Reduced Hippocampal GABA+ Is Associated With Poorer Episodic Memory in Healthy Older Women: A Pilot Study (original) (raw)
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The GABA–Working Memory Relationship in Alzheimer’s Disease
2017
Alzheimer’s disease (AD) is a highly debilitating neurodegenerative disease with no cure to date. Emerging evidence indicates aberrations of the primary inhibitory neurotransmitter GABA in the frontal, parietal and temporal cortices, and hippocampal regions of the AD brains. GABA levels have been reported to predict working memory (WM) load capacity in the healthy young population. Since working memory is impaired in AD, it opens an active area of research to investigate the influence of GABA on WM performance in AD. Advancements in neuroimaging techniques and signal processing tools can aid in neurochemical profiling of GABA in AD as well as facilitate in probing the role of GABA in AD-specific impairments of working memory.
Biological Psychiatry: Cognitive Neuroscience and Neuroimaging, 2017
BACKGROUND-Gamma-aminobutyric acid (GABA), the brain's principal inhibitory neurotransmitter, has been associated with perceptual and attentional functioning. Recent application of magnetic resonance spectroscopy (MRS) provides in vivo evidence for decreasing GABA concentrations during adulthood. It is unclear, however, how age-related decrements in cerebral GABA concentrations contribute to cognitive decline, or whether previously reported declines in cerebral GABA concentrations persist during healthy aging. We hypothesized that participants with higher GABA concentrations in the frontal cortex would exhibit superior cognitive function and that previously reported age-related decreases in cortical GABA concentrations continue into old age. METHODS-We measured GABA concentrations in frontal and posterior midline cerebral regions using a Mescher-Garwood point-resolved spectroscopy (MEGA-PRESS) 1 H-MRS approach in 94 older adults without history or clinical evidence of mild cognitive impairment or dementia (mean age, 73 years). We administered the Montreal Cognitive Assessment to assess cognitive functioning.
Hippocampal neurochemistry, neuromorphometry, and verbal memory in nondemented older adults
Neurology, 2008
Background-Characterization of the behavioral correlates of neuromorphometry and neurochemistry in older adults has important implications for an improved understanding of the aging process. The objective of this study was to test the hypothesis that a measure of hippocampal neuronal metabolism was associated with verbal memory in nondemented older adults after controlling for hippocampal volume.
Episodic memory loss is related to hippocampal-mediated -amyloid deposition in elderly subjects
Brain, 2009
Although b-amyloid (Ab) plaques are a primary diagnostic criterion for Alzheimer's disease, this pathology is commonly observed in the brains of non-demented older individuals. To explore the importance of this pathology in the absence of dementia, we compared levels of amyloid deposition (via 'Pittsburgh Compound-B' (PIB) positron emission tomography (PET) imaging) to hippocampus volume (HV) and episodic memory (EM) in three groups: (i) normal controls (NC) from the Berkeley Aging Cohort (BAC NC, n = 20); (ii) normal controls (NC) from the Alzheimer's disease neuroimaging initiative (ADNI NC, n = 17); and (iii) PIB+ mild cognitive impairment subjects from the ADNI (ADNI PIB+ MCI, n = 39). Age, gender and education were controlled for in each statistical model, and HV was adjusted for intracranial volume (aHV). In BAC NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.0016) and worse EM (P = 0.0086). Within ADNI NC, elevated PIB uptake was significantly associated with smaller aHV (P = 0.047) but not EM (P = 0.60); within ADNI PIB+ MCI, elevated PIB uptake was significantly associated with both smaller aHV (P = 0.00070) and worse EM (P = 0.046). To further understand these relationships, a recursive regression procedure was conducted within all ADNI NC and PIB+ MCI subjects (n = 56) to test the hypothesis that HV mediates the relationship between Ab and EM. Significant correlations were found between PIB index and EM (P = 0.0044), PIB index and aHV (P50.0001), as well as between aHV and EM (P50.0001). When both aHV and PIB were included in the same model to predict EM, aHV remained significant (P = 0.0015) whereas PIB index was no longer significantly associated with EM (P = 0.50). These results are consistent with a model in which Ab deposition, hippocampal atrophy, and EM occur sequentially in elderly subjects, with Ab deposition as the primary event in this cascade. This pattern suggests that declining EM in older individuals may be caused by Ab-induced hippocampus atrophy.
