Impact of white matter hyperintensity location on depressive symptoms in memory-clinic patients: a lesion–symptom mapping study

Abstract

Background: We investigated the association between white matter hyperintensity location and depressive symptoms in a memoryclinic population using lesion–symptom mapping.

Methods: We included 680 patients with vascular brain injury from the TRACE-VCI cohort (mean age ± standard deviation: 67 ± 8 years; 52% female): 168 patients with subjective cognitive decline, 164 with mild cognitive impairment and 348 with dementia. We assessed depressive symptoms using the Geriatric Depression Scale. We applied assumptionfree voxel-based lesion–symptom mapping, adjusted for age, sex, total white matter hyperintensity volume and multiple testing. Next, we applied exploratory region-of-interest linear regression analyses of major white matter tracts, with additional adjustment for diagnosis.

Results: Voxel-based lesion–symptom mapping identified voxel clusters related to the Geriatric Depression Scale in the left corticospinal tract. Region-of-interest analyses showed no relation between white matter hyperintensity volume and the Geriatric Depression Scale, but revealed an interaction with diagnosis in the forceps minor, where larger regional white matter hyperintensity volume was associated with more depressive symptoms in subjective cognitive decline (β = 0.26, p < 0.05), but not in mild cognitive impairment or dementia.

Limitations: We observed a lack of convergence of findings between voxel-based lesion–symptom mapping and region-of-interest analyses, which may have been due to small effect sizes and limited lesion coverage despite the large sample size. This warrants replication of our findings and further investigation in other cohorts.

Conclusion: This lesion–symptom mapping study in depressive symptoms indicates the corticospinal tract and forceps minor as strategic tracts in which white matter hyperintensity is associated with depressive symptoms in memory-clinic patients with vascular brain injury. The impact of white matter hyperintensity on depressive symptoms is modest, but it appears to depend on the location of white matter hyperintensity and disease severity.

Fig. 1

Flow chart for patient selection. GDS = Geriatric Depression Scale.

Fig. 2

Voxel-based lesion–symptom mapping: lesion prevalence map and results. (A) Voxel-wise lesion prevalence of white matter hyperintensities in the study population, projected on the Montreal Neurological Institute 152 T₁ template. A minimum threshold of 14 participants with damage in a given voxel was applied; z-coordinates: −5, 5, 15, 25, 35. Voxel-based lesion–symptom mapping results for the Geriatric Depression Scale score, shown in (B) axial, (C) sagittal and (D) coronal planes. Significant voxels after correction for multiple comparisons, age, sex and normalized total white matter hyperintensity volume are shown in red (settings: Brunner–Munzel test; FDR q < 0.05). Significant voxels were located in the corticospinal tract. Regions of interest were derived from the Johns Hopkins University diffusion tensor imaging atlas with a probability threshold of 10%. The corticospinal tract derived from the Johns Hopkins University atlas is shown in blue; the voxels included in the voxel-based lesion–symptom mapping analysis (i.e., damaged in ≥ 14 participants) are shown in yellow. Coordinates: sagittal: x = −25; coronal: y = −32; axial: z = 33, 38. CST = corticospinal tract; FDR = false detection rate; WMH = white matter hyperintensity.