Glutamatergic Metabolites and Gray Matter Losses in Schizophrenia: A Longitudinal Study Using In Vivo Proton Magnetic Resonance Spectroscopy

Approximately one in hundred people suffer from schizophrenia. Current medications partially improve the symptoms. There is no cure. Glutamate, an excitatory neurotransmitter, is a possible cause of the schizophrenia symptoms. Excessive glutamate release eventually leads to neurodegeneration. Longitudinal studies are necessary to observe the neurodegenerative process. Seventeen schizophrenia patients and 17 healthy volunteers underwent proton magnetic resonance spectroscopy (MRS) and imaging to measure neurochemical and structural changes in vivo. Metabolite levels were measured from a 1.5cm3 voxel in the anterior cingulate and thalamus using the stimulated echo acquisition mode sequence. Gray matter (GM) was assessed with voxel-based morphometry and ANALYZE. Total glutamatergic metabolite (tGL), N-acetylaspartate (NAA), and GM were significantly decreased in schizophrenia over 80 months. Reduced tGL and NAA levels were significantly correlated with GM changes. tGL loss was negatively correlated with social functioning. Significantly decreased tGL levels were possibly associated with GM loss in the spectroscopy voxel. Metabolite signal-to-noise ratio, but not quantification, was decreased as a function of MR system age. These findings demonstrate the feasibility of long-term MRS studies and implications for the pathophysiology of schizophrenia. tGL and GM losses were consistent with neurodegeneration but the effects of an early neurodevelopmental lesion or the effects of chronic medication cannot be ruled out. Structural and metabolite changes in these patients implicate glutamate as a possible target of medication in this disorder. The association between tGL loss and social functioning suggests it might be possible to arrest deterioration with pharmaceuticals that target glutamate

1H- und 31P-Magnetresonanzspektroskopie bei Ultra-High-Risk-Patienten für psychotische Störungen: Alterationen von glutamaterger Neurotransmission, Membranlipid- und Energiemetabolismus

Bei fast allen Individuen, welche später eine psychotische Störung entwickeln, finden sich bereits Jahre vor dem eigentlichen Ausbruch abgeschwächte Krankheitssymptome sowie meist eine deutliche Verschlechterung des allgemeinen Funktionsniveaus. Die Definition eines Hochrisikostadiums bezüglich der Entwicklung einer psychotischen Erkrankung (ultra-high-risk, UHR) zielte darauf ab, Individuen mit erkennbarer Prodromalsymptomatik möglichst frühzeitig zu identifizieren, im Verlauf zu beobachten und ggf. einer geeigneten Präventions- oder Therapiemaßnahme zuzuführen. Mit Hilfe der Magnetresonanzspektroskopie (MRS) und dem ihr inhärenten Prinzip des sog. chemical shifts gelingt die nicht-invasive in-vivo Analyse verschiedener zerebraler Metabolite. Mittels Protonen (1H)-MRS können so u.a. Rückschlüsse auf die glutamaterge Neurotransmission und mittels Phosphor (31P)-MRS auf den Energie- und strukturbedeutsamen Membranlipid-Stoffwechsel in umschriebenen Lokalisationen des Gehirns gezogen werden. Für diese Arbeit wurden 69 UHR-Patienten (Alter: 26,2 ± 6,2 Jahre) und 61 gesunde Kontrollen (Alter: 25,2 ± 4,8 J.) einer in gleicher Sitzung durchgeführten kombinierten 1H/31P -MRS unterzogen. Der Großteil der Patienten war zum Messzeitpunkt frei von antipsychotischer (neuroleptischer) Medikation. Es wurden insgesamt elf Metabolite untersucht, beidseits im Bereich des dorsolateralen und dorsomedialen präfrontalen Kortex, des anterioren Cingulums, des Thalamus sowie des Hippocampus. Die statistische Auswertung erfolgte u.a. mittels univariater ANOVA bzw. Kruskal-Wallis-Test. Zusammenfassend finden sich bei UHR-Patienten in mehreren Hirnregionen Hinweise für einen verminderten Energieumsatz, was als Hinweis auf ein lokales Funktionsdefizit im Sinne einer Hypofunktion interpretiert werden kann. Durch die zum Teil in gleicher Lokalisation nachweisbare Alteration von Metaboliten des Membran-Umsatzes können somit auch bei UHR-Patienten pathophysiologische Annahmen der ursprünglich für Schizophrenie eingebrachten Membranlipidhypothese partiell untermauert werden. Metabolitenabweichungen, die helfen könnten diejenigen UHR-Patienten zu identifizieren, bei denen eine psychotische Konversion hochwahrscheinlich ist, fanden sich nicht

