Resolving cognitive heterogeneity in white matter hyperintensities through integrated analyses of microbiome, metabolome, and brain glymphatic function.

Individuals with white matter hyperintensities and cognitive impairment differed from those with normal cognition in specific bacterial genera, plasma metabolites, and glymphatic markers.

• Study included 56 healthy controls, 40 WMH with normal cognition (WMH-NC), and 49 WMH with cognitive impairment (WMH-CI).
• Six bacterial genera showed differences across the three groups.
• Three plasma metabolites differed across groups.
• Five glymphatic markers differed across groups.
• Acetivibrio, 1,5-naphthalenediamine, beta-uridine, free water fraction within white matter, and ALPS index specifically distinguished WMH-CI from WMH-NC.

The association between gut microbiota and cognition in WMH patients was mediated by the plasma metabolite tetradecyldiethanolamine and the glymphatic ALPS index.

• Correlation and mediation analyses demonstrated these associations.
• The mediation pathway ran from microbiota through tetradecyldiethanolamine and then through ALPS index to cognition.
• This represents a microbiota-metabolites-glymphatic function-cognition axis in WMH.
• The ALPS index (index of diffusivity along the perivascular spaces) was used as a marker of glymphatic function.

The glymphatic marker ALPS index and free water fraction within white matter differed between WMH cognitive subgroups.

• Both ALPS index and free water fraction within the white matter were among the five glymphatic markers showing differences across groups.
• These markers specifically distinguished WMH-CI from WMH-NC.
• Multi-modal MRI was used to assess glymphatic function.
• ALPS index reflects diffusivity along perivascular spaces, a key route for glymphatic clearance.

The gut bacterium Acetivibrio was identified as differing between WMH patients with and without cognitive impairment.

• Acetivibrio was among six bacterial genera showing differences across the three study groups.
• Acetivibrio specifically showed differences between WMH-CI and WMH-NC groups.
• Gut microbiome was characterized using 16S rDNA sequencing.
• Microbiota differences were linked to cognitive outcomes through downstream metabolite and glymphatic pathways.

The study used an integrated multi-omics and neuroimaging approach to characterize biological heterogeneity in cognitive outcomes among WMH patients.

• Methods included 16S rDNA sequencing for gut microbiome, untargeted metabolomics for plasma metabolome, and multi-modal MRI for glymphatic function.
• Three groups were compared: 56 healthy controls, 40 WMH-NC, and 49 WMH-CI.
• The integrated approach aimed to explain why individuals with similar WMH burden show heterogeneous cognitive outcomes.
• Findings were described as 'preliminary insights' potentially informing 'more targeted interventions for vascular cognitive impairment.'

Plasma metabolites 1,5-naphthalenediamine and beta-uridine differed between WMH patients with and without cognitive impairment.

• Three total plasma metabolites differed across all three groups.
• 1,5-naphthalenediamine and beta-uridine specifically showed differences between WMH-CI and WMH-NC.
• Tetradecyldiethanolamine was identified as a mediator in the microbiota-cognition pathway.
• Plasma metabolome was assessed using untargeted metabolomics.