Abstract
Diffusion tensor imaging (DTI) has been used to study microstructural white matter alterations in a variety of conditions including normal aging and Alzheimer's disease (AD). White matter hyperintensities (WMH) are common in cognitively healthy elderly as well as in AD and exhibit elevated mean diffusivity (MD) and reduced fractional anisotropy (FA). However, the effect of WMH on statistical analysis of DTI estimates has not been thoroughly studied. In the present study we address this in two ways. First, we investigate the effect of WMH on MD and FA in the dorsal and ventral cingulum, the superior longitudinal fasciculus, and the corticospinal tract, by comparing two matched groups of cognitively healthy elderly (n = 21 + 21) with unequal WMH load. Second, we assess the effects of adjusting for WMH load when comparing MD and FA in prodromal AD subjects (n = 83) to cognitively healthy elderly (n = 132) in the abovementioned white matter tracts. Results showed the WMH in cognitively healthy elderly to have a generally large effect on DTI estimates (Cohen’s d = 0.63 to 1.27 for significant differences in MD and −1.06 to −0.69 for FA). These effect sizes were comparable to those of various neurological and psychiatric diseases (Cohen’s d = 0.57 to 2.20 for differences in MD and −1.76 to −0.61 for FA). Adjusting for WMH when comparing DTI estimates in prodromal AD subjects to cognitively healthy elderly improved the explanatory power as well as the outcome of the analysis, indicating that some of the differences in MD and FA were largely driven by unequal WMH load between the groups rather than alterations in normal-appearing white matter (NAWM). Thus, our findings suggest that if the purpose of a study is to compare alterations in NAWM between two groups using DTI it may be necessary to adjust the statistical analysis for WMH.
Highlights
Diffusion-weighted MRI is a non-invasive technique capable of detecting microstructural tissue alterations such as axonal loss and demyelination in the human brain in vivo [1,2,3]
Adjusting for White matter hyperintensities (WMH) when comparing Diffusion tensor imaging (DTI) estimates in prodromal Alzheimer’s disease (AD) subjects to cognitively healthy elderly improved the explanatory power as well as the outcome of the analysis, indicating that some of the differences in mean diffusivity (MD) and fractional anisotropy (FA) were largely driven by unequal WMH load between the groups rather than alterations in normal-appearing white matter (NAWM)
In cognitively healthy elderly with higher compared to lower WMH load (Table 2), MD was significantly elevated in the right superior longitudinal fasciculus (SLF) (0.81±0.06 vs. 0.75±0.03 μm2/ms, p = 2.47×10−4), the left SLF (0.79±0.06 vs. 0.73±0.03 μm2/ms, p = 1.83×10−4), and the right dorsal cingulum (0.76 ±0.04 vs. 0.74±0.03 μm2/ms, p = 0.04)
Summary
Diffusion-weighted MRI is a non-invasive technique capable of detecting microstructural tissue alterations such as axonal loss and demyelination in the human brain in vivo [1,2,3]. White matter hyperintensities (WMH) are, compared to normal-appearing white matter (NAWM), visualized as hyperintense regions in the white matter on T2-weighted MRI and are most commonly thought to be due to small vessel disease [9,10,11]. They are typically located in periventricular or deep cortical regions and are histopathologically characterized by ischemic changes and a varying degree of gliosis, axonal loss, and demyelination. Some studies report that more than 90% of individuals older than 60 years exhibit WMH [17]
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