Metabolites In Hippocampus Research Articles

Metabolomics reveals hippocampal metabolic fluctuations of postoperative fatigue syndrome and anti-fatigue effect of Carthamus tinctorius L extract in rat model.

Postoperative fatigue syndrome (POFS) is a common clinical complication followed by almost every major abdominal surgery. There is not a full explanation to the etiology of POFS, especially its central mechanism. Carthamus tinctorius L is a classic traditional Chinese medicine (TCM) which could exert the anti-fatigue effect on POFS. However, its mechanism is still lacking. Here, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOFMS) based metabonomic approach was used to characterize hippocampal metabolic fluctuations of POFS in a rat model induced by partial hepatectomy (PHx), and to evaluate the anti-fatigue effect of Carthamus tinctorius L extract (CTLE). With partial least-squares discriminant analysis for classification and selection of biomarkers, fifteen hippocampal metabolites related to POFS were identified, primarily involving alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine degradation, purine metabolism, phenylalanine metabolism, tryptophan metabolism, phospholipid metabolism and fatty acid metabolism. With these altered metabolic pathways as possible drug targets, we systematically analyzed the protective effect of CTLE, which showed that CTLE could provide anti-fatigue effect on POFS through partially regulating the perturbed metabolic pathways. This study indicated that UHPLC-Q-TOFMS-based metabolomics provided a powerful tool to reveal hippocampal metabolic fluctuations of POFS and study the mechanism of TCM. This article is protected by copyright. All rights reserved.

A Critical Proton MR Spectroscopy Marker of Alzheimer’s Disease Early Neurodegenerative Change: Low Hippocampal NAA/Cr Ratio Impacts APOE ɛ4 Mexico City Children and Their Parents

Severe air pollution exposures produce systemic, respiratory, myocardial, and brain inflammation and Alzheimer's disease (AD) hallmarks in clinically healthy children. We tested whether hippocampal metabolite ratios are associated with contrasting levels of air pollution, APOE, and body mass index (BMI) in paired healthy children and one parent sharing the same APOE alleles. We used 1H-MRS to interrogate bilateral hippocampal single-voxel in 57 children (12.45 ± 3.4 years) and their 48 parents (37.5 ± 6.78 years) from a low pollution city versus Mexico City (MC). NAA/Cr, Cho/Cr, and mI/Cr metabolite ratios were analyzed. The right hippocampus NAA/Cr ratio was significantly different between cohorts (p = 0.007). The NAA/Cr ratio in right hippocampus in controls versus APOE ɛ4 MC children and in left hippocampus in MC APOE ɛ4 parents versus their children was significantly different after adjusting for age, gender, and BMI (p = 0.027 and 0.01, respectively). The NAA/Cr ratio is considered reflective of neuronal density/functional integrity/loss of synapses/higher pTau burden, thus a significant decrease in hippocampal NAA/Cr ratios may constitute a spectral marker of early neurodegeneration in young urbanites. Decreases in NAA/Cr correlate well with cognitive function, behavioral symptoms, and dementia severity; thus, since the progression of AD starts decades before clinical diagnosis, our findings support the hypothesis that under chronic exposures to fine particulate matter and ozone above the standards, neurodegenerative processes start in childhood and APOE ɛ4 carriers are at higher risk. Gene and environmental factors are critical in the development of AD and the identification and neuroprotection of young urbanites at high risk must become a public health priority.

Does Long-Term High Fat Diet Always Lead to Smaller Hippocampi Volumes, Metabolite Concentrations, and Worse Learning and Memory? A Magnetic Resonance and Behavioral Study in Wistar Rats.

