2024 Top Story in Neurology: Neuroprotection in Patients With Parkinson's Disease: Are We There Yet?

The holy grail in the treatment of Parkinson’s disease (PD) is the prevention of progression, or neuroprotection. Symptomatic treatment options like dopamine replacement and deep brain stimulation (DBS) are certainly useful, but the disease progresses despite this treatment. There is reasonable evidence supporting the beneficial effects of exercise on PD,¹ but no other progress has been made in terms of treatment — numerous therapeutic trials have failed. This year, however, some clinical trials have shown benefit, and this is giving clinicians and patients some hope.

It has been known for some time that diabetes is a risk factor for PD. It was thought that patients being treated for diabetes with GLP-1 receptor agonists (GLP-1RAs) have lower rates of PD. Quantitative evidence for that was reported in a Story of the Week.² Older Medicare beneficiaries with type 2 diabetes were placed on either GLP-1RAs or dipeptidyl peptidase 4 inhibitors, and they had a 23% lower risk of developing PD.

The next step in this story was to ask whether GLP-1RAs could prevent PD development or slow PD progression. This was answered in another Story of the Week reporting on a trial of the GLP-1RA lixisenatide.³ Patients who had PD for less than 3 years and were on a stable medication dose were randomized equally to drug and placebo groups. After 1 year of treatment, patients on lixisenatide had approximately the same MDS-UPDRS Part III (the motor part) score, whereas those on placebo had worse scores, and this improvement lasted after a 2-month washout phase.

However, GLP-1RAs are not the whole story. Many patients with PD have a synucleinopathy as the apparent cause of their disorder. Misfolded α-synuclein accumulates in neurons, and it is thought that this process is toxic to the cell. If the α-synuclein could be removed, then the cell might survive longer. Many monoclonal antibodies have failed against α-synuclein; but, finally, there appears to be a success. A featured abstract from the American Academy of Neurology this year presented positive data, and this work has now been published. The PASADENA study is evaluating the effect of prasinezumab, a humanized monoclonal antibody that binds to aggregated α-synuclein. In a published phase II double-blind study conducted over a period of 1 year, there was no statistically significant benefit in the sum of Parts I, II, and III of the MDS-UPDRS, which was the primary endpoint.⁴ In a prespecified subanalysis, prasinezumab slowed motor progression in patients with rapidly progressing early-stage PD. In the featured abstract⁵ and the two new published articles,^6,7 data are presented on a 4-year open-label follow-up, and there was significant slowing of motor function deterioration in patients with rapidly progressive disease. Moreover, disease progression in treated patients was slower than that in the control group of the Parkinson’s Progression Markers Initiative.

Now, there is optimism that we can slow the progression of PD, but there is still more work to do to bring these drugs into routine clinical use.