Expression of neural markers in human umbilical cord blood.

A population of cells derived from human and rodent bone marrow has been shown by several groups of investigators to give rise to glia and neuron-like cells. Here we show that human umbilical cord blood cells treated with retinoic acid (RA) and nerve growth factor (NGF) exhibited a change in phenotype and expressed molecular markers usually associated with neurons and glia. Musashi-1 and beta-tubulin III, proteins found in early neuronal development, were expressed in the induced cord blood cells. Other molecules associated with neurons in the literature, such as glypican 4 and pleiotrophin mRNA, were detected using DNA microarray analysis and confirmed independently with reverse transcriptase polymerase chain reaction (RT-PCR). Glial fibrillary acidic protein (GFAP) and its mRNA were also detected in both the induced and untreated cord blood cells. Umbilical cord blood appears to be more versatile than previously known and may have therapeutic potential for neuronal replacement or gene delivery in neurodegenerative diseases, trauma, and genetic disorders.

Traditional and complementary therapies in Parkinson's disease.

Parkinson's disease has existed in different parts of the world since ancient times. The first clear description is found in the ancient Indian medical system of Ayurveda under the name Kampavata. Traditional therapies in the form of herbal preparations containing anticholinergics, levodopa, and monoamine oxidase inhibitors were used in the treatment of PD in India, China, and the Amazon basin. Scientific reevaluation of these therapies may be valuable, as shown in the case of Mucuna pruriens and Banisteria caapi. Complementary therapies such as massage therapy, biofeedback, and acupuncture may have beneficial effects for patients and deserve further study.

Transgenic murine dopaminergic neurons expressing human Cu/Zn superoxide dismutase exhibit increased density in culture, but no resistance to methylphenylpyridinium-induced degeneration.

Primary dopaminergic neuronal cultures with increased superoxide dismutase (SOD) activity were established for studying the role of superoxide anion (O2-) in 1-methyl-4-phenylpyridinium (MPP+)-induced degeneration of dopamine (DA) neurons. Mean SOD activity in cultures prepared from transgenic (human) Cu/Zn SOD (hSOD1) mice was 2.46-2.60 times greater than in cultures prepared from nontransgenic control mice. After 1 and 2 weeks in culture, the mean density of DA neurons [number of tyrosine hydroxylase-immunoreactive (TH-ir) cells per visual field] was significantly higher in cultures prepared from transgenic mice compared with those prepared from nontransgenic control mice (4.55-5.63 TH-ir neurons per field in hSOD1 cultures vs. 2.66-2.8 TH-ir neurons per field in control cultures). However, uptake of [3H]DA relative to uptake of [3H]GABA was only slightly greater in hSOD1 cultures than in normal cultures (14.1 nmol of DA/100 nmol of GABA vs. 12.1 nmol of DA/100 nmol of GABA). Resistance to MPP+ toxicity was not significantly different from that in normal cultures when based on density of surviving TH-ir cell bodies (EC50 = 0.54 microM in hSOD1 and EC50 = 0.37 microM in normal cultures). A more sensitive measure of DA neuron integrity and function ([3H]DA uptake) also failed to demonstrate increased resistance of hSOD1 cultures to the toxin (EC50 = 73.7 nM in hSOD1 and EC50 = 86.2 nM in controls). These results do not support the hypothesis that neurotoxicity of the active metabolite of MPTP, MPP+, is mediated by generation of O2- in the cytoplasm. Nevertheless, mesencephalic cultures with increased hSOD1 activity appear to survive better than normal control cultures in the oxidatively stressful environment of cell culture incubators, and such mesencephalic cells may be useful for cell grafting studies in animal models of Parkinson's disease.

Visual hallucinations associated with Parkinson disease.

OBJECTIVE: To determine factors that are predictive for the development of hallucinations associated with Parkinson disease (PD). BACKGROUND: Hallucinations are a common difficulty for patients with established PD, and hallucinations and psychosis may be the most common causes for nursing home placement. The characteristics of the hallucinations associated with PD differ from the hallucinations associated with schizophrenia or cocaine abuse. Multiple factors have been suggested as causal. DESIGN AND METHODS: A total of 214 consecutive patients were interviewed during routine visits to the Parkinson's Disease Clinics in Columbus, Ohio, and Miami, Fla, using a hallucination questionnaire, Folstein Mini-Mental State Examination, and an attempt to correlate age, duration of disease, medication, and psychological or sleep disorders with the hallucinations. RESULTS: Hallucinations were almost exclusively visual and were present in 55 of the 214 patients. Dementia, age, duration of disease, history of depression, or history of sleep disorder were strongly associated with the hallucinations. CONCLUSIONS: While reduction in levodopa and anticholinergic medication doses is appropriate in the management of hallucinations, the factors that predispose patients to hallucinations include dementia and advancing age. The phenomena of visual hallucinations associated with PD, while not fully explained, are unique enough to be of interest to all neurologists and neuroscientists.

