A voxel-based morphometry study of temporal lobe gray matter reductions in Alzheimer’s disease

Abstract

Several MRI studies have reported reductions in temporal lobe volumes in Alzheimer’s disease (AD). Measures have been usually obtained with regions-of-interest (ROI) drawn manually on selected medial and lateral portions of the temporal lobes, with variable choices of anatomical borders across different studies. We used the fully automated voxel-based morphometry (VBM) approach to investigate gray matter abnormalities over the entire extension of the temporal lobe in 14 AD patients (MMSE 14–25) and 14 healthy controls. Foci of significantly reduced gray matter volume in AD patients were detected in both medial and lateral temporal regions, most significantly in the right and left posterior parahippocampal gyri and the left posterior inferior temporal gyrus/fusiform gyrus (P<0.05, corrected for multiple comparisons). At a more flexible statistical threshold (P<0.001, uncorrected for multiple comparisons), circumscribed foci of significant gray matter reduction were also detected in the right amygdala/enthorinal cortex, the anterior and posterior borders of the superior temporal gyrus bilaterally, and the anterior portion of the left middle temporal gyrus. These VBM results confirm previous findings of temporal lobe atrophic changes in AD, and suggest that these abnormalities may be confined to specific sites within that lobe, rather than showing a widespread distribution.

Introduction

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and a wide range of behavioral disturbances. The disease is associated with an uneven and progressive loss of neurons, with the presence of amyloid-containing neuritic plaques and neurofibrillary tangles. These changes are particularly marked in medial temporal lobe structures, including the hippocampus and parahippocampal gyrus [1], [10]. These structures are critical for episodic memory processes and, as a consequence, AD pathology consistently produces deficits in this memory domain as its earliest clinical manifestation [55]. As the disease progresses, AD pathology spreads to other regions throughout the brain, including lateral portions of the temporal lobe that are relevant to language processes, which are also commonly impaired in AD [28].

Numerous studies have described medial temporal lobe atrophy in AD patients by performing quantitative volumetric measurements using structural magnetic resonance imaging (MRI) [8], [9], [17], [33], [37], [44], [45]. Volume measurements of medial temporal structures have been proposed as useful to aid clinicians in their diagnostic work up, with an accuracy to differentiate AD patients from age-matched healthy controls ranging from 85 to 100% among different studies [9], [33], [34], [36], [37], [38], [50]. Medial temporal volumes have also been found to correlate with the degree of memory impairment of AD patients in some MRI studies [9], [38], [47], even though others failed to replicate these findings [37], [45], [46]. Although with lesser power to discriminate between AD patients and healthy controls, reductions in lateral temporal lobe volumes have also been described in AD [32], [36], [45], [46]; in some studies, these atrophic findings were directly correlated with the severity of language and memory deficits [45], [46].

Most MRI studies to date have quantified volumetric abnormalities in AD by drawing regions-of-interest (ROIs) as irregular shapes around selected brain regions. Some studies took measures from a combination of medial temporal structures [45], while others separately measured distinct portions of the hippocampus, parahippocampal gyrus [8], [11], [17], [33], [34], [37], [61], and amygdala [11], [33], [36], [37]. Methods for delineating ROIs are labor intensive and subject to observer bias, and variable anatomical borders have been used across different studies. In regard to lateral temporal structures, volumes have been most often obtained with large ROIs [31], [32], [36], [45], rather than with separate measurements for specific gyri [12]. As a consequence, it is unclear whether the reported atrophic findings of the lateral temporal lobe represent an overall homogeneous change ore are confined to smaller, circumscribed sites.

Recently, automated methods have been developed to allow voxel-by-voxel comparisons of the local concentration of gray matter between different groups of subjects studied with MRI, without requiring the a priori selection of ROIs [2], [27]. This technique, referred to as voxel-based morphometry (VBM), is based on the statistical parametric mapping (SPM) method often employed for voxel-based analyses of functional imaging data. Structural MRI scans are subjected to spatial transformations into a standard stereotactic space in order to remove inter-individual variations in brain size and shape, and are subsequently segmented into gray and white matter compartments. Gray matter segments are then compared statistically between groups on a voxel-by-voxel basis, and statistical maps are produced in standardized brain space showing the location of voxel clusters where significant differences in mean gray matter volumes were detected.

The VBM approach has been increasingly used to investigate gray matter abnormalities in neuropsychiatric conditions such as schizophrenia [53], [60], depression [51], infectious organic disorders [25], and dementia [5], [43], [48]. In the first assessment of AD using the VBM approach, seven AD patients were compared to seven healthy controls with the purpose of investigating gray matter abnormalities over the entire cerebral volume in an unbiased fashion [48]. In addition to the expected bilateral atrophic changes in the medial temporal region, the authors found symmetric gray matter reductions in other brain regions not usually included in ROI-based morphometric studies of AD, such as the caudate nucleus and the insula [48]. More recently, a larger VBM study also detected multifocal gray matter reductions in mild AD patients relative to healthy controls, involving medial temporal structures and other brain regions, particularly the posterior cingulate gyrus and the precuneus [5].

In the present study, we used the VBM approach to conduct a more detailed assessment of the temporal lobe in a sample of probable AD patients (n=14) in comparison to healthy controls (n=14). Gray matter changes were investigated over the entire extension of the temporal lobe, rather than on selected portions of this brain region as in previous ROI-based studies. Our aims were: to replicate previous MRI findings of reduced volumes in medial temporal structures; and to assess the topographic distribution of gray matter changes across the separate gyri of the lateral temporal cortex.