantly diminished in PD patients with cognitive dysfunction. Further mechanistic exploration revealed that BOD1, a critical molecular regulator, plays a pivotal role in maintaining neural oscillatory coherence. The study also uncovered that the two M/T cell populations exhibit distinct spatial distributions and electrophysiological properties, underscoring their unique contributions to the cognitive processes.

This research represents a novel paradigm in understanding the connection between olfactory dysfunction and cognitive impairment in PD. By pinpointing the OB^M/T-aPC and OB^M/T-EC circuits as key mediators, the findings pave the way for novel diagnostic and therapeutic approaches. These neural circuits can serve as predictors and targets of cognitive decline and provide opportunities for improved prevention and treatment of PD.