BackgroundObesity is a worldwide epidemic with more than 600 million affected individuals. Human studies have demonstrated some alterations in brains of otherwise healthy obese individuals and elevated risk of neurodegenerative disease of old age; these studies have also pointed to slightly diminished memory and executive functions among healthy obese individuals. Similar findings were obtained in animal models of obesity induced by high fat diet. On the other hand, low carbohydrate high fat diets are currently promoted for losing weight (e.g., Atkin’s style diets). However, the long-term effects of such diets are not known. Additionally, high fat diets leading to (mild) ketonemia were shown to improve brain function in elderly humans and in some animal models.AimTo evaluate the hypothesis that long-term use of a high fat diet was associated with decreases in spatial memory, smaller hippocampi and hippocampi metabolite concentrations in Wistar rats.MethodsTwenty five male Wistar rats were put on high fat diet (HFD; 60% calories from fat, 30% from carbohydrates) on their 55th day of life, while 25 control male rats (CONs) remained on chow. Adequate levels of essential nutrients were provided. Both groups underwent memory tests in 8-arm radial maze at 3rd, 6th, 9th, and 12th month. 1H magnetic resonance spectroscopy was employed to measure concentrations of tNAA (marker of neuronal integrity) at one month and one year, whereas MRI was used to evaluate hippocampal volumes.ResultsObese rats (OBRs) consumed similar amount of calories as CONs, but less proteins. However, their protein intake was within recommended amounts. Throughout the experiment OBRs had statistically higher concentrations of blood ketone bodies than CONs, but still within normal values. At post-mortem assessment, OBRs had 38% larger fat deposits than CONs (p<0.05), as evaluated by volume of epididymis fat, an acknowledged marker of fat deposits in rats. Contrary to our expectations, OBRs had better scores of memory behavioral tasks than CONs throughout the experiment. At one year, their hippocampi were by 2.6% larger than in CONs (p = 0.05), whereas concentration of tNAA was 9.8% higher (p = 0.014).ConclusionLong-term HFD in our study resulted in better memory, larger hippocampal volumes, as well as higher hippocampal metabolite concentrations, possibly due to increased levels of blood ketone bodies. The results should be interpreted with caution, as results from animal models do not necessarily directly translate in human condition.

Volume, metabolites and neuroinflammation of the hippocampus in bipolar disorder – A combined magnetic resonance imaging and positron emission tomography study

BackgroundThe hippocampus is one of the brain regions that is involved in several pathophysiological theories about bipolar disorder (BD), such as the neuroinflammation theory and the corticolimbic metabolic dysregulation theory. We compared hippocampal volume and hippocampal metabolites in bipolar I disorder (BD-I) patients versus healthy controls (HCs) with magnetic resonance imaging (MRI) and spectroscopy (MRS). We post hoc investigated whether hippocampal volume and hippocampal metabolites were associated with microglial activation and explored if potential illness modifying factors affected these hippocampal measurements and whether these were associated with experienced mood and functioning. Materials and methodsTwenty-two BD-I patients and twenty-four HCs were included in the analyses. All subjects underwent psychiatric interviews as well as an MRI scan, including a T1 scan and PRESS magnetic resonance spectroscopy (MRS). Volumetric analysis was performed with Freesurfer. MRS quantification was performed with LC Model. A subgroup of 14 patients and 11 HCs also underwent a successful [11C]-(R)-PK11195 neuroinflammation positron emission tomography scan. ResultsIn contrast to our hypothesis, hippocampal volumes were not decreased in patients compared to HC after correcting for individual whole-brain volume variations. We demonstrated decreased N-acetylaspartate (NAA)+N-acetyl-aspartyl-glutamate (NAAG) and creatine (Cr)+phosphocreatine (PCr) concentrations in the left hippocampus. In the explorative analyses in the left hippocampus we identified positive associations between microglial activation and the NAA+NAAG concentration, between alcohol use and NAA+NAAG concentration, between microglial activation and the depression score and a negative relation between Cr+PCr concentration and experienced occupational disability. Duration of illness associated positively with volume bilaterally. ConclusionCompared to HCs, the decreased NAA+NAAG concentration in the left hippocampus of BD-I patients suggests a decreased neuronal integrity in this region. In addition we found a positive relation between microglial activation and neuronal integrity in vivo, corresponding to a differentiated microglial function where some microglia induce apoptosis while others stimulate neurogenesis.

NMR-Based Metabolic Profiling Reveals Neurochemical Alterations in the Brain of Rats Treated with Sorafenib.

