Cerebral vasomotor reactivity and cerebral white matter lesions in the elderly

Study population and methods.

For the current study, 80 individuals were randomly selected from the Rotterdam Scan Study. The Rotterdam Scan Study is a population-based study of causes and consequences of age-related brain changes as visible on MRI. Persons with dementia and contraindications for MRI were excluded. This study was carried out between July and September 1996 and based on the part of the cohort that also participated in the Rotterdam Study, which focuses on determinants of neurologic, cardiovascular, endocrinal, and ophthalmologic diseases in the elderly.21

TCD monitoring was performed (Multi-Dop X-4, DWL, Elektronische Systeme GmbH, Sipplingen, Germany), and mean cerebral blood flow velocity was continuously measured in the middle cerebral artery on both sides if possible, as follows. The subject breathed air and 5% CO₂ through an anesthetic mask tightly fitted over the mouth and nose. End-tidal CO₂ pressure (mm Hg) was recorded continuously with a CO₂ analyzer (Multinex, Datascope, Hoevelaken, the Netherlands). The subject first breathed room air until a steady expiratory end-tidal CO₂ was obtained and then was asked to inhale a mixture of 5% CO₂ in 95% oxygen for 2 minutes, and the end-tidal CO₂ was recorded. End-expiratory CO₂ was assumed to reflect arterial CO₂.11 TCD-8 DWL special software (VMR-CO₂, Elektronische Systeme GmbH) was used. All TCD data were stored on hard disk for off-line analysis. Vasomotor reactivity was defined as the percentage increase in blood flow velocity occurring during inspiration of 5% CO₂, divided by the absolute increase in end-tidal CO₂ in the same time period (percent/mm Hg). The mean of the right and left vasomotor reactivity was used for the analyses if both middle cerebral arteries could be insonated adequately. The one-sided vasomotor reactivity was used if a window failure appeared on one side.

Each subject underwent cerebral MRI scanning using a 1.5-Tesla (T) Siemens Gyroscan. From each participant, axial T1*- (repeat time [TR] 700 ms, echo time [TE] 14 ms), T2*- (TR 2200, TE 80 ms), and proton density- (PD) (TR 2200, TE 20 ms) weighted images were made. Slice thickness was 5 mm, with a gap of 1.0 mm. All MRI scans were examined independently by two experienced readers. White matter lesions were considered present if visible on both PD- and T2*-weighted images and not on the T1*-weighted image. White matter lesions were distinguished between deep subcortical lesions (figure 1) and those in the periventricular region (figure 2). The number of deep subcortical white matter lesions was counted on hard copy according to their largest diameter in categories of small (<3 mm), medium (3 to 10 mm), or large lesions (>10 mm). To calculate a deep subcortical white matter lesion volume, the white matter lesions were considered to be spherical with a fixed diameter per size category. Periventricular white matter lesions were scored semiquantitatively per region (adjacent to the frontal horn or frontal capping, adjacent to the lateral wall of the lateral ventricles or bands, and adjacent to the occipital horn or occipital capping) at a scale ranging from 0 (no white matter lesions) to 1 (pencil-thin periventricular lining), 2 (smooth halo or thick lining), and 3 (large confluent white matter lesions). The total severity of periventricular white matter lesions was calculated by adding up the scores of the three separate categories (range 0 to 9). All MRI scans were examined by two raters from a pool of four experienced raters. In case of a disagreement of more than one point, a consensus reading was held; in all other cases, the average of the two readers was calculated. Inter- and intrarater studies showed a good to excellent agreement. Weighted kappas were calculated with respect to scoring of the periventricular white matter lesions (weighted kappa between 0.79 and 0.90). Intraclass correlation coefficients were calculated for deep subcortical white matter lesions (r² = 0.88 for total volume of deep subcortical white matter lesions).

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Figure 1. MRI example of deep subcortical white matter lesions. Arrows indicate various deep subcortical white matter lesions.

