Teaching tape for the motor section of the unified Parkinson's disease rating scale.

We developed a teaching tape of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS) to provide investigators with a visual document of three raters' interpretations of the scoring system for each item except rigidity. The rate of agreement for the selected samples was always significant, with Kendall's coefficient of concordance W ranging between 0.97 and 0.62. We also provided full UPDRS ratings on sample patients that may be used for training and for multicenter studies to assure uniformity of rating. The study identified several items of the UPDRS motor examination for which written instructions were vague, including speech, action tremor, finger taps, rapid alternating movements, and postural stability. Future versions of the scale should address these problems and correct ambiguities. This project offers the first attempt to provide a visual analog for the UPDRS.

Cerebrospinal fluid from patients with Parkinson's disease alters the survival of dopamine neurons in mesencephalic culture.

We have previously demonstrated that extracts of striatal tissue from patients with Parkinson's disease (PD) increase the survival of dopamine neurons in mesencephalic cultures relative to striatal extracts from control patients. In the present study, ventricular cerebrospinal fluid (vCSF) from patients with PD, Alzheimer's disease (AD), and age-matched controls was similarly assessed. vCSF samples were separated into > 10-kDa and < 10-kDa fractions. Cultures incubated with the > 10-kDa fractions from PD and AD patients contained 73 and 13%, respectively, more tyrosine hydroxylase immunoreactive neurons than cultures incubated with vCSF from age-matched controls. This trophic activity was positively correlated with the trophic activity present in striatal extracts from the same patients. The < 10-kDa vCSF fractions from all patient groups inhibited culture growth. These data suggest that the trophic environment in the striatum is altered in PD and can be successfully monitored in CSF.

Striatal extracts from patients with Parkinson's disease promote dopamine neuron growth in mesencephalic cultures.

The caudate, putamen, and cerebellum from five patients with Parkinson's disease (PD) and five normal, aged controls were studied to determine if cell-free extracts from these tissues influenced dopamine neuron growth in culture. Cultures incubated with extracts of the caudate and putamen, but not the cerebellum, from PD patients contained more tyrosine hydroxylase immunoreactive neurons than aged controls. These data suggest that the parkinsonian striatum compensates for dopamine loss by increasing neurotrophic factor production.

Synaptic plasticity in the rat striatum following chronic haloperidol treatment.

Administration of the dopamine (DA) antagonist haloperidol leads to the development of behavioral hypersensitivity as well as enhanced neuronal growth when striatal extracts from these animals are incubated with mesencephalic cultures. For determining if alterations in neuronal growth also occur in vivo, the ultrastructure of the neuropil in the dorsolateral quadrant of the striatum from rats treated (24 days) with haloperidol (1.25 mg/kg) was examined by electron microscopy. Haloperidol-treated rats developed statistically significant behavioral hypersensitivity relative to vehicle-treated controls (p < 0.01). Evaluation of the neuropil revealed that haloperidol treatment enhanced, relative to vehicle-treated controls, the overall number of synaptic boutons by 9% (p < 0.01). The number of perforated synaptic profiles as well as the number of double synapses was increased by 20 and 50%, respectively, although this increase was not statistically significant. The number of myelinated axons remained unchanged, while the number of dendritic spines was increased by 21% (p < 0.05). These data suggest that chronic haloperidol treatment enhanced the growth and possible sprouting of presynaptic neurons and also induced postsynaptic plastic changes. These ultrastructural changes may contribute in part to hypersensitivity behaviors.

Blinded evaluation confirms long-term asymmetric effect of unilateral thalamotomy or subthalamotomy on tremor in Parkinson's disease.

