Transcranial stimulation of alpha oscillations up-regulates the default mode network.

The default mode network (DMN) is the most-prominent intrinsic connectivity network, serving as a key architecture of the brain's functional organization. Conversely, dysregulated DMN is characteristic of major neuropsychiatric disorders. However, the field still lacks mechanistic insights into the regulation of the DMN and effective interventions for DMN dysregulation. The current study approached this problem by manipulating neural synchrony, particularly alpha (8 to 12 Hz) oscillations, a dominant intrinsic oscillatory activity that has been increasingly associated with the DMN in both function and physiology. Using high-definition alpha-frequency transcranial alternating current stimulation (α-tACS) to stimulate the cortical source of alpha oscillations, in combination with simultaneous electroencephalography and functional MRI (EEG-fMRI), we demonstrated that α-tACS (versus Sham control) not only augmented EEG alpha oscillations but also strengthened fMRI and (source-level) alpha connectivity within the core of the DMN. Importantly, increase in alpha oscillations mediated the DMN connectivity enhancement. These findings thus identify a mechanistic link between alpha oscillations and DMN functioning. That transcranial alpha modulation can up-regulate the DMN further highlights an effective noninvasive intervention to normalize DMN functioning in various disorders.

Quantification approaches for magnetic resonance imaging following intravenous gadolinium injection: A window into brain-wide glymphatic function.

The glymphatic system is a brain-wide network of perivascular pathways along which cerebrospinal fluid and interstitial fluid rapidly exchange, facilitating solute and waste clearance from the brain parenchyma. The characterization of this exchange process in humans has relied primarily upon serial magnetic resonance imaging following intrathecal gadolinium-based contrast agent injection. However, less invasive approaches are needed. Here, we administered a gadolinium-based contrast agent intravenously in eight healthy participants and acquired magnetic resonance imaging scans prior to and 30, 90, 180, and 360 min post contrast injection. Using a region-of-interest approach, we observed that peripheral tissues and blood vessels exhibited high enhancement at 30 min after contrast administration, likely reflecting vascular and peripheral interstitial distribution of the gadolinium-based contrast agent. Ventricular, grey matter and white matter enhancement peaked at 90 min, declining thereafter. Using k-means clustering, we identify distinct distribution volumes reflecting the leptomeningeal perivascular network, superficial grey matter and deep grey/white matter that exhibit a sequential enhancement pattern consistent with parenchymal contrast enhancement via the subarachnoid cerebrospinal fluid compartment. We also outline the importance of correcting for (otherwise automatic) autoscaling of signal intensities, which could potentially lead to misinterpretation of gadolinium-based contrast agent distribution kinetics. In summary, we visualize and quantify delayed tissue enhancement following intravenous administration of gadolinium-based contrast agent in healthy human participants.

Olfactory bulb-targeted quantum dot (QD) bioconjugate and Kv1.3 blocking peptide improve metabolic health in obese male mice.

The olfactory system is a driver of feeding behavior, whereby olfactory acuity is modulated by the metabolic state of the individual. The excitability of the major output neurons of the olfactory bulb (OB) can be modulated through targeting a voltage-dependent potassium channel, Kv1.3, which responds to changes in metabolic factors such as insulin, glucose, and glucagon-like peptide-1. Because gene-targeted deletion or inhibition of Kv1.3 in the periphery has been found to increase energy metabolism and decrease body weight, we hypothesized that inhibition of Kv1.3 selectively in the OB could enhance excitability of the output neurons to evoke changes in energy homeostasis. We thereby employed metal-histidine coordination to self-assemble the Kv1.3 inhibitor margatoxin (MgTx) to fluorescent quantum dots (QDMgTx) as a means to label cells in vivo and test changes in neuronal excitability and metabolism when delivered to the OB. Using patch-clamp electrophysiology to measure Kv1.3 properties in heterologously expressed cells and native mitral cells in OB slices, we found that QDMgTx had a fast rate of inhibition, but with a reduced IC50, and increased action potential firing frequency. QDMgTx was capable of labeling cloned Kv1.3 channels but was not visible when delivered to native Kv1.3 in the OB. Diet-induced obese mice were observed to reduce body weight and clear glucose more quickly following osmotic mini-pump delivery of QDMgTx/MgTx to the OB, and following MgTx delivery, they increased the use of fats as fuels (reduced respiratory exchange ratio). These results suggest that enhanced excitability of bulbar output neurons can drive metabolic responses.