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Figure 2. MRI example showing the distinction between periventricular white matter lesions (large closed arrow) and deep subcortical white matter lesions (smaller partially open arrow).

To assess the relationship between vasomotor reactivity and white matter lesions, age- and sex-adjusted logistic regression was used. In these analyses, vasomotor reactivity was used as a continuous variable, and white matter lesions were dichotomized at the upper quintile. All analyses were performed with BMDP statistical software.22 To detect a possible threshold, the association between tertiles of vasomotor reactivity and extent of white matter lesions was assessed using age- and sex-adjusted linear regression.

Results.

Combined TCD and MRI data were obtained in 73 individuals (91%). The other individuals had either window failure on both sides (n = 4) or difficulties wearing the dose-fitting mask (n = 3). MRI examination was well tolerated. The mean age of the study population was 70.2 years, and 74% of all individuals were men. Except for age and sex, vascular risk factors were equally frequent in the Rotterdam Scan study and in the Rotterdam Study as a whole (table 1). Mean vasomotor reactivity was 3.4%/mm Hg and ranged from 0.8 to 6.3%/mm Hg with a normal distribution. A correlation coefficient of 0.94 was found between right and left vasomotor reactivity. Women tended to have a lower vasomotor reactivity than men: mean 3.0 versus 3.6 (p = 0.4). Sixty-eight percent of the individuals had at least some periventricular white matter lesions, and 86% had at least some deep subcortical white matter lesions. Fifty-seven percent of the individuals had periventricular white matter lesions adjacent to the lateral ventricular wall (bands).

Vasomotor reactivity was inversely associated with severe deep subcortical and total periventricular white matter lesions (OR 0.5, 95% CI 0.3 to 1.1; and OR 0.7, 95% CI 0.4 to 1.1 per 10% vasomotor reactivity, respectively). Figure 3 shows that individuals with higher vasomotor reactivity had a significantly lower mean score of total periventricular white matter lesions (p = 0.01). As shown in figure 4, individuals with higher vasomotor reactivity also had a significantly lower mean score of total deep subcortical white matter lesion volume (p = 0.02).

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Figure 3. The association between tertiles of cerebral vasomotor reactivity (%/mm Hg) and mean total score (SE) of periventricular white matter lesions, adjusted for age and sex. *p Value was calculated in a test for trend.

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Figure 4. The association between tertiles of cerebral vasomotor reactivity (%/mm Hg) and mean volume (SE) of total deep subcortical white matter lesions (mL), adjusted for age and sex. *p Value was calculated in a test for trend.

Table 2 gives the mean score of white matter lesions in each periventricular region per tertile of vasomotor reactivity and provides the mean scores for deep subcortical white matter lesions for each size in the different vasomotor reactivity groups. Individuals in the lowest tertile of vasomotor reactivity had the highest mean score of white matter lesions in all three periventricular regions, whereas individuals in the highest tertile of vasomotor reactivity had the lowest mean score. The inverse association between vasomotor reactivity and white matter lesions seemed strongest with periventricular white matter lesions adjacent to the lateral ventricular wall (p = 0.001). Better vasomotor reactivity was associated with less deep subcortical lesions, irrespective of the size of the lesions.

Discussion.

To our knowledge, this is the first study to show an association between vasomotor reactivity, assessed by means of CO₂-enhanced TCD, and the presence and extent of white matter lesions in a population-based study among elderly individuals. The results suggest that vasomotor reactivity is inversely associated with white matter lesions in the periventricular as well as in the deep subcortical regions. A strong association was found between impaired vasomotor reactivity and periventricular white matter lesions adjacent to the lateral ventricular wall (bands) in particular.

