Osteo-inductive effect of piezoelectric stimulation from the poly(l-lactic acid) scaffolds.

Piezoelectric biomaterials can generate piezoelectrical charges in response to mechanical activation. These generated charges can directly stimulate bone regeneration by triggering signaling pathway that is important for regulating osteogenesis of cells seeded on the materials. On the other hand, mechanical forces applied to the biomaterials play an important role in bone regeneration through the process called mechanotransduction. While mechanical force and electrical charges are both important contributing factors to bone tissue regeneration, they operate through different underlying mechanisms. The utilizations of piezoelectric biomaterials have been explored to serve as self-charged scaffolds which can promote stem cell differentiation and the formation of functional bone tissues. However, it is still not clear how mechanical activation and electrical charge act together on such a scaffold and which factors play more important role in the piezoelectric stimulation to induce osteogenesis. In our study, we found Poly(l-lactic acid) (PLLA)-based piezoelectric scaffolds with higher piezoelectric charges had a more pronounced osteoinductive effect than those with lower charges. This provided a new mechanistic insight that the observed osteoinductive effect of the piezoelectric PLLA scaffolds is likely due to the piezoelectric stimulation they provide, rather than mechanical stimulation alone. Our findings provide a crucial guide for the optimization of piezoelectric material design and usage.

Intense exercise increases dopamine transporter and neuromelanin concentrations in the substantia nigra in Parkinson's disease.

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons. Exercise has been reported to slow the clinical progression of PD. We evaluated the dopaminergic system of patients with mild and early PD before and after a six-month program of intense exercise. Using 18F-FE-PE2I PET imaging, we measured dopamine transporter (DAT) availability in the striatum and substantia nigra. Using NM-MRI, we evaluated the neuromelanin content in the substantia nigra. Exercise reversed the expected decrease in DAT availability into a significant increase in both the substantia nigra and putamen. Exercise also reversed the expected decrease in neuromelanin concentration in the substantia nigra into a significant increase. These findings suggest improved functionality in the remaining dopaminergic neurons after exercise. Further research is needed to validate our findings and to pinpoint the source of any true neuromodulatory and neuroprotective effects of exercise in PD in large clinical trials.

Multi-Echo Complex Quantitative Susceptibility Mapping and Quantitative Blood Oxygen Level-Dependent Magnitude (mcQSM + qBOLD or mcQQ) for Oxygen Extraction Fraction (OEF) Mapping.

Oxygen extraction fraction (OEF), the fraction of oxygen that tissue extracts from blood, is an essential biomarker used to directly assess tissue viability and function in neurologic disorders. In ischemic stroke, for example, increased OEF can indicate the presence of penumbra-tissue with low perfusion yet intact cellular integrity-making it a primary therapeutic target. However, practical OEF mapping methods are not currently available in clinical settings, owing to the impractical data acquisitions in positron emission tomography (PET) and the limitations of existing MRI techniques. Recently, a novel MRI-based OEF mapping technique, termed QQ, was proposed. It shows high potential for clinical use by utilizing a routine sequence and removing the need for impractical multiple gas inhalations. However, QQ relies on the assumptions of Gaussian noise in susceptibility and multi-echo gradient echo (mGRE) magnitude signals for OEF estimation. This assumption is unreliable in low signal-to-noise ratio (SNR) regions like disease-related lesions, risking inaccurate OEF estimation and potentially impacting clinical decisions. Addressing this, our study presents a novel multi-echo complex QQ (mcQQ) that models realistic Gaussian noise in mGRE complex signals. We implemented mcQQ using a deep learning framework (mcQQ-NET) and compared it with the existing QQ-NET in simulations, ischemic stroke patients, and healthy subjects, using identical training and testing datasets and schemes. In simulations, mcQQ-NET provided more accurate OEF than QQ-NET. In the subacute stroke patients, mcQQ-NET showed a lower average OEF ratio in lesions relative to unaffected contralateral normal tissue than QQ-NET. In the healthy subjects, mcQQ-NET provided uniform OEF maps, similar to QQ-NET, but without unrealistically high OEF outliers in areas of low SNR, such as SNR ≤ 15 (dB). Therefore, mcQQ-NET improves OEF accuracy by more accurately reflecting realistic Gaussian noise in complex mGRE signals. Its enhanced sensitivity to OEF abnormalities, based on more realistic biophysics modeling, suggests that mcQQ-NET has potential for investigating tissue variability in neurologic disorders.

