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Following severe injuries that result in disorders of consciousness, recovery can occur over many months or years post-injury. While post-injury synaptogenesis, axonal sprouting and functional reorganization are known to occur, the network-level processes underlying recovery are poorly understood. Here, we test a network-level functional rerouting hypothesis in recovery of patients with disorders of consciousness following severe brain injury. This hypothesis states that the brain recovers from injury by restoring normal functional connections via alternate structural pathways that circumvent impaired white matter connections. The so-called network diffusion model, which relates an individual's structural and functional connectomes by assuming that functional activation diffuses along structural pathways, is used here to capture this functional rerouting. We jointly examined functional and structural connectomes extracted from MRIs of 12 healthy and 16 brain-injured subjects. Connectome properties were quantified via graph theoretic measures and network diffusion model parameters. While a few graph metrics showed groupwise differences, they did not correlate with patients' level of consciousness as measured by the Coma Recovery Scale - Revised. There was, however, a strong and significant partial Pearson's correlation (accounting for age and years post-injury) between level of consciousness and network diffusion model propagation time (r = 0.76, p

Functional neuroimaging methods hold promise for the identification of cognitive function and communication capacity in some severely brain-injured patients who may not retain sufficient motor function to demonstrate their abilities. We studied seven severely brain-injured patients and a control group of 14 subjects using a novel hierarchical functional magnetic resonance imaging assessment utilizing mental imagery responses. Whereas the control group showed consistent and accurate (for communication) blood-oxygen-level-dependent responses without exception, the brain-injured subjects showed a wide variation in the correlation of blood-oxygen-level-dependent responses and overt behavioural responses. Specifically, the brain-injured subjects dissociated bedside and functional magnetic resonance imaging-based command following and communication capabilities. These observations reveal significant challenges in developing validated functional magnetic resonance imaging-based methods for clinical use and raise interesting questions about underlying brain function assayed using these methods in brain-injured subjects. [ABSTRACT FROM AUTHOR]

Purpose: Few studies have assessed trochanteric vascularity despite its implications for bone healing and surgical approaches. This study aimed to assess the regional arterial contributions of the medial femoral circumflex artery (MFCA) versus the lateral femoral circumflex artery (LFCA) to trochanteric vascularity., Methods: Ten adult human cadaveric pelvises to mid-femur specimens were obtained. One hip was randomly assigned experimental (either MFCA or LFCA MRI-contrast infusion) and contralateral as control (MFCA and LFCA magnetic resonance imaging [MRI]-contrast infusion). Vascular dissection was performed for MFCA and LFCA cannulation. Pre- and post-contrast 3T MRI was completed, and intra-osseous contributions were quantified by region: greater trochanter (GT), intertrochanteric (IT), lesser trochanter (LT) and subtrochanteric (ST). A polyurethane compound mixed with barium sulfate was injected into the LFCA cannula, and into the MFCA cannula for the contralateral hip. Computed tomography (CT) imaging was completed to assess terminal branch locations., Results: MFCA provided the majority of arterial contributions to the full trochanteric region (68.5% MFCA, 31.5% LFCA; standard deviation [SD]: 10.7%, p  < 0.001). Over 70% of arterial contributions to ST, LT and IT regions are derived from MFCA. GT contributions were more balanced (52.5% MFCA, 47.5% LFCA; SD: 33.7%; p  = 0.853). Significant differences were found between MFCA and LFCA contributions in all regions except for the GT. CT revealed multiple consistent MFCA and LFCA trochanteric terminal branches., Conclusions: MFCA provided the dominant trochanteric arterial supply, which highlights MFCA's importance to overall hip vascularity. LFCA's trochanteric contribution was smaller but still provided trochanteric contributions, especially the GT region. Knowledge of trochanteric arterial contributions can be beneficial for optimizing surgical approaches and fixation to protect terminal branches during trochanteric fracture, nonunion treatment and trochanteric osteotomies., Level of Evidence: Not applicable., Competing Interests: David L. Helfet reports ownership interest in Healthpoint Capital, LP and Advisory Board membership in Diamond Orthopaedics, and OHK Medical Devices, Inc., outside of the scope of the submitted work. David S. Wellman reports personal fees from DePuy Johnson and Johnson, and OrthoDevelopment outside of the scope of the submitted work. The remaining authors declare no conflict of interest., (© 2024 The Author(s). Journal of Experimental Orthopaedics published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Here, we report a magnetogenetic system, based on a single anti-ferritin nanobody-TRPV1 receptor fusion protein, which regulated neuronal activity when exposed to magnetic fields. Adeno-associated virus (AAV)-mediated delivery of a floxed nanobody-TRPV1 into the striatum of adenosine-2a receptor-Cre drivers resulted in motor freezing when placed in a magnetic resonance imaging machine or adjacent to a transcranial magnetic stimulation device. Functional imaging and fiber photometry confirmed activation in response to magnetic fields. Expression of the same construct in the striatum of wild-type mice along with a second injection of an AAVretro expressing Cre into the globus pallidus led to similar circuit specificity and motor responses. Last, a mutation was generated to gate chloride and inhibit neuronal activity. Expression of this variant in the subthalamic nucleus in PitX2-Cre parkinsonian mice resulted in reduced c-fos expression and motor rotational behavior. These data demonstrate that magnetogenetic constructs can bidirectionally regulate activity of specific neuronal circuits noninvasively in vivo using clinically available devices.

Background: Distal femur fractures remain treatment challenges with a considerable postoperative non-union rate. Concern remains that surgery may compromise osseous vascularity. This study aimed to determine effects of retrograde femoral intramedullary nailing (RFIN) on distal femur vascularity, and the locations of the middle genicular artery terminal branches in relation to the standard RFIN entry point., Methods: Five lower limb cadaveric pairs were obtained (ten specimens). Experimental limbs were randomly assigned, and contralateral limbs served as controls. An 11 mm femoral nail was implanted in experimental specimens. Controls only underwent a medial parapatellar incision with capsulotomy. Quantitative pre- and post-contrast-MRI was performed to assess arterial contributions to distal femur regions. Osseous vascularity was further evaluated with contrast-CT imaging. Next, specimens were injected with latex medium, and dissection was performed to assess extraosseous vasculature., Results: No statistically significant differences were found with quantitative-MRI in experimental and control groups for the entire distal femur or individual regions. The experimental group demonstrated a small mean decrease of 1.4% in distal femur arterial contributions. CT and anatomic dissection confirmed maintenance of middle genicular artery terminal branches. On average, 3.3 (±1.3) terminal branches entered along the posterior intercondylar notch. A mean distance of 15.2 mm (±6.9 mm) was found between the posterior RFIN entry point and these terminal branches., Conclusions: RFIN did not significantly alter arterial contributions to the distal femur or disrupt the middle genicular artery terminal branches. However, care must be taken to ensure nail entry point accuracy given proximity of the entry point to terminal branches., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

17β-estradiol, the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo brain 18 F-fluoroestradiol ( 18 F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age, plasma estradiol and sex hormone binding globulin, and were highly consistent, correctly classifying all women as being postmenopausal or premenopausal. Higher ER density in target regions was associated with poorer memory performance for both postmenopausal and perimenopausal groups, and predicted presence of self-reported mood and cognitive symptoms after menopause. These findings provide novel insights on brain ER density modulation by female neuroendocrine aging, with clinical implications for women's health., (© 2024. The Author(s).)

