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

Progressive dementia syndromes in adults are caused by a number of conditions associated with different structural lesions of the brain. In most clinical and autopsy series, senile dementia of the Alzheimer type is the most common cause of mental decline in the elderly accounting for up to 90%, whereas degenerative non-Alzheimer dementias range from 7 to 30% (mean 8-10%). They include a variety of disorders featured morphologically by neuron and synapse loss and gliosis, often associated with cytopathological changes involving specific cortical and subcortical circuits. These neuronal/glial inclusions and neuritic alterations show characteristic immunoreactions and ultrastructure indicating cytoskeletal mismetabolism. They are important diagnostic sign posts that, in addition to the distribution pattern of degenerative changes, indicate specific vulnerability of neuronal populations, but their pathogenic role and contribution to mental decline are still poorly understood. In some degenerative disorders no such cytopathological hallmarks have been observed; a small number is genetically determined. While in Alzheimer's disease (AD) mental decline is mainly related to synaptic and neuritic pathologies, other degenerative disorders show variable substrates of dementia involving different cortical and/or subcortical circuits which may or may not be superimposed by cortical Alzheimer lesions. In most demented patients with Lewy body disorders (Parkinson's disease, Lewy body dementia), they show similar distribution as in AD, while in Progressive Supranuclear Palsy (PSP), mainly prefrontal areas are involved. Lobar atrophies, increasingly apparent as causes of dementia, show fronto-temporal cortical neuron loss, spongiosis and gliosis with or without neuronal inclusions (Pick bodies) and ballooned cells, while dementing motor neuron disease and multisystem atrophies reveal ubiquitinated neuronal and oligodendroglial inclusions. There are overlaps or suggested relationships between some neurodegenerative disorders, e.g. between corticobasal degeneration, PSP and Pick's atrophy. In many of these disorders with involvement of the basal ganglia, degeneration of striatofrontal and hippocampo-cortical loops are important factors of mental decline which may be associated with isocortical neuronal degeneration and synapse loss or are superimposed by cortical AD pathology.
 ...
PMID:Structural basis of dementia in neurodegenerative disorders. 884 54

We used a paired-pulse magnetic stimulation technique to study ipsilateral cortico-cortical inhibition of the motor cortex in 48 patients with various neurological disorders and in 20 normal volunteers. In the normal subjects, the first subthreshold conditioning stimulus suppressed responses to the second suprathreshold test stimulus at interstimulus intervals (ISIs) of 1-5 ms (inhibition at short intervals), and facilitated them at ISIs of 8-15 ms (facilitation at long intervals). Patients with motor neuron disease, except those in whom brain stimulation produced control responses that were generated by direct activation of corticospinal neurons (D-waves), had normal inhibition at short intervals. Facilitation at long intervals was not elicited in some patients with amyotrophic lateral sclerosis. Less inhibition at short intervals and normal facilitation at long intervals was found for all the patients with progressive myoclonic epilepsy, a condition in which the excitability of cortical inhibitory interneurons is thought to be affected. Inhibition at short intervals was disturbed, but facilitation at long intervals was intact in the patients with movement disorders (Parkinson's disease, corticobasal degeneration, and Wilson's disease). In these patients, positron emission tomography (PET) studies showed decreased regional cerebral blood flow (rCBF) in the basal ganglia in the relaxed state. However, normal suppression was elicited in the patients with Parkinson's disease with normal rCBF. In four patients with chorea, the time-course of inhibition and facilitation was normal, even though PET studies showed decreased rCBF in the basal ganglia in two of them. Normal inhibition could not be elicited in patients who had a small lesion in the basal ganglia or in the pathway from basal ganglia to the primary motor cortex; the putamen, globus pallidus, and supplementary motor cortex. In contrast, patients who had a lesion in a sensory system (sensory cortex or sensory thalamus) or in the pontine nucleus had normal suppression. We conclude that the results of ipsilateral cortico-cortical inhibition with paired magnetic stimulation reflect the excitability of inhibitory interneurons in the motor cortex and that outputs from the basal ganglia markedly affect this inhibition, but outputs from somato-sensory systems or cerebellum do not. Moreover, dysfunction of the corticospinal tract or spinal motoneurons does not affect results obtained by the paired magnetic stimulation technique when the control responses are generated by I-waves (i.e. descending volleys are produced by transsynaptic activation of the corticospinal tract neurons.
 ...
PMID:Ipsilateral cortico-cortical inhibition of the motor cortex in various neurological disorders. 886 35

