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  • 1
    In: Human Molecular Genetics, Oxford University Press (OUP), Vol. 28, No. 1 ( 2019-01-01), p. 96-104
    Abstract: Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/−12.000 GLS protein sequences from 〉 1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal—but submaximal—GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstrated with magnetic resonance spectroscopic imaging at clinical field strength and subsequently supported at ultra-high field strength. Considering the neurotoxicity of glutamate when present in excess, the strikingly high glutamate concentrations measured in the brain provide an explanation for the developmental delay. Cataract, a known consequence of oxidative stress, was evoked in zebrafish expressing the hypermorphic Ser482Cys-GLS and could be alleviated by inhibition of GLS. The capacity to detoxify reactive oxygen species was reduced upon Ser482Cys-GLS expression, providing an explanation for cataract formation. In conclusion, we describe an inborn error of glutamate metabolism caused by a GLS hyperactivity variant, illustrating the importance of balanced GLS activity.
    Type of Medium: Online Resource
    ISSN: 0964-6906 , 1460-2083
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2019
    detail.hit.zdb_id: 1474816-2
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Wiley ; 2012
    In:  Magnetic Resonance in Medicine Vol. 68, No. 2 ( 2012-08), p. 339-348
    In: Magnetic Resonance in Medicine, Wiley, Vol. 68, No. 2 ( 2012-08), p. 339-348
    Abstract: This study presents quantified levels of phosphorylated metabolites in glandular tissue of human breast using 31 P magnetic resonance spectroscopy at 7 T. We used a homebuilt 1 H/ 31 P radiofrequency coil to obtain artifact‐free 31 P MR spectra of glandular tissue of healthy females by deploying whole breast free induction decay (FID) detection with adiabatic excitation and outer volume suppression. Using progressive saturation, the estimated apparent T 1 relaxation time of 31 P spins of phosphocholine and phosphoethanolamine was 4.4 and 5.7 s, respectively. Quantitative measures for phosphocholine and phosphoethanolamine levels in glandular tissue were established based on MR imaging. We used a 3D 1 H image of the breast to segment the glandular tissue; this was matched to a 3D 31 P image of the B field of the 31 P coil to correct for differences in glandular tissue volume and B 1 inhomogeneity of the 31 P coil. The 31 P MR spectra were calibrated using a phantom with known concentration. Average levels of phosphocholine and phosphoethanolamine in 11 volunteers were 0.84 ± 0.21 mM and 1.18 ± 0.41 mM, respectively. In addition, data of three patients with breast cancer showed higher levels of phosphocholine and phosphoethanolamine compared with healthy volunteers. This may indicate a potential role for the use of 31 P magnetic resonance spectroscopy for characterization, prognosis, and treatment monitoring in breast cancer. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2012
    detail.hit.zdb_id: 1493786-4
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  • 3
    In: Magnetic Resonance in Medicine, Wiley, Vol. 87, No. 2 ( 2022-02), p. 872-883
    Abstract: Current challenges of in vivo CEST imaging include overlapping signals from different pools. The overlap arises from closely resonating pools and/or the broad magnetization transfer contrast (MTC) from macromolecules. This study aimed to evaluate the feasibility of variable delay multipulse (VDMP) CEST to separately assess solute pools with different chemical exchange rates in the human brain in vivo , while mitigating the MTC. Methods VDMP saturation buildup curves were simulated for amines, amides, and relayed nuclear Overhauser effect. VDMP data were acquired from glutamate and bovine serum albumin phantoms, and from six healthy volunteers at 7T. For the in vivo data, MTC removal was performed via a three‐pool Lorentzian fitting. Different B 1 amplitudes and mixing times were used to evaluate CEST pools with different exchange rates. Results The results show the importance of removing MTC when applying VDMP in vivo and the influence of B 1 for distinguishing different pools. Finally, the optimal B 1 and mixing times to effectively saturate slow‐ and fast‐exchanging components are also reported. Slow‐exchanging amides and rNOE components could be distinguished when using B 1 = 1 μT and t mix = 10 ms and 40 ms, respectively. Fast‐exchanging components reached the highest saturation when using a B 1 = 2.8 μT and t mix = 0 ms. Conclusion VDMP is a powerful CEST‐editing tool, exploiting chemical exchange‐rate differences. After MTC removal, it allows separate assessment of slow‐ and fast‐exchanging solute pools in in vivo human brain.
