Parkinson's disease (PD) is a debilitating movement disorder that affects millions of individuals worldwide, especially older individuals. Given PD does not have a cure yet, early diagnoses and monitoring are essential for managing the disease effectively.
PD is known for its motor symptoms like slow movement, muscle stiffness, unstable posture, and abnormal walking. However, PD also includes non-motor symptoms such as cognitive issues, sleep problems, and mental health concerns. Traditionally, PD is associated with the degeneration of dopamine-producing neurons in a brain area called the substantia nigra. Recently, research has shown that PD also affects the cerebellum—a brain region mainly involved in coordinating movement.
In this regard, researchers from Dalian Medical University and Shanghai University of Medicine and Health Sciences Affiliated Zhoupu Hospital from China comprehensively reviewed cerebellar involvement in PD. The review, led by Professor Weidong Le (affiliated with the two participating institutions), was published in the Chinese Medical Journal and made available online on September 03, 2024.
Underscoring the importance of this review article, Prof. Le says, "This review provides a comprehensive summary of the cerebellar pathophysiology and results from neuroimaging studies related to both motor and non-motor symptoms of PD, highlighting the potential significance of cerebellar assessment in PD diagnosis, differential diagnosis, and disease monitoring."
The researchers highlighted multiple studies and corresponding findings about the cerebellar pathophysiology in PD. For example, a few studies showed the presence of abnormal aggregation of α-synuclein—pathological change associated with neurodegeneration—in the cerebellar cortex, deep cerebellar nuclei (DCN), and surrounding white matter of patients with PD. However, other studies reported a lack of substantial accumulation of α-synuclein in the cerebellum of patients with PD, suggesting variable pathological features depending on disease stages or subtypes.
Further, the review explored cerebellar imaging studies related to PD. Imaging studies, such as voxel-based morphometry, indicated a significant cerebellar reduction in patients with PD compared to healthy controls, implying neurodegeneration. Pathological analyses and postmortem examinations revealed neuronal damage in the cerebellum of patients with PD. Additionally, animal models of PD showed high levels of neuronal cell death and degeneration in the cerebellum. "While both animal and human studies have demonstrated pathological changes in the cerebellum of PD, further research is needed to explore its association with clinical symptoms," adds Prof. Le.
Furthermore, the researchers noted that many resting-state functional magnetic resonance imaging studies identified altered functional connectivity between the cerebellum and other brain regions in patients with PD. They found that patients with PD also exhibited significant metabolic changes in various cerebellar subregions, correlating with motor symptoms, cognitive impairment, and psychiatric symptoms. Thus, the neuroimaging results highlighted cerebellar changes in PD that potentially serve as biomarkers essential for PD management.
Contrary to previous beliefs, the researchers additionally emphasized cerebellar involvement in the dopaminergic system—multiple studies revealed relatively high levels of dopamine in the cerebellum of humans and other mammals. Studies on non-primates revealed that most dopaminergic fibers in the cerebellum originate from the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) in the midbrain. Dopaminergic fibers from the cerebellar cortex and DCN also extend to the VTA and SNpc.
The researchers further noted that tyrosine hydroxylase (TH) immunoreactive nerve fibers are present in various cerebellar layers, with a significant presence in the molecular layer. Both rodents and humans also have extensive dopamine receptor subtypes (DRD1–DRD5) expression in the cerebellum. In addition, reduced mRNA expression of TH and specific dopamine receptor subtypes (DRD1 and DRD3) has been seen in the cerebellum of patients with PD. These findings suggest that dopamine may play a significant role in the cerebellum in association with the progression of PD.
In conclusion, this deep dive into cerebellar changes in PD unravels the intricate complexities of the disease. By highlighting the cerebellum's role in both motor and non-motor symptoms, this study paves the way for innovative PD management strategies. The researchers' dedication and thoroughness offer renewed hope for better patient outcomes and represent a groundbreaking advancement in PD research.
