The paper reviewed here is ‘Low striatal glutamate levels underlie cognitive decline in the elderly. Evidence from In Vivo Molecular Spectroscopy’ published in the journal Cerebral Cortex.
The aims of the paper are clearly stated – to examine the levels of glutamate in three areas which are projected to from the cerebral cortex – these being the striatum, cerebellum and pons – and to identify any correlations with cognitive function in both the elderly and young.
In order to achieve this the researchers led by Natalie Zahr use Magnetic Resonance Spectroscopy which allows them to detect the signatures of molecules from the resonance waveforms that are detected using this technique. Apparently it has been difficult to detect Glutamate using this technique as the patterns it produces overlap with those of other molecules. I didn’t understand from reading this paper how these difficulties were overcome
The authors selected the three targets for the projections as mentioned above – cerebellum, striatum and pons – and by hand selecting areas on the images, then examined the relative signal intensities of the different molecules that were recognised. These included choline containing compounds, total creatinine, N-acetylaspartate and of course glutamate.
When the 12 elderly (67-84 years old) and 12 young (19-33 years old) subjects were compared, glutamate was found to be increased in the cerebellum and pons and decreased in the striatum in the elderly compared to the young group.
In terms of cognition, the elderly performed significantly worse on a number of tests including semantic and figure fluency, working memory (Blocks forwards and backward and stembeng), set shifting and the Stockings of Cambridge task which is a test of spatial planning.
A regression analysis of the test scores and the levels of Glutamate in the different regions was then carried out. The most convincing correlation was for blocks forward and striatal glutamate (p = 0.0004). The r value was 0.687 with the test scores increasing as did the striatal glutamate. Indeed the same positive correlation held for the four other displayed correlations – between glutamate and 2 tests of semantic fluency, figural fluency and blocks backward.
Initially on reading this paper I focused on the finding that the glutamate in the striatum decreased with age and in the pons and cerebellum it appeared to increase. It seems almost intuitive that the levels of neurotransmitters would decrease with age in the brain as the number of neurons decreases and presumably the rate of production of neurotransmitters. However the findings in the pons and cerebellum reversed that trend. I was intrigued by this and wondered if perhaps the sample size was too small and also if we could say anything more than this being just an association.
The authors persuaded me in later paragraphs to reconsider the striatal findings though. They show how these findings relate to a much wider literature including studies in people with excision of the frontal lobe and also Parkinson’s Disease. Thus the main hypothesis would seem to run along the lines of the following
Frontal-striatal pathways are important in a number of cognitive functions including executive tasks and working memory.
In the elderly population, performance of these cognitive functions deteriorates.
Glutamate in the striatum decreases in the elderly.
Glutamate in the striatum underlies the cognitive functions discussed above.
A decrease in the glutamate levels in the elderly accounts for the deteriorating cognitive functions.
There are many alternative explanatory hypotheses. For instance, the role of neuronal cell number or other neurotransmitter functions could be equally important. Nevertheless even if these arguments are valid, it would not detract from the hypothesis above which merits further testing. The hypothesis if correct would also inform treatment strategies.
STT5 (Further confirmatory studies required, which can then contribute to a model, which can inform clinical studies, which in turn should determine policy before being used in practice).
Zahr N, Mayer D, Pfefferbaum A and Sullivan E. Low striatal glutamate levels underlie cognitive decline in the elderly: Evidence from In Vivo Molecular Spectroscopy. Cerebral Cortex. 2008. 18. 2241-2250.
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