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)

To establish phenotype-genotype correlations in early-onset parkinsonism, we have compared the phenotype of a large series of 146 patients with and 250 patients without parkin mutations. Although no single sign distinguished the groups, patients with mutations had significantly earlier and more symmetrical onset, dystonia more often at onset and hyperreflexia, slower progression of the disease, and a tendency toward a greater response to levodopa despite lower doses. After forward stepwise multiple logistic regression analysis, dystonia at onset and brisk reflexes were not longer significantly different but were correlated with age at onset rather than the presence of the parkin mutation. Age at onset in carriers of parkin mutations varied as did the rate of progression of the disease: the younger the age at onset the slower the evolution. The genotype influenced the phenotype: carriers of at least one missense mutation had a higher United Parkinson's Disease Rating Scale motor score than those carrying two truncating mutations. The localization of the mutations was also important because missense mutations in functional domains of parkin resulted in earlier onset. Patients with a single heterozygous mutation had significantly later and more asymmetrical onset and more frequent levodopa-induced fluctuations and dystonia than patients with two mutations.
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PMID:How much phenotypic variation can be attributed to parkin genotype? 1289 70

A unilateral lesion of the rat nigrostriatal pathway with 6-hydroxydopamine (6-OHDA) results in a decrease in the basal extracellular level of striatal glutamate, a nearly complete loss of tyrosine hydroxylase (TH) immunolabeling, an increase in the density of glutamate immunogold labeling within nerve terminals making an asymmetrical synaptic contact, and an increase in the number of apomorphine-induced contralateral rotations. [Meshul et al. (1999) Neuroscience 88:1-16; Meshul and Allen (2000) Synapse 36:129-142]. In Parkinson's disease, a lesion of either the subthalamic nucleus (STN) or the motor thalamic nucleus relieves the patient of some of the motor difficulties associated with this disorder. In this rodent model, either the STN or motor thalamic nucleus was electrolytically destroyed 2 months following a unilateral 6-OHDA lesions. Following a lesion of either the STN or motor thalamic nucleus in 6-OHDA-treated rats, there was a significant decrease (40-60%) in the number of apomorphine-induced contralateral rotations compared to the 6-OHDA group. There was a significant decrease (<30%) in the basal extracellular level of striatal glutamate in all of the experimental groups compared to the sham group. Following an STN and/or 6-OHDA lesion, the decrease in striatal extracellular levels was inversely associated with an increase in the density of nerve terminal glutamate immunolabeling. There was no change in nerve terminal glutamate immunogold labeling in either the motor thalamic or motor thalamic plus 6-OHDA lesion groups compared to the sham group. The decrease in the number of apomorphine-induced rotations was not due to an increase in TH immunolabeling (i.e., sprouting) within the denervated striatum. This suggests that alterations in striatal glutamate appear not to be directly involved in the STN or motor thalamic lesion-induced reduction in contralateral rotations.
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PMID:Lesion of subthalamic or motor thalamic nucleus in 6-hydroxydopamine-treated rats: effects on striatal glutamate and apomorphine-induced contralateral rotations. 1469 16

Parkinson's disease (PD) is characterized by a minimum of two of three features: tremor, rigidity, and bradykinesia. Asymmetry of these features is often considered to support a diagnosis of PD in contrast to other parkinsonian syndromes. All major manifestations of PD are often more pronounced on the side first manifesting features of PD. Significant dissociation of features on the contralateral side, along with other variants of presentation involving the contralateral side, are rarely observed. To determine the frequency and significance of unusual asymmetry in parkinsonism, we retrospectively examined 613 patients clinically diagnosed as idiopathic PD for presence of unusual asymmetries of clinical features. Three groups of patients with unusual asymmetrical clinical findings were identified. Group 1 comprised 10 patients followed for an average of 6 years presenting with rest tremor most prominent in one lower limb and contralateral upper limb. Group 2 comprised 24 patients followed for an average of 5.5 years with action tremor most prominent on the side contralateral to the side of most prominent rest tremor. Group 3 comprised 33 patients followed for an average of 10 years who had parkinsonian signs of greatest severity on one side but subsequently, over an average of 5.4 years, became gradually more prominent on the opposite side. In Group 3, 15 of 33 patients (45%) demonstrated evolution to a rigid form of parkinsonism with disappearance of rest tremor over an average of 7.1 years after presentation. A small percentage (11%) of Parkinson's patients in our clinic demonstrated anomalous asymmetrical clinical findings, which indicates that (1) the disease process may begin in different topographic sites on each side; (2) rest tremor and action tremor may have different anatomical bases; (3) the disease process may progress at different rates on different sides; and (4) tremor becomes less pronounced with progression of disease in some patients with Parkinsonism.
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PMID:Anomalies of asymmetry of clinical signs in parkinsonism. 1497 69

