Background: Limitations have previously existed for the use of brain infusion catheters with extended delivery port designs to achieve larger distribution volumes using convection-enhanced delivery (CED), due to poor transmittance of materials and uncontrolled backflow. The goal of this study was to evaluate a novel brain catheter that has been designed to allow for extended delivery and larger distribution volumes with limited backflow of fluid. It was characterized using a broad range of therapeutic pore sizes both for transmittance across the membranes to address possible occlusion and for distribution in short term infusion studies, both in-vitro in gels and in-vivo in canines.
View Article and Find Full Text PDFBackground: Convection Enhanced Delivery (CED) into targeted brain areas has been tested in animal models and clinical trials for the treatment of various neurological diseases.
New Method: We used a series of techniques, to in effect, maintain positive pressure inside the catheter relative to the outside, that included a hollow stylet, a high volume bolus of solution to clear the line, a low and slow continuous flow rate during implantation, and heat sealing the catheter at the time of implantation.
Results: 120 catheters implanted into brain parenchyma of 89 adult female rhesus monkeys across four sets of experiments.
The cessation of driving is a difficult transition for the elderly, but it can be facilitated through interventions. The purpose of this study was to explore the satisfaction, usefulness and applicability of the CarFreeMe intervention in the French-Canadian context. A qualitative clinical research device was used on ten older adults aged between 61 and 90 years.
View Article and Find Full Text PDFUsing standardized guidelines in preclinical research has received increased interest in light of recent concerns about transparency in data reporting and apparent variation in data quality, as evidenced by irreproducibility of results. Although the costs associated with supporting quality through a quality management system are often obvious line items in laboratory budgets, the treatment of the costs associated with quality failure is often overlooked and difficult to quantify. Thus, general estimations of quality costs can be misleading and inaccurate, effectively undervaluing costs recovered by reducing quality defects.
View Article and Find Full Text PDFDegener Neurol Neuromuscul Dis
March 2019
Therapies targeting mutant huntingtin DNA, mRNA, and protein have a chance at becoming the first disease-modifying treatments for Huntington's disease, a fatal inherited neurodegenerative disorder for which only symptom management treatments are available today. This review focuses on evidence addressing several key questions pertinent to huntingtin-lowering, ranging from the functions of wild-type huntingtin (wtHTT) that may be disrupted by huntingtin-lowering treatments through the various ways huntingtin can be lowered, the tolerability of wtHTT-lowering in mice and primates, what has been found in the Ionis Pharmaceutical safety trial of a huntingtin-lowering therapy, and to the question of how much mutant huntingtin may need to be lowered for a therapy to be clinically effective. We conclude that adverse consequences of lowering wtHTT in animals appear to be brain region-specific, and/or dependent upon the animal's stage of development and the amount by which huntingtin is lowered.
View Article and Find Full Text PDFIdentification of Parkinson's disease at the earliest possible stage of the disease may provide the best opportunity for the use of disease modifying treatments. However, diagnosing the disease during the pre-symptomatic period remains an unmet goal. To that end, we used pharmacological MRI (phMRI) to assess the function of the cortico-basal ganglia circuit in a non-human primate model of dopamine deficiency to determine the possible relationships between phMRI signals with behavioral, neurochemical, and histological measurements.
View Article and Find Full Text PDFParkinson's disease (PD) is a disorder affecting dopamine neurons for which there is no cure. Glial cell line-derived neurotrophic factor (GDNF) and the closely related protein neurturin are two trophic factors with demonstrated neuroprotective and neurorestorative properties on dopamine neurons in multiple animal species. However, GDNF and neurturin Phase-2 clinical trials have failed to demonstrate a significant level of improvement over placebo controls.
View Article and Find Full Text PDFBackground: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed.
New Method: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques.
Acupuncture has increasingly been used as an alternative therapy for treatment of Parkinson's disease (PD). However, the efficacy of acupunture for PD still remains unclear. The present study was designed to objectively and safely monitor anti-parkinsonian effects of electroacupuncture (EA) and brain activity in nonhuman primates modeling human PD.
View Article and Find Full Text PDFOBJECTIVE A better understanding of the effects of chronically delivering compounds to the substantia nigra and nearby areas is important for the development of new therapeutic approaches to treat alpha-synucleinopathies, like Parkinson's disease. Whether chronic intranigral delivery of an infusate could be achieved without causing motor dysfunction or marked pathology remains unclear. The authors evaluated the tolerability of continuously delivering an infusate directly into the rhesus monkey substantia nigra via a programmable pump coupled to a novel intraparenchymal needle-tip catheter surgically implanted using MRI-guided techniques.
View Article and Find Full Text PDFThe kinetics of the gas-phase quenching reactions O((1)D) + N2, O((1)D) + O2, and O((1)D) + Ar have been studied over the 50-296 K temperature range using the Laval nozzle method. O((1)D) atoms were created in situ by the pulsed photolysis of O3 precursor molecules at 266 nm. Rate constants for these processes were measured directly, following the decay of O((1)D) atoms through vacuum ultraviolet laser-induced fluorescence at 115.
View Article and Find Full Text PDFOne possible treatment for Huntington's disease involves direct infusion of a small, interfering RNA (siRNA) designed to reduce huntingtin expression into brain tissue from a chronically implanted programmable pump. Here, we studied the suppression of huntingtin mRNA achievable with short infusion times, and investigated how long suppression may persist after infusion ceases. Rhesus monkeys received 3 days of infusion of Magnevist into the putamen to confirm catheter patency and fluid distribution.
