Regular articleLow episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla
Introduction
Low episodic memory performance in otherwise cognitively normal elderly subjects has been linked to increased risk for sporadic Alzheimer's disease (AD) (Elias et al., 2000, Grober et al., 2000, Linn et al., 1995, Pasquier, 1999, Small et al., 2000a) and may reflect preclinical brain change (Albert et al., 2011, Caselli et al., 2007). Several studies have provided evidence on the close relationship between episodic memory dysfunction and AD pathology, as initially observable in limbic brain regions and widespread cerebral neurodegeneration at later stages (Bennett et al., 2006, Kohler et al., 1998, Mormino et al., 2009, Pike et al., 2007, Storandt et al., 2009, Vyhnalek et al., 2014). Although AD pathology ultimately affects the entire brain, changes in the posterior cingulate and precuneus (PCP) region may have particular relevance for processing of episodic memory tasks (Brugnolo et al., 2014, Chetelat et al., 2003, Sperling et al., 2010), as the PCP region is a central hub in cognitive brain networks that include the default mode network (Buckner et al., 2008, Cavanna and Trimble, 2006, Raichle et al., 2001) and also limbic nuclei, such as the hippocampus (Greicius et al., 2004, Insel and Takehara-Nishiuchi, 2013, Wagner et al., 2005). Moreover, functional, metabolic and structural abnormalities in the PCP characterize individuals with and at risk for AD, as reflected by mild cognitive impairment (MCI) (Chetelat et al., 2005, Mintun et al., 2006, Sheline et al., 2010, Small et al., 2000b, Teipel et al., 2016).
Metabolic brain change can be assessed noninvasively by 1H-magnetic resonance spectroscopy (MRS), and significant alterations of brain metabolites have been reported for AD and also MCI (Kantarci et al., 2000, Metastasio et al., 2006, Moats et al., 1994, Pilatus et al., 2009, Riese et al., 2015, Yang et al., 2012). The metabolic markers N-acetylaspartate (NAA), total choline (tCho), myo-inositol (mI), glutamate-glutamine (Glx), and gamma-amino butyric acid (GABA) have been linked to various neurophysiological processes, including energy metabolism and mitochondrial capacity, lipid metabolism, inflammation, glial activation, and neurotransmission (Bitsch et al., 1999, Brand et al., 1993, Chen et al., 2009, Filibian et al., 2012, Kapogiannis et al., 2013, Moffett et al., 2007). Although reduced NAA may reflect neuronal loss in advanced AD dementia (Kantarci et al., 2000, Klunk et al., 1992, Moats et al., 1994, Schuff et al., 2002), NAA has furthermore been suggested to possibly represent a marker for treatment response and mitochondrial capacity in a context of neuronal recovery (Ellis et al., 1997, Jessen et al., 2006, Olson et al., 2008).
When performing magnetic resonance spectroscopic imaging (MRSI), effectively multiple MRS voxels are acquired in an integrated way for generation of metabolic maps, which allow the investigation of specific anatomical regions or cerebral gray and white matter (MacKay et al., 1996, Maudsley et al., 2009, Schuff et al., 2001, Schuff et al., 2002). Signal-to-noise ratio (SNR) and spectral resolution significantly improve by performing MRS at high magnetic field strength (Barker et al., 2001, Boer et al., 2011, Mekle et al., 2009, Pradhan et al., 2015, Tkac et al., 2009, Ugurbil et al., 1993). Moreover, MRSI at ultrahigh field strength may provide metabolic maps at high spatial resolution, as demonstrated for free induction decay (FID) 1H-MRSI at 7 Tesla (Bogner et al., 2012, Henning et al., 2009). At this point several MRS studies have been performed on AD and MCI. However, to our knowledge, variation of memory performance in cognitively normal elderly subjects at increased risk for sporadic AD due to their age has not been studied by MRS or MRSI. The present study therefore aims to investigate whether subtle deficits in episodic memory performance in the cognitively normal elderly may be linked to alterations of NAA and other metabolites in PCP gray and white matter by administering FID 1H-MRSI at ultrahigh field strength of 7 Tesla.
Section snippets
Study sample
Thirty participants were recruited at the Hospital for Psychogeriatric Medicine (Gerontopsychiatrisches Zentrum Hegibach), University of Zürich, Switzerland (Table 1). The study was conducted in accordance with good clinical practice guidelines issued by the local ethics committee (Kantonale Ethikkommission Zürich, http://www.kek.zh.ch), as well as with the declaration of Helsinki. All procedures were approved by the Kantonale Ethikkommission Zürich. Written informed consent was obtained from
Characteristics of the study population
The study sample included 30 healthy elderly subjects (12 females, 18 males), with a mean age of 70 ± 5.7 years, mean duration of institutional education of 15.9 ± 2.4 years, and mean MMSE of 29.4 ± 1. Median VLMT performance was 12 of a maximum score of 15 and used for dichotomizing the cohort into VLMT high and low performers based on median split. There were no group differences for age, education, or any cognitive task other than VLMT between VLMT high and low performers. Assessment of the
Discussion
High resolution ROI-based MRSI at 7 Tesla was used to investigate PCP neurometabolism and its potential association with low episodic memory performance in cognitively nonimpaired elderly subjects. To our knowledge, this is the first report on increased PCP gray matter NAA in a context of low episodic memory performance. Our findings suggest an increase of neuronal mitochondrial energy capacity in relation to low episodic memory and, thus, may be consistent with earlier reports on increased PCP
Disclosure statement
The authors have no actual or potential conflicts of interest.
Acknowledgements
The authors thank all subjects for their study participation. The authors also thank Daniel Summermatter from the Division of Psychiatry Research and Psychogeriatric Medicine, University of Zürich, Switzerland, for help in interpretation of neuropsychological test results. This work was funded by the Swiss National Science Foundation (Schweizerischer Nationalfonds, SNF, grant numbers 124111 and 125378), the Clinical Research Priority Program (CRPP) of the University of Zurich on Molecular
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