Maximum spherical mean value filtering for whole-brain QSM.

PURPOSE: To develop a tissue field-filtering algorithm, called maximum spherical mean value (mSMV), for reducing shadow artifacts in QSM of the brain without requiring brain-tissue erosion. THEORY AND METHODS: Residual background field is a major source of shadow artifacts in QSM. The mSMV algorithm filters large field-magnitude values near the border, where the maximum value of the harmonic background field is located. The effectiveness of mSMV for artifact removal was evaluated by comparing existing QSM algorithms in numerical brain simulation as well as using in vivo human data acquired from 11 healthy volunteers and 93 patients. RESULTS: Numerical simulation showed that mSMV reduces shadow artifacts and improves QSM accuracy. Better shadow reduction, as demonstrated by lower QSM variation in the gray matter and higher QSM image quality score, was also observed in healthy subjects and in patients with hemorrhages, stroke, and multiple sclerosis. CONCLUSION: The mSMV algorithm allows QSM maps that are substantially equivalent to those obtained using SMV-filtered dipole inversion without eroding the volume of interest.

Parenchymal CSF fraction is a measure of brain glymphatic clearance and positively associated with amyloid beta deposition on PET.

INTRODUCTION: Mapping of microscopic changes in the perivascular space (PVS) of the cerebral cortex, beyond magnetic resonance-visible PVS in white matter, may enhance our ability to diagnose Alzheimer's disease (AD) early. METHODS: We used the cerebrospinal fluid (CSF) water fraction (CSFF), a magnetic resonance imaging-based biomarker, to characterize brain parenchymal CSF water, reflecting microscopic PVS in parenchyma. We measured CSFF and amyloid beta (Aß) using 11 C Pittsburgh compound B positron emission tomography to investigate their relationship at both the subject and voxel levels. RESULTS: Our research has demonstrated a positive correlation between the parenchymal CSFF, a non-invasive imaging biomarker indicative of parenchymal glymphatic clearance, and Aß deposition, observed at both individual and voxel-based assessments in the posterior cingulate cortex. DISCUSSION: This study shows that an increased parenchymal CSFF is associated with Aß deposition, suggesting that CSFF could serve as a biomarker for brain glymphatic clearance, which can be used to detect early fluid changes in PVS predisposing individuals to the development of AD. HIGHLIGHTS: Cerebrospinal fluid fraction (CSFF) could be a biomarker of parenchymal perivascular space. CSFF is positively associated with amyloid beta (Aß) deposition at subject level. CSFF in an Aß+ region is higher than in an Aß- region in the posterior cingulate cortex. Correspondence is found between Aß deposition and glymphatic clearance deficits measured by CSFF.

Injectable and biodegradable piezoelectric hydrogel for osteoarthritis treatment.

Osteoarthritis affects millions of people worldwide but current treatments using analgesics or anti-inflammatory drugs only alleviate symptoms of this disease. Here, we present an injectable, biodegradable piezoelectric hydrogel, made of short electrospun poly-L-lactic acid nanofibers embedded inside a collagen matrix, which can be injected into the joints and self-produce localized electrical cues under ultrasound activation to drive cartilage healing. In vitro, data shows that the piezoelectric hydrogel with ultrasound can enhance cell migration and induce stem cells to secrete TGF-ß1, which promotes chondrogenesis. In vivo, the rabbits with osteochondral critical-size defects receiving the ultrasound-activated piezoelectric hydrogel show increased subchondral bone formation, improved hyaline-cartilage structure, and good mechanical properties, close to healthy native cartilage. This piezoelectric hydrogel is not only useful for cartilage healing but also potentially applicable to other tissue regeneration, offering a significant impact on the field of regenerative tissue engineering.

