Hippocampal N-acetylaspartate Research Articles

Simultaneous high-resolution whole-brain MR spectroscopy and [18F]FDG PET for temporal lobe epilepsy.

Precise lateralizing the epileptogenic zone in patients with drug-resistant mesial temporal lobe epilepsy (mTLE) remains challenging, particularly when routine MRI scans are inconclusive (MRI-negative). This study aimed to investigate the synergy of fast, high-resolution, whole-brain MRSI in conjunction with simultaneous [18F]FDG PET for the lateralization of mTLE. Forty-eight drug-resistant mTLE patients (M/F 31/17, age 12-58) underwent MRSI and [18F]FDG PET on a hybrid PET/MR scanner. Lateralization of mTLE was evaluated by visual inspection and statistical classifiers of metabolic mappings against routine MRI. Additionally, this study explored how disease status influences the associations between altered N-acetyl aspartate (NAA) and FDG uptake using hierarchical moderated multiple regression. The high-resolution whole-brain MRSI data offers metabolite maps at comparable resolution to [18F]FDG PET. Visual examinations of combined MRSI and [18F]FDG PET showed an mTLE lateralization accuracy rate of 91.7% in a 48-patient cohort, surpassing routine MRI (52.1%). Notably, out of 23 MRI-negative mTLE, combined MRSI and [18F]FDG PET helped detect 19 cases. Logistical regression models combining hippocampal NAA level and FDG uptake improved lateralization performance (AUC=0.856), while further incorporating extrahippocampal regions such as amygdala, thalamus, and superior temporal gyrus increased the AUC to 0.939. Concurrent MRSI/PET revealed a moderating influence of disease duration and hippocampal atrophy on the association between hippocampal NAA and glucose uptake, providing significant new insights into the disease's trajectory. This paper reports the first metabolic imaging study using simultaneous high-resolution MRSI and [18F]FDG PET, which help visualize MRI-unidentifiable lesions and may thus advance diagnostic tools and management strategies for drug-resistant mTLE.

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Brain Connectivity: A Journal of Clinical Neurology, Neuroscience, & Neuroimaging Advancing the Field of Neurology

Impact of adapted physical activity on hippocampal N-Acetyl Aspartate in patients with schizophrenia

IntroductionAdapted physical activity (APA) has beneficial neurobiological impact but the underlying pathophysiological mechanisms remain poorly described. APA is currently recognized as an adjuvant therapy to antipsychotic treatments in patients with schizophrenia (SCZs) to reduce the severity of negative symptoms and cognitive impairment. SCZs exhibit hippocampal N-acetylaspartate (NAA) reduction, a marker of neuronal viability and integrity whose concentrations can be assessed by proton magnetic resonance spectroscopy (1H-MRS).ObjectivesThe purpose of this study was to evaluate the impact of remote physical activity (e-APA) via the web on the NAA relative variations in the left hippocampus in SCZs compared to a patient control group benefiting from an health education program (HE). This study concerns one of the secondary objectives of the PEPsy V@SI study co-financed by the Pierre Deniker Foundation, the European Union and the Normandy Region within the framework of the FEDER/FSE 2014-2020 operational program.MethodsThirty-five SCZs were randomized in the e-APA active group or in the control group (HE). Participants received the interventions during 16 weeks, with two visioconference sessions per week. A 1H-MRS sequence positioned on the left hippocampus (MRI-3T) was acquired before and after both interventions. Absolute NAA concentrations in the left hippocampus were obtained using Osprey software after partial volume correction. After checking the quality criteria, the spectra of 6 SCZs in the e-APA group and 8 SCZs in the HE group were analyzed. To test the difference between interventions on the NAA relative variations, a Wilcoxon-Mann-Whitney test and effect size were performed. Paired Wilcoxon tests were used in each group before and after the interventions.ResultsNo significant difference was found in NAA relative variations in the left hippocampus between the e-APA group and the HE group (p = 0.18), although the effect size was 0.38 (considered as moderate). However, a trend towards an increase of NAA was observed in the e-APA group (before intervention: 12.08 International Units (I.U); after: 13.81 I.U) (p = 0.06) but not in the HE group (before intervention: 13.75 I.U ; after: 13.85 I.U) (p = 0.84).ConclusionsOur results showed a NAA significant increase in SCZs after an e-APA program, indicating a beneficial impact of e-APA on neuronal viability that might reflect an hippocampal plasticity. However, this increase did not differ significantly between active and control groups probably due to a weak statistical power.Disclosure of InterestL. Metivier: None Declared, F. Briend: None Declared, M. Tréhout: None Declared, L. Bigot: None Declared, G. Quarck: None Declared, A. Herbinet: None Declared, E. Leroux: None Declared, S. Dollfus Consultant of: Fabre,Gedeon,Roche and Takeda, inivited Conferences by Lundbeck, Otsuka, Janssen ; at contracts with Prophase MedAvances and NeuroCogTrials

