Dopamine antibodies in the pathogenesis of parkinsonism]

L-DOPA and dopamine (DA) binding antibodies were found in the blood serum of Parkinsonian patients and middle-aged and elderly normal persons. DA-binding serum gamma-globulins of parkinsonian patients injected into rat caudate nuclei induced the pathogenetic mechanism of Parkinson's syndrome (generator of pathologically enhanced excitation) in these brain part and evoked main parkinsonian symptoms (oligokinesia, rigidity, tremor). The serum gamma-globulins of Parkinsonian patients without Da-antibodies caused less pronounced EEG disturbances. Parkinsonian symptoms developed rarely and were shorter and less pronounced compared with the DA-antibody effect. The DA binding antibodies role in Parkinson's syndrome pathogenesis and is L-DOPA therapeutic tolerance formation was discussed.     

Determination of tetrahydropapaveroline in the urine of Parkinsonian patients receiving l-dopa—carbidopa (Sinemet) therapy by high-performance liquid chromatography

Tetrahydropapaveroline (THP) concentrations were measured in the urine of Parkinsonian patients receiving l-dopa—carbidopa (Sinemet) therapy, using a method that employs a separation scheme that selectively isolates THP from urine and utilizes the Pictet—Spengler condensation of THP with formaldehyde combined with high-performance liquid chromatography for identification and determination. The mean (± S.D.) recoveries of THP from normal urine with 0.2 pmol/ml added and from Parkinsonian patients' urines with 0.5 pmol/ml added were 48.6 ± 5.7 and 44.6 ± 3.1%, respectively. Three Parkinsonian patients who were receiving either 250, 750 or 1000 mg of l-dopa (as Sinemet) daily had 24-h urinary THP excretion levels of 989, 1017 and 1600 pmol, respectively.     

A dynamic model of motor basal ganglia functions

 Fast aiming movements were measured in a choice reaction paradigm in a healthy control group and in Parkinsonian patients. The patients were tested without (‘off ’) and with 3,4-dihydroxyphenylalanine (‘on’) (L-dopa) medication. The movement trajectories were used to estimate the parameters of a dynamic linear model. The model is based on the functional structure of the basal ganglia-thalamocortical circuit with direct and indirect pathways linking the putamen to the basal ganglia output nuclei (Albin et al. 1989). The output of the circuit is connected to a model for the motor neuron-musculo-skeletal system. The gain k _d for the direct pathway and the gain k _i for the indirect pathway were estimated. They were found to be significantly decreased for Parkinsonian patients in ‘off ’ compared with the control group. L-dopa therapy in Parkinsonian patients increased the gains of the direct and the indirect pathway almost to normal values which implies that the long-term dopamine level in the striatum was excitatory for the direct and for the indirect pathway. This result is restricted to movements of correct size. For movements of diminished size, which are typical for Parkinsonian patients, the model predicts that the dopamine level in the striatum is excitatory for the direct pathway but inhibitory for the indirect pathway. The simulated values for neuronal activities are in agreement with expected values according to the experimental data. The proposed model of the ‘motor’ basal ganglia thalamocortical circuit implies that information about biomechanical properties of the musculo-skeletal system is stored in the ‘motor’ basal ganglia-thalamocortical circuit, and that the basal ganglia are involved in computation of the desired movement amplitude. Received: 24 April 1996/Accepted in revised form: 25 February 1997     

Detection of feedback in the central nervous system using system identification techniques

An analysis method to detect the presence of feedback between biological signals, particularly those associated with the central nervous system, is presented. The technique is based on recent results in the system identification literature involving the concept of a feedback free process. It may be applied to volume conducted signals such as EEG and EMG, as well as to neuronal spike trains through the use of a data transformation procedure. The utility of the technique is then demonstrated in a study of the relationship between Parkinsonian tremor and certain tremor cells found in the thalamus of Parkinsonian patients, using data collected during thalamotomies. The results obtained suggest that feedback mechanisms may be an important factor contributing to Parkinsonian tremor.This research was supported by the Natural Sciences and Engineering Research Council of Canada, The Medical Research Council of Canada, and Bell-Northern Research     

Intracerebral grafting in the dopaminergic system: issues and controversy.