View Article and Find Full Text PDFAltered mitochondrial function in the basal ganglia has been hypothesized to underlie cellular senescence and promote age-related motor decline. We tested this hypothesis in a nonhuman primate model of human aging. Six young (6-8 years old) and 6 aged (20-25 years old) female Rhesus monkeys (Macaca mulatta) were behaviorally characterized from standardized video records.
View Article and Find Full Text PDFThe prevalence of both parkinsonian signs and Parkinson's disease (PD) per se increases with age. Although the pathophysiology of PD has been studied extensively, less is known about the functional changes taking place in the basal ganglia circuitry with age. To specifically address this issue, 3 groups of rhesus macaques were studied: normal middle-aged animals (used as controls), middle-aged animals with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism, and aged animals (>20 years old) with declines in motor function.
View Article and Find Full Text PDFBackground: Hypothyroidism has been associated with cognitive and motor impairments that are likely to constitute hazards in the operation of motor vehicles and a public safety risk. However, there is a paucity of data that would provide an evidence basis for recommendations to hypothyroid patients. The purpose of this study was to determine the specific neurological and psychological deficits consequent to hypothyroidism and whether they are of sufficient magnitude to impede the safe operation of motor vehicles.
View Article and Find Full Text PDFInt J Clin Exp Med
April 2013
Moyamoya disease (MMD) is a cerebrovascular occlusive disorder which causes recurrent strokes and transient ischemic attacks in children. The arteriopathy of MMD targets the internal carotid arteries (ICA) and their branches resulting in ischemia of the ICA circulation. Small perforator branches of the ICA dilate to provide collateral perfusion to ischemic areas.
View Article and Find Full Text PDFCribriform neuroepithelial tumor (CRINET) is a recently recognized central nervous system neoplasm that arises in the ventricles of young children and is characterized by primitive, non-rhabdoid SMARCB1-deficient cells with prominent cribriform architecture. We report a 14-month-old male who presented with signs of increased intracranial pressure. Neuroimaging revealed a large solid and cystic mass in the lateral ventricle.
View Article and Find Full Text PDFHuntington's disease is caused by expression of a mutant form of Huntingtin protein containing an expanded polyglutamine repeat. One possible treatment for Huntington's disease may be to reduce expression of mutant Huntingtin in the brain via RNA interference. Unless the therapeutic molecule is designed to be allele-specific, both wild-type and mutant protein will be suppressed by an RNA interference treatment.
View Article and Find Full Text PDFHuntington's disease is an autosomal dominant neurodegenerative disease caused by a toxic gain of function mutation in the huntingtin gene (Htt). Silencing of Htt with RNA interference using direct CNS delivery in rodent models of Huntington's disease has been shown to reduce pathology and promote neuronal recovery. A key translational step for this approach is extension to the larger non-human primate brain, achieving sufficient distribution of small interfering RNA targeting Htt (siHtt) and levels of Htt suppression that may have therapeutic benefit.
View Article and Find Full Text PDFOBJECT The primary goals of treatment in the infant with craniosynostosis are to correct the deformity and allow for adequate brain growth in as safe and effective a manner as possible. Herein, the authors present the results of treating craniosynostosis using an endoscope-assisted strip craniectomy and postoperative helmet therapy (EASC + PHT) in the hopes of providing further evidence of its role in the treatment of multiple different forms of craniosynostosis. This is a retrospective review of the patients treated with this technique at Children's Hospital Boston.
View Article and Find Full Text PDFObject: Suturectomy as a treatment for craniosynostosis was largely replaced in the late twentieth century by more extensive, but predictable, cranial remodeling procedures. Recent technical innovations, such as using the endoscope combined with postoperative orthotic reshaping, have led to a resurgence of interest in suturectomy as a safer, less invasive method.
Methods: A retrospective chart review was performed for all cases of sagittal synostosis treated with endoscopic sagittal suture strip craniectomy and helmet therapy between 2004 and 2008.
We evaluated the effect of heat challenge on cell viability, concanavalin A-induced proliferation and heat shock protein (HSPs) mRNA expression in peripheral mononuclear blood cells (PBMC) isolated from Creole (CR) and Large White (LW) pigs. The PBMCs were cultured for 9 h at 37 °C before being subjected to heat challenge: (1) at 42 °C or 45 °C for 2, 4, 6 and 9 h to monitor cell viability;(2) at 45 °C for 2 and 9 h followed by stimulation for 24 h at 37 °C with concanavalin A to evaluate mitogen-induced proliferation; and (3) at 45 °C for 3, 6 and 9 h to measure induction of HSP70.2 and HSP90 mRNA.
View Article and Find Full Text PDFBackground: ShuntCheck (Neuro Diagnostic Devices, Inc., Trevose, Pennsylvania) is a new device designed to detect cerebrospinal fluid (CSF) flow in a shunt by sensing skin temperature downstream from a region of CSF cooled by an ice cube.
Objective: To understand its accuracy and utility, we evaluated the use of this device during routine office visits as well as during workup for suspected shunt malfunction.
Although acupuncture has been widely and routinely used in healthcare in the USA, its use has been based more on empirical observation than on scientific knowledge. Therefore, there is a great need for better understanding the underlying mechanism(s) of action. A great body of evidence supports that nonhuman primates are a candidate for studying human diseases.
View Article and Find Full Text PDFAge-dependent metabolic syndrome (MetS) is a well established risk factor for cardiovascular disease, but it also confers major risk for impaired cognition in normal aging or Alzheimer's disease (AD). However, little is known about the specific pathways mediating MetS-brain interactions. Here, we performed the first studies quantitatively linking MetS variables to aging changes in brain genome-wide expression and mitochondrial function.
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