APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain

Gomar, Jesús J.; Gordon, M.S.; Dickinson, Dwight; Kingsley, Peter B.; Uluğ, Aziz M.; Keehlisen, Lynda; Huet, Sarah; Buthorn, Justin J.; Koppel, Jeremy; Christen, Erica; Conejero-Goldberg, Concepción; Davies, Peter; Goldberg, Terry E.

doi:10.1016/j.biopsych.2013.05.022

Cited by 31 publications

(36 citation statements)

References 40 publications

(45 reference statements)

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“…The associations of high Glx, mI, and GABA with low episodic memory performance did not remain significant after correction for multiple testing and, thus, need to be interpreted with caution. However, as mI is considered to be a glial marker of inflammation that has been reported to be increased in AD (Bitsch, et al, 1999,Miller, et al, 1993, and Glx, and GABA reflect activity of major cerebral neurotransmitter systems that also are affected by AD pathology (Gomar, et al, 2014,Kapogiannis and Mattson, 2011,Miller, et al, 1993,Olson, et al, 2008,Riese, et al, 2015, our findings might indicate a general increase of neuronal metabolic activity in a context of low episodic memory and thus be consistent with the effects observed for NAA. The fact that metabolic change was not associated with hippocampal or general brain atrophy may indicate potential reversibility due to absence of major neurodegenerative damage.…”

Section: Discussionsupporting

confidence: 85%

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla

Schreiner

Kirchner

Wyss

et al. 2016

Neurobiology of Aging

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Low episodic memory performance characterizes elderly subjects at increased risk for Alzheimer's disease (AD) and may reflect neuronal dysfunction within the posterior cingulate cortex and precuneus (PCP) region. To investigate a potential association between cerebral neurometabolism and low episodic memory in the absence of cognitive impairment, tissue-specific magnetic resonance spectroscopic imaging at ultrahigh field strength of 7 Tesla was used to investigate the PCP region in a healthy elderly study population (n = 30, age 70 ± 5.7 years, Mini-Mental State Examination 29.4 ± 4.1). The Verbal Learning and Memory Test (VLMT) was administered as part of a neuropsychological battery for assessment of episodic memory performance. Significant differences between PCP gray and white matter could be observed for glutamate-glutamine (p = 0.001), choline (p = 0.01), and myo-inositol (p = 0.02). Low Verbal Learning and Memory Test performance was associated with high N-acetylaspartate in PCP gray matter (p = 0.01) but not in PCP white matter. Our data suggest that subtle decreases in episodic memory performance in the elderly may be associated with increased levels of N-acetylaspartate as a reflection of increased mitochondrial energy capacity in PCP gray matter.

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Section: Discussionsupporting

confidence: 85%

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla

Schreiner

Kirchner

Wyss

et al. 2016

Neurobiology of Aging

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“…Another study by the same group looked at the contribution of the metabolites choline, myoinositol, and creatine in normal adults stratified according to age and APOEε4 genotype. They found that choline/creatine and myoinositol/creatine ratios were increased in older APOEε4 carriers and that the presence of these neurodegeneration markers was also linked to declining cognitive scores [34], an interesting finding that deserves replication.…”

Section: Novel Approaches and Clinical Meaningfulnessmentioning

confidence: 94%

Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools?

Snyder

Kahle-Wrobleski

Brannan

et al. 2014

Alzheimer's & Dementia

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Several lines of evidence from Alzheimer's disease (AD) research continue to support the notion that the biological changes associated with AD are occurring possibly several decades before an individual will experience the cognitive and functional changes associated with the disease. The National Institute on Aging-Alzheimer's Association revised criteria for AD provided a framework for this new thinking. As a result of this growing understanding, several research efforts have launched or will be launching large secondary prevention trials in AD. These and other efforts have clearly demonstrated a need for better measures of cognitive and functional change in people with the earliest changes associated with AD. Recent draft guidance from the US Food and Drug Administration further elevated the importance of cognitive and functional assessments in early stage clinical trials by proposing that even in the pre-symptomatic stages of the disease, approval will be contingent on demonstrating clinical meaningfulness. The Alzheimer's Association's Research Roundtable addressed these issues at its fall meeting October 28-29, 2013, in Washington, D.C. The focus of the discussion included the need for improved cognitive and functional outcome measures for clinical of participants with preclinical AD and those diagnosed with Mild Cognitive Impairment due to AD.

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“…Few other investigations have explored mediation effects of metabolites measured with MRS on cognitive function. Gomar et al [44] examined the precuneus in a sample older than 50 years of age and found that associations of Cho/Cre with a composite measure of broad cognitive ability varied as a function of APOE genotype (including APOE-4), but these investigators did not examine GABA. CSF and measures of Alzheimer pathology (e.g., estimates of amyloid concentration) were not included in this analysis.…”

Section: Association Of Cognitive Variables With Agementioning

confidence: 99%

Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition

Marenco

Meyer

Veen

et al. 2018

Neuropsychopharmacol

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GABAergic mechanisms have been shown to contribute to cognitive aging in animal models, but there is currently limited in vivo evidence to support this relationship in humans. It is also unclear whether aging is associated with changes in GABA levels measured with proton magnetic resonance spectroscopy (MRS). Spectral-editing MRS at 3 T was used to measure GABA in the dorsal anterior cingulate cortex (dACC) for a large sample of healthy volunteers (N = 229) aged 18-55. In a subset of 171 participants, age effects on several cognitive tasks were studied. We formally tested whether the MRS measures mediated the relationship between age and cognition. Robust associations of age with performance were found for the Wisconsin Card Sorting Test ([WCST], p < 0.0001). Age was also significantly associated with declining levels of GABA in the dACC (p < 0.001), and GABA levels significantly predicted WCST performance (p < 0.0004). Mediation analysis revealed that GABA in the dACC mediated the effect of age on WCST performance (p < 0.01). Other metabolites were similarly associated with age, but only GABA and creatine levels were significantly associated with WCST performance. No association with age or cognitive performance was found in a frontal white matter control region in a subset of participants. The association of GABA with WCST performance was not related to the amount of brain atrophy associated with aging as measured by the proportion of CSF, gray, and white matter in the MRS voxel. These results implicate GABAergic and possibly energetic metabolism in the dACC as mechanisms of age effects in executive function.

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APOE Genotype Modulates Proton Magnetic Resonance Spectroscopy Metabolites in the Aging Brain

Cited by 31 publications

References 40 publications

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla

Low episodic memory performance in cognitively normal elderly subjects is associated with increased posterior cingulate gray matter N-acetylaspartate: a 1H MRSI study at 7 Tesla

Assessing cognition and function in Alzheimer's disease clinical trials: Do we have the right tools?

Role of gamma-amino-butyric acid in the dorsal anterior cingulate in age-associated changes in cognition

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