Osteoarthritis (OA) is now considered as a multifaceted disease affecting various articular tissues, including cartilage, bone, synovium, and surrounding ligaments. The pathophysiology strongly implicates intricate chemical communication, primarily through cytokines, leading to the production of degradative enzymes in cartilage, inflammatory peptides in synovium, and structural changes in bone, resulting in characteristic clinical features such as joint deformities and loss of cartilage space seen on X-rays. Recent studies highlight the previously underestimated role of subchondral bone in OA, revealing its permeability to cytokines and raising questions about the influence of abnormal perfusion on OA pathophysiology, suggesting a vascular component in the disease's etiology. In essence, alterations in bone perfusion, including reduced venous outflow and intraosseous hypertension, play a crucial role in influencing the physicochemical environment of subchondral bone, impacting osteoblast cytokine expression and contributing to trabecular remodeling, changes in chondrocyte phenotype, and ultimately cartilage matrix degeneration in OA. Dynamic contrast (gadolinium) enhanced magnetic resonance imaging (DCE-MRI) was used to quantify perfusion kinetics in normal and osteoarthritic subchondral bone, demonstrating that decreased perfusion temporally precedes and spatially correlates with cartilage lesions in both young Dunkin-Hartley (D-H) guinea pigs and humans with osteoarthritis. Pharmacokinetic analysis of DCE-MRI generated data reveals decreased tracer clearance and outflow obstruction in the medial tibial plateau of osteoarthritic guinea pigs, coinciding with progressive cartilage degradation, loss of Safranin O staining, and increased expression of matrix metalloproteinases and interleukin-1. Positron emission tomographic (PET) scanning using 18F-Fluoride reveals a relationship among bone blood flow, cartilage lesions, and 18F-Fluoride influx rate in OA, highlighting the intricate relationships between decreased perfusion, altered bone metabolism, and the progression of osteoarthritis. These findings, supported by 18F-Fluoride PET data, suggest the presence of venous stasis associated with outflow obstruction, emphasizing the role of decreased subchondral bone perfusion in the pathophysiology of OA and its association with reduced osteoblast activity and advanced cartilage degeneration., Competing Interests: The authors declare no conflict of interest. Given the role as Guest Editor, Roy K. Aaron had no involvement in the peer-review of this article and has no access to information regarding its peer-review. Full responsibility for the editorial process for this article was delegated to Emerito Carlos Rodriguez-Merchan., (© 2024 The Author(s). Published by IMR Press.)

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer's disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher β-amyloid (Aβ) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aβ load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention., (© 2024. The Author(s).)

Background: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease., Methods: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete., Findings: Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths., Interpretation: Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment., Funding: BioMarin Pharmaceutical., Competing Interests: Declaration of interests AS and MN have received payments to their institution as a study site according to clinical trial budget, medical writing support, honoraria, and travel support from BioMarin Pharmaceutical. EDLR has received salary support as the primary investigator and salary support for the research personnel, honoraria, and travel support from BioMarin Pharmaceutical and consulting fees from Zogenix. NS has received consulting fees from BioMarin Pharmaceutical, JAZZ Pharma, UCB, Takeda, and Angeun; honoraria from BioMarin Pharmaceutical, JAZZ Pharma, UCB, and Zogenix; travel fees from BioMarin Pharmaceutical and Jazz Pharma; and current research funding from the Italian Ministry of Health. PG has received payments to his institution as a study site according to clinical trial budget and honoraria and travel support from BioMarin Pharmaceutical. MT has received honoraria from BioMarin Pharmaceutical and current research funding from the Italian Ministry of Health. SCA has received research salary support from BioMarin Pharmaceutical, research effort support for a study of erenumab from Amgen, research effort support for a study of rimegepant from Pfizer, grant support for fellowship training from NINDS/Neuronext, and honoraria as associate editor from Pediatric Neurology. DJB and JPD have received contractor fees paid by BioMarin Pharmaceutical for analysing imaging data that appears in the paper. PS is an employee and stockholder of BioMarin Pharmaceutical. SB and AChe are employees of BioMarin Pharmaceutical. JLCP is an employee and stockholder of BioMarin Pharmaceutical and a scientific advisor for NPKUA. ACha, CS, EW, and LMW reported no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Based on studies in experimental animals demonstrating that administration of adeno-associated virus (AAV) vectors to the cerebrospinal fluid (CSF) is an effective route to transfer genes to the nervous system, there are increasing number of clinical trials using the CSF route to treat nervous system disorders. With the knowledge that the CSF turns over four to five times daily, and evidence in experimental animals that at least some of CSF administered AAV vectors are distributed to systemic organs, we asked: with AAV administration to the CSF, what fraction of the total dose remains in the nervous system and what fraction goes off target and is delivered systemically? To quantify the biodistribution of AAV capsids immediately after administration, we covalently labeled AAV capsids with iodine 124 (I-124), a cyclotron generated positron emitter, enabling quantitative positron emission tomography scanning of capsid distribution for up to 96 h after AAV vector administration. We assessed the biodistribution to nonhuman primates of I-124-labeled capsids from different AAV clades, including 9 (clade F), rh.10 (E), PHP.eB (F), hu68 (F), and rh91(A). The analysis demonstrated that 60-90% of AAV vectors administered to the CSF through either the intracisternal or intrathecal (lumbar) routes distributed systemically to major organs. These observations have potentially significant clinical implications regarding accuracy of AAV vector dosing to the nervous system, evoking systemic immunity at levels similar to that with systemic administration, and potential toxicity of genes designed to treat nervous system disorders being expressed in non-nervous system organs. Based on these data, individuals in clinical trials using AAV vectors administered to the CSF should be monitored for systemic as well as nervous system adverse events and CNS dosing considerations should account for a significant AAV systemic distribution.

Objectives: To assess the effects of Krackow suture technique on the vascularity of the patellar tendon., Methods: Six fresh-frozen matched pair cadaveric knee specimens were used. The superficial femoral arteries were cannulated in all knees. The experimental knee underwent an anterior approach, patellar tendon transection from the inferior pole of the patella, 4-strand Krackow stitch placement, patellar tendon repair via 3-bone tunnels, and standard skin closure. The control knee underwent the identical procedure without Krackow stitching. All specimens then underwent precontrast and postcontrast enhanced quantitative magnetic resonance imaging assessment (with gadolinium-based contrast agent). Region of interest analysis was performed to assess for variation in signal enhancement between the experimental and control limbs in various patellar tendon regions and subregions. Latex infusion and anatomical dissection were performed to further evaluate vessel integrity and assess extrinsic vascularity., Results: Quantitative magnetic resonance imaging analysis demonstrated no statistically significant difference in overall arterial contributions. A small but nonsignificant decrease of 7.5% (SD ± 7.1%) in arterial contributions to the entire tendon was observed. Small nonstatistically significant regional decreases throughout the tendon were also detected. In the regional analysis, the largest to smallest decreases in arterial contributions after suture placement were found in the inferomedial, superolateral, lateral, and inferior tendon subregions. In the anatomical dissection, nutrient branches were seen dorsally and posteroinferiorly., Conclusion: The vascularity of the patellar tendon was not significantly affected by Krackow suture placement. Analysis demonstrated small and not statistically significant decreases in arterial contributions, suggesting this technique does not significantly compromise arterial perfusion., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Purpose: The choroid plexus (CP) within the brain ventricles is well-known to produce cerebrospinal fluid (CSF). Recently, the CP has been recognized as critical in modulating inflammation. MRI-measured CP enlargement has been reported in neuroinflammatory disorders like MS as well as with aging and neurodegeneration. The basis of MRI-measured CP enlargement is unknown. On the basis of tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously unmeasured CP calcification contributes to MRI-measured CP volume and may be more specifically associated with neuroinflammation., Materials and Methods: We analyzed 60 subjects (43 healthy controls and 17 subjects with Parkinson's disease) who underwent PET/CT using 11 C-PK11195, a radiotracer sensitive to the translocator protein expressed by activated microglia. Cortical inflammation was quantified as nondisplaceable binding potential. Choroid plexus calcium was measured via manual tracing on low-dose CT acquired with PET and automatically using a new CT/MRI method. Linear regression assessed the contribution of choroid plexus calcium, age, diagnosis, sex, overall volume of the choroid plexus, and ventricle volume to cortical inflammation., Results: Fully automated choroid plexus calcium quantification was accurate (intraclass correlation coefficient with manual tracing = .98). Subject age and choroid plexus calcium were the only significant predictors of neuroinflammation., Conclusions: Choroid plexus calcification can be accurately and automatically quantified using low-dose CT and MRI. Choroid plexus calcification-but not choroid plexus volume-predicted cortical inflammation. Previously unmeasured choroid plexus calcium may explain recent reports of choroid plexus enlargement in human inflammatory and other diseases. Choroid plexus calcification may be a specific and relatively easily acquired biomarker for neuroinflammation and choroid plexus pathology in humans., (© 2023 by American Journal of Neuroradiology.)

