Amygdala atrophy is prominent in early Alzheimer's disease and relates to symptom severity

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Abstract

Despite numerous studies on the role of medial temporal lobe structures in Alzheimer's disease (AD), the magnitude and clinical significance of amygdala atrophy have been relatively sparsely investigated. In this study, we used magnetic resonance imaging (MRI) to compare the level of amygdala atrophy to that of the hippocampus in very mild and mild AD subjects in two large samples (Sample 1 n = 90; Sample 2 n = 174). Using a series of linear regression analyses, we investigated whether amygdala atrophy is related to global cognitive functioning (Clinical Dementia Rating Sum of Boxes: CDR-SB; Mini Mental State Examination: MMSE) and neuropsychiatric status. Results indicated that amygdala atrophy was comparable to hippocampal atrophy in both samples. MMSE and CDR-SB were strongly related to amygdala atrophy, with amygdala atrophy predicting MMSE scores as well as hippocampal atrophy, but predicting CDR-SB scores less robustly. Amygdala atrophy was related to aberrant motor behavior, with potential relationships to anxiety and irritability. These results suggest that the magnitude of amygdala atrophy is comparable to that of the hippocampus in the earliest clinical stages of AD, and is related to global illness severity. There also appear to be specific relationships between the level of amygdala atrophy and neuropsychiatric symptoms that deserve further investigation.

Introduction

By the time patients exhibit the hallmark amnesic syndrome of Alzheimer's disease (AD), neuropathology has usually decimated medial temporal lobe (MTL) structures (Braak and Braak, 1991). In vivo evidence for this process can be plainly seen by viewing magnetic resonance images. Extensive investigations have demonstrated quantitative morphometric abnormalities of the hippocampal formation, entorhinal cortex, and perirhinal cortex early in the illness (prior to dementia). Furthermore, these abnormalities correlate with the overall severity of clinical impairment and are specifically related to episodic memory deficits (Di Paola et al., 2007). In post-mortem studies, amyloid (senile) plaques, neurofibrillary tangles, and neuronal loss have all been observed in the amygdala (Herzog and Kemper, 1980, Tsuchiya and Kosaka, 1990, Scott et al., 1991, Arriagada et al., 1992, Scott et al., 1992). Although these post-mortem studies have called attention to similar neuropathological abnormalities in the amygdala as are found in the hippocampus, there has been far less in vivo investigation of amygdala atrophy and its clinical correlates in AD.

With respect to amygdala atrophy in early AD, several important anatomic and clinical questions remain incompletely answered. First, across the 13 published studies of amygdala atrophy in AD, findings regarding the magnitude of atrophy have been very inconsistent, with reports of atrophy ranging from 15% to 41% compared to older controls (OC). Furthermore, it is unclear whether the magnitude of amygdala atrophy is greater than (Cuenod et al., 1993, Lehericy et al., 1994, Mori et al., 1997, Krasuski et al., 1998, Basso et al., 2006), less than (Jack et al., 1997, Callen et al., 2001, Horinek et al., 2006, Farrow et al., 2007), or similar to (Killiany et al., 1993, Mizuno et al., 2000, Barnes et al., 2006, Schultz et al., 2009) that of the hippocampus. Given the substantial variability in the frequency and types of socioaffective symptoms in AD, it seems reasonable to hypothesize that the amygdala would be more variably affected within a sample of AD patients than the hippocampus. Second, although amygdala atrophy has been shown to relate to global illness severity in AD (Jack et al., 1997, Mizuno et al., 2000), there has been little investigation comparing the strength of this relationship with that of the hippocampus. Since the size of these structures is collinear, it is important to try to understand which of them is most strongly related to illness severity and whether the amount of atrophy in the other explains additional variance in overall symptom severity. We hypothesized that hippocampal atrophy is most strongly related to illness severity but that the amount of amygdala atrophy present would explain additional variance in illness severity beyond that explained by the hippocampus. Finally, although behavioral (psychiatric) symptoms are a major contributor to patient-family dysfunction and distress in AD, there has been surprisingly little effort to investigate whether amygdala atrophy relates to this domain of symptoms. The only study to specifically examine the relation between amygdala atrophy and psychiatric symptoms in mild AD reported no relationship (Horinek et al., 2006).