The authors report the clinicopathological findings in a patient in whom levodopa-responsive parkinsonism developed at 45 years of age. The patient experienced asymmetrical onset of symptoms, sustained benefit from levodopa, and motor fluctuations and dyskinesias, but there were no prominent autonomic, cerebellar, or pyramidal signs. He was diagnosed clinically with Parkinson disease (PD) and underwent bilateral subthalamic nucleus deep brain stimulation (DBS) surgery 9 years after symptom onset. He did not respond to stimulation or medication postoperatively, however, and died 12 weeks after surgery of repeated aspiration pneumonias. Postmortem examination revealed neuron loss in the substantia nigra and basal ganglia, and numerous alpha-synuclein-positive glial cytoplasmic inclusions in the subcortical nuclei, cerebellum, and brainstem, findings that established a neuropathological diagnosis of multiple system atrophy (MSA). Furthermore, there was an atypical and robust inflammatory reaction, as well as numerous glial cytoplasmic inclusions surrounding both DBS electrode termination sites. The authors speculate that the presence of alpha-synuclein in the striatum, combined with the inflammation surrounding the electrodes, contributed to the ineffectiveness of stimulation and dopaminergic medications postoperatively. This case demonstrates the ineffectiveness of DBS in MSA, even when the patient is responsive to levodopa, and emphasizes the need for diagnostic modalities that can be used to distinguish PD from MSA and other parkinsonian syndromes in which the levodopa response pattern is typical of PD.
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PMID:Subthalamic nucleus deep brain stimulation in a patient with levodopa-responsive multiple system atrophy. Case report. 1503 94

Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide, exerting different actions in the central and peripheral nervous systems. Among others, it has neurotrophic and neuroprotective effects. In the present study, we investigated the effects of PACAP in a rat model of Parkinson's disease. Rats were given unilateral injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. PACAP-treated animals received 0.1 microg PACAP as a pretreatment. Control animals without PACAP treatment displayed severe hypokinesia at 1 and 10 days postlesion when compared to animals receiving saline only. In only 1 day postlesion, by contrast, PACAP-treated rats showed no hypokinesia. Asymmetrical signs, such as turning, rearing and biased thigmotaxic scanning were observed in all lesioned animals 1 day postlesion. PACAP-treated animals, however, showed better recovery as they ceased to display asymmetrical signs 10 days later and showed markedly less apomorphine-induced rotations. Tyrosine-hydroxylase immunohistochemistry revealed that control animals had more than 95% loss of the dopaminergic cells in the ipsilateral substantia nigra, while PACAP-treated animals had only approximately 50% loss of dopaminergic cells. In summary, the present results show the neuroprotective effect of PACAP in 6-OHDA-induced lesion of substantia nigra, with less severe acute neurological symptoms and a more rapid amelioration of behavioral deficits.
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PMID:Pituitary adenylate cyclase activating polypeptide protects dopaminergic neurons and improves behavioral deficits in a rat model of Parkinson's disease. 1508 46

Differential diagnosis of idiopathic Parkinson's Disease is still very difficult. Even in movement disorders centers 25% of patients with clinical diagnosis of Parkinson's disease is misdiagnosed with other neurodegenerative disorders. Clinical symptoms of so called atypical parkinsonian disorders may emerge late in the course of the disease, not at the same time and good or moderate response to levodopa at early stages may be a source of misdiagnosis. Most difficult to differentiate seems to be Progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and multiple system atrophy (MSA). Authors present in selected cases usefulness of neuroimaging with rCBF SPECT and MRI in clinical diagnosis of these disorders. For PSP typical (although not pathognomonic) is decrease of metabolism and flow in frontal lobes (hypofrontalism), and in CBD asymmetrical, contralateral to the side of dominating symptoms cerebral (frontal, parietal, temporal and within striatum) atrophy. In MSA more useful (but not seen in all cases) is MRI examination with hyperintensities in putamen, pons and cerebellum or cerebellar atrophy. Due to low sensitivity of clinical criteria other tests (EMG of anal sphincter or clonidine test) with specially neuroimaging examination may be helpful in establishing of the diagnosis.
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PMID:[Regional cerebral blood flow single photon emission tomography (SPECT) and magnetic resonance imaging (MRI) may be useful in the diagnosis of patients with cortico-basal degeneration, progressive supranuclear palsy and multiple system atrophy]. 1509 54

