Hippocampal N-acetylaspartate Concentration Research Articles

Cardiovascular, Cerebral and Behavioral Response to Anti‐Hypertensive Treatment in Female Dahl Salt Sensitive Rats

Background Cerebrovascular disease is associated with central arterial stiffness (CAS), which can lead to reduced brain blood supply, neuronal density loss and cognitive impairment. Dahl salt sensitive (DSS) rats represent a model of vascular dementia and have a compromised renin-angiotensin system, develop CAS, hypertension, and hippocampal memory decline with age on a normal salt (NS) diet. Lisinopril (LIS), an angiotensin converting enzyme inhibitor, effectively treated this pathology in aged male DSS rats. We investigated the relationship between systolic blood pressure (SBP), pulse wave velocity (PWV), a marker of CAS, hippocampal blood flow (CBF), neuronal density and anxiety in female DSS rats treated with LIS. Methods Female DSS rats (n=23) were fed a NS diet (0.5% NaCl) for the duration of the study. Rats were administered LIS (15mg/kg BW/day in drinking water, n=12) or control treatment (CTRL; n=11) for 7-mo beginning at 6-mo of age. The following measurements were assessed at 6-mo (baseline; BL) and at 13-mo of age: SBP (by plethysmography), PWV (by echocardiography), CBF (by continuous arterial spin labeling), and hippocampal N-acetyl aspartate concentration (NAA; by proton magnetic resonance spectroscopy). In open field test (OFT; a metric of anxiety, a precursor to symptoms of dementia) travel activity (distance) and rearing durations (vertical activity; VA) in the center of the field were collected as measures of exploratory behavior. Pearson's correlation matrix and 2-way ANOVA mixed effects model analyses were performed. Results At BL, the treatment groups were not different in any parameters except heart rate (HR). At 13-mo CTRL, SBP and PWV increased, CBF, total distance, total VA and distance in center of the OFT decreased compared to BL. In 13-mo LIS group, SBP and PWV were lower compared to 13-mo CTRL; 13-mo LIS group had higher HR and lower SBP, CBF and total VA in OFT compared to BL (Table 1). At 6-mo, NAA and VA were marginally correlated. HR and central distance were significantly correlated (Table 2A). For 13-mo CTRL, SBP positively correlated with PWV and NAA. NAA negatively correlated with distance in center. HR negatively correlated with distance in center and VA in center (Table 2B). This relationship with HR was reversed for 13-mo LIS group, for which PWV and CBF were negatively associated with central distance and central VA, while NAA was negatively correlated with central VA only (Table 2C). Conclusion In both CTRL and LIS groups, advancing age adversely affected hippocampal perfusion, but not neuronal density. ChronicLIS treatment reduced hypertension and PWV but did not affect cerebral parameters in aged female DSS rats. Increased level of anxiety, known to predate cognitive decline, was associated with PWV for LIS group, suggesting that CAS can adversely affect brain structures and function. CTRL and LIS groups showed differences in associations between cerebral, behavioral, and cardiovascular parameters. Further analyses will be conducted to investigate the role of sex hormones and their associations with age in the patterns observed.

Abstract 048: Association of Central Arterial Stiffness With Hippocampal Blood Flow, N-Acetyl Aspartate and Anxiety in Hypertensive Dahl Salt Sensitive Rats

Background: Hypertension and cardiovascular disease may be significant contributors to dementia and Alzheimer’s disease. However, the mechanism of this process is poorly understood. Central arterial stiffness (CAS) is accelerated by systemic hypertension and may be accompanied by increased stiffness in the cerebral arteries. Methods & Results: We used Dahl salt sensitive rats (Dahl-S) which develop CAS and hippocampal memory decline as they develop variable degrees of hypertension on a 0.5% salt diet with age. At 22 weeks, systolic blood pressure (SBP), pulse wave velocity (PWV), open field tests (OFT), hippocampal N-acetylaspartate (NAA) concentrations and blood flow (BF) data were all collected. The rats displayed moderate hypertension as compared to a 3 months baseline (SBP: 165±16 vs. 142±5 mmHg; P<0.01, t-test). SBP and PWV are positively correlated (a). PWV was negatively correlated with hippocampal BF (b), and positively correlated with hippocampal NAA (c). Ratio of central rearing duration to total rearing duration in the OFT, a negative measure of anxiety, positively correlated with hippocampal BF (d). Conclusion: In the Dahl-S model of hypertension, greater PWV, a marker for CAS, was associated with decreased hippocampal perfusion. Relationship between CAS and hippocampal BF was as hypothesized. Likewise, hippocampal BF correlates with hippocampal NAA concentration as expected. The positive correlation between hippocampal BF and increased central rearing duration suggests that higher cerebral BF is associated with a lower anxiety level. Supported entirely by the Intramural research Program of the NIH, National institute on Aging.