Fast chemical exchange saturation transfer imaging based on PROPELLER acquisition and deep neural network reconstruction.

PURPOSE: To develop a method for fast chemical exchange saturation transfer (CEST) imaging. METHODS: The periodically rotated overlapping parallel lines enhanced reconstruction (PROPELLER) sampling scheme was introduced to shorten the acquisition time. Deep neural network was employed to reconstruct CEST contrast images. Numerical simulation and experiments on a creatine phantom, hen egg, and in vivo tumor rat brain were performed to test the feasibility of this method. RESULTS: The results from numerical simulation and experiments show that there is no significant difference between reference images and CEST-PROPELLER reconstructed images under an acceleration factor of 8. CONCLUSION: Although the deep neural network is trained entirely on synthesized data, it works well on reconstructing experimental data. The proof of concept study demonstrates that the combination of the PROPELLER sampling scheme and the deep neural network enables considerable acceleration of saturated image acquisition and may find applications in CEST MRI.

Multiparametric classification of sub-acute ischemic stroke recovery with ultrafast diffusion, 23 Na, and MPIO-labeled stem cell MRI at 21.1 T.

MRI leverages multiple modes of contrast to characterize stroke. High-magnetic-field systems enhance the performance of these MRI measurements. Previously, we have demonstrated that individually sodium and stem cell tracking metrics are enhanced at ultrahigh field in a rat model of stroke, and we have developed robust single-scan diffusion-weighted imaging approaches that utilize spatiotemporal encoding (SPEN) of the apparent diffusion coefficient (ADC) for these challenging field strengths. Here, we performed a multiparametric study of middle cerebral artery occlusion (MCAO) biomarker evolution focusing on comparison of these MRI biomarkers for stroke assessment during sub-acute recovery in rat MCAO models at 21.1 T. T2 -weighted MRI was used as the benchmark for identification of the ischemic lesion over the course of the study. The number of MPIO-induced voids measured by gradient-recalled echo, the SPEN measurement of ADC, and 23 Na MRI values were determined in the ischemic area and contralateral hemisphere, and relative performances for stroke classification were compared by receiver operator characteristic analysis. These measurements were associated with unique time-dependent trajectories during stroke recovery that changed the sensitivity and specificity for stroke monitoring during its evolution. Advantages and limitations of these contrasts, and the use of ultrahigh field for multiparametric stroke assessment, are discussed.

Aggregation of human mesenchymal stem cells enhances survival and efficacy in stroke treatment.

Human mesenchymal stem cells (hMSCs) have been shown to enhance stroke lesion recovery by mediating inflammation and tissue repair through secretion of trophic factors. However, low cell survival and reduced primitive stem cell function of culture-expanded hMSCs are the major challenges limiting hMSC therapeutic efficacy in stroke treatment. In this study, we report the effects of short-term preconditioning of hMSCs via three-dimensional (3D) aggregation on stroke lesion recovery after intra-arterial (IA) transplantation of 3D aggregate-derived hMSCs (Agg-D hMSCs) in a transient middle cerebral artery occlusion (MCAO) stroke model. Compared with two-dimensional (2D) monolayer culture, Agg-D hMSCs exhibited increased resistance to ischemic stress, secretory function and therapeutic outcome. Short-term preconditioning via 3D aggregation reconfigured hMSC energy metabolism and altered redox cycle, which activated the PI3K/AKT pathway and enhanced resistance to in vitro oxidative stress. Analysis of transplanted hMSCs in MCAO rats using ultra-high-field magnetic resonance imaging at 21.1 T showed increased hMSC persistence and stroke lesion reduction by sodium (23Na) imaging in the Agg-D hMSC group compared with 2D hMSC control. Behavioral analyses further revealed functional improvement in MCAO animal treated with Agg-D hMSCs compared with saline control. Together, the results demonstrated the improved outcome for Agg-D hMSCs in the MCAO model and suggest short-term 3D aggregation as an effective preconditioning strategy for hMSC functional enhancement in stroke treatment.