Der Einfluss glutamaterger Regulationsstörungen auf den Membranlipid- und Energiemetabolismus bei schizophrener Erstmanifestation: eine kombinierte Untersuchung mittels 31P-/1H-MR Spektroskopie bei 3 Tesla

In der vorliegenden Studie wurde erstmals in einer Population schizophrener Patienten sowohl die 31Phosphor-Magnetresonanz-Spektroskopie (31P-MRS) als auch die 1Proton-Magnetresonanz-Spektroskopie (1H-MRS) angewendet. Die 31P-MRS dient der lokalen Bestimmung von Metaboliten des Phospholipid- und Energiestoffwechsels und erlaubt so Aussagen bezüglich membranbezogener Auf- und Abbauprozesse, aber auch Einblicke in den Energiehaushalt der grauen und weißen Substanz. Zusätzlich gibt die 1H-MRS Aufschluss über die Verteilung des Neurotransmitters Glutamat (Glu). Ziel der vorliegenden Arbeit ist es, bei Patienten mit unbehandelter schizophrener Erstmanifestation, Zusammenhänge zwischen einer veränderten glutamatergen Funktion und den vielfach vorbeschriebenen strukturmetabolischen Abweichungen im Gehirn, zu finden

IMAGING SPECIFIC ABSORPTION RATE WITH MR THERMOMETRY USING PARAMAGNETIC LANTHANIDE COMPLEXES AND IN VIVO GABA MR SPECTROSCOPY IN MOVEMENT DISORDERS

Magnetic Resonance Imaging (MRI) is a popular imaging modality due to its ability to provide excellent soft tissue contrast without exposure to ionizing radiation. It can be used for temperature monitoring (thermometry) as well as for assessing the biochemistry in vivo (MRS). This dissertation focuses separately on the development, application and quantitation issues of these two aspects of MRI

Neurobiochemische Alterationen während der ersten Jahre nach psychotischer Erstmanifestation: eine Längsschnittuntersuchung mittels kombinierter 1H- und 31P-Magnetresonanzspektroskopie

Aktuell wird angenommen, dass glutamaterge Dysfunktion sowie ein dysregulierter Energie- und Membranphospholipid-Stoffwechsel eine Schlüsselrolle in der Pathogenese psychotischer Störungen spielen. Mithilfe Magnetresonanzspektroskopie (MRS) untersuchte die vorliegende Arbeit neurobiochemische Alterationen bei Psychosepatienten zum Zeitpunkt (T0) und zwei Jahre (T1) nach psychotischer Erstmanifestation unter naturalistischen Therapiebedingungen. Mittels Kombination von 1H- and 31P- MRS wurden Daten von 29 Neuroleptika-naiven Patienten mit psychotischer Erstmanifestation (FEP) und 27 nach Alter und Geschlecht parallelisierten, Kontrollprobanden erhoben. Untersucht wurden: Glutamat (Glu) und N-Acetylaspartat (NAA) als Marker neuronaler Funktion, Myo-Inositol (mI) als Marker astrozytärer Funktion, Phosphokreatin (PCr) und Adenosintriphosphat als Repräsentanten des Energiemetabolismus sowie Phosphomono- und Phosphodiester (PME, PDE) als Marker des Auf- und Abbaus neuronaler Membranen. Die Psychopathologie wurde mittels SCL-90-R und BPRS-E miterfasst. Die statistische Analyse gruppenabhängiger Metabolitwertänderungen im Zeitverlauf erfolgte mittels linear gemischten Modells. Zu T0 zeigten FEP vermindertes NAA, Glu und PME im linken DLPFC und Thalamus, hier begleitet von vermindertem mI. Im rechten Hippocampus fanden sich erhöhte PCr- und verringerte PDE-Spiegel. Die Verlaufsanalyse ergab einen Anstieg von Glu im DLPFC beidseits und im rechten Thalamus sowie von mI im linken DLPFC. PCr zeigte im rechten Hippocampus einen Werteabfall. Das Metabolitmuster zu T0 weist insbesondere auf eine Unterfunktion glutamaterger Neuronen und eine Störung im Membranphospholipid-Metabolismus in fronto-thalamisch-hippocampalen Netzwerken bei psychotischer Erstmanifestation hin. Die Metabolitalterationen zu T1 können als Besserung neuronaler Funktion in diesen Netzwerken gedeutet werden und liegen vermutlich der beobachteten Besserung von Negativsymptomatik und kognitiven Störungen zugrunde