Background: The development of materials with tailored signal intensity in MR imaging is critically important both for the reduction of signal from non-tissue hardware, as well as for the construction of tissue-mimicking phantoms. Silicone-based phantoms are becoming more popular due to their structural stability, stretchability, longer shelf life, and ease of handling, as well as for their application in dynamic imaging of physiology in motion. Moreover, silicone can be also used for the design of stretchable receive radio-frequency (RF) coils., Purpose: Fabrication of materials with tailored signal intensity for MRI requires knowledge of precise T 1 and T 2 relaxation times of the materials used. In order to increase the range of possible relaxation times, silicone materials can be doped with gadolinium (Gd). In this work, we aim to systematically evaluate relaxation properties of Gd-doped silicone material at a broad range of Gd concentrations and at three clinically relevant magnetic field strengths (1.5 T, 3 T, and 7 T). We apply the findings for rendering silicone substrates of stretchable receive RF coils less visible in MRI. Moreover, we demonstrate early stage proof-of-concept applicability in tissue-mimicking phantom development., Materials and Methods: Ten samples of pure and Gd-doped Ecoflex silicone polymer samples were prepared with various Gd volume ratios ranging from 1:5000 to 1:10, and studied using 1.5 T and 3 T clinical and 7 T preclinical scanners. T 1 and T 2 relaxation times of each sample were derived by fitting the data to Bloch signal intensity equations. A receive coil made from Gd-doped Ecoflex silicone polymer was fabricated and evaluated in vitro at 3 T., Results: With the addition of a Gd-based contrast agent, it is possible to significantly change T 2 relaxation times of Ecoflex silicone polymer (from 213 ms to 20 ms at 1.5 T; from 135 ms to 17 ms at 3 T; and from 111.4 ms to 17.2 ms at 7 T). T 1 relaxation time is less affected by the introduction of the contrast agent (changes from 608 ms to 579 ms; from 802.5 ms to 713 ms at 3 T; from 1276 ms to 979 ms at 7 T). First results also indicate that liver, pancreas, and white matter tissues can potentially be closely mimicked using this phantom preparation technique. Gd-doping reduces the appearance of the silicone-based coil substrate during the MR scan by up to 81%., Conclusions: Gd-based contrast agents can be effectively used to create Ecoflex silicone polymer-based phantoms with tailored T 2 relaxation properties. The relative low cost, ease of preparation, stretchability, mechanical stability, and long shelf life of Ecoflex silicone polymer all make it a good candidate for "MR invisible" coil development and bears promise for tissue-mimicking phantom development applicability., (© 2023 American Association of Physicists in Medicine.)

Background: The most common chronic complication of preterm birth is bronchopulmonary dysplasia (BPD), widely referred to as chronic lung disease of prematurity. All current definitions rely on characterizing the disease based on respiratory support level and do not provide full understanding of the underlying cardiopulmonary pathophysiology., Objective: To evaluate a rapid functional lung imaging technique in premature infants and to quantitate pulmonary ventilation using 1.5 Tesla magnetic resonance imaging (MRI)., Materials and Methods: We conducted a prospective MRI study of 12 premature infants in the neonatal intensive care unit (NICU) using the phase resolved functional lung MRI technique to calculate pulmonary ventilation parameters in preterm infants with and without BPD grade 0/1 (n = 6) and grade 2/3 (n = 6)., Results: The total ventilation defect percentage showed a significant difference between groups (16.0% IQR (11.0%,18%) BPD grade 2/3 vs. 8.0% IQR (4.5%,9.0%) BPD grade 0/1, p = 0.01)., Conclusion: Phase-resolved functional lung MRI is feasible for assessment of ventilation defect percentages in preterm infants and shows regional variation in localized lung function in this population., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Normal pressure hydrocephalus (NPH) is a neurodegenerative disease that is potentially reversible by shunt surgery in approximately 60% of patients. Imaging may provide a means to investigate brain tissue viability and oxygen metabolism in NPH patients., Methods: Oxygen extraction fraction (OEF) mapping was generated from 3D multi-echo gradient echo MRI (mGRE) data using QQ-CCTV algorithm and cerebral blood flow (CBF) using 3D arterial spin labeling (ASL) MRI data, thereby calculating the cerebral metabolic rate of oxygen (CMRO 2  = CBF × OEF × [H] a ) in 16 NPH patients. Regression analyses using cortical gray matter and deep gray matter regions were conducted with age, gender, CSF stroke volume and normalized ventricular volume as independent variables., Results: OEF showed significant negative correlations with normalized brain ventricular volumes in the whole brain (p = 0.004, q = 0.01), cortical gray matter (p = 0.004, q = 0.01), caudate (p = 0.02, q = 0.04), and pallidum (p = 0.03, q = 0.04), but no significant correlation with CSF stroke volume (q > 0.05). There was no significant finding with CBF or CMRO 2 ., Conclusion: In NPH patients, low OEF in several regions was significantly correlated with large ventricular volumes, indicating decreased tissue oxygen metabolism with increased NPH severity. OEF mapping may provide a functional understanding of neurodegeneration in NPH and may improve monitoring of disease course and treatment outcomes., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Age, female sex, and APOE epsilon 4 (APOE4) genotype are the three greatest risk factors for late-onset Alzheimer's disease (AD). The convergence of these risks creates a hypometabolic AD-risk profile unique to women, which may help explain their higher lifetime risk of AD. Less is known about APOE4 effects in men, although APOE4 positive men also experience an increased AD risk. This study uses 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to examine effects of sex and APOE4 status on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters (PME), phosphodiesters (PDE)] in 209 cognitively normal individuals at risk for AD, ages 40-65, 80% female, 46% APOE4 carriers (APOE4+). Women exhibited lower PCr/ATP and PCr/Pi levels than men in AD-vulnerable regions, including frontal, posterior cingulate, lateral and medial temporal cortex (multi-variable adjusted p≤0.037). The APOE4+ group exhibited lower PCr/ATP and PCr/Pi in frontal regions as compared to non-carriers (APOE4-) (multi-variable adjusted p≤0.005). Sex by APOE4 status interactions were observed in frontal regions (multi-variable adjusted p≤0.046), where both female groups and APOE4+ men exhibited lower PCr/ATP and PCr/Pi than APOE4- men. Among men, APOE4 homozygotes exhibited lower frontal PCr/ATP than heterozygotes and non-carriers. There were no significant effects of sex or APOE4 status on Pi/ATP and PME/PDE measures. Among midlife individuals at risk for AD, women exhibit lower PCr/ATP (e.g. higher ATP utilization) and lower PCr/Pi (e.g. higher energy demand) than age-controlled men, independent of APOE4 status. However, a double dose of APOE4 allele shifted men's brains to a similar metabolic range as women's brains. Examination of brain metabolic heterogeneity can support identification of AD-specific pathways within at-risk subgroups, further advancing both preventive and precision medicine for AD., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: In preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women., Methods: We examined 191 women ages 40-65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11 C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses., Results: FSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P ≤0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted P FWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted P FWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores., Discussion: Increasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: A serious concern with surgical procedures around the hip joint is iatrogenic injury of the arterial supply to the femoral head (FH) and consequent development of FH osteonecrosis. Cam-type morphology can extend to the posterosuperior area. Understanding the limit of the posterior superior extension of the femoral osteochondroplasty is paramount to avoid underresection and residual impingement while maintaining FH vascularity., Purpose/hypothesis: The aim of this study was to quantify the impact of arthroscopic femoral osteochondroplasty on the FH vascular supply. It was hypothesized that keeping the superior extension of the resection zone anterior to the 12-o'clock position would maintain FH vascularity., Study Design: Case series; Level of evidence, 4., Methods: Ten adult patients undergoing arthroscopic femoroacetabular impingement (FAI) surgery were included in the study. Computed tomography (CT) scans were obtained before and after arthroscopic osteochondroplasty to define the extension of resection margins. To quantify FH vascularity, postoperative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was obtained at 2 time points: immediately after surgery and at the 3-month follow-up. Custom MRI analysis software was used to quantify perfusion., Results: CT scan analysis demonstrated that the superior resection margin was maintained anterior to the 12-o'clock position in half of the patients. The remining 5 patients had a mean posterior extension of 11.4° ± 7.5°. The immediate postoperative DCE-MRI revealed diminished venous outflow in the operative side but no difference in overall FH perfusion. At the 3-month follow-up DCE-MRI, there was no perfusion difference between the operative and nonoperative FHs., Conclusion: This study provides previously unreported quantitative MRI data on in vivo perfusion of the FH after the commonly performed arthroscopic femoral osteochondroplasty for the treatment of cam-type FAI. Maintaining resection margins anterior to the 12-o'clock position, or even 10° posteriorly, was not observed to impair perfusion to the FH., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: L.E.L. has received grant support from DJO, education payments from Arthrex and Smith & Nephew, and hospitality payments from Stryker. M.B.B. has received education payments from Arthrex, consulting fees from Stryker and Vericel, speaking fees from Arthrex and Smith & Nephew, and honoraria from Vericel. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2022.)

