A longitudinal MRI analysis reveals altered brain connectivity and microstructural changes in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is characterized by progressive cognitive decline and neuropathological changes, yet the underlying neurobiological mechanisms remain elusive. Here, we employed a multimodal longitudinal neuroimaging approach, using anatomical and functional sequences on a high field magnetic resonance imaging (MRI) preclinical scanner, to investigate alterations in brain connectivity and white matter microstructure in a transgenic mouse model of AD (J20) when compared to wild-type (WT) littermates. Functional connectivity analysis revealed distinct network disruptions in J20 mice, primarily involving connections between posterior and anterior brain regions; importantly, a significant interaction between group and age highlighted an exacerbation of these connectivity changes with advancing age in J20 mice. In addition, significant reductions in fractional anisotropy (FA) were observed in the corpus callosum of J20 mice compared to WT, indicative of microstructural alterations consistent with white matter pathology. The observed alterations in brain connectivity and microstructure provide valuable insights into the spatiotemporal processes underlying AD-related decline and underscore the utility of multimodal neuroimaging in elucidating the neurobiological substrates of AD pathology in animal models.

In vivo detection of carnosine and its derivatives using chemical exchange saturation transfer.

PURPOSE: To detect carnosine, anserine and homocarnosine in vivo with chemical exchange saturation transfer (CEST) at 17.2 T. METHODS: CEST MR acquisitions were performed using a CEST-linescan sequence developed in-house and optimized for carnosine detection. In vivo CEST data were collected from three different regions of interest (the lower leg muscle, the olfactory bulb and the neocortex) of eight rats. RESULTS: The CEST effect for carnosine, anserine and homocarnosine was characterized in phantoms, demonstrating the possibility to separate individual contributions by employing high spectral resolution (0.005 ppm) and low CEST saturation power (0.15 µ$$ \mu $$ T). The CEST signature of these peptides was evidenced, in vivo, in the rat brain and skeletal muscle. The presence of carnosine and anserine in the muscle was corroborated by in vivo localized spectroscopy (MRS). However, the sensitivity of MRS was insufficient for carnosine and homocarnosine detection in the brain. The absolute amounts of carnosine and derivatives in the investigated tissues were determined by liquid chromatography-electrospray ionization-tandem mass spectrometry using isotopic dilution standard methods and were in agreement with the CEST results. CONCLUSION: The robustness of the CEST-linescan approach and the favorable conditions for CEST at ultra-high magnetic field allowed the in vivo CEST MR detection of carnosine and related peptides. This approach could be useful to investigate noninvasively the (patho)-physiological roles of these molecules.

RF heating measurement using MR thermometry and field monitoring: Methodological considerations and first in vivo results.

PURPOSE: A MR thermometry (MRT) method with field monitoring is proposed to improve the measurement of small temperature variations induced in brain MRI exams. METHODS: MR thermometry experiments were performed at 7 Tesla with concurrent field monitoring and RF heating. Images were reconstructed with nominal k-space trajectories and with first-order spherical harmonics correction. Experiments were performed in vitro with deliberate field disturbances and on an anesthetized macaque in 2 different specific absorption rate regimes, that is, at 50% and 100% of the maximal specific absorption rate level allowed in the International Electrotechnical Commission normal mode of operation. Repeatability was assessed by running a second separate session on the same animal. RESULTS: Inclusion of magnetic field fluctuations in the reconstruction improved temperature measurement accuracy in vitro down to 0.02°C. Measurement precision in vivo was on the order of 0.15°C in areas little affected by motion. In the same region, temperature increase reached 0.5 to 0.8°C after 20 min of heating at 100% specific absorption rates and followed a rough factor of 2 with the 50% specific absorption rate scans. A horizontal temperature plateau, as predicted by Pennes bioheat model with thermal constants from the literature and constant blood temperature assumption, was not observed. CONCLUSION: Inclusion of field fluctuations in image reconstruction was beneficial for the measurement of small temperature rises encountered in standard brain exams. More work is needed to correct for motion-induced field disturbances to extract reliable temperature maps.

What can 7T sodium MRI tell us about cellular energy depletion and neurotransmission in Alzheimer's disease?

