Prefrontal GABA Levels Correlate with Memory in Older Adults at High Risk for Alzheimer’s Disease

Abstract

γ-aminobutyric acid (GABA), primary inhibitory neurotransmitter in the brain, plays a significant role in aging and in neurodegenerative disorders, including Alzheimer’s disease (AD). We investigated the relationship between GABA levels in the dorsomedial/dorsoanterolateral prefrontal cortex (DM/DA-PFC) and memory in high-AD risk participants. Thirty-eight participants (14 Cognitively Normal (CN), 11 with Subjective Cognitive Decline, and 13 Mild Cognitive Impairment (MCI)) underwent magnetic resonance spectroscopy at 3 Tesla. SCD and MCI participants were grouped together to form a single high-AD risk group (N = 24) for the purposes of statistical analyses. Partial correlations of GABA+/Cr level with verbal memory assessed on California Verbal Learning Test-II and non-verbal memory assessed on Brief Visuospatial Memory Test and Rey-Osterrieth test were examined separately within the high-AD risk and CN groups. GABA+/Cr levels were positively correlated with long- delayed verbal memory (r = 0.69, P = 0.009) and immediate non-verbal memory (r = 0.97, P = 0.03) in high-AD risk, but not in CN participants. These results remained significant after controlling for depression. These preliminary findings, which require replication due to the limited sample sizes, are the first report of an association between GABA+/Cr levels within the DM/DA-PFC and memory performance in high-AD risk individuals.

Imaging Methods Applicable in the Diagnostics of Alzheimer’s Disease, Considering the Involvement of Insulin Resistance

“…Its homeostasis regulates psychological manifestation. On the one hand, normal GABA levels inhibit neuronal hyper-excitability causing irritability, seizures, movement disorders, anxiety, insomnia, fatigue, and various psychiatric disorders; on the other hand, its excessive values cause sedation, sleepiness, and lethargy [ 76 , 77 , 78 ]. The synthesis of GABA depends on its major precursor, glutamate, forming a vital neurotransmitter cycle, namely the glutamate-glutamine-GABA cycle [ 20 ].…”

“…However, the detection of GABA is complicated because of interactions between nuclei and signal overlapping, which can be overcome by several methods enabling its quantification, chiefly by Mescher–Garwood-editing of MRS [ 20 , 47 , 71 , 79 ]. Several studies have reported decreased GABA in AD, focusing on the temporal, frontal, and parietal lobes [ 50 , 77 ], although no significant GABA changes in AD compared with controls have been confirmed across the frontal lobe, hippocampus, and cingulate gyrus [ 50 , 71 ]. Since the brain regions of AD subjects show changes in Glx but not in GABA, ongoing asymmetric involvement of glutamatergic and GABAergic neurons or different rates of excitation-inhibition might occur in AD-affected cortical areas [ 80 , 81 ].…”

“…Since the brain regions of AD subjects show changes in Glx but not in GABA, ongoing asymmetric involvement of glutamatergic and GABAergic neurons or different rates of excitation-inhibition might occur in AD-affected cortical areas [ 80 , 81 ]. Furthermore, in assessing GABA changes in AD, we need to consider the age of the patient, because decreased GABA has been confirmed in the cingulate cortex, hippocampus, and frontal and parietal cortex of normal-aging controls [ 71 , 77 , 82 ]. GABA levels in the frontal cortex have been reported to be correlated with verbal and nonverbal memory and, in the anterior cingulate and occipital cortex, with visuoperceptual functions, supporting the link between the GABAergic and cholinergic neuronal system, a link that is disrupted in AD [ 77 , 83 ].…”

“…Furthermore, in assessing GABA changes in AD, we need to consider the age of the patient, because decreased GABA has been confirmed in the cingulate cortex, hippocampus, and frontal and parietal cortex of normal-aging controls [ 71 , 77 , 82 ]. GABA levels in the frontal cortex have been reported to be correlated with verbal and nonverbal memory and, in the anterior cingulate and occipital cortex, with visuoperceptual functions, supporting the link between the GABAergic and cholinergic neuronal system, a link that is disrupted in AD [ 77 , 83 ]. Since episodic memory decline in individuals is supposed to be a risk factor for AD, GABA might represent an important predictive marker for AD pathology [ 83 ].…”

“Surviving and Thriving”: Evidence for Cortical GABA Stabilization in Cognitively-Intact Oldest-Old Adults

“…Lower cortical GABA levels are associated with worse global cognition, fluid processing, sensorimotor performance, and memory performance in normative aging (Porges et al, 2017; Simmonite et al, 2019; Cassady et al, 2019; Murari et al, 2020; Jiménez-Balado et al, 2021; reviewed in Li et al, 2022). However, few studies of cortical GABA levels have included oldest-old adults (85 years and older), and none have compared young-old and old-old adults (Porges et al, 2017; Simmonite et al, 2019).…”