Regionally-specific diffusion tensor imaging in mild cognitive impairment and Alzheimer's disease
Introduction
Diffusion tensor imaging (DTI), a relatively new magnetic resonance imaging procedure, was developed to examine the integrity of white matter fiber bundles in the nervous system (Basser and Jones, 2002, Beaulieu et al., 1996, Mori et al., 1999) by measuring fractional anisotrophy (FA) (Bozzali et al., 2002) and mean diffusivity. It can be used to assess the degradation of white matter tracts in the brain, and has therefore been applied to the study of a variety of neurodegenerative disorders, such as Alzheimer's disease (AD).
Using DTI, a number of studies have reported reduced FA and/or increased mean diffusivity in patients with established AD, compared to normal controls (Bozzali et al., 2002), within the splenium of the corpus callosum (Bozzali et al., 2002, Duan et al., 2006, Naggara et al., 2006, Rose et al., 2000, Sydykova et al., 2007) and the cingulum bundle (Cho et al., 2008, Ding et al., 2008, Fellgiebel et al., 2005, Fellgiebel et al., 2008, Takahashi et al., 2002, Zhang et al., 2007). DTI studies of white matter integrity within several cortical regions have also shown differences between patients with AD and controls (Bozzali et al., 2002, Choi et al., 2005, Fellgiebel et al., 2004, Medina et al., 2006, Naggara et al., 2006, Stahl et al., 2007, Takahashi et al., 2002).
A small number of studies have also used DTI to assess subjects with mild cognitive impairment (MCI) (Petersen, 2004, Petersen et al., 1999). Individuals with amnestic MCI have an increased risk of progressing to AD (Petersen and Morris, 2005), and recent studies indicate that the majority of amnestic MCI cases have AD pathology in their brains on autopsy (Bennett et al., 2005, Jicha et al., 2006). The DTI studies have demonstrated reduced FA and/or increased mean diffusivity in MCI cases relative to NC in the cingulum bundle (Zhang et al., 2007) and the splenium of the corpus callosum (Cho et al., 2008, Stahl et al., 2007). Differences in white matter integrity from selected cortical regions have also been reported in MCI cases compared to controls (Fellgiebel et al., 2004, Huang and Auchus, 2007, Stahl et al., 2007).
These findings suggest that FA in the cingulum bundle and splenium may be useful for assessing the evolution of disease as AD progresses. This is particularly important because of the continuing need to identify biological measures that can accurately assess the early progression of ongoing pathological change and, therefore, speed drug development for both prodromal and established AD. However, longitudinal DTI studies are necessary to understand the reliability of these measures over time, and their relation to change in clinical status, in order to determine whether DTI measures may be useful biomarkers of AD.
As part of an ongoing longitudinal study examining the utility of DTI as a biomarker of AD progression, the aims of the present analyses were to: (1) examine cross-sectional differences in FA, among a group of cognitively NC, and subjects with amnestic MCI and AD; (2) to examine the short-term stability of these measures between baseline and 3 months; and (3) to examine the relationship between FA in the regions of interest and assessments of cognitive status in the subjects. Regions of interest included ones that have been used in previous DTI studies of AD and MCI cases, specifically the corpus callosum and the cingulum bundle. A measure of the fornix was also included as one previous study that looked at asymptomatic individuals with a dominant genetic mutation for AD reported abnormalities in this region (Ringman et al., 2007). We hypothesized that there would be reductions in FA for the fornix, cingulum and splenium in AD compared to MCI and controls and that FA in these regions would remain stable over the 3-month follow-up.
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Subjects
Participants were primarily recruited from two sources: the Johns Hopkins Alzheimer's Disease Research Center and memory clinics associated with Johns Hopkins Hospital. Three groups of subjects were recruited: (1) Normal Controls (NC): subjects who were cognitively normal and had a Clinical Dementia Rating (CDR) of 0 (Hughes et al., 1982, Morris, 1993); (2) Mild Cognitive Impairment (MCI): subjects who were non-demented but had mild memory problems, had a CDR = 0.5, and met criteria for amnestic
Subject characteristics
The baseline demographic, health and clinical characteristics of the subjects (Table 1) were compared across diagnostic groups using Fisher's Exact test for categorical variables and ANOVAs for continuous variables (with t-tests for pairwise comparison when p < 0.05). There were no demographic differences between the groups with regards to age, sex, race, and education. In addition, the prevalence of vascular factors such as hypertension, hypercholesterolemia, and heart attack, did not differ
Discussion
The present findings demonstrate significant cross-sectional differences in fiber tract integrity (as measured by FA) including 1) for AD vs. NC: reduced FA in the fornix and the anterior portion of the cingulum bundle; 2) for AD vs. MCI: reduced FA in the fornix, the anterior portion of the cingulum, and the splenium; and 3) for MCI vs. NC: Cross-sectional differences for the fornix, but only among the most impaired subgroup of MCI cases (i.e. MCI2 vs. NC). Over a 3-month interval, during
Acknowledgments
This research was funded in part by grants from GlaxoSmithKline, the National Institute on Aging (P50-AG005146 and P50-AG 021334) and the National Institute of Research Resources (NCRR, P41-RR15241). NCRR is a component of the National Institutes of Health (NIH). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of NCRR or NIH. Equipment used in this study was manufactured by Philips. Dr. van Zijl is a paid lecturer for Philips Medical
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