Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Common marmosets show parkinsonian motor deficits following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration and develop dyskinesias during chronic L-dopa exposure. The D1 agonists A-77636 [(1R, 3S) 3-(1'-adamantyl)-1-aminomethyl-3, 4-dihydro-5, 6-dihydroxy-1H-2-benzopyran HCl] and A-86929 [(-)-trans 9, 10-hydroxy-2-propyl-4, 5, 5a, 6, 7, 11b-hexahydro-3-thia-5-azacyclopent-1-ena[c]phenanthrene hydrochloride] possess potent antiparkinsonian activity in the MPTP-treated marmoset and we now assess their influence on L-dopa-induced dyskinesias. MPTP-treated marmosets with stable motor deficits were treated with L-dopa plus carbidopa for 28 days to induce dyskinesias. Subsequently, they received A-86929 for 10 days, initially at 0.5 micromol/kg and then at 1.0 micromol/kg for a further 5 days. Several months later, L-dopa 12.5 mg/kg plus carbidopa 12.5 mg/kg was given orally twice daily for 7 days, followed by A-77636 1 micromol/kg for 10 days, and then both A-77636 and L-dopa plus carbidopa were given concurrently for 3 further days. In these L-dopa-primed animals, A-86929 effectively reversed akinesia and produced dose-dependent dyskinesias which were significantly less intense than those produced by L-dopa administration. A degree of behavioral tolerance was encountered, but antiparkinsonian activity was preserved and elicited behaviour was free of hyperkinesis and stereotypy and more naturalistic than that seen with L-dopa. After a week of twice-daily L-dopa dosing, administration of the long-acting D1 agonist A-77636 initially dramatically enhanced locomotion and reproduced dyskinesia with prominent dystonia, but after repeated administration of A-77636, dyskinesia and in particular chorea, gradually disappeared. Tolerance to locomotor stimulation greater than with A-86929 occurred, although activity remained significantly above baseline levels. There was a marked reduction in L-dopa-induced climbing, stereotypy and hyperkinesis and behaviour more closely resembled that of normal unlesioned marmosets. Upon reintroduction of L-dopa concurrently with continued A-77636 administration, dystonic, but virtually no choreic dyskinesias appeared and behaviour was once again free of stereotypy and hyperkinesis, contrasting dramatically with the presence of these behaviours along with abundant chorea when L-dopa is given alone. These results show a lesser liability of A-86929 and A-77636 to reproduce dyskinesia in L-dopa-primed MPTP-lesioned subjects while maintaining effective antiparkinsonian activity and producing a more naturalistic motor response. The differential effects of A-77636 on chorea and dystonia, with suppression of chorea and stereotypy on co-administration with L-dopa, may reflect an altered balance of activity in the direct and indirect striatofugal pathways. These results suggest a possible role for D1 agonists in the treatment of Parkinson's disease.
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PMID:Actions of the D1 agonists A-77636 and A-86929 on locomotion and dyskinesia in MPTP-treated L-dopa-primed common marmosets. 1010 82

Intracortical inhibition of the motor cortex was investigated using a paired pulse magnetic stimulation method in 14 patients with chorea caused by various aetiologies (six patients with Huntington's disease, one with chorea acanthocytosis, a patient with systemic lupus erythematosus with a vascular lesion in the caudate, three with senile chorea and three with chorea of unknown aetiology). The time course and amount of inhibition was the same in the patients as in normal subjects, suggesting that the inhibitory mechanisms of the motor cortex studied with this method are intact in chorea. This is in striking contrast with the abnormal inhibition seen in patients with Parkinson's disease or focal hand dystonia, or those with a lesion in the putamen or globus pallidus. It is concluded that the pathophysiological mechanisms responsible for chorea are different from those producing other involuntary movements.
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PMID:Intracortical inhibition of the motor cortex is normal in chorea. 1067 Nov 34

