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)

The temporal discrimination threshold (TDT), the shortest time interval that allows two temporally separated successive stimuli to be perceived as two different stimuli, is a constituent of kinesthetic sensation. Intact kinesthesia is a necessity for well-controlled voluntary movements. In patients with Parkinson's disease and dystonia, abnormally increased TDT has been reported and it may contribute to the pathophysiology of motor deficits. We explored the integrity and clinical significance of TDT in patients with multiple system atrophy (MSA). A total of 30 de novo patients with MSA and 11 age-matched normal controls were included. The TDT values were measured in the feet with four different paradigms (ascending and descending interstimuli intervals; same and different point stimulation). The Unified Parkinson's Disease Rating Scale (UPDRS) Motor and the International Cooperative Ataxia Rating Scale (ICARS) scores were measured for parkinsonian and cerebellar deficits, respectively. Means of the TDT values of the patients with MSA were higher than those of the controls. The TDT values correlated with UPDRS Motor scores independent of ICARS scores. Among the parkinsonian motor deficits, only the UPDRS Motor subscores representing bradykinesia correlated with the TDT values. In patients with MSA, abnormal somatic sensory processing seems to be associated with damage to the nigrostriatal dopaminergic and/or striatal neurons.
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PMID:Abnormal temporal discrimination threshold in patients with multiple system atrophy. 1726 Mar 39

Cerebellar ataxic gait is characterized by unsteady movements and variable gait patterns. Previous studies have successfully identified pathological changes of balance-related gait parameters. However, it has been difficult to demonstrate deficits of joint coordination and the control of limb dynamics. This has motivated the hypothesis that cerebellar ataxic gait might be affected predominantly by balance impairments. We investigated the influences of different types of cerebellar dysfunction on the gait patterns of patients suffering from degenerative cerebellar disease (13 patients, five females, 50.4 +/- 14.4 years). Walking patterns were quantitatively analysed combining standard gait measures and novel measures for the characterization of the spatial and the temporal variability of intra-joint coordination patterns. The temporal variability of gait patterns was significantly correlated with a subscale of the clinical ataxia scale (ICARS) that rates deficits of the control of limb dynamics and intra-limb coordination for goal-directed movements. This suggests that common cerebellar mechanisms might be involved in coordination during voluntary limb control and ataxic gait. The tested standard gait parameters correlated predominantly with clinical measures for balance-related abnormalities. These results imply that ataxic gait is influenced by both balance-related impairments and deficits related to limb control and intra-limb coordination. Applying the same analysis to gait patterns from patients with peripheral vestibular failure (six patients, four females, 47.8 +/- 14.3 years) and Parkinson's disease (eight patients, two females, 60.7 +/- 10.6 years), we found comparable abnormalities in balance-related gait parameters and general gait variability, but significantly lower increases of temporal variability. This implies that increased temporal variability of intra-limb coordination is a specific characteristic of cerebellar dysfunction, which does not arise for other movement disorders that also cause balance deficits and increased gait variability.
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PMID:Specific influences of cerebellar dysfunctions on gait. 1728 87