In the present study, we used automated measurements of in-vivo human brain volumes derived from magnetic resonance imaging (MRI) to investigate the magnitude and consistency of amygdala atrophy in two large and independent samples of patients with AD (and older controls). The main goal of having a second sample in this study design was to demonstrate the reliability of the findings, supporting their generalizability. Both samples included a large number of patients with very mild (CDR = 0.5) and mild (CDR = 1) AD, allowing for measurement of amygdala atrophy early in the illness. To address the question of whether the amygdala shows comparable atrophy to the hippocampus, the magnitude and variance of atrophy in the two structures were compared.

Second, we explored the clinical significance of amygdala atrophy in mild AD, investigating the relationship between amygdala atrophy and cognitive function using the Mini Mental State Examination (MMSE) and the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB). In addition, to try to determine the specificity of the relationship, we performed an additional analysis controlling for hippocampal volume. The goal of these analyses was to determine whether the magnitude of amygdala atrophy is a reflection of global severity of the illness and whether it accounts for illness severity beyond its shared variance with hippocampal atrophy.

Finally, to address questions regarding specific relationships between amygdala atrophy and types and severity of neuropsychiatric symptoms in AD, data from the Neuropsychiatric Inventory (NPI) were analyzed. Animal and human studies have suggested that amygdala lesions are associated with agitation/aggression and irritability (less) (Wright et al., 2007), anxiety (less)(Davidson, 2002), and apathy (more) (Kile et al., 2009). Data are conflicting in regard to depression (Omura et al., 2005). We examined the level of amygdala atrophy in AD patients with either no, mild or moderate/severe impairment using the NPI items reflecting these symptoms, testing hypotheses based on prior findings as well as exploring the current data de novo.

Section snippets

Participants

Sample 1. This sample consisted of AD and OC participants in a longitudinal study at the Washington University Alzheimer's Disease Research Center, conducted in accordance with guidelines of the Washington University Human Studies Committee. There were 177 subjects (60 males and 117 females; mean age 77.4 ± 7.3; mean education 14.0 ± 2.2). Data from subsets of these subjects have been published in previous studies (Buckner et al., 2004, Salat et al., 2004, Fotenos et al., 2005). At study

Results

In Sample 1, AD and OC groups were equivalent in age (P = 0.653) but there were more men in the AD (41%) versus the OC (26%) groups (χ2 = 4.2, df = 2, P = 0.041) and the education level was lower in the AD (13.7 ± 2.2) versus the OC (14.4 ± 2.2) groups (t = 2.12, df = 178, P = 0.035). In Sample 2, AD and OC groups did not differ in age (P = 0.945) or sex (P > 0.93) but the education level was lower in the AD (14.8 ± 3.1) versus the OC (16.2 ± 2.8) groups (t = 4.65, df = 367, P < 0.001). Demographic and clinical data are

Discussion

To date, the magnitude and consistency of amygdala atrophy early in the course of AD dementia has been unclear, with conflicting reports in the literature. The results of this study help to resolve this issue by showing that amygdala atrophy is comparable to hippocampal atrophy in two very large, independent samples of very mild and mild AD dementia patients. Furthermore, the magnitude of amygdala atrophy is related to the severity of cognitive impairment (as measured by MMSE and CDR-SB), even

Disclosures

Dr. Poulin reports no disclosure.

Ms. Dautoff reports no disclosure.

Dr. Morris reports no disclosure.

Dr. Barrett reports no disclosure.

Dr. Dickerson reports no disclosure.

Acknowledgment

Data used in the preparation of this article were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). As such, the investigators within the ADNI contributed to the design and implementation of ADNI and/or provided data but did not participate in analysis or writing of this report. ADNI investigators include (complete listing available at http://adni.loni.ucla.edu/wp-content/uploads/how_to_apply/ADNI_Authorship_List.pdf.)

Data collection and

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    Authors contributed equally to this work.

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