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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.

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.

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.

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.

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, Highlights • A “functional rerouting” hypothesis in recovery from brain injury is tested. • The connectome-based network diffusion model measures functional rerouting. • Recovery in severe brain injury correlates with a network diffusion model parameter. • Simulation in healthy connectomes independently validates the results in patients.

The delivery of therapeutics to neural tissue is greatly hindered by the blood brain barrier (BBB). Direct local delivery via diffusive release from degradable implants or direct intra-cerebral injection can bypass the BBB and obtain high concentrations of the therapeutic in the targeted tissue, however the total volume of tissue that can be treated using these techniques is limited. One treatment modality that can potentially access large volumes of neural tissue in a single treatment is intra-arterial (IA) injection after osmotic blood brain barrier disruption. In this technique, the therapeutic of interest is injected directly into the arteries that feed the target tissue after the blood brain barrier has been disrupted by exposure to a hyperosmolar mannitol solution, permitting the transluminal transport of the therapy. In this work we used contrast enhanced magnetic resonance imaging (MRI) studies of IA injections in mice to establish parameters that allow for extensive and reproducible BBB disruption. We found that the volume but not the flow rate of the mannitol injection has a significant effect on the degree of disruption. To determine whether the degree of disruption that we observed with this method was sufficient for delivery of nanoscale therapeutics, we performed IA injections of an adeno-associated viral vector containing the CLN2 gene (AAVrh.10CLN2), which is mutated in the lysosomal storage disorder Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL). We demonstrated that IA injection of AAVrh.10CLN2 after BBB disruption can achieve widespread transgene production in the mouse brain after a single administration. Further, we showed that there exists a minimum threshold of BBB disruption necessary to permit the AAV.rh10 vector to pass into the brain parenchyma from the vascular system. These results suggest that IA administration may be used to obtain widespread delivery of nanoscale therapeutics throughout the murine brain after a single administration.

Summary Objective To confirm altered perfusion within tibial bone marrow lesions (BMLs) and improve our understanding on the relationship between BMLs and pain in knee osteoarthritis (OA). Methods Participants with moderate to severe knee OA were recruited and pain was assessed using the pain subscale of the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Subchondral tibial BMLs were identified and graded on magnetic resonance imaging (MRI) proton density-weighted (PDW) fat suppressed images. A pharmacokinetic model was used to analyze perfusion parameters on dynamic contrast enhanced (DCE) MRI which represent transfer rates in and out of the BMLs. The relation between perfusion and pain was evaluated using multivariable linear regression after adjustment for BML grade, age, gender and body mass index (BMI). Results There were 37 participants (mean age 64.9 years, range 46–86) with radiographic Kellgren and Lawrence grades of 3 and 4 in the study knee; 75.6% had BMLs that were classified grades 1 and 2. The mean WOMAC pain score was 10.3 (0–20 scale). There was a significant correlation between BML K el (rate of contrast elimination) and BML grade ( P = 0.001 univariate, P = 0.002 multivariate analyses), although we did not demonstrate any significant multivariate association between BML perfusion and pain. We also found an inverse relationship between pain at sleep and BML grade ( P Conclusions The absence of any significant association between bone perfusion and pain implies that the relationship of tibial BMLs to pain in OA is still incompletely understood. BMLs are just one component of the whole knee joint and are formed from various causes, all of which interact and collectively contribute to the genesis of pain in OA.

Osteoarthritis and avascular necrosis are common clinical entities with unknown origins. Recently, vascular changes were implicated in the pathogenesis of both conditions. This article discusses the use of novel noninvasive imaging techniques as a means of assessing bone perfusion and quantifying differences seen in osteoarthritis and avascular necrosis. Review of our human data suggests that the MRI contrast dye is retained for longer periods of time, suggesting decreased perfusion out of regions of osteoarthritis and avascular necrosis. Use of such a noninvasive measure of assessing bone perfusion could be useful in the diagnosis, prevention, and treatment of not only osteoarthritis and avascular necrosis but also other entities that affect the musculoskeletal system.

