Designing the First Trials for Parkinson's Prevention.

For decades the greatest goal of Parkinson's disease (PD) research has often been distilled to the discovery of treatments that prevent the disease or its progression. However, until recently only the latter has been realistically pursued through randomized clinical trials of candidate disease-modifying therapy (DMT) conducted on individuals after they received traditional clinical diagnosis of PD (i.e., tertiary prevention trials). Now, in light of major advances in our understanding of the prodromal stages of PD, as well as its genetics and biomarkers, the first secondary prevention trials for PD are beginning. In this review, we take stock of DMT trials to date, summarize the breakthroughs that allow the identification of cohorts at high risk of developing a traditional diagnosis of PD, and describe key design elements of secondary prevention trials and how they depend on the prodromal stage being targeted. These elements address whom to enroll, what interventions to test, and how to measure secondary prevention (i.e., slowed progression during the prodromal stages of PD). Although these design strategies, along with the biological definition, subtype classification, and staging of the disease are evolving, all are driven by continued progress in the underlying science and integrated by a broad motivated community of stakeholders. While considerable methodological challenges remain, opportunities to move clinical trials of DMT to earlier points in the disease process than ever before have begun to unfold, and the prospects for PD prevention are nowtangible.

Short-term lipopolysaccharide treatment leads to astrocyte activation in LRRK2 G2019S knock-in mice without loss of dopaminergic neurons.

Background: The G2019S mutation of LRRK2, which enhances kinase activity of the protein, confers a substantial risk of developing Parkinson's disease (PD). However, the mutation demonstrates incomplete penetrance, suggesting the involvement of other genetic or environmental modulating factors. Here, we investigated whether LRRK2 G2019S knock-in (KI) mice treated with the inflammogen lipopolysaccharide (LPS) could model LRRK2 PD. Results: We found that short-term (2 weeks) treatment with LPS did not result in the loss of dopaminergic neurons in either LRRK2 G2019S KI or wild-type (WT) mice. Compared with WT mice, LRRK2 G2019S-KI mice showed incomplete recovery from LPS-induced weight loss. In LRRK2 G2019S KI mice, LPS treatment led to upregulated phosphorylation of LRRK2 at the autophosphorylation site Serine 1292, which is known as a direct readout of LRRK2 kinase activity. LPS treatment caused a greater increase in the activated astrocyte marker glial fibrillary acidic protein (GFAP) in the striatum and substantia nigra of LRRK2 G2019S mice than in those of WT mice. The administration of caffeine, which was recently identified as a biomarker of resistance to developing PD in individuals with LRRK2 mutations, attenuated LPS-induced astrocyte activation specifically in LRRK2 G2019S KI mice. Conclusions: Our findings suggest that 2 weeks of exposure to LPS is not sufficient to cause dopaminergic neuronal loss in LRRK2 G2019S KI mice but rather results in increased astrocyte activation, which can be ameliorated by caffeine.