Microstructure-Informed Myelin Mapping (MIMM) from Gradient Echo MRI using Stochastic Matching Pursuit.

Quantification of the myelin content of the white matter is important for studying demyelination in neurodegenerative diseases such as Multiple Sclerosis (MS), particularly for longitudinal monitoring. A novel noninvasive MRI method, called Microstructure-Informed Myelin Mapping (MIMM), is developed to quantify the myelin volume fraction (MVF) by utilizing a multi gradient echo sequence (mGRE) and a detailed biophysical model of tissue microstructure. Myelin is modeled as anisotropic negative susceptibility source based on the Hollow Cylindrical Fiber Model (HCFM), and iron as isotropic positive susceptibility source in the extracellular region. Voxels with a range of biophysical parameters are simulated to create a dictionary of MR echo time magnitude signals and total susceptibility values. MRI signals measured using a mGRE sequence are then matched voxel-by-voxel to the created dictionary to obtain the spatial distributions of myelin and iron. Three different MIMM versions are presented to deal with the fiber orientation dependent susceptibility effects of the myelin sheaths: a basic variation, which assumes fiber orientation is an unknown to fit, two orientation informed variations, which assume the fiber orientation distribution is available either from a separate diffusion tensor imaging (DTI) acquisition or from a DTI atlas based fiber orientation map. While all showed a significant linear correlation with the reference method based on T2-relaxometry (p < 0.0001), DTI orientation informed and atlas orientation informed variations reduced overestimation at white matter tracts compared to the basic variation. Finally, the implications and usefulness of attaining an additional iron susceptibility distribution map are discussed. Highlights: novel stochastic matching pursuit algorithm called microstructure-informed myelin mapping (MIMM) is developed to quantify Myelin Volume Fraction (MVF) using Magnetic Resonance Imaging (MRI) and microstructural modeling.utilizes a detailed biophysical model to capture the susceptibility effects on both magnitude and phase to quantify myelin and iron.matter fiber orientation effects are considered for the improved MVF quantification in the major fiber tracts.acquired myelin and iron maps may be utilized to monitor longitudinal disease progress.

Biodegradable piezoelectric skin-wound scaffold.

Electrical stimulation (ES) induces wound healing and skin regeneration. Combining ES with the tissue-engineering approach, which relies on biomaterials to construct a replacement tissue graft, could offer a self-stimulated scaffold to heal skin-wounds without using potentially toxic growth factors and exogenous cells. Unfortunately, current ES technologies are either ineffective (external stimulations) or unsafe (implanted electrical devices using toxic batteries). Hence, we propose a novel wound-healing strategy that integrates ES with tissue engineering techniques by utilizing a biodegradable self-charged piezoelectric PLLA (Poly (l-lactic acid)) nanofiber matrix. This unique, safe, and stable piezoelectric scaffold can be activated by an external ultrasound (US) to produce well-controlled surface-charges with different polarities, thus serving multiple functions to suppress bacterial growth (negative surface charge) and promote skin regeneration (positive surface charge) at the same time. We demonstrate that the scaffold activated by low intensity/low frequency US can facilitate the proliferation of fibroblast/epithelial cells, enhance expression of genes (collagen I, III, and fibronectin) typical for the wound healing process, and suppress the growth of S. aureus and P. aeruginosa bacteria in vitro simultaneously. This approach induces rapid skin regeneration in a critical-sized skin wound mouse model in vivo. The piezoelectric PLLA skin scaffold thus assumes the role of a multi-tasking, biodegradable, battery-free electrical stimulator which is important for skin-wound healing and bacterial infection prevention simultaneuosly.

Association of brain tissue cerebrospinal fluid fraction with age in healthy cognitively normal adults.