    Type of Medium: Online Resource
    ISSN: 0740-3194 , 1522-2594
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 1493786-4
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  • 4
    In: Human Brain Mapping, Wiley, Vol. 37, No. 9 ( 2016-09), p. 3337-3352
    Abstract: The inhibitory gamma‐aminobutyric acid (GABA) system is involved in the etiology of most psychiatric disorders, including schizophrenia, autism spectrum disorder (ASD) and major depressive disorder (MDD). It is therefore not surprising that proton magnetic resonance spectroscopy ( 1 H‐MRS) is increasingly used to investigate in vivo brain GABA levels. However, integration of the evidence for altered in vivo GABA levels across psychiatric disorders is lacking. We therefore systematically searched the clinical 1 H‐MRS literature and performed a meta‐analysis. A total of 40 studies ( N  = 1,591) in seven different psychiatric disorders were included in the meta‐analysis: MDD ( N  = 437), schizophrenia ( N  = 517), ASD ( N  = 150), bipolar disorder ( N  = 129), panic disorder ( N  = 81), posttraumatic stress disorder (PTSD) ( N  = 104), and attention deficit/hyperactivity disorder (ADHD) ( N  = 173). Brain GABA levels were lower in ASD ( standardized mean difference [SMD] = −0.74, P = 0.001 ) and in depressed MDD patients ( SMD = −0.52, P = 0.005 ), but not in remitted MDD patients ( SMD = −0.24, P = 0.310 ) compared with controls. In schizophrenia this finding did not reach statistical significance ( SMD = −0.23, P = 0.089 ). No significant differences in GABA levels were found in bipolar disorder, panic disorder, PTSD, and ADHD compared with controls. In conclusion, this meta‐analysis provided evidence for lower brain GABA levels in ASD and in depressed (but not remitted) MDD patients compared with healthy controls. Findings in schizophrenia were more equivocal. Even though future 1 H‐MRS studies could greatly benefit from a longitudinal design and consensus on the preferred analytical approach, it is apparent that 1 H‐MRS studies have great potential in advancing our understanding of the role of the GABA system in the pathogenesis of psychiatric disorders. Hum Brain Mapp 37:3337–3352, 2016 . © 2016 Wiley Periodicals, Inc.
    Type of Medium: Online Resource
    ISSN: 1065-9471 , 1097-0193
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 1492703-2
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  • 5
    Online Resource
    Online Resource
    Elsevier BV ; 2013
    In:  European Neuropsychopharmacology Vol. 23, No. 11 ( 2013-11), p. 1484-1490
    In: European Neuropsychopharmacology, Elsevier BV, Vol. 23, No. 11 ( 2013-11), p. 1484-1490
    Type of Medium: Online Resource
    ISSN: 0924-977X
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2013
    detail.hit.zdb_id: 2019305-1
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  • 6
    In: Frontiers in Psychiatry, Frontiers Media SA, Vol. 12 ( 2022-1-21)
    Abstract: Physical exercise affects hippocampal structure and function, but the underlying neural mechanisms and the effects of exercise intensity remain incompletely understood. Therefore, we undertook a comprehensive, multi-modal 3T and 7T MRI randomized controlled trial (Netherlands Trial Register - NL5847) in which we randomized 52 young, non-athletic volunteers to a 12-week low- or high-intensity exercise program. Using state-of-the-art methods, we investigated changes in hippocampal volume, as well as changes in vasculature, neuro-metabolites, and peripheral growth factors as potential underpinnings. Cardiorespiratory fitness improved over time ( p & lt; 0.001), but no interaction with exercise intensity was found ( p = 0.48). Accordingly, we did not observe significant interactions between exercise condition and time on MRI measures (all p & gt; 0.06). However, we found a significant decrease in right hippocampal volume ( p & lt; 0.01), an increase in left hippocampal glutathione ( p & lt; 0.01), and a decrease of left hippocampal cerebral blood volume ( p = 0.01) over time, regardless of exercise condition. Additional exploratory analyses showed that changes in brain-derived neurotrophic factor ( p = 0.01), insulin-like growth-factor ( p = 0.03), and dorsal anterior cingulate cortex N-acetyl-aspartate levels ( p = 0.01) were positively associated with cardiorespiratory fitness changes. Furthermore, a trend toward a positive association of fitness and gray-matter cerebral blood flow ( p = 0.06) was found. Our results do not provide evidence for differential effects between high-intensity (aerobic) and low-intensity (toning) exercise on hippocampal structure and function in young adults. However, we show small but significant effects of exercise on hippocampal volume, neurometabolism and vasculature across exercise conditions. Moreover, our exploratory results suggest that exercise might not specifically only benefit hippocampal structure and function, but rather has a more widespread effect. These findings suggest that, in agreement with previous MRI studies demonstrating moderate to strong effects in elderly and diseased populations, but none to only mild effects in young healthy cohorts, the benefits of exercise on the studied brain measures may be age-dependent and restorative rather than stimulatory. Our study highlights the importance of a multi-modal, whole-brain approach to assess macroscopic and microscopic changes underlying exercise-induced brain changes, to better understand the role of exercise as a potential non-pharmacological intervention.