The use of pramipexole, a novel dopamine (DA) agonist, in advanced Parkinson's disease.

We evaluated the efficacy, safety and tolerability of a new dopamine D-2 receptor agonist, pramipexole [(S)-2-amino-4,5,6,7-tetrahydro-6-propylamino-benzathiazol-dihydro chloride], as adjunctive therapy in patients with advanced Parkinson's disease (PD). Twenty-four PD patients with motor fluctuations were treated in an 11 week prospective, single-blind parallel-group, placebo-controlled trial. The pramipexole treated group experienced a significant improvement in "off" time functioning as measured by the activities of daily living portion of the United Parkinson's Disease Rating Scale. In addition, the active treatment group was able to reduce total levodopa dose by 30% (p < 0.05). Pramipexole was well tolerated and the side effects reported were typical of other dopamine agonists. We conclude that pramipexole has antiparkinsonian effects which make it potentially useful in the treatment of motor fluctuations in PD.

Parkinson's disease and brain levels of organochlorine pesticides.

Epidemiological studies have suggested an etiologic relationship between pesticide exposure and Parkinson's disease (PD). Organochlorine pesticides were assayed in postmortem brain samples from 20 PD, 7 Alzheimer's disease (AD), and 14 nonneurological control cases. The three groups were similar in age at death, sex, and demographic variables. Only two of 16 pesticide residues screened were detected. A long-lasting residue of DDT (pp-DDE) was found in the majority of cases of PD and AD, as well as in all the control cases; pp-DDT was significantly more likely to be found in AD controls than the PD cases (Fisher's exact two-tailed, p = 0.04). Dieldrin was detected in 6 of 20 PD brains, 1 of 7 AD, and in none of 14 control samples. Despite the relatively small number of brains assayed, the association between Dieldrin and the diagnosis of PD was highly significant (p = 0.03). Dieldrin, a lipid-soluble, long-lasting mitochondrial poison, should be investigated as a potential etiological agent of Parkinsonism.

Psychostimulants.

Psychomotor stimulants possess intrinsic reinforcing properties that may lead to dependence and abuse. Epidemics of stimulant abuse have occurred historically in cycles related to introduction of new stimulants or new routes of administration. The actions and toxic effects of stimulants are related primarily to interaction with the central and peripheral SNS. The most common complications of stimulant use that result in visits to emergency rooms and hospital admissions are referrable to psychiatric, cardiopulmonary, and neurologic symptoms. Neurologic complications most commonly include seizure and stroke, but relative to the prevalence of stimulant abuse in most cities, the incidence of stroke and seizures is small. Cocaine-associated stroke can be linked to underlying abnormalities of the cerebrovascular system in almost one half of the cases. Other complications such as sudden death, movement disorders, and infection are rare. With repeated use of stimulants, a state of drug dependence develops for which there is at present inadequate treatment. As a consequence, pharmacotherapeutic strategies for treatment of dependence are being explored.

Levodopa, melanoma, and Parkinson's disease.

Previous reports and the Physicians' Desk Reference caution against the use of levodopa in Parkinson's disease (PD) patients with melanoma. A critical review of the literature reveals only anecdotal evidence to support a link between levodopa and melanoma. In fact, levodopa has an antitumor effect on melanoma. We report nine patients with PD and melanoma who were treated with levodopa/carbidopa (L/C). Current evidence suggests that L/C can be used safely in PD patients with a history of melanoma.

Early combination therapy (bromocriptine and levodopa) does not prevent motor fluctuations in Parkinson's disease.

Early combination therapy with bromocriptine (Br) and levodopa (LD) is believed to delay or prevent the onset of late treatment complications typically associated with LD monotherapy in Parkinson's disease (PD). Studies recommending this regimen have been uncontrolled. We evaluated this possibility in a 4-year, double-blind, randomized, parallel group trial comparing Br and LD both alone and in combination in 22 PD patients never before treated with dopaminergic medications. In the group receiving Br monotherapy, 17% had motor fluctuations (end-of-dose failure or on-off), 17% chorea, 33% dystonia, and 83% freezing. In the LD group, 33% had motor fluctuations, 56% chorea, 100% dystonia, and 22% freezing. In the combination group, 71% had motor fluctuations, 57% chorea, 71% dystonia, and 57% freezing. The frequency of dystonia was significantly lower with Br monotherapy than in the other two treatment groups. No other significant differences were observed. LD monotherapy appeared to have superior efficacy in the treatment of PD. Mean final doses of LD and Br were similar for the different treatment groups. Early combination therapy does not prevent or delay the onset of motor fluctuations or dyskinesia in PD.