The pathophysiological processes underlying the development and progression of Alzheimer's disease (AD) on the neuronal level are still unclear. Previous research has hinted at metabolic energy deficits and altered sodium homeostasis with impaired neuronal function as a potential metabolic marker relevant for neurotransmission in AD. Using sodium (23 Na) magnetic resonance (MR) imaging on an ultra-high-field 7 Tesla MR scanner, we found increased cerebral tissue sodium concentration (TSC) in 17 biomarker-defined AD patients compared to 22 age-matched control subjects in vivo. TSC was highly discriminative between controls and early AD stages and was predictive for cognitive state, and associated with regional tau load assessed with flortaucipir-positron emission tomography as a possible mediator of TSC-associated neurodegeneration. TSC could therefore serve as a non-invasive, stage-dependent, metabolic imaging marker. Setting a focus on cellular metabolism and potentially disturbed interneuronal communication due to energy-dependent altered cell homeostasis could hamper progressive cognitive decline by targeting these processes in future interventions.

A Resting-State Functional MR Imaging and Spectroscopy Study of the Dorsal Hippocampus in the Chronic Unpredictable Stress Rat Model.

Exposure to chronic stress leads to an array of anatomical, functional, and metabolic changes in the brain that play a key role in triggering psychiatric disorders such as depression. The hippocampus is particularly well known as a target of maladaptive responses to stress. To capture stress-induced changes in metabolic and functional connectivity in the hippocampus, stress-resistant (low-responders) or -susceptible (high-responders) rats exposed to a chronic unpredictable stress paradigm (categorized according to their hormonal and behavioral responses) were assessed by multimodal neuroimaging; the latter was achieved by using localized 1H MR spectroscopy and resting-state functional MRI (fMRI) at 11,7T data from stressed (n = 25) but also control (n = 15) male Wistar rats.Susceptible animals displayed increased GABA-glutamine (+19%) and glutamate-glutamine (+17%) ratios and decreased levels of macromolecules (-11%); these changes were positively correlated with plasma corticosterone levels. In addition, the neurotransmitter levels showed differential associations with functional connectivity between the hippocampus and the amygdala, the piriform cortex and thalamus between stress-resistant and -susceptible animals. Our observations are consistent with previously reported stress-induced metabolomic changes that suggest overall neurotransmitter dysfunction in the hippocampus. Their association with the fMRI data in this study reveals how local adjustments in neurochemistry relate to changes in the neurocircuitry of the hippocampus, with implications for its stress-associated dysfunctions.SIGNIFICANCE STATEMENT Chronic stress disrupts brain homeostasis, which may increase the vulnerability of susceptible individuals to neuropsychiatric disorders such as depression. Characterization of the differences between stress-resistant and -susceptible individuals on the basis of noninvasive imaging tools, such as magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI), contributes to improved understanding of the mechanisms underpinning individual differences in vulnerability and can facilitate the design of new diagnostic and intervention strategies. Using a combined functional MRI/MRS approach, our results demonstrate that susceptible- and non-susceptible subjects show differential alterations in hippocampal GABA and glutamate metabolism that, in turn, associate with changes in functional connectivity.

Alterations of peripheral nerve excitability in an experimental autoimmune encephalomyelitis mouse model for multiple sclerosis.

BACKGROUND: Experimental autoimmune encephalomyelitis (EAE) is the most commonly used and clinically relevant murine model for human multiple sclerosis (MS), a demyelinating autoimmune disease characterized by mononuclear cell infiltration into the central nervous system (CNS). The aim of the present study was to appraise the alterations, poorly documented in the literature, which may occur at the peripheral nervous system (PNS) level. METHODS: To this purpose, a multiple evaluation of peripheral nerve excitability was undertaken, by means of a minimally invasive electrophysiological method, in EAE mice immunized with the myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide, an experimental model for MS that reproduces, in animals, the anatomical and behavioral alterations observed in humans with MS, including CNS inflammation, demyelination of neurons, and motor abnormalities. Additionally, the myelin sheath thickness of mouse sciatic nerves was evaluated using transmission electronic microscopy. RESULTS: As expected, the mean clinical score of mice, daily determined to describe the symptoms associated to the EAE progression, increased within about 18 days after immunization for EAE mice while it remained null for all control animals. The multiple evaluation of peripheral nerve excitability, performed in vivo 2 and 4 weeks after immunization, reveals that the main modifications of EAE mice, compared to control animals, are a decrease of the maximal compound action potential (CAP) amplitude and of the stimulation intensity necessary to generate a CAP with a 50% maximum amplitude. In addition, and in contrast to control mice, at least 2 CAPs were recorded following a single stimulation in EAE animals, reflecting various populations of sensory and motor nerve fibers having different CAP conduction speeds, as expected if a demyelinating process occurred in the PNS of these animals. In contrast, single CAPs were always recorded from the sensory and motor nerve fibers of control mice having more homogeneous CAP conduction speeds. Finally, the myelin sheath thickness of sciatic nerves of EAE mice was decreased 4 weeks after immunization when compared to control animals. CONCLUSIONS: In conclusion, the loss of immunological self-tolerance to MOG in EAE mice or in MS patients may not be only attributed to the restricted expression of this antigen in the immunologically privileged environment of the CNS but also of the PNS.

