Impact of Strategically Located White Matter Hyperintensities on Cognition in Memory Clinic Patients with Small Vessel Disease

<div><p>Background and Purpose</p><p>Studies on the impact of small vessel disease (SVD) on cognition generally focus on white matter hyperintensity (WMH) volume. The extent to which WMH location relates to cognitive performance has received less attention, but is likely to be functionally important. We examined the relation between WMH location and cognition in a memory clinic cohort of patients with sporadic SVD.</p><p>Methods</p><p>A total of 167 patients with SVD were recruited from memory clinics. Assumption-free region of interest-based analyses based on major white matter tracts and voxel-wise analyses were used to determine the association between WMH location and executive functioning, visuomotor speed and memory.</p><p>Results</p><p>Region of interest-based analyses showed that WMHs located particularly within the anterior thalamic radiation and forceps minor were inversely associated with both executive functioning and visuomotor speed, independent of total WMH volume. Memory was significantly associated with WMH volume in the forceps minor, independent of total WMH volume. An independent assumption-free voxel-wise analysis identified strategic voxels in these same tracts. Region of interest-based analyses showed that WMH volume within the anterior thalamic radiation explained 6.8% of variance in executive functioning, compared to 3.9% for total WMH volume; WMH volume within the forceps minor explained 4.6% of variance in visuomotor speed and 4.2% of variance in memory, compared to 1.8% and 1.3% respectively for total WMH volume.</p><p>Conclusions</p><p>Our findings identify the anterior thalamic radiation and forceps minor as strategic white matter tracts in which WMHs are most strongly associated with cognitive impairment in memory clinic patients with SVD. WMH volumes in individual tracts explained more variance in cognition than total WMH burden, emphasizing the importance of lesion location when addressing the functional consequences of WMHs.</p></div

Voxel-based lesion-symptom mapping results: tested and significant voxels for each anatomical region, after additional correction for total WMH volume and the presence of lacunes.

<p>Voxel-based lesion-symptom mapping results: tested and significant voxels for each anatomical region, after additional correction for total WMH volume and the presence of lacunes.</p

Comparison of the impact of total WMH volume, regional WMH volume and brain atrophy on executive functioning, visuomotor speed and memory.

<p>Comparison of the impact of total WMH volume, regional WMH volume and brain atrophy on executive functioning, visuomotor speed and memory.</p

Cognitive profile of the study cohort.

<p>Cognitive profile of the study cohort.</p

Relation between WMH volume within 11 white matter tracts and executive functioning, visuomotor speed and memory.

<p>Relation between WMH volume within 11 white matter tracts and executive functioning, visuomotor speed and memory.</p

Sensitivity analysis, restricted to patients without a diagnosis of AD (n = 125).

<p>Sensitivity analysis, restricted to patients without a diagnosis of AD (n = 125).</p

Characteristics of the study cohort.

<p>Characteristics of the study cohort.</p

Lesion prevalence map and voxel-based lesion-symptom mapping results.

<p>(A) Lesion prevalence map. Voxels with white matter lesions in at least 10 patients are projected onto the MNI-152 template. (B-C): VLSM results for executive functioning (panel B), visuomotor speed (panel C) and memory (panel D) after correction for age, sex, level of education and multiple testing (settings: BM-test; FDR q<0.05). Significant voxels are shown in red. Z-coordinates: -20, -10, 0, 10, 20, 30, 40, 50. (E-F) VLSM results for executive functioning (panel E; coordinate Z-17) and visuomotor speed (panel F; coordinate Z-16) after additional correction for total WMH volume and presence of lacunes. One representative slice is shown per cognitive domain that depicts the location of several significant voxels (in red) in relation to the forceps minor (blue) and anterior thalamic radiation (green). The location of all significant voxels are provided in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0166261#pone.0166261.t004" target="_blank">Table 4</a>.</p

Association between overweight (BMI between 25.0 and 29.9 kg/m²) and CRAE (<i>A</i>), and CRVE (<i>B</i>) in adults (maximum level of adjustment).

<p>Association between overweight (BMI between 25.0 and 29.9 kg/m²) and CRAE (<i>A</i>), and CRVE (<i>B</i>) in adults (maximum level of adjustment).</p

Association between obesity (BMI >30.0 kg/m²) and CRAE (<i>A</i>), and CRVE (<i>B</i>) in adults (maximum level of adjustment).

<p>Association between obesity (BMI >30.0 kg/m²) and CRAE (<i>A</i>), and CRVE (<i>B</i>) in adults (maximum level of adjustment).</p