Hippocampal Neuronal Integrity and Functional Connectivity Within the Default Mode Network in Mild Cognitive Impairment: A Multimodal Investigation.

Background: In older people with mild cognitive impairment (MCI), the relationship between early changes in functional connectivity and in vivo changes in key neurometabolites is not known. Two established correlates of MCI diagnosis are decreased N-acetylaspartate (NAA) in the hippocampus, indicative of decreased neuronal integrity, and changes in the default mode network (DMN) functional network. If and how these measures interrelate is yet to be established, and such understanding may provide insight into the processes underpinning observed cognitive decline. Objectives: To determine the relationship between NAA levels in the left hippocampus and functional connectivity within the DMN in an aging cohort. Methods: In a sample of 51 participants with MCI and 30 controls, hippocampal NAA was determined using magnetic resonance spectroscopy, and DMN connectivity was quantified using resting-state functional MRI. The association between hippocampal NAA and the DMN functional connectivity was tested within the MCI group and separately within the control group. Results: In the DMN, we showed a significant inverse association between functional connectivity and hippocampal NAA in 20 specific brain connections for patients with MCI. This was despite no evidence of any associations in the healthy control group or group differences in either of these measures alone. Conclusions: This study suggests that decreased neuronal integrity in the hippocampus is associated with functional change within the DMN for those with MCI, in contrast to healthy older adults. These results highlight the potential of multimodal investigations to better understand the processes associated with cognitive decline. Impact statement This study measured activity within the default mode network (DMN) and quantified N-acetylaspartate (NAA), a measure of neuronal integrity, within the hippocampus in participants with mild cognitive impairment (MCI) and healthy controls. In participants with MCI, NAA levels were inversely associated with connectivity between specific regions of the DMN, a relationship not evident in healthy controls. This association was present even in the absence of group differences in DMN connectivity or NAA levels. This research illustrates the possibility of using multiple magnetic resonance modalities for more sensitive measures of early cognitive decline to identify and intervene earlier.

Effect of high-intensity interval training on hippocampal metabolism in older adolescents.

Although well-evidenced in older adults, the effects of exercise on the hippocampus in youth are relatively unknown. This study examined the impact of a 6-month school-based physical activity intervention on hippocampal metabolism in adolescents using magnetic resonance spectroscopy. A subset of lower fit older adolescents [N=56, 61% female, 16.1 ± 0.4 years] was included from four secondary schools (10 classes) in New South Wales, Australia, who were participating in a larger cluster randomized controlled trial. Participants were randomized to the Burn 2 Learn (B2L) intervention (five classes, 30 participants) or a control group (five classes, 26 participants). Changes in hippocampal metabolism were assessed using linear mixed models adjusted for clustering at the class level. We observed group-by-time effects for the B2L intervention on N-acetylaspartate (NAA) (+2.66 mmol/L, 95% CI 0.20 to 5.11, d=0.66) and glutamate+glutamine (Glx) (+3.38 mmol/L, 95% CI 0.34 to 6.42, d=0.67) in the left hippocampus. Increases in left hippocampal NAA and Glx concentrations were associated with improvements in cardiorespiratory fitness (NAA: rs =0.52, p=.016; Glx: rs =0.57, p=.007), lower body muscular fitness (NAA: rs =0.49, p=.018; Glx: rs =0.59, p=.003), and working memory (NAA: rs =0.42, p=.032; Glx: rs =0.43, p=.028) in the intervention group. Our findings suggest physical activity may improve hippocampal metabolism in lower fit older adolescents with implications for working memory. Further studies involving larger samples are needed to replicate our findings.

Systemic Administration of the TLR7/8 Agonist Resiquimod (R848) to Mice Is Associated with Transient, In Vivo-Detectable Brain Swelling.