Longitudinal mouse-PET imaging: a reliable method for estimating binding parameters without a reference region or blood sampling.

Longitudinal mouse PET imaging is becoming increasingly popular due to the large number of transgenic and disease models available but faces challenges. These challenges are related to the small size of the mouse brain and the limited spatial resolution of microPET scanners, along with the small blood volume making arterial blood sampling challenging and impossible for longitudinal studies. The ability to extract an input function directly from the image would be useful for quantification in longitudinal small animal studies where there is no true reference region available such as TSPO imaging. METHODS: Using dynamic, whole-body 18F-DPA-714 PET scans (60 min) in a mouse model of hippocampal sclerosis, we applied a factor analysis (FA) approach to extract an image-derived input function (IDIF). This mouse-specific IDIF was then used for 4D-resolution recovery and denoising (4D-RRD) that outputs a dynamic image with better spatial resolution and noise properties, and a map of the total volume of distribution (VT) was obtained using a basis function approach in a total of 9 mice with 4 longitudinal PET scans each. We also calculated percent injected dose (%ID) with and without 4D-RRD. The VT and %ID parameters were compared to quantified ex vivo autoradiography using regional correlations of the specific binding from autoradiography against VT and %ID parameters. RESULTS: The peaks of the IDIFs were strongly correlated with the injected dose (Pearson R = 0.79). The regional correlations between the %ID estimates and autoradiography were R = 0.53 without 4D-RRD and 0.72 with 4D-RRD over all mice and scans. The regional correlations between the VT estimates and autoradiography were R = 0.66 without 4D-RRD and 0.79 with application of 4D-RRD over all mice and scans. CONCLUSION: We present a FA approach for IDIF extraction which is robust, reproducible and can be used in quantification methods for resolution recovery, denoising and parameter estimation. We demonstrated that the proposed quantification method yields parameter estimates closer to ex vivo measurements than semi-quantitative methods such as %ID and is immune to tracer binding in tissue unlike reference tissue methods. This approach allows for accurate quantification in longitudinal PET studies in mice while avoiding repeated blood sampling.

Investigation of lithium distribution in the rat brain ex vivo using lithium-7 magnetic resonance spectroscopy and imaging at 17.2 T.

Lithium is the first-line mood stabilizer for the treatment of patients with bipolar disorder. However, its mechanisms of action and transport across the blood-brain barrier remain poorly understood. The contribution of lithium-7 magnetic resonance imaging (7 Li MRI) to investigate brain lithium distribution remains limited because of the modest sensitivity of the lithium nucleus and the expected low brain concentrations in humans and animal models. Therefore, we decided to image lithium distribution in the rat brain ex vivo using a turbo-spin-echo imaging sequence at 17.2 T. The estimation of lithium concentrations was performed using a phantom replacement approach accounting for B1 inhomogeneities and differential T1 and T2 weighting. Our MRI-derived lithium concentrations were validated by comparison with inductively coupled plasma-mass spectrometry (ICP-MS) measurements ([Li]MRI  = 1.18[Li]MS , R = 0.95). Overall, a sensitivity of 0.03 mmol/L was achieved for a spatial resolution of 16 µL. Lithium distribution was uneven throughout the brain (normalized lithium content ranged from 0.4 to 1.4) and was mostly symmetrical, with consistently lower concentrations in the metencephalon (cerebellum and brainstem) and higher concentrations in the cortex. Interestingly, low lithium concentrations were also observed close to the lateral ventricles. The average brain-to-plasma lithium ratio was 0.34 ± 0.04, ranging from 0.29 to 0.39. Brain lithium concentrations were reasonably correlated with plasma lithium concentrations, with Pearson correlation factors ranging from 0.63 to 0.90.

