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)

Although the cause of Parkinson's disease is still unknown it has become clear that dopaminergic cell loss in the substantia nigra is a prominent feature of the disease. The study of cerebral dopaminergic function-dominated by the nigrostriatal system-in relation to motor abnormalities and their response to treatment has been in the centre of research for many years. However, until recently it was not possible to approach metabolism or neurotransmitter function in brain directly in vivo. To be able to do so seems highly necessary since Parkinson's disease is a slowly progressive condition and one wishes to know how cerebral functions are deranged in the beginning of the disease. Positron emission tomography (PET) using specific tracers (labelled with short-lived radionuclides like oxygen-15, carbon-11 or fluorine-18) can measure certain physiological or biochemical functions focally in brain directly in patients or healthy volunteers (for an extensive overview, see Phelps, 1986).
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PMID:Parkinson's disease and PET tracer studies. 313 28

Patterns of local cerebral glucose utilization were measured with positron emission tomography using the fluorine-18-labeled fluorodeoxyglucose (18FDG) method in 8 patients with Parkinson's disease, in 13 patients with Huntington's disease, in 15 subjects at risk for Huntington's disease, and in aged-matched normal control subjects. On the average, global cerebral metabolism in patients with Parkinson's disease was moderately reduced (20%), but the relative distribution of glucose utilization throughout the brain in these patients was normal. These results support the conclusion that alterations of the nigrostriatal pathway in Parkinson's disease have no major selective effect on the metabolism of particular cerebral regions. In Huntington's disease, however, there was a characteristic decrease in glucose utilization in the caudate nuclei and putamen, and this local hypometabolism appeared early and preceded bulk tissue loss. In patients with Huntington's disease, glucose utilization typically was normal throughout the rest of the brain, regardless of the severity of symptoms and despite the apparent shrinkage of brain tissue. The results also suggest the possibility that the caudate nuclei may be hypometabolic in some asymptomatic subjects who are potential carriers of the autosomal dominant gene for Huntington's disease.
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PMID:Patterns of cerebral glucose utilization in Parkinson's disease and Huntington's disease. 623 56

The neurotransmitter dopamine has biological attributes that make it amenable to study by positron emission tomography, unlike many of the 40 or so neurotransmitters that have been identified in the brain. Dopamine deficiency in the nigrostriatal system is a characteristic of Parkinson's disease, and a disturbance of dopamine metabolism is still widely held to be responsible for the syndrome of schizophrenia. Despite its importance in the regulation of locomotion and mood, it has been impossible to visualize the intracerebral distribution of dopamine and measure its regional metabolism in man. In the first demonstration of the regional distribution of a neurotransmitter in the brain of conscious normal man, we show here that L-3,4-dihydroxyphenylalanine (L-dopa) labelled in the 6-position with the positron-emitting radionuclide fluorine-18, localizes specifically in the dopaminergic pathways of the human brain where its turnover could be measured atraumatically by positron emission tomography.
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PMID:Dopamine visualized in the basal ganglia of living man. 660 27

From its characteristic clinical features, decrease of tyrosine hydroxylase (TH) in the terminal of the nigrostriatal (NS) dopamine (DA) neuron is considered the main lesion of HPD and the decrease of neopterin as well as biopterin in the cerebrospinal fluid suggested GTP cyclohydrolase I (GCH-I) as the responsible enzyme. By detecting the gene locus of GCH-I, Ichinose and his colleagues showed the abnormalities of GCH-I gene located on 14q 22.1 q22.2 as the cause of HPD. Since the first report of Ichinose et al, 11 mutations and frame shifts of the gene have been detected, in which the locus of abnormality differed among families but is identical in a family, but more than several families have been left with undetected abnormalities including those having linkage to 14q. However, the DNA of these families as well as those with detected gene abnormalities failed to synthesize GCH-I if inoculated with E. coli and the levels of GCH-I in mononuclear blood cells were below 20% of normal values in HPD patients while they were 37 and 38% in two asymptomatic carriers. Ratio of mutant mRNA of GCH-I gene was 28% in a patient and 8.3% in an asymptomatic case. These lines of evidence on GCH-I show HPD is a dominant inherited disorder with abnormalities of GCH-I gene. GCH-I is the limiting enzyme for synthesizing tetrahydrobiopterin (BH4), coenzyme transmitters for the synthesizing hydroxylases of aminergic neurotransmitters, but the affinity is the least for TH. This might cause a rather selective involvement of TH preserving serotonin synthesis un- or less affected. Fluoro-DOPA and [11C] racropride PET studies were normal in HPD. Studies of an autopsied case with dopa responsive dystonia, which was confirmed to have GCH-I gene abnormalities, neuropathologically revealed no abnormalities except for a decrease in melanin pigmentation in the substantia nigra and histochemically a decrease in TH enzyme activities and its protein only in the striatum. There was mild decrease of DA content, the interregional caudate/putamen and subregional rostrocaudal patterns which were similar to Parkinson disease, but subdivisionally different with predominant reduction in the ventral subdivision of the caudate nucleus. In the ventral part of the basal ganglia the striatal direct projection exists predominantly. Cases with recessive abnormalities of pteridin metabolism other than HPD, 6-pyruvoyl-tetra-hydropterin synthase (PSPS) deficiency and dihydropteridine reductase deficiency also show dystonia with diurnal fluctuation responding to levodopa, though not as marked as HPD. MPTP monkey studies revealed no involvement of striatal indirect pathway for peak dose dystonia. So it is suggested that in HPD, decrease of TH at the terminal of the NS-DA neuron due to partial reduction of GCH-I develops postural dystonia through the striatal direct projection in childhood with diurnal fluctuation depending on age and circadian variation of TH activities at the terminals.
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PMID:[Segawa disease (hereditary progressive dystonia with marked diurnal fluctuation-HPD) and abnormalities in pteridin metabolism]. 912 93

