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Walter G Bradley

Publications and source records attributed to Walter G Bradley.

16 recordsLinked to original sources
PubMed2006

Premorbid personality characteristics of patients with ALS.

Experienced neurologists caring for patients with amyotrophic lateral sclerosis (ALS) have commented that these patients commonly exhibit similar personality features. Previous research studies on the premorbid personality characteristics of ALS patients have however not clearly substantiated this observation. In the present study, caregivers of newly diagnosed ALS patients provided ratings of patients' premorbid personality traits, and these ratings were compared with those of caregivers of patients newly diagnosed with other chronic, progressive diseases. Results indicated that ALS patients were rated as significantly lower than the other medical patients in the Openness trait on the NEO-Personality Inventory. This finding is discussed in relation to past research findings, prevailing clinical characterizations of ALS patients, and current research on cognitive and behavioral changes in ALS.

Adult↗
PubMed2006

Mitochondrial involvement in amyotrophic lateral sclerosis: trigger or target?

Despite numerous reports demonstrating mitochondrial abnormalities associated with amyotrophic lateral sclerosis (ALS), the role of mitochondrial dysfunction in the disease onset and progression remains unknown. The intrinsic mitochondrial apoptotic program is activated in the central nervous system of mouse models of ALS harboring mutant superoxide dismutase 1 protein. This is associated with the release of cytochrome-c from the mitochondrial intermembrane space and mitochondrial swelling. However, it is unclear if the observed mitochondrial changes are caused by the decreasing cellular viability or if these changes precede and actually trigger apoptosis. This article discusses the current evidence for mitochondrial involvement in familial and sporadic ALS and concludes that mitochondria is likely to be both a trigger and a target in ALS and that their demise is a critical step in the motor neuron death.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Collaborative National ALS Study Group. Patient orientated research and clinical trials.

The time is now ripe for the ALS community in the United States to set up a national ALS Study Group. The National Institutes of Health and other granting agencies should fund a program to set up and run the ALS Study Group for 5 years renewable. This program should result in a competitive request for applications. The benefits likely to derive from a national ALS Study Group would include cheaper and more cost-effective clinical therapeutic trials, the development of better techniques for pilot trials, an increased number of potential new drugs brought from bench to bedside for ALS trials, increased research on biological and surrogate markers of disease, and increased physician-initiated research.

Amyotrophic Lateral Sclerosis↗
PubMed2005

Cytochrome c association with the inner mitochondrial membrane is impaired in the CNS of G93A-SOD1 mice.

A "gain-of-function" toxic property of mutant Cu-Zn superoxide dismutase 1 (SOD1) is involved in the pathogenesis of some familial cases of amyotrophic lateral sclerosis (ALS). Expression of a mutant form of the human SOD1 gene in mice causes a degeneration of motor neurons, leading to progressive muscle weakness and hindlimb paralysis. Transgenic mice overexpressing a mutant human SOD1 gene (G93A-SOD1) were used to examine the mitochondrial involvement in familial ALS. We observed a decrease in mitochondrial respiration in brain and spinal cord of the G93A-SOD1 mice. This decrease was significant only at the last step of the respiratory chain (complex IV), and it was not observed in transgenic wild-type SOD1 and nontransgenic mice. Interestingly, this decrease was evident even at a very early age in mice, long before any clinical symptoms arose. The effect seemed to be CNS specific, because no decrease was observed in liver mitochondria. Differences in complex IV respiration between brain mitochondria of G93A-SOD1 and control mice were abolished when reduced cytochrome c was used as an electron donor, pinpointing the defect to cytochrome c. Submitochondrial studies showed that cytochrome c in the brain of G93A-SOD1 mice had a reduced association with the inner mitochondrial membrane (IMM). Brain mitochondrial lipids, including cardiolipin, had increased peroxidation in G93A-SOD1 mice. These results suggest a mechanism by which mutant SOD1 can disrupt the association of cytochrome c with the IMM, thereby priming an apoptotic program.

Aging↗
PubMed2005

Aberrant deltaPKC activation in the spinal cord of Wobbler mouse: a model of motor neuron disease.

