Objective: To identify predictors of survival and progression in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).

Background: Reported median survival in PSP and CBD is 7.3 and 7.0 years from symptom onset, respectively, but this is highly variable. The role of clinical and biological factors is uncertain.

Method: We collected clinical data and biosamples from 825 participants with PSP and CBS from the PROSPECT-M-UK study between March 2015 and February 2024. We performed whole genome sequencing through the Global Parkinson’s Genetics Project (GP2) and analysed baseline serum proteomics with the Nucleic Acid-Linked Immuno-Sandwich Assay with detection by next generation sequencing (NULISAseq) assay. We applied MDS PSP subtype classification where detailed clinical evaluation was available and grouped patients as PSP-Richardson’s syndrome (PSP-RS) (n = 203), PSP-subcortical (PSP-SC) (n = 82), and PSP-cortical (PSP-C) (n = 45). We grouped CBS patients as CBS-AD (n = 23) and CBS-non-AD (n = 27), according to Alzheimer’s disease (AD) biomarkers (CSF and amyloid-PET). We used Cox-proportional hazard analysis to identify baseline predictors of independent survival (time to death or <40% on Schwab and England Activities of Daily Living scale). We used linear mixed effects models to identify baseline predictors of rate of change in clinical scale measures.

Results: Median independent survival was 6.0 years (IQR 4.4 – 8.4) for PSP and 6.4 years (IQR 4.3 – 8.5) for CBS. Longer independent survival was associated with PSP-SC phenotypes (Hazard ratio [HR] = 0.63 [95% CI 0.46 – 0.85] P = 0.003), MAPT H2 haplotype (HR = 0.51 [0.37 – 0.70], P <0.01), and serum levels of synaptic biomarker contactin-2 (HR = 0.75 [0.75 – 0.87], P = 0.02). Increasing baseline severity measured on clinical and cognitive scales predicted shorter independent survival (PSP Rating Scale (PSPRS) HR = 1.02 [1.01 – 1.03]; Montreal Cognitive Assessment (MoCA) HR = 1.03 [1.00 to 1.05] P < 0.05). Sensitivity analyses using scores in the upper tertile showed larger effects (PSPRS HR = 1.51 [1.18 to 1.94], P = 0.001). The minor allele at LRRK2 SNPs rs2242367 and rs7690498 predicted faster motor progression on PSPRS (β = 4.77 ± 1.55, P = 0.003; β = 4.86 ± 1.86, P = 0.01).

Conclusion: Baseline features including presenting phenotype, measures of disease severity, genetic variants and blood protein biomarkers can predict progression in PSP and CBS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/predictors-of-disease-progression-in-progressive-supranuclear-palsy-and-corticobasal-syndrome/