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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.

Background and ObjectivesTo examine associations between indicators of estrogen exposure from women's reproductive history and brain MRI biomarkers of Alzheimer disease (AD) in midlife.MethodsWe 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).ResultsAll 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.DiscussionReproductive 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.

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.

BackgroundChoroid plexus (CP) within brain ventricles is well-known to produce CSF. Additional important CP functions are now recognized including critical modulation of inflammation. Recent MRI studies have demonstrated CP enlargement in human diseases including Multiple Sclerosis and Alzheimer’s Disease, and in association with neuroinflammation measured using translocator protein (TSPO) PET. The basis of MRI-visible CP enlargement is unknown.PurposeBased on tissue studies demonstrating CP calcification as a common pathology associated with aging and disease, we hypothesized that previously-unmeasured calcium within CP contributes to MRI-measured CP volume, and may be more specifically associated with neuroinflammation.Materials and MethodsWe performed a retrospective analysis of PET-CT studies performed between 2013-2019 on a single scanner using the TSPO radiotracer 11C-PK11195. Subjects included controls (n=43) and patients diagnosed with several non-inflammatory neuropsychiatric conditions (n=46.) Cortical inflammation / microglial activation was quantified as non-displaceable Binding Potential (BPnd.) CP and ventricle volume were measured using Freesurfer. CP calcium was measured semi-manually via tracing of low-dose CT acquired with PET and automatically using a new CT/MRI method. The contribution of CP calcium, CP overall volume, ventricle volume, subject age, sex and diagnosis to BPnd was assessed using linear regression.Results89 subjects (mean age 54+/-7 years; 52 men) were included. Fully-automated CP calcium quantification was accurate (ICC with semi-manual tracing = .98.) The significant predictors of cortical neuroinflammation were subject age (p=.002) and CP calcium volume (p=.041), but not ventricle or CP volume.ConclusionCP calcium volume can be accurately measured using low-dose CT acquired routinely with PET-CT. CP calcification – but not CP overall volume – was associated with cortical inflammation. Unmeasured CP calcification may be relevant to recent reports of CP enlargement in human inflammatory and other diseases. CP calcification may be a specific and relatively easily-acquired biomarker for neuroinflammation and CP pathology.Key ResultsChoroid plexus (CP) calcification volume can be reliably quantified using semi-manual tracing on low-dose CT acquired with PET-CT, and fully automatically using our new, accurate (ICC with semi-manual tracing = .98) CT/MRI method.CP calcification and age –but not overall CP volume– significantly predicted 11C-PK11195 PET-measured cortical neuroinflammation in 89 subjects.CP calcification is a relatively easily-assessed, previously-overlooked potential biomarker for neuroinflammation and CP pathology.

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.

Background: The most common complication of preterm birth is bronchopulmonary dysplasia (BPD), widely referred to as the 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 in the Neonatal Intensive Care Unit (NICU) to quantitate pulmonary ventilation and perfusion using 1.5 Tesla Magnetic Resonance Imaging (MRI).Methods: We conducted a prospective MRI study of 12 premature infants in the NICU using the phase resolved lung (PREFUL) MRI technique to calculate pulmonary ventilation and perfusion parameters in preterm infants with and without bronchopulmonary dysplasia (BPD) Grade 0/1 (n=6) and Grade 2/3 (n=6).Results: The exclusive ventilation defect percentage (VDP%) showed a significant increase in premature infants with Grade 2/3 BPD vs. Grade 0/1 BPD [15.0% vs. 7.0%, p=0.008]. The total VDP% also showed a significant increase between groups [16.0% vs. 8.0%, p=0.013]. No significant perfusion defect percentages (QDP%) were found between groups. Conclusion: PREFUL lung MRI is feasible for assessment of ventilation and perfusion defect percentages in preterm infants in the NICU and shows regional variation in localized lung function in this vulnerable population.

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.

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.

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.

The availability of non-invasive means to evaluate and monitor tendon-bone healing processesUnilateral autograft ACL reconstruction was performed in six rats. µPET/CT-scans usingSUVs in both bone tunnels showed an increasedSerial

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 18F-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 18F-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 18F-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.