A review of work in the dopaminergic system reveals both progress and controversy. More than 100 papers on intracerebral grafting were published last year. Several groups have published the clinical outcome of fetal substantia nigra implants in Parkinsonian patients and studies suggest that sprouting of dopaminergic fibers in response to grafting procedures ameliorates the behavioral deficits of dopamine-depleted animals. Trophic factors for dopamine neurons have also been identified. In addition, genetically modified cells continue to be developed as an alternative method for delivering molecules to the brain. The speed with which neural grafting has become a therapeutic procedure in Parkinsonian patients continues to stimulate debate.     

Electrophysiological and pharmacological analysis of L-dopa-induced dyskinesia and tardive dyskinesia (author's transl)

Electrophysiological and pharmacological analysis of L-Dopa-induced dyskinesia and tardive dyskinesia (L.DD) due to neuroleptics was performed on 12 patients with Parkinson's disease and on 12 others with psychotic diseases. This analysis included the examination of spinal reflexes, monosynaptic H reflex, polysynaptic cutaneous reflex of the lower limb, muscular responses to passive movement [stretch reflex and shortening reaction (SR)] and the study of the motor response to a dopaminergic stimulus (I.V. injection of Piribedil (PBD), a dopamine agonist). There was no difference in EMG activity between L.DD and TD. Three EMG patterns can be distinguished: anarchic discharge pattern (ADA), tonic grouping discharge pattern (AST) and rhythmic burst pattern (ABR). PBD effects indicate a possible relationship between the EMG patterns and the sensitivity level of the motor dopamine receptors. During L-Dopa dyskinesia and tardive dyskinesia, the same changes in spinal reflexes were observed. Muscle tone tested by muscular responses to passive movement (shortening and myotatic reaction) was normal. Monosynaptic excitability explored by H/M ratio was within the normal range. In contrast, the polysynaptic nociceptive reflex was increased in every case. In Parkinsonian patients with L-Dopa dyskinesia, this pattern of the spinal reflexes was significantly different in comparison to the rigid phase. Intravenous infusion of PBD suppressed tremor and provoked the occurrence of dyskinetic activity in Parkinsonian patients with L-Dopa dyskinesia during the rigid phase. During the dyskinetic phase, as in tardive dyskinesia, PBD increases these phenomena and changes EMG activity in rhythmic pattern. It is suggested that L-Dopa dyskinesia and tardive dyskinesia can be determined by testing EMG activity, spinal reflexes and dopaminergic reactivity. There is evidence to suggest that the various types of involuntary abnormal movement represent a single entity, and that dopamine receptor supersensitivity may be involved.     

Electromyographic Manifestations of Hereditary Signs of Extrapyramidal Insufficiency

In clinically healthy kinsmen of patients suffering from Parkinson’s disease, we studied the amplitude/frequency characteristics of EMG activity recorded from flexors and extensors of the elbow joint in order to reveal symptoms of extrapyramidal insufficiency (EPI) in these persons and to propose necessary recommendations to such a risk group. We examined four groups of persons: group 1 consisting of 37 healthy kinsmen of patients with clinical diagnosis of Parkinson’s disease; control group 2 consisting of 20 tested persons whose age was analogous to that of persons of group 1; group 3 including 33 Parkinsonian patients; and group 4 of 24 virtually healthy persons of elderly age, i.e., the group considered to be the control one with respect to group 3. In Parkinsonian patients, the main EPI correlates were the following: (i) significantly increased amplitude of EMG recorded from the arm muscles in the resting state, (ii) bursting discharges in such EMGs generated with a 4-9 sec–1 frequency (type III of EMG), and (iii) abnormally increased coefficients of reflex involvement (CRI) for the muscles of the opposite arm at retention of a load by one arm. One symptom of EPI or another were found in 20 (54.1%) kinsmen of the Parkinsonian patients; in this case, increased EMG amplitudes were observed in 13 persons (35.1%). We also observed significant correlation of the level of rise in the amplitude of the resting EMG with the age of the tested persons. In 29.7% kinsmen of the Parkinsonian patients, burst discharges with a 5-10 sec^–1 frequency were present in their EMGs, while in 16.2% of these persons we observed increased CRIs at retention of a load. For comparison, in the corresponding control group, increased amplitudes of the resting EMG, generation of burst EMG dischargers, and increased CRIs were observed in 15, 5, and 10% of the tested persons, respectively. Therefore, in kinsmen of the Parkinsonian patients, some EMG EPI manifestations were observed 2.3 to 5.9 times more frequently that those in the corresponding control group. For the members of the risk group, recommendations concerning the daily routine (mode of life) and the dietary intake, as well as a list of drugs to be avoided for long-term administration, were proposed.     