Simple SummaryPhysiological changes to the body can affect the brain. For example, inflammation that originates in the body can be sensed by the brain. In this study, we used an agent called resiquimod (R848) to stimulate inflammation in the periphery and measured structural and metabolic brain responses in anesthetized mice using in vivo magnetic resonance imaging. Relative to baseline prior to drug administration, a high dose of R848 caused sickness behaviors and volume expansion in several cortical regions at 3 h that were no longer evident at 24 h. Transient volume expansion in response to peripheral immune stimulation is consistent with brain swelling.Peripheral administration of the E. coli endotoxin lipopolysaccharide (LPS) to rats promotes secretion of pro-inflammatory cytokines and in previous studies was associated with transient enlargement of cortical volumes. Here, resiquimod (R848) was administered to mice to stimulate peripheral immune activation, and the effects on brain volumes and neurometabolites determined. After baseline scans, 24 male, wild-type C57BL mice were triaged into three groups including R848 at low (50 μg) and high (100 μg) doses and saline controls. Animals were scanned again at 3 h and 24 h following treatment. Sickness indices of elevated temperature and body weight loss were observed in all R848 animals. Animals that received 50 μg R848 exhibited decreases in hippocampal N-acetylaspartate and phosphocreatine at the 3 h time point that returned to baseline levels at 24 h. Animals that received the 100 μg R848 dose demonstrated transient, localized, volume expansion (~5%) detectable at 3 h in motor, somatosensory, and olfactory cortices; and pons. A metabolic response evident at the lower dose and a volumetric change at the higher dose suggests a temporal evolution of the effect wherein the neurochemical change is demonstrable earlier than neurostructural change. Transient volume expansion in response to peripheral immune stimulation corresponds with previous results and is consistent with brain swelling that may reflect CNS edema.

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.

Weight gain as a risk factor for progressive neurochemical abnormalities in first episode mania patients: a longitudinal magnetic resonance spectroscopy study.

We previously reported that bipolar disorder (BD) patients with clinically significant weight gain (CSWG; ⩾7% of baseline weight) in the 12 months after their first manic episode experienced greater limbic brain volume loss than patients without CSWG. It is unknown whether CSWG is also a risk factor for progressive neurochemical abnormalities. We investigated whether 12-month CSWG predicted greater 12-month decreases in hippocampal N-acetylaspartate (NAA) and greater increases in glutamate + glutamine (Glx) following a first manic episode. In BD patients (n = 58) and healthy comparator subjects (HS; n = 34), we measured baseline and 12-month hippocampal NAA and Glx using bilateral 3-Tesla single-voxel proton magnetic resonance spectroscopy. We used general linear models for repeated measures to investigate whether CSWG predicted neurochemical changes. Thirty-three percent of patients and 18% of HS experienced CSWG. After correcting for multiple comparisons, CSWG in patients predicted a greater decrease in left hippocampal NAA (effect size = -0.52, p = 0.005). CSWG also predicted a greater decrease in left hippocampal NAA in HS with a similar effect size (-0.53). A model including patients and HS found an effect of CSWG on Δleft NAA (p = 0.007), but no diagnosis effect and no diagnosis × CSWG interaction, confirming that CSWG had similar effects in patients and HS. CSWG is a risk factor for decreasing hippocampal NAA in BD patients and HS. These results suggest that the well-known finding of reduced NAA in BD may result from higher body mass index in patients rather than BD diagnosis.

Effects of Lisinopril on Arterial Stiffness, Cerebral Blood Flow and Cortical Thickness in Hypertensive Dahl‐S Rats