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.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.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.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.

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.

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 18F-fluoride positron emission tomography / computed tomography (PET/CT). Methods: Nine subjects (5 M/4 F) aged 68.9 ± 8.2 years were enrolled for 18F-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 K1 (bone blood flow) and ki (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). K1 was 0.84 ± 0.16 mL/min/mL preoperatively vs 1.51 ± 0.23 mL/min/mL postoperatively ( P = .026). ki 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 18F-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.

All women undergo the menopause transition (MT), a neuro-endocrinological process that impacts aging trajectories of multiple organ systems including brain. The MT occurs over time and is characterized by clinically defined stages with specific neurological symptoms. Yet, little is known of how this process impacts the human brain. This multi-modality neuroimaging study indicates substantial differences in brain structure, connectivity, and energy metabolism across MT stages (pre-menopause, peri-menopause, and post-menopause). These effects involved brain regions subserving higher-order cognitive processes and were specific to menopausal endocrine aging rather than chronological aging, as determined by comparison to age-matched males. Brain biomarkers largely stabilized post-menopause, and gray matter volume (GMV) recovered in key brain regions for cognitive aging. Notably, GMV recovery and in vivo brain mitochondria ATP production correlated with preservation of cognitive performance post-menopause, suggesting adaptive compensatory processes. In parallel to the adaptive process, amyloid-β deposition was more pronounced in peri-menopausal and post-menopausal women carrying apolipoprotein E-4 (APOE-4) genotype, the major genetic risk factor for late-onset Alzheimer’s disease, relative to genotype-matched males. These data show that human menopause is a dynamic neurological transition that significantly impacts brain structure, connectivity, and metabolic profile during midlife endocrine aging of the female brain.

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.

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.

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.

Late infantile Batten disease (CLN2 disease) is a rare, 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 non-randomized trial consisting of 2 arms assessed over 18 months: an 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 6 burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, 5 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. Post-therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of grey matter volume in 4 of 7 children by MRI; and a 42.4% and a 47.5% reduction in the rate of decline of motor and language function, compared to the Weill Cornell natural history cohort (p

Background: Despite advances in surgical techniques, implant technology, and biological augmentation, one innate limitation to meniscus healing is lack of vascularity. Ability to quantify meniscal vascularity has been limited with previous techniques, and minimal data exists describing differential vascular zones in the skeletally immature meniscus. Purpose/Hypothesis: The objective of this study is to use quantitative contrast-enhanced magnetic resonance imaging (MRI) to compare meniscal vascularity in pediatric cadaveric specimens to adults. We hypothesize that the developing meniscus has greater and more uniform vascularity throughout all zones. Methods: We utilized 10 fresh-frozen human cadaveric knees (5 immature knees, age 0-6 months; 5 mature knees, age 34-67 years). Gadolinium-enhanced MRI was performed using a previously 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 (normalized against background tissue) was compared between pre-and post-contrast images (Figure 1). Results: Quantitative MRI demonstrated increased perfusion in the peripheral zones compared to the central zones (2.3:1 in immature knees and 3:1 in mature knees) in the medial and lateral menisci separately, and both menisci aggregated. Overall, the medial and lateral menisci had similar levels of perfusion in all specimens (45.9% ± 8.3% medial vs. 54.1% ± 8.3% lateral in immature knees; 50.5% ± 11.3% medial vs. 49.5% ± 11.3% lateral in mature knees). Immature specimens demonstrated greater overall normalized meniscal signal uptake, with the 0-month specimen demonstrating the greatest proportional signal enhancement. Conclusion: While blood flow to peripheral zones is greater than to central zones in both immature and adult menisci, younger menisci receive proportionally greater overall blood flow compared to adults, including greater blood flow to the inner zone, challenging the conventional wisdom of the central zone being avascular. As younger patients become increasingly active in sports, thorough understanding of the immature meniscus is required. Greater overall vascularity, including centrally, to the developing meniscus suggests improved healing potential following injury, and further encourages meniscal preservation when possible. Figure 1. Analysis of meniscal vascularity using contract-enhanced magnetic resonance imaging. A:Schematic drawing of peripheral and central zones of the medial and lateral menisci used for quantification.B:Mid-coronal images showing pre-and post contract images with ROIs delineated in adult and pediatric specimens; there is significatly increased perfusion to the epiphysis in the immature knee. Figure 2. Quantification of mensical vascularity in each specimen Comparsion of relative vascularity of peripheral versus central zones shows significantly greater blood flow to outer zone across all specimens.Quantification of total vascular contribution from the medial and lateral menisci aggregated showed a trend towards greater proportional blood flow in younger specimens.