Early life socioeconomic status, chronic physiological stress and hippocampal N-acetyl aspartate concentrations

ObjectiveEarly life socioeconomic deprivation has been associated with cognitive and behavioural changes that persist through towards adulthood. In this study, we investigated whether early life socioeconomic status is associated with changes in the hippocampus N-acetyl aspartate (NAA), using the non-invasive technique of magnetic resonance spectroscopy (MRS). MethodsWe performed proton magnetic resonance spectroscopy (1H-MRS) of the hippocampus at 3T in 30 adult males, selected from the PSOBID cohort. We conducted multiple regression analysis to examine the relationship between early socioeconomic status (SES) and concentration of N-acetyl-aspartate in the hippocampus. We also examined whether the relationship between these variables was mediated by markers of chronic physiological stress. ResultsGreater socioeconomic deprivation was associated with lower hippocampal NAA concentrations bilaterally. The relationship between early life SES and hippocampal NAA concentrations was mediated by allostatic load index – a marker of chronic physiological stress. ConclusionsGreater early life socioeconomic deprivation was associated with lower concentrations of NAA reflecting lesser neuronal integrity. This relationship was mediated by greater physiological stress. Further work, to better understand the biological processes underlying the effects of poverty, physiological stress on hippocampal metabolites is necessary.

A pilot study of hippocampal volume and N-acetylaspartate (NAA) as response biomarkers in riluzole-treated patients with GAD

Anxiolytic benefit following chronic treatment with the glutamate modulating agent riluzole in patients with generalized anxiety disorder (GAD) was previously associated with differential changes in hippocampal NAA concentrations. Here, we investigated the association between hippocampal volume and hippocampal NAA in the context of riluzole response in GAD. Eighteen medication-free adult patients with GAD received 8-week of open-label riluzole. Ten healthy subjects served as a comparison group. Participants underwent magnetic resonance imaging and spectroscopy at baseline and at the end of Week 8. GAD patients who completed all interventions were classified as remitters (n=7) or non-remitters (n=6), based on final Hamilton Anxiety Rating Scale (HAM-A) scores ≤7. At baseline, GAD patients had a significant reduction in total hippocampal volume compared to healthy subjects (F(1,21)=6.55, p=0.02). This reduction was most pronounced in the remitters, compared to non-remitters and healthy subjects. Delta (final−baseline) hippocampal volume was positively correlated with delta NAA in GAD. This positive association was highly significant in the right hippocampus in GAD [r=0.81, p=0.002], with no significant association in healthy subjects [Fisher r-to-z p=0.017]. Across all GAD patients, delta hippocampal volume was positively associated with improvement in HAM-A (rspearman=0.62, p=0.03). These preliminary findings support hippocampal NAA and volume as neural biomarkers substantially associated with therapeutic response to a glutamatergic drug.

Learning and Memory Alterations Are Associated with Hippocampal N-acetylaspartate in a Rat Model of Depression as Measured by 1H-MRS

It is generally accepted that cognitive processes, such as learning and memory, are affected in depression. The present study used a rat model of depression, chronic unpredictable mild stress (CUMS), to determine whether hippocampal volume and neurochemical changes were involved in learning and memory alterations. A further aim was to determine whether these effects could be ameliorated by escitalopram treatment, as assessed with the non-invasive techniques of structural magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). Our results demonstrated that CUMS had a dramatic influence on spatial cognitive performance in the Morris water maze task, and CUMS reduced the concentration of neuronal marker N-acetylaspartate (NAA) in the hippocampus. These effects could be significantly reversed by repeated administration of escitalopram. However, neither chronic stress nor escitalopram treatment influenced hippocampal volume. Of note, the learning and memory alterations of the rats were associated with right hippocampal NAA concentration. Our results indicate that in depression, NAA may be a more sensitive measure of cognitive function than hippocampal volume.