Fluorine-19 MRI at 21.1 T: enhanced spin-lattice relaxation of perfluoro-15-crown-5-ether and sensitivity as demonstrated in ex vivo murine neuroinflammation.

OBJECTIVE: Fluorine MR would benefit greatly from enhancements in signal-to-noise ratio (SNR). This study examines the sensitivity gain of 19F MR that can be practically achieved when moving from 9.4 to 21.1 T. MATERIALS AND METHODS: We studied perfluoro-15-crown-5-ether (PFCE) at both field strengths (B0), as a pure compound, in the form of nanoparticles (NP) as employed to study inflammation in vivo, as well as in inflamed tissue. Brains, lymph nodes (LNs) and spleens were obtained from mice with experimental autoimmune encephalomyelitis (EAE) that had been administered PFCE NPs. All samples were measured at both B0 with 2D-RARE and 2D-FLASH using 19F volume radiofrequency resonators together. T1 and T2 of PFCE were measured at both B0 strengths. RESULTS: Compared to 9.4 T, an SNR gain of > 3 was observed for pure PFCE and > 2 for PFCE NPs at 21.1 T using 2D-FLASH. A dependency of 19F T1 and T2 relaxation on B0 was demonstrated. High spatially resolved 19F MRI of EAE brains and LNs at 21.1 T revealed signals not seen at 9.4 T. DISCUSSION: Enhanced SNR and T1 shortening indicate the potential benefit of in vivo 19F MR at higher B0 to study inflammatory processes with greater detail.

Cationic carrier peptide enhances cerebrovascular targeting of nanoparticles in Alzheimer's disease brain.

Accumulation of amyloid beta (Aß) peptides in the cerebral vasculature, referred to as cerebral amyloid angiopathy (CAA), is widely observed in Alzheimer's disease (AD) brain and was shown to accelerate cognitive decline. There is no effective method for detecting cerebrovascular amyloid (CVA) and treat CAA. The targeted nanoparticles developed in this study effectively migrated from the blood flow to the vascular endothelium as determined by using quartz crystal microbalance with dissipation monitoring (QCM-D) technology. We also improved the stability, and blood-brain barrier (BBB) transcytosis of targeted nanoparticles by coating them with a cationic BBB penetrating peptide (K16ApoE). The K16ApoE-Targeted nanoparticles demonstrated specific targeting of vasculotropic DutchAß40 peptide accumulated in the cerebral vasculature. Moreover, K16ApoE-Targeted nanoparticles demonstrated significantly greater uptake into brain and provided specific MRI contrast to detect brain amyloid plaques.

Metabolic assessment of a migraine model using relaxation-enhanced 1 H spectroscopy at ultrahigh field.

PURPOSE: This study evaluates biochemical imbalances in a rat model that reflects dysfunctional pathways in migraine. The high sensitivity and spectral dispersion available to 1 H MRS at 21.1 T expands metabolic profiling in this migraine model to include lactate (Lac), taurine (Tau), aspartate, and Gly-a mixture of glycine, glutamine, and glutamate. METHODS: Sprague-Dawley male rats were administered in situ an intraperitoneal injection of nitroglycerin (NTG) to induce the migraine analogue or saline as a control. A selective relaxation-enhanced MR spectroscopy sequence was used to target upfield metabolites from a 4-mm3 voxel for 2.5 h after injection. RESULTS: Significant increases were evident for Lac as early as 10 min after NTG injection, peaking over 50% compared with baseline and control (normalized Lac/N-acetyl aspartate with NTG = 1.54 ± 0.65 versus with saline = 0.99 ± 0.08). Tau decreased progressively in controls over 2 h after injection, but remained elevated with NTG, peaking at 105 min after injection (normalized Tau/N-acetyl aspartate with NTG = 1.10 ± 0.18 versus with saline = 0.85 ± 0.14). Total creatine under NTG showed significant decreases with time and compared with saline; Gly demonstrated temporal increases for NTG. CONCLUSIONS: These changes indicate an altered metabolic profile in the migraine analogue consistent with early changes in neural activity and/or vasodilation consistent with progressively enhanced neuroprotection and osmoregulation. Magn Reson Med 79:1266-1275, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Brain investigations of rodent disease models by chemical exchange saturation transfer at 21.1 T.

