Reduced hippocampal glutamate in Alzheimer disease

https://doi.org/10.1016/j.neurobiolaging.2009.05.002Get rights and content

Abstract

Altered neurometabolic profiles have been detected in Alzheimer disease (AD) using 1H magnetic resonance spectroscopy (MRS), but no definitive biomarker of mild cognitive impairment (MCI) or AD has been established. This study used MRS to compare hippocampal metabolite levels between normal elderly controls (NEC) and subjects with MCI and AD. Short echo-time (TE = 46 ms) 1H spectra were acquired at 4 T from the right hippocampus of 23 subjects with AD, 12 subjects with MCI and 15 NEC. Absolute metabolite levels and metabolite ratios were compared between groups using a multivariate analysis of covariance (covariates: age, sex) followed by post hoc Tukey's test (p < 0.05 significant). Subjects with AD had decreased glutamate (Glu) as well as decreased Glu/creatine (Cr), Glu/myo-inositol (mI), Glu/N-acetylaspartate (NAA), and NAA/Cr ratios compared to NEC. Subjects with AD also had decreased Glu/mI ratio compared to MCI. There were no differences between subjects with MCI and NEC. Therefore, in addition to NAA/Cr, decreased hippocampal Glu may be an indicator of AD.

Introduction

Alzheimer disease (AD) is the most common form of dementia, and is characterized by progressive loss of cognitive function as well as a distinct pathological profile of neurofibrillary tangles and amyloid plaques that begins in the mediotemporal lobe (hippocampus and enthorhinal cortex) and limbic areas as early as decades before clinical diagnosis (Braak and Braak, 1994). Mild cognitive impairment (MCI) is an intermediate clinical stage along the cognitive spectrum between healthy aging and dementia that many consider to be prodromal AD. Subjects with MCI progress to AD at a rate of up to 15%/year compared to 2%/year for normal elderly to AD (Solfrizzi et al., 2004). The diagnosis of AD and monitoring of disease progression typically involves cognitive assessments to detect changes in memory, language, visuo-spatial and executive function.

The molecular neuropathology of Alzheimer disease is thought to precede structural brain alteration by several years. Hence, measurements of tissue metabolism may be sensitive biomarkers of very early disease processes. Proton magnetic resonance spectroscopy (1H MRS) provides a non-invasive method of assessing brain metabolites in vivo. Short echo-time proton MRS is capable of detecting several metabolic by-products, including N-acetylaspartate (NAA), glutamate (Glu), glutamine (Gln), myo-inositol (mI), choline (Cho) and creatine (Cr). 1H MRS has been applied previously to the study of AD and has most consistently detected decreased NAA or NAA/Cr in the parietal and occipital cortex (Miller et al., 1993), gray matter (Adalsteinsson et al., 2000, Moats et al., 1994), hippocampus (Dixon et al., 2002, Schuff et al., 1997), and posterior cingulate (Kantarci et al., 2000) as well as increased mI in parietal and occipital cortex (Miller et al., 1993), gray matter (Moats et al., 1994), and posterior cingulate (Kantarci et al., 2000).

Although Glu has been less well studied, it is the principal excitatory neurotransmitter involved in learning, memory and cognition and can be detected directly by short echo-time MRS. Previous MRS studies have reported decreased Glu levels in the cortex and hippocampus of transgenic AD mice (Marjanska et al., 2005) but only relative decreases in the sum of Glu and glutamine over creatine in subjects with AD in the cingulate cortex (Antuono et al., 2001, Hattori et al., 2002) and posterior cingulate gyrus, precuneus, and portions of the cuneus (Hattori et al., 2002).

The purpose of this study was to compare hippocampal metabolite levels measured by high magnetic field MRS, particularly Glu, NAA and mI, in subjects with MCI, AD, and normal elderly controls (NEC). The secondary objective was to correlate these metabolite measures with cognitive test results.

Section snippets

Subjects

All study participants (30 probable AD, 13 MCI and 17 NEC) were recruited from the Aging Brain and Memory Clinic in London, Ontario, Canada. This study was approved by the University of Western Ontario Health Sciences Research Ethics Board. Informed consent was acquired according to the Declaration of Helsinki. Several subjects did not complete their MRI scan due to discomfort or claustrophobia (2 AD, 1 MCI, 1 NEC) and several datasets were excluded due to poor spectral quality (5 AD, 1 NEC)

Results

Demographic data for each patient population is summarized in Table 1. There was a significant difference in gender between groups (χ2[2,47] = 8.8, p < 0.01), with more males in the MCI and AD groups compared to the NEC group. Subjects with MCI and AD were younger than the NEC group (p < 0.05). Subjects with MCI had significantly higher education levels than the other groups. The MMSE scores were significantly lower in subjects with AD (p < 0.01) compared to NEC and subjects with MCI (Table 1).

Fig. 2

Discussion

This study utilized high magnetic field (4 T) short echo-time magnetic resonance spectroscopy to compare metabolite levels in the right hippocampus of subjects with MCI, subjects with AD, and NEC. As expected, decreased levels of NAA/Cr were found in subjects with AD compared to NEC. Additionally, absolute Glu and Glu/Cr levels were reduced in subjects with AD verses NEC. Subjects with MCI showed NAA/Cr and Glu levels that were intermediate to NEC and subjects with AD. There were no changes

Conclusion

This cross-sectional analysis of absolute metabolite levels and metabolite ratios in the hippocampus of subjects with AD has shown a distinct neurochemical profile that includes decreased Glu, NAA/Cr, Glu/Cr, Glu/mI, and Glu/NAA compared to normal elderly as well as decreased Glu/mI in AD compared to MCI. The MCI metabolite levels and metabolite ratios were generally intermediate to NEC and AD values, supporting the hypothesis of a pathological continuum.

Disclosure

The authors have no actual or potential conflicts of interest and the contents of this manuscript have not been previously published. The authors and their respective institutions have no financial interests conflicting with this work. This study was approved by the University of Western Ontario Health Sciences Research Ethics Board. Informed consent was acquired according to the Declaration of Helsinki.

Acknowledgements

Financial support for this study was provided by the Ivey-BMO Financial Group Scientist in Brain Disorders Imaging Award, the Natural Sciences and Engineering Research Council of Canada CGS Scholarship, the Physicians’ Services Incorporated Foundation, the Parkwood Hospital Foundation, the Canadian Institutes of Health Research (Resource Grant), and the Alzheimer Society of Canada. The authors acknowledge the important contribution of the study coordinators with the Geriatric Clinical Trials

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    Financial support for this study was provided by the Ivey-BMO Financial Group Scientist in Brain Disorders Imaging Award, the Natural Sciences and Engineering Research Council of Canada CGS Scholarship, the Physicians’ Services Incorporated Foundation, the Parkwood Hospital Foundation, the Canadian Institutes of Health Research (Resource Grant), and the Alzheimer Society of Canada.

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