Performance-Related Increases in Hippocampal N-acetylaspartate (NAA) Induced by Spatial Navigation Training Are Restricted to BDNF Val Homozygotes

Recent evidence indicates experience-dependent brain volume changes in humans, but the functional and histological nature of such changes is unknown. Here, we report that adult men performing a cognitively demanding spatial navigation task every other day over 4 months display increases in hippocampal N-acetylaspartate (NAA) as measured with magnetic resonance spectroscopy. Unlike measures of brain volume, changes in NAA are sensitive to metabolic and functional aspects of neural and glia tissue and unlikely to reflect changes in microvasculature. Training-induced changes in NAA were, however, absent in carriers of the Met substitution in the brain-derived neurotrophic factor (BDNF) gene, which is known to reduce activity-dependent secretion of BDNF. Among BDNF Val homozygotes, increases in NAA were strongly related to the degree of practice-related improvement in navigation performance and normalized to pretraining levels 4 months after the last training session. We conclude that changes in demands on spatial navigation can alter hippocampal NAA concentrations, confirming epidemiological studies suggesting that mental experience may have direct effects on neural integrity and cognitive performance. BDNF genotype moderates these plastic changes, in line with the contention that gene-context interactions shape the ontogeny of complex phenotypes.

Differential regional N-acetylaspartate deficits in postmortem brain in schizophrenia, bipolar disorder and major depressive disorder

There is substantial evidence for the involvement of the hippocampus and subcortical regions in the neuropathology of schizophrenia. Deficits of N-acetylaspartate (NAA) have been found in schizophrenia and bipolar disorder which may reflect neuronal loss and/or dysfunction. N-acetylaspartylglutamate (NAAG) is the most abundant peptide transmitter in the mammalian nervous system. It is an agonist at presynaptic metabotropic glutamate receptors mGluR3, inhibiting glutamate release. NAA and NAAG and were measured in hippocampal, striatal, amygdala and cingulate gyrus regions of human postmortem tissue from controls and subjects with schizophrenia, bipolar disorder and major depressive disorder. There are significant deficits in hippocampal NAA concentrations in all patient groups. In the amygdala there are significant NAA deficits in schizophrenia and depression and significant deficits of NAAG in the amygdala in the depression group. The deficits in NAA reported in this study confirm the importance of hippocampal and other subcortical structures in the neuropathology of the major psychiatric disorders.

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

Hippocampal N-Acetylaspartate Concentration and Response to Riluzole in Generalized Anxiety Disorder

Previous research has suggested the therapeutic potential of glutamate-modulating agents for severe mood and anxiety disorders, potentially resulting from enhancement of neuroplasticity. We used proton magnetic resonance spectroscopic imaging ((1)H MRSI) to examine the acute and chronic effects of the glutamate-release inhibitor riluzole on hippocampal N-acetylaspartate (NAA), a neuronal marker, in patients with generalized anxiety disorder (GAD) and examined the relationship between changes in NAA and clinical outcome. Fourteen medication-free GAD patients were administered open-label riluzole and then evaluated by (1)H MRSI before drug administration, and 24 hours and 8 weeks following treatment. Patients were identified as responders (n = 9) or nonresponders (n = 5). Seven untreated, medically healthy volunteers, comparable in age, sex, IQ, and body mass index to the patients, received scans at the same time intervals. Molar NAA concentrations in bilateral hippocampus, and change in anxiety ratings were the primary outcome measures. A group-by-time interaction was found, with riluzole responders showing mean increases in hippocampal NAA across the three time points, whereas nonresponders had decreases over time. In GAD patients at Week 8, hippocampal NAA concentration and proportional increase in NAA from baseline both were positively associated with improvements in worry and clinician-rated anxiety. These preliminary data support a specific association between hippocampal NAA and symptom alleviation following riluzole treatment in GAD. Placebo-controlled investigations that examine hippocampal NAA as a viable surrogate endpoint for clinical trials of neuroprotective and plasticity-enhancing agents are warranted.

