White matter changes in mild cognitive impairment and AD: A diffusion tensor imaging study

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Abstract

Diffusion tensor imaging (DTI) can detect, in vivo, the directionality of molecular diffusion and estimate the microstructural integrity of white matter (WM) tracts. In this study, we examined WM changes in patients with Alzheimer's disease (AD) and in subjects with amnestic mild cognitive impairment (MCI) who are at greater risk for developing AD. A DTI index of WM integrity, fractional anisotropy (FA), was calculated in 14 patients with probable mild AD, 14 participants with MCI and 21 elderly healthy controls (NC). Voxel-by-voxel comparisons showed significant regional reductions of FA in participants with MCI and AD compared to controls in multiple posterior white matter regions. Moreover, there was substantial overlap of locations of regional decrease in FA in the MCI and AD groups. These data demonstrate that white matter changes occur in MCI, prior to the development of dementia.

Introduction

Mild cognitive impairment (MCI) may be a transitional state between normal aging and Alzheimer's disease (AD). Individuals with amnestic MCI differ from healthy elderly in their level of cognitive function, performing more poorly than controls on measures of memory. Despite impaired memory performance, individuals with MCI do not meet diagnostic criteria for dementia [10], [43], [59], [60], [61]. MCI is associated with a significantly increased risk of developing AD compared to the elderly population without cognitive impairment [14], [23], [59], [60], [61]. Neuropathological and neuroimaging studies report no significant difference in entorhinal volume [26], [29] or the extent of cell loss in layer II of the entorhinal cortex [49] in individuals with cognitive complaints and in patients with MCI compared to those with a diagnosis of AD. Since the entorhinal cortex is one of the earliest sites of pathology in AD, these results indicate that patients with MCI may be in the incipient phase of the disease process. Thus, studies of individuals with MCI provide a unique opportunity to investigate prodromal AD.

Structural magnetic resonance imaging (MRI) techniques have been extensively used to investigate the pathophysiology of Alzheimer's disease (AD) in vivo. Additionally, individuals with MCI are now being studied in order to identify anatomical changes that precede a clinical diagnosis and to develop sensitive in vivo markers that may be predictive of conversion to AD. The major emphasis of these studies has been on the detection of atrophy in regions of interest known to be pathologically involved in the disease process. Mesial temporal lobe structures critically important for memory function, such as the hippocampal formation and the entorhinal cortex, have received special attention in these investigations [13], [21], [22], [26], [27], [28], [29], [30], [41], [42], [47], [48], [73] because a disturbance in the acquisition of new information is a hallmark of MCI and AD [26], [27], [29], [47], [48].

Although most imaging studies of MCI and mild AD have focused on gray matter alterations, a number of post-mortem investigations have documented white matter pathology associated with AD [18], [19], [31], [44], [45]. White matter changes associated with AD may reflect different underlying causes or mechanisms. First, white matter changes in AD may be indicative of anterograde Wallerian degeneration, especially in regions close to cortical areas with the greatest pathological burden. Secondly, there may be white matter rarefaction [31] with axonal damage and gliosis. This type of change is diffuse, does not follow the regional extension of pathologically involved gray matter, and may be vascular or ischemic in origin. Third, it has recently been suggested that myelin breakdown is an important component of the disease process in AD [4], [5], [6]. According to this hypothesis, damage to oligodendrocytes may be a critical initiating step in the disease. Furthermore, since late developing oligodendrocytes may be more vulnerable, late-mylenating association areas are predicted to be more susceptible to myelin breakdown.

The results of imaging studies tend to support post-mortem findings of white matter abnormalities in MCI and AD. Increased white matter hyperintensities (WMH) have been found in both MCI and AD using either semi-quantitative radiologic ratings scales [2], [51] or quantitative measurements [5], [12], [24], [32]. The role of WMH in the pathology or disease severity of MCI or AD is not established, however. Independence between WMH and diagnosis or cognitive impairment has been reported by some authors [12], [40], [51], while others report significant correlations between WMH and diagnosis or cognitive impairment [2], [24], [32]. These discrepancies may be due to differences in the sample studied, analytic methods, or sensitivity of the MRI methodology.

A recently developed structural MRI technique, diffusion tensor imaging (DTI), provides increased sensitivity to alterations in the microstructure of white matter in vivo and is especially indicative for diseases causing axonal damage and demyelination [7], [8], [9], [52], [70]. DTI detects microstructural alterations in white matter by measuring the directionality of molecular diffusion (fractional anisotropy: FA). Highly organized white matter tracts have high FA because diffusion is highly constrained by the tract's cellular organization. As white matter is damaged, FA decreases due to decreased anisotropic diffusion.