Summary. Background: Recurrent hemarthroses in hemophilia results in synovitis and joint arthropathy. Primary prophylaxis when universally instituted at current doses can prevent joint deterioration but is expensive. Alternatively, the selective implementation of prophylaxis would require a more sensitive tool for detecting synovitis than possible with clinical surveillance or plain radiographs. Magnetic resonance imaging (MRI) is such a tool and is utilized for the evaluation of hemophilic joint disease (HJD). However, it is expensive, and requires sedation in younger children precluding its utility for monitoring of synovitis. Ultrasonography (USG) with power Doppler (USG-PDS) has been utilized to detect and quantitate synovial vascularity in other arthritides and could provide an equally effective but less costly tool for HJD, particularly in children who would not require sedation. Objectives: To determine whether USG-PDS is comparable to MRI in the evaluation of hemophilic synovitis. Patients: A prospective cohort of 31 subjects including 33 joints (knees, elbows, ankles) underwent dynamic contrast enhanced (DCE)-MRI and USG-PDS. Results: USG-PDS measurements of synovial thickness(r = 0.70, P

Purpose: Recent studies have demonstrated that magnetic-resonance spectroscopic imaging (MRSI) of the prostate may effectively distinguish between regions of cancer and normal prostatic epithelium. This diagnostic imaging tool takes advantage of the increased choline plus creatine versus citrate ratio found in malignant compared to normal prostate tissue. The purpose of this study is to describe a novel brachytherapy treatment-planning optimization module using an integer programming technique that will utilize biologic-based optimization. A method is described that registers MRSI to intraoperative-obtained ultrasound images and incorporates this information into a treatment-planning system to achieve dose escalation to intraprostatic tumor deposits. Methods: MRSI was obtained for a patient with Gleason 7 clinically localized prostate cancer. The ratios of choline plus creatine to citrate for the prostate were analyzed, and regions of high risk for malignant cells were identified. The ratios representing peaks on the MR spectrum were calculated on a spatial grid covering the prostate tissue. A procedure for mapping points of interest from the MRSI to the ultrasound images is described. An integer-programming technique is described as an optimization module to determine optimal seed distribution for permanent interstitial implantation. MRSI data are incorporated into the treatment-planning system to test the feasibility of dose escalation to positive voxels with relative sparing of surrounding normal tissues. The resultant tumor control probability (TCP) is estimated and compared to TCP for standard brachytherapy-planned implantation. Results: The proposed brachytherapy treatment-planning system is able to achieve a minimum dose of 120% of the 144 Gy prescription to the MRS positive voxels using 125 I seeds. The preset dose bounds of 100–150% to the prostate and 100–120% to the urethra were maintained. When compared to a standard plan without MRS-guided optimization, the estimated TCP for the MRS-optimized plan is superior. The enhanced TCP was more pronounced for smaller volumes of intraprostatic tumor deposits compared to estimated TCP values for larger lesions. Conclusions: Using this brachytherapy-optimization system, we could demonstrate the feasibility of MRS-optimized dose distributions for 125 I permanent prostate implants. Based on probability estimates of anticipated improved TCP, this approach may have an impact on the ability to safely escalate dose and potentially improve outcome for patients with organ-confined but aggressive prostatic cancers. The magnitude of the TCP enhancement, and therefore the risks of ignoring the MR data, appear to be more substantial when the tumor is well localized; however, the gain achievable in TCP may depend quite considerably on the MRS tumor-detection efficiency.

Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of glioblastoma (GBM), where deregulated expression or activity of EGFR has been associated to tumor development, progression and spread, and decreased survival. Systemic administration of an anti-EGFR antibody (CetuximabTM) reduces cellular proliferation in a variety of cancer models, but for GBM, efficacy is limited by the blood-brain barrier, where only ~ 0.1% of circulating antibodies reach the brain. To circumvent these limitations, we have developed a strategy to deliver the cDNA sequence for the anti-EGFR antibody directly to the CNS via adeno-associated virus (AAV) gene transfer vectors, resulting in local, persistent expression in the CNS. Efficacy of this therapeutic approach was evaluated by assessment of survival of NOD/SCID immunodeficient mice after CNS administration of human U87MG glioblastoma cells modified to express wild type EGFR to the striatum, either at the same time or 8 days prior to the administration of an AAVrh. 10-based vector coding for the anti-EGFR monoclonal antibody Cetuximab (AAVrh. 10CetMab). Localized expression of the antibody was confirmed by Western analysis and ELISA. Simultaneous administration of AAVrh. 10CetMab and GBM xenograft to the CNS was associated with survival of the treated animals compared to controls that received PBS (AAVrh. 10CetMab treated 5 ± days vs PBS-treated, 31±2 days, p

