The brain specific member of the metallothionein (MT) family of proteins, metallothionein-3, inhi... more The brain specific member of the metallothionein (MT) family of proteins, metallothionein-3, inhibits the growth and survival of neurons, in contrast to the ubiquitous mammalian MT isoforms, MT-1 and MT-2, that are found in most tissues and are thought to function in metal ion homeostasis and detoxification. Solution NMR was utilized to determine the structural and dynamic differences of MT-3 from MT-1 and 2. The high-resolution solution structure of the C-terminal alpha-domain of recombinant mouse MT-3 revealed a tertiary fold very similar to MT-1 and 2, except for a loop that accommodates an acidic insertion relative to these isoforms. This loop was distinguished from the rest of the domain by dynamics of the backbone on the nano- to picosecond time-scale shown by (15)N relaxation studies and was identified as a possible interaction site with other proteins. The N-terminal beta-domain contains the region responsible for the growth inhibitory activity, a CPCP tetrapeptide close to the N-terminus. Because of exchange broadening of a large number of the NMR signals from this domain, homology modeling was utilized to calculate models for the beta-domain and suggested that while the backbone fold of the MT-3 beta-domain is identical to MT-1 and 2, the second proline responsible for the activity, Pro9, may show structural heterogeneity. (15)N relaxation analyses implied fast internal motions for the beta-domain. On the basis of these observations, we conclude that the growth inhibitory activity exhibited by MT-3 is a result of a combination of local structural differences and global dynamics in the beta-domain.
The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric ac... more The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-qua...
Advanced MRS protocols improve data quality and reproducibility relative to vendor‐provided proto... more Advanced MRS protocols improve data quality and reproducibility relative to vendor‐provided protocols; however, they are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high‐quality spectroscopic data without local MRS expertise.
Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological cha... more Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.
Introduction: Increased precision of metabolite quantification by H MRS at 7T relative to lower f... more Introduction: Increased precision of metabolite quantification by H MRS at 7T relative to lower field strengths has been demonstrated via lower Cramér-Rao lower bounds (CRLB). This project was designed to determine whether lower CRLB at 7T relative to 3T lead to greater inter-session test-retest repeatability, a critical factor when designing longitudinal clinical studies. The experimental approach was to use a large number of repeat scans, extensively optimized single-voxel MRS methodology and optimal hardware at both fields. This included commercially available components at 3T, while an in-house built coil together with B1 shimming was utilized at 7T to optimize available B1 and minimize chemical shift displacement errors. Methods: Spectra were measured using body excitation and a 32 channel receive array coil at 3T and a 16-channel transceiver array coil and B1 phase shimming at 7T. Four healthy participants were each scanned 4 times at 3T and 4 times at 7T on a weekly basis. Se...
1 Institut du Cerveau et de la Moelle epiniere, INSERM U1127, CNRS UMR7225, UPMC Paris VI UMR_S97... more 1 Institut du Cerveau et de la Moelle epiniere, INSERM U1127, CNRS UMR7225, UPMC Paris VI UMR_S975, 75013 Paris, France; 2 Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States; 3 Center for NeuroImaging Research, Institut du Cerveau et de la Moelle epiniere, 75013 Paris, France; 4 Assistance Publique-Hopitaux de Paris, Federation de Genetique, Salpetriere University Hospital, 75013 Paris, France.
A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is ... more A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is critical to qualify the role of glycogen in the brain. These molecular and metabolic features are under the control of neuronal activity through the interdependent action of neuromodulatory tone, ionic homeostasis and availability of metabolic substrates, all variables that concur to define the state of the system. In this chapter, we briefly describe how glycogen responds to selected behavioral, nutritional, environmental, hormonal, developmental and pathological conditions. We argue that interpreting glycogen metabolism through the lens of brain state is an effective approach to establish the relevance of energetics in connecting molecular and cellular neurophysiology to behavior.
BackgroundHuntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide... more BackgroundHuntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. This mutation causes HTT protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated whether protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), participates in the regulation of neuroinflammation and synaptic function during HD progression.MethodsWe used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’. We performed neuropathological analyses using immunohistochemistry, cytok...
Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) an... more Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.
