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Biomedical subjects

Bruce T Volpe

Publications and source records attributed to Bruce T Volpe.

At least 19 recordsLinked to original sources
PubMed2006

Human lupus autoantibodies against NMDA receptors mediate cognitive impairment.

Neuropsychiatric systemic lupus erythematosus, which often entails cognitive disturbances and memory loss, has become a major complication for lupus patients. Previously, we developed a murine model of neuropsychiatric lupus based on Abs that cross-react with dsDNA and the NMDA receptor (NMDAR). We showed that these murine Abs impair cognition when they access the CNS through a breach in the blood-brain barrier (BBB) triggered by lipopolysaccharide. Because studies show that lupus patients possess anti-NMDAR Abs in their serum and cerebrospinal fluid, we decided to investigate whether these human Abs contribute to cognitive dysfunction. Here, we show that serum with reactivity to DNA and NMDAR extracted from lupus patients elicited cognitive impairment in mice receiving the serum intravenously and given lipopolysaccharide to compromise the BBB integrity. Brain histopathology showed hippocampal neuron damage, and behavioral testing revealed hippocampus-dependent memory impairment. To determine whether anti-NMDAR Abs exist in the brains of systemic lupus erythematosus patients, we eluted IgG from a patient's brain. The IgG bound DNA and NMDAR and caused neuronal apoptosis when injected into mouse brains. We examined four more brains of patients with neuropsychiatric lupus and found that they displayed endogenous IgG colocalizing with anti-NMDAR Abs. Our results indicate that lupus patients have circulating anti-NMDAR Abs capable of causing neuronal damage and memory deficit, if they breach the BBB, and that the Abs exist within patients' brains. Which aspects of neuropsychiatric lupus may be mediated by anti-NMDAR Abs, how often, and in which patients are now important clinical questions.

Animals↗
PubMed2006

Immunity and behavior: antibodies alter emotion.

Systemic lupus erythematosus is an autoimmune disease in which most patients express Abs that bind double-stranded DNA. Recent work has shown that a subset of lupus Abs can crossreact with the NR2A and NR2B subunits of the NMDA receptor. This receptor is expressed in neurons throughout the brain but is at highest density within cells of the hippocampus, amygdala, and hypothalamus. The neurons in the CNS are normally protected from brain-reactive Abs by the blood-brain barrier (BBB); however, a breach in the barrier's integrity exposes neurons to potentially pathogenic Abs. Previously, we have shown that mice that are immunized with a peptide mimetope of DNA produce lupus-like Abs that crossreact with DNA and the NMDA receptor. Moreover, after abrogation of the BBB by treatment with lipopolysaccharide, the immunized mice display hippocampal neuron damage with ensuing memory impairment. Given that rises in epinephrine can increase cerebral blood flow and can cause leaks in the BBB, we decided to investigate whether epinephrine could act as a permissive agent for Ab-mediated neurotoxicity. Here, we show that peptide-immunized mice, given epinephrine to open the BBB, lose neurons in the lateral amygdala and develop a behavioral disorder characterized by a deficient response to fear-conditioning paradigms. Thus, the agent used to open the BBB determines which brain region is made vulnerable to neurotoxic Abs, and Abs that penetrate brain tissue can cause changes not only in cognitive competence, but also in emotional behavior.

Amygdala↗
PubMed2006

Immunity and acquired alterations in cognition and emotion: lessons from SLE.

Classic immunologic teaching describes the brain as an immunologically privileged site. Studies of neuroimmunology have focused for many years almost exclusively on multiple sclerosis, a disease in which inflammatory cells actually infiltrate brain tissue, and the rodent model of this disease, experimental allergic encephalitis. Over the past decade, however, increasingly, brain-reactive antibodies have been demonstrated in the serum of patients with numerous neurological diseases. The contribution these antibodies make to neuronal dysfunction has, in general, not been determined. Here, we describe recent studies showing that serum antibodies to the N-methyl-D-aspartate receptor occur frequently in patients with systemic lupus erythematosus and can cause alterations in cognition and behavior following a breach in the blood-brain barrier.