Background and purpose: Our objective was to apply multi-compartment T2 relaxometry in cognitively normal individuals aged 20-80 years to study the effect of aging on the parenchymal CSF fraction (CSFF), a potential measure of the subvoxel CSF space. Materials and methods: A total of 60 volunteers (age range, 22-80 years) were enrolled. Voxel-wise maps of short-T2 myelin water fraction (MWF), intermediate-T2 intra/extra-cellular water fraction (IEWF), and long-T2 CSFF were obtained using fast acquisition with spiral trajectory and adiabatic T2prep (FAST-T2) sequence and three-pool non-linear least squares fitting. Multiple linear regression analyses were performed to study the association between age and regional MWF, IEWF, and CSFF measurements, adjusting for sex and region of interest (ROI) volume. ROIs include the cerebral white matter (WM), cerebral cortex, and subcortical deep gray matter (GM). In each model, a quadratic term for age was tested using an ANOVA test. A Spearman's correlation between the normalized lateral ventricle volume, a measure of organ-level CSF space, and the regional CSFF, a measure of tissue-level CSF space, was computed. Results: Regression analyses showed that there was a statistically significant quadratic relationship with age for CSFF in the cortex (p = 0.018), MWF in the cerebral WM (p = 0.033), deep GM (p = 0.017) and cortex (p = 0.029); and IEWF in the deep GM (p = 0.033). There was a statistically highly significant positive linear relationship between age and regional CSFF in the cerebral WM (p < 0.001) and deep GM (p < 0.001). In addition, there was a statistically significant negative linear association between IEWF and age in the cerebral WM (p = 0.017) and cortex (p < 0.001). In the univariate correlation analysis, the normalized lateral ventricle volume correlated with the regional CSFF measurement in the cerebral WM (ρ = 0.64, p < 0.001), cortex (ρ = 0.62, p < 0.001), and deep GM (ρ = 0.66, p < 0.001). Conclusion: Our cross-sectional data demonstrate that brain tissue water in different compartments shows complex age-dependent patterns. Parenchymal CSFF, a measure of subvoxel CSF-like water in the brain tissue, is quadratically associated with age in the cerebral cortex and linearly associated with age in the cerebral deep GM and WM.

Highly piezoelectric, biodegradable, and flexible amino acid nanofibers for medical applications.

Amino acid crystals are an attractive piezoelectric material as they have an ultrahigh piezoelectric coefficient and have an appealing safety profile for medical implant applications. Unfortunately, solvent-cast films made from glycine crystals are brittle, quickly dissolve in body fluid, and lack crystal orientation control, reducing the overall piezoelectric effect. Here, we present a material processing strategy to create biodegradable, flexible, and piezoelectric nanofibers of glycine crystals embedded inside polycaprolactone (PCL). The glycine-PCL nanofiber film exhibits stable piezoelectric performance with a high ultrasound output of 334 kPa [under 0.15 voltage root-mean-square (Vrms)], which outperforms the state-of-the-art biodegradable transducers. We use this material to fabricate a biodegradable ultrasound transducer for facilitating the delivery of chemotherapeutic drug to the brain. The device remarkably enhances the animal survival time (twofold) in mice-bearing orthotopic glioblastoma models. The piezoelectric glycine-PCL presented here could offer an excellent platform not only for glioblastoma therapy but also for developing medical implantation fields.

Utilization of 2-nitrophenols in annulations with aryl isothiocyanates towards the synthesis of 2-aminobenzoxazoles.

A method for the annulation of 2-nitrophenols with aryl isothiocyanates is reported. The reactions proceeded in the presence of an iron(iii) acetylacetonate catalyst, elemental sulfur, NaOH as a base, and DMSO as a solvent. Derivatives of 2-aminobenzoxazoles bearing nitro, cyano, acetyl, sulfone, secondary amine, and pyrrolyl groups were successfully isolated.

Single-Administration Long-Acting Microarray Patch with Ultrahigh Loading Capacity and Multiple Releases of Thermally Stable Antibodies.