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer's disease (AD) in women. We conducted 31 Phosphorus Magnetic Resonance Spectroscopy ( 31 P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aβ) 11 C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aβ load were not significant, individuals with the highest Aβ load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging., (© 2022. The Author(s).)

Cerebrospinal fluid (CSF), predominantly produced in the ventricles and circulating throughout the brain and spinal cord, is a key protective mechanism of the central nervous system (CNS). Physical cushioning, nutrient delivery, metabolic waste, including protein clearance, are key functions of the CSF in humans. CSF volume and flow dynamics regulate intracranial pressure and are fundamental to diagnosing disorders including normal pressure hydrocephalus, intracranial hypotension, CSF leaks, and possibly Alzheimer's disease (AD). The ability of CSF to clear normal and pathological proteins, such as amyloid-beta (Aβ), tau, alpha synuclein and others, implicates it production, circulation, and composition, in many neuropathologies. Several neuroimaging modalities have been developed to probe CSF fluid dynamics and better relate CSF volume and flow to anatomy and clinical conditions. Approaches include 2-photon microscopic techniques, MRI (tracer-based, gadolinium contrast, endogenous phase-contrast), and dynamic positron emission tomography (PET) using existing approved radiotracers. Here, we discuss CSF flow neuroimaging, from animal models to recent clinical-research advances, summarizing current endeavors to quantify and map CSF flow with implications towards pathophysiology, new biomarkers, and treatments of neurological diseases., (Copyright © 2022. Published by Elsevier Inc.)

Ovarian hormones, particularly 17β-estradiol, are involved in numerous neurophysiological and neurochemical processes, including those subserving cognitive function. Estradiol plays a key role in the neurobiology of aging, in part due to extensive interconnectivity of the neural and endocrine system. This aspect of aging is fundamental for women's brains as all women experience a drop in circulating estradiol levels in midlife, after menopause. Given the importance of estradiol for brain function, it is not surprising that up to 80% of peri-menopausal and post-menopausal women report neurological symptoms including changes in thermoregulation (vasomotor symptoms), mood, sleep, and cognitive performance. Preclinical evidence for neuroprotective effects of 17β-estradiol also indicate associations between menopause, cognitive aging, and Alzheimer's disease (AD), the most common cause of dementia affecting nearly twice more women than men. Brain imaging studies demonstrated that middle-aged women exhibit increased indicators of AD endophenotype as compared to men of the same age, with onset in perimenopause. Herein, we take a translational approach to illustrate the contribution of ovarian hormones in maintaining cognition in women, with evidence implicating menopause-related declines in 17β-estradiol in cognitive aging and AD risk. We will review research focused on the role of endogenous and exogenous estrogen exposure as a key underlying mechanism to neuropathological aging in women, with a focus on whether brain structure, function and neurochemistry respond to hormone treatment. While still in development, this research area offers a new sex-based perspective on brain aging and risk of AD, while also highlighting an urgent need for better integration between neurology, psychiatry, and women's health practices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jett, Schelbaum, Jang, Boneu Yepez, Dyke, Pahlajani, Diaz Brinton and Mosconi.)

Purpose: Surgical reconstruction is the current standard for ACL rupture treatment in active individuals. Recently, there is renewed interest in primary repair of proximal ACL tears. Despite this, ACL biology and healing potential are currently not well understood. Vascularity is paramount in ACL healing; however, previous ACL vascularity studies have been limited to qualitative histological and dissection-based techniques. The study objective was to use contrast-enhanced quantitative-MRI to compare relative perfusion of proximal, middle, and distal thirds of the in situ ACL. We hypothesized perfusion would be greatest in the proximal third., Methods: Fourteen cadaveric knees were studied (8 females, 6 males), age 25-61 years. Superficial femoral, anterior tibial, and posterior tibial arteries were cannulated; without intraarticular dissection. Contrast-enhanced quantitative-MRI was performed using a previously established protocol. ACL regions corresponding to proximal, middle, and distal thirds were identified on sagittal-oblique pre-contrast images. Signal enhancement (normalized to tibial plateau cartilage) was quantified to represent regional perfusion as a percentage of total ACL perfusion. Comparative statistics were computed using repeated measures ANOVA, and pairwise comparisons performed using the Bonferroni method., Results: Relative perfusion to proximal, middle, and distal ACL zones were 56.0% ±17.4%, 28.2% ±14.6%, and 15.8% ±16.3%, respectively (p = 0.002). Relative perfusion to the proximal third was significantly greater than middle (p = 0.007) and distal (p = 0.001). No statistically relevant difference in relative perfusion was found to middle and distal thirds (p = 0.281). Post-hoc subgroup analysis demonstrated greater proximal perfusion in males (66.9% ± 17.3%) than females (47.8% ± 13.0%), p = 0.036., Conclusion: Using quantitative-MRI, in situ adult ACL demonstrated greatest relative perfusion to the proximal third, nearly 2 times greater than the middle third and 3 times greater than the distal third. Knowledge of differential ACL vascular supply is important for understanding pathogenesis of ACL injury and the process of biological healing following various forms of surgical treatment., (© 2022. The Author(s).)