Recent physiological and pathophysiological aspects of Parkinsonian movement disorders

Deficits in the neural control of limb movements constitute a major part of Parkinsonian symptoms and are linked to a decay of dopaminergic neurotransmission. In animal models, Parkinsonian-like hypokinesia is consistently reproduced with large nigrostriatal dopamine depletions, while tremor and rigidity are less readily obtained. Lesions leading to a less than 70% striatal dopamine depletion are largely compensated by an increased activity of dopamine terminals. With more important lesions, supersensitivity of striatal non-adenylate cyclase-linked dopamine receptors occurs. Electrophysiological studies in Parkinsonian patients demonstrate increased reaction times and a reduced build-up of movement-related muscular activity underlying hypokinesia and provide circumstantial evidence for a central origin of tremor and rigidity. Single cell activity in unlesioned, behaving monkeys shows an increasingly direct relationship to movements when following the neural connections from mid-brain dopamine cells via striatum, globus pallidus, thalamus to pyramidal tract neurons of motor cortex. These data corroborate experimentally the concept that Parkinsonian hypokinesia is due to a failure of basic behavioral activating mechanisms.     

A model of Parkinson's disease: effect of L-dopa therapy on movement parameters and electromyographic activity in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

A primate model of Parkinson's disease was obtained by i. v. administration of 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). A behavioural, a mechanographic and an electromyographic (EMG) study were carried out during the execution of a rapid elbow movement, in two normal monkeys and, after the MPTP administration, before and after a L-DOPA therapy. Disturbances in behavior, movement parameters and EMG activity observed in MPTP-treated monkeys mimic those reported in Parkinsonian patients. Treatment with L-DOPA was effective in greatly correcting these disturbances. These results lend weight to the assumption that use of MPTP in primate provides a good model to study Parkinson's disease.     

Increased dopamine peroxidation in postmortem Parkinsonian brain

We have previously reported the presence, in human midbrain, of an enzymatic activity which catalyzes the formation of dopaminochrome from dopamine (DA) and hydrogen peroxide. Here, we report, for the first time, an increased DA peroxidizing activity in the midbrain and basal ganglia of autoptic Parkinsonian brains. The crude activity was determined spectrophotometrically in extracts of paraffin-embedded slices obtained from autopsied brain. No addition of substrate was necessary since endogenous substrates such as DA and hydrogen peroxide were present in the samples. In Parkinson's patients' midbrain, this activity was substantially increased compared to normal midbrain. Moreover, the DA peroxidizing activity, which was absent in basal ganglia of normal people, was detectable in all our Parkinson's patients. These observations suggest that a peroxidizing pathway of DA may be present in human brain. The increased peroxidizing activity in Parkinson's patients generates the toxic compound dopaminochrome which may play a role in the pathogenesis of this disease.     

Decrease in lymphocyte [3H]spiroperidol binding sites in parkinsonism

[³H]spiroperidol binding has been measured in lymphocytes from patients with Parkinson's disease and age matched healthy volunteers. A dramatic decrease (73%) in the number of binding sites (^Bmax) without any variation of the affinity (^KD) has been observed in Parkinsonian patients. This decrease in ^Bmax is linearly correlated with the degree of disability of the Parkinsonian patients (r = 0.891, p <0.001). This decrease appeared to be relatively selective since no variation was observed with patients suffering of other neurological disorders (vascular hemiplegia, Alzeihmer's disease, olivopontocerebellar degeneration, Huntington's chorea).     

