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C W Olanow

Publications and source records attributed to C W Olanow.

At least 91 records · Page 5Linked to original sources
PubMed1996

Fetal nigral transplantation as a therapy for Parkinson's disease.

Fetal nigral grafts have been demonstrated to survive, secrete dopamine, form synaptic connections with host neurons, and reverse behavioral disturbances in experimental models of parkinsonism. These findings suggest that fetal nigral grafting may be a useful therapy for patients with Parkinson's disease (PD). Recent preliminary clinical trials of transplantation in PD have shown increased striatal fluorodopa uptake (measured using positron emission tomography) and clinical benefit in some patients. An autopsy study of one patient who had received fetal nigral transplants demonstrated robust graft survival and striatal reinnervation, with no evidence of host-derived sprouting or immune rejection. The development of a successful clinical transplantation program depends on a careful consideration of the transplantation variables and the related long-term risks and benefits to the patients.

Female↗
PubMed1996

Blood manganese correlates with brain magnetic resonance imaging changes in patients with liver disease.

BACKGROUND: Chronic liver failure is associated with high signal abnormalities in the basal ganglia on T1-weighted magnetic resonance imaging of the brain. These abnormalities are strikingly similar to those seen following manganese intoxication. As dietary manganese is normally cleared by the liver, we hypothesize that hepatic dysfunction could lead to manganese overload and account for the MRI abnormalities seen in patients with chronic liver disease. METHODS: We measured blood manganese concentrations in eleven patients with biopsy-proven hepatic cirrhosis and eleven healthy age and sex-matched controls. We also performed semi-quantitative measures of T1 signal abnormalities on MRI in the patients with chronic liver disease. RESULTS: Patients with cirrhosis had significantly higher blood manganese concentrations (20.6 +/- 10.2 mcg/L) than controls (7.2 +/- 2.7, p = .0013). In addition, semi-quantitative scores of T1-weighted signal hyperintensity on MRI correlated with blood manganese concentration in patients with cirrhosis (r = .65, p = .029). CONCLUSIONS: These findings demonstrate that chronic liver disease is associated with manganese overload and suggest that manganese is responsible for the T1-weighted signal hyperintensity seen on MRI of patients with liver disease. As manganese intoxication is known to cause parkinsonism and an encephalopathy similar to those which occur with chronic liver disease, it is possible that manganese toxicity contributes to the development of these symptoms in liver damaged patients and that therapies which prevent or reduce manganese overload may have clinical benefit.

Adult↗
PubMed1996

Magnetic resonance imaging of corticobasal degeneration.

Corticobasal degeneration (CBD) is an adult-onset, progressive parkinsonian syndrome with strikingly asymmetrical features, and signs and symptoms referable to both cerebral cortex and basal ganglia. Although once considered rare, it is now recognized with increasing frequency during life. Eight patients with clinically diagnosed CBD and 8 age- and sex-matched patients with Parkinson's disease underwent high-field-strength magnetic resonance imaging (MRI) of the brain. MRIs were graded by a blinded neuroradiologist using a semiquantitative (0-3) scale. MRI of patients with CBD revealed significantly greater T2-weighted signal hypointensity in the putamena and globi pallidi, and ventricular enlargement. When specifically sought, asymmetrical cortical atrophy was identified in 5 of 8 CBD patients. Increased T2-weighted lenticular signal hypointensity, ventricular enlargement, and asymmetrical cortical atrophy are supportive MRI findings of CBD.

Aged↗
PubMed1996

Manganese intoxication in the rhesus monkey: a clinical, imaging, pathologic, and biochemical study.

We gave three adult rhesus monkeys seven IV injections of manganese chloride at approximately 1-week intervals. We evaluated neurologic status by serial clinical examinations and performed a levodopa test if the animal developed features of basal ganglia dysfunction. After the animals were killed, we performed neuropathologic, neurochemical, and laser microprobe mass analysis (LAMMA) studies. Two of three animals developed a parkinsonian syndrome characterized by bradykinesia, rigidity, and facial grimacing suggestive of dystonia but not tremor. Neither animal responded to levodopa. Autopsy demonstrated gliosis primarily confined to the globus pallidus (GP) and the substantia nigra pars reticularis (SNr). We detected focal mineral deposits throughout the GP and SNr, particularly in a perivascular distribution. LAMMA studies noted that mineral deposits were primarily comprised of iron and aluminum. The severity of pathologic change correlated with the degree of clinical dysfunction. These studies demonstrate that, in contrast to Parkinson's disease (PD) and MPTP-induced parkinsonism, manganese primarily damages the GP and SNr and relatively spares the nigrostriatal dopaminergic system. Further, the results suggest that Mn-induced parkinsonism can be differentiated from PD and MPTP-induced parkinsonism by the clinical syndrome and response to levodopa. The accumulation of iron and aluminum suggests that iron/aluminum-induced oxidant stress may contribute to the damage associated with Mn toxicity.