BackgroundNo treatment exists for the most common dominantly inherited ataxia Machado-Joseph dise... more BackgroundNo treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of aspects of disease pathology recapitulated by animal models.ObjectiveWe sought to identify shared neurochemical signatures in two mouse models of SCA3 that reflect aspects of the human disease pathology.MethodsCerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by magnetic resonance spectroscopy at 9.4 tesla. Motivated by the shared neurochemical abnormalities in the two models, we determined the levels of neurofilament medium (NFL, indicator of neuroaxonal integrity) and myelin basic protein (MBP, indicator of myelination) in cerebellar lysates from a subset of mice and from patients with SCA3. Finally, NFL and MBP levels were measured in cerebellar extracts of Q8...
The Journal of Clinical Endocrinology & Metabolism, 2019
Context Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical p... more Context Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). Impact of T1D on hippocampal neurochemical profile and glucose transport is unknown. Objective To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH. Design and participants Hippocampal neurochemical profile was measured with single-voxel MR spectroscopy (MRS) at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling. Setting University medical center Main Outcome Measures C...
To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for sing... more To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for single-voxel MRS that removes the need for manual VOI placement, allows flexible VOI planning in any brain region, and enables high inter- and intra-subject consistency of VOI prescription. AutoVOI was designed to transfer pre-defined VOIs from an atlas to the 3D anatomical data of the subject during the scan. The AutoVOI pipeline was optimized for consistency in VOI placement (precision), enhanced coverage of the targeted tissue (accuracy), and fast computation speed. The tool was evaluated against manual VOI placement using existing T -weighted data sets and corresponding VOI prescriptions. Finally, it was implemented on 2 scanner platforms to acquire MRS data from clinically relevant VOIs that span the cerebrum, cerebellum, and the brainstem. The AutoVOI pipeline includes skull stripping, non-linear registration of the atlas to the subject's brain, and computation of the VOI coordinat...
The brain specific member of the metallothionein (MT) family of proteins, metallothionein-3, inhi... more The brain specific member of the metallothionein (MT) family of proteins, metallothionein-3, inhibits the growth and survival of neurons, in contrast to the ubiquitous mammalian MT isoforms, MT-1 and MT-2, that are found in most tissues and are thought to function in metal ion homeostasis and detoxification. Solution NMR was utilized to determine the structural and dynamic differences of MT-3 from MT-1 and 2. The high-resolution solution structure of the C-terminal alpha-domain of recombinant mouse MT-3 revealed a tertiary fold very similar to MT-1 and 2, except for a loop that accommodates an acidic insertion relative to these isoforms. This loop was distinguished from the rest of the domain by dynamics of the backbone on the nano- to picosecond time-scale shown by (15)N relaxation studies and was identified as a possible interaction site with other proteins. The N-terminal beta-domain contains the region responsible for the growth inhibitory activity, a CPCP tetrapeptide close to the N-terminus. Because of exchange broadening of a large number of the NMR signals from this domain, homology modeling was utilized to calculate models for the beta-domain and suggested that while the backbone fold of the MT-3 beta-domain is identical to MT-1 and 2, the second proline responsible for the activity, Pro9, may show structural heterogeneity. (15)N relaxation analyses implied fast internal motions for the beta-domain. On the basis of these observations, we conclude that the growth inhibitory activity exhibited by MT-3 is a result of a combination of local structural differences and global dynamics in the beta-domain.
The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric ac... more The primary excitatory and inhibitory neurotransmitters glutamate (Glu) and gamma-aminobutyric acid (GABA) are thought to be involved in the response of the brain to changes in glycemia. Therefore, their reliable measurement is critical for understanding the dynamics of these responses. The concentrations of Glu and GABA, as well as glucose (Glc) in brain tissue, can be measured in vivo using proton (1H) magnetic resonance spectroscopy (MRS). Advanced MRS methodology at ultrahigh field allows reliable monitoring of these metabolites under changing metabolic states. However, the long acquisition times needed for these experiments while maintaining blood Glc levels at predetermined targets present many challenges. We present an advanced MRS acquisition protocol that combines commercial 7T hardware (Siemens Scanner and Nova Medical head coil), BaTiO3 dielectric padding, optical motion tracking, and dynamic frequency and B0 shim updates to ensure the acquisition of reproducibly high-qua...