Experimental strategies for in vivo13C NMR spectroscopy.

In vivo carbon-13 (13C) MRS opens unique insights into the metabolism of intact organisms, and has led to major advancements in the understanding of cellular metabolism under normal and pathological conditions in various organs such as skeletal muscles, the heart, the liver and the brain. However, the technique comes at the expense of significant experimental difficulties. In this review we focus on the experimental aspects of non-hyperpolarized 13C MRS in vivo. Some of the enrichment strategies which have been proposed so far are described; the various MRS acquisition paradigms to measure 13C labeling are then presented. Finally, practical aspects of 13C spectral quantification are discussed.

Metabolite and macromolecule T1 and T2 relaxation times in the rat brain in vivo at 17.2T.

PURPOSE: To measure the T1 and T2 relaxation times of water, metabolites, and macromolecules in the rat brain in vivo at 17.2T and achieve absolute quantification of the neurochemical profile. Relaxation times were compared with values from the literature found at lower magnetic fields. METHODS: (1) H NMR spectra were measured using a LASER localization sequence. T1 - and T2 -weighted spectra were analyzed using LCModel with an original parameterization of the macromolecule baseline. RESULTS: The T1 relaxation times of 20 metabolites and the T2 relaxation times of 16 singlets and J-coupled metabolites were measured. The mean T1 and T2 relaxation times for metabolites were 1721 ± 237 ms and 148 ± 53 ms, respectively. In addition, we measured the T1 and T2 relaxation times of 4 macromolecule resonance groups, their mean T1 and T2 relaxation times being 690 ± 100 ms and 37 ± 15 ms, respectively. Absolute quantification of 21 metabolites and 4 groups of macromolecule resonances was achieved with Cramer-Rao Lower Bounds below 5% for Cr, Gln, Glu, GPC, Ins, NAA, PCr, and Tau and below 25% for the remaining resonances. CONCLUSION: Comparison of our relaxation times to previously published values suggests a small increase of T1 values and a clear decrease of T2 values between 11.7 and 17.2T.

Neuroenergetic alterations in neurodegenerative diseases: A systematic review and meta-analysis of in vivo31P-MRS studies.

Phosphorus magnetic resonance spectroscopy (31P-MRS) is applied for non-invasive studies of neuroenergetic metabolism in neurodegenerative diseases. However, the findings are inconsistent and have not yet been tested in meta-analyses. To address this gap, we performed a systematic review of 29 studies and conducted meta-analyses for 9 studies on Alzheimer's disease (AD, n = 140 patients), 9 studies on Parkinson's disease (PD, n = 183 patients), 3 studies on Progressive Supranuclear Palsy (PSP, n = 42 patients), and 2 studies on Multiple System Atrophy (MSA, n = 24 patients). Compared to controls, AD patients had a higher ratio of phosphomonoesters/phosphodiesters (PME/PDE) in the frontal lobe (MD = 0.049, p = 0.0003); PD patients showed decreases in PME/PDE in the putamen (MD = -0.050, p = 0.023) and adenosine triphosphate/inorganic phosphate (ATP/Pi) in the midbrain (MD = -0.274, p = 0.002); PSP patients presented increased phosphocreatine (PCr)/Pi in the basal ganglia (MD = 0.556, p = 0.030) and adenosine diphosphate (ADP)/Pi in the occipital lobe (MD = 0.005, p = 0.009); no significant effects were observed in MSA. Here, our review underlines the importance of 31P-MRS in the characterization of distinct neuroenergetic changes and its potential to improve the diagnosis and follow-up of neurodegenerative diseases.

19F molecular MR imaging for detection of brain tumor angiogenesis: in vivo validation using targeted PFOB nanoparticles.

Molecular imaging with magnetic resonance imaging (MRI) targeted contrast agents has emerged as a promising diagnostic approach in cancer research to detect associated biomarkers. In this work, the potential of (19)F MRI was investigated to detect angiogenesis with α(ν)ß(3)-targeted perfluorooctylbromide nanoparticles (PFOB NP) in a U87 glioblastoma mouse model at 7 Tesla. Mice were injected intravenously with targeted or non-targeted NP and (19)F images were immediately acquired for 90 min using a PFOB-dedicated MRI sequence. Mice infused with targeted NP exhibited higher concentrations in tumors than mice of the control group, despite the presence of nonspecific signal originating from the blood. Imaging results were corroborated by histology and fluorescence imaging, suggesting specific binding of targeted NP to α(ν)ß(3) integrin. Two other groups of mice were injected 24 h before imaging to allow blood clearance but no significant differences were found between both groups, probably due to a loss of specificity of PFOB NP. This is the first demonstration of the ability of (19)F MRI to detect α(ν)ß(3)-integrin endothelial expression in brain tumors in vivo.

