Stroke risk modifies regional white matter differences in mild cognitive impairment
Introduction
Over the past two decades, there has been considerable evidence of gray matter alterations in mild cognitive impairment (MCI), a clinical construct that describes individuals with mildly impaired performance on objective neuropsychological tests but relatively intact global cognition and daily functioning (Petersen et al., 1999, Petersen et al., 2001). It is accepted that MCI, which has been validated as qualitatively different from both normal aging and dementia (Petersen, 2004, Smith and Ivnik, 2003), is a well-known risk factor for the development of dementia, particularly Alzheimer's disease (AD). Research has shown that gray matter changes are widespread throughout the cortex and are particularly striking in mesial temporal lobe (MTL) structures such as the entorhinal cortex (deToledo-Morrell et al., 2000, Dickerson et al., 2001) and hippocampal formation (Callen et al., 2001, deToledo-Morrell et al., 2004, Du et al., 2001), brain areas known to be especially important for memory formation and pathologically involved early in the AD process. In addition to degenerative changes in the MTL, research suggests that there is increased gray matter pathology in posterior brain regions relative to anterior regions in early AD (Arnold et al., 1991, Braak and Braak, 1995). While these gray matter alterations have been well typified and described in the literature, the exact mechanisms underlying these brain changes have not yet been fully elucidated and understood.
Recently, there has been a growing body of research in the literature to suggest that white matter pathology may contribute to age-related cognitive impairment and possibly potentiate the development of dementia (Raz and Rodrigue, 2006, Sullivan and Pfefferbaum, 2006). In general, numerous post-mortem and volumetric studies have shown that macroscopic white matter alterations such as demyelination, white matter lesion (WML) pathology, and degeneration occur in both normal aging (Raz, 2000, Jernigan et al., 2001) and dementia (Barber et al., 2000, Gurol et al., 2006). Although these studies have advanced our knowledge considerably, the majority have employed conventional magnetic resonance imaging (MRI) which is limited in its ability to reflect white matter microstructural integrity, and thus it is not clear if the extent and pattern of white matter changes differ in aging and dementia, or whether these changes play a role in the evolution and expression of dementia such as AD (Wozniak and Lim, 2006). More recently, diffusion tensor imaging (DTI) — an MRI technique that produces contrast between healthy and pathologic tissue (Basser and Pierpaoli, 1996) — has shown particular promise in helping to elucidate the nature and pattern of white matter changes that occur across the aging spectrum (see Minati et al., 2007 for review).
To date, only a few studies have employed DTI to examine early white matter changes in older adults who are at high risk for the development of dementia due to the presence of MCI. Most studies that have examined white matter changes in MCI have focused primarily on the cingulum (Rose et al., 2000, Takahashi et al., 2002) and medial temporal lobe regions because they are known to be affected early in the course of AD (Kantarci et al., 2001, Fellgiebel et al., 2006). In contrast, studies of normal aging have typically investigated changes in the corpus callosum (Pfefferbaum et al., 2000, Salat et al., 2005, Hasan et al., 2004) and have shown that white matter integrity decreases with increasing age, particularly in frontal regions (Head et al., 2004, Ota et al., 2006). Although several studies have shown greater posterior callosal white matter degradation in MCI (Naggara et al., 2006, Cho et al., 2008, Medina et al., 2006, Ukmar et al., 2007), other studies have not found white matter changes in the splenium in this population (Fellgiebel et al., 2004, Zhang et al., 2007, Stahl et al., 2007). In general, little is known about changes in the tissue characteristics of callosal subregions in MCI and how any observed changes may be associated with the presence and severity of either vascular risk or neuropsychological functioning.
The present study used DTI to compare and contrast white matter changes in older adults with MCI and age-matched normal control (NC) participants. Subregions of the corpus callosum (i.e., the genu and splenium) were selected given the heterogeneity of its microstructure (Aboitz et al., 1996) as well as its heterotopic nature (i.e., anteroposterior cortical connectivity) (Huang et al., 2005). We hypothesized that more widespread, global white matter changes would be evident in MCI participants (i.e., poorer integrity of both callosal regions). In addition, given the predilection for frontal white matter alterations in aging (Head et al., 2004, Head et al., 2005) and the sensitivity of DTI to early hypoxic-ischemic injury, we expected that anterior white matter (i.e., genu) would be primarily affected in normal aging and that integrity of this white matter bundle would be inversely associated with stroke risk. Finally, we expected that regional DTI indices of white matter integrity would be associated with cognition such that temporoparietal white matter (i.e., splenium) would be related to memory whereas frontal white matter (i.e., genu) would be associated with executive functions. To our knowledge, the present study is the first to relate DTI indices to stroke risk and neuropsychological functioning in a sample diagnosed with MCI.
Section snippets
Participants
This study included 40 age- and education-matched non-demented participants (MCI: n = 20, NC = 20; see Table 1 for demographic comparisons). This cohort was recruited solely for research purposes, and they were subsequently drawn from a larger pool of 115 individuals enrolled in a longitudinal study of aging. Participants were consecutively accrued and selected because they had undergone both neuroimaging as well as a comprehensive neuropsychological evaluation. The determination of cognitive
Regional differences in morphometry and callosal DTI indices by group
As shown in Table 1, there were no significant differences between MCI and NC participants on structural MR whole-brain segmentation volumetric measurements or in total hippocampal volumes (all p-values > 0.20). For FA measurements, a group (MCI vs. NC) by callosal subregion (genu vs. splenium) mixed-model ANOVA demonstrated an expected significant main effect of region (F(1,38) = 139.76, p < 0.001, ) indicating that splenium FA was higher than genu FA when collapsed across groups. Although
Discussion
The present study used DTI to investigate differences in regional callosal white matter integrity between normally aging older adults and those with MCI. The relationship between callosal white matter integrity, stroke risk, and neuropsychological functioning was also examined. Results demonstrated that older adults with MCI had diminished white matter integrity in the splenium relative to cognitively normal older adults. Across the entire sample, elevated stroke risk was associated with
Acknowledgements
This work was supported by grants from the National Institutes of Health (K24 AG026431, R01 AG012674, R01 MH64729, R01 MH75870, and P50 AG05131), by a Career Development Award and Merit Review Research Program from the Department of Veterans Affairs, and by Investigator-Initiated and New Investigator Research Grants from the Alzheimer's Association. The authors gratefully acknowledge the assistance of staff, patients, and volunteers of the UCSD Alzheimer's Disease Research Center, and the UCSD
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