Neurology · 21 h ago
Multiomics study links cathepsin B to lower white matter lesion burden
A four-stage proteogenomic study using UK Biobank data and postmortem brain samples identified cathepsin B (CTSB) as a candidate factor in cerebral small vessel disease. Higher CTSB levels were associated with lower white matter hyperintensity volume and better cognitive performance, but the findings do not establish a treatment effect.
- Higher CTSB was associated with lower WMH volume.
- Genetic analyses showed directionally consistent CTSB estimates.
- Lesions showed lower CTSB expression in several cell types.
- Findings do not establish therapeutic benefit.
Researchers conducted a four-stage proteogenomic analysis. They screened 2,923 plasma proteins in 52,560 UK Biobank participants, assessed candidate proteins against white matter hyperintensity (WMH) volume in an imaging subset, and used Mendelian randomization and other genetic analyses to investigate potential causal relationships. Single-nucleus RNA sequencing examined eight postmortem periventricular white matter samples: four with WMH lesions and four controls. The study also assessed cognitive performance in UK Biobank participants.
Higher plasma CTSB was associated with lower WMH volume (β=−0.09; 95% CI, −0.13 to −0.05; n=5,260). Genetic estimates were directionally consistent across five instrument sets. CTSB was downregulated in lesions, particularly in astrocytes and oligodendrocytes. Higher circulating CTSB and a CTSB-related genetic score were also associated with better cognitive performance. ECHDC3, another initial candidate, showed no consistent associations beyond the first stage.
The results nominate CTSB as a possible contributor to WMH burden and cognition, and as a candidate for further therapeutic research. The study is observational and genetic evidence, not an intervention trial; it does not show that raising CTSB would prevent lesions or improve cognition. The supplied abstract does not report study funding.
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Stroke: Multiomics Profiling Supports Cathepsin B as a Protective Factor in White Matter Hyperintensities and Cognition ↗This is an automated AI-condensed summary that has not yet been reviewed by an editor. Always consult the full item at the original source.