Animals↗
PubMed2005

Robotics and other devices in the treatment of patients recovering from stroke.

Stroke is the leading cause of permanent disability in the United States despite advances in prevention and novel interventional treatments. Randomized controlled studies have demonstrated the effectiveness of specialized post-stroke rehabilitation units, but administrative orders have severely limited the length of stay, so novel approaches to the treatment of recovery need to be tested in outpatients. Although the mechanisms of stroke recovery depend on multiple factors, a number of techniques that concentrate on enhanced exercise of the paralyzed limb have demonstrated effectiveness in reducing the motor impairment. For example, interactive robotic devices are new tools for therapists to deliver enhanced sensorimotor training for the paralyzed upper limb, which can potentially improve patient outcome and increase patient productivity. New data support the idea that for some post-stroke patients and for some aspects of training-induced recovery, timing of the training may be less important than the quality and intensity of the training. The positive outcome that resulted in the interactive robotic trials contrasts with the failure to find a beneficial result in trials that used a noninteractive device that delivered continuous passive motion only. New pilot data from novel devices to move the wrist demonstrate benefit and suggest that successive improvement of the function of the arm progressing to the distal muscles may eventually lead to significant disability reduction. These data from robotic trials continue to contribute to the emerging scientific basis of neuro-rehabilitation.

Clinical Trials as Topic↗
PubMed2005

CD40L deletion delays neuronal death in a model of neurodegeneration due to mild impairment of oxidative metabolism.

Inflammatory/immune processes are important in the pathogenesis of neurodegenerative diseases. Thiamine deficiency (TD) models the region selective neuronal loss in brain that accompanies mild impairment of oxidative metabolism. TD induces well-defined alterations in neurons, microglia, astrocytes, and endothelial cells. To test the role of inflammatory/immune mechanisms in TD-induced neurodegeneration, the temporal profile of neurodegeneration was compared to the activation of CD68-positive microglia and ICAM-1-positive endothelial cells during TD in wild type mice and in CD40L-/- mice. CD40L-/- delayed the onset of TD-induced neuronal death as well as the activation of microglia and endothelial cells. The current results suggest that CD40L-mediated immune and inflammatory responses have a role in TD-induced neuronal death.

Analysis of Variance↗
PubMed2005

CD40-CD40L interactions promote neuronal death in a model of neurodegeneration due to mild impairment of oxidative metabolism.

Abnormalities in oxidative processes, region-selective neuron loss, inflammation and diminished activity of thiamine-dependent enzymes characterize age-related neurodegenerative diseases. Thiamine deficiency (TD) models the selective neurodegeneration that accompanies mild impairment of oxidative metabolism. As in human neurodegenerative diseases, alterations in multiple cell types accompany the TD-induced neurodegeneration. The current studies demonstrate that CD40 and CD40 ligand (CD40L), two co-stimulatory immune molecules, are involved in TD-induced selective neuronal death. TD induced CD40 immunoreactivity in microglia and CD40L immunoreactivity in astrocytes. Both CD40-positive microglia and CD40L-positive astrocytes increased during the progressive TD-induced neuronal death. In early stages of TD, targeted deletion of CD40 diminished the number of CD40L-positive astrocytes and reduced neuronal death by 35%. The number of CD40L-positive astrocytes increased whenever the number of NeuN-positive neurons decreased. In early stages of TD, deletion of CD40L diminished CD40-positive microglia and reduced the neuronal death by 64%. In advanced phases of TD, neither CD40 nor CD40L deletion protected against neuronal death. The data show for the first time that TD induces expression of CD40 by the microglia and CD40L by astrocytes. The results indicate that CD40-CD40L interactions promote neuronal death in early stages of TD, but that at later phases the protective effects of the diminished CD40 or CD40L are over-ridden by other mechanisms.