In vivo CEST MR imaging of U87 mice brain tumor angiogenesis using targeted LipoCEST contrast agent at 7 T.

LipoCEST are liposome-encapsulating paramagnetic contrast agents (CA) based on chemical exchange saturation transfer with applications in biomolecular MRI. Their attractive features include biocompatibility, subnanomolar sensitivity, and amenability to functionalization for targeting biomarkers. We demonstrate MR imaging using a targeted lipoCEST, injected intravenously. A lipoCEST carrying Tm(III)-complexes was conjugated to RGD tripeptide (RGD-lipoCEST), to target integrin α(ν)ß(3) receptors involved in tumor angiogenesis and was compared with an unconjugated lipoCEST. Brain tumors were induced in athymic nude mice by intracerebral injection of U87MG cells and were imaged at 7 T after intravenous injection of either of the two contrast agents (n = 12 for each group). Chemical exchange saturation transfer-MSME sequence was applied over 2 h with an average acquisition time interval of 13.5 min. The chemical exchange saturation transfer signal was ∼1% in the tumor and controlateral regions, and decreased to ∼0.3% after 2 h; while RGD-lipoCEST signal was ∼1.4% in the tumor region and persisted for up to 2 h. Immunohistochemical staining revealed a persistent colocalization of RGD-lipoCEST with α(ν)ß(3) receptors in the tumor region. These results constitute an encouraging step toward in vivo MRI imaging of tumor angiogenesis using intravenously injected lipoCEST.

Astrocytes Undergo Metabolic Reprogramming in the Multiple Sclerosis Animal Model.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system that presents a largely unknown etiopathology. The presence of reactive astrocytes in MS lesions has been described for a long time; however, the role that these cells play in the pathophysiology of MS is still not fully understood. Recently, we used an MS animal model to perform high-throughput sequencing of astrocytes' transcriptome during disease progression. Our data show that astrocytes isolated from the cerebellum (a brain region typically affected in MS) showed a strong alteration in the genes that encode for proteins related to several metabolic pathways. Specifically, we found a significant increase in glycogen degradation, glycolytic, and TCA cycle enzymes. Together with these alterations, we detected an upregulation of genes that characterize "astrocyte reactivity". Additionally, at each disease time point we also reconstructed the morphology of cerebellum astrocytes in non-induced controls and in EAE animals, near lesion regions and in the normal-appearing white mater (NAWM). We found that near lesions, astrocytes presented increased length and complexity compared to control astrocytes, while no significant alterations were observed in the NAWM. How these metabolic alterations are linked with disease progression is yet to be uncovered. Herein, we bring to the literature the hypothesis of performing metabolic reprogramming as a novel therapeutic approach in MS.

XLF/Cernunnos loss impairs mouse brain development by altering symmetric proliferative divisions of neural progenitors.

XLF/Cernunnos is a component of the ligation complex used in classical non-homologous end-joining (cNHEJ), a major DNA double-strand break (DSB) repair pathway. We report neurodevelopmental delays and significant behavioral alterations associated with microcephaly in Xlf-/- mice. This phenotype, reminiscent of clinical and neuropathologic features in humans deficient in cNHEJ, is associated with a low level of apoptosis of neural cells and premature neurogenesis, which consists of an early shift of neural progenitors from proliferative to neurogenic divisions during brain development. We show that premature neurogenesis is related to an increase in chromatid breaks affecting mitotic spindle orientation, highlighting a direct link between asymmetric chromosome segregation and asymmetric neurogenic divisions. This study reveals thus that XLF is required for maintaining symmetric proliferative divisions of neural progenitors during brain development and shows that premature neurogenesis may play a major role in neurodevelopmental pathologies caused by NHEJ deficiency and/or genotoxic stress.

High sensitivity 19F MRI of a perfluorooctyl bromide emulsion: application to a dynamic biodistribution study and oxygen tension mapping in the mouse liver and spleen.

