Causal relationship between multiparameter brain MRI phenotypes and age: evidence from Mendelian randomization

To explore the causal relationship between age and brain health (cortical atrophy, white matter integrity, white matter hyperintensities, and cerebral microbleeds in various brain regions) related multiparameter imaging features using two-sample Mendelian randomization. Age was determined as chronological age of the subject. Cortical volume, white matter micro-integrity, white matter hyperintensity volume, and cerebral microbleeds of each brain region were included as phenotypes for brain health. Age and imaging of brain health related genetic data were analyzed to determine the causal relationship using inverse-variance weighted model, validated by heterogeneity and horizontal pleiotropy variables. Age is causally related to increased volumes of white matter hyperintensities (β= 0.151). For white matter micro-integrity, fibers of the inferior cerebellar peduncle (Axial diffusivity β= -0.128, orientation dispersion index β= 0.173), cerebral peduncle (Axial diffusivity β= -0.136), superior fronto-occipital fasciculus (isotropic volume fraction β= 0.163) and fibers within the limbic system were causally deteriorated. We also detected decreased cortical thickness of multiple frontal and temporal regions (p<0.05). Microbleeds were not related with aging p＞0.05). Aging is a threaten of brain health, leading to cortical atrophy mainly in the frontal lobes, as well as the white matter degeneration especially abnormal hyperintensity and deteriorated white matter integrity around the hippocampus.