Volumetry of amygdala and hippocampus and memory performance in Alzheimer's disease

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Abstract

Magnetic resonance imaging (MRI) is showing increased utility in examining medial temporal lobe atrophy and its relationship to memory performance in Alzheimer's disease (AD). We studied 56 AD patients and 42 older healthy subjects with neuropsychological assessment and MRI. Hippocampal and amygdaloid volumes (normalized to intracranial volume) were contrasted between AD patients and healthy controls and correlated with neuropsychological performance. Comparisons between AD patients and healthy controls revealed highly significant differences in the normalized volume of hippocampus and amygdala by analysis of covariance. Group differences tended to be at least as large for amygdaloid as hippocampal volume, including when the subset of AD patients with the mildest symptoms was considered separately. Within the AD group, performance on the Memory–Orientation subscale of the Alzheimer's Disease Assessment Scale-Cognition (ADAS-Cog) was significantly correlated with normalized amygdaloid volume but not with normalized hippocampal volume. Other ADAS-Cog subscales (Language, Praxis) were uncorrelated with either volume. In the healthy control sample, neither hippocampal nor amygdaloid volumes were significant predictors of any neuropsychological measure. While a substantial literature continues to justify the focus on the hippocampus in MRI studies of AD, these results suggest that the amygdala should receive similar attention, including in studies of the prodromal stages of AD.

Introduction

The neuropathological hallmarks of Alzheimer's disease (AD) include neurofibrillary tangles, β-amyloid plaques, and neuronal and synaptic loss. Although these findings occur in a range of brain structures, the site of earliest and most severe pathology in AD is the medial temporal lobe (Hyman et al., 1990, Braak and Braak, 1991). These pathological features have been found to correlate with the severity of dementia (Wilcock and Esiri, 1982, Terry et al., 1991), and their early occurrence in the medial temporal lobe may account for the memory impairment that is typically the earliest and most prominent symptom in AD (Hyman et al., 1990).

Although a link between the medial temporal lobes and memory is well established (Squire et al., 2004), the precise role of specific medial temporal lobe structures in memory functions continues to be elucidated. The hippocampus is believed to play a central role in declarative memory (Squire et al., 2004), and this is borne out by most human (Zola-Morgan et al., 1986, Press et al., 1989) and animal (Alvarez et al., 1995, Beason-Held et al., 1999, Zola et al., 2000) lesion studies. The role of the amygdala in emotional memory is well established (LeDoux, 1993), but that in declarative memory is less clear. Amygdala lesions produce declarative memory impairment in humans (Tranel and Hyman, 1990, Markowitsh et al., 1994) and nonhuman primates (Murray and Gaffan, 1994), although one primate study suggests that lesions of the amygdala that spare adjacent cortical regions do not impair memory (Zola-Morgan et al., 1989a).

In recent years, magnetic resonance imaging (MRI) has been used to examine medial temporal lobe atrophy and its relationship to memory performance in AD. These studies have confirmed volume differences between AD patients and healthy controls for the hippocampus (Jack et al., 1992, Lehéricy et al., 1994, Jack et al., 1997, Mori et al., 1997, Krasuski et al., 1998, Laakso et al., 2000, Mizuno et al., 2000, Pennanen et al., 2004) and/or the amygdala (Cuénod et al., 1993, Lehéricy et al., 1994, Laakso et al., 1995a, Maunoury et al., 1996, Mori et al., 1997, Krasuski et al., 1998, Mauri et al., 1998, Mizuno et al., 2000). Studies of mild cognitive impairment (considered prodromal for AD in most cases) have generally neglected the amygdala and focused on hippocampal volume (Jack et al., 1999, Grundman et al., 2003, Pennanen et al., 2004), despite the fact that those studies that have examined both hippocampal and amygdaloid volumes in the mildest stages of AD suggest that amygdaloid deficits are at least as robust (Lehéricy et al., 1994, Krasuski et al., 1998, Mizuno et al., 2000). Some MRI studies have also shown a correlation between hippocampal (Deweer et al., 1995, Laakso et al., 1995b, Fama et al., 1997, Laakso et al., 2000, Petersen et al., 2000, Kramer et al., 2004) or amygdaloid (Mori et al., 1997, Mizuno et al., 2000) volumes and memory performance in AD.

In the present study, we compared normalized hippocampal and amygdaloid volumes by MRI between older healthy subjects and patients with AD, including a subsample of patients with the mildest symptoms. We examined the relationship between these volumes and an index of memory performance in the AD patients, hypothesizing that memory performance would be correlated with both hippocampal and amygdaloid volumes. We examined the specificity of these correlations by contrasting them with non-memory cognitive performance and also by examining similar correlates in the older control sample.

Section snippets

Methods

The study sample comprised 56 patients with probable AD who received MRI scanning in research protocols in the Yale Alzheimer's Disease Research Unit (ADRU). Patients had been referred to the ADRU from a variety of sources or were self-referred. Five of these patients have subsequently died and had autopsy confirming definite AD (Mirra et al., 1991). Forty-two healthy elderly control subjects (most spouses of participating AD patients) were recruited for MRI scanning. The demographics and

Results

The characteristics of AD patients and healthy controls are shown in Table 1. The two groups did not differ in age (t = 1.24, df = 96, P = 0.22), gender distribution (χ2 = 0.0009, df = 1, P = 0.98), handedness (χ2 = 0.27, df = 1, P = 0.61), or years of education (t = 0.23, df = 96, P = 0.82). The AD patients scored significantly worse on the MMSE and the ADAS-Cog (P < 10 7, Student's t test).

Discussion

This study compared normalized hippocampal and amygdaloid volumes between patients with AD and older healthy subjects and examined neuropsychological correlates with MRI measures in the AD patients. Highly significant group differences were observed in normalized hippocampal and amygdaloid volumes. Group differences tended to be at least as large for amygdaloid as hippocampal volume, including when the subset of AD patients with the mildest symptoms (MMSE ≥ 23) was considered separately. Within

Acknowledgments

The authors thank Hedy Sarofin and Terri Hickey for assistance with MRI scanning, Larry Staib, Ph.D., for technical assistance, and Jung Kim, M.D., for histopathological diagnosis in a subset of the AD cases.

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