Animals↗
PubMed2005

Customized interactive robotic treatment for stroke: EMG-triggered therapy.

A system for electromyographic (EMG) triggering of robot-assisted therapy (dubbed the EMG game) for stroke patients is presented. The onset of a patient's attempt to move is detected by monitoring EMG in selected muscles, whereupon the robot assists her or him to perform point-to-point movements in a horizontal plane. Besides delivering customized robot-assisted therapy, the system can record signals that may be useful to better understand the process of recovery from stroke. Preliminary experiments aimed at testing the proposed system and gaining insight into the potential of EMG-triggered, robot-assisted therapy are reported.

Aged↗
PubMed2005

Continuous passive motion improves shoulder joint integrity following stroke.

OBJECTIVE: In a pilot study of patients with a first stroke and hemiparesis, we sought to determine whether treatment of the upper limb with continuous passive motion (CPM) that was device delivered would alter impairment, disability or the associated adverse symptoms of shoulder joint instability, pain and tone. DESIGN: Patients were randomly assigned to receive daily CPM treatments or participate in self-range of motion groups under the supervision of an occupational therapist. All patients received standard daily poststroke therapy for 3.5 h per day. A blinded evaluator at admission and discharge assessed patients using standardized scales of impairment, disability and adverse symptoms. SETTING: Specialized stroke unit of an acute rehabilitation hospital. SUBJECTS: Two hundred and eighty consecutive patients were screened and 35 of these with a first unilateral stroke, 13 +/- 6 days following the acute event, provided informed consent and were randomly assigned to CPM treatment or supervised group self-range exercise. MAIN MEASURES: Thirty-two completed the study and were evaluated using standardized measures for motor impairment (Fugl-Meyer, Motor Status Scale and Medical Research Council Motor Power), adverse symptoms (gleno-humeral stability, pain and tone), and disability (Functional Independence Measure). RESULTS: CPM-treated patients demonstrated positive trends towards improved shoulder joint stability (p = 0.06, confidence interval -0.03, 2.3) when compared with patients performing therapist-supervised self-range of motion. There were no significant differences in motor impairment, disability, pain or tone. CONCLUSIONS: Device-delivered continuous passive range of motion may offer an enhanced benefit for some adverse symptom reduction in the hemiplegic arm after stroke over traditional self-range of motion exercise.

Aged↗
PubMed2005

Overwhelming leukoencephalopathy as the only sign of neuropsychiatric lupus.

We describe a patient with diffuse leukoencephalopathy, a rare central nervous system complication of systemic lupus erythematosus, who died of brain herniation despite aggressive management. Brain magnetic resonance imaging revealed diffuse white matter hyperintensities consistent with vasogenic edema. Autopsy revealed only widespread cerebral edema. Early recognition and persistent, aggressive treatment will be required to avoid this fatal and rare manifestation of neuropsychiatric lupus.

Adult↗
PubMed2004

Differentiation of the dopaminergic phenotype in the olfactory system of neonatal and adult mice.

Olfactory bulb (OB) interneurons are derived primarily postnatally from progenitors in the anterior subventricular zone (SVZa) and migrate to the OB in the rostral migratory stream (RMS). Progenitors differentiate into phenotypically diverse granule and periglomerular cells by as yet undefined mechanisms. To visualize spatiotemporal aspects of periglomerular dopamine (DA) neuron differentiation, two independently derived transgenic mouse lines were analyzed with a 9-kb tyrosine hydroxylase (TH) promoter to drive either a LacZ or an enhanced green fluorescent protein (EGFP) reporter gene. Both reporters showed similar neonatal expression that varied from low levels in RMS, to moderate in the superficial granule cell layer, to strong in relatively large cells, possibly external tufted cells, in the periglomerular region. TH mRNA and protein were not detected in the RMS but were colocalized with the transgenes in neonatal superficial granule and periglomerular cells. By comparison, TH protein in adults was further limited to periglomerular cells. To demonstrate that transcriptional regulation was the same for EGFP and TH, expression was shown to decline similarly in the OB ipsilateral to odor deprivation produced by adult unilateral naris closure. Of two genes previously hypothesized to regulate OB DA expression, only regulated expression of the orphan receptor Nurr1, but not the homeobox-containing genes Dlx-1 and -2, was consistent with a role in regulation of the DA phenotype. These data demonstrate for the first time that DA phenotypic differentiation in neonates begins with low-level transcription in migrating progenitors in the RMS and culminates with activity-dependent protein expression in periglomerular cells innervated by olfactory receptor cells.