Sorafenib, an active multi-kinase inhibitor, has been widely used as a chemotherapy drug to treat advanced clear-cell renal cell carcinoma patients. In spite of the relative safety, sorafenib has been shown to exert a negative impact on cognitive functioning in cancer patients, specifically on learning and memory; however, the underlying mechanism remains unclear. In this study, an NMR-based metabolomics approach was applied to investigate the neurochemical effects of sorafenib in rats. Male rats were once daily administrated with 120 mg/kg sorafenib by gavage for 3, 7, and 28 days, respectively. NMR-based metabolomics coupled with histopathology examinations for hippocampus, prefrontal cortex (PFC), and striatum were performed. The (1)H NMR spectra data were analyzed by using multivariate pattern recognition techniques to show the time-dependent biochemical variations induced by sorafenib. Excellent separation was obtained and distinguishing metabolites were observed between sorafenib-treated and control rats. A total of 36 differential metabolites in hippocampus of rats treated with sorafenib were identified, some of which were significantly changed. Furthermore, these modified metabolites mainly reflected the disturbances in neurotransmitters, energy metabolism, membrane, and amino acids. However, only a few metabolites in PFC and striatum were altered by sorafenib. Additionally, no apparent histological changes in these three brain regions were observed in sorafenib-treated rats. Together, our findings demonstrate the disturbed metabonomics pathways, especially, in hippocampus, which may underlie the sorafenib-induced cognitive deficits in patients. This work also shows the advantage of NMR-based metabolomics over traditional approach on the study of biochemical effects of drugs.

Associations of hippocampal metabolism and regional brain grey matter in neuroleptic-naïve ultra-high-risk subjects and first-episode schizophrenia

Hippocampal pathology has been shown to be central to the pathophysiology of schizophrenia and a putative risk marker for developing psychosis. We applied both 1H MRS (proton magnetic resonance spectroscopy) at 3Tesla and voxel-based morphometry (VBM) of high-resolution brain structural images in order to study the association of the metabolites glutamate (Glu) and N-acetyl-aspartate (NAA) in the hippocampus with whole-brain morphometry in 31 persons at ultra-high-risk for psychosis (UHR), 18 first-episode schizophrenia patients (Sz), and 42 healthy controls (all subjects being neuroleptic-naïve). Significantly diverging associations emerged for UHR subjects hippocampal glutamate showed positive correlation with the left superior frontal cortex, not seen in Sz or controls, while in first-episode schizophrenia patients a negative correlation was significant between glutamate and a left prefrontal area. For NAA, we observed different associations for left prefrontal and caudate clusters bilaterally for both high-risk and first-episode schizophrenia subjects, diverging from the pattern seen in healthy subjects. Our results suggest that associations of hippocampal metabolites in key areas of schizophrenia might vary due to liability to or onset of the disorder.

Effect of Electro-Acupuncture on Behavioral Changes,Aβ and LRP1 level in Cortex of APP/PS1 Transgenic Mice

Purpose: To observe the effects of EA on the expression of PS1protein level inhippocampusof SAMP8mice. Investigating themechanismof EA in therapeutic intervention of Alzheimer Disease (AD). Methods: Ten male SAMR1 mice as the Normal control group. Twenty male SAMP8 mice were randomly divided into Model group and EA group (n=10 in each group). EAwas stimulated at Baihui (GV20) andYintang (GV29) for 20min once a day (2V, 1mA). After 15 days, learning and memorizing abilities of mice were detected through Morris water maze. Observe the morphologic changes of PS1 and related metabolites in hippocampus through immunohistochemistry. Detecting PS1 level in hippocampus through Western blot method. Results: 1) Each group showed a significant difference in latency time in different days. 2) Compared with normal control group, Model group showed an increasing latency time and a decreasing swimming time to passing through the platform and quadrants (P < 0.05, P < 0.01), while EA group showed an obvious decreasing latency time (P<0.05, P < 0.01) and an increasing swimming time (P<0.01). 3) Immunohistochemical detection showedmice in EA group had a significant reduction in the expression of PS1 level in hippocampuswhile compared with theModel group. 4) Findings ofWestern blot revealed that compared with Model group, mice in Normal control group and EA group both had a reduction of PS1 content in hippocampus (P<0.05). Conclusion: EA could have a certain effect to improve the learning andmemorizing abilities of SAMP8mice and, to some extent, may be able to help prevent AD. However, the regulating effect of EA on PS1 level is much greater, this outcome could be seen as one of the mechanisms of treating AD. Contact: Jin Cao, jade cao@yeah.net

Effects of Electro-acupuncture (EA) on the Behavioral changes and presenilian-1 (PS1) level in hippocampus of SAMP8 mice