The effect of chronic bilateral high-frequency stimulation of the subthalamic nucleus (STN) on levodopa-induced dyskinaesias was investigated in eight patients with fluctuating Parkinson's disease complicated by functionally disabling off-period dystonia. All of the patients also had severe diphasic and peak-dose chorea, so that it was possible to study the effect of high-frequency stimulation on the different types of levodopa-induced dyskinaesias. Off-period fixed dystonia was reduced by 90% and off-period pain by 66%. After acute levodopa challenge, high-frequency stimulation of the STN reduced diphasic mobile dystonia by 50% and peak-dose choreic dyskinaesias by 30%. The effect of bilateral high-frequency stimulation of the STN on the Unified Parkinson's Disease Rating Scale motor score had the same magnitude as the preoperative effect of levodopa. This allowed the levodopa dose to be reduced by 47%. The combination of reduced medication and continuous high-frequency stimulation of the STN reduced the duration of on-period diphasic and peak-dose dyskinaesias by 52% and the intensity by 68%. Acute high-frequency stimulation of the STN mimics an acute levodopa challenge, concerning both parkinsonism and dyskinaesias, and suppresses off-period dystonia. Increasing the voltage can induce repetitive dystonic dyskinaesias, mimicking diphasic levodopa-induced dyskinaesias. A further increase in voltage leads to a shift from a diphasic-pattern dystonia to a peak-dose pattern choreodystonia. Chronic high-frequency stimulation of the STN also mimics the benefit of levodopa on parkinsonism and improves all kinds of levodopa-induced dyskinaesias to varying degrees. Off-period dystonia, associated with neuronal hyperactivity in the STN is directly affected by stimulation and disappears immediately. The effect of chronic high-frequency stimulation of the STN on diphasic and peak-dose dyskinaesias is more complex and is related directly to the functional inhibition of the STN and indirectly to the replacement of the pulsatile dopaminergic stimulation by continuous functional inhibition of the STN. Chronic high-frequency stimulation of the STN allows a very gradual increase in stimulation parameters with increasing beneficial effect on parkinsonism while reducing the threshold for the elicitation of stimulation-induced dyskinaesias. In parallel with improvement of parkinsonism, the levodopa dose can be gradually decreased. As diphasic dystonic dyskinaesias are improved to a greater degree than peak-dose dyskinaesias, both direct and indirect mechanisms may be involved. Peak-dose choreatic dyskinaesias, associated with little evidence of parkinsonism and thus with low neuronal activity in the STN, are improved, mostly indirectly. Fixed off-period dystonia, mobile diphasic dystonia and peak-dose choreodystonia seem to represent a continuous clinical spectrum reflecting a continuous spectrum of underlying activity patterns of STN neurons.
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PMID:From off-period dystonia to peak-dose chorea. The clinical spectrum of varying subthalamic nucleus activity. 1035 65

Female sex hormones, and more specifically estrogen, can have biochemical and behavioral effects on the dopaminergic system. The effects of estrogen on the dopaminergic system can be classified as either neuroprotective or symptomatic. The neuroprotective effects refer to the ability of estrogen to prevent or modulate insults to the dopaminergic system and therefore to alter the natural history of disease processes affecting the dopaminergic circuitry in the brain. With regard to the symptomatic effects, support for suppressive and enhancing effects has been documented in humans and laboratory animals. The preclinical literature for neuroprotective and symptomatic effects of estrogen on the mesostriatal dopaminergic system forms the basis for studies on the influence of estrogen on the prevalence, disease progression, clinical signs, and medication effects of movement disorders, including Parkinson's disease, chorea, dystonia, tics, and myoclonus. Understanding the role of estrogen in modulating the dopaminergic system will allow clinicians to tailor therapies for women with movement disorders and optimize therapies for menstrually related symptom fluctuations. Such clarifications may also guide recommendations on the use of postmenopausal hormonal replacement therapy in women with movement disorders or those genetically at risk.
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PMID:Estrogen and movement disorders. 1062 91

The most common types of levodopa-induced dyskinesias in patients with Parkinson's disease (PD) are chorea and dystonia, and often the two types are intermixed. Myoclonus is a far less common problem. The dyskinesias tend to develop over time, not usually being encountered at the initiation of levodopa therapy. Eventually, they affect more than 50% of patients on long-term levodopa treatment. Once they appear, they are difficult to eliminate. Substituting weaker dopaminergic agents for levodopa often fails to eliminate the dyskinesias. Most of the dyskinesias occur at the time of the highest brain concentration of levodopa and its product, dopamine--so-called peak-dose dyskinesias. Chorea and dystonia, usually in the legs, occur less commonly at the beginning and end of dosing, and these are called diphasic dyskinesias. Dystonia can also occur during the 'off' state, i.e. when the levodopa concentration is low. These 'off' dystonias are often painful and must be distinguished from peak-dose dystonia and from dystonia that may be a feature of PD itself.
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PMID:The spectrum of levodopa-induced dyskinesias. 1076 27

Metabolite levels in cerebrospinal fluid from patients with Parkinson disease or Huntington chorea were compared with the levels in healthy controls using proton magnetic resonance spectroscopy. No significant differences were found for any metabolite measured in cerebrospinal fluid from patients with Parkinson disease compared to controls. Slight but significantly reduced levels of both lactate and citrate, however, were found in cerebrospinal fluid from patients with Huntington chorea compared to controls. This suggests possible impairment of both glycolysis and tricarboxylic acid cycle function. The reduction in lactate found in the present study may reflect neuronal loss. The decrease in citrate supports the theory of mitochondrial dysfunction in the brain of patients with Huntington chorea, but also suggests that there may be an important astrocytic component in this disease. If so, it would certainly have implications for neuronal function.
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PMID:Proton magnetic resonance spectroscopy of cerebrospinal fluid in neurodegenerative disease: indication of glial energy impairment in Huntington chorea, but not Parkinson disease. 1086 90