Striatal function in action selection

A review of neurophysiological studies of human goal-directed behaviour performed with the aid of indwelled electrodes in Parkinsonian and epileptic patients. Functional role of the thalamo-cortical circuits is discussed.     

Neurotransmitter receptor alterations in Parkinson's disease.

Neurotransmitter receptor binding for GABA, serotonin, cholinergic muscarinic and dopamine receptors and choline acetyltransferase (ChAc) activity were measured in the frontal cortex, caudate nucleus, putamen and globus pallidus from postmortem brains of 10 Parkinsonian patients and 10 controls. No changes in any of these systems were observed in the frontal cortex. In the caudaye nucleus, only the apparent dopamine receptor binding was altered with a significant 30% decrease in the Parkinsonian brain. Both cholinergic muscarinic and serotonin receptor binding were significantly altered in the putamen, the former increasing and the latter decreasing with respect to controls. In addition, ChAc activity was decreased in the putamen. In the globus pallidus, only ChAc activity was significantly changed, decreasing about 60%, with no change in neurotransmitter receptor binding. The results suggest that a progressive loss of dopaminergic receptors in the caudate nucleus may contribute to the decreased response of Parkinsonian patients to L-dopa and dopamine agonist therapy.     

Energy and fractal characteristics of physiological and pathological tremors of the human hand

Tremors (involuntary shaking) were compared in healthy subjects and patients with the tremulous form of Parkinsonism sustaining isometric effort of the hand. For this purpose, fractal analysis and multilevel wavelet decomposition of tremor were used, and the energy characteristics determined on the basis of the spectral density of the energy of detailed components obtained at different levels of decomposition. The calculated fractal and energy characteristics of the tremor of healthy subjects were significantly lower than those of patients. If the patients took antiparkinsonian drugs at their usual doses, the characteristics shifted towards normal values. The decrease in the fractal dimension indicates an increase in the strength of the correlation in the dynamics of involuntary shaking. Thus, the characteristics studied allow not only physiological and pathological tremors to be discriminated, but also the strategy of selection of optimal drugs for relieving Parkinsonian tremor to be developed.     

Dynamical correlation of non-stationary signals in time domain—A comparative study

In a thorough study, the multitaper (MTM) and the extended continuous wavelet-transform (CWT) coherence-analysis methods were compared in terms of there application in determining the dynamics from the electroencephalogram (EEG) and electromyogram (EMG) signals of patients with Parkinsonian tremor. The main aim of the study in a biological point of view is to analyze whether the basic tremor frequency and its “first harmonic” frequency of Parkinsonian tremor are really harmonically related or are in fact distinct processes.The extension of the CWT is achieved by using a Morlet wavelet as the analysis window with an adjustable relative bandwidth which gives the flexibility in setting a desired frequency resolution. In order to obtain a perspective view of the two methods, they were applied to two different model signals to determine their actual threshold in detecting short-lived changes in the analysis of non-stationary signals and to determine their noise thresholds by adding external noise to the signals to test the reduction in coherence to be not merely due to the random fluctuations in stochastic signals. Beyond applying an autoregressive 2nd-order and a coupled van der Pol model system, however, also true EEG and EMG data from five Parkinson patients were used. The results were compared in terms of the time and frequency resolutions of these two methods, and it was determined that the multitaper method was able to detect reduction in power and coherence as short as 1 s. The extended CWT analysis only revealed gaps that were longer than 3 s.The time gaps in the coherence indicate the loss of connection between the cortex and muscle during the respective time intervals. This more accurate analysis of the MTM was also seen in the dynamical EEG–EMG coherence at the tremor frequency and its “first harmonic” of Parkinsonian patients.In terms of our “biological” aim, this shows distinct prevalence of the corticomuscular coupling at those frequencies over time. Applying this method to biological data reveals important aspects about their dynamics, e.g., the distinct dynamics between basic frequency and “first harmonic” frequency over time in Parkinsonian tremor.     