Study objectivesCentral arterial stiffness (CAS), associated with hypertension, is likely underlies the stiffening of cerebral arterial wall resulting in cerebral hypoperfusion, neuronal density loss and cognitive decline. We previously found associations between pulse wave velocity (PWV), a marker of CAS, and hippocampal cerebral blood flow (CBF) and neuronal density in 6‐mo old hypertensive Dahl salt‐sensitive (Dahl‐S) rats. This study examined the effect of ACE inhibitor, Lisinopril, on cardiovascular and brain parameters in hypertensive Dahl‐S rats.MethodsMale Dahl‐S rats (n=32) were fed with a normal salt diet (0.5% NaCl) for a duration of study. Systolic blood pressure (SBP), PWV (by echocardiography); hippocampal N‐acetyl aspartate (NAA) concentration, hippocampal CBF were measured at 6‐mo of age (baseline) and after 3‐mo and 6‐mo of Lisinopril (15mg/kg body weight/day in drinking water; n=14) or control (n=18) treatment. NAA was measured using proton spectroscopy in a 7T Bruker Biospec MRI scanner; CBF was measured using continuous arterial spin labeling (CASL) in the coronal slice with the largest hippocampal area; cortical thickness (CT) analysis was done using a T2 weighted RARE 3D image (n=12). Advanced Normalization Tools (ANTs) were used for the CT estimation. T‐test and 2‐way ANOVA linear mix effect model analyses were performed in R, EXCEL and MATLAB. Data presented as mean±SE.ResultsAt 6‐mo of age, the Dahl‐S rats developed advanced hypertension vs. 3‐mo (SBP: 164±4 vs. 141±3 mmHg; P<0.01, t‐test). SBP of non‐treated (NT) animals was steadily high at all time points while treated animals exhibited a decrease in SBP at 9‐mo vs. 6‐mo of age. SBP remained low from 9‐mo to 12‐mo of age (Fig. 1a). In treated animals, PWV decreased at all timepoints after 6‐mo of age. For NT animals, PWV remained steady from 6‐mo to 9‐mo but increases from 9‐mo to12‐mo of age (Fig. 1b). Hippocampal CBF of NT animals decreased in a downwards trend but remain stabilized in the treated group across timepoints (Fig. 1c). Likewise, the hippocampal NAA, among treated animals remained stabilized, while in NT animals this parameter fluctuated with an eventual downwards trend (Fig. 1d). The mean difference maps of the CT for the NT and treated rats are similar except for the regions denoted by the red arrows when comparing treated to NT (Fig. 2a–b). The occipital region showed cortical thickening (blue) and parietal region showed cortical thinning (yellow). The P value maps show that those regions of significant thickening and thinning are greater in the treated vs. NT rats (Fig. 2c–d).ConclusionThe posterior cerebral artery is a dominant source of perfusion to the hippocampus and the occipital lobe; thus, our findings suggest a coherent pattern through which CAS can affect the cerebral arteries in hypertensive Dahl‐S rats. Lisinopril treatment decrease CAS and improve regional CBF and neuronal density. Therefore, CAS may be a therapeutic target for vascular dementia.Support or Funding InformationThe work was supported by the Intramural Research Program of the National Institute on Aging of the National Institutes of Health.Longitudinal changes in cardiovascular parameters in Lisinopril treated Dahl‐S rats. Systolic blood pressure SBP (a), pulse wave velocity PWV (b), hippocampal CBF (c), and NAA (d) in Lisinopril treated (T) and nontreated (NT) rats. By 2‐way ANOVA Linear Mixed Effects: *p < 0.001 vs. age‐matched treated rats; #p < 0.03 vs. 6‐mo, ## p <0.001 vs. 6‐mo; by paired T‐test (c, d): * p = 0.07 vs. 6‐mo; # p = 0.06 vs. 9‐mo NT.Figure 1Mean Differences in Cortical Thickness and their p value maps (6‐mo subtracted by 12‐mo). Mean difference between age 6‐mo and 12‐mo of (a) nontreated animals and (b) lisinopril treated animals. Blue indicates regions of thickening. Yellow indicated regions of thinning. Occipital and parietal regions indicated by the red arrows. P value map of nontreated animals (c) and lisinopril treated animals (d). All insignificant p values > 0.05 were revalued as 0.05 for visualization purposes.Figure 2

Effects of Lisinopril on Arterial Stiffness, Cerebral Blood Flow, Neuronal Viability and Cortical Thickness in Late‐Life Hypertension in Dahl‐S Rats

Effects of Lisinopril on Arterial Stiffness, Cerebral Blood Flow, Neuronal Viability and Cortical Thickness in Late‐Life Hypertension in Dahl‐S Rats

1HMRS in the Hippocampus of the Female Patients with Conversion Disorder.