In the past, stereotactic surgery was a regular treatment for prominent unilateral tremor in Parkinson's disease (PD), but follow-up studies were usually short-term and always unblinded. We examined 17 PD patients in long-term follow-up (mean, 10.9 years after surgery) and used videotapes and the Unified Parkinson's Disease Rating Scale to blindly compare tremor ipsilateral and contralateral to the side of surgery. Since the patients were specifically selected for stereotactic surgery because of asymmetric tremor, and the surgical side chosen was contralateral to the predominant tremor, a sign of long-term efficacy would be current postoperative reversal of tremor side predominance. Upper extremity tremor was significantly better contralateral to the surgery compared with the ipsilateral side. We conclude that stereotactic surgery improved the absolute magnitude of tremor or ameliorated its rate of progression. Since asymmetric bradykinesia and dyskinesia were not a prerequisite for the choice of surgical side, we cannot make any conclusion about long-term impact of surgery on these features.

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up.

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as "not improved," only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in "off" function after neurotransplantation, but a serious level of mortality and morbidity.

Levodopa reduces the growth promoting effects of striatal extracts on rostral mesencephalic tegmentum cultures.

Rats with unilateral 6-hydroxydopamine lesions (6-OHDA) of the mesencephalon and vehicle controls (SHAM) were chronically treated with carbidopa (CD) or CD plus levodopa (CD/LD) for 18 days. Seventy-two hours following the last treatment, ipsilateral striata, contralateral striata, and cerebellums from each treatment group were homogenized separately and the supernatant extracts were incubated with rostral mesencephalic tegmentum cultures. As indices of growth-promoting activity (GPA), number of viable neurons and their process lengths were measured 40 h later. In all cultures exposed to striatal extracts, the 6-OHDA lesion was associated with greater GPA than the SHAM extracts. CD/LD consumption reduced this GPA in a dose-dependent fashion in both the lesioned and the SHAM animals. These data suggest that denervation of the striatum enhances the production of a striatally derived neurotrophic factor, the production of which is sensitive to levodopa. Chronic levodopa treatment in Parkinson's disease may therefore contribute to disease progression by reducing the compensating effects of this neurotrophic factor on remaining mesencephalic neurons.

The potential use of a dopamine neuron antibody and a striatal-derived neurotrophic factor as diagnostic markers in Parkinson's disease.

The cerebral spinal fluid (CSF) of patients with Parkinson's disease (PD) contains an antibody that immunocytochemically reacts with dopamine (DA) neurons in the substantia nigra (SN). This antibody was found in 78% of the CSF samples taken from patients with clinical PD. In contrast, only 3% of the CSF samples taken from control patients or patients with neurologic symptoms other than PD possessed this antibody. The production of this antibody might contribute to disease progression but does not appear to be the etiologic factor responsible for PD. In other experiments, concentrates of the CSF of patients with PD enhanced growth of mesencephalic cultures relative to control CSF. Both the antibody and the growth-promoting activity found in CSF are associated with degeneration of the SN and might therefore be useful as potential diagnostic markers for PD.

Clinical improvement in parkinsonian patients undergoing adrenal to caudate transplantation is not reflected by chromogranin A or basic fibroblast growth factor in ventricular fluid.

Fifteen patients with Parkinson's disease underwent open transplantation of autologous adrenal medulla to the caudate nucleus. Motor function was evaluated before and after surgery and was found to be significantly improved at 5-9 months following surgery. Cerebrospinal fluid was taken from the ventricle adjacent to the implant site at the beginning of the operation and at 1 week, 3 months, and 5-9 months following surgery. The cerebrospinal fluid was assayed for chromogranin A (CgA), the major soluble protein in chromaffin granules, and basic fibroblast growth factor (bFGF), a neurotrophic growth factor found in normal brain and adrenal medulla. CgA levels did not increase following surgery, suggesting that a significant number of chromaffin cells did not survive or that surviving chromaffin cells did not secrete a significant amount of CgA. Basic fibroblast growth factor was undetectable in the ventricular cerebrospinal fluid.

Dopamine distribution and behavioral alterations resulting from dopamine infusion into the brain of the lesioned rat.