Numerous evidences indicate that the phenotype of a neurodegenerative disease and its pathogenetic mechanism are only loosely linked. The phenotype is directly related to the topography of the lesions and is reproduced whatever the mechanism as soon as the same neurons are destroyed or deficient: the symptoms of Parkinson disease are mimicked by any destruction of the neurons of the substantia nigra, caused for instance by the toxin MPTP. This does not mean that idiopathic Parkinson disease is due to MPTP. In the same way, mouse lines such as Reeler, Weaver and Staggerer in which ataxia occurs spontaneously does not help to understand human ataxias: now that mutations responsible for these phenotypes have been identified, it appears that one is responsible for lissencephaly (mutation of the reelin gene) and the other two have no equivalent in man. Therapeutic attempts, however, rely on the understanding of the pathogenetic mechanisms. Introducing a mutated human transgene in the genome of an animal has, in many instances, significantly improved this understanding. Transgenic mice have proven useful in reproducing lesions seen in neurodegenerative disease such as the plaques of Alzheimer disease (in the APP mouse which has integrated the mutated gene of the amyloid protein precursor), the tau glial and neuronal accumulation (seen in cases of frontotemporal dementias due to tau mutation), the nuclear inclusions caused by CAG triplet expansion (seen in the mutation of Huntington disease and autosomal dominant spinocerebellar ataxias). These recent advances have fostered numerous therapeutic attempts. Transgenesis in drosophila and in the worm Caenorhabditis elegans have opened new possibilities in the screening of protein partners, modifier genes, and potential therapeutic molecules. However, it is also becoming clear that introducing a human mutated gene in an animal does not necessarily trigger pathogenetic cascades identical to those seen in the human disease. Human diseases have to be studied in parallel with their animal models to ensure that the model mimic at least a few original mechanisms, on which new therapeutics may be tested.
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PMID:[Animal models of neurodegenerative diseases]. 1729 28

Vitamin E is essential for neurological function. This fact, together with a growing body of evidence indicating that neurodegenerative processes are associated with oxidative stress, lead to the convincing idea that several neurological disorders may be prevented and/or cured by the antioxidant properties of vitamin E. In this review, some aspects related to the role of vitamin E against Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and ataxia with vitamin E deficiency will be presented.
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PMID:Vitamin E and neurodegenerative diseases. 1730 57

We report a 53-year-old woman with probable Bassen-Kornzweig syndrome. Her parents were a consanguineous marriage. At two years of age, she developed night blindness. During her childhood she had severe diarrhea that disappeared in adulthood. At 26 years of age, she was diagnosed as having retinitis pigmentosa and her visual acuity became worse thereafter. She noted tremor in the right hand at 37 years of age, gait ataxia at 42, and developed tremor in the bilateral lower extremities at 48. On admission, bilateral visual disturbance, resting and postural tremor, moderately poor coordination, mild distal dominant sensory impairment, an absence of tendon reflex in all four extremities, moderate to severe gait ataxia, and positive Romberg sign were found. Muscle rigidity and akinesia were not observed. Intelligence and muscle power were normal and pathological reflexes were absent. Acanthocytes were found in blood. Serum chemistry showed remarkable decreases in total cholesterol (54 mg/dl, normal 180-220), triglyceride (0 mg/dl, normal 30-150), beta-lipoprotein (3 mg/dl, normal 190-500), apoA-1 protein (66 mg/dl, normal 105-184), apoA-2 protein (11 mg/dl, normal 26-46), apoB protein (0 mg/dl, normal 38-104), apoC-2 protein (1.1 mg/dl, normal 1.2-6.4), vitamin A (297 ng/ml, normal 431-1,041), and vitamin E (0.19 ng/dl, normal 0.75-1.41). While, a marked increase in PIVKA II (703 mAU/ml, normal<40) due to a decrease in vitamin K was found. She was thus diagnosed as having Bassen-Kornzweig syndrome or hypo-betalipoproteinemia. Although brain MRI was normal, single-photon emission CT (SPECT) showed mildly decreased perfusion in the left parietal cortex and right striatum. Motor nerve conduction velocities were normal, but sensory nerve action potentials were not evoked in all four extremities. Surface EMG recorded on the right radial extensor and flexor carpi muscles at rest showed a 4.5 Hz tremor. Vitamin replacement therapy with vitamin A (10,000 IU/day), E (200 mg/day), and K (10 mg/day) was initiated. Several days after treatment, amplitude of resting tremor ameliorated mildly. Clonazepam was administered (0.5 mg/day) for further treatment. After one-month of treatment, vitamin A (656 ng/ml) and E (0.39 mg/dl) levels were elevated and PIVKA II level (29 mAU/ml) decreased. Only a mild right hand tremor remained, but sensory impairment and gait ataxia were not changed. The cause of Bassen-Kornzweig syndrome is a deletion of the microsomal triglyceride transfer protein (MTP) gene. While, familial hypo-betalipoproteinemia, due to a mutation of apolipoprotein B gene, is known to show the same phenotype. Because of the patient's refusal of genetic examination, which disease she has cannot be conclusively determined. Intention tremor was reported in Bassen-Kornzweig syndrome. However, her 4.5 Hz tremor was also present at rest, which resembled resting tremor in Parkinson's disease. Pathophysiology of Bassen-Kornzweig syndrome is known to be due to hypo-vitaminosis. Decreased [18F]-dopa uptake in striatum of patients with long-term hypo-vitamin E has been reported in PET study. Mild hypoperfusion was found in the striatum of the present cases: indicating that her tremor was associated with striatonigral damage. Thus, careful observation of extrapyramidal signs is necessary in abeta- or hypo-betalipoproteinemia.
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PMID:[An adult case of probable Bassen-Kornzweig syndrome, presenting resting tremor]. 1732 79