Purpose: Injury to or abnormality of developing distal femoral chondroepiphysis blood supply has been implicated in osteochondritis dissecans development. Progressive decrease in epiphyseal cartilage blood supply occurs in normal development; however, based on animal studies, it is hypothesized that there is greater decrease in regions more prone to osteochondritis dissecans lesions. We aimed to quantify differential regional perfusion of the immature distal femoral chondroepiphysis. We hypothesized there is decreased perfusion in the lateral aspect of the medial femoral condyle, the classic osteochondritis dissecans lesion location., Methods: Five fresh-frozen human cadaveric knees (0-6 months old) were utilized. The superficial femoral artery was cannulated proximally and contrast-enhanced magnetic resonance imaging performed using a previously reported protocol for quantifying osseous and soft tissue perfusion. Regions of interest were defined, and signal enhancement changes between pre- and post-contrast images, normalized to background muscle, were compared., Results: When comparing average normalized post-contrast signal enhancement of whole condyles, as well as distal, posterior, and inner (toward the notch) aspects of the medial and lateral condyles, no significant perfusion differences between condyles were found. In the medial condyle, no significant perfusion difference was found between the medial and lateral aspects., Conclusion: We quantified immature distal femoral chondroepiphysis regional vascularity in the early post-natal knee. In specimens aged 0-6 months, no distinct watershed region was detected. Despite possible limitations, given small sample size, as well as resolution of magnetic resonance imaging and analysis, our results suggest the hypothesized vascular abnormality predisposing osteochondritis dissecans either does not occur universally or occurs after this developmental age., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: N.E.G., K.M.L., C.E.K., L.J.K., K.G.S., J.P.D., D.L.H., D.W.G., and L.E.L. declare that they have no conflict of interest. S.A.R. reports personal fees from Advance Medical/Teladoc, personal fees from Ortho RTI, Inc., outside the submitted work., (© The Author(s) 2022.)

Repeated mild Traumatic Brain Injury (TBI) is a risk factor for Chronic Traumatic Encephalopathy (CTE), characterized pathologically by neurofibrillary tau deposition in the depths of brain sulci and surrounding blood vessels. The mechanism by which TBI leads to CTE remains unknown but has been posited to relate to axonal shear injury leading to release and possibly deposition of tau at the time of injury. As part of an IRB-approved study designed to learn how processes occurring acutely after TBI may predict later proteinopathy and neurodegeneration, we performed tau PET using 18F-MK6240 and MRI within 14 days of complicated mild TBI in three subjects. PET radiotracer accumulation was apparent in regions of traumatic hemorrhage in all subjects, with prominent intraparenchymal PET signal in one young subject with a history of repeated sports-related concussions. These results are consistent with off-target tracer binding to blood products as well as possible on-target binding to chronically and/or acutely-deposited neurofibrillary tau. Both explanations are highly relevant to applying tau PET to understanding TBI and CTE. Additional study is needed to assess the potential utility of tau PET in understanding how processes occurring acutely after TBI, such as release and deposition of tau and blood from damaged axons and blood vessels, may relate to development CTE years later., Competing Interests: Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: The availability of non-invasive means to evaluate and monitor tendon-bone healing processes in-vivo is limited. Micro Positron-Emission-Tomography (µPET) using 18 F-Fluoride is a minimally invasive imaging modality, with which osteoblast activity and bone turnover can be assessed. The aim of this study was to investigate the use of serial in-vivo µPET/CT scans to evaluate bone turnover along the graft-tunnel interface in a rat ACL (anterior cruciate ligament) reconstruction model., Methods: Unilateral autograft ACL reconstruction was performed in six rats. µPET/CT-scans using 18 F-Fluoride were performed 7, 14, 21, and 28 days postoperatively. Standard uptake values (SUV) were calculated for three tunnel regions (intraarticular aperture (IAA), mid-tunnel, and extraarticular aperture (EAA)) of the proximal tibia. Animals were sacrificed at 28 days and evaluated with µCT and histological analysis., Results: SUVs in both bone tunnels showed an increased 18 F-Fluoride uptake at 7 days when compared to 14, 21, and 28 days. SUVs showed a gradient on the tibial side, with most bone turnover in the IAA and least in the EAA. At 7, 14, 21, and 28 days, there were significantly higher SUV values in the IAA compared to the EAA ( p = .01, < .01, < .01, < .01). SUVs positively correlated with new bone volumetric density obtained with μCT (r = 0.449, p = .013). Volumetric density of newly formed bone detected on μCT correlated with osteoblast numbers observed along the tunnels in histological sections (r = 0.452, p < .016)., Conclusions: Serial in-vivo µPET/CT-scanning has the potential to provide insight into bone turnover and therefore osteoblastic activity during the healing process. As a result, it allows us to directly measure the effect of interventional strategies in tendon-bone healing.

Background and Objectives: To examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife., Methods: We evaluated 99 cognitively normal women 52 ± 6 years of age and 29 men 52 ± 7 years of age with reproductive history data, neuropsychological testing, and volumetric MRI scans. We used multiple regressions to examine associations among reproductive history indicators, voxel-wise gray matter volume (GMV), and memory and global cognition scores, adjusting for demographics and midlife health indicators. Exposure variables were menopause status, age at menarche, age at menopause, reproductive span, hysterectomy status, number of children and pregnancies, and use of menopause hormonal therapy (HT) and hormonal contraceptives (HC)., Results: All menopausal groups exhibited lower GMV in AD-vulnerable regions compared to men, with perimenopausal and postmenopausal groups also exhibiting lower GMV in temporal cortex compared to the premenopausal group. Reproductive span, number of children and pregnancies, and use of HT and HC were positively associated with GMV, chiefly in temporal cortex, frontal cortex, and precuneus, independent of age, APOE ε4 status, and midlife health indicators. Although reproductive history indicators were not directly associated with cognitive measures, GMV in temporal regions was positively associated with memory and global cognition scores., Discussion: Reproductive history events signaling more estrogen exposure such as premenopausal status, longer reproductive span, higher number of children, and use of HT and HC were associated with larger GMV in women in midlife. Further studies are needed to elucidate sex-specific biological pathways through which reproductive history influences cognitive aging and AD risk., (© 2021 American Academy of Neurology.)

Objective . Quantification of meniscus vascularity has been limited with previous techniques, and minimal data exist describing differential vascular zones in the skeletally immature meniscus. The objective of this study is to use quantitative contrast-enhanced magnetic resonance imaging (MRI) to compare meniscal vascularity in neonatal specimens with adults. We hypothesized that the developing meniscus has greater and more uniform vascularity throughout all zones. Design . Ten fresh-frozen human cadaveric knees (5 neonatal, age 0-6 months; 5 adult, 34-67 years) underwent gadolinium-enhanced MRI using an established vascularity quantification protocol. Regions of interest corresponding to peripheral and central zones of the meniscus were identified on pre-contrast coronal images, and signal enhancement within the same regions (normalized against background tissue) was compared between pre- and post-contrast images. Results . The medial and lateral menisci had similar distribution of perfusion (45.8% ± 8.1% medial vs. 54.2% ± 8.1% lateral in neonatal knees; 50.6% ± 11.3% medial vs. 49.4% ± 11.3% lateral in adult knees, P = 0.47). Increased perfusion was demonstrated in the periphery compared with the central zone (2.3:1 in neonatal knees and 3.25:1 in adult knees, P = 0.31). Neonatal specimens demonstrated 6.0-fold greater overall post-contrast meniscal signal enhancement compared with adults ( P < 0.0001), with the 0-month specimen demonstrating the greatest proportional signal enhancement. Conclusions . While blood flow to the periphery is greater than to central zones in all menisci, younger menisci receive proportionally greater overall blood flow compared to adults, including to the central zone, suggesting that the immature meniscus is a more biologically active tissue than its adult counterpart.

