Date Published: August 17, 2017
Publisher: BioMed Central
Author(s): Fang Ji, Ofer Pasternak, Siwei Liu, Yng Miin Loke, Boon Linn Choo, Saima Hilal, Xin Xu, Mohammad Kamran Ikram, Narayanaswamy Venketasubramanian, Christopher Li-Hsian Chen, Juan Zhou.
Mixed vascular and neurodegenerative dementia, such as Alzheimer’s disease (AD) with concomitant cerebrovascular disease, has emerged as the leading cause of age-related cognitive impairment. The brain white matter (WM) microstructural changes in neurodegeneration well-documented by diffusion tensor imaging (DTI) can originate from brain tissue or extracellular free water changes. The differential microstructural and free water changes in AD with and without cerebrovascular disease, especially in normal-appearing WM, remain largely unknown. To cover these gaps, we aimed to characterize the WM free water and tissue microstructural changes in AD and mixed dementia as well as their associations with cognition using a novel free water imaging method.
We compared WM free water and free water-corrected DTI measures as well as white matter hyperintensity (WMH) in patients with AD with and without cerebrovascular disease, patients with vascular dementia, and age-matched healthy control subjects.
The cerebrovascular disease groups had higher free water than the non-cerebrovascular disease groups. Importantly, besides the cerebrovascular disease groups, patients with AD without cerebrovascular disease also had increased free water in normal-appearing WM compared with healthy control subjects, reflecting mild vascular damage. Such free water increases in WM or normal-appearing WM (but not WMH) contributed to dementia severity. Whole-brain voxel-wise analysis revealed a close association between widespread free water increases and poorer attention, executive functioning, visual construction, and motor performance, whereas only left hemispheric free water increases were related to language deficits. Moreover, compared with the original DTI metrics, the free water-corrected DTI metric revealed tissue damage-specific (frontal and occipital) microstructural differences between the cerebrovascular disease and non-cerebrovascular disease groups. In contrast to both lobar and subcortical/brainstem free water increases, only focal lobar microstructural damage was associated with poorer cognitive performance.
Our findings suggest that free water analysis isolates probable mild vascular damage from WM microstructural alterations and underscore the importance of normal-appearing WM changes underlying cognitive and functional impairment in AD with and without cerebrovascular disease. Further developed, the combined free water and tissue neuroimaging assays could help in differential diagnosis, treatment planning, and disease monitoring of patients with mixed dementia.
The online version of this article (doi:10.1186/s13195-017-0292-4) contains supplementary material, which is available to authorized users.
Mixed vascular and neurodegenerative dementia such as patients with Alzheimer’s disease (AD) with concomitant cerebrovascular disease (CeVD) has emerged as the leading cause of age-related cognitive impairment . Accumulating evidence suggests that AD and CeVD share multiple risk factors and overlap neuropathologically, leading to additive or synergistic effects on cognitive decline . White matter hyperintensity (WMH), which is associated with increased water content and vascular changes , serves as an important clinical diagnostic criterion by which to identify CeVD status . WMH may be due to vessel disease causing infarction or a failure in the clearance of interstitial fluid from white matter (WM), which is associated with blood-brain barrier (BBB) permeability modulation . However, WMH visual rating suffers from interrater variability. More importantly, WMH usually reflects a severe water increase such as edema. It is not sensitive to detection of changes, owing to small vessel damage and inflammation, particularly in normal-appearing WM [6, 7], which might exacerbate neurological dysfunction and brain damage in dementia.
Our findings provide new insights into differential WM microstructural and FW alterations in normal-appearing tissue in mixed vascular and neurodegenerative dementia. All patients, including patients with AD without CeVD, had increased FW compared with HC. Importantly, increased FW was detected in normal-appearing WM regions in patients with AD, reflecting mild vascular changes. Widespread FW increases in the whole WM and normal-appearing WM (but not the WMH ratio) were associated with symptom severity. Both lobar and subcortical FW increases were associated with poorer cognitive performance, such as in attention and executive functioning, whereas only left hemispheric FW increases were related to language deficits. In parallel, compared with the original DTI metrics, which might overestimate axonal damage or demyelination, the FW-corrected tissue compartment had better clinical specificity because it showed tissue-specific microstructural differences between the CeVD and non-CeVD groups. In addition, these region-specific tissue changes were associated with poorer cognitive performance. Our findings underscore the value of FW corrections in isolating vascular damage from WM microstructural alterations and help connect both extracellular FW and microstructural abnormalities with cognitive impairment in mixed vascular and neurodegenerative dementia.
We have demonstrated the importance of FW analysis in separating vascular-related extracellular FW increases and WM microstructural disruptions in mixed vascular and neurodegenerative dementia. Importantly, these FW increases in normal-appearing WM contribute to dementia severity and cognitive deficits. Future longitudinal studies on preclinical AD with and without CeVD are needed to examine the early changes, temporal trajectories, and possible interplay between vascular and tissue abnormalities. Further developed, the combined FW and tissue assays could help in the differential diagnosis, individual treatment planning, and disease monitoring for patients with mixed dementia.