Purpose: To observe the effects of EA on the expression of PS1protein level inhippocampusof SAMP8mice. Investigating themechanismof EA in therapeutic intervention of Alzheimer Disease (AD). Methods: Ten male SAMR1 mice as the Normal control group. Twenty male SAMP8 mice were randomly divided into Model group and EA group (n=10 in each group). EAwas stimulated at Baihui (GV20) andYintang (GV29) for 20min once a day (2V, 1mA). After 15 days, learning and memorizing abilities of mice were detected through Morris water maze. Observe the morphologic changes of PS1 and related metabolites in hippocampus through immunohistochemistry. Detecting PS1 level in hippocampus through Western blot method. Results: 1) Each group showed a significant difference in latency time in different days. 2) Compared with normal control group, Model group showed an increasing latency time and a decreasing swimming time to passing through the platform and quadrants (P < 0.05, P < 0.01), while EA group showed an obvious decreasing latency time (P<0.05, P < 0.01) and an increasing swimming time (P<0.01). 3) Immunohistochemical detection showedmice in EA group had a significant reduction in the expression of PS1 level in hippocampuswhile compared with theModel group. 4) Findings ofWestern blot revealed that compared with Model group, mice in Normal control group and EA group both had a reduction of PS1 content in hippocampus (P<0.05). Conclusion: EA could have a certain effect to improve the learning andmemorizing abilities of SAMP8mice and, to some extent, may be able to help prevent AD. However, the regulating effect of EA on PS1 level is much greater, this outcome could be seen as one of the mechanisms of treating AD. Contact: Jin Cao, jade cao@yeah.net

Neurodevelopment in Piglets is Influenced by Perinatal Choline Status as Evidenced by Magnetic Resonance Imaging

Adequate choline supply during the perinatal period is critical for proper brain formation when robust neurogenesis and neuronal maturation are occurring. To examine the impact of perinatal choline on neurodevelopment, sows (n = 8) were fed a choline deficient (CD) or sufficient (CS) diet during the last 65 d of the 114 d gestation period. At 2 d of age, piglets from sows within each prenatal treatment group were stratified into postnatal treatment groups and provided either a CD or CS milk replacer, resulting in a 2 x 2 factorial arrangement (N = 32, n = 6‐9 piglets treatment). At 30 d of age, piglets underwent magnetic resonance imaging procedures to examine brain morphology and metabolite concentrations. Fractional anisotropy (FA) values, obtained from diffusion tensor imaging, revealed an interaction (P = 0.02) between prenatal and postnatal treatments in the right hippocampus. Pigs of a continuous perinatal CD status exhibited lower FA values than CS/CD and CD/CS piglets, highlighting the importance of perinatal choline supplementation for white matter development. Voxel‐based morphometry illustrated differences (P 蠄 0.01) between prenatal choline status in grey and white matter volumes of cortical, cerebellar, and hippocampal regions. Volumes of whole brain, cortical, and subcortical regions were greater (P 蠄 0.05) in prenatal CS compared with prenatal CD piglets. Hippocampal metabolites, assessed using single‐voxel spectroscopy, indicated a decrease (P &lt; 0.01) in glycerophosphocholine + phosphocholine concentration in postnatal CD piglets and a decrease (P = 0.01) in glutamate + glutamine concentration in prenatal CD piglets. These results suggest that adequate dietary choline provided prenatally or postnatally, promotes neuronal growth and maturation.

Hippocampal Metabolites Correlate with Neuroimaging Outcomes in the Piglet

By combining magnetic resonance imaging (MRI) and metabolomic profiling techniques, the objective of this study was to elucidate relationships between brain structure and hippocampal metabolites in the piglet. Two-day-old, vaginally-delivered male piglets (n=24) were artificially reared using standardized procedures and feeding a custom milk replacer formulated to meet piglet nutrient requirements. At 30 d of age, piglets underwent MRI procedures, and brain tissue was collected 24 h post-imaging for metabolomic and lipodomic profiling of hippocampal tissue. Analysis of MRI data in 19 brain regions yielded volumetric estimates as well as microstructural details measured by diffusion tensor fractional anisotropy (FA), and radial (RD), axial (AD), and mean (MD) diffusivities, which provide directional characterization of water movement within axons. Comparison of fatty acids in n-3, n-6, and n-9 categories with MRI measures yielded correlations (P < 0.05) in 150 of 2726, 162 of 3596, and 129 of 2494 possible outcomes, respectively. Neuroimaging outcomes that were highly correlative across fatty acid categories included MD, RD, and AD in the internal capsule and right hippocampus, suggesting ongoing myelination in the piglet brain. Nervonic acid, a fatty acid known to be prevalent at peak myelination, was correlated with 26 of 58 total outcomes, further supporting the link between metabolism and neurodevelopment. In conclusion, significant correlations between metabolic and structural outcomes in the neonatal piglet brain emphasize targets whereby dietary manipulation may alter neurodevelopmental patterns. Supported by Mead Johnson Nutrition.