Current antibody (Ab) therapies require development of stable formulations and an optimal delivery system. Here, we present a new strategy to create a single-administration long-lasting Ab-delivery microarray (MA) patch, which can carry high doses of thermally stabilized Abs. The MA fabricated by an additive three-dimensional manufacturing technology can be fully embedded into the skin via a single application to deliver doses of Abs at multiple programmable time points, thus sustaining Ab concentrations in systemic circulation. We developed an MA formulation that stabilized and delivered human immunoglobulins (hIg) in a time-controlled manner while maintaining their structure and functionality. As an example, the b12 Ab─a broadly neutralizing Ab against HIV-1─maintained antiviral activity in vitro after MA manufacturing and heat exposure. Pharmacokinetic studies of MA patch-delivered hIg in rats successfully provided a proof of concept for concurrent and time-delayed Ab delivery. These MA patches codeliver different Abs, providing a tool for expanded protection against viral infections or combination HIV therapy and prevention.

Peripheral and Central Iron Measures in Alcohol Use Disorder and Aging: A Quantitative Susceptibility Mapping Pilot Study.

Chronic excessive alcohol use has neurotoxic effects, which may contribute to cognitive decline and the risk of early-onset dementia. Elevated peripheral iron levels have been reported in individuals with alcohol use disorder (AUD), but its association with brain iron loading has not been explored. We evaluated whether (1) serum and brain iron loading are higher in individuals with AUD than non-dependent healthy controls and (2) serum and brain iron loading increase with age. A fasting serum iron panel was obtained and a magnetic resonance imaging scan with quantitative susceptibility mapping (QSM) was used to quantify brain iron concentrations. Although serum ferritin levels were higher in the AUD group than in controls, whole-brain iron susceptibility did not differ between groups. Voxel-wise QSM analyses revealed higher susceptibility in a cluster in the left globus pallidus in individuals with AUD than controls. Whole-brain iron increased with age and voxel-wise QSM indicated higher susceptibility with age in various brain areas including the basal ganglia. This is the first study to analyze both serum and brain iron loading in individuals with AUD. Larger studies are needed to examine the effects of alcohol use on iron loading and its associations with alcohol use severity, structural and functional brain changes, and alcohol-induced cognitive impairments.

QSM Throughout the Body.

Magnetic materials in tissue, such as iron, calcium, or collagen, can be studied using quantitative susceptibility mapping (QSM). To date, QSM has been overwhelmingly applied in the brain, but is increasingly utilized outside the brain. QSM relies on the effect of tissue magnetic susceptibility sources on the MR signal phase obtained with gradient echo sequence. However, in the body, the chemical shift of fat present within the region of interest contributes to the MR signal phase as well. Therefore, correcting for the chemical shift effect by means of water-fat separation is essential for body QSM. By employing techniques to compensate for cardiac and respiratory motion artifacts, body QSM has been applied to study liver iron and fibrosis, heart chamber blood and placenta oxygenation, myocardial hemorrhage, atherosclerotic plaque, cartilage, bone, prostate, breast calcification, and kidney stone.

LARO: Learned acquisition and reconstruction optimization to accelerate quantitative susceptibility mapping.

Quantitative susceptibility mapping (QSM) involves acquisition and reconstruction of a series of images at multi-echo time points to estimate tissue field, which prolongs scan time and requires specific reconstruction technique. In this paper, we present our new framework, called Learned Acquisition and Reconstruction Optimization (LARO), which aims to accelerate the multi-echo gradient echo (mGRE) pulse sequence for QSM. Our approach involves optimizing a Cartesian multi-echo k-space sampling pattern with a deep reconstruction network. Next, this optimized sampling pattern was implemented in an mGRE sequence using Cartesian fan-beam k-space segmenting and ordering for prospective scans. Furthermore, we propose to insert a recurrent temporal feature fusion module into the reconstruction network to capture signal redundancies along echo time. Our ablation studies show that both the optimized sampling pattern and proposed reconstruction strategy help improve the quality of the multi-echo image reconstructions. Generalization experiments show that LARO is robust on the test data with new pathologies and different sequence parameters. Our code is available at https://github.com/Jinwei1209/LARO-QSM.git.

Photoresponsive polymeric microneedles: An innovative way to monitor and treat diseases.