This study explores opportunities opened up by ultrahigh fields for in vivo saturation transfer brain magnetic resonance imaging experiments. Fast spin-echo images weighted by chemical exchange saturation transfer (CEST) effects were collected on Sprague-Dawley rats at 21.1 T, focusing on two neurological models. One involved a middle cerebral artery occlusion emulating ischemic stroke; the other involved xenografted glioma cells that were followed over the course of several days as they developed into brain tumors. A remarkably strong saturation-derived contrast was observed for the growing tumors when calculating magnetization transfer ratios at c. 3.8 ppm. This large contrast originated partially from an increase in the contribution of the amide CEST effect, but mostly from strong decreases in the Overhauser and magnetization transfer contributions to the upfield region, whose differential attenuations could be clearly discerned thanks to the ultrahigh field. The high spectral separation arising at 21.1 T also revealed numerous CEST signals usually overlapping at lower fields. Ischemic lesions were also investigated but, remarkably, magnetization and saturation transfer contrasts were nearly absent when computing transfer asymmetries using either high or low saturation power schemes. These behaviors were consistently observed at 24 hours post-occlusion, regardless of the data processing approach assayed. Considerations related to how various parameters defining these experiments depend on the magnetic field, primarily chemical shifts and T1 values, are discussed.

Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

Cardiovascular dysfunction is highly comorbid with mood disorders, such as anxiety and depression. However, the mechanisms linking cardiovascular dysfunction with the core behavioral features of mood disorder remain poorly understood. In this study, we used mice bearing a knock-in sarcomeric mutation, which is exhibited in human hypertrophic cardiomyopathy (HCM), to investigate the influence of HCM over the development of anxiety and depression. We employed behavioral, MRI, and biochemical techniques in young (3-4 mo) and aged adult (7-8 mo) female mice to examine the effects of HCM on the development of anxiety- and depression-like behaviors. We focused on females because in both humans and rodents, they experience a 2-fold increase in mood disorder prevalence vs. males. Our results showed that young and aged HCM mice displayed echocardiographic characteristics of the heart disease condition, yet only aged HCM females displayed anxiety- and depression-like behaviors. Electrocardiographic parameters of sympathetic nervous system activation were increased in aged HCM females vs. controls and correlated with mood disorder-related symptoms. In addition, when compared with controls, aged HCM females exhibited adrenal gland hypertrophy, reduced volume in mood-related brain regions, and reduced hippocampal signaling proteins, such as brain-derived neurotrophic factor and its downstream targets vs. controls. In conclusion, prolonged systemic HCM stress can lead to development of mood disorders, possibly through inducing structural and functional brain changes, and thus, mood disorders in patients with heart disease should not be considered solely a psychologic or situational condition.-Dossat, A. M., Sanchez-Gonzalez, M. A., Koutnik, A. P., Leitner, S., Ruiz, E. L., Griffin, B., Rosenberg, J. T., Grant, S. C., Fincham, F. D., Pinto, J. R. Kabbaj, M. Pathogenesis of depression- and anxiety-like behavior in an animal model of hypertrophic cardiomyopathy.

Transverse relaxation of selectively excited metabolites in stroke at 21.1 T.

