Relationship between Systemic and Cerebral Vascular Disease and Brain Structure Integrity in Normal Elderly Individuals

Abstract

Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.

Keywords: Cognitive impairment; cystatin C; gray matter volume; white matter lesions.

Figure 1

Schematic representation of the participants’ selection process.

Figure 2

Main effect of cystatin C on regional gray matter volume projected onto the SPM single subject cortical surface. Higher cystatin C levels were associated with lower GM volumes most prominently in the superior frontal gyrus bilaterally, but also in the right lateral occipital cortex and in the left inferior parietal lobe. We applied a Family Wise Error Rate threshold (p < 0.05) with an extent threshold of 100 voxels.

Figure 3

This figure shows the overlap of main effects of age (red), white matter grade (yellow) and body mass index (blue) on gray matter volume projected onto the Standard Single Subject MNI template (maps created using MRIcron, http://www.cabiatl.com/mricro/mricron/index.html).

Figure 4

Graphic representation of the results of a series of logistic regression models. The arrows indicate the direction of the relationships, and the numbers are the odds ratios associated with each of the pathways. Age (± 75), BMI (± 30), GM volume (± 44.38%), log₁₀ blocks walked (± 0.47) were dichotomized prior to the analysis; all variables were coded so that a value of ‘1’ was abnormal, and ‘0’ was considered normal. GM volume (normal vs. atrophic) was regressed (forward, stepwise, Wald criteria) on all of the variables shown in the figure, as well as blocks walked, and education. Only those variables that significantly altered the risk of atrophy were shown in the first level (i.e., age, ApoE4, and WML). WML was then regressed on the remaining variables, and age, Cystatin C, and HTN were significant. Finally, the factors associated with risk for elevated Cystatin C were assessed, and only age, race, sex and HTN remained in the model.