Previously, we found a lower NAA (N-acetyl aspartate)/CRE (creatine) ratio in conversion disorder patients, when compared to healthy controls. In this context, the present study was designed to determine the changes in hippocampal NAA, CHO (choline), and CRE values in conversion disorder female patients, which has similar symptom basement and hypothesize that the patients with conversion disorder would have also changed neurochemicals in their hippocampal regions. Twenty female patients and healthy controls were included in the study. Proton magnetic resonance spectroscopy (1HMRS) method was used to determine the NAA/CHO, NAA/CRE, and CHO/CRE ratios. The data were analyzed via age-controlled General Linear Model and it was found that the ratio of NAA/CHO was significantly lower in conversion disorder female patients when compared to healthy controls. However, NAA/CRE or CHO/CRE ratios were similar for conversion disorder patients and healthy controls. It was concluded that conversion disorder female patients might have reduced NAA/CHO ratio which implicates reduced neuronal viability, possibly related to anxiety and indirectly to somatoform symptoms.

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.

Sex differences in the effect of acute administration of nicotine on MRS-measured metabolic profile of the rat brain

Women are less able to stop smoking than men. Elucidation of sex differences in the tobacco addiction could facilitate personalized treatment. Specialized brain reward systems are controlling the behavior through reinforcement using specific neuromediators. Using non-invasive magnetic resonance spectroscopy (MRS) to ascertain addiction/harm biomarkers could lead to better management of public health through advancements in regulatory and translational research. Proton MRS was used to monitor changes of specific neurometabolites in hippocampus (HC), nucleus accumbens (NAC), and anterior cingulate cortex (ACC) of rats of both sexes after single intraperitoneal injection of nicotine. At the baseline, male rats showed higher level of GABA, taurine, N-acetyl aspartate, and creatine in HC, and taurine in NAC. Also, there were stronger correlations between neurometabolites in females than in males at the baseline. Nicotine administration changed taurine, GABA, myo-inositol, choline, and N-acetyl aspartate in HC, and taurine in NAC. Significant interactions between time, treatment, and sex were detected for taurine and choline in HC. The number of inter-metabolite correlations increased significantly in ACC and decreased in NAC and HC in females after nicotine administration, while in males it was unchanged. There are distinct sex differences in neurometabolic profiles at the baseline and after acute nicotine administration. Nicotine changes inter-metabolite correlations in females more than in males.

ASSOCIATION OF CENTRAL ARTERIAL STIFFNESS WITH HIPPOCAMPAL BLOOD FLOW, N-ACETYL-ASPARTATE AND ANXIETY IN HYPERTENSIVE DAHL SALT SENSITIVE RATS

Hypertension and diseases of the vascular wall contribute to dementia, including Alzheimer's disease. Central arterial stiffness (CAS) is known to be accelerated by systemic hypertension and may be accompanied by increased stiffness in the cerebral arteries. To study this, we used adult Dahl salt-sensitive (Dahl-S) rats which exhibit increased CAS, indexed by pulse wave velocity (PWV), and hippocampal memory decline as they develop a variable degree of moderate hypertension with age while on a normal salt diet. With this model, we sought to understand the link between CAS in the systemic circulation with a behavioral parameter like anxiety, and with hippocampal perfusion and neuronal density. Dahl-S rats (n=29; Charles River Laboratories) were fed with normal salt diet (0.5% NaCl) until 6 months, when the measurements of systolic blood pressure (SBP), PWV, open field test (OFT) and brain MRI were performed. Central and periphery rearing durations in OFT was conducted as a metric of anxiety. Hippocampal N-acetyl-aspartate (NAA) concentrations, a marker of neuronal density, and blood flow was collected with proton spectroscopy and continuous arterial spin labeling respectively. Six months old males Dahl-S rats displayed hypertension (SBP: 165±16 vs. 142±5 mmHg, 6-mo vs. 3-mo; mean±SD). Linear regression revealed a positive correlation between SBP and PWV (Figure 1). PWV was negatively correlated with cerebral perfusion in the hippocampus (Figure 2). Hippocampal CBF positively correlated with hippocampal NAA (Figure 3). Ratio of central rearing duration to total rearing duration positive correlated with hippocampal blood flow (Figure 4).

