Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Zahr, Natalie M.; Mayer, Dirk; Pfefferbaum, Adolf; Sullivan, Edith V.

doi:10.1093/cercor/bhm250

Cited by 71 publications

(64 citation statements)

References 100 publications

(118 reference statements)

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“…These opposing effects may have mitigated any age-related difference in overall Glx concentration here, but an underlying age-related imbalance may still account for the relationship with RAVLT performance. Outside of the hippocampus, age-related decreases in glutamate have been reported in the striatum (Zahr et al, 2008; but see Choi et al (2014) for the opposite pattern), but not the cerebellum (Zahr et al, 2008, 2013), emphasizing the possible regional specificity of these metabolic imbalances. Additionally, the opposing dynamics of the glutamate-glutamine cycle may be completely masked by the combined Glx metric.…”

Section: Discussionmentioning

confidence: 98%

“…Higher levels of glutamate in the striatum have been associated with better performance on tests of executive functioning in a group of older adults, provided a potential mechanism for age-related decline in the frontostriatal system (Zahr et al, 2008). N-methyl-D-asparate (NMDA) receptors represent one of the glutamate receptors that are present in high density in the hippocampus and cerebral cortex, even in aging and Alzheimer’s disease (Cotman et al, 1989), but there is mounting evidence that NMDA receptor function declines with age (Barnes et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

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3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging

Nikolova

Stark

2017

Neurobiology of Aging

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The hippocampus is a critical site for alterations that are responsible for age-related changes in memory. Here, we present a relatively novel approach of examining the relationship between memory performance and Glutamate-Glutamine levels using short echo time magnetic resonance spectroscopy (MRS). Specifically, we investigated the relationship between Glx (a composite of glutamate and glutamine) levels in the hippocampus, performance on a word recall task and resting state functional connectivity (RSFC). While there was no overall difference in Glx intensity between young and aging adults, we identified a positive correlation between delayed word-list recall and Glx, bilaterally in older adults, but not in young adults. Collapsed across age, we also discovered a negative relationship between Glx intensity and RSFC between the anterior hippocampus and regions in the subcallosal gyrus, replicating a recent finding by Wagner et al., (2016). These findings demonstrate the possibly utility of Glx in identifying age-related changes in the brain and behavior and provide encouragement that MRS can be useful in predicting age-related decline before any physical abnormalities are present.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging

Nikolova

Stark

2017

Neurobiology of Aging

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“…The frontal cortex has been implicated in mediating many cognitive functions often found to be altered in multiple neurobehavioral disorders, including cognitive deficits, autism spectrum disorder (ASD), which affects an individuals social cognition, communication, and behavior, and schizophrenia (DeLorey et al 2008; Fatemi et al 2010; Gaspar et al 2009; Lewis and Sweet 2009; Mohler 2007; Zahr et al 2008). The frontal cortex is extensively innervated by the GABAergic, glutamatergic and dopaminergic neurotransmitter systems (Monaghan et al 1989; Rushworth et al 2007; Schoch et al 1985).…”

Section: 0 Introductionmentioning

confidence: 99%

Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71

Bradner¹,

Suragh²,

Caudle³

2013

Toxicology

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Recent studies have identified exposure to polybrominated diphenyl ethers (PBDEs) as a risk factor for deficits in cognitive functioning seen in children as well as adults. Additionally, similar alterations in learning and memory have also been observed in animal models of PBDE exposure. However, given these findings, the molecular alterations that may underlie these neurobehavioral endpoints have not been identified. As the frontal cortex is involved in modulating several cognitive functions, the purpose of our study was to investigate the possible changes to the GABAergic and glutamatergic neurotransmitter systems located in the frontal cortex following exposure to the PBDE mixture, DE-71. Primary cultured neurons isolated from the frontal cortex showed a dose-dependent reduction in neurons as well as neurite outgrowth. Furthermore, evaluation of DE-71 neurotoxicity in the frontal cortex using an in vivo model showed alterations to specific proteins involved in mediating GABA and glutamate neurotransmission, including GAD67, vGAT, vGlut, and GABA(A) 2α receptor subunit. Interestingly, these alterations appeared to be preferential for the GABA and glutamate systems located in the frontal cortex. These findings identify specific targets of PBDE neurotoxicity and provide a possible molecular mechanism for PBDE-mediated neurobehavioral deficits that arise from the frontal cortex.

