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

Abstract

BackgroundDown syndrome (DS), or trisomy 21, is one of the most common autosomal mutations. People with DS have intellectual disability (ID) and are at significantly increased risk of developing Alzheimer’s disease (AD). The biological associates of both ID and AD in DS are poorly understood, but glutamate has been proposed to play a key role. In non-DS populations, glutamate is essential to learning and memory and glutamate-mediated excitotoxicity has been implicated in AD. However, the concentration of hippocampal glutamate in DS individuals with and without dementia has not previously been directly investigated. Proton magnetic resonance spectroscopy (1H MRS) can be used to measure in vivo the concentrations of glutamate-glutamine (Glx). The objective of the current study was to examine the hippocampal Glx concentration in non-demented DS (DS-) and demented DS (DS+) individuals.MethodsWe examined 46 adults with DS (35 without dementia and 11 with dementia) and 39 healthy controls (HC) using 1H MRS and measured their hippocampal Glx concentrations.ResultsThere was no significant difference in the hippocampal Glx concentration between DS+ and DS-, or between either of the DS groups and the healthy controls. Also, within DS, there was no significant correlation between hippocampal Glx concentration and measures of overall cognitive ability. Last, a sample size calculation based on the effect sizes from this study showed that it would have required 6,257 participants to provide 80% power to detect a significant difference between the groups which would indicate that there is a very low likelihood of a type 2 error accounting for the findings in this study.ConclusionsIndividuals with DS do not have clinically detectable differences in hippocampal Glx concentration. Other pathophysiological processes likely account for ID and AD in people with DS.

1 H-MRS metabolites in adults with Down syndrome: Effects of dementia

“…In DS, decreased NAA and increased MI have been observed in the hippocampus of adults by MRS ( Beacher et al, 2005 , Lamar et al, 2011 ) and in an early report of one individual with DS in the posterior parietal cortex (PCC) ( Shonk et al, 1995 ). Interestingly, in a larger study using MRS in people with DS with and without dementia, hippocampal measures of Glx did not distinguish these two groups, and neither was different from controls ( Tan et al, 2014 ).In this study, we hypothesized that signatures of neuronal health would be reduced, and those of inflammation increased in DS as a function of cognitive status particularly in the PCC as it is a region where hypometabolism is observed in adults with DS ( Haier et al, 2003 ). Our long-term goal is to develop in vivo 1 H-MRS criteria for future clinical settings that enable early identification of neurochemical differences, prediction of dementia development, and consequently treatment efficacy, in adults with DS.…”

“…Decreased NAA and increased MI have also been observed in the hippocampus of DS adults by MRS ( Beacher et al, 2005 , Lamar et al, 2011 ) and in an early report of one individual with DS in the PCC ( Shonk et al, 1995 ). In people with DS with and without dementia, hippocampal measures of Glx did not distinguish these two groups, and neither was different from controls ( Tan et al, 2014 ). In this study, we chose a priori to do the measurements in PCC because PCC demonstrates early metabolic deficits and astrocytic inflammation in AD ( Leech and Sharp, 2014 , Minoshima et al, 1997 ) and may provide a more reliable set of measures as it is less sensitive to head movement.…”

Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis

“…Decreased NAA and increased MI is observed relatively consistently across studies in non-demented adults with DS compared with age matched non-DS controls (Shonk and Ross, 1995 ; Berry et al, 1999 ; Huang et al, 1999 ; Beacher et al, 2005 ; Lamar et al, 2011 ; Lin et al, 2016 ) with a few exceptions (Murata et al, 1993 ; Smigielska-Kuzia et al, 2010 ). Hippocampal Glx was not different in people with DS from controls (Tan et al, 2014 ). It may not be surprising that MI levels are generally higher in people with DS as the MI cotransporter (SLC5A3) gene is on chromosome 21 and is overexpressed in DS (Berry et al, 1995 ).…”

Human astrocytes in the diseased brain

“…Contradictory observations have been reported regarding the level of glutamate in DS: some post-mortem studies found no difference in glutamate or glutamine concentrations in the frontal lobes of foetal DS brains ( Whittle et al, 2007 ), while others reported decreased levels in the hippocampus or unchanged levels in temporal and frontal lobe of adult DS subjects ( Reynolds and Warner, 1988 , Risser et al, 1997 , Seidl et al, 2001 ). A more recent study found no significant difference in hippocampal glutamate-glutamine levels between adult DS subjects and controls ( Tan et al, 2014 ), using in vivo proton magnetic resonance spectroscopy to overcome the limitations deriving from post-mortem analysis of neurotransmitters. This suggests that glutamate levels do not account for the cognitive impairment in DS.…”