In this Review, familial and sporadic neurological disorders reported to have an etiological link with DNA repair defects are discussed, with special emphasis placed on the molecular link between the disease phenotype and the precise DNA repair defect. Of the 15 neurological disorders listed, some of which have symptoms of progeria, six--spinocerebellar ataxia with axonal neuropathy-1, Huntington's disease, Alzheimer's disease, Parkinson's disease, Down syndrome and amyotrophic lateral sclerosis--seem to result from increased oxidative stress, and the inability of the base excision repair pathway to handle the damage to DNA that this induces. Five of the conditions (xeroderma pigmentosum, Cockayne's syndrome, trichothiodystrophy, Down syndrome, and triple-A syndrome) display a defect in the nucleotide excision repair pathway, four (Huntington's disease, various spinocerebellar ataxias, Friedreich's ataxia and myotonic dystrophy types 1 and 2) exhibit an unusual expansion of repeat sequences in DNA, and four (ataxia-telangiectasia, ataxia-telangiectasia-like disorder, Nijmegen breakage syndrome and Alzheimer's disease) exhibit defects in genes involved in repairing double-strand breaks. The current overall picture indicates that oxidative stress is a major causative factor in genomic instability in the brain, and that the nature of the resulting neurological phenotype depends on the pathway through which the instability is normally repaired.
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PMID:Mechanisms of disease: DNA repair defects and neurological disease. 1734 92

We identified 221 patients with probable multiple system atrophy (MSA) among 4770 patients enrolled in the multicentre registry of the German Competence Network on Parkinson's disease (PD) according to the established consensus criteria to characterize their clinical presentation. Analyses of more than 100 recorded clinical items revealed several specifics: I) 50% of patients with probable MSA had asymmetry of symptoms at disease onset and tremor at rest was present in 25%; II) a positive response to levodopa was recorded in 51% of patients identified initially with severe autonomic failure and cerebellar ataxia; III) a positive family history was recorded in 11% (n = 23), two of these patients were identified with spinocerebellar ataxia type 3 (SCA3). Thus asymmetry of symptoms, tremor at rest and a positive response to levodopa are not as specific for idiopathic PD as believed previously. Patients with SCA3 may present with the clinical features of MSA.
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PMID:Features of probable multiple system atrophy patients identified among 4770 patients with parkinsonism enrolled in the multicentre registry of the German Competence Network on Parkinson's disease. 1751 Jul 32