PURPOSE: This study seeks to evaluate in vivo T2 relaxation times of selectively excited stroke-relevant metabolites via 1 H relaxation-enhanced magnetic resonance spectroscopy (RE-MRS) at 21.1 T (900 MHz). METHODS: A quadrature surface coil was designed and optimized for investigations of rodents at 21.1 T. With voxel localization, a RE-MRS pulse sequence incorporating the excitation of selected metabolites was modified to include a variable echo delay for T2 measurements. A middle cerebral artery occlusion (MCAO) animal model for stroke was examined with spectra taken 24 h post occlusion. Fourteen echo times were acquired, with each measurement completed in less than 2 min. RESULTS: The RE-MRS approach produced high-quality spectra of the selectively excited metabolites in the stroked and contralateral regions. T2 measurements reveal differential results between these regions, with significance achieved for lactic acid. CONCLUSION: Using the RE-MRS technique at ultra-high magnetic field and an optimized quadrature surface coil design, full metabolic T2 quantifications in a localized voxel is now possible in less than 27 min. Magn Reson Med 77:520-528, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Ultrafast in vivo diffusion imaging of stroke at 21.1 T by spatiotemporal encoding.

PURPOSE: This study quantifies in vivo ischemic stroke brain injuries in rats using ultrahigh-field single-scan MRI methods to assess variations in apparent diffusion coefficients (ADCs). METHODS: Magnitude and diffusion-weighted spatiotemporally encoded imaging sequences were implemented on a 21.1 T imaging system, and compared with spin-echo and echo-planar imaging diffusion-weighted imaging strategies. ADC maps were calculated and used to evaluate the sequences according to the statistical comparisons of the ipsilateral and contralateral ADC measurements at 24, 48, and 72 h poststroke. RESULTS: Susceptibility artifacts resulting from normative anatomy and pathological stroke conditions were particularly intense at 21.1 T. These artifacts strongly distorted single-shot diffusion-weighted echo-planar imaging experiments, but were reduced in four-segment interleaved echo-planar imaging acquisitions. By contrast, nonsegmented diffusion-weighted spatiotemporally encoded images were largely immune to field-dependent artifacts. Effects of stroke were apparent in both magnitude images and ADC maps of all sequences. When stroke recovery was followed by ADC variations, spatiotemporally encoded, echo-planar imaging, and spin-echo acquisitions revealed statistically significant increase in ADCs. CONCLUSIONS: Consideration of experiment duration, image quality, and mapped ADC values provided by spatiotemporally encoded demonstrates that this single-shot acquisition is a method of choice for high-throughput, ultrahigh-field in vivo stroke quantification.

Intracellular labeling of mouse embryonic stem cell-derived neural progenitor aggregates with micron-sized particles of iron oxide.

BACKGROUND AIMS: Pluripotent stem cell (PSC)-derived neural progenitor cells (NPCs) represent an unlimited source for the treatment of various neurological disorders. NPCs are usually derived from PSCs through the formation of embryoid body (EB), an aggregate structure mimicking embryonic development. This study investigated the effect of labeling multicellular EB-NPC aggregates with micron-sized particles of iron oxide (MPIO) for cell tracking using magnetic resonance imaging (MRI). METHODS: Intact and dissociated EB-NPC aggregates were labeled with various concentrations of MPIOs (0, 2.5, 5 and 10 µg Fe/mL). The labeled cells were analyzed by fluorescent imaging, flow cytometry and in vitro MRI for labeling efficiency and detectability. Moreover, the biological effects of intracellular MPIO on cell viability, cytotoxicity, proliferation and neural differentiation were evaluated. RESULTS: Intact EB-NPC aggregates showed higher cell proliferation and viability compared with the dissociated cells. Despite diffusion limitation at low MPIO concentration, higher concentration of MPIO (i.e., 10 µg Fe/mL) was able to label EB-NPC aggregates at similar efficiency to the single cells. In vitro MRI showed concentration-dependent MPIO detection in EB-NPCs over 2.0-2.6 population doublings. More important, MPIO incorporation did not affect the proliferation and neural differentiation of EB-NPCs. CONCLUSIONS: Multicellular EB-NPC aggregates can be efficiently labeled and tracked with MPIO while maintaining cell proliferation, phenotype and neural differentiation potential. This study demonstrated the feasibility of labeling EB-NPC aggregates with MPIO for cellular monitoring of in vitro cultures and in vivo transplantation.

