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 distribution of the vesicular monoamine transporter was investigated post mortem in the human ventral mesencephalon of control subjects (n = 7) and patients with Parkinson's disease (n = 4) using tritiated dihydrotetrabenzine binding and autoradiography. Tritiated dihydrotetrabenazine binding was characterized by a single class of sites with a Kd of 7 nM and a Bmax of 180 fmol/mg of protein in the substantia nigra. Tritiated dihydrotetrabenazine binding sites were heterogeneously distributed in the mesencephalon of control subjects: the density of tritiated dihydrotetrabenazine binding sites was high in the substantia nigra pars compacta, locus coeruleus and nucleus raphe dorsalis, moderate in the ventral tegmental area and low in the substantia nigra pars reticulata and catecholaminergic cell group A8. Within the substantia nigra, a zone with maximal density of tritiated dihydrotetrabenazine binding, two times higher than the mean estimate for the whole substantia nigra pars compacta, was detected in the medial part of the structure. The anatomical organization of the human ventral mesencephalon was analyzed on adjacent sections stained for acetylcholinesterase histochemistry and tyrosine hydroxylase immunohistochemistry. Tritiated dihydrotetrabenazine binding displayed the same characteristic regional pattern of distribution as that observed with tyrosine hydroxylase immunohistochemistry except in the nucleus raphe dorsalis, where no tyrosine hydroxylase immunoreactivity was detected. In parkinsonian brains, the level of tritiated dihydrotetrabenazine binding was dramatically decreased in all regions of the ventral mesencephalon analyzed except in the substantia nigra pars reticulata. In the substantia nigra pars compacta, the reduction was by 55% for the whole structure and by 65% in its medial zone, where binding site density was maximal. In most nigral subsectors analyzed, the decrease in density of tritiated dihydrotetrabenazine binding sites reached the level expected given the loss of tyrosine hydroxylase-positive cells observed. By contrast, the ratio of [3H]dihydrotetrabenazine binding to the number of tyrosine hydroxylase positive neurons was significantly increased in the zone of high [3H]dihydrotetrabenazine binding sites. This relative sparing of tritiated dihydrotetrabenazine binding sites may be due either to the contribution of other monoaminergic neurons such as serotoninergic neurons or more likely to hyperactivity of the still surviving dopaminergic neurons.
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PMID:Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine. 854 9

Sudomotor function in 83 patients with Parkinson's disease (PD) was evaluated using the sympathetic skin response (SSR) and sweat response to intradermal acetylcholine (ACh) injection. The incidence of abnormal SSRs (36.1%) increased, and the size of the response decrease with the severity of the illness. Neither the incidence of abnormal SSRs nor the amplitudes of the responses were influenced by levodopa or an anticholinergic agent. The SSR therefore can be used to evaluate the sudomotor efferent pathway in PD patients. In all the patients who had no SSR response, the local sweat response to ACh showed a reduced number of excitable sweat glands and low sweat volume. One patient, whose local sweat response to ACh was markedly impaired, had unmyelinated and acetylcholinesterase-positive fiber densities that were in the normal range in his biopsied sural nerve. The abnormal sweat response to ACh is considered to reflect the dysfunction of postganglionic sympathetic fibers in PD patients.
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PMID:Sympathetic skin response in Parkinson's disease. 874 Nov 31

