Extent and distribution of white matter hyperintensities in normal aging, MCI, and AD

Abstract

Objective: To analyze the extent and spatial distribution of white matter hyperintensities (WMH) in brain regions from cognitively normal older individuals (CN) and patients with mild cognitive impairment (MCI) and Alzheimer disease (AD).

Methods: We studied 26 mild AD, 28 MCI, and 33 CN. MRI analysis included quantification of WMH volume, nonlinear mapping onto a common anatomic image, and spatial localization of each WMH voxel to create an anatomically precise frequency distribution map. Areas of greatest frequency of WMH from the WMH composite map were used to identify 10 anatomic regions involving periventricular areas and the corpus callosum (CC) for group comparisons.

Results: Total WMH volumes were associated with age, extent of concurrent vascular risk factors, and diagnosis. After correcting for age, total WMH volumes remained significantly associated with diagnosis and extent of vascular risk. Regional WMH analyses revealed significant differences in WMH across regions that also differed significantly according to diagnosis. In post-hoc analyses, significant differences were seen between CN and AD in posterior periventricular regions and the splenium of the CC. MCI subjects had intermediate values at all regions. Repeated measures analysis including vascular risk factors in the model found a significant relationship between periventricular WMH and vascular risk that differed by region, but regional differences according to diagnosis remained significant and there was no interaction between diagnosis and vascular risk.

Conclusions: Differences in white matter hyperintensities (WMH) associated with increasing cognitive impairment appear related to both extent and spatial location. Multiple regression analysis of regional WMH, vascular risk factors, and diagnosis suggest that these spatial differences may result from the additive effects of vascular and degenerative injury. Posterior periventricular and corpus callosum extension of WMH associated with mild cognitive impairment and Alzheimer disease indicate involvement of strategic white matter bundles that may contribute to the cognitive deficits seen with these syndromes.

Figure 1

Composite white matter hyperintensity (WMH) frequency maps for all study subjects in anatomic Montreal Neurologic Institute reference space. Orange color indicates voxels containing WMH with a frequency of more than 10%; yellow color indicates a frequency of more than 50%.

Figure 2

Graphical display of 10 regions of interest (ROIs) overlaid on the target image. (A) Axial slice; (B) slightly oblique view of sagittal slice. Red areas indicate each ROI. Cg = genu of corpus callosum; Cs = splenium of corpus callosum; Pa = anterior periventricular region; Pm = middle of periventricular region; Pp = posterior periventricular region; Po = occipital periventricular region.

Figure 3

Three-dimensional white matter hyperintensity (WMH) frequency maps for each cognitive group displayed in two separate orientations for enhanced visualization. (A) Cognitively normal older individuals (CN); (B) mild cognitive impairment (MCI); (C) Alzheimer disease (AD). Orange area indicates voxels containing WMH with a frequency of 10% or higher.

Figure 4

Graphic displays of mean white matter hyperintensity (WMH) for periventricular regions and corpus callosum according to diagnostic group. (A) Periventricular regions; (B) corpus callosum. White columns = patients with Alzheimer disease (AD); gray columns = patients with mild cognitive impairment (MCI); black column = cognitively normal (CN) older subjects. Error bars indicate SD. *p < 0.004, ^**p < 0.0001, when comparing AD with CN.

Figure 5

Graph displays of mean white matter hyperintensity (WMH) for each region of interest comparing subjects with to those without hypertension. White columns = subjects with hypertension; gray columns = subjects without hypertension. Error bars indicate SD. *p < 0.01, ^**p < 0.0005, ^***p < 0.0001. (Top right) Two-dimensional axial slice of WMH having a frequency of 10% or higher for subjects with and without hypertension. Green = subjects with hypertension; orange–yellow = subjects without hypertension.

Figure 6

Three-dimensional white matter hyperintensity (WMH) frequency maps for each cognitive group. (A) First quartile Mini-Mental State Examination (MMSE) 29 to 30; (B) second quartile, MMSE 28; (C) third quartile, MMSE 25 to 27; (D) fourth quartile MMSE 0 to 24. Orange area indicates voxels containing WMH with a frequency of 10% or higher.