25.2 UNDERSTANDING WHITE MATTER PATHOLOGY IN SCHIZOPHRENIA USING DIFFUSION TENSOR IMAGING AND MAGNETIC RESONANCE SPECTROSCOPY

BackgroundDiffusion tensor imaging (DTI) studies in schizophrenia consistently show global reductions in fractional anisotropy (FA), a putative marker of white matter integrity. Because magnetic resonance spectroscopy (MRS) studies permit for the non-invasive measurements of neurometabolites, such as N-acetylaspartate (NAA), a marker of neuronal integrity, and glutamate, which can be neurotoxic when over-released, this technique provides further understanding of the relationship between white matter microstructure and neuronal function.MethodsTwenty-nine schizophrenia patients and twenty controls participated in this 3T imaging study where we used DTI and tract-based spatial statistics (TBSS) to assess white matter integrity of the cingulum bundle and MRS to quantify NAA and glutamate in the anterior cingulate cortex (ACC) and hippocampus, i.e. in cortico-limbic regions connected by the cingulum bundle.ResultsWe found FA reductions with overlapping radial diffusivity (RD) elevations in patients in multiple tracts, suggesting white matter abnormalities in schizophrenia are driven by loss of myelin integrity. In controls, but not in patients, high hippocampal NAA levels were significantly associated with low RD in the hippocampal part of the cingulum, and low ACC glutamate levels were significantly associated with high FA in the hippocampus part of the cingulum.DiscussionIn conclusion, we demonstrate the potential utility of a multi-modal neuroimaging approach to help further our understanding of the relationship between white matter microstructure and neurochemistry in distinct cortical regions connected by white matter tracts.

A Longitudinal, Observational Study of the Effect of Dimethyl Fumarate on Hippocampal Metabolites in RRMS using 1H-MR Spectroscopy

Background: Dimethyl fumarate (DMF), an oral diseasemodifying treatment for Multiple Sclerosis (MS), displays anti-oxidative properties, thought to be via modulation of glutathione (GSH). However, to date, the effect of DMF on the metabolic profile of MS brains has not been evaluated. The aim of this study was to measure cross-sectional changes in hippocampal neurometabolites in Relapsing- Remitting MS (RRMS) patients, compared to Healthy Controls (HCs) and then evaluate the metabolic impact of DMF treatment longitudinally over 24 months. Methods: 1H-MRS was undertaken on 20 RRMS patients prior to and up to 24 months post-inception of DMF treatment and 20 age sex-matched HCs. Spectroscopic data was acquired from the hippocampus using single voxel spectroscopy (6.75 mL, PRESS, TE 30 ms) at 3T. Results: We identified a significant reduction in hippocampal N-acetylaspartate (NAA, -13%, p=0.0001) and increased myoinositol (mI, +9%, p=0.02) in RRMS patients, before starting DMF, compared to HCs. Following treatment onset, GSH levels differed significantly over 24 months in the RRMS group (F=3.5, p<0.05). There was a reduction in GSH from baseline to 1 month of treatment (p=0.014). This reduction remained statistically significant after 6 months of treatment (p=0.04), but slightly increased after 12 and 24 months of treatment (p=0.15 and 0.18, respectively), approaching levels seen in HCs. Conclusions: The trend for the rebound effect of GSH following 24 months of DMF treatment is suggestive of recovery from the inflammatory event and is the first demonstration of an anti-oxidative effect in the MS brain following DMF treatment.

Hippocampal metabolites in asthma and their implications for cognitive function.

Emerging research indicates that individuals with asthma have an increased risk of cognitive impairment, yet the associations of asthma with neural correlates of memory remain relatively unknown. The hippocampus is the predominant neural structure involved in memory, and alterations in the hippocampal metabolic profile are observed in individuals with mild cognitive impairment. We therefore hypothesized that individuals with asthma may have altered hippocampal metabolites compared to healthy controls.Structural magnetic resonance imaging (sMRI) and proton magnetic resonance spectroscopy (1H-MRS) were used to compare hippocampal volume and metabolites of otherwise healthy adults with and without asthma (N = 40), and to study the association of these measures with cognitive function and asthma-related variables. Participants underwent 3-Tesla sMRI and 1H-MRS, with the volume of interest placed in the left hippocampus to measure levels of N-acetylaspartate (NAA), glutamate (Glu), creatine (Cr), and myo-inositol (MI), as indicators of neuronal viability, cellular activity, cellular energy reserve, as well as glial activation.Individuals with asthma had lower hippocampal NAA compared to healthy controls. For all participants, poorer cognitive function was associated with reduced NAA and Glu. For individuals with asthma, poorer cognitive function was associated with reduced disease control. Additionally, short-acting rescue bronchodilator use was associated with significantly lower NAA, and Glu, whereas inhaled corticosteroid use was related to significantly higher Cr and in tendency higher NAA and Glu. All findings controlled for left hippocampal volume, which was not different between groups.These findings highlight that asthma and/or its treatment may affect hippocampal chemistry. It is possible that the observed reductions in hippocampal metabolites in younger individuals with asthma may precede cognitive and hippocampal structural deficits observed in older individuals with asthma.