Recent neuropathologic autopsy studies found that 15 to 25% of elderly demented patients have Lewy bodies (LB) in their brainstem and cortex, and in hospital series this may constitute the most common pathologic subgroup after pure Alzheimer's disease (AD). The Consortium on Dementia with Lewy bodies met to establish consensus guidelines for the clinical diagnosis of dementia with Lewy bodies (DLB) and to establish a common framework for the assessment and characterization of pathologic lesions at autopsy. The importance of accurate antemortem diagnosis of DLB includes a characteristic and often rapidly progressive clinical syndrome, a need for particular caution with neuroleptic medication, and the possibility that DLB patients may be particularly responsive to cholinesterase inhibitors. We identified progressive disabling mental impairment progressing to dementia as the central feature of DLB. Attentional impairments and disproportionate problem solving and visuospatial difficulties are often early and prominent. Fluctuation in cognitive function, persistent well-formed visual hallucinations, and spontaneous motor features of parkinsonism are core features with diagnostic significance in discriminating DLB from AD and other dementias. Appropriate clinical methods for eliciting these key symptoms are described. Brainstem or cortical LB are the only features considered essential for a pathologic diagnosis of DLB, although Lewy-related neurites, Alzheimer pathology, and spongiform change may also be seen. We identified optimal staining methods for each of these and devised a protocol for the evaluation of cortical LB frequency based on a brain sampling procedure consistent with CERAD. This allows cases to be classified into brainstem predominant, limbic (transitional), and neocortical subtypes, using a simple scoring system based on the relative distribution of semiquantitative LB counts. Alzheimer pathology is also frequently present in DLB, usually as diffuse or neuritic plaques, neocortical neurofibrillary tangles being much less common. The precise nosological relationship between DLB and AD remains uncertain, as does that between DLB and patients with Parkinson's disease who subsequently develop neuropsychiatric features. Finally, we recommend procedures for the selective sampling and storage of frozen tissue for a variety of neurochemical assays, which together with developments in molecular genetics, should assist future refinements of diagnosis and classification.
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PMID:Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. 890 16

New strategies have recently been developed where infusion of neurotrophic factors into the brain can rescue different populations of neurons. Infusion of nerve growth factor (NGF) has been used in combination with transplants of chromaffin tissue to the striatum in the rat model of Parkinson's disease as well as to patients suffering from Alzheimer's disease. In this study we have evaluated the distribution of recombinant human NGF (rhNGF) in different brain areas and evaluated morphological and electrophysiological effects after continuous infusion for 2 weeks of rhNGF (500 micrograms/ml) into the striatum of normal rats. One week after termination of rhNGF infusion, NGF levels in the infused striata were 10-fold increased while in contralateral striata normal levels were found. Extracellular recordings from striatal neurons revealed a significantly decreased spontaneous firing rate (0.76 +/- 0.07 Hz) in rats infused with rhNGF compared to vehicle-infused control animals (1.36 +/- 0.16 Hz). Local application of rhNGF during recordings showed no direct inhibitory effect of NGF on neuronal discharge rate. Immunohistochemistry, using antibodies against acetyl cholinesterase (AChE) and glial fibrillary acidic protein (GFAP), revealed a 38.7 +/- 7.0% increase in optical density of AChE immunoreactivity close to the NGF source and an increase in GFAP-positive profiles that was restricted close to the implanted dialysis fibre. In situ hybridization showed an increase in mRNAs for choline acetyltransferase, trkA, p75 and muscarinic m2 receptor in the large neurons of rhNGF-infused striatum. Messenger RNAs for m1 and m4 receptors in striatal neurons were not changed. Thus, chronic infusion of rhNGF into the striatum caused a cholinergic hyperinnervation and reduced spontaneous activity of striatal neurons.
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PMID:Chronic infusion of nerve growth factor into rat striatum increases cholinergic markers and inhibits striatal neuronal discharge rate. 892 Dec 73

The effect of the neurotoxicant 1-methyl-4-phenyl-2,3-dihydropyridinium ion (MPDP+) on acetylcholinesterase (AchE) activity was investigated. The MPDP+ was found to inhibit the enzyme in a dose-dependent manner. The kinetic parameter, Km, for the substrate acetylthiocholine was found to be 0.22 mM, and the Kis and Kii for MPDP+ inhibition of AChE were found to be 0.265 and 0.578 mM, respectively. It was found that MPDP+ is neither a substrate of AChE nor a time-dependent inactivator. The studies of reaction kinetics indicate the inhibition of AChE to be a noncompetitive inhibition. The inhibition of AchE by MPDP+ was virtually reversed by either dilution or gel exclusion chromatography. These data suggest that once MPDP+ enters the basal ganglia of the brain, it can inhibit the AChE and thereby increase the acetylcholine level in the basal ganglia, leading to potential cell dysfunction. It appears likely that the nigrostriatal toxicity by MPDP+ leading to Parkinson's disease-like syndrome may, at least in part, be mediated via the AChE inhibition.
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PMID:Inhibition of acetylcholinesterase by the neurotoxicant, 1-methyl-4-phenyl-2,3-dihydropyridinium ion. 895 Oct 45