Autonomic dysfunction in men with Parkinson's disease.

Forty-eight men with Parkinson's disease (PD) were interviewed utilizing a questionnaire which evaluated autonomic function. The study population included PD patients (mean age: 65.8 years, mean duration of PD: 8 years) and 32 elderly healthy nonparkinsonian males (mean age: 70.4 years). We found a significantly higher prevalence of the following symptoms of autonomic dysfunction in the parkinsonian patients: erectile dysfunction (60.4 vs. 37.5%), sensation of incomplete bladder emptying (41.6 vs. 15.6%), urgency (45.8 vs. 3.125%), constipation (43.9 vs. 6.25%), dysphagia (22.9 vs. 6.25%) and orthostatic dizziness (21.95 vs. 0%). Eighty-nine percent of parkinsonian patients had at least one of these autonomic symptoms, compared to 43% of control subjects (p less than 0.05). This study is the first comprehensive survey of autonomic symptomatology in PD compared to elderly healthy controls and confirms that autonomic nervous system dysfunction is a pervasive problem in PD. Erectile dysfunction is a significant problem in this patient group and contributes to deterioration in the quality of life.

21-aminosteroids interact with the dopamine transporter to protect against 1-methyl-4-phenylpyridinium-induced neurotoxicity.

U-78518F, a 21-aminosteroid from the novel family of lipid peroxidation inhibitors (lazaroids), increased survival of dopamine (DA) neurons in mesencephalic cell cultures incubated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Protection against DA neuron death occurred with increasing concentrations of U-78518F up to 30 microM. Non-specific toxicity produced with higher concentrations of MPP+ was not affected by the lazaroid. U-78518F inhibited cellular uptake of [3H]MPP+ and [3H]DA, but not that of gamma-[3H]aminobutyric acid. In human striatal membrane preparations, U-78518F competed with [3H]mazindol for binding to the DA transporter, with a calculated Ki value of 10 microM. Two of four lazaroids tested inhibited [3H]DA uptake in the cell culture system. The protective effects of 21-aminosteroids in MPP(+)-induced neurotoxicity are, in part, a function of the interaction of these agents with the DA transporter.

Banisterine and Parkinson's disease.

It is of historical interest that 63 years ago Louis Lewin reported the use of a hallucinogenic compound prepared from the South American vine, Banisteria Caapi, to treat Parkinson's disease (PD). This psychoactive compound, named banisterine, proved to be identical to harmine, but 30 years were to pass before it was shown to be a reversible monoamine oxidase (MAO) inhibitor. The first reports of the use of banisterine to treat postencephalitic parkinsonism in 1929 created a stir in the popular press and banisterine was hailed as a "magic drug." Despite continued studies of the harmala alkaloids by other researchers, interest in the therapeutic value of these compounds vanished during the 1930's. The story of banisterine is reviewed because it was the first MAO inhibitor to be used in parkinsonism, and illustrates the historical role of psychoactive drugs in the development of effective therapies, and in elucidating the pathophysiology of PD.

Sleep disorders and sleep effect in Parkinson's disease.

It has been suggested that sleep may have a positive effect on morning motor symptoms in Parkinson's disease (PD). We examined this possibility and also looked at common sleep disorders in PD. Seventy-eight PD patients and 43 normal elderly subjects answered a questionnaire. Of the PD patients, 43.6% reported improved motor symptoms in the morning, 37.2% worse, and 19.2% unchanged compared to the rest of the day. No difference was found between morning-better and -worse groups with respect to age, duration or stage of PD; antiparkinsonian medications utilized, and predominant motor symptoms. However, the morning-same group had a shorter duration of PD and less severe disease and required fewer dopaminergic medications. Sleep disorders were seen with equal frequency in the morning-better and -worse groups. Our results suggest that sleep does not have a direct effect on morning motor function. Alterations in morning motor symptomatology probably represent a manifestation of motor fluctuations. Sleep fragmentation and spontaneous daytime dozing occurred much more frequently in PD patients than controls. In addition, nocturnal vocalizations and daytime hallucinations occurred only in the PD group.

The efficacy of (+)-4-propyl-9-hydroxynaphthoxazine as adjunctive therapy in Parkinson's disease.