Decreases in Short Term Memory, IQ, and Altered Brain Metabolic Ratios in Urban Apolipoprotein ε4 Children Exposed to Air Pollution.

Children's urban air pollution exposures result in systemic and brain inflammation and the early hallmarks of Alzheimer's disease (AD). The apolipoprotein E (APOE) ε4 allele is the most prevalent genetic risk for AD. We assessed whether APOE in healthy children modulates cognition, olfaction, and metabolic brain indices. The Wechsler Intelligence Scale for Children (WISC-R) and the University of Pennsylvania Smell Identification Test were administered to 50 Mexico City Metropolitan Area children (13.4 ± 4.8 years, 28 APOE ε3 and 22 APOE ε4). N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, and NAA/mI were calculated using proton magnetic resonance spectroscopy in the white matter of the frontal and parietal lobes, hippocampus, and pons. APOE ε4 versus ε3 children had a reduced NAA/Cr ratio in the right frontal white matter and decrements on attention, short-term memory, and below-average scores in Verbal and Full Scale IQ (>10 points). APOE modulated the group effects between WISC-R and left frontal and parietal white matter, and hippocampus metabolites. Soap was the predominantly failed odor in urban children and, in APOE ε4 versus ε3 carriers, strongly correlated with left hippocampus mI/Cr ratio. APOE modulates responses to air pollution in the developing brain. APOE ε4 carriers could have a higher risk of developing early AD if they reside in a polluted environment. APOE, cognition, and olfaction testing and targeted magnetic resonance spectroscopy may contribute to the assessment of urban children and their results could provide new paths toward the unprecedented opportunity for early neuroprotection and AD prevention.

Time-dependent metabolomic profiling of Ketamine drug action reveals hippocampal pathway alterations and biomarker candidates.

Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, has fast-acting antidepressant activities and is used for major depressive disorder (MDD) patients who show treatment resistance towards drugs of the selective serotonin reuptake inhibitor (SSRI) type. In order to better understand Ketamine's mode of action, a prerequisite for improved drug development efforts, a detailed understanding of the molecular events elicited by the drug is mandatory. In the present study we have carried out a time-dependent hippocampal metabolite profiling analysis of mice treated with Ketamine. After a single injection of Ketamine, our metabolomics data indicate time-dependent metabolite level alterations starting already after 2 h reflecting the fast antidepressant effect of the drug. In silico pathway analyses revealed that several hippocampal pathways including glycolysis/gluconeogenesis, pentose phosphate pathway and citrate cycle are affected, apparent by changes not only in metabolite levels but also connected metabolite level ratios. The results show that a single injection of Ketamine has an impact on the major energy metabolism pathways. Furthermore, seven of the identified metabolites qualify as biomarkers for the Ketamine drug response.

Short call abstracts.

Short call abstracts.

Metabolic Profiling of Dividing Cells in Live Rodent Brain by Proton Magnetic Resonance Spectroscopy (1HMRS) and LCModel Analysis