The paper reports 4-years results of a pilot study concerning the influence of a stereotactic pallidotomy on somatosensory evoked potentials in idiopathic Parkinson's disease. Potentials were recorded through the scalp surface from sensorimotor cortex of both hemispheres. Amplitudes and latencies of early and late waves were compared before and after the surgery. The surgery was recommended after 4 years of L-dopa therapy when bradykinesia and rigidity of right leg led to gait difficulty and postural instability. The dominant features of the syndrome were accompanied by tremor, micrography, chorea and lower responsiveness to L-dopa. Following the surgery a clear improvement of motor activity was observed. Increase of 20-90 ms waves amplitudes and P45 latency prolongation of 6-11 ms appeared due to the attenuation of pallidal inhibition exerted upon the thalamo-cortical transmission and a new arrangement of a cortical motor program. These electrophysiological changes, correlated with a clinical amelioration, may indicate as a favourable prognosis for a patient. Five months after pallidotomy a slight decrease of amplitudes occurred in relation to the previous examinations. Four years after surgery increase of most amplitudes and latencies and reconfiguration of later waves were related to deterioration of clinical course and worsening of left-side signs. We believe that somatosensory evoked potentials change may be a sensible indicator of motor state in Parkinson's disease. As far as we know the present study is one of the first presentation of somatosensory evoked potentials after pallidotomy.
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PMID:[Cryopallidotomy in Parkinson disease. Effect on somatosensory potentials]. 1096 25

The early stages of Huntington's disease (HD) present with motor, cognitive, and emotional symptoms. Correspondingly, current models implicate dysfunction of the motor, associative, and limbic basal ganglia-thalamocortical circuits. Available data, however, indicate that in the early stages of the disease, striatal damage is mainly restricted to the associative striatum. Based on an open interconnected model of basal ganglia-thalamocortical organization, we provide a detailed account of the mechanisms by which associative striatal pathology may lead to the complex pattern of motor, cognitive, and emotional symptoms of early HD. According to this account, the degeneration of a direct and several indirect pathways arising from the associative striatum leads to impaired functioning of: (1) the motor circuit, resulting in chorea and bradykinesia, (2) the associative circuit, resulting in abnormal eye movements, "frontal-like" cognitive deficits and "cognitive disinhibition," and (3) the limbic circuit, resulting in affective and psychiatric symptoms. When relevant, this analysis is aided by comparing the symptomatology of HD patients to that of patients with mild to moderate Parkinson's disease, since in the latter there is similar dysfunction of direct pathways but opposite dysfunction of indirect pathways. Finally, we suggest a potential novel treatment of HD and provide supportive evidence from a rat model of the disease.
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PMID:Open interconnected model of basal ganglia-thalamocortical circuitry and its relevance to the clinical syndrome of Huntington's disease. 1192 Nov 44

Dysfunction of the autonomic nervous system is an under-recognised but important aspect of the aetiological and clinical manifestation of primary degenerative dysautonomias such as multiple system atrophy (MSA) and Parkinson's disease (PD). Although the clinical presentation of dysautonomia in these two disorders may overlap, yet pathological and in vivo imaging studies suggest considerable differences. Functional imaging studies suggest that selective cardiac sympathetic denervation may occur early in PD but not in other parkinsonian syndromes. The clinical implication of this apparently disease specific peripheral dysautonomia is unknown and would be the subject of much interest in future years. Dysautonomia in degenerative disorders also affect respiration, genitourinary function and sleep. Sleep related disorders such as rapid eye movement behaviour disorder and urinary voiding dysfunction appear to precede the development of PD related symptoms while patients with sporadic ataxia have been shown to progress to develop MSA. Dysautonomia has also been recognised in other movement disorders, examples being the combination of dystonia and complex regional pain syndrome with elevated HLA-DR13 and late onset Huntington's disease presenting with dominant parkinsonism and minimal chorea. These studies have helped progress in various diagnostic and management parameters in relation to autonomic dysfunction and movement disorders.
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PMID:Autonomic dysfunction in movement disorders. 1147 Sep 68

Advances in neuroradiological and neurosurgical techniques have lead to a growing interest in functional neurosurgical interventions for medically intractable movement disorders. The majority of these procedures are performed in patients with hypokinetic movement disorders, especially Parkinson's disease. However, relatively few interventions were done in hyperkinetic disorders such as Huntington's disease (HD), mainly owing to the lack of an adequate target nucleus. We have recently described the case of a reversible chorea in a genetically confirmed HD patient. We subsequently identified a marked bilateral degeneration of the substantia nigra as the probable reason for choreatic cessation. We therefore suggest that primary striatal atrophy causing hyperkinesia and secondary substantia nigra atrophy favouring hypokinesia were balanced in this patient, thus resulting in a close-to-physiologic GABAergic basal ganglia output. We postulate that deep brain stimulation of the substantia nigra pars compacta may ameliorate hyperkinesia in choreatic movement disorders, thus representing the first effective therapy in Huntington's chorea. Several lines of evidence in recent neurophysiological research support our hypothesis and are discussed below.
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PMID:Compactotomy in Huntington's chorea. 1160 77


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