In vivo brain estrogen receptor density by neuroendocrine aging and relationships with cognition and symptomatology.

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 F-fluoroestradiol (F-FES) Positron Emission Tomography (PET) study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks.

Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study.

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.

Positron Emission Tomography Quantitative Assessment of Off-Target Whole-Body Biodistribution of I-124-Labeled Adeno-Associated Virus Capsids Administered to Cerebral Spinal Fluid.

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.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

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 multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks.

A Novel Hands-on Approach Towards Teaching Diagnostic Radiology Residents MRI Scanning and Physics.

Rationale And Objectives: Traditional approaches towards teaching magnetic resonance imaging (MRI) scanning and physics have limitations that a hands-on course may help overcome. A dedicated week of MRI instruction may help improve radiology resident confidence and competence. Additional benefits may include improved physician-technologist communication and accelerated mastery of MRI safety.

A pathway towards a two-dimensional, bore-mounted, volume body coil concept for ultra high-field magnetic resonance imaging.

Lack of a body-sized, bore-mounted, radiofrequency (RF) body coil for ultrahigh field (UHF) magnetic resonance imaging (MRI) is one of the major drawbacks of UHF, hampering the clinical potential of the technology. Transmit field (B ) nonuniformity and low specific absorption rate (SAR) efficiencies in UHF MRI are two challenges to be overcome. To address these problems, and ultimately provide a pathway for the full clinical potential of the modality, we have designed and simulated two-dimensional cylindrical high-pass ladder (2D c-HPL) architectures for clinical bore-size dimensions, and demonstrated a simplified proof of concept with a head-sized prototype at 7 T.

Use of small animal PET-CT imaging for assessment of tendon-to-bone healing: A pilot study.

Background: The availability of non-invasive means to evaluate and monitor tendon-bone healing processes is limited. Micro Positron-Emission-Tomography (µPET) using 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 µPET/CT scans to evaluate bone turnover along the graft-tunnel interface in a rat ACL (anterior cruciate ligament) reconstruction model.

Safety of Direct Intraparenchymal AAVrh.10-Mediated Central Nervous System Gene Therapy for Metachromatic Leukodystrophy.

Metachromatic leukodystrophy, a fatal pediatric neurodegenerative lysosomal storage disease caused by mutations in the arylsulfatase A () 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.

Slowing late infantile Batten disease by direct brain parenchymal administration of a rh.10 adeno-associated virus expressing .

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.

Quantitative Whole-Body Imaging of I-124-Labeled Adeno-Associated Viral Vector Biodistribution in Nonhuman Primates.

A method is presented for quantitative analysis of the biodistribution of adeno-associated virus (AAV) gene transfer vectors following administration. We used iodine-124 (I-124) radiolabeling of the AAV capsid and positron emission tomography combined with compartmental modeling to quantify whole-body and organ-specific biodistribution of AAV capsids from 1 to 72 h following administration. Using intravenous (IV) and intracisternal (IC) routes of administration of AAVrh.

Untargeted Metabolite Profiling of Cerebrospinal Fluid Uncovers Biomarkers for Severity of Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2, Batten Disease).

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.

Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound.

Objective: Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR-guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation.

Study of Intraventricular Cerliponase Alfa for CLN2 Disease.

Background: 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.

Methods: 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.

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective" APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage.

Clinical improvement associated with targeted interruption of the cerebellothalamic tract following MR-guided focused ultrasound for essential tremor.

OBJECTIVE The objective of this study was to evaluate the utility of diffusion tensor imaging (DTI) tractography-based targeting of the dentatorubrothalamic tract (DRT) for magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy in patients with essential tremor (ET) and correlate postprocedural tract disruption with clinical outcomes. METHODS Four patients received preprocedural and immediate postprocedural DTI in addition to traditional anatomical MRI sequences for MRgFUS thalamotomy. Optimal ablation sites were selected based on the patient-specific location of the DRT as demonstrated by DTI (direct targeting) and correlated with traditional atlas-based measurements for thalamic ventral intermediate nucleus (Vim) lesioning (indirect targeting).

Detection of Botulinum Toxin Muscle Effect in Humans Using Magnetic Resonance Imaging: A Qualitative Case Series.

Background: Although important for dosing and dilution, there are few data describing botulinum toxin (BT) movement in human muscle.

