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)

Olfactory threshold to differing concentrations of amyl acetate was determined in 78 subjects with idiopathic Parkinson's disease and 40 age-matched controls. Impaired olfactory threshold (previously reported by others) was confirmed in Parkinsonian subjects compared with controls. There was no significant correlation between olfactory threshold and age, sex, duration of disease, or current therapy with levodopa or anticholinergic drugs. In a sub-group of 14 levodopa-treated patients with severe "on-off" fluctuations, no change in olfactory threshold between the two states was demonstrable. Olfactory impairment in Parkinson's disease may involve mechanisms that are not influenced by pharmacologic manipulation of dopaminergic or cholinergic status.
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PMID:Olfactory threshold in Parkinson's disease. 381 60

Rats were trained for several months to perform a radial arm maze task and then given either sham or ibotenic acid lesions of the nucleus basalis magnocellularis (NBM), the primary cholinergic projection to the neocortex. The lesion produced a profound and apparently selective disturbance in memory for recent events. Further testing revealed that although the memory deficit persisted for several weeks, a gradual but complete recovery eventually occurred. Moreover, when these functionally recovered rats were later tested on a passive avoidance task that is normally sensitive to lesions of the NBM, no deficit was found. Thus, the post-lesion recovery of function generalized to a different memory test, upon which no post-lesion practice had been given. Post-mortem determinations revealed that the lesions caused marked neurodegeneration of the NBM, and decreases in both cortical choline acetyltransferase activity and high affinity choline uptake, but had no effect on density of muscarinic receptors. No evidence of neuronal recovery or neurochemical compensatory changes in the cholinergic system was found in the cortical projection areas, lesion site, or in parallel cholinergic systems terminating in the hippocampus or olfactory bulb. These results support the idea that the cortically-projecting cholinergic cells of the NBM normally play an important role in mediating recent memory. However, they also demonstrate that any simple relationship between the function of this brain region and the mediation of recent memory is unlikely. Finally, the results of this study direct attention toward issues related to the mechanisms involved with the recovery of function, and the extent to which degeneration of this brain area may contribute directly to the severe disturbance of cognitive function associated with certain neurodegenerative diseases (e.g., Alzheimer's, Pick's and Parkinson's disease).
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PMID:Selective memory loss following nucleus basalis lesions: long term behavioral recovery despite persistent cholinergic deficiencies. 404 Oct 42

Administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (NMPTP) (daily injections of 8 mg/kg for 5 days via tail vein) reduced [3H]dopamine uptake in striatal synaptosomes by 63% and reduced [3H]cocaine binding to striatal membranes by 61%. [3H]Cocaine binding was not affected in olfactory tubercle, suggesting a selective effect of NMPTP on the nigro-striatal but not on the mesolimbic dopaminergic system. The destruction of dopamine terminals in the striatum did not alter (up-regulate) [3H]spiroperidol binding. The results suggest that NMPTP causes a degenerative destruction of the striatal dopamine pathway and that NMPTP may be useful in developing a rodent model of Parkinson's disease.
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PMID:Reduction of dopamine uptake and cocaine binding in mouse striatum by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 633 38

The MAO activity (tyramine substrate) was measured in 17 different brain regions, the spinal cord, and 13 different organs of four patients with Huntington's disease and three patients with Parkinson's disease. The values were compared with those measured in corresponding tissues from neurologically healthy patients. The serum MAO activities of 12 patients with Huntington's disease were compared with those of 137 normal persons (benzylamine substrate). A comparison of the MAO activities in the brain regions of patients with Huntington's disease, Parkinson's disease, and normal controls showed only minor differences in the cerebral gray matter, corpus callosum, striatum, caudate nucleus, pons, putamen, nucleus niger, dentatus, cerebellar gray matter, and cerebellar white matter. Larger differences in MAO activity were observed in the Ammon's horn, the striatal fundus, and the olfactory region. Slightly increased MAO activities were found in the pallidum of patients with Huntington's disease and Parkinson's disease. In patients with Huntington's disease the MAO activity is considerably increased in the medulla oblongata (25%) and the spinal cord (nearly 50%) as compared to patients with Parkinson's disease and normal controls. The brain MAO activity in the rat remained unchanged after movement anomalies had been induced by application of 2,3-diaminobutyric acid; the neurolathyrogenic substance iminodipropionitrile (IDPN), which causes chloreiform movements in the rat that last for life did not considerably change the MAO activity of the brain. The enzyme values were essentially the same in pancreas, spleen, kidney, adrenal, jejunum, ileum, colon, rectum, and testis of patients and control individuals. The MAO activities in the thyroid glands of patients with Parkinson's disease and Huntington's disease were slightly reduced in comparison with the control group. MAO activity in the liver of patients with Huntington's disease was reduced to approximately 50%. In the heart it was increased by approximately 30%, and that in the lungs was five times higher. A comparison of serum MAO activities in Huntington's disease patients and normal subjects did not reveal any essential differences. The increased MAO values in the sera of female patients with Huntington's disease may be related to hormonal influences.
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PMID:[Monoamine oxidase activity in brain regions and organs of patients with Parkinson's disease and Huntington's disease and serum MAO activity of patients with Huntington's disease as compared with neurologically healthy individuals (author's transl)]. 645 4

