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Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships.

ABSTRACT: Because of similarities between brain and kidney microvascular disease, there may be a relationship between measures of renal microvascular disease and brain structural changes in middle aged or elderly individuals.To determine whether the urine albumin/creatinine ratio (UACR), a measure of renal microvascular disease, is associated with brain atrophy and white matter hyperintensities.As part of a larger study of the genetics of hypertension, we performed brain imaging and assessed microalbuminuria and other vascular risk factors including diabetes, hypertension, hyperlipidemia and hyperhomocysteinemia in 1253 individuals from hypertensive sibships (age mean 63.8 years, range 50 to 91; 65% women; 49% African-American; 78% hypertensive). Semi-automated quantitative measurements of brain atrophy (BA) ventricular volume, and white matter hyperintensities (WMH) were carried out on the brain MR scans.In logistic regression models, elevated UACR was associated with greater BA (odds ratio (OR)=1.70 (95% CI 1.14, 2.54) and burden of WMH (OR=2.06 (95% CI 1.37, 3.10) after controlling for demographic factors, blood glucose, hypertension severity, duration of smoking and serum homocysteine. In contrast to elevated UACR, the associations with elevated creatinine or reduced glomerular filtration rate and WMH were not significant in the fully adjusted models.In this cohort with an overrepresentation of hypertensives, elevated UACR was independently associated with both brain atrophy and white matter hyperintensities. Brain volume loss and WMH burden might represent expressions of microvascular disease that share common mechanisms with nephrosclerosis.

SUBMITTER: Knopman DS

PROVIDER: S-EPMC2527625 | biostudies-literature | 2008 Aug

REPOSITORIES: biostudies-literature

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Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships.

Knopman David S DS Mosley Thomas H TH Bailey Kent R KR Jack Clifford R CR Schwartz Gary L GL Turner Stephen T ST

Journal of the neurological sciences 20080428 1-2

<h4>Background</h4>Because of similarities between brain and kidney microvascular disease, there may be a relationship between measures of renal microvascular disease and brain structural changes in middle aged or elderly individuals.<h4>Objective</h4>To determine whether the urine albumin/creatinine ratio (UACR), a measure of renal microvascular disease, is associated with brain atrophy and white matter hyperintensities.<h4>Methods</h4>As part of a larger study of the genetics of hypertension, ...[more]

PMID: 18442832

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Project description:ObjectiveTo localize susceptibility genes for alterations in brain structure associated with risk of stroke and dementia. We conducted genomewide linkage analyses for magnetic resonance imaging (MRI) measures of brain atrophy, ventricular, and subcortical white matter hyperintensity (leukoaraiosis) in 689 non-Hispanic white (673 sibling pairs; median age, 61 years) and 544 non-Hispanic black participants (503 sibling pairs; median age, 64 years) from sibships with at least 2 members with essential hypertension.Design, setting, and patientsWe determined brain, ventricular, and leukoaraiosis volumes from axial fluid-attenuated inversion recovery MRI; we calculated brain atrophy as the difference between total intracranial and brain volumes. Microsatellite markers (n = 451) distributed across the 22 autosomes were genotyped, and we used variance components methods to estimate heritability and assess evidence of genetic linkage for each MRI measure.Main outcome measuresBrain atrophy ventricular volume, and leukoaraiosis determined from fluid-attenuated inversion recovery MRI.ResultsIn both races, the heritability of each MRI measure was statistically greater than 0 (P < .001), ranging in magnitude from 0.42 (for ventricular volume in blacks) to 0.69 (for brain atrophy in blacks). Based on multipoint logarithm of odds scores (MLS), the strongest evidence of genetic linkage was observed for brain atrophy on chromosomes 1 (MLS, 3.49 at 161 cM; P < .001) and 17 (MLS, 3.08 at 18 cM; P < .001) in whites; for ventricular volume on chromosome 12 (MLS, 3.67 at 49 cM; P < .001) in blacks and chromosome 10 (MLS, 2.47 at 110 cM; P < .001) in whites; and for leukoaraiosis on chromosome 11 (MLS, 2.21 at 118 cM; P < .001) in whites and chromosome 22 (MLS, 2.02 at 36 cM; P = .001) in blacks.ConclusionsThe MRI measures of structural brain injury are heritable in non-Hispanic black and white sibships ascertained through hypertensive sibling pairs. The susceptibility loci for brain atrophy, ventricular volume, and leukoaraiosis identified by linkage analyses differ among MRI measures and between races.

Project description:Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-ɛ4, APOE-ɛ2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-ɛ4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among ɛ4/ɛ4 carriers, followed by ɛ4 heterozygouts, and lowest among ɛ3 homozygouts and ɛ2/ɛ2 and ɛ2/ɛ3 carriers, who did not differ from one another. The negative associations of APOE-ɛ4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-ɛ4 status. APOE-ɛ2 status (ɛ2/ɛ2 and ɛ2/ɛ3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-ɛ4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-ɛ4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-ɛ4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-ɛ2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.

Dataset Information

Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships.

Publications

Associations of microalbuminuria with brain atrophy and white matter hyperintensities in hypertensive sibships.

Similar Datasets

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