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“…Furthermore, reductions in striatal glutamate levels have correlated selectively with performance on cognitive tests showing age-related decline (Zahr et al, 2008). This is consistent with AVD deficiency in BALB/c male mice, in which we have shown an imbalance between excitatory and inhibitory neurotransmission with reductions in glutamate, glutamine and the enzymes GAD65 and 67, as well as increased levels of GABA across the whole brain (Groves et al, 2013).…”

Section: Discussionsupporting

confidence: 83%

The role of adult vitamin D deficiency in cognition and brain function in mice

Groves¹

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Vitamin D deficiency is prevalent throughout the world. Even in a temperate climate such as Australia, one-third of the adult population has insufficient levels of serum vitamin D (25-hydroxyvitamin D levels <50 nmol/L). Epidemiological studies have shown significant associations between vitamin D deficiency and an increased risk of various neuropsychiatric and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's disease and cognitive impairment. However, studies based on observational epidemiology cannot address questions of causality; they cannot determine if vitamin D deficiency is a causal factor leading to the adverse health outcome. The use of animal experiments can examine the biological plausibility of the relationship between vitamin D deficiency and adverse brain outcomes.Vitamin D is a neurosteroid that has a wide range of functions within the brain including calcium maintenance, regulation of neurotrophic factors, neurogenesis, and neuroprotection. Using a model of adult vitamin D (AVD) deficiency in BALB/c mice, we have previously shown alterations in a range of behaviours and an imbalance between excitatory and inhibitory neurotransmission, which may be relevant to a range of neuropsychiatric disorders. Therefore, we have provided experimental evidence demonstrating that vitamin D deficiency in adulthood impacts on a range of brain functions, and is therefore a biologically plausible risk factor for the development of neuropsychiatric disorders. However, there is currently insufficient evidence to account for the mechanism(s) by which this occurs.There were four main aims of the thesis; to determine whether AVD deficiency impacts on (1) cognition, (2) adult hippocampal neurogenesis, and (3) glutamate and GABA signaling in BALB/c mice; and to determine if AVD deficiency would (4) exacerbate the effects of a secondary exposure, in this case social stress, in BALB/c mice and in the more resilient C57BL/6J mice.To address these aims I assessed attentional processing in BALB/c mice using the 5 choice serial reaction time task and found sex-dependent impairments in AVD-deficient male mice only.Structural and diffusion tensor imaging was assessed using MRI in male mice, however we found no significant alterations in gross brain structure or connectivity within the brain in the group exposed to AVD deficiency. I used immunohistological techniques to assess two measures of hippocampal neurogenesis, cell proliferation and survival of newborn neurons, and found that hippocampal neurogenesis was not affected by AVD deficiency at baseline or following wheel running stimulated neurogenesis.iii Despite no cellular level change in neurogenesis, the analysis of the proteomics of the hippocampus, although preliminary, provided clues that AVD deficiency may have an effect on synapse formation and plasticity, and dendritic arborisation and that these changes may be responsible for impaired learning and memory. The proteomics also provided convergent evidence of an effect on glutamate and...

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Low Striatal Glutamate Levels Underlie Cognitive Decline in the Elderly: Evidence from In Vivo Molecular Spectroscopy

Cited by 71 publications

References 100 publications

3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging

3T hippocampal glutamate-glutamine complex reflects verbal memory decline in aging

Alterations to the circuitry of the frontal cortex following exposure to the polybrominated diphenyl ether mixture, DE-71

The role of adult vitamin D deficiency in cognition and brain function in mice

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