The development of neuroprotective agents for the prevention of neuronal loss in acute conditions such as stroke and epilepsy or chronic neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, Huntington's chorea, and motor neuron disease is currently focusing on drugs that inhibit excitatory amino acid neurotransmission or exhibit antioxidant properties. Unfortunately, potent antagonists at the N-methyl-D-aspartate (NMDA) type glutamate receptor, which is thought to mediate excitotoxic neuronal injury, e.g., MK-801 or phencyclidine (PCP), share a high probability of inducing psychotomimetic side effects. Further, these drugs have been associated with acute neurotoxicity in vitro and in vivo, precluding their clinical use. In contrast, low affinity NMDA receptor antagonists like amantadine and its dimethyl derivative, memantine, have been administered clinically for the management of Parkinson's disease, dementia, neuroleptic drug-induced side effects, and spasticity. These agents have only rarely induced significant psychotomimetic side effects. Recent pharmacologic advances have helped to elucidate how high drug affinity for the PCP binding site of the NMDA receptor may enhance psychotogenicity. Low affinity and associated fast voltage-dependent channel unblocking kinetics are likely to be responsible for the better tolerance of amantadine and memantine compared with MK-801 and PCP. Further factors apparently modulating psychotogenicity of glutamate receptor antagonists include differential actions on neuronal populations in various brain regions and interactions with neurotransmitter receptors other than the NMDA type glutamate receptor.
 ...
PMID:Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. 901 83

To determine at the tissue level whether the proteasome (Ps), a unique nonlysosomal protease, is involved in the metabolism of ubiquitinated proteins, we examined for the first time the immunocytochemical localizations of both Ps and ubiquitin (Ub) in sections of various abnormal structures that are known to be ubiquitinated in various neurodegenerative diseases and in the elderly. Concomitant increases of Ps and Ub were observed at the sites of most dystrophic neurites in Alzheimer disease (AD) and parkinsonism-dementia complex on Guam (PDC) and in Lewy bodies in Parkinson's disease and diffuse Lewy body disease, but not in neurofibrillary tangles in AD or PDC, in filamentous inclusions within anterior horn cells in sporadic motor neuron disease, or in eosinophilic granules in the olivary nucleus of the elderly. These results at the tissue level indicated that Ps is involved in the metabolism of some, but not all, ubiquitinated proteins and structures in various neurodegenerative disorders. This suggests that the involvement of Ps in the metabolism of ubiquitinated structures differs in different cases and at different stages of disease. These results and our previous immunocytochemical studies of lysosomal cathepsin proteases suggest that both nonlysosomal and lysosomal systems are involved in the metabolism of various ubiquitinated proteins and that their involvements differ in different structures and at different stages of degeneration of the structures.
 ...
PMID:Immunocytochemical co-localization of the proteasome in ubiquitinated structures in neurodegenerative diseases and the elderly. 903 65

Other chapters in this issue discuss the evidence that implicates infection during infancy and childhood in the etiology of respiratory disease. Here I argue that experience of infection in early life may also be involved in the aetiology of some diseases of the adult nervous system. The descriptive epidemiology of three neurological diseases is compatible with the hypothesis that they are delayed consequences of childhood infection. It is not difficult to imagine that the effects of an infection which results in loss of cells from an organ system, like the central nervous system, whose cell populations have lost the capacity to replace themselves by mitotic division could remain hidden until unmasked by ageing. Such a mechanism may be important in the aetiology of motor neuron disease and Parkinson's disease. Age-related differences in host response, which may be partly related to a maturing immune system, are known to influence both short- and long-term outcome for several infections. Perhaps the immune response to infection with Epstein-Barr virus, or another common micro-organism with similar epidemiology, in adolescence or early adult life is sometimes directed at antigens that are also present in the central nervous system. At present, the evidence that supports these hypotheses is largely circumstantial. But it may be possible to devise ways of testing them both epidemiologically and in the laboratory.
 ...
PMID:Infection in childhood and neurological diseases in adult life. 915 82

The nontoxic C fragment of tetanus toxin (TC) can transport other proteins from the circulation to central nervous system (CNS) motor neurons. Increased levels of CuZn superoxide dismutase (SOD) are protective in experimental models of stroke and Parkinson's disease, whereas mutations in SOD can cause motor neuron disease. We have linked TC to SOD and purified the active recombinant proteins in both the TC-SOD and SOD-TC orientations. Light microscopic immunohistochemistry and quantitative enzyme-linked immunosorbant assays (ELISA) of mouse brainstem, after intramuscular injection, demonstrate that the fusion proteins undergo retrograde axonal transport and transsynaptic transfer as efficiently as TC alone.
 ...
PMID:Delivery of recombinant tetanus-superoxide dismutase proteins to central nervous system neurons by retrograde axonal transport. 921 90