Magnetic resonance contrast and biological effects of intracellular superparamagnetic iron oxides on human mesenchymal stem cells with long-term culture and hypoxic exposure.

BACKGROUND AIMS: Human mesenchymal stem cells (hMSCs) have gained interest for treatment of stroke injury. Using in vitro culture, the purpose of this study was to investigate the long-term detectability of hMSCs by magnetic resonance imaging (MRI) after transfection with a superparamagnetic iron oxide (SPIO) and evaluate the effects of SPIO on cellular activity, particularly under an ischemic environment. METHODS: hMSCs were exposed to low doses of SPIOs. After a short incubation period, cells were cultured for additional 1, 7 and 14 d to evaluate proliferation, colony formation and multilinear potential. Labeled cells were imaged and evaluated in agarose to quantify R2 and R2∗ contrast at each time point. Cells were placed in a low-oxygen, low-serum environment and tested for cytotoxicity. In addition, labeled cells were transplanted into an ischemic stroke model and evaluated with ex vivo MRI and histology. RESULTS: Cellular events such as proliferation and differentiation were not affected at any of the exposures tested when cultured for 14 d. The low iron exposure and short incubation time are sufficient for detectability with MRI. However, the higher iron dosage results in higher calcification and cytotoxicity under in vitro ischemic conditions. Transplantation of the hMSCs labeled with an initial exposure of 22.4 µg of Fe showed excellent retention of contrast in stroke-induced rats. CONCLUSIONS: Although SPIO labeling is stable for long-term MRI detection and has limited effects on the multilineage potential of hMSCs, high-dose SPIO labeling may affect hMSC survival under serum and oxygen withdrawal.

Frontal adenosine triphosphate markers from 31P MRS are associated with cognitive performance in healthy older adults: preliminary findings.

Aging is associated with declines in mitochondrial efficiency and energy production which directly impacts the availability of adenosine triphosphate (ATP), which contains high energy phosphates critical for a variety of cellular functions. Previous phosphorous magnetic resonance spectroscopy (31P MRS) studies demonstrate cerebral ATP declines with age. The purpose of this study was to explore the functional relationships of frontal and posterior ATP levels with cognition in healthy aging. Here, we measured frontal and posterior ATP levels using 31P MRS at 3 Tesla (3 T) and assessed cognition using the Montreal Cognitive Assessment (MoCA) in 30 healthy older adults. We found that greater frontal, but not posterior, ATP levels were significantly associated with better MoCA performance. This relationship remained significant after controlling for age, sex, years of education, and brain atrophy. In conclusion, our findings indicate that cognition is related to ATP in the frontal cortex. These preliminary findings may have important implications in the search for non-invasive markers of in vivo mitochondrial function and the impact of ATP availability on cognition. Future studies are needed to confirm the functional significance of regional ATP and cognition across the lifespan.

Nonparametric 5D D-R2 distribution imaging with single-shot EPI at 21.1 T: Initial results for in vivo rat brain.

In vivo human diffusion MRI is by default performed using single-shot EPI with greater than 50-ms echo times and associated signal loss from transverse relaxation. The individual benefits of the current trends of increasing B0 to boost SNR and employing more advanced signal preparation schemes to improve the specificity for selected microstructural properties eventually may be cancelled by increased relaxation rates at high B0 and echo times with advanced encoding. Here, initial attempts to translate state-of-the-art diffusion-relaxation correlation methods from 3 T to 21.1 T are made to identify hurdles that need to be overcome to fulfill the promises of both high SNR and readily interpretable microstructural information.

Extended Ischemic Recovery After Implantation of Human Mesenchymal Stem Cell Aggregates Indicated by Sodium MRI at 21.1 T.

