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Biomedical subjects

C W Olanow

Publications and source records attributed to C W Olanow.

At least 19 recordsLinked to original sources
PubMed2005

Occupation and parkinsonism in three movement disorders clinics.

BACKGROUND: Few occupational risk factors for Parkinson disease (PD) have been identified. Healthcare, teaching, and farming have been associated with increased risk, while welding has been proposed to accelerate age at PD onset. The aim of the present study was to investigate occupational associations with PD or parkinsonism drawing from three different movement disorders clinics. METHODS: Medical records of 2,249 consecutive patients with PD or parkinsonism from specialty clinics in Sunnyvale, CA, New York, NY, and Atlanta, GA, were reviewed for primary lifetime occupation. Job frequencies were compared with Department of Labor regional statistics. PD diagnosis age and risk of diagnosis < or =50 were determined for each job. RESULTS: Physicians/dentists, farmers, and teachers were significantly more common than expected among PD patients, as were lawyers, scientists, and religion-related jobs. Computer programmers had a younger age at PD diagnosis, and risk of diagnosis < or =50 was greater in computer programmers and technicians. CONCLUSIONS: Consistent with prior studies, healthcare, teaching, and farming were common occupations in Parkinson disease (PD) patients, but welders were not over-represented. Even though several occupations were associated with younger age at PD diagnosis, these results may reflect biases inherent in specialty clinic surveys, including over-representation of younger, employed, and insured patients. Carefully designed analytic studies utilizing appropriate control populations will be required to test hypotheses regarding occupation and PD risk.

Adult↗
PubMed2004

Transgenic mouse model of early-onset DYT1 dystonia.

Early-onset dystonia is an autosomal dominant movement disorder associated with deletion of a glutamic acid residue in torsinA. We generated four independent lines of transgenic mice by overexpressing human DeltaE-torsinA using a neuron specific enolase promoter. The transgenic mice developed abnormal involuntary movements with dystonic-appearing, self-clasping of limbs, as early as 3 weeks after birth. Animals also showed hyperkinesia and rapid bi-directional circling. Approximately 40% of transgenic mice from each line demonstrated these severe behavioral abnormalities. Neurochemical analyses revealed decreases in striatal dopamine in affected transgenic mice, although levels were increased in those that had no behavioral changes. Immunohistochemistry demonstrated perinuclear inclusions and aggregates that stained positively for ubiquitin, torsinA and lamin, a marker of the nuclear envelope. Inclusions were detected in neurons of the pedunculopontine nucleus and in other brain stem regions in a pattern similar to what has been described in DYT1 patients. This transgenic mouse model demonstrates behavioral and pathologic features similar to patients with early-onset dystonia and may help to better understand the pathophysiology of this disorder and to develop more effective therapies.

Amino Acid Sequence↗
PubMed2004

Effects of levodopa on cognitive functioning in moderate-to-severe Parkinson's disease (MSPD).

Although improved cognition has been reported in patients with mild Parkinson's disease (PD) following the administration of levodopa, mixed results have been found in moderately-to-severely affected PD patients (MSPD), particularly in studies conducted since 1980. In the present study, 16 MSPD patients were tested on separate days, once following overnight levodopa withdrawal and once while optimally treated. A battery of neuropsychological tests that assess a range of cognitive functions (i.e., attention, language, visuospatial, memory, and executive), as well as a measure of depression, were used. Although patients performed better on a measure of confrontation naming in the untreated than in the treated condition, there were no significant differences for any of the other cognitive variables or for the depression scale variable. Thus, these data suggest that there are generally no adverse or beneficial effects of levodopa therapy on cognition in MSPD patients.

Aged↗
PubMed2004

Double-blind, placebo-controlled study of entacapone in levodopa-treated patients with stable Parkinson disease.