    Type of Medium: Online Resource
    ISSN: 1664-0640
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2564218-2
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  • 7
    In: Journal of Psychopharmacology, SAGE Publications, Vol. 36, No. 4 ( 2022-04), p. 489-497
    Abstract: Patients with psychotic disorders often show prominent cognitive impairment. Glutamate seems to play a prominent role, but its role in deep gray matter (DGM) regions is unclear. Aims: To evaluate glutamate levels within deep gray matter structures in patients with a psychotic disorder in relation to cognitive functioning, using advanced spectroscopic acquisition, reconstruction, and post-processing techniques. Methods: A 7-Tesla magnetic resonance imaging scanner combined with a lipid suppression coil and subject-specific water suppression pulses was used to acquire high-resolution magnetic resonance spectroscopic imaging data. Tissue fraction correction and registration to a standard brain were performed for group comparison in specifically delineated DGM regions. The brief assessment of cognition in schizophrenia was used to evaluate cognitive status. Results: Average glutamate levels across DGM structures (i.e. caudate, pallidum, putamen, and thalamus) in mostly medicated patients with a psychotic disorder ( n = 16, age = 33, 4 females) were lower compared to healthy controls ( n = 23, age = 24, 7 females; p = 0.005, d = 1.06). Stratified analyses showed lower glutamate levels in the caudate ( p = 0.046, d = 0.76) and putamen p = 0.013, d = 0.94). These findings were largely explained by age differences between groups. DGM glutamate levels were positively correlated with psychomotor speed ( r(30) = 0.49, p = 0.028), but not with other cognitive domains. Conclusions: We find reduced glutamate levels across DGM structures including the caudate and putamen in patients with a psychotic disorder that are linked to psychomotor speed. Despite limitations concerning age differences, these results underscore the potential role of detailed in vivo glutamate assessments to understand cognitive deficits in psychotic disorders.
    Type of Medium: Online Resource
    ISSN: 0269-8811 , 1461-7285
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2028926-1
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  • 8
    In: NeuroImage: Clinical, Elsevier BV, Vol. 32 ( 2021), p. 102889-
    Type of Medium: Online Resource
    ISSN: 2213-1582
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2701571-3
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  • 9
    In: Brain and Behavior, Wiley, Vol. 10, No. 12 ( 2020-12)
    Abstract: Magnetic resonance spectroscopic imaging (MRSI) has the potential to add a layer of understanding of the neurobiological mechanisms underlying brain diseases, disease progression, and treatment efficacy. Limitations related to metabolite fitting of low signal‐to‐noise ratios data, signal variations due to partial‐volume effects, acquisition and extracranial lipid artifacts, along with clinically relevant aspects such as scan time constraints, are among the challenges associated with in vivo MRSI. Methods The aim of this work was to address some of these factors and to develop an acquisition, reconstruction, and postprocessing pipeline to derive lipid‐suppressed metabolite values of central brain structures based on free‐induction decay measurements made using a 7 T MR scanner. Anatomical images were used to perform high‐resolution (1 mm 3 ) partial‐volume correction to account for gray matter, white matter (WM), and cerebral‐spinal fluid signal contributions. Implementation of automatic quality control thresholds and normalization of metabolic maps from 23 subjects to the Montreal Neurological Institute (MNI) standard atlas facilitated the creation of high‐resolution average metabolite maps of several clinically relevant metabolites in central brain regions, while accounting for macromolecular distributions. Partial‐volume correction improved the delineation of deep brain nuclei. We report average metabolite values including glutamate + glutamine (Glx), glycerophosphocholine, choline and phosphocholine (tCho), (phospo)creatine, myo‐inositol and glycine (mI‐Gly), glutathione, N‐acetyl‐aspartyl glutamate(and glutamine), and N‐acetyl‐aspartate in the basal ganglia, central WM (thalamic radiation, corpus callosum) as well as insular cortex and intracalcarine sulcus. Conclusion MNI‐registered average metabolite maps facilitate group‐based analysis, thus offering the possibility to mitigate uncertainty in variable MRSI data.
    Type of Medium: Online Resource
    ISSN: 2162-3279 , 2162-3279
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2020
    detail.hit.zdb_id: 2623587-0
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  • 10
    Online Resource
    Online Resource
    Oxford University Press (OUP) ; 2017
    In:  Brain Vol. 140, No. 7 ( 2017-07), p. 1859-1871
    In: Brain, Oxford University Press (OUP), Vol. 140, No. 7 ( 2017-07), p. 1859-1871
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2017
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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