Calcium-activated potassium channels modulate calcium signaling cascades and membrane potential in both excitable and non-excitable cells. In this article we will review the physiological properties, the structure activity relationships of the existing peptide and small molecule modulators and the therapeutic importance of the three small-conductance channels KCa2.1-KCa2.3 (a.k.a. SK1-SK3) and the intermediate-conductance channel KCa3.1 (a.k.a. IKCa1). The apamin-sensitive KCa2 channels contribute to the medium afterhyperpolarization and are crucial regulators of neuronal excitability. Based on behavioral studies with apamin and on observations made in several transgenic mouse models, KCa2 channels have been proposed as targets for the treatment of ataxia, epilepsy, memory disorders and possibly schizophrenia and Parkinson's disease. In contrast, KCa3.1 channels are found in lymphocytes, erythrocytes, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelium and intestinal and airway epithelia and are therefore regarded as targets for various diseases involving these tissues. Since two classes of potent and selective small molecule KCa3.1 blocker, triarylmethanes and cyclohexadienes, have been identified, several of these postulates have already been validated in animal models. The triarylmethane ICA-17043 is currently in phase III clinical trials for sickle cell anemia while another triarylmethane, TRAM-34, has been shown to prevent vascular restenosis in rats and experimental autoimmune encephalomyelitis in mice. Experiments showing that a cyclohexadiene KCa3.1 blocker reduces infarct volume in a rat subdural hematoma model further suggest KCa3.1 as a target for the treatment of traumatic and possibly ischemic brain injury. Taken together KCa2 and KCa3.1 channels constitute attractive new targets for several diseases that currently have no effective therapies.
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PMID:Modulators of small- and intermediate-conductance calcium-activated potassium channels and their therapeutic indications. 1758 55

Spasticity is a complex disorder characterized by a velocity-dependent increase in muscle tone associated with exaggerated deep tendon reflexes. It can be caused by numerous diffuse or focal cerebral and spinal pathologic conditions. Spasticity indicates upper motor neuron dysfunction and if severe, can lead to considerable motion restriction and eventually to more serious disability. The therapeutic interventions available to treat spasticity are often of limited benefit. In the last decade, many open-label and several double-blind, placebo-controlled, studies have demonstrated the effectiveness of intramuscular botulinum toxin (BTX) injections for the management of spasticity caused by multiple sclerosis, brain / spinal cord injury, cerebral palsy, and stroke. BTX can also be beneficial in the treatment of spasticity, or a mixture of spasticity and rigidity, in many neurodegenerative conditions; including Parkinson disease, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia and parkinsonism linked to chromosome 17, and in various sporadic and familial spinocerebellar ataxia syndromes. Currently, two BTX serotypes, which are serologically different but share a common subunit structure, are commercially available: type A (Botox(R), manufactured by Allergan, Inc, Irvine, California, USA; and Dysport(R), distributed by Beaufour-Ipsen Pharmaceuticals, Paris, France); and type B (manufactured by Elan Corporation, Dublin, Ireland, and available in the United States as MyoBloc(R) and in Europe as NeuroBloc(R)). BTX primarily affects the neuromuscular junction by inhibiting acetylcholine release. Dosages vary considerably depending on the particular preparation used, the muscle injected, the severity of the condition, and the duration of treatment.
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PMID:Treatment of spasticity with botulinum toxin. 1761 18

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with progressive cell death of upper and lower motor neurons. In this study, we measured monocyte chemotactic protein-1 (MCP-1) and vascular endothelial growth factor (VEGF) levels in cerebrospinal fluid (CSF) and serum by enzyme-linked immunosorbent assay (ELISA) in 42 ALS patients, and compared these levels with those of control subjects with other neurodegenerative disorders or with those of normal controls. MCP-1 levels in CSF were significantly higher in ALS patients than in the control group. VEGF levels in CSF tended to be lower in ALS patients than in the control group, but not significantly. A positive correlation was found between MCP-1 levels in CSF of ALS patients and the total Norris scale. The elevation of MCP-1/VEGF ratio in CSF was more specific to ALS patients compared to other neurological diseases such as Parkinson's disease (PD) and spinocerebellar ataxia (SCA) and to controls. Our data suggested that both MCP-1 levels and MCP-1/VEGF ratio in CSF may be useful markers for the clinical diagnosis of ALS.
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PMID:Elevation of MCP-1 and MCP-1/VEGF ratio in cerebrospinal fluid of amyotrophic lateral sclerosis patients. 1767 28


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