Regular paperAtrophy and dysfunction of parahippocampal white matter in mild Alzheimer's disease
Introduction
High resolution, quantitative magnetic resonance imaging (MRI) is a valuable tool for evaluating alterations in brain anatomy in vivo in age-related degenerative diseases and may provide a surrogate marker for the underlying pathology. One of the early clinical hallmarks of Alzheimer's disease (AD) is a disturbance in memory, especially characterized by difficulty in the acquisition of new declarative knowledge. The nature of this mnemonic dysfunction is similar to that seen with bilateral lesions, dysfunction or disconnection of the hippocampal formation and related structures (Squire and Zola-Morgan, 1991), thus implicating the pathophysiologic disruption of this neural system in the early stages of AD.
Post mortem pathological studies have shown the entorhinal cortex and trans-entorhinal region to be early sites of involvement in AD and in individuals with mild cognitive impairment (MCI) who are at high risk of developing AD (Braak and Braak, 1991, Braak and Braak, 1995, Gomez-Isla et al., 1996, Kordower et al., 2001). In vivo MRI investigations have also demonstrated atrophy of both the entorhinal cortex and hippocampus not only in patients with mild AD, but also in people with amnestic MCI and subjective cognitive complaints (e.g., deToledo-Morrell et al., 2004, Dickerson et al., 2001, Du et al., 2001, Jack et al., 1997, Jack et al., 1999, Jessen et al., 2006, Killiany et al., 2000, Killiany et al., 2002, Saykin et al., 2006, Stoub et al., 2005).
In addition to pathology and atrophy in gray matter regions, there may be changes in white matter that could disconnect different cortical regions and accentuate cognitive dysfunction. However, such white matter changes have received less attention in investigations on the pathophysiology of AD. Entorhinal cortex neurons receive multimodal sensory input from primary sensory and association cortices and relay this information to the hippocampus via the perforant path, a white matter tract located in the anterior medial portion of the parahippocampal gyrus (Amaral et al., 1987, Van Hoesen and Pandya, 1975, Van Hoesen et al., 1975). Post mortem studies have demonstrated loss of entorhinal layer II neurons in patients with mild AD (Hyman et al., 1984) and in those with MCI (Gomez-Isla et al., 1996, Kordower et al., 2001) that could results in a partial disconnection of information flow to the hippocampus. In addition, damage to the parahippocampal white matter could disrupt afferent connections to the entorhinal cortex and ultimately degrade multimodal sensory information relayed to the hippocampus.
These changes in white matter may be detectable with high resolution MRI techniques, such as diffusion tensor imaging (DTI). DTI is a newer MRI technique that allows examination of the microstructural integrity of white matter in vivo. This emerging technique combines MR diffusion-weighted pulse sequences with tensor mathematics to measure molecular diffusion in three dimensions. In fact, recently there has been a proliferation of investigations using DTI to examine white matter changes in AD (e.g., Hanyu et al., 1998, Head et al., 2004, Kalus et al., 2006, Medina et al., 2006, Salat et al., 2010, Zhang et al., 2007). Many of these investigations explored whole brain white matter changes in patients with AD, while two studies further examined the parahippocampal white matter region that includes the perforant path (Kalus et al., 2006, Salat et al., 2010). In addition to the volume of the parahippocampal white matter region, Kalus et al. (2006) reported the coherence index (CI) that measures the similarity in diffusion between adjoining voxels as the measure of white matter integrity, rather than the commonly used measures of fractional anisotropy (FA) and mean diffusivity (MD). Salat et al. (2008) defined anatomical regions of interest (ROIs) on DTI maps. Defining anatomical regions using the dependent variable map (e.g., FA map) may have methodological shortcomings as it precludes the identification of abnormal tissue with low FA (Pfefferbaum and Sullivan, 2003).
In the present study, we used a high-resolution DTI protocol and high-resolution structural imaging to examine microstructural and macrostructural alterations in parahippocampal white matter and their relation to memory function in patients with mild AD compared with elderly controls. DTI analysis was restricted to the parahippocampal white matter by applying manually traced ROIs derived from high-resolution structural images to DTI scans. FA or MD values were quantified without direct manipulation of the DTI volumes. FA is a scalar metric that describes the directionality of the diffusion tensor, while MD is a nondirectional measure of free translational diffusion and provides an index of general tissue integrity. These two measures are the most commonly used and sensitive indexes of microstructural integrity of white matter. We also examined the relationship between ApoE ε4 allele status and parahippocampal white matter changes. ApoE is a group of proteins that bind reversibly with lipoprotein for transporting endogenous lipids for uptake and use in myelin repair, growth and structural integrity maintenance (Bartzokis et al., 2006). In fact, previous studies have demonstrated a reduction in ApoE concentration in brain tissue from ApoE ε4 allele carriers (Poirier, 2005). The ApoE ε4 allele is known to be a risk factor for Alzheimer's disease (Saunders et al., 1993) and may affect white matter integrity even in healthy carriers of the ApoE ε4 allele (Persson et al., 2006).
Section snippets
Participants
Participants in the study consisted of 17 patients with mild AD (mean age 77.18 ± 5.23 yr) and 26 elderly individuals with no cognitive impairment (NCI; mean age 74.92 ± 8.03 yr). They were recruited from the Rush Alzheimer's Disease Center (RADC) clinic, the community, and the Rush Memory and Aging Project (MAP). MAP is a longitudinal, clinicopathologic study of aging in older participants who have agreed to annual evaluations and brain autopsy at the time of death (Bennett et al., 2005).
All
Results
Demographic characteristics of participants are listed in Table 1. Patients with mild AD did not differ from the controls in age [t(41) = 1.02, p = 0.31], education [t(41) = 0.54, p = 0.59], or gender distribution [χ2(1) = 0.67, p = 0.53]. In addition, these two groups did not differ in systolic or diastolic blood pressure, or in vascular risk factor summary scores. In addition, analysis of white matter hyperintensities revealed no significant difference between the two groups in T2 signal
Discussion
The results of the present study indicate that, in addition to volume loss, there was a significant decrease in FA and an increase in MD in parahippocampal white matter in patients with mild AD, indicating that remaining normal appearing white matter in this region was not really “normal”. These white matter changes reflect not only loss of afferent and efferent fibers in the region, but also may indicate partial demyelination or other damage to remaining fibers. These results suggest that
Disclosure statement
The authors do not have any actual or potential conflicts of financial or personal interest. This research was supported by grants P01 AG09466, P30 AG10161 and R01 AG17917 from the National Institute on Aging, National Institutes of Health and the Illinois Department of Public Health. The data contained in this manuscript have not been previously published, have not been submitted elsewhere and will not be submitted elsewhere while under consideration at Neurobiology of Aging. All participants
Acknowledgements
This research was supported by grants P01 AG09466, P30 AG10161 and R01 AG17917 from the National Institute on Aging, National Institutes of Health and the Illinois Department of Public Health.
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