Microneedles (MN) technology is an emerging technology for the transdermal delivery of therapeutics. When combined with photoresponsive (PR) materials, MNs can deliver therapeutics precisely and effectively with enhanced efficacy or synergistic effects. This review systematically summarizes the therapeutic applications of PRMNs in cancer therapy, wound healing, diabetes treatment, and diagnostics. Different PR approaches to activate and control the release of therapeutic agents from MNs are also discussed. Overall, PRMNs are a powerful tool for stimuli-responsive controlled-release therapeutic delivery to treat various diseases.

Fluid Mechanics Approach to Perfusion Quantification: Vasculature Computational Fluid Dynamics Simulation, Quantitative Transport Mapping (QTM) Analysis of Dynamics Contrast Enhanced MRI, and Application in Nonalcoholic Fatty Liver Disease Classification.

OBJECTIVE: We quantify liver perfusion using quantitative transport mapping (QTM) method that is free of arterial input function (AIF). QTM method is validated in a vasculature computational fluid dynamics (CFD) simulation and is applied for processing dynamic contrast enhanced (DCE) MRI images in differentiating liver with nonalcoholic fatty liver disease (NAFLD) from healthy controls using pathology reference in a preclinical rabbit model. METHODS: QTM method was validated on a liver perfusion simulation based on fluid dynamics using a rat liver vasculature model and the mass transport equation. In the NAFLD grading task, DCE MRI images of 7 adult rabbits with methionine choline-deficient diet-induced nonalcoholic steatohepatitis (NASH), 8 adult rabbits with simple steatosis (SS) were acquired and processed using QTM method and dual-input two compartment Kety's method respectively. Statistical analysis was performed on six perfusion parameters: velocity magnitude | u | derived from QTM, liver arterial blood flow LBFa, liver venous blood flow LBFv, permeability Ktrans, blood volume Vp and extravascular space volume Ve averaged in liver ROI. RESULTS: In the simulation, QTM method successfully reconstructed blood flow, reduced error by 48% compared to Kety's method. In the preclinical study, only QTM |u| showed significant difference between high grade NAFLD group and low grade NAFLD group. CONCLUSION: QTM postprocesses DCE-MRI automatically through deconvolution in space and time to solve the inverse problem of the transport equation. Comparing with Kety's method, QTM method showed higher accuracy and better differentiation in NAFLD classification task. SIGNIFICANCE: We propose to apply QTM method in liver DCE MRI perfusion quantification.

A comparative assessment of myelin-sensitive measures in multiple sclerosis patients and healthy subjects.

INTRODUCTION: Multiple Sclerosis (MS) is a common neurological disease primarily characterized by myelin damage in lesions and in normal - appearing white and gray matter (NAWM, NAGM). Several quantitative MRI (qMRI) methods are sensitive to myelin characteristics by measuring specific tissue biophysical properties. However, there are currently few studies assessing the relative reproducibility and sensitivity of qMRI measures to MS pathology in vivo in patients. METHODS: We performed two studies. The first study assessed of the sensitivity of qMRI measures to MS pathology: in this work, we recruited 150 MS and 100 healthy subjects, who underwent brain MRI at 3 T including quantitative T1 mapping (qT1), quantitative susceptibility mapping (QSM), magnetization transfer saturation imaging (MTsat) and myelin water imaging for myelin water fraction (MWF). The sensitivity of qMRIs to MS focal pathology (MS lesions vs peri-plaque white/gray matter (PPWM/PPGM)) was studied lesion-wise; the sensitivity to diffuse normal appearing (NA) pathology was measured using voxel-wise threshold-free cluster enhancement (TFCE) in NAWM and vertex-wise inflated cortex analysis in NAGM. Furthermore, the sensitivity of qMRI to the identification of lesion tissue was investigated using a voxel-wise logistic regression analysis to distinguish MS lesion and PP voxels. The second study assessed the reproducibility of myelin-sensitive qMRI measures in a single scanner. To evaluate the intra-session and inter-session reproducibility of qMRI measures, we have investigated 10 healthy subjects, who underwent two brain 3 T MRIs within the same day (without repositioning), and one after 1-week interval. Five region of interest (ROIs) in white and deep grey matter areas were segmented, and inter- and intra- session reproducibility was studied using the intra-class correlation coefficient (ICC). Further, we also investigated the voxel-wise reproducibility of qMRI measures in NAWM and NAGM. RESULTS: qT1 and QSM showed the highest sensitivity to distinguish MS focal WM and cortical pathology from peri-plaque WM (P < 0.0001), although QSM also showed the highest variance when applied to lesions. MWF and MTsat exhibited the highest sensitivity to NAWM pathology (P < 0.01). On the other hand, qT1 appeared to be the most sensitive measure to NAGM pathology (P < 0.01). All myelin-sensitive qMRI measures exhibited high inter/intra sessional ICCs in various WM and deep GM ROIs, in NAWM and in NAGM (ICC 0.82 ± 0.12). CONCLUSION: This work shows that the applied qT1, MWF, MTsat and QSM are highly reproducible and exhibit differential sensitivity to focal and diffuse WM and GM pathology in MS patients.