Animals↗
PubMed2004

Rehabilitation robotics: pilot trial of a spatial extension for MIT-Manus.

BACKGROUND: Previous results with the planar robot MIT-MANUS demonstrated positive benefits in trials with over 250 stroke patients. Consistent with motor learning, the positive effects did not generalize to other muscle groups or limb segments. Therefore we are designing a new class of robots to exercise other muscle groups or limb segments. This paper presents basic engineering aspects of a novel robotic module that extends our approach to anti-gravity movements out of the horizontal plane and a pilot study with 10 outpatients. Patients were trained during the initial six-weeks with the planar module (i.e., performance-based training limited to horizontal movements with gravity compensation). This training was followed by six-weeks of robotic therapy that focused on performing vertical arm movements against gravity. The 12-week protocol includes three one-hour robot therapy sessions per week (total 36 robot treatment sessions). RESULTS: Pilot study demonstrated that the protocol was safe and well tolerated with no patient presenting any adverse effect. Consistent with our past experience with persons with chronic strokes, there was a statistically significant reduction in tone measurement from admission to discharge of performance-based planar robot therapy and we have not observed increases in muscle tone or spasticity during the anti-gravity training protocol. Pilot results showed also a reduction in shoulder-elbow impairment following planar horizontal training. Furthermore, it suggested an additional reduction in shoulder-elbow impairment following the anti-gravity training. CONCLUSION: Our clinical experiments have focused on a fundamental question of whether task specific robotic training influences brain recovery. To date several studies demonstrate that in mature and damaged nervous systems, nurture indeed has an effect on nature. The improved recovery is most pronounced in the trained limb segments. We have now embarked on experiments that test whether we can continue to influence recovery, long after the acute insult, with a novel class of spatial robotic devices. This pilot results support the pursuit of further clinical trials to test efficacy and the pursuit of optimal therapy following brain injury.

Journal Article↗
PubMed2004

Cross-linking cellular prion protein triggers neuronal apoptosis in vivo.

Neuronal death is a prominent, but poorly understood, pathological hallmark of prion disease. Notably, in the absence of the cellular prion protein (PrPC), the disease-associated isoform, PrPSc, appears not to be intrinsically neurotoxic, suggesting that PrPC itself may participate directly in the prion neurodegenerative cascade. Here, cross-linking PrPC in vivo with specific monoclonal antibodies was found to trigger rapid and extensive apoptosis in hippocampal and cerebellar neurons. These findings suggest that PrPC functions in the control of neuronal survival and provides a model to explore whether cross-linking of PrPC by oligomeric PrPSc can promote neuronal loss during prion infection.

Animals↗
PubMed2004

Robotics and other devices in the treatment of patients recovering from stroke.