Extended therapeutic application remains a significant issue in the use of stem cell therapies to treat ischemic stroke. Along these lines, neurological recovery in a rodent model of ischemic stroke was evaluated following implantation of human mesenchymal stem cell aggregates (hMSC-agg), labeled with micron-sized particles of iron oxide, directly into the lateral ventricle contralateral to the ischemic lesion hemisphere. Longitudinally, disease progression and response to hMSC-agg therapy were assessed by 1H and 23Na magnetic resonance imaging (MRI) at 21.1 T to investigate cellular localization, migration, and recovery over an extended timeframe. MRI provides quantifiable metrics of tissue status through sodium distributions in addition to traditional proton imaging. Quantitative 23Na MRI revealed a significant decrease of sodium concentrations following hMSC aggregate implantation, indicating recovery of homeostasis. This result correlates positively with extended neurological recovery assessed by behavioral analysis and immunohistochemistry. These findings demonstrate the potential of implanted hMSC aggregate therapy to provide extended treatment for ischemic stroke, as well as the robustness of MRI for monitoring such approaches. This method potentially can be translated to a clinical setting for the assessment of extended cell therapy efficacy.

A natural history study to track brain and spinal cord changes in individuals with Friedreich's ataxia: TRACK-FA study protocol.

INTRODUCTION: Drug development for neurodegenerative diseases such as Friedreich's ataxia (FRDA) is limited by a lack of validated, sensitive biomarkers of pharmacodynamic response in affected tissue and disease progression. Studies employing neuroimaging measures to track FRDA have thus far been limited by their small sample sizes and limited follow up. TRACK-FA, a longitudinal, multi-site, and multi-modal neuroimaging natural history study, aims to address these shortcomings by enabling better understanding of underlying pathology and identifying sensitive, clinical trial ready, neuroimaging biomarkers for FRDA. METHODS: 200 individuals with FRDA and 104 control participants will be recruited across seven international study sites. Inclusion criteria for participants with genetically confirmed FRDA involves, age of disease onset ≤ 25 years, Friedreich's Ataxia Rating Scale (FARS) functional staging score of ≤ 5, and a total modified FARS (mFARS) score of ≤ 65 upon enrolment. The control cohort is matched to the FRDA cohort for age, sex, handedness, and years of education. Participants will be evaluated at three study visits over two years. Each visit comprises of a harmonized multimodal Magnetic Resonance Imaging (MRI) and Spectroscopy (MRS) scan of the brain and spinal cord; clinical, cognitive, mood and speech assessments and collection of a blood sample. Primary outcome measures, informed by previous neuroimaging studies, include measures of: spinal cord and brain morphometry, spinal cord and brain microstructure (measured using diffusion MRI), brain iron accumulation (using Quantitative Susceptibility Mapping) and spinal cord biochemistry (using MRS). Secondary and exploratory outcome measures include clinical, cognitive assessments and blood biomarkers. DISCUSSION: Prioritising immediate areas of need, TRACK-FA aims to deliver a set of sensitive, clinical trial-ready neuroimaging biomarkers to accelerate drug discovery efforts and better understand disease trajectory. Once validated, these potential pharmacodynamic biomarkers can be used to measure the efficacy of new therapeutics in forestalling disease progression. CLINICAL TRIAL REGISTRATION: ClinicalTrails.gov Identifier: NCT04349514.

Intracellular bimodal nanoparticles based on quantum dots for high-field MRI at 21.1 T.

Multimodal, biocompatible contrast agents for high magnetic field applications represent a new class of nanomaterials with significant potential for tracking of fluorescence and MR in vitro and vivo. Optimized for high-field MR applications-including biomedical imaging at 21.1 T, the highest magnetic field available for MRI-these nanoparticles capitalize on the improved performance of chelated Dy(3+) with increasing magnetic field coupled to a noncytotoxic Indium Phosphide/Zinc Sulfide (InP/ZnS) quantum dot that provides fluorescence detection, MR responsiveness, and payload delivery. By surface modifying the quantum dot with a cell-penetrating peptide sequence coupled to an MR contrast agent, the bimodal nanomaterial functions as a self-transfecting high-field MR/optical contrast agent for nonspecific intracellular labeling. Fluorescent images confirm sequestration in perinuclear vesicles of labeled cells, with no apparent cytotoxicity. These techniques can be extended to impart cell selectivity or act as a delivery vehicle for genetic or pharmaceutical interventions.