Vascular perturbations and cerebral hypometabolism are emerging as important components of Alzheimer's disease (AD). While various in vivo imaging modalities have been designed to detect changes of cerebral perfusion and metabolism in AD patients and animal models, study results were often heterogenous with respect to imaging techniques and animal models. We therefore evaluated cerebral perfusion and glucose metabolism of two popular transgenic AD mouse strains, TgCRND8 and 5xFAD, at 7 and 12 months-of-age under identical conditions and analyzed possible molecular mechanisms underlying heterogeneous cerebrovascular phenotypes. Results revealed disparate findings in these two strains, displaying important aspects of AD progression. TgCRND8 mice showed significantly decreased cerebral blood flow and glucose metabolism with unchanged cerebral blood volume (CBV) at 12 months-of-age whereas 5xFAD mice showed unaltered glucose metabolism with significant increase in CBV at 12 months-of-age and a biphasic pattern of early hypoperfusion followed by a rebound to normal cerebral blood flow in late disease. Finally, immunoblotting assays suggested that VEGF dependent vascular tone change may restore normoperfusion and increase CBV in 5xFAD., (Copyright © 2021. Published by Elsevier Inc.)

Aims: Surgical treatment of young femoral neck fractures often requires an open approach to achieve an anatomical reduction. The application of a calcar plate has recently been described to aid in femoral neck fracture reduction and to augment fixation. However, application of a plate may potentially compromise the regional vascularity of the femoral head and neck. The purpose of this study was to investigate the effect of calcar femoral neck plating on the vascularity of the femoral head and neck., Methods: A Hueter approach and capsulotomy were performed bilaterally in six cadaveric hips. In the experimental group, a one-third tubular plate was secured to the inferomedial femoral neck at 6:00 on the clockface. The contralateral hip served as a control with surgical approach and capsulotomy without fixation. Pre- and post-contrast MRI was then performed to quantify signal intensity in the femoral head and neck. Qualitative assessment of the terminal arterial branches to the femoral head, specifically the inferior retinacular artery (IRA), was also performed., Results: Quantitative MRI revealed a mean reduction of 1.8% (SD 3.1%) of arterial contribution in the femoral head and a mean reduction of 7.1% (SD 10.6%) in the femoral neck in the plating group compared to non-plated controls. Based on femoral head quadrant analysis, the largest mean decrease in arterial contribution was in the inferomedial quadrant (4.0%, SD 6.6%). No significant differences were found between control and experimental hips for any femoral neck or femoral head regions. The inferior retinaculum of Weitbrecht (containing the IRA) was directly visualized in six of 12 specimens. Qualitative MRI assessment confirmed IRA integrity in all specimens., Conclusion: Calcar femoral neck plating at the 6:00 position on the clockface resulted in minimal decrease in femoral head and neck vascularity, and therefore it may be considered as an adjunct to laterally-based fixation for reduction and fixation of femoral neck fractures, especially in younger patients. Cite this article: Bone Jt Open  2021;2(8):611-617.

Metachromatic leukodystrophy, a fatal pediatric neurodegenerative lysosomal storage disease caused by mutations in the arylsulfatase A ( ARSA ) gene, is characterized by intracellular accumulation of sulfatides in the lysosomes of cells of the central nervous system (CNS). In previous studies, we have demonstrated efficacy of AAVrh.10hARSA, an adeno-associated virus (AAV) serotype rh.10 vector coding for the human ARSA gene to the CNS of a mouse model of the disease, and that catheter-based intraparenchymal administration of AAVrh.10hARSA to the CNS of nonhuman primates (NHPs) white matter results in widespread expression of ARSA. As a formal dose-escalating safety/toxicology study, we assessed the safety of intraparenchymal delivery of AAVrh.10hARSA vector to 12 sites in the white matter of the CNS of NHPs at 2.85 × 10 10 (total low dose, 2.4 × 10 9 genome copies [gc]/site) and 1.5 × 10 12 (total high dose, 1.3 × 10 11 gc/site) gc, compared to AAVrh.10Null (1.5 × 10 12 gc total, 1.3 × 10 11 gc/site) as a vector control, and phosphate buffered saline for a sham surgical control. No significant adverse effects were observed in animals treated with low dose AAVrh.10hARSA. However, animals treated with the high dose AAVrh.10ARSA and the high dose Null vector had highly localized CNS abnormalities on magnetic resonance imaging scans at the sites of catheter infusions, and histopathology demonstrated that these sites were associated with infiltrates of T cells, B cells, microglial cells, and/or macrophages. Although these findings had no clinical consequences, these safety data contribute to understanding the dose limits for CNS white matter direct intraparenchymal administration of AAVrh.10 vectors for treatment of CNS disorders.

Purpose: While predominant blood supply to the adult patella enters inferomedially, little is known about skeletally immature patellar perfusion. Improved knowledge of immature patella vascularity can further understanding of osteochondritis dissecans, dorsal defects of the patella and bipartite patella, and help ensure safe surgical approaches. We hypothesized that the immature patella would exhibit more uniform blood flow. The study purpose was to quantify immature patella regional perfusion in comparison with adults., Methods: Ten cadaveric knees were utilized (five immature, five mature). The superficial femoral artery was cannulated proximally. Signal enhancement increases were compared from pre- to post-contrast MRI to assess relative arterial contributions to patella regions (quadrants, anterior/posterior, superior/inferior, medial/lateral, and outer/inner)., Results: Quantitative-MRI analysis revealed similar distribution of enhancement between the immature and mature patella. The inferior pole exhibited significantly higher arterial contribution versus superior pole in both immature and mature groups (p = 0.009; both groups), while the inferomedial quadrant had the highest arterial contribution of all quadrants in both groups. The superolateral quadrant demonstrated the lowest arterial contribution in the immature group and second lowest in the adult group. The patella outer periphery had significantly greater arterial contribution than the inner central region in both immature (p = 0.009) and mature (p = 0.009) groups., Conclusion: Distribution of arterial contributions between the immature and mature patella was similar. Our results highlight the importance of inferior and inferomedial blood supply in both immature and mature patellas. These findings have implications for paediatric and adult patients; surgical damage to inferior patellar vessels should be avoided to prevent associated complications., (Copyright © 2021, The author(s).)

New large neuroimaging studies, such as the Adolescent Brain Cognitive Development study (ABCD) and Human Connectome Project (HCP) Development studies are adopting a new T1-weighted imaging sequence with prospective motion correction (PMC) in favor of the more traditional 3-Dimensional Magnetization-Prepared Rapid Gradient-Echo Imaging (MPRAGE) sequence. Here, we used a developmental dataset (ages 5-21, N = 348) from the Healthy Brain Network (HBN) Initiative to directly compare two widely used MRI structural sequences: one based on the Human Connectome Project (MPRAGE) and another based on the ABCD study (MPRAGE+PMC). We aimed to determine if the morphometric measurements obtained from both protocols are equivalent or if one sequence has a clear advantage over the other. The sequences were also compared through quality control measurements. Inter- and intra-sequence reliability were assessed with another set of participants (N = 71) from HBN that performed two MPRAGE and two MPRAGE+PMC sequences within the same imaging session, with one MPRAGE (MPRAGE1) and MPRAGE+PMC (MPRAGE+PMC1) pair at the beginning of the session and another pair (MPRAGE2 and MPRAGE+PMC2) at the end of the session. Intraclass correlation coefficients (ICC) scores for morphometric measurements such as volume and cortical thickness showed that intra-sequence reliability is the highest with the two MPRAGE+PMC sequences and lowest with the two MPRAGE sequences. Regarding inter-sequence reliability, ICC scores were higher for the MPRAGE1 - MPRAGE+PMC1 pair at the beginning of the session than the MPRAGE1 - MPRAGE2 pair, possibly due to the higher motion artifacts in the MPRAGE2 run. Results also indicated that the MPRAGE+PMC sequence is robust, but not impervious, to high head motion. For quality control metrics, the traditional MPRAGE yielded better results than MPRAGE+PMC in 5 of the 8 measurements. In conclusion, morphometric measurements evaluated here showed high inter-sequence reliability between the MPRAGE and MPRAGE+PMC sequences, especially in images with low head motion. We suggest that studies targeting hyperkinetic populations use the MPRAGE+PMC sequence, given its robustness to head motion and higher reliability scores. However, neuroimaging researchers studying non-hyperkinetic participants can choose either MPRAGE or MPRAGE+PMC sequences, but should carefully consider the apparent tradeoff between relatively increased reliability, but reduced quality control metrics when using the MPRAGE+PMC sequence., Competing Interests: Declaration of Competing Interest All authors declare that they do not have any conflicts of interest., (Copyright © 2020. Published by Elsevier Inc.)