Previous investigations of white matter changes in AD or MCI using diffusion weighted MRI have reported changes in mean diffusivity and anisotropic diffusion [15], [16], [33], [36], [37], [39], [46], [64], [65], [74]. Most of these studies have been based on analyses of a priori defined regions of interest. The exact regions of alterations in diffusivity or anisotropic diffusion vary between studies, with some reporting greater anterior differences (e.g. [15]) in AD, while others demonstrate posterior or temporal lobe changes in AD and MCI [33], [39], [46], [64], [65].

These conflicting results from prior studies may be due to multiple causes such as differences in sample composition (e.g., mild versus moderate cognitive impairment in AD; amnestic MCI versus MCI involving other cognitive domains), imaging technique (diffusion weighted [16], [36], [37], [46], [65] versus diffusion tensor imaging [15], [33], [39], [64], [68], [74]) or location of brain regions chosen for examination of MRI differences. Most studies used a “region-of-interest” (ROI) approach to examine MRI differences between groups. This approach can be subjective with inconsistent definitions of anatomical borders across studies [20] and poor reproducibility [3]. Even when applied by trained individuals with established reliability and reproducibility, differential regional placement of ROIs across studies could contribute to inconsistent reports of differences in DTI indices.

Whole-brain, voxel-based methods applied to the analysis of DTI differences between samples provide a global and comprehensive assessment un-complicated by the potential biases of ROI approaches. These techniques are automated and, therefore, are not subject to issues of human based tracing reliability and/or reproducibility. In addition, voxel-based analyses assess regional changes in DTI parameters independent of a priori constraints and may reveal differences that are not encompassed by specific ROIs.

In the present study, we examined white matter changes in patients with probable mild AD and in those with amnestic MCI compared to controls using whole-brain, voxel-based analyses. We were especially interested in determining whether patients with MCI who are presumed to be in the pre-clinical phases of AD could be differentiated from elderly controls based on white matter changes. To our knowledge, this is the first investigation to use a whole brain analysis of white matter changes in MCI.

Section snippets

Subjects

Data reported here were obtained from the following three groups of participants: (1) 21 elderly control subjects (NC) with no cognitive impairment, (2) 16 patients who met criteria for amnestic MCI, and (3) 14 patients diagnosed with mild AD. All participants were recruited from the Rush Alzheimer's Disease Center (RADC, Chicago, IL), the community and the Religious Order Study (ROS), a longitudinal, clinico-pathologic investigation of aging and AD in older nuns, priests and brothers who have

Statistical methods

Differences between the three groups of participants in demographic and disease related measures, as well as volumes of white matter masks, were assessed by one-way analyses of variance (ANOVA) followed by post hoc tests (Fisher's). χ2-tests were used to determine the relationship between variables such as gender or cardiovascular risk factors, and diagnostic classification.

Voxel-wise group differences in FA and DW were assessed using the ANOVA module in SPM99 followed by group-wise t-test

Results

Demographic and cognitive status information on the participants is listed in Table 1. Two participants with the diagnosis of MCI were excluded from analyses because of radiologically confirmed cerebral vascular accidents. The age of participants was equitably distributed among the three diagnostic groups [F(2,46) = 0.02, p = 0.974], with similar medians and ranges. Analyses of independence revealed no significant relationships between diagnostic groups and variables such as gender (χ2[2] = 2.488, p = 

Discussion

In the present study we characterized in vivo changes in normal-appearing white matter microstructural integrity of participants with MCI and mild AD using whole brain diffusion tensor imaging. We found significant regional decreases of white matter anisotropy in the two patient groups compared to age-matched healthy controls in voxel-by-voxel comparisons. While no differences in regional molecular diffusion variables were detected between the MCI and mild AD groups, the anatomical pattern of

Acknowledgement

We thank all participants for their enthusiastic support of our efforts and for their diligence in complying with the evaluations. We also thank the staff of the RADC clinic, especially Barbara Eubler, for an outstanding job in recruiting participants in the study, and the reviewers for their insightful comments on an earlier draft of the paper.

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    This research was supported by grants AG09466, AG10161 and AG17917 from the National Institute on Aging, National Institutes of Health.

    1

    Present address: Department of Psychiatry, Chicago Medical College, Chicago, IL, USA.

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