RationaleDividing cells can be detected in the live brain by positron emission tomography or optical imaging. Here we apply proton magnetic resonance spectroscopy (1HMRS) and a widely used spectral fitting algorithm to characterize the effect of increased neurogenesis after electroconvulsive shock in the live rodent brain via spectral signatures representing mobile lipids resonating at ∼1.30 ppm. In addition, we also apply the same 1HMRS methodology to metabolically profile glioblastomas with actively dividing cells growing in RCAS-PDGF mice.Methods 1HMRS metabolic profiles were acquired on a 9.4T MRI instrument in combination with LCModel spectral analysis of: 1) rat brains before and after ECS or sham treatments and 2) RCAS-PDGF mice with glioblastomas and wild-type controls. Quantified 1HMRS data were compared to post-mortem histology.ResultsDividing cells in the rat hippocampus increased ∼3-fold after ECS compared to sham treatment. Quantification of hippocampal metabolites revealed significant decreases in N-acetyl-aspartate but no evidence of an elevated signal at ∼1.3 ppm (Lip13a+Lip13b) in the ECS compared to the sham group. In RCAS-PDGF mice a high density (22%) of dividing cells characterized glioblastomas. Nile Red staining revealed a small fraction (3%) of dying cells with intracellular lipid droplets in the tumors of RCAS-PDGF mice. Concentrations of NAA were lower, whereas lactate and Lip13a+Lip13b were found to be significantly higher in glioblastomas of RCAS-PDGF mice, when compared to normal brain tissue in the control mice.ConclusionsMetabolic profiling using 1HMRS in combination with LCModel analysis did not reveal correlation between Lip13a+Lip13b spectral signatures and an increase in neurogenesis in adult rat hippocampus after ECS. However, increases in Lip13a+Lip13b were evident in glioblastomas suggesting that a higher density of actively dividing cells and/or the presence of lipid droplets is necessary for LCModel to reveal mobile lipids.

Aspartic acid in the hippocampus: a biomarker for postoperative cognitive dysfunction.

This study established an aged rat model of cognitive dysfunction using anesthesia with 2% isoflurane and 80% oxygen for 2 hours. Twenty-four hours later, Y-maze test results showed that isoflurane significantly impaired cognitive function in aged rats. Gas chromatography-mass spectrometry results showed that isoflurane also significantly increased the levels of N,N-diethylacetamide, n-ethylacetamide, aspartic acid, malic acid and arabinonic acid in the hippocampus of isoflurane-treated rats. Moreover, aspartic acid, N,N-diethylacetamide, n-ethylacetamide and malic acid concentration was positively correlated with the degree of cognitive dysfunction in the isoflurane-treated rats. It is evident that hippocampal metabolite changes are involved in the formation of cognitive dysfunction after isoflurane anesthesia. To further verify these results, this study cultured hippocampal neurons in vitro, which were then treated with aspartic acid (100 μmol/L). Results suggested that aspartic acid concentration in the hippocampus may be a biomarker for predicting the occurrence and disease progress of cognitive dysfunction.

Increased ratio of glutamate/glutamine to creatine in the right hippocampus contributes to depressive symptoms in patients with epilepsy

PurposeOur study aimed to investigate whether the glutamatergic system in the hippocampus is correlated with depressive symptoms in patients with epilepsy. MethodsFifty patients with epilepsy were recruited and divided into three groups on the basis of their Hamilton Depression Rating Scale (HAMD) scores. Single-voxel proton magnetic resonance spectroscopy (1H-MRS) was carried out. Pearson correlation analysis and multiple linear regression analysis were performed to investigate any correlation between the variables of hippocampal metabolites and HAMD scores. ResultsProton magnetic resonance spectroscopy analysis showed that the ratio of glutamate/glutamine to creatine (Glx/Cr) in the right hippocampus was significantly increased in patients with moderate depression and correlated positively with HAMD scores. Multiple linear regression analysis showed that the ratio of Glx/Cr in the right hippocampus was an independent risk factor relating to depressive symptoms in patients with epilepsy. ConclusionA disturbance of the hippocampal glutamatergic system may be involved in the pathogenesis of depression in epilepsy.

A Longitudinal Study of Cognition, Proton MR Spectroscopy and Synaptic and Neuronal Pathology in Aging Wild-type and AβPPswe-PS1dE9 Mice