Positron emission tomography with appropriate tracers provides unique opportunity to study neurotransmitter systems in the living human brain. PET with [18F] 6-fluoro-L-dopa (FD) provides an index of the integrity of nigrostriatal pathway, and striatal FD uptake correlates linearly with the density of nigral neurons. PET allows us to assess the progression of the nigral lesions in Parkinson's disease (PD). A 68-year-old normal female volunteer was scanned by FD-PET. Subsequently, she developed parkinsonism 3.7 years after the scan. A repeated FD-PET scan revealed a significant reduction of FD uptake by 20% over the 5.2 year interval. The results suggest a relatively short presymptomatic period with fast initial losses of nigral neurons in PD. FD-PET has been used to determine the viability of fetal graft implanted in the striatum for the treatment of PD. PET imaging of dopamine D1 and D2 receptors may be useful for the differential diagnosis of PD and striatonigral degeneration. PET reveals significant reduction of dopamine D1 and D2 receptor binding in the putamen of patients with SND, while D1 and D2 receptor binding is normal or slightly upregulated in PD. We found hypersensitivity of muscarinic cholinergic receptors in the frontal cortex of patients with PD by using PET. The result suggests a loss of ascending cholinergic system in the frontal cortex in PD, which may cause the frontal lobe dysfunction in PD. Recently, acetylcholine analogs labelled with positron emitter have been developed for measurement of brain acetylcholinesterase activity in vivo. These tracers may be useful for the assessment of ascending cholinergic system in Alzheimer's disease and PD.
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PMID:[Neurotransmitter systems in the human brain studied by positron emission tomography]. 912 90

The galanin (GAL) containing peptide fiber system innervates the basal forebrain and has been shown to hyperinnervate remaining cholinergic neurons in Alzheimer's disease (AD). GAL modulates the release of acetylcholine and, therefore, may depress this neurotransmitter in surviving cholinergic basal forebrain (CBF) neurons in AD. The aim of this study was to identify putative synaptic contacts between GAL immunoreactive processes and CBF neurons and evaluate whether these processes hypertrophy in AD patients. We observed by confocal laser microscopy a hyperinnervation of GAL-containing fibers in both AD and Parkinson's disease patients with concurrent AD (PD/AD). Galaninergic fibers were often seen in direct apposition to remaining CBF neurons and enwrapped cholinergic cell soma and dendrites. Our results demonstrate that GAL-containing fibers are in direct apposition to CBF neurons in normal-aged humans and that this phenotype is enhanced in AD and PD/AD, suggesting that direct synaptic contacts occur between GAL-containing fibers and CBF neurons. Because GAL can modulate acetylcholine release from cholinergic neurons, hyperinnervation of GAL fibers in AD and PD/AD patients may further decrease release of acetylcholine from remaining CBF neurons. We propose that therapies based solely on acetylcholinesterase inhibitors may be insufficient to effectively increase cortical levels of acetylcholine.
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PMID:A confocal microscopic analysis of galaninergic hyperinnervation of cholinergic basal forebrain neurons in Alzheimer's disease. 916 23