Unsupervised Spike Sorting of extracellular electrophysiological recording in subthalamic nucleus of Parkinsonian patients

The present study demonstrates the application of the Unsupervised Spike Sorting algorithm (USS) to separation of multi-unit recordings and investigation of neuronal activity patterns in the subthalamic nucleus (STN). This nucleus is the main target for deep brain stimulation (DBS) in Parkinsonian patients. The USS comprises a fast unsupervised learning procedure and allows sorting of multiple single units, if any, out of a bioelectric signal. The algorithm was tested on a simulated signal with different levels of noise and with application of Time and Spatial Adaptation (TSA) algorithm for denoising. The results of the test showed a good quality of spike separation and allow its application to investigation of neuronal activity patterns in a medical application. One hundred twenty-four single channel multi-unit records from STN of 6 Parkinsonian patients were separated with USS into 492 single unit trains. Auto- and crosscorrellograms for each unit were analyzed in order to reveal oscillatory, bursting and synchronized activity patterns. We analyzed separately two brain hemispheres. For each hemisphere the percentage of units of each activity pattern were calculated. The results were compared for the first and the second operated hemispheres of each patient and in total.     

Adrenergic receptors on cerebral microvessels in control and parkinsonian subjects

The binding of adrenergic ligands (3H-prazosin, 3H-clonidine, 3H-dihydroalprenolol) was studied on a preparation of cerebral microvessels in the prefrontal cortex and putamen of control and Parkinsonian subjects. The adrenergic receptor density in microvessels of control patients was less than 0.5% and 3.3% respectively of the total binding. A significant decrease in the number of alpha-1 binding sites was observed on microvessels in the putamen of patients with Parkinson's disease.     

Mucuna pruriens seed extract reduces oxidative stress in nigrostriatal tissue and improves neurobehavioral activity in paraquat-induced Parkinsonian mouse model

Parkinson’s disease (PD) is a neurodegenerative disease which causes rigidity, resting tremor and postural instability. Treatment for this disease is still under investigation. Mucuna pruriens (L.), is a traditional herbal medicine, used in India since 1500 B.C., as a neuroprotective agent. In this present study, we evaluated the therapeutic effects of aqueous extract of M. pruriens (Mp) seed in Parkinsonian mouse model developed by chronic exposure to paraquat (PQ). Results of our study revealed that the nigrostriatal portion of Parkinsonian mouse brain showed significantly increased levels of nitrite, malondialdehyde (MDA) and reduced levels of catalase compared to the control. In the Parkinsonian mice hanging time was decreased, whereas narrow beam walk time and foot printing errors were increased.     

Idiopathic Parkinsonism Treated with an Extracerebral Decarboxylase Inhibitor in Combination with Levodopa

The clinical actions of levodopa in Parkinsonism, given with and without an extracerebral decarboxylase in hibitor, L-alpha-methyldopahydrazine, were compared. Twenty-one patients were investigated in a “double-blind cross-over” study, administering levodopa in maximum tolerated dosage. L-Alpha-methyldopahydrazine failed to augment the overall therapeutic actions of levodopa but it consistently alleviated nausea. It is concluded that L-alpha-methyldopahydrazine will prove useful in the management of some Parkinsonian patients who have difficulty in taking levodopa alone.     

Parkinson syndrome after administration of acetylcholine into the caudate nuclei

Rats with the Parkinsonian syndrome induced by administration of acetyl choline and proserine into the rostral part of both caudate nuclei manifest an increased electrical activity (EA) in this part. Tremor, oligokinesia and rigidity are characterized by the appearance of paroxysmal EA with high amplitude of slow and rapid waves. The data obtained allow to conclude that neuropathophysiological basis of the Parkinsonian syndrome is the formation of the generator of pathologically enhanced excitation (GPEE) in the caudate nuclei. Some peculiarities of the GPEE activity in tremor and akinetic rigidity syndromes were observed. Intrarostral administration of dopamine or intraperitoneal administration of cyclodol resulted in the inhibition of GPEE and disappearance of clinical manifestations of Parkinsonian syndrome.