Conversion to dementia in mild cognitive impairment is associated with decline of N-actylaspartate and creatine as revealed by magnetic resonance spectroscopy

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Abstract

The purpose of the present study was to longitudinally track changes of metabolite markers detectable by magnetic resonance spectroscopy (MRS) in subjects with mild cognitive impairment (MCI) and to analyze these changes with respect to the rate of cognitive decline and clinical disease progression. Fifteen subjects with MCI and 12 healthy elderly controls were investigated longitudinally (average follow-up period: 3.4 years) using absolute quantification of metabolites within the mid-parietal grey matter and the parietal white matter [N-acetylaspartate (NAA), myo-inositol, choline, creatine, glutamine)] Our main findings include that a longitudinal decline in cognitive function (particularly in memory function) within the MCI group was predicted by a decline in absolute concentrations of the metabolic markers NAA and creatine. This effect was mainly explained by a significant decrease of NAA and creatine in those MCI subjects who converted to Alzheimer's dementia (AD) during the follow-up period. No differences were found at baseline between MCI converters and stable subjects, indicating that at least in the present study MRS did provide a predictive discrimination between converters and stable subjects. Our findings support the use of MRS as a tool for objectively monitoring disease progression even during the earliest stages of AD.

Introduction

The diagnostic entity “mild cognitive impairment” refers to cognitive deficits in elderly subjects that exceed age-related cognitive decline but do not fulfil the criteria for dementia. The syndrome is associated with an increased risk for the development of dementia such as Alzheimer's disease (AD), and it is generally assumed that mild cognitive impairment (MCI) reflects preclinical AD in a considerable portion of the affected individuals.

Magnetic resonance spectroscopy (MRS) noninvasively provides information on the concentration of cerebral metabolites in vivo. Changes of these metabolites can be used as markers for neurodegenerative diseases like AD. While it is widely accepted that the MRS-detectable neuronal marker N-acetylasparte (NAA) is decreased in AD (Valenzuela and Sachdev, 2001), the potential of MRS in detecting metabolic changes at the beginning of the disease is still under discussion. Previous cross-sectional studies explicitly investigating NAA changes in MCI compared with cognitively healthy subjects were inconclusive and yielded positive (Ackl et al., 2005, Chantal et al., 2004, Falini et al., 2005, Kantarci et al., 2007) as well as negative findings (Catani et al., 2001, Kantarci et al., 2000, Kantarci et al., 2002).

Diverging results are partly attributable to methodological issues but also reflect the fact that MCI is indeed a heterogeneous condition: While some of the affected subjects develop dementia at follow-up (“converters”), some improve and others remain in a cognitively impaired but stable state (Schönknecht et al., 2005). Accordingly, several recent studies have prospectively addressed the predictive power of MRS-derived metabolic markers with regard to conversion to dementia and revealed some indications that baseline NAA levels were decreased in those subjects who developed dementia at follow-up (Chao et al., 2005, Metastasio et al., 2006, Modrego et al., 2005). Although these findings suggest that NAA can be used as an early (preclinical) marker of AD, little is known about the dynamics of MRS-derived metabolic changes which occur at the onset of clinical manifestations of AD. In particular, it would be relevant to study NAA changes associated with progression of cognitive deficits in MCI subjects converting to dementia. This would not only shed light on the cerebral metabolic changes underlying cognitive decline in MCI but would also support the utility of NAA as an objective surrogate marker of progressive decline in neuronal integrity in early AD.

Accordingly, the purpose of the present study was (1) to longitudinally investigate changes of NAA and other relevant MRS-detectable cerebral metabolites in subjects with MCI compared with cognitively healthy elderly controls, and (2) to analyze these changes with respect to rate of cognitive decline and clinical disease progression.

Section snippets

Subjects and clinical examinations

Fifteen patients with MCI recruited at the Memory Clinic of the Psychiatric Hospital of Frankfurt University and 12 healthy elderly volunteers from the local community were included.

Diagnostic assessment of the MCI patients was performed involving a cooperating multiprofessional team (neurologists, psychiatrists and psychologists). The clinical diagnosis was based on a detailed medical history from both the patient and the spouse or relative; general physical, neurological, and psychiatric

Results

There were no gender differences between the control group and the MCI group. However, patients with MCI were significantly older (68.1 ± 5 vs. 73.1 ± 5.9 years/Table 1). An age-matched comparison can be achieved by comparing the second visit of the controls with the first visit of the patients. The F-values for such a comparison are listed in parentheses in the last column of Table 1, Table 2, Table 3. Already at baseline MCI patients were characterized by a significantly lower MMSE score (29.8 ± 

Discussion

In this study we have longitudinally measured MRS-detectable changes of metabolite concentrations in a group of subjects with clinically diagnosed MCI in comparison to a group of healthy age-matched volunteers.

Our main findings include that a longitudinal decline in cognitive function (particularly in memory function) within the MCI group was predicted by a decline in absolute concentrations of the metabolic markers NAA. In the grey matter volume a decline of creatine was observed as well.

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