1. Extracellular single-unit recording and iontophoresis were used to examine the effects of different cholinoceptor agonists and antagonists on the firing rate and firing pattern of A9 and A10 presumed dopaminergic neurones in the anaesthetized rat. 2. Administration of low currents (1-5 nA) of the selective muscarinic agonists oxotremorine M (Oxo M) and muscarine and of the non-selective muscarinic/nicotinic agonist carbamylcholine (CCh) produced a dose-dependent increase in firing rate in most of the A9 and A10 presumed dopaminergic neurones tested. Oxo M-induced activation could be completely blocked by iontophoretic application of the muscarinic antagonist butyl-scopolamine or systemic administration of the muscarinic antagonist scopolamine (300 microg kg(-1), i.v.). 3. Iontophoretic application of the selective nicotinic agonist methylcarbamylcholine (MCCh), but not nicotine, induced a consistent increase in firing rate. Surprisingly, the excitatory effect of MCCh was significantly reduced by the selective muscarinic antagonist scopolamine (300 microg kg(-1), i.v.), but not by the selective nicotinic antagonist mecamylamine (2.2 mg kg(-1), i.v.). Mecamylamine (3 mg kg(-1), i.v.) was also ineffective in reducing the CCh-induced activation of presumed dopamine neurones, suggesting that both CCh and MCCh increased the activity of dopamine neurones via an interaction with muscarinic receptors. 4. Iontophoretic application of the endogenous agonist acetylcholine (ACh) had no or little effect on the firing activity of A10 presumed dopaminergic neurones. However, concomitant application of neostigmine, a potent cholinesterase inhibitor, with acetylcholine induced a substantial activation of these neurones. This activation consisted of two components; one, which was prevalent, was scopolamine (300 microg kg(-1), i.v.)-sensitive, and the other was mecamylamine (2 mg kg(-1), i.v.)-sensitive. 5. In addition to their effect on firing activity, Oxo M, muscarine and concomitant neostigmine/ACh caused a significant increase in burst firing of A10 neurones, but not of A9 neurones. 6. These data suggest that dopamine cells, both in the A9 and A10 regions, possess functional muscarinic receptors, the activation of which can increase their firing rate and, for A10 neurones, their amount of burst activity. These cholinoceptors would be able to influence the activity of the midbrain dopamine system greatly and may play a role in, and/or be a therapeutic target for, brain disorders in which dopamine is involved (e.g., Parkinson's disease, drug addiction and schizophrenia).
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PMID:Activation of midbrain presumed dopaminergic neurones by muscarinic cholinergic receptors: an in vivo electrophysiological study in the rat. 964 68

It is now widely recognized that histamine acts as a neurotransmitter in the mammalian central nervous system. Three selective histamine receptors have been described, all of which are present in the basal ganglia. This study is a detailed, quantitative, autoradiographical examination of the densities of histamine H3-receptors in coronal sections of human basal ganglia, using the selective ligand [3H]-(R)-alpha-methylhistamine. [3H]-(R)-alpha-methylhistamine binding was highest within the external and internal segments of the globus pallidus together with the substantia nigra. High levels were also found in the striatum, where density was significantly higher (P < 0.05) at a pre-, as opposed to post-, anterior commissure coronal level. Within the striatum, binding was noticeably higher in both the nucleus accumbens and acetylcholinesterase-deficient striosomes, while being undetectable in the subthalamic nucleus and very low in both the ventroanterior and ventrolateral thalamic nuclei. An intermediate level of binding, often with a laminar distribution, was seen in the insular cortex. [3H]-(R)-alpha-methylhistamine binding was also examined in both Parkinson's disease and Huntington's disease. No difference from control receptor density was found in any area examined in Parkinson's disease, while values were significantly lower in caudate (P < 0.001), putamen (P < 0.001), external (P < 0.001) and internal (P < 0.05) globus pallidus, although not the insular cortex, in Huntington's disease cases. These data suggest that H3-receptors are present upon striatonigral projection neurons of the direct and indirect movement pathways thus providing histaminergic control over the activity of both these circuits.
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PMID:Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington's and Parkinson's disease cases. 1005 46

Recently, we have developed a method to measure acetylcholinesterase (AChE) activity, a functional marker for cholinergic system, by positron emission tomography (PET) and carbon-11 labeled N-methyl-4-piperidyl acetate. Kinetic analysis of the radioactivity in the brain and the plasma yielded a rate constant "k 3" as an index of AChE activity. The ratios for the k 3 values for the cerebral cortex/thalamus/cerebellum/striatum found in healthy participants were 1/3/8/10, respectively, corresponding well with AChE activity ratios in the brain at necropsy (1/3/8/38), except for the striatum. In 23 healthy volunteers (age range: 24-89 years), there was no age-related decline of k 3 values in the cerebral cortex, suggesting AChE activity is preserved in aged cerebral cortex. In 11 patients with Alzheimer's disease, there was a significant reduction (-24%) of k 3 values in the cerebral cortex and hippocampus, suggesting a loss of ascending cholinergic system from the basal forebrain to the cerebral cortex and hippocampus. In 16 patients with Parkinson's disease, there was a significant reduction (-18%) of k 3 values in the cerebral cortex. In 10 patients with progressive supranuclear palsy, there was a significant reduction (-38%) of k 3 values in the thalamus. This technique is useful for investigating central cholinergic system in neurodegenerative disorders with dementia.
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PMID:[PET study of cholinergic system in the brain]. 1037 94


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