We have recently developed an optimized multi-spin echo (MSE) sequence dedicated to perfluorooctyl bromide (PFOB) imaging yielding an excellent sensitivity in vitro. The aim of the present study was to apply this sequence to quantitative measurements in the mouse liver and spleen after intravenous (i.v.) injection of PFOB emulsions. We first performed oxygenation maps 25.5 min after a single infusion of emulsion and, contrary to previous studies, shortly after injection. The signal-to-noise ratio (SNR) in the liver and spleen was as high as 45 and 120, respectively, for 3-min images with 11.7-µL pixels. Values of oxygen tension tended to be slightly higher in the spleen than in the liver. Dynamic biodistribution experiments were then performed immediately after intravenous (i.v.) injection of PFOB emulsions grafted with different quantities of polyethylene glycol (PEG) for stealth. Images were acquired every 7 min for 84 min and the SNR measured in the liver and spleen was at least four from the first time point. Uptake rates could be assessed for each PEG amount and, in spite of high standard deviations (SDs) owing to interanimal variability, our data confirmed that increasing quantities of PEG allow more gradual uptake of the emulsion particles by the liver and spleen. In conclusion, our method seems to be a powerful tool to non-invasively perform accurate in vivo quantitative measurements in the liver and spleen using (19)F MRI.

Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating 31P MRS for measuring brain ATP synthesis.

Neuroimaging methods have considerably developed over the last decades and offer various noninvasive approaches for measuring cerebral metabolic fluxes connected to energy metabolism, including PET and magnetic resonance spectroscopy (MRS). Among these methods, (31)P MRS has the particularity and advantage to directly measure cerebral ATP synthesis without injection of labeled precursor. However, this approach is methodologically challenging, and further validation studies are required to establish (31)P MRS as a robust method to measure brain energy synthesis. In the present study, we performed a multimodal imaging study based on the combination of 3 neuroimaging techniques, which allowed us to obtain an integrated picture of brain energy metabolism and, at the same time, to validate the saturation transfer (31)P MRS method as a quantitative measurement of brain ATP synthesis. A total of 29 imaging sessions were conducted to measure glucose consumption (CMRglc), TCA cycle flux (V(TCA)), and the rate of ATP synthesis (V(ATP)) in primate monkeys by using (18)F-FDG PET scan, indirect (13)C MRS, and saturation transfer (31)P MRS, respectively. These 3 complementary measurements were performed within the exact same area of the brain under identical physiological conditions, leading to: CMRglc = 0.27 +/- 0.07 micromol x g(-1) x min(-1), V(TCA) = 0.63 +/- 0.12 micromol x g(-1) x min(-1), and V(ATP) = 7.8 +/- 2.3 micromol x g(-1) x min(-1). The consistency of these 3 fluxes with literature and, more interestingly, one with each other, demonstrates the robustness of saturation transfer (31)P MRS for directly evaluating ATP synthesis in the living brain.

Fiber-based lactate recordings with fluorescence resonance energy transfer sensors by applying an magnetic resonance-informed correction of hemodynamic artifacts.

Significance: Fluorescence resonance energy transfer (FRET) sensors offer enormous benefits when studying neurophysiology through confocal microscopy. Yet, their use for fiber-based in vivo recordings is hampered by massive confounding effects and has therefore been scarcely reported. Aim: We aim to investigate whether in vivo fiber-based lactate recordings in the rodent brain are feasible with FRET sensors and implement a correction algorithm for the predominant hemodynamic artifact. Approach: We performed fiber-based FRET recordings of lactate (Laconic) and calcium (Twitch-2B) simultaneously with functional MRI and pharmacological MRI. MR-derived parameters were applied to correct hemodynamic artifacts. Results of FRET measurements were validated by local field potential, magnetic resonance spectroscopy, and blood analysis. Results: Hemodynamic artifacts dominated fiber-based in vivo FRET measurements with both Laconic and Twitch-2B. Our MR-based correction algorithm enabled to remove the artifacts and detect lactate and calcium changes during sensory stimulation or intravenous lactate injections. Conclusions: In vivo fiber-based lactate recordings are feasible using FRET-based sensors. However, signal corrections are required. MR-derived hemodynamic parameters can successfully be applied for artifact correction.

Glutamate cycle changes in the putamen of patients with de novo Parkinson's disease using 1H MRS.