Advanced MRS protocols improve data quality and reproducibility relative to vendor‐provided proto... more Advanced MRS protocols improve data quality and reproducibility relative to vendor‐provided protocols; however, they are challenging to incorporate into the clinical workflow and require local MRS expertise for successful implementation. Here, we developed an automated advanced MRS acquisition protocol at 3T to facilitate acquisition of high‐quality spectroscopic data without local MRS expertise.
Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological cha... more Proton magnetic resonance spectroscopy (1H MRS) may provide information on pathophysiological changes associated with tau deposition in cognitively unimpaired older adults. In this study, the associations of posterior cingulate gyrus tau and amyloid beta (Aβ) deposition on PET with 1H MRS metabolite ratios acquired from bilateral posterior cingulate gyri were investigated in cognitively unimpaired older adults. Participants (n = 40) from the Mayo Clinic Study of Aging underwent single-voxel sLASER 1H MRS from the posterior cingulate gyrus at 3 Tesla, 18F-flortaucipir, and 11C- Pittsburgh Compound B (PiB) PET. An increase in posterior cingulate gyrus tau deposition, but not elevated Aβ, was associated with lower N-acetylaspartate/total creatine (tCr) and glutamate (Glu)/tCr ratios, and sex by tau interaction was observed in association with Glu/tCr. Higher tau levels in cognitively unimpaired older adults are associated with biomarkers of neural and synaptic injury even in the absence of cognitive impairment and these relationships appear to be stronger in women than in men.
Introduction: Increased precision of metabolite quantification by H MRS at 7T relative to lower f... more Introduction: Increased precision of metabolite quantification by H MRS at 7T relative to lower field strengths has been demonstrated via lower Cramér-Rao lower bounds (CRLB). This project was designed to determine whether lower CRLB at 7T relative to 3T lead to greater inter-session test-retest repeatability, a critical factor when designing longitudinal clinical studies. The experimental approach was to use a large number of repeat scans, extensively optimized single-voxel MRS methodology and optimal hardware at both fields. This included commercially available components at 3T, while an in-house built coil together with B1 shimming was utilized at 7T to optimize available B1 and minimize chemical shift displacement errors. Methods: Spectra were measured using body excitation and a 32 channel receive array coil at 3T and a 16-channel transceiver array coil and B1 phase shimming at 7T. Four healthy participants were each scanned 4 times at 3T and 4 times at 7T on a weekly basis. Se...
1 Institut du Cerveau et de la Moelle epiniere, INSERM U1127, CNRS UMR7225, UPMC Paris VI UMR_S97... more 1 Institut du Cerveau et de la Moelle epiniere, INSERM U1127, CNRS UMR7225, UPMC Paris VI UMR_S975, 75013 Paris, France; 2 Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States; 3 Center for NeuroImaging Research, Institut du Cerveau et de la Moelle epiniere, 75013 Paris, France; 4 Assistance Publique-Hopitaux de Paris, Federation de Genetique, Salpetriere University Hospital, 75013 Paris, France.
A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is ... more A fundamental understanding of glycogen structure, concentration, polydispersity and turnover is critical to qualify the role of glycogen in the brain. These molecular and metabolic features are under the control of neuronal activity through the interdependent action of neuromodulatory tone, ionic homeostasis and availability of metabolic substrates, all variables that concur to define the state of the system. In this chapter, we briefly describe how glycogen responds to selected behavioral, nutritional, environmental, hormonal, developmental and pathological conditions. We argue that interpreting glycogen metabolism through the lens of brain state is an effective approach to establish the relevance of energetics in connecting molecular and cellular neurophysiology to behavior.
BackgroundHuntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide... more BackgroundHuntington’s Disease (HD) is a neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene for which no therapies are available. This mutation causes HTT protein misfolding and aggregation, preferentially affecting medium spiny neurons (MSNs) of the basal ganglia. Transcriptional perturbations in synaptic genes and neuroinflammation are key processes that precede MSN dysfunction and motor symptom onset. Understanding the interplay between these processes is crucial to develop effective therapeutic strategies to treat HD. We investigated whether protein kinase CK2α’, a kinase upregulated in MSNs in HD and previously associated with Parkinson’s disease (PD), participates in the regulation of neuroinflammation and synaptic function during HD progression.MethodsWe used the heterozygous knock-in zQ175 HD mouse model and compared that to zQ175 mice lacking one allele of CK2α’. We performed neuropathological analyses using immunohistochemistry, cytok...
Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) an... more Clinicians involved with different aspects of the care of persons with multiple sclerosis (MS) and scientists with expertise on clinical and imaging techniques convened in Dallas, TX, USA on February 27, 2019 at a North American Imaging in Multiple Sclerosis Cooperative workshop meeting. The aim of the workshop was to discuss cardinal pathobiological mechanisms implicated in the progression of MS and novel imaging techniques, beyond brain atrophy, to unravel these pathologies. Indeed, although brain volume assessment demonstrates changes linked to disease progression, identifying the biological mechanisms leading up to that volume loss are key for understanding disease mechanisms. To this end, the workshop focused on the application of advanced magnetic resonance imaging (MRI) and positron emission tomography (PET) imaging techniques to assess and measure disease progression in both the brain and the spinal cord. Clinical translation of quantitative MRI was recognized as of vital importance, although the need to maintain a relatively short acquisition time mandated by most radiology departments remains the major obstacle toward this effort. Regarding PET, the panel agreed upon its utility to identify ongoing pathological processes. However, due to costs, required expertise, and the use of ionizing radiation, PET was not considered to be a viable option for ongoing care of persons with MS. Collaborative efforts fostering robust study designs and imaging technique standardization across scanners and centers are needed to unravel disease mechanisms leading to progression and discovering medications halting neurodegeneration and/or promoting repair.
BackgroundNo treatment exists for the most common dominantly inherited ataxia Machado-Joseph dise... more BackgroundNo treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of aspects of disease pathology recapitulated by animal models.ObjectiveWe sought to identify shared neurochemical signatures in two mouse models of SCA3 that reflect aspects of the human disease pathology.MethodsCerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by magnetic resonance spectroscopy at 9.4 tesla. Motivated by the shared neurochemical abnormalities in the two models, we determined the levels of neurofilament medium (NFL, indicator of neuroaxonal integrity) and myelin basic protein (MBP, indicator of myelination) in cerebellar lysates from a subset of mice and from patients with SCA3. Finally, NFL and MBP levels were measured in cerebellar extracts of Q8...
The Journal of Clinical Endocrinology & Metabolism, 2019
Context Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical p... more Context Longstanding type 1 diabetes (T1D) may lead to alterations in hippocampal neurochemical profile. Upregulation of hippocampal glucose transport as a result of recurrent exposure to hypoglycemia may preserve cognitive function during future hypoglycemia in subjects with T1D and impaired awareness of hypoglycemia (IAH). Impact of T1D on hippocampal neurochemical profile and glucose transport is unknown. Objective To test the hypothesis that hippocampal neurochemical composition is altered in T1D and glucose transport is upregulated in T1D with IAH. Design and participants Hippocampal neurochemical profile was measured with single-voxel MR spectroscopy (MRS) at 3T during euglycemia in 18 healthy controls (HC), 10 T1D with IAH and 12 T1D with normal awareness to hypoglycemia (NAH). Additionally, 12 HC, 8 T1D-IAH and 6 T1D-NAH were scanned during hyperglycemia to assess hippocampal glucose transport with metabolic modeling. Setting University medical center Main Outcome Measures C...
To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for sing... more To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for single-voxel MRS that removes the need for manual VOI placement, allows flexible VOI planning in any brain region, and enables high inter- and intra-subject consistency of VOI prescription. AutoVOI was designed to transfer pre-defined VOIs from an atlas to the 3D anatomical data of the subject during the scan. The AutoVOI pipeline was optimized for consistency in VOI placement (precision), enhanced coverage of the targeted tissue (accuracy), and fast computation speed. The tool was evaluated against manual VOI placement using existing T -weighted data sets and corresponding VOI prescriptions. Finally, it was implemented on 2 scanner platforms to acquire MRS data from clinically relevant VOIs that span the cerebrum, cerebellum, and the brainstem. The AutoVOI pipeline includes skull stripping, non-linear registration of the atlas to the subject's brain, and computation of the VOI coordinat...
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Papers by Gülin Öz