There are few reports on the relationship between magnetic resonance white matter lesions, cerebral blood flow, and the subject’s ability to increase cerebral blood flow in response to hypercapnia. Most investigators have found no significant changes in resting cerebral blood flow in individuals with asymptomatic periventricular white matter lesions,23,24 although one study with PET showed that in such patients cerebral blood flow was low compared with the oxygen requirements of the (surrounding) healthy brain.25 Others have found decreased cerebral blood flow values in areas of white matter lesions compared with areas with normal white matter.23,25-27 For the detection of reductions in cerebral perfusion, measurements of resting cerebral blood flow alone may be insufficient. Cerebral perfusion may be impaired only in situations where there is increasing demand caused by failure of normal compensatory mechanisms. This can be estimated by the determination of vasomotor reactivity, which provides a more sensitive hemodynamic index than the level of resting blood flow.12

In one study with asymptomatic individuals, the severity of periventricular white matter lesions was significantly and negatively correlated with a decrease in vasomotor reactivity and not with resting cerebral blood flow, which led the authors to suggest that the reduction of vasomotor reactivity is a more important hemodynamic marker in the pathogenesis of periventricular white matter lesions than is a decrease in the level of resting blood flow.19 This inverse association between a decrease in vasomotor reactivity and the severity of white matter lesions was subsequently found in hypertensive patients with leukoaraiosis.20

In our study, we found an increased mean score of periventricular white matter lesions, as well as an increase in severe deep subcortical white matter lesion volume in individuals with the lowest vasomotor reactivity scores. A strong and inverse association was found between low vasomotor reactivity and bands, which suggests that periventricular regions adjacent to the lateral ventricle wall harbor a circulatory border zone and may have fewer microcirculatory anastomoses than the other periventricular zones. The relationship between cerebral hemodynamics and white matter lesions has not been fully explored. Hypoxia-ischemia, disturbances in the circulation of the CSF, and changes in the permeability of the blood–brain barrier to macromolecules are thought to play an important role in the pathogenesis of white matter lesions.7 Several arguments support the hypothesis that some types of white matter lesions may be the result of ischemic injury to the brain.7-10 The region of the white matter immediately adjacent to the lateral ventricular walls receives its blood supply from the ventriculofugal vessels arising from the subependymal arteries, which originate either from the choroidal arteries or from terminal branches of the lenticulostriatal arteries.7,25 Anastomoses between the vessels originating at the surface, as well as those branching off the subependymal system, are either scarce or absent, leading to a minimal overlap between the territories of the different end arteries.28-31 This pattern of vascularization suggests that the periventricular white matter harbors an arterial border zone, particularly susceptible to injury from systemic or focal decreases in cerebral blood flow,7,32 although this has been challenged by others.33-35 Hypoperfusion can result either from arteriolosclerotic changes affecting the small intraparenchymal arteries and arterioles that are associated with aging and with stroke risk factors7,32,36,37 or by hemodynamic mechanisms in case these arteries are already maximally dilated, for instance, in high-grade carotid artery stenosis or occlusion, in which cerebral perfusion can become directly dependent on the systemic arterial blood pressure. This may explain the inability to increase focal blood flow in response to hypercapnia in these individuals. In the former, a drop in blood pressure may result in hypoperfusion and ischemic changes in the deep white matter. It is very unlikely that high-grade internal carotid artery stenosis contributed to our findings. Data on the prevalence of significant stenosis or occlusion of the carotid artery in a nonhospitalized elderly population are limited, but results from the Rotterdam Study show a prevalence of about 0.5% to 1.0%.38 We therefore consider it unlikely that this will affect the association we found. An association between white matter lesions and atherosclerotic abnormalities in the carotid artery, the coronary arteries, and the peripheral vessels has already been established.39 It is unclear, however, how different types of ischemia may induce selected structural changes in the white matter. We did not determine systemic blood pressure. Although systolic and diastolic blood pressure rise during hypercapnia, it is unclear whether and how this affects flow velocity in the cerebral arteries.

Future studies should elucidate the clinical and pathogenetic relevance of vasomotor reactivity in individuals with white matter lesions.