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

Article type: Research Article

Authors: Riverol, Mario^{a; b} | Becker, James T.^{b; c; d; *} | López, Oscar L.^b | Raji, Cyrus A.^b | Thompson, Paul M.^e | Carmichael, Owen T.^f | Gach, H. Michael^{g; h} | Longstreth Jr., William T.ⁱ | Fried, Linda^{j; k} | Tracy, Russell P.^l | Kuller, Lewis H.^m

Affiliations: [a] Department of Neurology, University of Navarra, Pamplona, Spain | [b] Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA | [c] Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA | [d] Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA | [e] Laboratory of Neuro Imaging, UCLA School of Medicine, Los Angeles, CA, USA | [f] Department of Neurology, University of California Davis, Davis, CA, USA | [g] Department of Radiology, University of Pittsburgh, Pittsburgh, PA, USA | [h] Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA | [i] Departments of Neurology and Epidemiology, University of Washington, Seattle, WA, USA | [j] Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA | [k] Renal Section, VA Pittsburgh Medical Center, Pittsburgh, PA, USA | [l] University of Vermont, Burlington, VT, USA | [m] Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USA

Correspondence: [*] Correspondence to: James T. Becker, PhD, Suite 830, 3501 Forbes Avenue, Pittsburgh, PA 15213, USA. Tel.: +1 412 246 6970; Fax: +1 412 246 6873; E-mail: [email protected].

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

DOI: 10.3233/JAD-141077

Journal: Journal of Alzheimer's Disease, vol. 44, no. 1, pp. 319-328, 2015