Magnetic Susceptibility Source Separation Solely from Gradient Echo Data: Histological Validation.

Quantitative susceptibility mapping (QSM) facilitates mapping of the bulk magnetic susceptibility of tissue from the phase of complex gradient echo (GRE) MRI data. QSM phase processing combined with an R2* model of magnitude of multiecho gradient echo data (R2*QSM) allows separation of dia- and para-magnetic components (e.g., myelin and iron) that contribute constructively to R2* value but destructively to the QSM value of a voxel. This R2*QSM technique is validated against quantitative histology­optical density of myelin basic protein and Perls' iron histological stains of rim and core of 10 ex vivo multiple sclerosis lesions, as well as neighboring normal appearing white matter. We found that R2*QSM source maps are in good qualitative agreement with histology, e.g., showing increased iron concentration at the edge of the rim+ lesions and myelin loss in the lesions' core. Furthermore, our results indicate statistically significant correlation between paramagnetic and diamagnetic tissue components estimated with R2*QSM and optical densities of Perls' and MPB stains. These findings provide direct support for the use of R2*QSM magnetic source separation based solely on GRE complex data to characterize MS lesion composition.

A New Advanced MRI Biomarker for Remyelinated Lesions in Multiple Sclerosis.

OBJECTIVES: Neuropathological studies have shown that multiple sclerosis (MS) lesions are heterogeneous in terms of myelin/axon damage and repair as well as iron content. However, it remains a challenge to identify specific chronic lesion types, especially remyelinated lesions, in vivo in patients with MS. METHODS: We performed 3 studies: (1) a cross-sectional study in a prospective cohort of 115 patients with MS and 76 healthy controls, who underwent 3 T magnetic resonance imaging (MRI) for quantitative susceptibility mapping (QSM), myelin water fraction (MWF), and neurite density index (NDI) maps. White matter (WM) lesions in QSM were classified into 5 QSM lesion types (iso-intense, hypo-intense, hyperintense, lesions with hypo-intense rims, and lesions with paramagnetic rim legions [PRLs]); (2) a longitudinal study of 40 patients with MS to study the evolution of lesions over 2 years; (3) a postmortem histopathology-QSM validation study in 3 brains of patients with MS to assess the accuracy of QSM classification to identify neuropathological lesion types in 63 WM lesions. RESULTS: At baseline, hypo- and isointense lesions showed higher mean MWF and NDI values compared to other QSM lesion types (p < 0.0001). Further, at 2-year follow-up, hypo-/iso-intense lesions showed an increase in MWF. Postmortem analyses revealed that QSM highly accurately identifies (1) fully remyelinated areas as hypo-/iso-intense (sensitivity = 88.89% and specificity = 100%), (2) chronic inactive lesions as hyperintense (sensitivity = 71.43% and specificity = 92.00%), and (3) chronic active/smoldering lesions as PRLs (sensitivity = 92.86% and specificity = 86.36%). INTERPRETATION: These results provide the first evidence that it is possible to distinguish chronic MS lesions in a clinical setting, hereby supporting with new biomarkers to develop and assess remyelinating treatments. ANN NEUROL 2022;92:486-502.