Objective: To better understand BT movement within human muscle.

Design: Proof-of-concept study with descriptive case series.

Radioiodinated Capsids Facilitate In Vivo Non-Invasive Tracking of Adeno-Associated Gene Transfer Vectors.

Viral vector mediated gene therapy has become commonplace in clinical trials for a wide range of inherited disorders. Successful gene transfer depends on a number of factors, of which tissue tropism is among the most important. To date, definitive mapping of the spatial and temporal distribution of viral vectors in vivo has generally required postmortem examination of tissue.

Anti-Epidermal Growth Factor Receptor Gene Therapy for Glioblastoma.

Glioblastoma multiforme (GBM) is the most common and aggressive primary intracranial brain tumor in adults with a mean survival of 14 to 15 months. Aberrant activation of the epidermal growth factor receptor (EGFR) plays a significant role in GBM progression, with amplification or overexpression of EGFR in 60% of GBM tumors. To target EGFR expressed by GBM, we have developed a strategy to deliver the coding sequence for cetuximab, an anti-EGFR antibody, directly to the CNS using an adeno-associated virus serotype rh.

Magnetic resonance advection imaging of cerebrovascular pulse dynamics.

We analyze the pulsatile signal component of dynamic echo planar imaging data from the brain by modeling the dependence between local temporal and spatial signal variability. The resulting magnetic resonance advection imaging maps depict the location of major arteries. Color direction maps allow for visualization of the direction of blood vessels.

Magnetic resonance microscopy may enable distinction between normal histomorphological features and prostate cancer in the resected prostate gland.

Objectives: To determine imaging protocol parameters for characterization of prostate tissue at histological length scales.

Material And Methods: Rapid acquisition with relaxation enhancement, spin echo and gradient echo fast low angle shot data were acquired using ex vivo 3-Tesla or 7-Tesla magnetic field strengths from fresh prostatectomy specimens (n = 15) obtained from either organ donor or patients with prostate cancer (PCa). To achieve the closest correspondence between histopathological components and magnetic resonance imaging (MRI) results, in terms of resolution and sectioning planes, multiple high-resolution imaging protocols (ranging from a few minutes to overnight) were tested.

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model.

Background And Purpose: Permeability surface-area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface-area product and BBB permeability in a murine model by histologic confirmation.

Brain Region-Specific Degeneration with Disease Progression in Late Infantile Neuronal Ceroid Lipofuscinosis (CLN2 Disease).

Background And Purpose: Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene. Our hypothesis was that regional analysis of cortical brain degeneration may identify brain regions that are affected earliest and most severely by the disease.

Materials And Methods: Fifty-two high-resolution 3T MR imaging datasets were prospectively acquired on 38 subjects with CLN2.

The Potential of High Resolution Magnetic Resonance Microscopy in the Pathologic Analysis of Resected Breast and Lymph Tissue.

Pathologic evaluation of breast specimens requires a fixation and staining procedure of at least 12 hours duration, delaying diagnosis and post-operative planning. Here we introduce an MRI technique with a custom-designed radiofrequency resonator for imaging breast and lymph tissue with sufficient spatial resolution and speed to guide pathologic interpretation and offer value in clinical decision making. In this study, we demonstrate the ability to image breast and lymphatic tissue using 7.

Genetic modification of neurons to express bevacizumab for local anti-angiogenesis treatment of glioblastoma.

The median survival of glioblastoma multiforme (GBM) is approximately 1 year. Following surgical removal, systemic therapies are limited by the blood-brain barrier. To circumvent this, we developed a method to modify neurons with the genetic sequence for therapeutic monoclonal antibodies using adeno-associated virus (AAV) gene transfer vectors, directing persistent, local expression in the tumor milieu.

Characterization of bone perfusion by dynamic contrast-enhanced magnetic resonance imaging and positron emission tomography in the Dunkin-Hartley guinea pig model of advanced osteoarthritis.

This study characterizes changes in subchondral bone circulation in OA and examines relationships to bone structure and cartilage degeneration in Dunkin-Hartley guinea pigs. We have used dynamic contrast-enhanced MRI (DCE-MRI) and PET, with pharmacokinetic modeling, to characterize subchondral bone perfusion. Assessments are made of perfusion kinetics and vascular permeability by MRI, and blood volume and flow, and radionuclide incorporation into bone, by PET.