Microstructural white matter integrity and risk of mortality

Abstract

While several studies reported a link between presence of white matter lesions and shorter survival, it is not yet clear whether this link extends to more subtle cerebral white matter changes. We investigated the independent association of cerebral white matter microstructural integrity with mortality. We included 4294 stroke and dementia free individuals (mean age 63.6 years, 44% male) from the population-based Rotterdam Study. Diffusion-MRI was used to assess microstructural integrity of the normal-appearing white matter. Mean diffusivity (MD) and fractional anisotropy (FA) were evaluated as markers of white matter integrity. During a follow up time of 5.4 years all-cause mortality was recorded. For cause-specific mortality follow up was available for 3.6 years. Death due to cardiovascular mortality was classified as ICD-10 codes I00-I99 and death due to other reasons was recorded as non-cardiovascular mortality. Cox regression models, adjusted for age, sex, cardiovascular risk factors and macrostructural MRI changes, were used to estimate hazard ratios. White matter in the population had an average MD of 0.74±0.03 10−3 mm2/s and average FA of 0.34±0.01. Figure 1 shows mortality rates in relation to FA and MD tertiles. Subjects with highest MD and lowest FA measures, reflecting impaired white matter integrity, had highest mortality risk. Each standard deviation lower FA and each standard deviation higher MD were associated with 1.37 fold (95%CI: 1.20, 1.57) and 1.49 fold (95%CI: 1.28, 1.75) higher risk of all-cause mortality, respectively. The associations were more prominent with cardiovascular mortality than non-cardiovascular mortality. Subtle changes in the microstructure of cerebral white matter are independently associated with higher mortality from both cardiovascular and non-cardiovascular causes. Mortality rates and 95% CI per 1000 person-years in tertiles of fractional anisotropy (FA) and mean diffusivity (MD)