Magnetic Resonance Spectroscopy as applied to epilepsy

Epilepsy is the most common serious disease of the brain. Magnetic Resonance Spectroscopy (MRS) is a novel imaging technique that offers the opportunity for co-localising biochemical information relating to metabolites specific to the study of epilepsy with high resolution MRI. Aims: The work included in this thesis was undertaken with two fundamental aims. The first was to apply a standardised MRS methodology in order to gain reproducible semi-quantitative information about the variation of relevant neuro-metabolites such as gamma amino butyric acid (GABA), glutamate (as glutamate plus glutamine [GLX]), N acetyl aspartate (NAA), myo-inositol (Ins) and creatine plus phosphocreatine (Cr) within epilepsy syndromes or pathological groups. The second main aim was to test a series of hypotheses relating to the regulation of the concentrations of these metabolites in the region of epileptic seizures, immediately following seizures and associated with particular medical and surgical treatment interventions. Methods: Seven experiments were performed in this thesis. In all seven studies the findings in the patient groups were compared against results from an acquired control group made up of healthy volunteers. In the first experiment [3.1] twenty patients with temporal lobe epilepsy, with (10), and without hippocampal sclerosis were studied using multi voxel magnetic resonance spectroscopic imaging (MRSI) sequences in order to examine for differences in the obtained metabolites N acetyl aspartate (NAA), creatine plus phosphocreatine (Cr), choline containing compounds (Cho), GLX and myo-inositol (Ins) across the pathological groups and against a control population. In experiments [3.2], [3.3], [3.4] and [3.6] an MRS protocol that incorporated a double quantum filter acquisition sequence was applied in order to allow measurement of GABA+ (a combined measure of GABA plus homocarnosine) in addition to measurement of the metabolites examined in [3.1]. Studies were performed in the occipital lobes in patients with idiopathic generalised epilepsy (IGE) (n =10) or occipital lobe epilepsy (n = 10) [3.2], in the frontal lobes in patients with IGE (n = 21) and within regions of the MRI visible pathology in patients with large focal malformations of cortical development (MCD, n =10) [3.4]. In the last experiment using this technique patients with hippocampal sclerosis and temporal lobe epilepsy (n = 16) were studied in the ipsilateral and also in the contralateral temporal lobes and following temporal lobe surgery (n = 10) [3.6]. In experiment [3.5] ten patients were examined whilst taking and when not taking sodium valproate in order to further examine for an effect of this medication on the measured metabolite concentrations. In experiment [3.7] ten patients were studied immediately after an epileptic seizure and then again during a subsequent inter-ictal period in order to examine for an influence of the recent seizure on the measured concentrations of the main metabolites. Results: MRSI in the temporal lobes in patients with temporal lobe epilepsy identified low NAA in the anterior hippocampus that was most severe in those patients with hippocampal sclerosis. GLX elevation was a feature in the patients without hippocampal sclerosis. Metabolic abnormality was most marked in the anterior compared to the posterior hippocampal regions. GABA+ levels were elevated in patients with MCD and in the ipsilateral temporal lobe in temporal lobe epilepsy associated with hippocampal sclerosis but levels were not altered in patients with IGE or OLE. GLX was also elevated in MCD in the region of MRI visible abnormality and in IGE patients when measured in the frontal lobes. Low NAA was a feature of TLE and MCD. Patients with IGE showed normal NAA levels in the occipital lobes but reduced frontal lobe concentrations. Cr concentrations were abnormal in the immediate post ictal period but normalised within 120 minutes. NAA was not altered and no significant change in lactate concentrations was observed. Finally sodium valproate treatment was associated with a reduction in the levels of Ins and with unchanged NAA and GLX levels. Main Conclusions: MRS techniques demonstrate metabolite abnormalities in epileptic patients. NAA is the most sensitive metabolite marker of chronic pathology but levels are insensitive to recent seizure history. These findings repeat earlier observations of the usefulness of NAA measurement in the assessment of chronic epilepsy whilst illustrating ongoing uncertainty as to the correct patho-physiological interpretation of reduced NAA levels. Measurable changes in the combined Cr signal are detectable whilst elevated lactate is not reliably observed following brief epileptic seizures at 1.5T. This finding indicates a potential role for MRS in functional activation studies. Malformations of cortical development have abnormal levels of both GABA+ and GLX and MCD sub-types may well demonstrate different metabolite profiles. This finding suggests that MRS could be a useful tool in the MRI classification of MCD and in the pre-surgical assessment of patients with focal malformations. Following successful temporal lobe surgery levels of NAA remain unchanged but NAA/Cr levels appear to normalise in the contralateral temporal lobe. NAA and GLX/NAA levels were altered in the frontal lobes but not in the occipital lobes in Idiopathic Generalised Epilepsy. This finding provides imaging support for frontal lobe dysfunction as a cause or consequence of IGE. Metabolite levels are affected by administered antiepileptic drugs. Sodium valproate reduces the levels of MRS visible Ins levels whilst topiramate and gabapentin appear to be associated with higher GABA+ levels. These findings may be of major importance in the assessment of treatment effect or in the investigation of patients with possible drug resistance. The effect of valproate on Ins levels may become particularly interesting in the light of a growing understanding of the role of astrocyte dysfunction in a range of neurological conditions which include migraine, epilepsy, Alzheimer’s disease, motor neurone disease and in ischaemic lesions