Animals↗
PubMed1996

Oxidative stress and the pathogenesis of Parkinson's disease.

Current concepts of the pathogenesis of Parkinson's disease (PD) center on the formation of reactive oxygen species and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism. A loss of GSH is associated with incidental Lewy body disease and may represent the earliest biochemical marker of nigral cell loss. GSH depletion alone may not result in damage to nigral neurons but may increase susceptibility to subsequent toxic or free radical exposure. The nature of the free radical species responsible for cell death in PD remains unknown, but there is evidence of involvement of hydroxyl radical (OH.), peroxynitrite, and nitric oxide. Indeed, OH. and peroxynitrite formation may be critically dependent on nitric oxide formation. Central to many of the processes involved in oxidative stress and oxidative damage in PD are the actions of monoamine oxidase-B (MAO-B). MAO-B is essential for the activation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to 1-methyl-4-phenylpyridinium ion, for a component of the enzymatic conversion of dopamine to hydrogen peroxide (H2O2), and for the activation of other potential toxins such as isoquinolines and beta-carbolines. Thus, the inhibition of MAO-B by drugs such as selegiline may protect against activation of some toxins and free radicals formed from the MAO-B oxidation of dopamine. In addition, selegiline may act through a mechanism unrelated to MAO-B to increase neurotrophic factor activity and upregulate molecules such as glutathione, SOD, catalase, and BCL-2 protein, which protect against oxidant stress and apoptosis. Consequently, selegiline may be advantageous in the long-term treatment of PD.

Humans↗
PubMed1996

Evidence of neuronal oxidative damage in Alzheimer's disease.

Oxidative stress has been proposed as a pathogenetic mechanism in Alzheimer's disease. One mechanism of oxidative damage is the nitration of tyrosine residues in proteins, mediated by peroxynitrite breakdown. Peroxynitrite, a reaction product of nitric oxide and superoxide radicals, has been implicated in N-methyl-D-aspartate receptor-mediated excitotoxic damage. Reported evidence of oxidative stress in Alzheimer's disease includes increased iron, alterations in protective enzymes, and markers of oxidative damage to proteins and lipids. In this report, we demonstrate the presence of nitrotyrosine in neurofibrillary tangles of Alzheimer's disease. Nitrotyrosine was not detected in controls lacking neurofibrillary tangles. Immunolabeling was demonstrated to be specific nitrotyrosine in a series of control experiments. These observations link oxidative stress with a key pathological lesion of Alzheimer's disease, the neurofibrillary tangle, and demonstrate a pathogenetic mechanism in common with the other major neurodegenerative diseases of aging, Parkinson's disease and amyotrophic lateral sclerosis. These findings further implicate nitric oxide expression and excitotoxicity in the pathogenesis of cell death in Alzheimer's disease.

Adolescent↗
PubMed1995

Factors predictive of the need for levodopa therapy in early, untreated Parkinson's disease. The Parkinson Study Group.

OBJECTIVE: To identify characteristics of patients with early, untreated Parkinson's disease that are the most important predictors of rapid functional decline. DESIGN: Prospective observational study of a cohort of 800 patients with early, untreated Parkinson's disease who were involved in a multicenter, randomized, double-blind, controlled clinical trial of selegiline hydrochloride (L-deprenyl) and vitamin E (alpha-tocopherol). PRIMARY OUTCOME VARIABLE: Time from randomization to the onset of disability that necessitated levodopa therapy (end point), as judged by the enrolling investigator. METHODS: Stepwise Cox regression was used in combination with clinical judgment to identify the most important independent baseline predictors of the primary end point among a host of variables, including treatment with selegiline and vitamin E, global and specific clinical measures of disease severity, demographic variables, and neuropsychological test results. RESULTS: In addition to selegiline treatment and global disease severity measures, such as the stage according to the criteria of Hoehn and Yahr, impaired domestic capacity, and the activities of daily living score, the complex of postural instability/gait difficulty and bradykinesia were found to be the factors that were most highly associated with the risk of reaching the end point. CONCLUSIONS: The findings suggest that patients with Parkinson's disease whose early clinical presentation includes either postural instability/gait difficulty or bradykinesia are at high risk for rapid functional decline.

Adult↗
PubMed1995

Bilateral fetal nigral transplantation into the postcommissural putamen in Parkinson's disease.