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 (R2 = 0.90, p Conclusions Gadolinium enhancement after lumbar intrathecal injection demonstrated differential CSF flow and brain parenchymal penetration, which illustrated the distributory function of the glymphatic system.

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.

Purpose To quantify the reliability and agreement of sodium (23Na) 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 23Na 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 23Na MRI in the calf muscle and skin show promise for accurately assessing serial changes in patients.

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.

Introduction Essential tremor (ET) is increasingly recognized as a multi-dimensional disorder with both motor and non-motor features. For this reason, imaging studies are more broadly examining regions outside the cerebellar motor loop. Reliable detection of cerebral gray matter (GM) atrophy requires optimized processing, adapted to high-resolution magnetic resonance imaging (MRI). We investigated cerebral GM volume loss in ET cases using automated segmentation of MRI T1-weighted images. Methods MRI was acquired on 47 ET cases and 36 controls. Automated segmentation and voxel-wise comparisons of volume were performed using Statistical Parametric Mapping (SPM) software. To improve upon standard protocols, the high-resolution International Consortium for Brain Mapping (ICBM) 2009a atlas and tissue probability maps were used to process each subject image. Group comparisons were performed: all ET vs. Controls, ET with head tremor (ETH) vs. Controls, and severe ET vs. Controls. An analysis of variance (ANOVA) was performed between ET with and without head tremor and controls. Age, sex, and Montreal Cognitive Assessment (MoCA) score were regressed out from each comparison. Results We were able to consistently identify regions of cerebral GM volume loss in ET and in ET subgroups in the posterior insula, superior temporal gyri, cingulate cortex, inferior frontal gyri and other occipital and parietal regions. There were no significant increases in GM volume in ET in any comparisons with controls. Conclusion This study, which uses improved methodologies, provides evidence that GM volume loss in ET is present beyond the cerebellum, and in fact, is widespread throughout the cerebrum as well.

Recombinant human tripeptidyl peptidase 1 (cerliponase alfa) is an enzyme-replacement therapy that has been developed to treat neuronal ceroid lipofuscinosis type 2 (CLN2) disease, a rare lysosomal disorder that causes progressive dementia in children.In a multicenter, open-label study, we evaluated the effect of intraventricular infusion of cerliponase alfa every 2 weeks in children with CLN2 disease who were between the ages of 3 and 16 years. Treatment was initiated at a dose of 30 mg, 100 mg, or 300 mg; all the patients then received the 300-mg dose for at least 96 weeks. The primary outcome was the time until a 2-point decline in the score on the motor and language domains of the CLN2 Clinical Rating Scale (which ranges from 0 to 6, with 0 representing no function and 3 representing normal function in each of the two domains), which was compared with the time until a 2-point decline in 42 historical controls. We also compared the rate of decline in the motor-language score between the two groups, using data from baseline to the last assessment with a score of more than 0, divided by the length of follow-up (in units of 48 weeks).Twenty-four patients were enrolled, 23 of whom constituted the efficacy population. The median time until a 2-point decline in the motor-language score was not reached for treated patients and was 345 days for historical controls. The mean (±SD) unadjusted rate of decline in the motor-language score per 48-week period was 0.27±0.35 points in treated patients and 2.12±0.98 points in 42 historical controls (mean difference, 1.85; P0.001). Common adverse events included convulsions, pyrexia, vomiting, hypersensitivity reactions, and failure of the intraventricular device. In 2 patients, infections developed in the intraventricular device that was used to administer the infusion, which required antibiotic treatment and device replacement.Intraventricular infusion of cerliponase alfa in patients with CLN2 disease resulted in less decline in motor and language function than that in historical controls. Serious adverse events included failure of the intraventricular device and device-related infections. (Funded by BioMarin Pharmaceutical and others; CLN2 ClinicalTrials.gov numbers, NCT01907087 and NCT02485899 .).

