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Evidence for genetic correlation between human cerebral white matter microstructure and inflammation.

ABSTRACT: White matter microstructure is affected by immune system activity via the actions of circulating pro-inflammatory cytokines. Although white matter microstructure and inflammatory measures are significantly heritable, it is unclear if overlapping genetic factors influence these traits in humans. We conducted genetic correlation analyses of these traits using randomly ascertained extended pedigrees from the Genetics of Brain Structure and Function Study (N = 1862, 59% females, ages 18-97 years; 42 ± 15.7). White matter microstructure was assessed using fractional anisotropy (FA) calculated from diffusion tensor imaging (DTI). Circulating levels (pg/mL) of pro-inflammatory cytokines (IL-6, IL-8, and TNFα) phenotypically associated with white matter microstructure were quantified from blood serum. All traits were significantly heritable (h² ranging from 0.41 to 0.66 for DTI measures and from 0.18 to 0.30 for inflammatory markers). Phenotypically, higher levels of circulating inflammatory markers were associated with lower FA values across the brain (r = -.03 to r = -.17). There were significant negative genetic correlations between most DTI measures and IL-8 and TNFα, although effects for TNFα were no longer significant when covarying for body mass index. Genetic correlations between DTI measures and IL-6 were not significant. Understanding the genetic correlation between specific inflammatory markers and DTI measures may help researchers focus questions related to inflammatory processes and brain structure.

SUBMITTER: Rodrigue AL

PROVIDER: S-EPMC6707845 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:To explore the correlation between the number of lenticulostriate arteries (LSAs) and the white matter features in cerebral small vessel diseases (CSVD) by 3T magnetic resonance imaging (MRI). Seventy-one patients with diagnoses of CSVD were prospectively enrolled to undergo 3T MRI examination, including high-resolution vascular wall imaging (VWI) and diffusion tensor imaging (DTI). The LSAs were observed and counted on VWI, and the patients were divided into three groups according to the LSA counts. The presence of white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (EPVS) was assessed in each patient, and a composite CSVD score was calculated. Periventricular and deep white matter hyperintensity (PVWMH, DWMH) volume ratios were obtained based on automatic segmentation. Fractional anisotropy (FA) and mean diffusivity (MD) were processed by using tract-based spatial statistics (TBSS) analysis. These parameters were compared among the three groups. Correlations between the LSA counts and white matter features were also analyzed. There were differences in WMHs (P = 0.001), CMBs (P < 0.001), EPVS (P = 0.017), composite CSVD scores (P < 0.001), PVWMH volume ratios (P = 0.001), DWMH volume ratios (P < 0.001), global FA (P = 0.001), and global MD (P = 0.002) among the three groups. There were correlations between the LSA counts and WMHs (r = -0.45, P < 0.001), CMBs (r = -0.44, P < 0.001), EPVS (r = -0.28, P = 0.020), the composite CSVD score (r = -0.52, P < 0.001), DWMH volume ratio (r = -0.47, P < 0.001), PWMH volume ratio (r = -0.34, P = 0.004), global FA (r = 0.36, P = 0.002), and global MD (r = -0.33, P = 0.005). Diabetes mellitus (OR 3.36, 95% CI 1.06-10.63; P = 0.039) and increased DWMH volume ratios (OR 1.04, 95% CI 1.00-1.08; P = 0.048) were independent risk factors for a decrease in LSA counts. TBSS analysis showed differences among the three groups in global FA and MD after adjusting for age and sex (P < 0.05). The LSA counts was associated with white matter microstructure changes in CSVD and has the potential to represent the extent of subcortical microvascular damage in CSVD patients.

Project description:ImportanceThere is a dearth of studies that examine the association between poorer hearing and change in cerebral white matter (WM) microstructure.ObjectiveTo examine the association of poorer hearing with baseline and change in WM microstructure among older adults.Design, setting, and participantsThis was a prospective cohort study that evaluated speech-in-noise, pure-tone audiometry, and WM microstructure, as measured by mean diffusivity (MD) and fractional anisotropy (FA), both of which were evaluated by diffusion tensor imaging (DTI) in 17 WM regions. Data were collected between October 2012 and December 2018 and analyzed between March 2019 and August 2019 with a mean follow-up time of 1.7 years. The study evaluated responses to the Baltimore Longitudinal Study of Aging among 356 cognitively normal adults who had at least 1 hearing assessment and DTI session. Excluded were those with baseline cognitive impairment, stroke, head injuries, Parkinson disease, and/or bipolar disorder.ExposuresPeripheral auditory function was measured by pure-tone average in the better-hearing ear. Central auditory function was measured by signal-to-noise ratio score from a speech-in-noise task and adjusted by pure-tone average.Main outcomes and measuresLinear mixed-effects models with random intercepts and slopes were used to examine the association of poorer peripheral and central auditory function with baseline and longitudinal DTI metrics in 17 WM regions, adjusting for baseline characteristics (age, sex, race, hypertension, elevated total cholesterol, and obesity).ResultsOf 356 cognitively normal adults included in the study, the mean (SD) age was 73.5 (8.8) years, and 204 (57.3%) were women. There were no baseline associations between hearing and DTI measures. Longitudinally, poorer peripheral hearing was associated with increases in MD in the inferior fronto-occipital fasciculus (β = 0.025; 95% CI, 0.008-0.042) and the body (β = 0.050; 95% CI, 0.015-0.085) of the corpus callosum, but there were no associations of peripheral hearing with FA changes in these tracts. Poorer central auditory function was associated with longitudinal MD increases (β = 0.031; 95% CI, 0.010-0.052) and FA declines (β = -1.624; 95% CI, -2.511 to -0.738) in the uncinate fasciculus.Conclusions and relevanceFindings of this cohort study suggest that poorer hearing is related to change in integrity of specific WM regions involved with auditory processing.

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Evidence for genetic correlation between human cerebral white matter microstructure and inflammation.

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