We performed fetal nigral transplantations in 4 Parkinson's disease (PD) patients. Solid grafts were bilaterally implanted into the postcommissural putamen using 3 to 4 donors per side aged 6 1/2 to 9 weeks postconception. Transplant deposits were separated by no more than 5 mm in three dimensions. Cyclosporine was employed for a total of 6 months. Patients were evaluated at baseline and at 1, 3, and 6 months postoperatively. Striatal 18-fluorodopa uptake was assessed by positron emission tomography at baseline and at 6 months postoperatively. The procedure was well tolerated in all patients. One patient had a clinically asymptomatic superficial cortical hemorrhage along the needle tract and a second had transient postoperative confusion and hallucinations. All patients experienced clinically meaningful benefit. Significant improvement (p < 0.05) was detected in total UPDRS score during the "off" state, Schwab-England disability score during the "off" state, percent "off" time, and percent "on" time with dyskinesia. Increased striatal fluorodopa uptake was observed bilaterally in each patient, with mean increases of 53% on the right (p = 0.01) and 33% on the left (p = 0.08). Our study demonstrated clear and consistent improvement in clinical features and striatal fluorodopa uptake following fetal tissue transplantation in patients with advanced PD whose condition was not improved preoperatively by drug manipulation. These preliminary results are encouraging and support further studies to evaluate grafting strategies as a therapy for PD.

Adult↗
PubMed1995

The effect of deprenyl and levodopa on the progression of Parkinson's disease.

We have performed a 14-month, prospective, randomized, double-blind, placebo-controlled study to evaluate the effect of deprenyl and levodopa/carbidopa (Sinemet) on the progression of signs and symptoms in patients with mild Parkinson's disease (PD). One hundred one untreated PD patients were randomly assigned to one of the following four treatment groups: Group I, deprenyl + Sinemet; Group II, placebo-deprenyl + Sinemet; Group III, deprenyl + bromocriptine; and Group IV, placebo-deprenyl + bromocriptine. The final visit was performed at 14 months, i.e., 2 months after withdrawal of deprenyl or its placebo and 7 days after withdrawal of Sinemet or bromocriptine. Deterioration in Unified Parkinson's Disease Rating Score (UPDRS) between untreated baseline and final visits was used as an index of disease progression. Placebo-treated patients deteriorated by 5.8 +/- 1.4 points, while deprenyl-treated patients deteriorated by 0.4 +/- 1.3 points (p < 0.001). This effect was sufficiently powerful that a significant deprenyl effect could be detected in the subgroup of 41 patients randomized to Sinemet (p < 0.01) as well as in the 23 patients who completed a 14-day washout of Sinemet or bromocriptine (p < 0.05). No difference in the extent of deterioration was detected in patients randomized to Sinemet versus bromocriptine. This study demonstrates that deprenyl attenuates deterioration in UPDRS score in patients with early PD. These findings are not readily explained by the drug's symptomatic effects and are consistent with the hypothesis that deprenyl has a neuroprotective effect.

Aged↗
PubMed1994

Degeneration of nigrostriatal dopaminergic neurons increases iron within the substantia nigra: a histochemical and neurochemical study.

Parkinson's-diseased (PD) brains have increased levels of iron in the zona compacta of the substantia nigra (SNc). To determine whether these elevated nigral iron levels may be caused secondarily by degeneration of nigrostriatal dopaminergic (NS-DA) neurons, the NS-DA pathway was unilaterally lesioned in rats through 6-hydroxydopamine (6-OHDA) infusion and nigral iron levels evaluated three weeks later. A significant increase was observed in both iron concentration (+35%) and iron content (+33) within the substantia nigra (SN) ipsilateral to comprehensive 6-OHDA lesions. Moreover, ferric iron staining was dramatically increased within the SNc following 6-OHDA lesions, primarily due to the appearance of iron-positive SNc neurons and infiltrating reactive glial cells. Iron staining in the SN zona reticularis was modestly increased after 6-OHDA lesions, but staining in the neostriatum and globus pallidus was unaffected. These results indicate that loss of NS-DA neurons is associated with increased iron levels in the SN. This suggests that increased nigral iron levels in PD may be secondary to some neurodegenerative process. Nonetheless, even a secondary increase in nigral iron levels may be of pathogenic importance in PD because of iron's ability to catalyze neurotoxic free radical formation and perpetuate neurodegeneration.

Amphetamine↗
PubMed1994

Manganese intoxication and chronic liver failure.

