Vascular dementia in leukoaraiosis may be a consequence of capillary loss not only in the lesions, but in normal-appearing white matter and cortex as well

Abstract

We investigated capillary density in 12 subjects with leukoaraiosis (LA), in 9 age-matched normal subjects, in 7 cases of Alzheimer's disease (AD), and 4 after whole-brain irradiation for brain tumors. In the LA study (which as been published), autopsy brains were evaluated by MRI. The presence of LA was indicated by confluent or patchy areas of hyperintensity in the deep white matter. We employed a stereology method using computerized image processing and analysis to determine microvascular density. Afferent vessels (arterioles and capillaries, but not veins or venules) were stained for alkaline phosphatase in 100 microm thick celloidin sections. Microvascular density in LA lesions in the deep white matter (2.56%) was significantly lower than in the corresponding deep white matter of normal subjects (3.20%, p=0.0180). LA subjects demonstrated decreased vascular density at early ages (55-65 years) when compared to normal subjects. Our findings indicate that LA affects the brain globally, with capillary loss, although the parenchymal damage is found primarily in the deep white matter. In ongoing studies of the deep white matter in AD brains, we found a pattern of decreased vascular density compared to normal, as well as an age-related decline. In the four irradiated brains, we found very low vessel densities, similar to those found in LA, without an additional age-related decline.

Figure 1

(a–f) AP stained, 100 μm celloidin sections from normal subjects (a–c) and LA subjects (d–f). Only afferent vessels are stained. (a) DWM of normal, (b) LA lesion, (c) normal white matter away from ventricle, (d) normal-appearing white matter in LA subject, (e) cortex of normal subject, (f) cortex of LA subject. Note the decrease in vessels in the LA subjects.

Figure 2

Graphs of vascular density (% area) in deep white matter, white matter, and cortex of normal and leukoaraosis subjects. The vessel density in normal subjects (closed circles, solid lines) and LA subjects (open circles, dashed lines) are shown as a function of age. The statistical analysis was based on computer-generated regression lines from the data points shown. However, the lines drawn here are our interpretation of the data. They are based on the regression lines, but the scatter of the data points offers wide latitude for interpretation. A great many more data points would be needed to clearly establish the true shape of these curves. Note that the normal and LA lines meet at about 90 years of age. The computer-generated regression lines always crossed at about 75 years of age, giving the impression that vessel density in the normal subjects was lower than in the LA subjects after 75 years of age. That is biologically implausible. (a) Vessel density in the deep white matter of normal subjects was significantly greater than that in LA (p=0.0180). In normal subjects, vessel density decreased with age from approximately 6% at 55–60 years to 2% at 85–90 years. Vessel density in the LA lesion in the deep white matter was 2% to 3% at 55–60 years, less than half the level observed in normal subjects, and it did not show much tendency to decline further with increasing age. (b) The average vessel density in superficial white matter in normal subjects was not significantly different than that in normal-appearing, superficial white matter of LA subjects. In the normal subjects, vessel density decreased from approximately 8% at 55–60 years to 2% at 85–90 years. For the LA subjects, vessel density in normal-appearing white matter was 3% to 4% at 55–60 years, almost half of that seen in similar areas in normal subjects, and it did not show much decline with increasing age. (c) The density of vessels in the cortex of normal subjects was not significantly different from that in the cortex of LA subjects. Vessel density in normal cortex declined from approximately 16% at 55–60 years to approximately 6% by 90 years. Vessel density in cortex of LA subjects appeared somewhat reduced at 55–60 years, and it did not show much decline with increasing age.

Figure 3

Graph of vascular density in normal, LA, AD, and brain irradiation.