(+)-4-propyl-9-hydroxynaphthoxazine (PHNO) is a novel selective D2 agonist. The efficacy and safety of PHNO was studied in 10 Parkinsonian patients (Hoehn and Yahr Stage II or III) who continued to receive levodopa/carbidopa. At the lowest dose administered (0.25 mg tid), nine of the 10 patients improved with respect to rigidity, bradykinesia and tremor. At this dose there was one dropout because of severe orthostasis. Although there was a trend towards improvement in motor scores with the higher doses (0.5-1.0 mg tid), this was not statistically significant. At higher doses there were a total of four dropouts because of adverse effects such as nausea, vomiting and orthostatic hypotension. It appears that PHNO may prove to be efficacious in the treatment of Parkinson's disease.

MPP+-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices.

Since MPTP and its metabolite MPP+ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP+ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP+ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP+ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP+ provoked large (80%) oxidations of cytochrome b and large K+o increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP+-induced changes suggest that while MPP+ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP+ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intracellular relationships as in intact brain.

Efficacy of sinemet CR4 in subgroups of patients with Parkinson's disease.

The efficacy of Sinemet CR4 (50/200) was compared to standard Sinemet (25/100) in an open label crossover study in 22 patients with Parkinson's disease. All patients experienced end of dose failure and 11 had dyskinesia. Unified Parkinson's disease, Hoehn and Yahr, Schwab and England scores, number of hours on per day, number of hours of dyskinesia per day, daily dose of levodopa, and number of doses per day were monitored at the end of each treatment period and the results compared. The only significant difference in these parameters between the CR4 and standard Sinemet treatment periods in the entire group was a decrease in hours of dyskinesia per day. Two subgroups of CR4 responders were specifically examined. The first subgroup was characterised by a significant increase in on time per day with CR4 therapy. These patients had an older age of onset of Parkinson's disease and a shorter duration of disease and fluctuations than the rest of the patients. The second subgroup was characterised by the presence of dyskinesia with standard Sinemet therapy and a significant decrease in hours of dyskinesia per day with CR4 therapy. Both subgroups required a significantly higher daily dose of levodopa while on CR4. It is concluded that CR4 may be useful in increasing hours on per day in subgroups of Parkinson's disease patients who have less severe fluctuations. It may also be useful in decreasing the number of hours of dyskinesia per day.

Hemichorea-hemiballismus associated with acquired immune deficiency syndrome and cerebral toxoplasmosis.

A young woman had hemichorea-hemiballismus subsequently found to be secondary to a cerebral toxoplasmosis infection complicating human immunodeficiency virus infection. This patient had the sixth reported case of acquired immune deficiency syndrome (AIDS) with hemichorea-hemiballismus, and each has been secondary to cerebral toxoplasmosis. The presence of hemichorea-hemiballismus in a young patient should suggest a diagnosis of AIDS and in particular the diagnosis of secondary cerebral toxoplasmosis. Other movement disorders that occur in AIDS are discussed.

MPP+-induced increases in extracellular potassium ion activity in rat striatal slices suggest that consequences of MPP+ neurotoxicity are spread beyond dopaminergic terminals.

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) produces symptoms similar to idiopathic Parkinson's disease in primates. A metabolite of MPTP, MPP+ (1-methyl-4-phenylpyridinium), is actively accumulated by dopaminergic (DA) terminals and selectively destroys nigrostriatal DA neurons. The mechanism of this effect remains unknown but reports that MPP+ inhibits electron transport in isolated mitochondria and increases oxidation of cytochrome b in striatal slices suggest that depression of ATP production is involved. To relate metabolic effects of MPP+ with tissue electrophysiology, extracellular potassium ion activity [K+]o was measured by microelectrodes simultaneous to optical monitoring of reduction/oxidation (redox) activity of cytochrome b during superfusion of MPP+ onto rat striatal and hippocampal slices. MPP+ increased oxidation of cytochrome b and increased [K+]o in slices of striatum. These increases were greater than expected from a selective effect of MPP+ on DA terminals which likely comprise no more than 3% of the total striatal mass. These effects of MPP+ were slowed by a dopamine uptake inhibitor (mazindol) and did not occur in hippocampal slices. These findings indicate that MPP+ influences ion transport as well as metabolic activity and that these actions require the presence of functioning DA terminals. However, the large amplitudes of the MPP+-induced changes suggest that consequences of MPP+-neurotoxicity are not ultimately confined to DA terminals. Two hypothesis are proposed: that energy failure in DA terminals results in leakage of neurotoxic substances or metabolites altering membrane conductance properties of adjacent cells and thereby placing additional demand upon ion transport pumps and mitochondrial oxidative phosphorylation; or that there is secondary uptake of MPP+ leading to mitochondrial inhibition in cells neighboring DA terminals.