Free Water in White Matter Differentiates MCI and AD From Control Subjects

Abstract

Recent evidence shows that neuroinflammation plays a role in many neurological diseases including mild cognitive impairment (MCI) and Alzheimer's disease (AD), and that free water (FW) modeling from clinically acquired diffusion MRI (DTI-like acquisitions) can be sensitive to this phenomenon. This FW index measures the fraction of the diffusion signal explained by isotropically unconstrained water, as estimated from a bi-tensor model. In this study, we developed a simple but powerful whole-brain FW measure designed for easy translation to clinical settings and potential use as a priori outcome measure in clinical trials. These simple FW measures use a “safe” white matter (WM) mask without gray matter (GM)/CSF partial volume contamination (WMsafe) near ventricles and sulci. We investigated if FW inside the WMsafe mask, including and excluding areas of white matter damage such as white matter hyperintensities (WMHs) as shown on T2 FLAIR, computed across the whole white matter could be indicative of diagnostic grouping along the AD continuum. After careful quality control, 81 cognitively normal controls (NC), 103 subjects with MCI and 42 with AD were selected from the ADNIGO and ADNI2 databases. We show that MCI and AD have significantly higher FW measures even after removing all partial volume contamination. We also show, for the first time, that when WMHs are removed from the masks, the significant results are maintained, which demonstrates that the FW measures are not just a byproduct of WMHs. Our new and simple FW measures can be used to increase our understanding of the role of inflammation-associated edema in AD and may aid in the differentiation of healthy subjects from MCI and AD patients.

MR Biomarkers of Degenerative Brain Disorders Derived From Diffusion Imaging

“…Lower FA T was also shown to be associated with lower memory score in the body of the fornix. 58 In a study by Dumont et al, 34 patients with MCI and AlzD exhibited elevated FW in corticospinal tracts and bundles of the limbic system (such as the cingulum and the fornix) compared with healthy controls; in addition, patients with AlzD showed broader pathology as compared with patients with MCI. Higher FW was maintained even after removing GM and CSF partial volume contamination using a WM mask.…”

“…Thus, in these voxels the metrics of bi-tensor DTI are liable to misestimation, since some signals arising from the fiber bundles not fitted to the single fiber tensor will be considered FW. 34 Finally, the bi-tensor model does not account for the non-Gaussian part of the diffusion decay. 8 Neurite Orientation Dispersion and Density Imaging NODDI is a multishell diffusion technique that enables more specific characterization of the tissue microstructure in the whole brain using a clinically feasible protocol.…”

“…Significant results were maintained even after removal of WM hyperintensities from the mask, which showed that the between-group differences with respect to FW metrics were not due to WM lesions. 34 NODDI IN ALZD. NDI and ODI were significantly lower in AlzD patients with early onset compared with healthy controls in some predefined ROIs in the cortical GM areas that demonstrated early atrophy in AlzD (entorhinal [only in NDI], inferior temporal, middle temporal, fusiform, and precuneus cortices) (Fig.…”

Nonparenchymal fluid is the source of increased mean diffusivity in preclinical Alzheimer's disease

“…More recently, Dumont et al. showed that the free water compartment differentiates MCI from AD [69] . Our results corroborate these findings.…”

Analyzing the effects of free water modeling by deep learning on diffusion MRI structural connectivity estimates in glioma patients

“…The majority of studies analyzing the effects of including a FWM focus on scalar-valued maps such as fractional anisotropy (FA) derived from dMRI measurements. Measurable effects were shown for associations with delusions in chronic schizophrenia [6], stress-related neural pathology in depression [7], classification of Parkinson's disease and atypical parkinsonism [8], target definition in glioblastoma radiotherapy [9], as well as for the diagnosis of mild cognitive impairment and Alzheimer's disease [10].…”