Ungerstedt observed that the dopamine-containing innervation of the forebrain can be divided into two parts: a nigrostriatal system, originating mainly in the pars compacta of the substantia nigra and innervating the caudoputamen; and a mesolimbic system arising mainly in the ventral tegmental area and innervating the nucleus accumbens and olfactory tubercle. This classification has since been modified and extended with the discovery of the mesocortical dopamine system. The original distinction between nigrostriatal and mesolimbic systems nevertheless was pivotal in suggesting that the basal ganglia are related to limbic as well as to sensorimotor functions, and remains of interest because dopaminergic mechanisms may be implicated not only in the aetiology of sensorimotor impairments such as those of Parkinson's disease, but also in neuropsychiatric disorders such as schizophrenia. The striatal targets of the mesolimbic and nigrostriatal systems are now known to be distinct also in terms of forebrain connections, despite some overlap of fibre projections. The nucleus accumbens-olfactory tubercle region and abutting caudoputamen (together called the 'ventral' or 'limbic' striatum) are characteristically related to limbic parts of the forebrain, whereas the large remainder of the caudoputamen (the 'dorsal' or 'non-limbic' striatum) is most closely related to sensorimotor regions. We report here evidence that the mesolimbic and nigrostriatal systems are differentially affected in the mutant mouse weaver, and in particular that dopamine is severely depleted in the dorsal striatum of weaver but relatively spared in the ventral striatum. We conclude that dopamine-containing fibre systems innervating the limbic and non-limbic striatum can be influenced separately in genetic disease and that genetic control, whether direct or indirect, may be exerted at the single-gene level.
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PMID:Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum. 669 Sep 83

The dopamine transporter (DAT) is a primary site for the action of cocaine in inducing euphoria. Its action is necessary for the selectivities of dopaminergic neurotoxins that provide the best current experimental models of Parkinson's disease. In the present report, rat dopamine transporter-like immunoreactivity (iDAT) was assessed by immunohistochemistry using newly developed polyclonal antisera raised against conjugated peptides corresponding to sequences found in the dopamine transporter's carboxy- and amino-termini. Dense iDAT was observed in patterns consistent with neural processes and terminals in the striatum, nucleus accumbens, olfactory tubercle, nigrostriatal bundle, and lateral habenula. Perikarya in the substantia nigra pars compacta were immunostained with moderate intensity using one of two immunohistochemical methods, while scattered ventral tegmental area perikarya were stained with somewhat less intensity. Immunoreactive neuronal processes with axonal and dendritic morphologies were stained in the substantia nigra and the paranigral and parabrachialis pigmentosus nuclei of the ventral tegmental area, while sparser processes were noted more medially in the ventral tegmental area. Neuronal processes were found in several laminae in the cingulate cortex, with notable fiber densities in the superficial aspects of lamina I and laminae II/III. The intensities of immunoreactivities in striatum and cerebral cortex were dramatically attenuated ipsilateral to nigrostriatal bundle 6-hydroxydopamine lesions. Specificity of immunostaining was supported by agreement of the results using sera directed against two distinct DAT segments, studies with preimmune and preadsorbed sera and studies of the extracted protein. These antisera identify and reveal details of the distribution of DAT immunoreactivity in rat brain and display variations in levels of DAT expression of likely functional significance.
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PMID:Dopamine transporter immunoreactivity in rat brain. 749 33