Neurobiology of Aging, 2016
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 region (PCP). To investigate a potential association between cerebral neuro-metabolism and low episodic memory in the absence of cognitive impairment, tissue specific magnetic resonance spectroscopic imaging (MRSI) at ultra-high 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 VLMT 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 NAA as a reflection of increased mitochondrial energy capacity in PCP-gray matter.
Frontiers in Aging Neuroscience
We aimed to longitudinally assess the relationship between changing brain energy metabolism (glucose and acetoacetate) and cognition during healthy aging. Participants aged 71 ± 5 year underwent cognitive evaluation and quantitative positron emission tomography (PET) and magnetic resonance imaging (MRI) scans at baseline (N = 25) and two (N = 25) and four (N = 16) years later. During the follow-up, the rate constant for brain extraction of glucose (K glc) declined by 6%-12% mainly in the temporo-parietal lobes and cingulate gyri (p ≤ 0.05), whereas brain acetoacetate extraction (Kacac) and utilization remained unchanged in all brain regions (p ≥ 0.06). Over the 4 years, cognitive results remained within the normal age range but an age-related decline was observed in processing speed. K glc in the caudate was directly related to performance on several cognitive tests (r = +0.41 to +0.43, all p ≤ 0.04). Peripheral insulin resistance assessed by the homeostasis model assessment of insulin resistance (HOMA-IR) was significantly inversely related to K glc in the thalamus (r = −0.44, p = 0.04) and in the caudate (r = −0.43, p = 0.05), and also inversely related to executive function, attention and processing speed (r = −0.45 to −0.53, all p ≤ 0.03). We confirm in a longitudinal setting that the age-related decline in K glc is directly associated with declining performance on some tests of cognition but does not significantly affect Kacac.
Hippocampal volumes are important predictors for memory function in elderly women
BMC Medical Imaging, 2009
Background: Normal aging involves a decline in cognitive function that has been shown to correlate with volumetric change in the hippocampus, and with genetic variability in the APOEgene. In the present study we utilize 3D MR imaging, genetic analysis and assessment of verbal memory function to investigate relationships between these factors in a sample of 170 healthy volunteers (age range 46-77 years).
2006
Background: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. Methods: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. Results: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. Conclusion: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline.
Individual differences in GABA content are reliable but are not uniform across the human cortex
H magnetic resonance spectroscopy (MRS) provides a powerful tool to measure gamma-aminobutyric acid (GABA), the principle inhibitory neurotransmitter in the human brain. We asked whether individual differences in MRS estimates of GABA are uniform across the cortex or vary between regions. In two sessions, resting GABA concentrations in the lateral prefrontal, sensorimotor, dorsal premotor, and occipital cortices were measured in twenty-eight healthy individuals. GABA estimates within each region were stable across weeks, with low coefficients of variation. Despite this stability, the GABA estimates were not correlated between regions. In contrast, the percentage of brain tissue per volume, a control measure, was correlated between the three anterior regions. These results provide an interesting dissociation between an anatomical measure of individual differences and a neurochemical measure. The different patterns of anatomy and GABA concentrations have implications for understanding regional variation in the molecular topography of the brain in health and disease.
Cerebral Cortex, 2013
A potential mechanism that enables intellectual preservation in cognitively normal elderly that harbor beta-amyloid (Aβ) pathology is heightened cerebral glucose metabolism. To investigate cross-sectional interrelationships between Aβ, glucose metabolism, and cognition, 81 subjects (mean age: 75 ± 7 years) underwent [ 11 C] Pittsburgh Compound-B and [ 18 F]fluorodeoxyglucose positron emission tomography scans and neuropsychological testing. They were divided into low-Aβ (n = 53), intermediate-Aβ (n = 13) and high-Aβ (n = 15) groups as defined by their global cortical [ 11 C]PIB retention. Glucose metabolism was assessed using a MetaROI mask that covers metabolically critical regions in Alzheimer's disease (AD) (i.e., posterior cingulate and bilateral angular and inferior temporal gyri). Previously validated factor scores for verbal and visual episodic memory, semantic memory, working memory, and executive functioning were used to evaluate cognitive performances. Greater Aβ deposition in the precuneus was associated with higher metabolic activity (at trend level) and lower visual episodic memory scores. Glucose metabolism did not correlate with cognition across all subjects. However, heightened metabolic activity was associated with better verbal episodic memory performance in subjects with elevated amyloid levels. This preliminary study suggests that neural compensation, as a manifestation of brain reserve, enables elderly supposedly on the path to AD, at least temporarily, to preserve cognitive function.