INTRODUCTION: To investigate glutamatergic metabolism changes in the putamen of patients with de novo Parkinson's Disease (PD) and test the hypothesis that glutamate (Glu) levels are abnormally elevated in the putamen contralateral to where the motor clinical signs predominate as expected from observations in animal models. METHODS: 1H NMR spectra from 17 healthy control volunteers were compared with spectra from 17 de novo PD patients of who 14 were evaluated again after 2-3 years of disease progression. Statistical analysis used random-effects models. RESULTS: The only significant difference between PD patients and controls was a higher glutamine (Gln) concentration in the putamen ipsilateral to the hemibody with predominant motor signs (Visit 1: 6.0 ± 0.4 mM vs. 5.2 ± 0.2 mM, p < 0.05; Visit 2: 6.2 ± 0.3 mM vs. 5.2 ± 0.2 mM, p < 0.05). At Visit 1, PD patients had higher Glu and Gln levels in the putamen ipsilateral versus contralateral to dominant clinical signs (Glu: 12.2 ± 0.6 mM vs. 10.4 ± 0.6 mM, p < 0.05; Gln: 6.0 ± 0.4 mM vs. 4.8 ± 0.4 mM, p < 0.05; Glu and Gln pool (Glx): 17.9 ± 0.8 mM vs. 14.7 ± 1.1 mM, p < 0.05). At Visit 2, the sum of the two metabolites remained significantly higher in the ipsilateral versus contralateral putamen (Glx: 18.3 ± 0.6 mM vs. 16.1 ± 0.9 mM, p < 0.05). CONCLUSION: In de novo PD patients, the putamen ipsilateral to the more affected hemibody showed elevated Gln versus controls and elevated Glu and Gln concentrations versus the contralateral side. Abnormalities in Glu metabolism therefore occur early in PD but unexpectedly in the putamen contralateral to the more damaged hemisphere, suggesting they are not dependent solely on dopamine loss.

3T sodium MR imaging in Alzheimer's disease shows stage-dependent sodium increase influenced by age and local brain volume.

INTRODUCTION: Application of MRI in clinical routine mainly addresses structural alterations. However, pathological changes at a cellular level are expected to precede the occurrence of brain atrophy clusters and of clinical symptoms. In this context, 23Na-MRI examines sodium changes in the brain as a potential metabolic parameter. Recently, we have shown that 23Na-MRI at ultra-high-field (7 T) was able to detect increased tissue sodium concentration (TSC) in Alzheimer's disease (AD). In this work, we aimed at assessing AD-pathology with 23Na-MRI in a larger cohort and on a clinical 3T MR scanner. METHODS: We used a multimodal MRI protocol on 52 prodromal to mild AD patients and 34 cognitively healthy control subjects on a clinical 3T MR scanner. We examined the TSC, brain volume, and cortical thickness in association with clinical parameters. We further compared TSC with intra-individual normalized TSC for the reduction of inter-individual TSC variability resulting from physiological as well as experimental conditions. Normalized TSC maps were created by normalizing each voxel to the mean TSC inside the brain stem. RESULTS: We found increased normalized TSC in the AD cohort compared to elderly control subjects both on global as well as on a region-of-interest-based level. We further confirmed a significant association of local brain volume as well as age with TSC. TSC increase in the left temporal lobe was further associated with the cognitive state, evaluated via the Montreal cognitive assessment (MoCA) screening test. An increase of normalized TSC depending on disease stage reflected by the Clinical Dementia Rating (CDR) was found in our AD patients in temporal lobe regions. In comparison to classical brain volume and cortical thickness assessments, normalized TSC had a higher discriminative power between controls and prodromal AD patients in several regions of the temporal lobe. DISCUSSION: We confirm the feasibility of 23Na-MRI at 3T and report an increase of TSC in AD in several regions of the brain, particularly in brain regions of the temporal lobe. Furthermore, to reduce inter-subject variability caused by physiological factors such as circadian rhythms and experimental conditions, we introduced normalized TSC maps. This showed a higher discriminative potential between different clinical groups in comparison to the classical TSC analysis. In conclusion, 23Na-MRI represents a potential translational imaging marker applicable e.g.for diagnostics and the assessment of intervention outcomes in AD even under clinically available field strengths such as 3T. Implication of 23Na-MRI in association with other metabolic imaging marker needs to be further elucidated.