Protein kinase C (PKC) was suggested to play a role in the pathology of amyotrophic lateral sclerosis (ALS) patients. Activation of PKC delta (deltaPKC) modulates mitochondrially induced apoptosis. The goal of the present study was to define whether deltaPKC activation occurs in Wobbler mouse spinal cord (a model of motor neuron disease). The level of deltaPKC in the soluble fraction was significantly decreased in the spinal cord of Wobbler mice, which was associated with a significant increase in deltaPKC cleavage. Since caspase-3 is known to cleave deltaPKC, we determined caspase-3 activation in the Wobbler mice spinal cord, immunohistochemically. The results demonstrated intense immunoreactivity for activated caspase-3 in corticospinal tract motor neurons of Wobbler mice spinal cord. We hypothesize from these results that caspase-3 activation cleaves deltaPKC, which in turn promotes an aberrant signal transduction pathway in the Wobbler spinal cord.

Amyotrophic Lateral Sclerosis↗
PubMed2004

An ALS mouse model with a permeable blood-brain barrier benefits from systemic cyclosporine A treatment.

To test potentially beneficial drugs to amyotrophic lateral sclerosis (ALS), we created an ALS mouse model with a permeable blood-brain barrier, by crossing the G93A-SOD1 transgenic mouse with a multiple drug resistance type 1a/b (mdr1a/b) gene knockout mouse. To validate the model, we administered cyclosporine A intraperitoneally to the mice. Cyclosporine A accumulated in the brain and spinal cord of this mouse model, whereas it was unable to penetrate the CNS of mdr1a/b wild-type animals. Systemic administration of cyclosporine A extended the life of the double-mutant male mice by approximately 12%. Surprisingly, the effect was more robust in male mice and only marginal in female mice. These results demonstrate the usefulness of this combined mouse model for the testing of potentially therapeutic drugs and support the role of mitochondrial-mediated apoptosis in the pathway to motor neuron death in SOD1-associated ALS.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

A Phase I safety study of hyperbaric oxygen therapy for amyotrophic lateral sclerosis.

BACKGROUND: Vascular endothelial growth factor and mitochondrial abnormalities have been described in ALS and its animal models. We have reported that hyperbaric oxygen (HBO) treatment delayed the onset of weakness in the wobbler mouse. OBJECTIVE: To perform a Phase I safety study of HBO in patients with ALS. METHODS: Five patients with ALS were treated for 60min with 100% oxygen at 2 atmospheres pressure daily for five days a week for four weeks. The patients reported any deterioration in their condition after each treatment, and their neurological condition was measured serially during the four weeks of the treatment, and for four further weeks. RESULTS: Four patients reported decreased fatigue, while one patient dropped out at three weeks because of increased fatigue. Maximum isometric voluntary contraction (MVIC) of all muscle groups except right hand grip improved significantly by up to 97%. Most improvement occurred during the four weeks after treatment. It is possible that the improvement in muscle strength was a placebo or a learning effect, though no such effects have been detected in prior therapeutic trials in ALS using MVIC. No change was detected in other measures of neuromuscular function. CONCLUSIONS: A longer duration, placebo controlled trial in a larger number of patients is needed to determine the safety and efficacy of HBO. Until that is completed, it is not recommended that ALS patients should be treated with HBO.

Aged↗
PubMed2004

AALSS.

Explore the source record for details and available documents.

Activities of Daily Living↗
PubMed2003

Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis.

We tested whether a regular exercise regimen was associated with a change in the life span of G93A-SOD1 transgenic mice, a model of familial ALS. Regular treadmill running for 10 weeks led to a significant increase in the life span of G93A-SOD1 mice. The effect was stronger in male mice, whereas there was only a trend between exercised and sedentary female G93A-SOD1 mice. The data suggest that regular exercise has a beneficial effect on the progression of ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Early mitochondrial dysfunction occurs in motor cortex and spinal cord at the onset of disease in the Wobbler mouse.

The Wobbler mouse is recognized as an animal model for motoneuron disease that exhibits motoneuron pathology. We have recently demonstrated the occurrence of mitochondrial dysfunction in the Wobbler mouse brain. The aim of the present study was to evaluate whether mitochondrial dysfunction occurred at an early age at the time where disease symptoms appear, and whether it was more pronounced in the motor cortex or in the spinal cord. We report here a significant decrease in mitochondrial state 3 and 4 respiration rates at an early age in the Wobbler spinal cord. In addition, there was a pronounced decrease in oxidative phosphorylation in mitochondria isolated from both spinal cord and motor cortex in both age groups. This mitochondrial dysfunction was accompanied by impairment of complex I activity in mitochondria isolated from spinal cord at an early age. Decreases in complex III and IV activities were observed only in mitochondria isolated from the motor cortex at an early age, but impairment of complex III activity prevailed until later in the disease. We conclude that mitochondrial dysfunction ensues at an early stage of the disease and is more pronounced in the spinal cord, which correlates with previous studies that reported degeneration of spinal cord motorneurons.