In Parkinson's disease and Alzheimer's disease there is profound disorder of olfaction. The extent to which this modality is involved in motor neuron disease (MND) has been studied little. To address this further we assessed olfaction by three methods-a smell identification test ("UPSIT") in 58 patients and 135 controls; olfactory-evoked response (OEP) to H2S in 15 patients, and pathological examination of olfactory bulbs obtained from 8 cadavers. It was found that smell identification compared with the controls was slightly worse overall in the MND group as a whole, but only the bulbar patients scored significantly less on the UPSIT. Patients displayed a subtle defect in cheese odor recognition. OEPs were normal in 9 subjects and delayed in 1 subject. The remaining 5 OEPs were unsuccessful. Histopathological studies of olfactory bulbs showed excess lipofuscin deposition in all 8 cases examined, indicating subclinical neuronal damage. Olfactory neurons with a degree of antioxidant defect may be more susceptible to cellular damage than other neuronal groups because of their direct relationship to environmental agents. Overall we found the degree of olfactory dysfunction in MND to be mild and in contrast with the marked changes described by others.
 ...
PMID:Olfactory disorder in motor neuron disease. 952 94

1. Correlations between deletions in two glutathione S-transferase (GST) genes, GSTM1 and GSTT1 and susceptibility to Alzheimer's disease (AD), motor neuron disease (MND) and Parkinson's disease (PD) have been investigated by PCR, using primers specific for both genes. 2. It was found that males with a deletion of the GSTM1 gene were more susceptible to PD and males with a deletion of the GSTT1 gene more susceptible to MND and PD, possibly implying that environmental factors which specifically target men may be involved. Furthermore, subjects with a deletion of the GSTT1 gene were more susceptible to AD.
 ...
PMID:Determination of glutathione S-transferase mu and theta polymorphisms in neurological disease. 1021 3

A total of 61 human brain specimens were analyzed with both ELISA and Western Blot using the ALZ50 monoclonal antibody. The brain specimens included: Alzheimer's Disease (AD, n=31), AD/Down's (n=2), Normal (n=14), Parkinson's Disease (n=7), Huntington's chorea (n=2), Wernicke-Korsakov's Encephalopathy (n=3), and Motor Neuron Disease (n=2). The non-AD cases (n=28) had no detectable A68 by ELISA, and showed no A68 bands by Western blot. The AD cases (n=33), all were positive for A68 by the ELISA, but only 31 of 33 had visible A68 band by Western blot. Additionally, a method for solubilization of A68 is reported.
 ...
PMID:Comparison of A68 levels in Alzheimer diseased and non-Alzheimer's diseased brain by two ALZ50 based methods. 1057 93

Differential expression of the amyloid precursor protein gene (APP) may be important in the development of amyloidosis in Alzheimer's disease (AD) and experimentally in the brain's response to injury. Controversial data suggests that APP isoforms containing the Kunitz protease inhibitor isoform (APP KPI+) are over expressed in the brains of patients with AD when compared to the non-Kunitz protease inhibitor containing isoforms (APP KPI-). We have investigated this hypothesis using a quantitative analysis of gene expression on brain tissue collected at post-mortem. In situ hybridization has been used with synthetic oligonucleotide probes labelled with 35S to detect the two principal splice variants of APP: APP 695 (KPI-) and APP 751 (KPI+). A prospective brain bank of frozen brain specimens has been established and includes pathologically proven AD (n=15) and other neurodegenerative disorders as controls (n=18). The controls consist of frontal lobe atrophy (n=4), Huntington's disease (n=5), Parkinson's disease (n=4), motor neuron disease (n=2), multi-infarct dementia (n=1), multisystem atrophy (n=1), and subacute sclerosing panencephalitis (n=1). We have observed no significant differences in the expression of APP 695 KPI- mRNA in frontal lobe: 17.49+/-3.26 optical density (OD) units of mRNA expression in AD vs. 16.13+/-1.76 OD units mRNA in controls (P=0.80, linear regression); or temporal lobe: 14.73+/-2.96 in AD vs. 16.49+/-2.15 in controls (P=0.55). No significant differences have been found in APP 751 KPI+ in frontal lobe: 12.86+/-2.98 in AD vs. 13.70+/-2.88 in controls (P=0.97); and temporal lobe: 13.31+/-4.93 in AD vs. 11.07+/-1.99 in controls (P=0. 65). Analysis of the ratios of APP 751 KPI+ OD units of mRNA to APP 695 KPI- mRNA revealed a trend to an increased ratio which did not reach statistical significance: frontal lobe APP 751 KPI+/APP 695 KPI- 1.92+/-1.04 in AD vs. 0.86+/-0.17 in controls (P=0.54); temporal lobe 2.54+/-1.59 in AD vs. 0.96+/-0.11 controls (P=0.34). Our data has not revealed differential expression of APP mRNA isoforms in AD and supports the hypothesis that post-translational events in APP metabolism are important in amyloidogenesis and the pathogenesis of AD.
 ...
PMID:Amyloid precursor protein gene isoforms in Alzheimer's disease and other neurodegenerative disorders. 1067 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>