Objective: Developing a computer model integrating the PSP pathology to support clinical trial for new disease-modifying therapies

Background: Progressive Supranuclear Palsy is a fast progressing neurodegenerative tauopathy, Because there is no approved medication, patients tend to be treated with symptomatic interventions such as anti-Parkinsonian drugs.

Method: This first of a kind Quantitative Systems Pharmacology (QSP) model uses a MMSE calibrated computational neuroscience approach of hippocampal microcircuitry for cognitive symptoms and a basal ganglia motor circuit for motor symptoms with the well validated in silico biomarker of motor rigidity and bradykinesia, beta/gamma (b/g) ratio of local field potentials in the subthalamic nucleus.  Tau pathology affects voltage-gated ion channels.

Results: Using the observation of a 1.8 points change on MMSE for 1 year progression corresponding to a yearly progression of 9 points on the PSP-RS scale, we defined the effect size of tau pathology on voltage gated ion channels. This leads to a shift between 0.2 and 0.3 – depending on the disease state – in the ratio of the subthalamic nucleus b/g power.  The model also identified a modest effect of L-DOPA of about 2-3 points on the PSP_RS scale, mostly driven by bradykinesia and rigidity, while no effect was observed on cognitive symptoms, in line with clinical data.  We also identified activation of the striatal cholinergic Tonically Active Neurons (TAN) as a novel mechanism to reduce motor symptoms and cognitive dysfunction.

Conclusion: This is the first mechanism-based QSP model of Progressive Supranuclear Palsy, both for cognitive and motor symptoms that will support development of new symptomatic treatments as well as disease-modifying clinical trials. In combination with our mechanism-based tau QSP model, this approach is a powerful tool for supporting clinical trials of tau pathology interventions.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-quantitative-systems-disease-model-for-progressive-supranuclear-palsy/