Association between memory impairment and brain metabolite concentrations in North Korean refugees with posttraumatic stress disorder.

Individuals with posttraumatic stress disorder (PTSD) had experiences of enormous psychological stress that can result in neurocognitive and neurochemical changes. To date, the causal relationship between them remains unclear. The present study is to investigate the association between neurocognitive characteristics and neural metabolite concentrations in North Korean refugees with PTSD. A total of 53 North Korean refugees with or without PTSD underwent neurocognitive function tests. For neural metabolite scanning, magnetic resonance spectroscopy of the hippocampus and anterior cingulate cortex (ACC) has been conducted. We assessed between-group differences in neurocognitive test scores and metabolite levels. Additionally, a multiple regression analysis was carried out to evaluate the association between neurocognitive function and metabolite levels in patients with PTSD. Memory function, but not other neurocognitive functions, was significantly lower in the PTSD group compared with the non-PTSD group. Hippocampal N-acetylaspartate (NAA) levels were not different between groups; however, NAA levels were significantly lower in the ACC of the PTSD group than the non-PTSD group (t = 2.424, p = 0.019). The multiple regression analysis showed a negative association between hippocampal NAA levels and delayed recall score on the auditory verbal learning test (β = -1.744, p = 0.011) in the non-PTSD group, but not in the PTSD group. We identified specific memory impairment and the role of NAA levels in PTSD. Our findings suggest that hippocampal NAA has a protective role in memory impairment and development of PTSD after exposure to traumatic events.

Hippocampal metabolism and prefrontal brain structure: A combined 1H-MR spectroscopy, neuropsychological, and voxel-based morphometry (VBM) study

Hippocampal structural and functional integrity impacts on multiple remote areas of the brain, and this connectivity is central to multiple cognitive functions in healthy and disease. We studied associations of hippocampal metabolic markers N-acetyl aspartate (NAA) and glutamate (Glu and Glx; assessed with 1H magnetic resonance spectroscopy) and brain grey matter (studied with voxel-based morphometry, VBM) in 20 healthy subjects. We found a significant correlation between right hippocampal NAA and left ventrolateral prefrontal cortical grey matter (TFCE, p<0.05, FWE-corrected), as well as verbal fluency markers, and right hippocampal Glx (glutamate/glutamine) and left cerebellar volume. Our studies demonstrate a structure-function correlation that might underlie the interaction of the hippocampus with prefrontal cortex and cerebellum, which might be central to several neurological and psychiatric disorders, including schizophrenia or depression.

Brain volumetric and metabolic correlates of electroconvulsive therapy for treatment-resistant depression: a longitudinal neuroimaging study

Recent research suggests that neuroplastic and neuroinflammatory changes may account for the mode of action of electroconvulsive therapy (ECT), although extant data do not allow for a clear disambiguation between these two hypotheses. Multimodal neuroimaging approaches (for example, combining structural and metabolic information) may help in clarifying this issue. Here we aimed to assess longitudinal changes in (i) regional gray matter (GM) volumes and (ii) hippocampal metabolite concentrations throughout an acute course of bitemporal ECT, as well as (iii) to determine the association between imaging changes and clinical improvement. We assessed 12 patients with treatment-resistant depression (TRD) at four time points (pre-treatment, after the first ECT session, after the ninth ECT session and 15 days after ECT course completion) and 10 healthy participants at two time points, 5 weeks apart. Patients with TRD showed bilateral medial temporal lobe (MTL) and perigenual anterior cingulate cortex volume increases. Left MTL volume increase was associated with (i) a hippocampal N-acetylaspartate concentration decrease, (ii) a hippocampal Glutamate+Glutamine concentration increase and (iii) significant clinical improvement. The observed findings are, in part, compatible with both neuroplastic and neuroinflammatory changes induced by ECT. We postulate that such phenomena may be interrelated, therefore reconciling the neuroplasticity and neuroinflammatory hypotheses of ECT action.