Pramipexole (PPX) is currently being evaluated for treatment of schizophrenia and Parkinson's disease. In studies with cloned subtypes of the dopamine (DA) D2 receptor subfamily, PPX has higher affinity for the D3 compared to the D2 and D4 subtypes; unlike 7-[3H]hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), it does not bind to sigma sites. Receptor binding autoradiography with [3H]PPX (5 nM, 62 Ci/mmol) was used to evaluate the distribution of PPX binding sites within the rat brain. Consistent with its preference for D3-binding sites, the highest concentrations of [3H]PPX binding sites were found in the islets of Calleja (ICj), previously reported to contain D3 but not D2 or D4 mRNA. [3H]PPX binding was also high in other mesolimbic areas such as the nucleus accumbens (N. accum), olfactory tubercle, and amygdala. [3H]PPX binding was also high in caudate (Cd), although slightly less than in mesolimbic areas. Less [3H]PPX binding sites were found in ventral tegmental area (VTA) and substantia nigra, areas rich in cell bodies for DA neurons. Thus, although PPX most potently stimulates DA autoreceptors, PPX binding sites have their highest concentrations in projection areas containing both DA terminal and postsynaptic receptors. Because of PPX's preferential affinity for the D3 receptor subtype and its resultant high mesolimbic binding, it could have a unique therapeutic profile for treatment of psychiatric and/or neurological diseases.
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PMID:Rat brain binding sites for pramipexole, a clinically useful D3-preferring dopamine agonist. 750 Dec 68

Monoamine-activated alpha 2-macroglobulin (alpha 2M) has been shown to inhibit choline acetyltransferase in basal forebrain neurons as well as neurotrophin-dependent neuronal functions. The objective of this study was to determine whether monoamine-activated alpha 2M can affect the caudate putamen (CP) dopaminergic system in vivo. Male rats received intracranial infusions of methylamine-activated alpha 2M (0.6 nmole) and contralateral infusions of its vehicle, phosphate-buffered saline (PBS). Five days following infusion, the animals were killed, the CP dissected into three rostral-caudal segments, and assayed for dopamine (DA) using a high-performance liquid chromatography system. Within the two rostral CP segments (the approximate site of cannula placement), statistically significant (26%) reductions of DA concentrations were obtained on the alpha 2M-infused side of the CP with 90-100% of the animals showing decreases. At a more distal (caudal) site of the CP, DA concentrations showed only an insignificant (12%) reduction. No differences in DA concentrations between sides infused with bovine serum albumin versus PBS or from olfactory tubercle samples were obtained in these animals. These results demonstrate that monoamine-activated alpha 2M is capable of producing significant degeneration of the nigrostriatal dopaminergic system in vivo and suggest that this factor may play a role in age-related neurodegenerative disorders such as Parkinson's disease.
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PMID:Intracranial infusion of monoamine-activated alpha 2-macroglobulin decreases dopamine concentrations within the rat caudate putamen. 752 25

Deprenyl is a selective monoamine oxidase B (MAO-B) inhibitor and has been used in the treatment of Parkinson's disease. However, it is not known whether deprenyl effects are symptomatic or pharmacological. Aging mice were partially lesioned with MPTP. Control and MPTP-treated mice were given deprenyl in drinking water for 14 days. Brain tissue (including the striatum, olfactory tubercle and cerebral cortex) was assayed for MAO-B and neurotransmitter levels. The results show that deprenyl treatment, given alone or after MPTP, reduced MAO-B activity in all the three regions. No change was seen in dopamine (DA), 3,4-dihydroxyphenyl acetic acid (DOPAC), and homovanillic acid (HVA) content in any of the three areas. Cortical norepinephrine (NE) levels were also unaltered. However, striatal serotonin (5-HT) levels were decreased while its metabolite, 5-HIAA levels were significantly increased in the olfactory tubercle in animals receiving deprenyl alone. These data suggest that deprenyl treatment reduces MAO-B activity in regions in addition to the striatum without affecting norepinephrine, dopamine (DA) and its metabolites.
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PMID:Effects of deprenyl on monoamine oxidase and neurotransmitters in the brains of MPTP-treated aging mice. 754 44

Since olfactory dysfunction is among the first signs of idiopathic Parkinson's disease (PD), olfactory testing may aid in the early of 'preclinical' diagnosis of this disorder. Indeed, the proportion of early-stage PD patients with olfactory dysfunction appears to be greater than the proportion of early-stage PD patients exhibiting some of the cardinal signs of PD. Because olfactory function varies in the general population and declines with age, empirically-based criteria are needed by the clinician to establish whether the degree of olfactory loss observed in a given patient is concordant with the presence of PD. In this study, we present cutoff criteria for the optimal assessment of olfactory dysfunction in the evaluation of PD. Specifically, we present scores for the University of Pennsylvania Smell Identification Test (UPSIT) that best discriminate between PD patients and age-matched controls. Receiver operating characteristic (ROC) curves, based upon sensitivity and specificity estimates, were computed for three age groups (< or = 60 yrs, 61-70 yrs, and > or = 71 yrs) and scores with highest sensitivity and specificity were determined. Sex- and age-related differences in the test scores were observed, with lower scores occurring for men and for the older patient groups.
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PMID:Olfactory testing as an aid in the diagnosis of Parkinson's disease: development of optimal discrimination criteria. 760 Jan 89


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