Pituitary adenylate cyclase activating polypeptide (PACAP) has several different actions in the nervous system, including neuroprotective effects. In the present study, we investigated the effects of different doses of PACAP on the functional and morphological outcome in a rat model of Parkinson's disease. Rats were given unilateral injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra. PACAP-treated animals received 1, 0.1 or 0.01 microg PACAP as a pretreatment. Control animals without PACAP treatment displayed severe hypokinesia at 1 and 10 days post-lesion when compared to normal animals or those receiving saline only. PACAP treatment resulted in less severe acute hypokinesia, and complete recovery by 10 days. Asymmetrical signs were observed in all lesioned animals 1 day post-lesion. PACAP-treated animals, however, showed better recovery as they ceased to display asymmetrical signs 10 days later and showed markedly less apomorphine-induced rotations. Best behavioral outcome was observed in animals treated with 0.1 microg PACAP. Tyrosine-hydroxylase (TH) immunohistochemistry revealed increased number of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area in all PACAP-treated rats in contrast to the severe cell loss in control animals. These results indicate that PACAP may be a promising therapeutic agent in Parkinson's disease.
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PMID:Morphological and functional effects of PACAP in 6-hydroxydopamine-induced lesion of the substantia nigra in rats. 1551 97

Recently, it has been shown that rhythmic inter-limb coordination is disturbed in patients with Parkinson's disease (PD). The present study aims to investigate whether this coordination deficit is primarily the result of an impaired coupling, related to hypoactivation of the supplementary motor area (SMA), or primarily the indirect result of an asymmetrical distribution of PD symptoms over the left and right limbs (a peripheral process). Thirty PD patients and 30 matched control participants tapped with the index fingers anti-phase and left and right leading gallop patterns in four visual feedback conditions. Symmetrically affected participants performed significantly worse than asymmetrically affected and control participants in the gallop patterns. This result suggested that the central deficit has a stronger effect on inter-limb coupling in PD than the neuromuscular and biomechanical asymmetry between the limbs. Detailed analysis of inter-tap intervals (variability and correlation) suggested that this deficit leads to a compensatory asymmetrical inter-limb coupling in the primarily right-affected patient group, and under specific circumstances also in the primarily left-affected patient group. The difference in coordination strategy between left- and right-affected patients suggested that pre-morbid hand preference is an important structural constraint on the coupling strategies available to the participants.
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PMID:Inter-limb coupling in bimanual rhythmic coordination in Parkinson's disease. 1554 32

The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural polarity of neurons that are essential for neuronal physiology. Cytoskeletal reorganization plays a key role in neuritogenesis. In neurodegenerative diseases, the cytoskeleton is abnormally assembled and impairment of neurotransmission occurs. In Alzheimer's disease, abundant amyloid plaques and neurofibrillary tangles constitute the two major neuropathologic alterations present in the brain. Neurofibrillary tangles are formed of paired helical filaments consisting nearly entirely of the microtubule-associated protein tau. Under normal conditions tau binds to microtubules, stabilizing neuron structure and integrity. Hyperphosphorylation of tau is assumed to be the cause of formation of paired helical filaments. Another example of cytoskeletal abnormalities present in neurodegenerative diseases are the Lewy bodies considered as cytopathologic markers of Parkinson's disease. Lewy bodies are constituted of tubulin, MAP1, and MAP2. Neuronal shape, loss of dendrites and spines, as well as irregular distribution of neuronal elongations occur in specific brain areas of schizophrenic patients. Increase in non-phosphorylated MAP2 and MAP1B at hippocampus has been suggested as responsible for somatodendritic and cytoarchitectural abnormalities found in schizophrenia. In addition, neurofibrillary tangles are more frequent among schizophrenic patients who received pharmacologic antipsychotic treatment. Cumulative evidence suggests that neurodegenerative diseases and psychiatric illnesses are associated with cytoskeletal alterations in neurons that, in turn, loose synaptic connectivity and the ability to transmit incoming axonal information to the somatodendritic domain. We will review evidence supporting that the neuronal cytoskeleton is disrupted in neurodegenerative and some psychiatric diseases, and therefore could be a target for drug therapy. In addition, current data indicating that melatonin, a hormone secreted by the pineal gland, promotes neuritogenesis through cytoskeletal rearrangements and in addition to the potential therapeutic use of melatonin in neurodegenerative diseases will be discussed.
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PMID:The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. 1558 21

The present study was undertaken to explore involvement of nitric oxide (NO) in the experimental models of Parkinson's disease. Neurodegeneration was induced by unilateral injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) in the right striatum. Lesions were functionally evaluated by amphetamine-induced asymmetrical behaviour and by decrease in the tyrosine hydroxylase (TH) immunostaining. An induction in the expression of iNOS and augmentation in nitrite content was observed in both the models. The extent of increase in iNOS expression was, however, different but the elevation in the nitrite content was comparable in both the models. The increase in iNOS expression inversely correlated with the tyrosine hydroxylase (TH) immunolabeling. Animals pretreated with a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exhibited complete protection against amphetamine induced rotations in both the models. Thus, augmented NO availability subsequent to iNOS induction seems to play an important role in the initial phase of neurodegeneration.
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PMID:Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson's disease. 1594 31


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