BACKGROUND: The catechol O-methyltransferase inhibitor entacapone acts by extending the elimination half-life of levodopa and is currently approved as an adjunct to levodopa for the treatment of patients with Parkinson disease (PD) with motor fluctuations. OBJECTIVE: To determine if the addition of entacapone administration provides benefit to levodopa-treated PD patients who have a stable response to levodopa and do not experience motor complications. DESIGN: Prospective, double-blind, placebo-controlled trial. SETTING: Outpatient multicenter study. PATIENTS: Female and male patients 30 years or older with idiopathic PD receiving stable doses of levodopa or carbidopa with or without other dopaminergic therapies and who did not experience motor fluctuations were eligible for the study. MAIN OUTCOME MEASURES: Parkinsonian function and quality of life. RESULTS: The addition of entacapone did not improve motor scores on the Unified Parkinson's Disease Rating Scale in levodopa-treated PD patients who did not experience motor fluctuations. The mean +/- SE adjusted change between baseline and final treatment visit was -0.9 +/- 0.35 in the entacapone group and -0.8 +/- 0.35 in the placebo group (P = .83). Significant improvement with entacapone treatment was detected in several quality-of-life measures, including the Parkinson Disease Questionnaire 39, the 36-item Short-Form Health Survey, the Parkinson's Symptom Inventory, and investigator and subject Clinical Global Assessments. The drug was well tolerated by patients in this population. CONCLUSIONS: The catechol O-methyltransferase inhibitor entacapone, used as an adjunct to levodopa in PD patients who do not experience motor fluctuations, does not improve Unified Parkinson's Disease Rating Scale motor scores but does improve a variety of quality-of-life measures.

Aged↗
PubMed2004

Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress.

Impairment in the capacity of the ubiquitin-proteasome pathway to clear unwanted proteins has been implicated in the cell death that occurs in Parkinson's disease (PD). In support of this concept, defects in proteasomal structure and function, as well as protein aggregates and increased levels of oxidized proteins are found in the substantia nigra of PD patients. We have previously demonstrated that inhibition of proteasome activity in mesencephalic cultures induces degeneration of dopaminergic neurons coupled with the formation of proteinaceous intracellular inclusions. In this study we examined the effect of proteasome inhibition on cultured dopamine neurons when combined with oxidative stress and protein misfolding, in order to better simulate the condition in PD. We demonstrate that two structurally unrelated inhibitors of proteasome activity, lactacystin and carbobenzoxy-L-leucul-L-leucyl-L-leucinal (MG132), cause dose-dependent cell loss that preferentially affects dopaminergic neurons. Conditions that promote protein damage and misfolding such as oxidative stress, heat shock, and canavanine also induce neuronal degeneration with preferential loss of dopamine neurons and cell death is markedly increased when any of these is combined with a proteasome inhibitor. These studies demonstrate a synergistic effect between conditions that promote the formation of damaged proteins and those in which proteasomal function is impaired, and provide further support for the notion that cell loss in PD could be related to a defect in protein handling.

Acetylcysteine↗
PubMed2004

Neuropsychological functioning following bilateral subthalamic nucleus stimulation in Parkinson's disease.

The cognitive effects of subthalamic nucleus (STN) stimulation in Parkinson's disease (PD) have been examined. However, there are no reported studies that evaluate, by incorporating a disease control group, whether neuropsychological performance in surgical patients changes beyond the variability of the assessment measures. To examine this issue, 17 PD patients were tested before and after bilateral STN stimulator implantation, both on and off stimulation. Eleven matched PD controls were administered the same repeatable neuropsychological test battery twice. Relative to changes seen in the controls, the surgery for electrode placement mildly adversely affected attention and language functions. STN stimulation, per se, had little effect on cognition. The STN DBS procedure as a whole resulted in a mild decline in delayed verbal recall and language functions. There were no surgery, stimulation, or procedure effects on depression scale scores. In contrast to these group findings, one DBS patient demonstrated significant cognitive decline following surgery.

Aged↗
PubMed2004

Manganese-induced parkinsonism and Parkinson's disease.

It has long been appreciated that manganese exposure can cause neurotoxicity and a neurologic syndrome that resembles Parkinson's disease (PD). Current evidence indicates that manganese-induced parkinsonism can be differentiated from PD because of its predilection to accumulate in and damage the pallidum and striatum rather than the SNc. The clinical syndrome, response to levodopa, imaging studies with MRI and PET, and pathologic features all help to distinguish these two conditions and permit the correct diagnosis to be established. This is of particular relevance in differentiating patients with parkinsonism due to manganese intoxication from patients with idiopathic PD who have incidental manganese exposure.