Stroke is the leading cause of permanent disability in the United States despite advances in prevention and novel interventional treatments. Randomized controlled studies have demonstrated the effectiveness of specialized post-stroke rehabilitation units, but administrative orders have severely limited the length of stay, so novel approaches to the treatment of recovery need to be tested in outpatients. Although the mechanisms of stroke recovery depend on multiple factors, a number of techniques that concentrate on enhanced exercise of the paralyzed limb have demonstrated effectiveness in reducing the motor impairment. For example, interactive robotic devices are new tools for therapists to deliver enhanced sensorimotor training for the paralyzed upper limb, which can potentially improve patient outcome and increase their productivity. New data support the idea that for some post-stroke patients and for some aspects of training-induced recovery, timing of the training may be less important than the quality and intensity of the training. The positive outcome that resulted in the interactive robotic trials contrasts with the failure to find a beneficial result in trials that used a noninteractive device that delivered continuous passive motion only. New pilot data from novel devices to move the wrist demonstrate benefit and suggest that successive improvement of the function of the arm progressing to the distal muscles may eventually lead to significant disability reduction. These data from robotic trials continue to contribute to the emerging scientific basis of neuro-rehabilitation.

Equipment Design↗
PubMed2004

Cognition and immunity; antibody impairs memory.

Patients with lupus (SLE) experience progressive cognitive loss without evidence of CNS vascular disease or inflammation. SLE patients produce anti-DNA antibodies that crossreact with NMDA receptors and are capable of mediating excitotoxic death. We now show that mice induced by antigen to express these antibodies have no neuronal damage until breakdown of the blood-brain barrier occurs. Following administration of lipopolysaccharide (LPS) to immunized mice, antibodies gain access to the brain. They bind preferentially to hippocampal neurons and cause neuronal death with resulting cognitive dysfunction and altered hippocampal metabolism on magnetic resonance spectroscopy. Memantine, an NMDA receptor antagonist, given prior to LPS administration, prevents neuronal damage. Thus, systemic immune responses can cause cognitive impairment in the absence of an inflammatory cascade, implicating the immune system in yet another arena of human pathobiology. Furthermore, NMDA receptor antagonists prevent antibody-mediated damage and may constitute a new approach to therapy in SLE.

Animals↗
PubMed2004

Does shorter rehabilitation limit potential recovery poststroke?

OBJECTIVE: To examine retrospectively the recovery of patients engaged in robotic research during a 6 to 7-week course of inpatient rehabilitation. Because timing of the Interim evaluation at 3 1/2 weeks was comparable to the present length of inpatient stroke rehabilitation, the authors assessed whether significant gains in motor abilities occurred after the time when most stroke patients today are discharged home. METHODS: Fifty-six inpatients with a single, unilateral stroke were randomly assigned to a robot therapy or robot exposure group. Therapists blinded to group assignment administered the Fugl-Meyer, Motor Status Score, and MRC motor power test. RESULTS: Significant improvements in upper-limb motor abilities occurred throughout a period approximately twice the present length of stay in inpatient rehabilitation. However, in the latter half of this period, patients who received conventional therapy showed little improvement, whereas patients who received robot training plus conventional therapy continued to improve. CONCLUSION: Further opportunities for recovery after stroke are possible by extending intensive therapy beyond present inpatient rehabilitation stays.

Adult↗
PubMed2003

Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice.

Microglial activation was investigated in the brains of young (3 months old) and older (9-12 months old) mice following administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Tyrosine hydroxylase (TH)-positive neuronal loss differed significantly between young and older mice. Importantly, the two groups clearly demonstrated a distinct microglial activation pattern. In young mice which showed TH neuronal loss at 1 day (33.4%), 3 days (45.1%), 7 days (47.1%) and 14 days (46.9%), microglial activation was first observed at 1 day, with lesser activation at 3 days and none shown later than 7 days. In contrast, in older mice which showed TH neuronal loss at 1 day (49.6%), 3 days (56.1%), 7 days (71.7%) and 14 days (72.1%), microglial activation occurred at 1 day, further intensified at 3-7 days, and was largely abated by 14 days. The double immunohistochemistry further demonstrated that the activated microglia surrounded dopaminergic neurons in older mice at 7 days, which was sharply in contrast to the young mice which were devoid of massive microglial activation in the SN later than 3 days after MPTP treatment. The present study suggests that age-related microglial activation in the SN may be relevant to the higher susceptibility to MPTP neurotoxicity in older mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