BACKGROUND Disruption of the arterial supply to the femoral head, and subsequent development of femoral head osteonecrosis, is of serious concern with intracapsular hip procedures. However, the effect of arthroscopic femoral osteochondroplasty on femoral head perfusion is unknown. We aimed to quantify the effects of both standard and posterosuperior extension of arthroscopic femoral osteochondroplasty on femoral head vascularity. We hypothesized that extension of the superior resection zone posteriorly would negatively affect femoral head perfusion. METHODS In 12 cadaveric pelvic specimens, we cannulated the medial femoral circumflex artery (MFCA). One hip per pelvis was randomly selected to be in 1 of 2 experimental groups based on the superior extent of the osteochondroplasty: standard resection (resection anterior to the 12 o'clock [0° of 360°] position) or extended resection (resection extended posterior to the 12 o'clock position). Computed tomography (CT) scans were obtained prior to and following arthroscopic resection to delineate the resection margins. Gadolinium enhancement on magnetic resonance imaging (MRI) was quantified in the femoral head by volumetric analysis using custom software. A polyurethane compound was injected and gross dissection of the vasculature was performed. RESULTS Extension of the osteochondroplasty posteriorly (the extended-resection group), to a mean of 41.3° (range, 34° to 47°) posterior to the 12 o'clock position, decreased femoral head perfusion by a mean of 28% (range, 18% to 38%). The standard-resection group demonstrated a mean decrease in femoral head perfusion of 7% (range, 4% to 11%). Correlation analysis demonstrated a significant negative correlation (correlation coefficient, -0.877; p < 0.001; R = 0.747). For every 1° that the superior resection margin extended posteriorly, a corresponding 0.88% decrease in femoral head perfusion was found. CONCLUSIONS Femoral head perfusion is almost fully maintained with arthroscopic osteochondroplasty when the superior resection margin is anterior to the 12 o'clock position. Perfusion is also well maintained if the superior resection margin is extended no more than 10° posterior to 12 o'clock. Further posterior extension correlated with greater decreases in femoral head perfusion. CLINICAL RELEVANCE Our study provides previously unreported quantitative MRI data on femoral head perfusion following arthroscopic femoral osteochondroplasty for the treatment of cam-type femoroacetabular impingement.

The activities we choose to spend our leisure time with are intrinsically motivating and vary across individuals. Yet it is unknown how impulse control or neural activity changes when processing a preferred stimulus related to a hobby or interest. Developing a task that assesses the response to preferred interests is of importance as it would be relevant to a range of psychiatric disorders that have hyper- or hypo-arousal to such cues. During functional Magnetic Resonance Imaging (fMRI), 39 healthy adults completed a novel task to test approach behavior and cognitive control to cues that were personalized to the participants’ interests compared to stimuli the participants identified as being of non-interest and colored shapes. fMRI results showed that cues of one’s interest elicited activation in the anterior insula compared to colored shapes. Interests did not change inhibition compared to non-interests and colored shapes and all stimuli equally engaged a frontostriatal circuit. Together the results suggest that adults were sensitive to their interests but were effective at regulating their impulses towards these cues, a skill that is critical for navigating the temptations and distractions in our daily environment.