Biochemical correlates of cognition: exploring the relationships between blood, brain and behaviour

This multi-modal investigation aimed to refine analytic tools including proton magnetic resonance spectroscopy (1H-MRS) and fatty acid gas chromatography-mass spectrometry (GC-MS) analysis, for use with adult and paediatric populations, to investigate potential biochemical underpinnings of cognition (Chapter 1). Essential fatty acids (EFAs) are vital for the normal development and function of neural cells. There is increasing evidence of behavioural impairments arising from dietary deprivation of EFAs and their long-chain fatty acid metabolites (Chapter 2). Paediatric liver disease was used as a deficiency model to examine the relationships between EFA status and cognitive outcomes. Age-appropriate Wechsler assessments measured Full-scale IQ (FSIQ) and Information Processing Speed (IPS) in clinical and healthy cohorts; GC-MS quantified surrogate markers of EFA status in erythrocyte membranes; and 1H-MRS quantified neurometabolite markers of neuronal viability and function in cortical tissue (Chapter 3). Post-transplant children with early-onset liver disease demonstrated specific deficits in IPS compared to age-matched acute liver failure transplant patients and sibling controls, suggesting that the time-course of the illness is a key factor (Chapter 4). No signs of EFA deficiency were observed in the clinical cohort, suggesting that EFA metabolism was not significantly impacted by liver disease. A strong, negative correlation was observed between omega-6 fatty acids and FSIQ, independent of disease diagnosis (Chapter 5). In a study of healthy adults, effect sizes for the relationship between 1H-MRS- detectable neurometabolites and cognition fell within the range of previous work, but were not statistically significant. Based on these findings, recommendations are made emphasising the need for hypothesis-driven enquiry and greater subtlety of data analysis (Chapter 6). Consistency of metabolite values between paediatric clinical cohorts and controls indicate normal neurodevelopment, but the lack of normative, age-matched data makes it difficult to assess the true strength of liver disease-associated metabolite changes (Chapter 7). Converging methods offer a challenging but promising and novel approach to exploring brain-behaviour relationships from micro- to macroscopic levels of analysis (Chapter 8)

