Anti-alpha synuclein and anti-tau immunotherapies: Can a cocktail approach work?

The hypothesis that neurodegenerative diseases are proteinopathies due to toxic effect of different underlying proteins, such as amyloid-beta and 3+4R-tau in Alzheimer's disease (AD) and alpha-synuclein in Parkinson's disease (PD), while still controversial is supported by several studies in the literature. This has led to conduct clinical trials attempting to reduce the load of these allegedly toxic proteins by immunotherapy, mostly but not solely based on antibodies against these proteins. Already completed clinical trials have ranged from initially negative results to recently partial positive outcomes, specifically for anti-amyloid antibodies in AD but also albeit to lesser degree for anti-synuclein antibodies in PD. Currently, there are several ongoing clinical trials in degenerative parkinsonisms with anti-synuclein approaches in PD and multiple system atrophy (MSA), as well as with anti-tau antibodies in 4R-tauopathies such as progressive supranuclear palsy (PSP). While it can be argued that expectations that part of these clinical trials will be positive can be hope or hype, it is reasonable to consider the future possibility of "cocktail" combination of different antibodies after the available experimental evidence of cross-talk between these proteins and neuropathological evidence of coexistence of these proteinopathies more frequently than expected by chance. Moreover, such "cocktail" approaches are widespread and accepted common practice in other fields such as oncology, and the complexity of neurodegenerative parkinsonisms makes reasonable the option for testing and eventually applying such combined approaches, should these prove useful separately, in the setting of patients with evidence of underlying concomitant proteinopathies, for example through biomarkers.

Image-guided programming deep brain stimulation improves clinical outcomes in patients with Parkinson's disease.

Deep brain stimulation (DBS) is an effective treatment for patients with Parkinson's disease (PD). However, some patients may not respond optimally to clinical programming adjustments. Advances in DBS technology have led to more complex and time-consuming programming. Image-guided programming (IGP) could optimize and improve programming leading to better clinical outcomes in patients for whom DBS programming is not ideal due to sub-optimal response. We conducted a prospective single-center study including 31 PD patients with subthalamic nucleus (STN) DBS and suboptimal responses refractory to clinical programming. Programming settings were adjusted according to the volumetric reconstruction of the stimulation field using commercial postoperative imaging software. Clinical outcomes were assessed at baseline and at 3-month follow-up after IGP, using motor and quality of life (QoL) scales. Additionally, between these two assessment points, follow-up visits for fine-tuning amplitude intensity and medication were conducted at weeks 2, 4, 6, and 9. After IGP, twenty-six patients (83.9%) experienced motor and QoL improvements, with 25.8% feeling much better and 38.7% feeling moderately better according to the patient global impression scale. Five patients (16.1%) had no clinical or QoL changes after IGP. The MDS-UPDRS III motor scale showed a 21.9% improvement and the DBS-IS global score improved by 41.5%. IGP optimizes STN-DBS therapy for PD patients who are experiencing suboptimal clinical outcomes. These findings support using IGP as a standard tool in clinical practice, which could save programming time and improve patients' QoL.