Bulimia nervosa (BN) emerges in the late teen years and is characterized by binge eating and related compensatory behaviors. These behaviors often co-occur with periods of negative affect suggesting an association between emotions and control over eating behavior. In the current study, we examined how cognitive control and neural processes change under emotional states of arousal in 46 participants with (n=19) and without (n=27) BN from the ages of 18-33 years. Participants performed a go/nogo task consisting of brief negative, positive and neutral emotional cues and sustained negative, positive and neutral emotional states of arousal during functional magnetic resonance imaging (fMRI). Overall task performance improved with age for healthy participants, but not for patients with BN. These age-dependent behavioral effects were paralleled by diminished recruitment of prefrontal control circuitry in patients with BN with age. Although patients with BN showed no difference in performance on the experimental manipulations of negative emotions, sustained positive emotions related to improved performance among patients with BN. Together the findings highlight a neurodevelopmental approach towards understanding markers of psychopathology and suggest that sustained positive affect may have potential therapeutic effects on maintaining behavioral control in BN.

An accurate non-invasive method to determine total body cerebrospinal fluid volume has a number of potential diagnostic and therapeutic applications. Herein we describe a technique for automated segmentation of total body MRI data to determine cranial and spinal CSF volume in 15 healthy adults. These in vivo estimates of CSF volume exceed the standard reported volume of 150mL in human adults and provide normative data for diagnosis of disease states such as hydrocephalus and therapy including pharmacologic dosimetry. No correlation was observed between patient height or weight and total body CSF volume.

Category: Ankle Arthritis Introduction/Purpose: Total ankle replacement (TAR) continues to exhibit a relatively high incidence of complications and need for revision surgery, particularly when compared to knee and hip arthroplasty. One common mode of failure in TAR is talar component subsidence. This may be caused by disruption in the talar blood supply related to the surgical technique. Positron emission tomography (PET) imaging with [18F]-Fluoride has demonstrated utility in evaluating bone perfusion, and PET-CT in particular is useful in the setting of total joint replacement. In this study we aim to quantify changes in talar perfusion before and after TAR with the INBONE II system (Wright Medical Technology, Inc., Memphis, TN) using [18F]-Fluoride PET-CT. It is our hypothesis that perfusion to the talus would decrease after TAR. Methods: Eight subjects (5M/3F) aged 70.4 ± 7.5 years [Range 61-83] were enrolled for 18F-PET/CT imaging prior to and 3 months following TAR. 5–10 mCi of 18F-Fluoride was administered and dynamic acquisition in list mode for 45 minutes was performed on the operative and non-operative ankles simultaneously on a Siemens mCT Biograph scanner. Static acquisition of the whole body was also performed one hour after injection. Regions of interest (ROI’s) were placed on the postoperative CT images in the body of the talus beneath the INBONE II talar component. These regions were manually delineated on the preoperative CT scans, and were drawn to replicate the ROIs placed on the postoperative studies. ROI’s were overlaid on the fused static 18F-PET images and standard uptake values (SUVs) calculated for these regions as well as the whole foot. Changes in SUVs were analyzed using a paired t-tests with a significance level of 0.05. Results: We found no significant difference in bone perfusion in the talus after TAR in our cohort of patients. 18F uptake in the ROI underneath the talar component compared to that measured at baseline prior to surgery was 3.36 +/- 1.44 SUV postoperatively vs. 2.65 ± 1.24 SUV preoperatively, (p=0.33). Similar results were seen in the whole foot: 2.99 +/- 1.22 SUV postoperatively vs. 2.47 ± 0.75 SUV preoperatively (p=0.16). Figure 1 displays preoperative and postoperative uptake in the bone in the area corresponding to the base of the talar component. Although we did not find a significant difference in our initial study, the observed increase in perfusion to the talus after TAR may reach significance with a larger cohort of patients. Conclusion: 18F-PET demonstrates the ability to quantify changes in bone perfusion and metabolism following TAR. Our results suggest that the vascular blood supply to the talus is not disrupted after TAR. Additional pharmacokinetic analysis of the dynamic activity curves will also allow for estimates of bone blood flow and osteoblastic turnover via compartmental modeling. These results may be used to confirm the presence of adequate bone blood flow and vascularity in the body of the talus following total ankle replacement.