Proton magnetic resonance spectroscopy (1H MRS) is a valuable tool in Alzheimer’s disease research, investigating the functional integrity of the brain. The present longitudinal study set out to characterize the neurochemical profile of the hippocampus, measured by single voxel 1H MRS at 7 Tesla, in the brains of AβPPSswe-PS1dE9 and wild-type mice at 8 and 12 months of age. Furthermore, we wanted to determine whether alterations in hippocampal metabolite levels coincided with behavioral changes, cognitive decline and neuropathological features, to gain a better understanding of the underlying neurodegenerative processes. Moreover, correlation analyses were performed in the 12-month-old AβPP-PS1 animals with the hippocampal amyloid-β deposition, TBS-T soluble Aβ levels and high-molecular weight Aβ aggregate levels to gain a better understanding of the possible involvement of Aβ in neurochemical and behavioral changes, cognitive decline and neuropathological features in AβPP-PS1 transgenic mice. Our results show that at 8 months of age AβPPswe-PS1dE9 mice display behavioral and cognitive changes compared to age-matched wild-type mice, as determined in the open field and the (reverse) Morris water maze. However, there were no variations in hippocampal metabolite levels at this age. AβPP-PS1 mice at 12 months of age display more severe behavioral and cognitive impairment, which coincided with alterations in hippocampal metabolite levels that suggest reduced neuronal integrity. Furthermore, correlation analyses suggest a possible role of Aβ in inflammatory processes, synaptic dysfunction and impaired neurogenesis.

Longitudinal in vivo developmental changes of metabolites in the hippocampus of Fmr1 knockout mice

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is studied in the Fmr1 knockout (KO) mouse, which models both the anatomical and behavioral changes observed in FXS patients. In vitro studies have shown many alterations in synaptic plasticity and increased density of immature dendritic spines in the hippocampus, a region involved in learning and memory. In this study, magnetic resonance imaging (MRI) and (1) H magnetic resonance spectroscopy (MRS) were used to determine in vivo longitudinal changes in volume and metabolites in the hippocampus during the critical period of early myelination and synaptogenesis at post-natal days (PND) 18, 21, and 30 in Fmr1 KO mice compared with wild-type (WT) controls. MRI demonstrated an increase in volume of the hippocampus in the Fmr1 KO mouse compared with controls. MRS revealed significant developmental changes in the ratios of hippocampal metabolites N-acetylaspartate (NAA), myo-inositol (Ins), and taurine to total creatine (tCr) in Fmr1 KO mice compared with WT controls. Ins was decreased at PND 30, and taurine was increased at all ages studied in Fmr1 KO mice compared with controls. An imbalance of brain metabolites in the hippocampus of Fmr1 KO mice during the critical developmental period of synaptogenesis and early myelination could have long-lasting effects that adversely affect brain development and contribute to ongoing alterations in brain function.

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.

S1‐02‐01: Multiplexed analysis of plasma in Alzheimer's disease

Alzheimer's disease (AD) is the most common form of dementia. Worldwide 28 million dementia suffers have yet to receive a diagnosis - at least partly due to a lack of a non-invasive diagnostic test. The development and use of potential disease modifying agents is also limited by the absence of fully approved biomarkers; especially those that can be used on repeated occasions and have predictive value. We set out to discover peripheral plasma-based biomarkers using two-dimensional gel electrophoresis in combination with mass spectrometry (MS). We showed differential expression of two proteins; complement factor H (CFH) and alpha-2-microglobulin (A2M) in a case versus control study. Subsequently, using 1 H-magnetic resonance spectroscopy, we have also demonstrated that CFH and A2M are associated with hippocampal metabolite abnormalities in AD. There is considerable heterogeneity in disease progression in AD. In order to address complexity of the condition, we then sought to discoverer markers correlating with other measures or endophenotypes of disease. These included neuroimaging and cognitive measures. We identified an association of plasma clusterin concentration with brain atrophy, disease severity and rate of progression. We further related peripheral clusterin with another distinct endophenotype of AD pathology, specifically in vivo brain amyloid burden, in both man using 11 C Pittsburgh Compound B PET imaging, and in a transgenic mouse model of AD over expressing APP and presenilin (PS)1 mutations 3. Furthermore, to address disease progression we stratified our AD subjects into fast and slow decliners and identified two novel markers; gelsolin and transtyhretin. I will review here the current approaches we have undertaken to multiplex our discovery biomarkers to achieve sensitive and robust measurements. Since our first studies, multiple analytes have now been identified and the advent of multiplexing has made validation studies easier. We have therefore adopted two approaches; Luminex xMAP and SRM (Single reaction monitoring) mass spectrometry techniques to validate our findings. Our findings suggest that plasma-based markers have the potential to be a companion diagnostic tool. Our aim is to combine plasma based biomarkers with clinical, imaging and genomic measures, to achieve a sensitive and specific multimodal Alzheimer's disease biomarker panel.