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2 , in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort ( P < 0.04) and European natural history cohort ( P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: To quantify CSF transport kinetics and brain glymphatic distribution using MRI following intrathecal injection of gadolinium contrast in healthy adults., Subjects and Methods: Eight completely healthy volunteer subjects underwent intrathecal injection of gadolinium via image guided lumbar puncture and serial MRI's at six subsequent time points up to 11 h post-injection. Rate of enhancement and deposition were calculated for various regions and lobes of the brain., Results: Normalized cranial data revealed that gadolinium in the intracranial CSF spaces peaked within 1-3 h and started to decrease at 7 h. In some regions of the brain parenchyma, such as the cerebral cortex and white matter, enhancement was increasing after 11 h. Differential rates of uptake between the parietal and frontal (p = 0.0003), cingulate (p = 0.002) and temporal (p = 0.018) lobes were shown as well as a several fold change between various cortical regions. Lastly, a linear regression comparing laterality between 35 cortical regions yielded (R 2  = 0.90, p < 0.001) with a slope of 1.01 showing symmetry in uptake., Conclusions: Gadolinium enhancement after lumbar intrathecal injection demonstrated differential CSF flow and brain parenchymal penetration, which illustrated the distributory function of the glymphatic system., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Disrupted blood supply has been proposed as an underlying cause for delayed union in tibial shaft fractures (OTA/AO 42). Although tibial blood supply has been qualitatively evaluated, quantitative studies are lacking. The purpose of this project was to quantify the relative contribution of the endosteal supply to the tibial diaphysis., Methods: The superficial femoral artery of 8 fresh frozen cadaveric matched pair lower extremities was cannulated. The nutrient artery was ligated at its proximal branch point in experimental limbs. Pregadolinium and postgadolinium enhanced magnetic resonance imaging was performed with high resolution fat-suppressed ultrashort echo time magnetic resonance imaging sequences. Perfusion was assessed in 3 zones (outer, central, and inner cortex) for the proximal, middle, and distal diaphysis, respectively, using custom software to quantify and compare signal intensity between experimental and control limbs., Results: On average, the endosteal system supplied 91.4% (±3.9%) of the cortex and was the predominant blood supply for the inner, central, and outer thirds. The dominance of the endosteal contribution was most pronounced in the inner two-third of the cortex, with more than 97% loss of perfusion. Disruption of the nutrient artery also resulted in 76.3% (±11.2%) loss of perfusion of the outer one-third of the cortex., Conclusion: This quantitative study revealed a predominance of endosteal blood supply to all areas (inner, middle, and outer thirds) of the tibial diaphyseal cortex. To prevent delayed bone healing, surgeons should take care to preserve the remaining periosteal vascular network in fracture patterns in which the nutrient artery has likely been disrupted., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Parkinson disease (PD) is the second most common neurodegenerative disorder, characterized by loss of nigrostriatal dopaminergic neurons. Impairment of the neurovascular unit (NVU) has been hypothesized to play a critical role in early PD pathophysiology, and to precede neurodegenerative mechanisms. [C-11]-PE2I ( N -(3-iodoprop-2E-enyl)-2b-carbomethoxy-3b-(4-methyl-phenyl)nortropane) (PE2I) is a PET radiotracer targeting neuronal dopamine transporters (DaT) with high specificity, allowing for highly accurate and specific DaT quantification. We investigated NVU integrity using arterial spin labeling (ASL) MRI in a prospective cohort of 26 patients with PD, and correlated our findings with analysis of striatal DaT density using PE2I PET in a subcohort of 17 patients. Analysis was performed in FreeSurfer to obtain rCBF and mean standardized regional PET avidity. Pearson correlations and Mann-Whitney tests were performed. Significantly lower mean normalized striatal PE2I SUV values were seen in multiple regions in patients with greater disease duration ( p < 0.05). PET uptake in the putamen correlated with disease duration independent of patient age. Stratifying patients based on Montreal Cognitive Assessment (MoCA) scores (stratified into ≥ 27 vs. < 27), there was statistically significantly lower PE2I PET avidity in the higher MoCA score group in both more and less affected sides of the caudate, putamen and pallidum ( p < 0.05). A moderate negative correlation between MDS-UPDRS part 3 (motor) "off" and rCBF values was also seen in the L and R cerebellum WM ( r = -0.43 and -0.47, p < 0.05). A statistically significant negative correlation was found between dominant hand pegboard test results and rCBF in the less affected pallidum ( r = -0.41; p = 0.046). A statistically significant negative correlation of ASL MRI with [11C]-PE2I PET was also found ( r = -0.53 to -0.58; p -value 0.017-0.033) between left cerebral WM rCBF and more and less affected striatal PET regions. Our ROI-based analyses suggest that longer disease duration is associated with lower rCBF and lower PE2I mean SUV, implying greater NVU dysfunction and dopaminergic neuronal loss, respectively. Combined ASL MRI and PE2I PET imaging could inform future prospective clinical trials providing an improved mechanistic understanding of the disease, laying the foundation for the development of early disease biomarkers and potential therapeutic targets., (Copyright © 2020 Ivanidze, Skafida, Pandya, Patel, Osborne, Raj, Gupta, Henchcliffe and Dyke.)

Aims: Dual plating of distal femoral fractures with medial and lateral implants has been performed to improve construct mechanics and alignment, in cases where isolated lateral plating would be insufficient. This may potentially compromise vascularity, paradoxically impairing healing. This study investigates effects of single versus dual plating on distal femoral vascularity., Methods: A total of eight cadaveric lower limb pairs were arbitrarily assigned to either 1) isolated lateral plating, or 2) lateral and medial plating of the distal femur, with four specimens per group. Contralateral limbs served as matched controls. Pre- and post-contrast MRI was performed to quantify signal intensity enhancement in the distal femur. Further evaluation of intraosseous vascularity was done with barium sulphate infusion with CT scan imaging. Specimens were then injected with latex medium and dissection was completed to assess extraosseous vasculature., Results: Quantitative MRI revealed a mean reduction of 21.2% (SD 1.3%) of arterial contribution in the lateral plating group and 25.4% (SD 3.2%) in the dual plating group (p = 0.051); representing a mean decrease in arterial contribution of 4.2%. The only significant difference found between both experimental groups was regionally, at the lateral aspect of the distal femur with a mean drop in arterial contribution in the lateral plating group of 18.9% (SD 2.6%) versus 24.0% (SD 3.2%) in the dual plating group (p = 0.048), representing a mean decrease in arterial contribution of 5.1%. Gross dissection revealed complete destruction of periosteal vessels underneath either medial or lateral plates in both groups. The network of genicular branches contributing to the posterior and distal femoral condyles was preserved in all specimens. A medial vascular pedicle was found dividing from the superficial femoral artery at a mean 12.7 cm (SD 1.7) proximal to the medial epicondyle and was undisrupted in the dual plating group., Conclusion: Lateral locking-plate application resulted in mean 21.2% reduction in distal femur vascularity. Addition of medial plates did not further markedly decrease vascularity. As such, the majority of the vascular insult occurred with lateral plating alone. Supplemental medially based fixation did not lead to marked devascularization of the distal femur, and should therefore be considered in the setting of comminution and poor bone stock in distal femoral fractures. Further clinical research is required to confirm the results of this study. Cite this article: Bone Joint J 2020;102-B(4):530-538.