Animals↗
PubMed2003

Selegiline in the treatment of Parkinson's disease: its impact on orthostatic hypotension.

Less than a consensus exists as to whether chronic treatment with selegiline in combination with levodopa/carbidopa in patients with Parkinson's disease, is associated with more pronounced orthostatic hypotension than treatment with levodopa/carbidopa alone. To resolve this issue, we compared orthostatic tolerance and autonomic reflexes in 95 patients with Parkinson's disease treated chronically with either selegiline alone (n = 10), levodopa/carbidopa alone (n = 49) or both agents combined (n = 36). Supine heart rate and blood pressure, autonomic cardiovascular reflexes and the frequency and magnitude of orthostatic hypotension were similar in all three treatment groups.

Adult↗
PubMed2002

Lipopolysaccharide prevents cell death caused by glutathione depletion: possible mechanisms of protection.

Glutathione is an important cellular antioxidant present at high concentrations in the brain. We have previously demonstrated that depletion of glutathione in mesencephalic cultures results in cell death and that the presence of glia is necessary for the expression of toxicity. Cell death following glutathione depletion can be prevented by inhibition of lipoxygenase activity, implicating arachidonic acid metabolism in the toxic events. In this study we examined the effect of glial activation, known to cause secretion of cytokines and release of arachidonic acid, on the toxicity induced by glutathione depletion. Our data show that treatment with the endotoxin lipopolysaccharide activated glial cells in mesencephalic cultures, increased interleukin-1beta in microglia and caused depletion of glutathione. The overall effect of lipopolysaccharide treatment, however, was protection from damage caused by glutathione depletion. Addition of cytokines or growth factors, normally secreted by activated glia, did not modify L-buthionine sulfoximine toxicity, although basic fibroblast growth factor provided some protection. A large increase in the protein content and the activity of Mn-superoxide dismutase, observed after lipopolysaccharide treatment, may indicate a role for this mitochondrial antioxidant enzyme in the protective effect of lipopolysaccharide. This was supported by the suppression of toxicity by exogenous superoxide dismutase. Our data suggest that superoxide contributes to the damage caused by glutathione depletion and that up-regulation of superoxide dismutase may offer protection in neurodegenerative diseases associated with glutathione depletion and oxidative stress.

Animals↗
PubMed2002

Surgical therapy for Parkinson's disease.

Surgical therapies for Parkinson's disease (PD) are now being performed with increasing frequency due to the limitations of conventional dopaminergic therapies, improvements in operative procedures, and increased information on the organization of the basal ganglia in normal and pathologic conditions. Ablation procedures have now been largely replaced with deep brain stimulation, which permits benefits to be obtained without the need to make a destructive brain lesion. Several studies now demonstrate the value of stimulating the subthalamic nucleus or the globus pallidus pars interna in patients with advanced PD. Nonetheless, there are limitations associated with these procedures and benefits do not exceed those obtained with levodopa, albeit with reduced motor complications. Fetal transplantation remains an experimental procedure that has shown limited benefits in a double-blind trial and is complicated by persistent dyskinesia. Stem cell, trophic factor, and gene therapy approaches are promising and are currently under intensive investigation.

Brain Tissue Transplantation↗
PubMed2001

Deep-brain stimulation of the subthalamic nucleus or the pars interna of the globus pallidus in Parkinson's disease.