Association of human hippocampal neurochemistry, serotonin transporter genetic variation, and anxiety

The impact of the serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) on anxiety-related behavior and related cerebral activation has facilitated the understanding of neurobiological mechanisms of anxiety. However, the influence of the 5-HTTLPR genotype on hippocampal neuronal development and neurochemistry, which is relevant to anxiety behavior, has not been investigated. In 38 healthy subjects, absolute concentrations of N-acetylaspartate (NAA) were measured as a main surrogate parameter for hippocampal neurochemistry on a 3-T scanner. A significantly lower hippocampal NAA concentration in s allele carriers was observed as compared to l/l genotype. Other metabolites (choline, creatine + phosphocreatine, glutamate) were unaffected by genotype. The hippocampal NAA concentration was negatively correlated with trait anxiety scores (STAI). Metabolites measured in the anterior cingulate cortex (reference region) were not associated with genotype. The results are in accordance with the recently reported relationship between hippocampal neuronal development and anxiety behavior in adult animals and show an association between human limbic neurochemistry and genetically driven serotonergic neurotransmission relevant to anxiety.

Hippocampal N‐acetyl aspartate levels do not mirror neuronal cell densities in creatine‐supplemented epileptic rats

For neuroprotective therapy of neurodegenerative diseases creatine treatment has gained special interest because creatine has been shown to cross the blood-brain barrier, accumulate in the human brain in vivo and cause delayed neuronal cell death in a large number of animal models. Here, we used the pilocarpine model of temporal lobe epilepsy to determine whether creatine administration is able to attenuate the epilepsy-associated decrease in hippocampal N-acetyl aspartate (NAA) concentrations, impairment of mitochondrial function and neuronal cell loss. In vivo1H-NMR spectroscopy showed, in epileptic rats after creatine administration, higher hippocampal NAA concentrations, suggesting improved neuronal survival. However, in vitro observation of hippocampal slices from creatine-treated epileptic rats revealed a more pronounced loss of pyramidal neurons and decrease in activity of mitochondrial enzymes in hippocampal subfields. This indicates that NAA concentrations measured by in vivo1H-NMR spectroscopy reflect alterations of metabolism rather than neuronal cell densities. Our data indicate an adverse effect of creatine on neuronal survival under conditions of enhanced neuronal activity.

Functional brain imaging in the dementias: role in early detection, differential diagnosis, and longitudinal studies.

This review considers the role of functional brain imaging techniques in the dementias. The substantial assistance that especially single-photon emission tomography and positron emission tomography can play in the initial diagnosis of dementia and in the differential diagnosis of the specific dementing disorder is discussed. These techniques alone essentially match the sensitivity and specificity of clinical diagnoses in distinguishing Alzheimer's dementia (AD) from age-matched controls, from frontal lobe dementia and vascular dementia, and even from Lewy body dementia. Newer analytic techniques such as voxel-based correlational analyses and discriminant function analyses enhance the power of such differential diagnoses. Functional brain imaging techniques can also significantly assist in patient screening for clinical trials. The correlation of the observed deficits with specific patterns of cognitive abnormalities permits enhanced patient management and treatment planning and improved longitudinal assessment of outcome. It is also noteworthy that the classic abnormalities of temporoparietal and posterior cingulate hypoperfusion or hypometabolism appear to be present prior to symptom onset. These abnormalities predict progression to AD in the presence of the earliest of symptoms, and are present even in cognitively normal but at-risk subjects, with a severity proportional to the risk status. Even greater predictive ability for progression to AD is obtained by combining measures of perfusion or metabolism with risk factors, tau protein levels, hippocampal N-Acetyl aspartate concentrations, or hippocampal volume measures.

Proton magnetic resonance spectroscopy of the hippocampus and occipital white matter in PTSD: preliminary results.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies in posttraumatic stress disorder (PTSD) report decreased hippocampal N-acetylaspartate (NAA), an indicator of neuronal integrity. However, other areas of the brain need to be explored. The objective of this study was to investigate the specificity of hippocampal NAA concentration changes in PTSD by also examining a control region, the occipital white matter (OWM). Eight patients with PTSD and 5 control subjects underwent single-voxel 1H-MRS of the hippocampi and bilateral OWM. Absolute neurometabolite concentrations were determined. Trends toward reduced left hippocampal NAA and creatine (Cre) were found in the PTSD group. PTSD subjects also had reduced bilateral OWM Cre. The preliminary results of our study in civilians with PTSD replicate previous MRS studies and are consistent with decreased hippocampal neuronal integrity without effects in the OWM. Replication of our findings is needed.