Brain development in fetal ventriculomegaly

Introduction Fetal ventriculomegaly is the most common detectable central nervous system abnormality affecting 1% of fetuses and is associated with abnormal neurodevelopment in childhood. Neurodevelopmental outcome is partially predictable by the 2D size of the ventricles in the absence of other abnormalities while the aetiology of the dilatation remains unknown. The main aim of this study was to investigate brain development in the presence of isolated ventriculomegaly during fetal and neonatal life. Methods Fetal brain MRI (1.5T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly from 22-38 gestational weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3D reconstructed datasets while cortical maturation was assessed using a detailed cortical scoring system. The metabolic profile of the fetal brain was assessed using magnetic resonance spectroscopy. During neonatal life, volumetric analysis of ventricular and supratentorial brain tissue was performed while white matter microstructure was assessed using Diffusion Tensor Imaging. The neurodevelopmental outcome of these children was evaluated at 1 and 2 years of age. Results Fetuses with isolated ventriculomegaly had significantly increased cortical volumes when compared to controls while cortical maturation of the calcarine sulcus and parieto-occipital fissure was delayed. NAA:Cho, MI:Cho and MI:Cr ratios were lower whilst Cho:Cr ratios were higher in fetuses with ventriculomegaly. Neonates with prenatally diagnosed ventriculomegaly had increased ventricular and supratentorial brain tissue volumes and reduced FA values in the splenium of the corpus callosum, sagittal striatum and corona radiata. At year 2 of age, only 37.5% of the children assessed had a normal neurodevelopment. Conclusions The presence of relative cortical overgrowth, delayed cortical maturation and aberrant white matter development in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language and behavioural deficits in these children

Key clinical benefits of neuroimaging at 7 T

The growing interest in ultra-high field MRI, with more than 35.000 MR examinations already performed at 7 T, is related to improved clinical results with regard to morphological as well as functional and metabolic capabilities. Since the signal-to-noise ratio increases with the field strength of the MR scanner, the most evident application at 7 T is to gain higher spatial resolution in the brain compared to 3 T. Of specific clinical interest for neuro applications is the cerebral cortex at 7 T, for the detection of changes in cortical structure, like the visualization of cortical microinfarcts and cortical plaques in Multiple Sclerosis. In imaging of the hippocampus, even subfields of the internal hippocampal anatomy and pathology may be visualized with excellent spatial resolution. Using Susceptibility Weighted Imaging, the plaque-vessel relationship and iron accumulations in Multiple Sclerosis can be visualized, which may provide a prognostic factor of disease. Vascular imaging is a highly promising field for 7 T which is dealt with in a separate dedicated article in this special issue. The static and dynamic blood oxygenation level-dependent contrast also increases with the field strength, which significantly improves the accuracy of pre-surgical evaluation of vital brain areas before tumor removal. Improvement in acquisition and hardware technology have also resulted in an increasing number of MR spectroscopic imaging studies in patients at 7 T. More recent parallel imaging and short-TR acquisition approaches have overcome the limitations of scan time and spatial resolution, thereby allowing imaging matrix sizes of up to 128×128. The benefits of these acquisition approaches for investigation of brain tumors and Multiple Sclerosis have been shown recently. Together, these possibilities demonstrate the feasibility and advantages of conducting routine diagnostic imaging and clinical research at 7 T