In an effort to verify the "dopamine secretion hypothesis" as the mechanism responsible for the antiparkinsonian efficacy of adrenal medullary transplants into the brain, the effects of dopamine infusion into the brains of rats with unilateral substantia nigra lesions were examined. The apomorphine-induced rotation, characteristic of this animal model, was diminished after 7 days of continuous dopamine infusion (10 micrograms/hr) into the ipsilateral striatum, whereas intraventricular infusion was without effect. Chromatographic analysis of the dopamine distribution after 10 days of infusion into either region revealed that ipsilateral delivery of dopamine did not result in contralateral increases in dopamine content. Examination of the adjacent striatum following ipsilateral intraventricular delivery indicated that dopamine had only penetrated 1 mm. Even with intrastriatal delivery, there were still parts of the infused striatum which had below-normal levels of dopamine. The fact that striatal tissue presents a significant barrier to the penetration of dopamine is discussed in relation to adrenal medullary and fetal nigral transplants.

Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results.

Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.

Clozapine fails to prevent the development of haloperidol-induced behavioral hypersensitivity in a cotreatment paradigm.

We have previously established that chronic cotreatments involving antimuscarinic agents and haloperidol attenuate the development of behavioral hypersensitivity without affecting dopamine receptor proliferation. The antipsychotic agent clozapine also has significant antimuscarinic activity and was coadministered with haloperidol in rats for 2 months to determine if it would similarly attenuate the development of hypersensitivity. Clozapine or chlorpromazine cotreatment, unlike thioridazine cotreatment, did not attenuate the development of haloperidol-induced behavioral hypersensitivity. Clozapine or thioridazine cotreatment also failed to prevent the development of haloperidol-induced D2 receptor proliferation, whereas chlorpromazine cotreatment enhanced D2 receptor proliferation relative to haloperidol-treated animals. Alterations in dopamine biochemistry in the striatum or nucleus accumbens could not explain this dissociation between behavioral hypersensitivity and dopamine receptor proliferation. It is therefore hypothesized that dopamine receptor proliferation is permissive for behavioral hypersensitivity and that factors in addition to alterations in dopamine function contribute to the expression of dopamine hypersensitivity states.

Adrenal medullary transplant to the striatum of patients with advanced Parkinson's disease: 1-year motor and psychomotor data.

We studied motor and psychomotor changes over 1 year after surgery in 7 patients with severe idiopathic Parkinson's disease (PD) who underwent intrastriatal autologous adrenal medulla transplant. Significant clinical improvements were present 1 year after surgery and primarily involved increased quantity of "on" time and increased quality of "off" time: "on" time increased from a mean 60.7% of the waking day to 82.7%, and "off" function improved. In contrast, although "on" function also improved, statistically significant improvement occurred in only 1 measure, the Unified Parkinson's Disease Rating Scale activities of daily living subscale. Medications did not change, and motor fluctuations persisted. Improvement began several weeks after surgery, was maximal at 4 to 6 months, and was sustained thereafter. There was significant group improvement in quality of life measures of sleep and rest, social isolation, and ambulation. One patient had severe, recurrent depression postoperatively. The efficacy of adrenal transplant surgery is not transient, and specific functional improvements can be prolonged.

Dopaminergic alterations in cotreatments attenuating haloperidol-induced hypersensitivity.

Chronic treatment of the laboratory rat with haloperidol results in an increased stereotypic behavioral response to subsequent dopamine agonist challenge. This behavioral hypersensitivity (BH) is thought to reflect an increase in DA receptor number following chronic pharmacologic denervation. Using a cotreatment strategy, we demonstrate here that a variety of agents can attenuate or prevent the development of BH when administered chronically with haloperidol. Cotreatment with lithium and amantadine prevented the changes in DA biochemistry as well as the proliferation of DA receptors normally associated with chronic haloperidol treatment. Cotreatment with thioridazine or scopolamine did alter the changes in DA biochemistry normally associated with haloperidol treatment, but failed to attenuate the DA receptor proliferation. Taken together, these data suggest that mechanisms in addition to DA biochemical and receptor changes participate in the development and subsequent expression of BH. DA receptor proliferation must, therefore, be considered permissive to the development of BH.