Manganese intoxication and chronic liver failure are associated with strikingly similar clinical, imaging, and pathological abnormalities. As manganese is primarily cleared by the liver, inadequate elimination of manganese absorbed from the normal diet may lead to manganese overload in patients with liver disease. We report a significant elevation of blood manganese concentration in 3 patients with biopsy-proved hepatic cirrhosis who exhibited neurological dysfunction and characteristic abnormal signal hyperintensity in the globi pallidi and substantia nigra on T1-weighted magnetic resonance imaging. We speculate that manganese accumulation in the brain accounts for the magnetic resonance imaging abnormalities and contributes to neurological dysfunction in patients with liver disease.

Aged↗
PubMed1994

A multicenter double-blind placebo-controlled trial of pergolide as an adjunct to Sinemet in Parkinson's disease.

Three hundred and seventy-six subjects with advanced Parkinson's disease participated in a prospective, double-blind placebo-controlled study of the dopamine agonist pergolide mesylate as an adjunct to Sinemet. At 6 months, patients randomized to pergolide had a statistically significant improvement in total Parkinson's score, scores of activities of daily living, motor function, number of "off" hours, Hoehn and Yahr stage, and numerous parameters of parkinsonian function including bradykinesia, rigidity, gait, and dexterity. This benefit was obtained with the addition of a mean dose of 2.94 mg of pergolide, which permitted a 24.7% reduction in dose of levodopa. Adverse reactions were, for the most part, mild, reversible, and not of major clinical significance. No significant cardiac or electrocardiographic abnormalities were detected. This study demonstrates that pergolide mesylate, as an adjunct to levodopa, is an effective antiparkinsonian agent that provides clinical improvement while permitting a reduction in levodopa dose.

Activities of Daily Living↗
PubMed1994

Progressive changes in striatal dopaminergic markers, nigral volume, and rotational behavior following iron infusion into the rat substantia nigra.

Excess iron (Fe) within the substantia nigra zona compacta (SNc) has been implicated in the pathogenesis of Parkinson's disease (PD). We recently reported that intranigral Fe infusion into the rat substantia nigra (SN) induces dose-dependent SN neurodegeneration and associated reductions in striatal dopaminergic (DA) markers. The objective of the present study was to determine whether infused Fe is capable of inducing persistent/progressive neurodegenerative changes relevant to PD. Following unilateral infusions of vehicle, 1.25 or 2.10 nmol Fe into the rat SN, SNc neuronal loss, SN volume, striatal neurochemical markers, and apomorphine-induced rotational behavior were assessed at 2, 4, and 6 months. Semiquantitative analysis of thionine-stained SNc neurons demonstrated an initial modest neuronal loss which remained stable through 6 months postinfusion. Fe-induced SN atrophy was dose-dependent and progressive through 6 months. Striatal DA and homovanillic acid levels were progressively decreased at least through 4 months following 1.25 nmol Fe infusion; both doses of Fe induced significant reductions of both DA markers at 4 months with no recovery evident through 6 months. Apomorphine-induced rotational behavior progressively increased for both Fe infusion groups through the 6 months of testing. These data indicate that a single exposure of the SN to a modest amount of Fe can induce persistent/progressive changes occurring through a number of months postinfusion and further establishes intranigral Fe infusion as an animal model for PD.

Animals↗
PubMed1994

Metals and free radicals in neurodegeneration.

Substantial evidence has accumulated implicating metals and free radicals in the pathogenesis of the major neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant stress can damage critical biological molecules and initiate a cascade of events including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease there is evidence of oxidative stress in affected brain regions, as indicated by increased metal accumulation (which promotes free radical formation), decreased antioxidant levels (which protect against free radical formation), and oxidative damage. Recently, studies of the familial form of amyotrophic lateral sclerosis have detected mutations in the gene that encodes superoxide dismutase, which is one of the body's primary oxidant defense mechanisms. Mice that are transfected with the human mutant superoxide dismutase gene develop an amyotrophic lateral sclerosis syndrome. These studies demonstrate that oxidant stress can initiate the development of a chronic progressive neurodegenerative disorder.

Alzheimer Disease↗
PubMed1994

Magnetic resonance imaging of neurodegenerative diseases.

Magnetic resonance imaging (MRI) has become an important diagnostic tool in the evaluation of neurodegenerative diseases. Although MRI currently does not yield sufficient predictive power to provide a diagnosis in most individual cases, important features have been identified in population studies that help support or exclude a clinical diagnosis under consideration. In parkinsonian patients, putamenal signal hypointensity is commonly observed in patients with atypical parkinsonism. In demented patients, hippocampal atrophy and prolonged T2 relaxation may help identify individuals with Alzheimer's disease. Caudate and putamenal atrophy are seen in Huntington's disease and may serve as markers of disease progression.

Alzheimer Disease↗