Background: Total ankle arthroplasty (TAA) continues to exhibit a relatively high incidence of complications and need for revision surgery compared to knee and hip arthroplasty. One common mode of failure in TAA is talar component subsidence. This may be caused by disruption in the talar blood supply related to the operative technique. The purpose of this study was to quantify changes in talar bone perfusion and turnover before and after TAA with the INBONE II system using 18 F-fluoride positron emission tomography / computed tomography (PET/CT)., Methods: Nine subjects (5 M/4 F) aged 68.9 ± 8.2 years were enrolled for 18 F-fluoride PET/CT imaging before and 3 months after TAA. Regions of interest (ROI) were placed on the postoperative CT images in the body of the talus beneath the talar component and overlaid on the fused static PET images. Standard uptake values (SUVs) along with dynamic K 1 (bone blood flow) and k i (bone metabolism or osteoblastic turnover) were calculated., Results: The SUV underneath the talar component compared to that measured at baseline before surgery was 1.93 ± 0.29 preoperatively vs 2.47 ± 0.37 postoperatively ( P > .05). K 1 was 0.84 ± 0.16 mL/min/mL preoperatively vs 1.51 ± 0.23 mL/min/mL postoperatively ( P = .026). k i was constant at 0.09 ± 0.03 mL/min/mL preoperatively vs 0.12 ± 0.03 mL/min/mL postoperatively ( P > .05)., Conclusion: Our study was the first to link 18 F-fluoride PET/CT with pre-post evaluation of total ankle replacements. The study quantified perfusion within the talus beneath the TAA implant supporting the hypothesis that perfusion of the talus remained intact after surgery., Level of Evidence: Level II, prospective cohort study with development of diagnostic criteria.

Post-transcriptional regulation by microRNAs (miRNAs) is essential for complex molecular responses to physiological insult and disease. Although many disease-associated miRNAs are known, their global targets and culminating network effects on pathophysiology remain poorly understood. We applied Argonaute (AGO) crosslinking immunoprecipitation (CLIP) to systematically elucidate altered miRNA-target interactions in brain following ischemia and reperfusion (I/R) injury. Among 1,190 interactions identified, the most prominent was the cumulative loss of target regulation by miR-29 family members. Integration of translational and time-course RNA profiles revealed a dynamic mode of miR-29 target de-regulation, led by acute translational activation and a later increase in RNA levels, allowing rapid proteomic changes to take effect. These functional regulatory events rely on canonical and non-canonical miR-29 binding and engage glutamate reuptake signals, such as glial glutamate transporter (GLT-1), to control local glutamate levels. These results uncover a miRNA target network that acts acutely to maintain brain homeostasis after ischemic stroke., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To quantify the reliability and agreement of sodium ( 23 Na) MRI in calf muscle and skin of healthy subjects and to measure the smallest real difference (SRD) in each., Subjects and Methods: Thirty healthy subjects underwent 23 Na MRI studies of the calf. A scan-rescan protocol was performed the same day and 1 week later. Relative sodium concentration was measured in the calf muscle and skin and compared between studies., Results: A high degree of reliability was confirmed between the scan and rescan tests using linear regression analysis. The Bland-Altman plots indicated high agreement between runs in all regions. The SRD was measured between scans taken the same day and one week later. Correlations were also reported with age, gender and race., Conclusions: Reliability and agreement of 23 Na MRI in the calf muscle and skin show promise for accurately assessing serial changes in patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a rare lysosomal storage disorder caused by a monogenetic deficiency of tripeptidyl peptidase-1 (TPP1). Despite knowledge that lipofuscin is the hallmark disease product, the relevant TPP1 substrate and its role in neuronal physiology/pathology is unknown. We hypothesized that untargeted metabolite profiling of cerebrospinal fluid (CSF) could be used as an effective tool to identify disease-associated metabolic disruptions in CLN2 disease, offering the potential to identify biomarkers that inform on disease severity and progression. Accordingly, a mass spectrometry-based untargeted metabolite profiling approach was employed to differentiate CSF from normal vs. CLN2 deficient individuals. Of 1,433 metabolite features surveyed, 29 linearly correlated with currently employed disease severity scores. With tandem mass spectrometry 8 distinct metabolite identities were structurally confirmed based on retention time and fragmentation pattern matches, vs. standards. These putative CLN2 biomarkers include 7 acetylated species - all attenuated in CLN2 compared to controls. Because acetate is the major bioenergetic fuel for support of mitochondrial respiration, deficient acetylated species in CSF suggests a brain energy defect that may drive neurodegeneration. Targeted analysis of these metabolites in CSF of CLN2 patients offers a powerful new approach for monitoring CLN2 disease progression and response to therapy.

Background: We compared different surgical techniques for nerve regeneration in a rabbit sciatic nerve gap model using magnetic resonance diffusion tensor imaging (DTI), electrophysiology, limb function, and histology., Methods: A total of 24 male New Zealand white rabbits were randomized into three groups: autograft ( n  = 8), hollow conduit ( n  = 8), and collagen-filled conduit ( n  = 8). A 10-mm segment of the rabbit proximal sciatic nerve was cut, and autograft or collagen conduit was used to bridge the gap. DTI on a 3-T system was performed preoperatively and 13 weeks after surgery using the contralateral, nonoperated nerve as a control., Results: Overall, autograft performed better compared with both conduit groups. Differences in axonal diameter were significant (autograft > hollow conduit > collagen-filled conduit) at 13 weeks (autograft vs. hollow conduit, p  = 0.001, and hollow conduit vs. collagen-filled conduit, p  < 0.001). Significant group differences were found for axial diffusivity but not for any of the other DTI metrics (autograft > hollow conduit > collagen-filled conduit) (autograft vs. hollow conduit, p  = 0.001 and hollow conduit vs. collagen-filled conduit, p  = 0.021). As compared with hollow conduit (autograft > collagen-filled conduit > hollow conduit), collagen-filled conduit animals demonstrated a nonsignificant increased maximum tetanic force., Conclusions: Autograft-treated rabbits demonstrated improved sciatic nerve regeneration compared with collagen-filled and hollow conduits as assessed by histologic, functional, and DTI parameters at 13 weeks., Competing Interests: This study was approved by the Institutional Animal Care and Use Committee at Weill Cornell Medical College.Not applicableThe authors of this manuscript declare relationships with Toyobo Co. Ltd.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: The hypothesis of this study is that human subchondral bone exhibits abnormal patterns of perfusion in osteoarthritis (OA) that can be characterized by kinetic parameters of blood flow using dynamic contrast enhanced (DCE) MRI., Design: Fifteen subjects with advanced OA of the knee and seven control subjects without OA were studied at 1.5 T with DCE-MRI. Region of interest (ROIs) analysis of pharmacokinetic perfusion parameters were used to examine initial uptake and washout of the contrast agent in the lateral tibial plateau., Results: Arterial and venous perfusion kinetics were abnormal in subchondral OA bone compared to those of normal controls. Time-intensity curves (TIC) exhibited delayed contrast clearance in OA knees compared to normal. Quantitatively, changes were observed in the kinetic parameters, k ep , Ak ep , and k el . The mean k ep and Ak ep were reduced in OA, compared to normal bone, indicating a reduction of arterial inflow and delayed signal enhancement. The k el in OA bone was lower than in normal bone, the negative k el indicating a reduction in venous outflow. The area under the TIC (AUC 60 ) indicated greater residual contrast in OA bone., Conclusions: DCE-MRI can quantitatively assess subchondral bone perfusion kinetics in human OA and identify heterogeneous regions of perfusion deficits. The results are consistent with venous stasis in OA, reflecting venous outflow obstruction, and can affect intraosseous pressure, reduce arterial inflow, reduce oxygen content, and may contribute to altered cell signaling in, and the pathophysiology of, OA., (Copyright © 2018 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)