BACKGROUND: Increased neuronal activity in the subthalamic nucleus and the pars interna of the globus pallidus is thought to account for motor dysfunction in patients with Parkinson's disease. Although creating lesions in these structures improves motor function in monkeys with induced parkinsonism and patients with Parkinson's disease, such lesions are associated with neurologic deficits, particularly when they are created bilaterally. Deep-brain stimulation simulates the effects of a lesion without destroying brain tissue. METHODS: We performed a prospective, double-blind, crossover study in patients with advanced Parkinson's disease, in whom electrodes were implanted in the subthalamic nucleus or pars interna of the globus pallidus and who then underwent bilateral high-frequency deep-brain stimulation. We compared scores on the motor portion of the Unified Parkinson's Disease Rating Scale when the stimulation was randomly assigned to be turned on or off. We performed unblinded evaluations of motor function preoperatively and one, three, and six months postoperatively. RESULTS: Electrodes were implanted bilaterally in 96 patients in the subthalamic-nucleus group and 38 patients in the globus-pallidus group. Three months after the procedures were performed, double-blind, crossover evaluations demonstrated that stimulation of the subthalamic nucleus was associated with a median improvement in the motor score (as compared with no stimulation) of 49 percent, and stimulation of the pars interna of the globus pallidus with a median improvement of 37 percent (P<0.001 for both comparisons). Between the preoperative and six-month visits, the percentage of time during the day that patients had good mobility without involuntary movements increased from 27 percent to 74 percent (P<0.001) with subthalamic stimulation and from 28 percent to 64 percent (P<0.001) with pallidal stimulation. Adverse events included intracranial hemorrhage in seven patients and infection necessitating removal of the leads in two. CONCLUSIONS: Bilateral stimulation of the subthalamic nucleus or pars interna of the globus pallidus is associated with significant improvement in motor function in patients with Parkinson's disease whose condition cannot be further improved with medical therapy.

Activities of Daily Living↗
PubMed2001

Early morning off-medication dyskinesias, dystonia, and choreic subtypes.

BACKGROUND: Abnormal involuntary movements (dyskinesias) are common in patients with Parkinson disease (PD) as a consequence of the disease and dopaminergic replacement therapy. Early morning off-medication choreic dyskinesias have been recently reported after fetal dopaminergic cell transplantations in patients with advanced PD. OBJECTIVE: To determine the frequency and severity of the early morning off-medication dyskinesias in consecutive patients with advanced PD and an insufficient response to medical management before they undergo neurosurgery. METHODS: Consecutive patients with advanced idiopathic PD were examined and videotaped before undergoing neurosurgery that included pallidotomy, fetal transplantation, or deep brain stimulation. The examination took place in the morning in the practically defined off state, at least 12 hours after the last dose of dopaminergic drugs. Parkinson disease was characterized using the Unified Parkinson's Disease Rating Scale and the Hoehn and Yahr stage. Dyskinesias were rated with the Abnormal Involuntary Movements Scale and the Rush Dyskinesia Rating Scale. Patients' characteristics and medications were compared using the Wilcoxon rank sum and the Fisher exact tests. RESULTS: Of 68 consecutive patients (44 [65%] men and 24 [35%] women), 11 (16%) had early morning off-medication dyskinesia, with a 95% upper confidence limit of 24%. Focal dystonia was the most common off-medication dyskinesia, and occurred in 10 patients (15%), with a 95% upper confidence limit of 22%; and off-choreic dyskinesia occurred in 1 patient (1.5%), with a 95% upper confidence limit of 4%. There was no difference in PD medications between the patients with and those without dyskinesias. CONCLUSIONS: The most common form of off-medication dyskinesia seen in patients with advanced PD is dystonia. Early morning off-medication choreic dyskinesias are rare but do occur in patients with advanced PD before surgical intervention. The presence and type of off-medication dyskinesias should be monitored in clinical and surgical studies in patients with PD as part of the safety and evaluation of clinical benefits.

Adult↗
PubMed2000

TorsinA accumulation in Lewy bodies in sporadic Parkinson's disease.

Parkinson's disease (PD) is a neurodegnerative disorder that is pathologically characterized by the presence of Lewy bodies in the brain. We show that Lewy bodies in PD are strongly immunoreactive for torsinA, the protein product of the DYT1 gene, which is associated with primary generalized dystonia. In the substantia nigra, torsinA immunoreactivity is localized to the periphery of Lewy bodies, whereas, in cortical Lewy bodies it is uniformly distributed. The significance of this finding is unknown, but may implicate torsinA in neuronal dysfunction that occurs in PD as well as in primary dystonia.

Carrier Proteins↗