Atrophy and dysfunction of parahippocampal white matter in mild Alzheimer's disease

Abstract

In addition to atrophy of mesial temporal lobe structures critical for memory function, white matter projections to the hippocampus may be compromised in individuals with mild Alzheimer's disease (AD), thereby compounding the memory difficulty. In the present study, high-resolution structural imaging and diffusion tensor imaging techniques were used to examine microstructural alterations in the parahippocampal white matter (PWM) region that includes the perforant path. Results demonstrated white matter volume loss bilaterally in the PWM in patients with mild AD. In addition, the remaining white matter had significantly lower fractional anisotropy and higher mean diffusivity values. Both increased mean diffusivity and volume reduction in the PWM were associated with memory performance and ApoE ε4 allele status. These findings indicate that, in addition to partial disconnection of the hippocampus from incoming sensory information due to volume loss in PWM, microstructural alterations in remaining fibers may further degrade impulse transmission to the hippocampus and accentuate memory dysfunction. The results reported here also suggest that ApoE ε4 may exacerbate PWM changes.

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).