Hippocampal glutamate-glutamine (Glx) in adults with Down syndrome: a preliminary study using in vivo proton magnetic resonance spectroscopy (¹H MRS)

Down syndrome (DS) is one of the most common chromosomal disorders and is caused by trisomy 21 or a translocation involving chromosome 21[1]. A prominent feature of DS is intellectual disability (ID) and there is an increased risk of developing Alzheimer’s disease (AD)[2]. For example, it has been estimated that the prevalence of AD in DS increases dramatically from 11% between ages 40 to 49 to as high as 77% between 60 and 69[3‐5].

The underlying cause(s) for both the ID and AD is likely to be multifactorial. For instance, it has been hypothesised that in the DS brain, the presence of an extra copy of the amyloid precursor protein (APP) gene (which is localised to chromosome 21) leads to abnormalities in amyloid precursor protein processing in neuronal membranes and subsequently to amyloid plaques and AD[6]. In addition, reduced levels of serotonin (5HT) and gamma-aminobutyric acid (GABA) have been observed in foetal DS brains[7]. Further, it has been reported that in a DS mouse model, the selective serotonin reuptake inhibitor fluoxetine normalises hippocampal neurogenesis and performance on a hippocampus-dependent memory task[8]—whereas excessive GABA-mediated inhibition impairs the induction of long-term potentiation (LTP) and memory processes in the same region[9]. We previously reported our findings of myo-inositol (mI), N-acetylaspartate (NAA), choline-containing compounds (Cho) and creatine and phosphocreatine (Cr + Pr) from the current study sample in an earlier paper which showed that adults with DS have a significantly increased hippocampal concentration of myo-inositol as compared to healthy controls[10] and that this is associated with reduced cognitive ability. Increased concentration of myo-inositol within individuals with DS may also be associated with increased risk for AD[11]. Hence, there is increasing evidence that a number of neurochemical systems likely contribute to the DS cognitive phenotype—but there have been relatively few studies on the putative role of glutamate within individuals with DS.

Normal cognitive function (including attention, learning, memory and executive processes) is supported by a number of neurotransmitters—central to which is the glutamatergic system[12]. Glutamate is the primary excitatory neurotransmitter in the brain and is involved in synaptic transmission, plasticity and excitotoxicity[13]. Enhanced glutamate release from presynaptic neurons and subsequent activation of postsynaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors are crucial for LTP[14, 15] and successful performance of numerous higher cognitive functions—including memory and learning[16, 17]. Also, it has been suggested that within the non-DS population, glutamate-mediated excitotoxicity contributes to the neurodegeneration and cognitive dysfunction typically observed in people with AD[18‐21].

The importance of this neurotransmitter pathway in non-DS people with AD is further supported by evidence from clinical trials in these populations which showed the efficacy of drugs that target glutamatergic neurotransmission. For example, it has been reported that memantine (an NMDA receptor antagonist) reduces hippocampal glutamate concentration[22] and improves the behavioural, cognitive and functional symptoms in people with AD[23]. Therefore, there is evidence that reduction in hippocampal glutamate concentrations is associated with improved cognitive function by modulating glutamatergic neurotransmission and reducing excitotoxicity in non-DS people with AD.

Further, murine models of DS suggest 1) that there is an imbalance between hippocampal inhibitory and excitatory inputs[9, 24], 2) there are changes in the levels of the glutamate transporter and vesicular glutamate transporter 1 (VGLUT1)[25] and 3) that there are impairments in signalling mechanisms downstream of the NMDA receptor[26]. Therefore, based on the above considered evidence, it is possible that abnormalities in glutamate metabolism may partly account for both the ID and increased risk for AD in people with DS.

There is initial indirect evidence (from studies of platelets and fibroblasts) that glutamate uptake may be significantly decreased in DS individuals[27]. There have also been a small number of postmortem studies. For instance, some have reported no difference in glutamine or glutamate concentration in the frontal lobes of foetal DS brains as compared to controls[7]. In contrast, some (but not all) autopsy studies of adult DS brains reported decreased glutamate levels in the hippocampus[28] or no differences in the temporal lobes[29] or frontal lobes[30]. These studies were important first steps—but postmortem studies have inherent (and significant) limitations for measuring glutamate, and this prior work was confounded by medication effects. Also, to date, there are few studies that have directly examined in vivo brain glutamate in DS.

The results are summarised in Table 1 and Figure 2. The DS+ group were older than both the DS- and healthy control groups. Therefore, age was added as a covariate in the analyses. As expected, the groups also differed in their CAMCOG (total cognition and short-term memory) scores—with the demented DS+ group having the lowest scores and the HC having the highest.

Grey and white matter composition of the MRS voxels did not differ between the groups, although there were differences between the groups for CSF composition. Overall, we found no significance between group differences in Glx concentrations. Furthermore, there was no correlation between hippocampal Glx concentration and cognitive ability and memory as measured by the CAMCOG (total and short-term memory) scores in either of the DS groups (see Table 2).

We found no evidence that DS individuals (with or without dementia) have significant dysregulation of glutamatergic neurotransmission. Other factors may be more crucial in the development of both ID and AD in people with DS.