CO RR EC TE D P RO OF these abnormalities through motor tests. Homozyous mice performed poorly and showed no improvement on the inverted grip and rotarod tests. Together, these data suggest that the mice are impaired in their motor ability and strength, which may be due to gross accumulative manifestations in the brain. Additionally, they demonstrated increased stereotypic behavior in the open field test by entering the center zone less frequently and in categorized observation by spending more time chewing, but decreased stereotypic behavior in the marble burying test by burying fewer marbles. This study implicates particular sphingolipids in highly specific functions within the brain and a complex, but specific, system to regulate their expression. The detailed ceramide composition of the mouse brain illustrated in this study can serve as a reference point upon which brains from other neurological and storage disorders can be compared.

s / Osteoarthritis and Cartilage 20 (2012) S10–S53 S13 Conclusions: These results show that the shape of the hip as quantified by an SSM is able to predict the risk of THR, whereas variation in shape can not predict the development of clinical OA. The latter might be a result of the poor reliability of the ACR criteria. We observed that 87% of the individuals who had clinical OA at baseline, did not have clinical OA anymore after 5 years. In conclusion, minor shape variations at baseline have a good predictive value for the development of end-stage OA and may be used as a biomarker to predict the future risk for THR. 8 ASSESSMENT OF PERFUSION IN OSTEOARTHRITIS INDUCED BONE MARROW LESIONS USING DYNAMIC CONTRAST ENHANCED MAGNETIC RESONANCE IMAGING J.P. Dyke , D. Wheaton , L. Ling , C. Talmo , W.F. Harvey , D.J. Hunter . Weill Cornell Med. Coll., New York, NY, USA; New England Baptist Hosp., Boston, MA, USA; Royal North Shore Hosp. and Northern Clinical Sch., Sydney, Australia Purpose: Osteoarthritis (OA) is the most common joint disease in modern, aging societies and causes substantial physical and psychosocial disability. During the initiation and progression of OA, subchondral bone is the site of numerous dynamic morphological transformations due to an altered osteoblast metabolism, which is part of the pathological process. These in situ structural changes in subchondral bone can be readily observed using imaging techniques such as fat suppressed T2-weighted MRI during the course of OA. Whilst previous studies in the OA literature support a link between BMLs and knee pain, few have evaluated bone perfusion in relation to knee pain in OA. This study characterizes BML in OA by assessing perfusion in Ă subchondral bone with dynamic contrast-enhanced (DCE) MRI. Correlation of imaging parameters wasmadewith BML grade and size as well as WOMAC pain subscores. Methods: There were 37 participants with moderate to severe knee OA (mean 64.9 years, range 46 to 86) with radiographic Kellgren and Lawrencegradesof 3 and4. Themeanpain subscale of the Likert versionof the WOMAC index was 10.3 (0-20 scale). Subjects had an MRI performed of their knee on a 1.5T Twin Speed GE Excite scanner with a dedicated knee coil. BML localization was performed using a sagittal dual echo FSE fat suppressed sequencewithTR/TEof 4000ms/15ms, 60ms, 2.53mmslices, no skip/gap, 256X256matrix and 12 cm FOV. Each BMLwas graded from 0-3 on the basis of lesion size according to the BLOKS scoring system. Gadolinium-diethylenetriaminepenta -acetic acid (Gd-DTPA) was injected at a standard concentration (0.1 mmol/kg) using a power injector followed by a saline flush. Dynamic contrast enhanced (DCE) MRI was performed using a 3D FSPGR sequence with 20 sagittal slices of 3 mm thickness over 7 minutes with a 7.5 second time resolution with a TR/TE of 5.5ms/2.9ms with a 12 degree flip angle and 256x128 matrix. Subchondral BMLs were identified on T2W fat suppressed images as discrete areas of increased signal adjacent to subcortical bone and used for DCE-MRI perfusion analysis. A pharmacokinetic model was used to analyze perfusion parameters using in-house software to model transfer rates into and out of the BMLs using adjacent areas of muscle as internal controls. The relation between perfusion and pain was evaluated using multivariate linear regression and its relationship with pain at night was performed using ordinal logistic regression separately after adjustment for BML grade, age, gender and BMI. Results: There was a significant correlation between BML kel /Muscle kel (rate of contrast elimination) and BML grade (p1⁄40.001/0.002 in uni/ multivariate analyses). No significant associationwas foundbetweenBML DCE-MRI perfusionparameters and pain or pain at night.Moreover, BMLs Grades 1 and2 had small volumes compared to the total joint volume and may not contribute to the overall knee pain. An inverse relationship was also foundbetweenpainatnightandBMLgradedetermined fromtheprecontrast T2W fat suppressed images (p