Location matters: Attributing cognitive symptoms to white matter hyperintensities in 3,481 memory clinic patients

Background and aim: In memory clinic patients, assessing diagnostic relevance of white matter hyperintensities (WMHs), as a marker to explain cognitive deficits, can be challenging. Here, we aimed to quantify this relevance by measuring the variance in cognitive function they explain, and consider, beyond total WMH volume, WMH location in specific tracts and normative WMH values. Methods: We analyzed previously pooled and harmonized individual patient data (n=3,481, 71±9 years old, 50% females) from 11 international memory clinic cohorts from the Meta-VCI-Map consortium. Cognitive function was assessed in 4 domains: attention and executive function, information processing speed, verbal memory and language. We measured WMH volumes in 20 white matter tracts. These were also norm-adjusted for age and sex, using normative WMH values from 14,876 community-dwelling individuals. Explained variance in cognitive function was measured for demographics only (age, sex and education) and demographics combined with total WMH volume, tract-specific WMH volumes and norm-adjusted and tract-specific WMH z-scores. Results: Beyond demographics, total and tract-specific WMH volumes explained significantly more variance in attention and executive functioning (ΔR2total=3.7%, 95%CI=[3.3%;4.1%], ΔR2tracts=6.2%, 95%CI=[5.6%;6.7%]) and verbal memory (ΔR2total=3.6%, 95%CI=[3.2%;3.9%], ΔR2tracts=8.0%, 95%CI=[7.5%;8.6%]). In processing speed, tract-specific (ΔR2=2.5%, 95%CI=[2.1%;3.0%]) —but not total— WMH volumes explained more variance than demographics. Norm-adjusting tract-specific volumes explained no additional variance. Conclusion: Considering location of WMHs increased their diagnostic relevance, compared to total volume, explaining more variance in attention and executive function, processing speed and verbal memory. This advocates considering WMH location beyond total volume as a diagnostic marker.