Abstract WP208: Lower Fractional Anisotropy in White Matter Tracts is Associated With Decreased Manipulative Manual Dexterity Higher Circulating Ceramide Levels in Healthy High-Risk Middle-Aged Individuals

Abstract

Introduction: We previously reported impaired manipulative manual dexterity measured by grooved peg-board test (GPBT) in healthypeople with increased total brain ischemic white matter hyperintensities. We hypothesized that preclinical white matter tract damage (WMTD), measured as lower regional fractional anisotropy (rFA), is associated with functional decrements measured with GPBT, and with a biomarker of white matter disease, serum ceramides. Methods: Participants were recruited from the GeneSTAR study in families with a history of coronary artery disease. Diffusion tensor imaging was acquired on a Phillips 3T MRI and rFA was calculated using the 181 Eve segmented atlas. 48 susceptible regions for WMTD were analyzed.Liquid chromatography was used to measure ceramides (C). Spearman’s rank correlation (SRC) was used to test statistical associations and Bonferroni method was used to correct for multiple comparisons. Multivariate analysis (GEE) adjusting for age, sex, race and education was performed for associations that were significant in the univariate analyses. Result: Subjects (n=112) were 49±11 years; 49% male and 39% African American. rFA was correlated with decrements on GPBT in the left (L) anterior corona radiata, L genu of the corpus callosum (LGCC), L external capsule, and L & right fornix (RF) (P=0.0009, 0.0008, 0.0002, 0.0003 and 8.2E-07, respectively). Additionally, rFA was negatively correlated with C18:0 in the RF and LGCC (P=1.27E-05 and 2.58E-05, respectively) and C20:0 in RF (P=6.09E-06). C18:0 was correlated with decrements on GPBT (P=0.0025). GEE showed associations between decremental GPBT and rFA in the RF (B = -0.52, 95% CI -1 - 0.03, p= 0.037), between rFA in the RF and Ceramide (C18:0, B= -0.03, 95% CI -0.046--0.0073, p=0.007, C20:0, B=-0.0002, 95%CI -0.0003-0, P= 0.018), as well as rFA in LGCC and Ceramide (C18:0, B=-0.0097, 95% CI -0.019--0.006, P=0.037). GBPT and ceramides were not associated when adjusted for rFA (B = 0.0002 95% CI -0.052 - 0.052 P= 0.99). Conclusion: These analyses support our hypothesis that preclinical WMTD represented by reduced rFA, may undermine neural networks affecting manipulative manual dexterity, with concomitant elevation in serum ceramides in healthy high risk people.