MRI free water as a biomarker for cognitive performance: Validation in the markvcid consortium

Abstract

AbstractBackgroundFree Water (FW), a Diffusion Tensor Imaging‐based biomarker kit has been demonstrated by the MarkVCID consortium to have excellent instrumental validity1. We sought to determine its clinical relevance by investigating association of FW with clinically meaningful aspects of vascular contributions to cognitive impairment and dementia (VCID) in the MarkVCID consortium cohort as well as 5 independent settings.MethodThis study included individuals from the MarkVCID UH3 phase cohort2 (N = 523) and 5 independent legacy cohorts: University of California Davis Alzheimer Disease Research Center3 (ADRC UCD, N = 173), MarkVCID UH2‐ phase data from University of California San Francisco4 (UH2 UCSF, N = 182) and RUSH Alzheimer Disease Center5 (N = 302), Framingham Heart Study6,7 (FHS, N = 2902) and Atherosclerosis Risk in Communities8 (ARIC, N = 1837). Table 1 summarizes participants’ characteristics. Our goal was to evaluate whether mean FW (mFW) computed within the white matter tissue as provided by the kit1 is cross‐sectionally associated with a composite measure of executive functions (EFC) derived from item‐response theory (IRT) generated score9,10, which incorporates scores from NACC Uniform Data Set Version 3 neuropsychological tests11. To test this hypothesis, a linear regression was used with EFC score as the dependent variable and mFW as the independent variable, adjusting for age, sex and education. In a second model, this model was additionally adjusted for presence of diabetes, smoking and hypertension to estimate the added contribution of mFW above vascular risk factors.ResultHigher mFW was associated with lower EFC scores (see Figure 1) in all the subject groups studied. In the MarkVCID cohort (ß = ‐3.54, p<0.0001), as well as in the five legacy cohorts (UH2 UCSF: ß = ‐3.54, p<0.0001, RUSH: ß = ‐1.905, p = 0.00597, ADRC: ß = ‐6.18, p<0.0001, FHS: ß = ‐4.06, p<0.0001, ARIC: ß = ‐1.24, p<0.0001). Adjusting for vascular risk factors did not significantly change these associations (p values< 0.01).ConclusionFindings from this study indicated that mean FW is a sensitive biomarker of cognitive performances, providing strong evidence of the clinical rational of FW as a sensitive biomarker of WM injury in association with cognition for future observational studies and clinical trials in the context of VCID.