Progressive noradrenergic degeneration and motor cortical dysfunction in Parkinson's disease

The locus coeruleus norepinephrine (LC-NE) system plays an important role in regulating brain function, and its neuronal loss has been well-documented in Parkinson's disease (PD). The LC-NE neurodegeneration is believed to underlie various nonmotor symptoms in people with PD, including neuropsychiatric deficits, sleep disruptions, and cognitive impairments. Of particular interest, LC-NE neurons send intensive axonal projections to the motor regions of the cerebral cortex. However, how NE depletion in the motor cortex contributes to PD pathophysiology remains poorly understood. In addition, recent studies provided increasing mechanistic insights into secondary changes in the cerebral cortex as LC-NE degenerates, which might involve its interaction with dopaminergic signaling during the chronic course of the disease. In the present article, we briefly discuss clinical and preclinical studies that support the critical roles of LC-NE neurodegeneration and motor cortical dysfunction in both motor and nonmotor deficits in Parkinsonian states. We focus our discussion on the potential impact of LC-NE neurodegeneration on motor cortical function and the subsequent symptom manifestation. Last, we propose future research directions that can advance our understanding of cortical pathophysiology in PD by integrating noradrenergic degeneration.