Decreased Glutamine and Glutamate: An Early Biomarker of Neurodegeneration

Proton magnetic resonance spectroscopy (¹H-MRS) is a noninvasive and efficient advanced neuroimaging technique, which quantitatively measures metabolite changes associated with Alzheimer’s disease (AD)-type pathology (Kantarci et al., 2008; Ross et al., 1998). ¹H-MRS metabolite changes have been shown to associate with neuropathological changes in AD such as amyloid-β plaque and neurofibrillary tangle pathologies (Kantarci et al., 2008; Murray et al., 2014).

In this issue of International Psychogeriatrics, Motegi et al. report the glutamine+glutamate (Glx) and gamma-aminobutyric acid (GABA) concentrations in the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) using MRS in healthy elderly individuals (Motegi et al., 2019). The authors choose these specific regions to study with single-voxel spectroscopy based on prior work showing alterations in Glx and GABA in these regions due to aging, mild cognitive impairment and AD. Furthermore, they investigate the association of MRS findings with diffusion tensor MRI (DTI) to the basis of Glx alterations through the cortical mean diffusivity (MD) measurements of microstructural alterations in the gray matter. They report that disruption of microstructural organization in the gray matter determined by the elevation in MD is accompanied by the reduction in Glx levels.

Glutamate is the primary excitatory neurotransmitter of the central nervous system. Excess glutamate is recycled by astrocytes from the synapse after being transformed to glutamine. Glutamine is then sent back to the pre-synaptic neuron for glutamate synthesis. This process is external energy-dependent, but acts mostly as a closed circuit with minimal amounts of glutamate or glutamine released into the blood stream (Nedergaard et al., 2002). Therefore, total glutamate and glutamine levels in a brain region would be constant as long as the integrity of the neuron-astrocyte complex and associated blood-CNS barrier is preserved. As a feature of neurodegeneration, in prolonged excitation with sub-optimal astrocyte compensation, excitotoxicity and post-synaptic neuronal death can ensue. If the neuron-astrocyte complex integrity is significantly disrupted, the total glutamate levels are expected to decrease ultimately followed by atrophy. Thus, a decrease in glutamate, which makes up most of the Glx signal, is expected to precede macrostructural changes measured with atrophy on structural MRI. However, a decrease in Glx may be associated with the microstructural alterations in the gray matter as demonstrated in the current study.

Previous studies have shown that Glx concentration is reduced in patients with amnestic MCI (Riese et al., 2015) and AD (Antuono et al., 2001; Hattori et al., 2002; Walecki et al., 2011). With a newly optimized semi-Localization with Adiabatic Selective Refocusing spectroscopy (sLASER) ¹H-MRS technique (Oz and Tkac, 2011), it was possible to isolate glutamate and glutamine peaks in the 3T MR spectra. Using sLASER MRS, glutamate concentration was found to be lower in the PCC in patients with amnestic MCI compared to cognitively unimpaired individuals (Zeydan et al., 2017). Hence, it is likely that the reduced Glx signal identified in the current study is mostly due to a reduction in glutamate.

In the current study, Motegi et al. reported that higher cortical MD on DTI in both mPFC and PCC was associated with lower Glx levels in cognitively unimpaired older individuals (Motegi et al., 2019). Elevated MD on DTI suggests neuronal loss associated with neurodegenerative pathologies in older adults without dementia (Kantarci et al., 2011). Such pathologies may include AD-related tau neurofibrillary tangle and β-amyloid pathologies, TAR-DNA binding protein 43 (TDP-43) and α-synuclein pathologies that are common and may be overlapping in older adults. While this study demonstrates that reduced Glx measured by MRS is a cellular marker of neurodegeneration even in cognitively unimpaired older individuals, it does not relate these changes to a specific neurodegenerative pathologic process. Based on the fact that AD-related pathology is the most common pathology observed in older adults, we can assume that a majority of these alterations would be explained with AD biomarkers. For example, reduced glutamate in cognitively impaired elderly with MCI was associated with β-amyloid deposition on Pittsburgh compound-B positron emission tomography (Zeydan et al., 2017) and MD on DTI was associated with the neurofibrillary tangle tau pathology at autopsy within the AD spectrum (Kantarci et al., 2017). Thus, future studies with AD biomarkers may explain the basis of the relationship between these biochemical and structural alterations more clearly.

The results of the current study are intriguing, since the basis of Glx alterations in neurodegenerative diseases is relatively unknown. It shows that the disruption of gray matter microstructure is associated with changes in glutamate+glutamine metabolism, making Glx concentration a potential biomarker for early detection of neurodegeneration.