Age Factors↗
PubMed2002

Diabetic demyelinating polyneuropathy responsive to intravenous immunoglobulin therapy.

BACKGROUND: There is growing evidence that idiopathic chronic inflammatory demyelinating polyneuropathy (CIDP) and polyneuropathy in patients with diabetes mellitus (DM) that meets the electrophysiological criteria for CIDP (DM-CIDP) have many similarities. OBJECTIVE: To evaluate whether DM-CIDP responds to intravenous immunoglobulin (IVIG) therapy. PATIENTS AND METHODS: Twenty-six patients (mean [SD] age, 64 [8.9] years; age range, 40-80 years) with type 2 DM (n = 25), who met the electrophysiological criteria for CIDP, were given IVIG therapy (400 mg/kg body weight per day for 5 days) in a prospective open-label pilot study. All patients had quantitative evaluation using the Neuropathy Impairment Score at baseline and at the end of 4 weeks from the initiation of IVIG therapy. RESULTS: The mean Neuropathy Impairment Score improved significantly from baseline (mean [SD], 61.5 [26.0] points) to the end of the fourth week (33 [29.6] points; P<.00l). This clinically significant improvement occurred in 21 (80.8%) of the 26 patients. Conduction block occurred in 11 (42.3%) of the 26 patients; improvement in the Neuropathy Impairment Score was more frequent in patients who had a conduction block (11 of 11 patients) than in those who did not (10/15 [66.7%]; P =.03). Adverse reactions to IVIG included reversible renal dysfunction in 3 patients, flulike symptoms in 5, headache in 5, and chest pain and shortness of breath in 1. CONCLUSION: Although IVIG therapy seemed to improve DM-CIDP in this uncontrolled trial, a controlled trial is required for confirmation of our findings.

Adult↗
PubMed2002

Demyelinating neuropathy in diabetes mellitus.

BACKGROUND: Recent studies have reported that patients with diabetes mellitus (DM) have a predisposition to develop chronic inflammatory demyelinating polyneuropathy (CIDP). OBJECTIVES: To determine whether patients with DM have a polyneuropathy fulfilling electrophysiologic criteria for CIDP, and whether CIDP is more frequent in patients with type 1 than in patients with type 2 DM. METHODS: We prospectively studied the frequency of electrophysiologic changes meeting the criteria for CIDP in patients with DM seen in our electrophysiology laboratory during a 51-month period (period 1). To evaluate the relationship between DM and CIDP, we prospectively determined during a 14-month period (period 2) the frequency of DM in patients seen in our electrophysiology laboratory with other neuromuscular diseases, and the frequency of idiopathic CIDP. RESULTS: During period 1, 120 patients with DM met the electrophysiologic criteria for CIDP (DM-CIDP). The most frequent clinical features of DM-CIDP were those of a predominantly large-fiber sensorimotor neuropathy, with recent motor deterioration and a moderately increased cerebrospinal fluid protein concentration. Twenty-six of the 120 patients were given intravenous immunoglobulin (400 mg/kg per day for 5 days), and 21 patients (80.8%) had significant improvement in the neurologic deficit at the end of 4 weeks of therapy. The DM-CIDP occurred equally in type 1 and type 2 DM. During period 2, 1127 patients were seen. Of these, 189 (16.8%) had DM with various neurologic disorders, including 32 patients (16.9%) with DM-CIDP. Among the remaining 938 patients without DM, 17 (1.8%) had idiopathic CIDP. The odds of occurrence of DM-CIDP was 11 times higher among diabetic than nondiabetic patients (P<.001). CONCLUSIONS: Demyelinating neuropathy meeting the electrophysiologic criteria for CIDP occurred in both types of DM, and its occurrence was significantly higher in diabetic than in nondiabetic patients.

Adolescent↗