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a known neurotoxicant primarily selective for catecholaminergic neurons, including those of the nigrostriatal dopaminergic system, thereby mimicking the pathology of Parkinson's disease (PD). In this study, serial transbrain sectioning, followed by staining with a newly developed fluorochrome (Fluoro-Jade) specific for degenerating neurons, was used to detect additional sites of MPTP-induced neuronal degeneration in mice. Male CD-1 mice received a single 50 mg/kg dose of MPTP intraperitoneally at room temperature or at a reduced temperature (6 degrees C), which has been shown to potentiate striatal dopamine depletion. Neuronal degeneration was observed in the substantia nigra pars compacta (SN), ventral tegmental area (VTA) and retrorubral field (RRF) of only animals dosed in the low temperature environment. Neuronal degeneration was also observed in other catecholaminergic nuclei in both treatment groups. In addition, degenerating cell bodies and fibers were detected in the midline and intralaminar thalamic nuclei of all dosed animals, regardless of the dosing environment. Pharmacological manipulations which prevented nigral degeneration (deprenyl and nomifensine pretreatment) also prevented the degeneration of thalamic neurons. MK-801 pretreatment, however, resulted in a disproportionate protection of the thalamic neurons. These findings confirm and extend our previous observations regarding the protective effect of hyperthermia in CD-1 mice and also suggest that regions of the thalamus may be relevant to the pathophysiology of PD.
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PMID:Systemic administration of MPTP induces thalamic neuronal degeneration in mice. 921 57

Ro41-0960 is a potent, fluorine containing COMT inhibitor which has be en reported to cross the blood brain barrier and to inhibit COMT in the brain. It is structurally similar to Ro40-7592 which is currently undergoing clinical trials in Parkinson's disease. Positron emission tomographic (PET) studies in baboon using F-18 labeled Ro41-0960 demonstrated a negligible uptake in the brain both at tracer doses and with the addition of unlabeled drug (1.5 mg/kg) at all times through a 90 min experimental interval. The brain to plasma ratios of F-18 averaged about 0.025. Region of interest analysis of the brain tissue area suggests that most of F-18 in the brain was due to the blood in the brain and not the brain tissue itself. However, high uptake was observed in the kidneys and in other organs which are known to have high COMT activity. Studies in mice showed that at 30 min after injection of tracer, F-18 in kidneys was largely as unchanged [18F]Ro41-0960 and that it could be displaced with unlabeled Ro41-0960. The fact that the average brain to blood ratio for mice (n=12) was 0.04, and that similar HPLC metabolite patterns were observed for brain and blood, provides consistent evidence that nearly all the F-18 in the brain represents F-18 in the cerebral blood vessels. These studies raise the question of whether the central pharmacological effects of Ro41-0960 are due to its presence in the brain. They also provide the first example of a positron emitter labeled radiotracer for COMT, and provide initial encouraging evidence that [18F]Ro41-0960 may be used to examine COMT in peripheral organs in vivo.
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PMID:Mapping catechol-O-methyltransferase in vivo: initial studies with [18F]Ro41-0960. 949 60

A 76-year old woman was affected by lethargic encephalitis in 1918, at the age of 3 months. Long-term clinical follow-up with late neuropsychological evaluation revealed post-encephalitic parkinsonism, which worsened very slowly and was improved by levodopa. Obsessive and compulsive disorders (OCD) were associated to nosophobia. Neuropsychological evaluation showed mild visuocontructional memory deficit, which was isolated. 18 Fluoro-Dopa PET demonstrated a severe bilateral and symmetrical reduction in fluoro-dopa uptake, which was more marked in the putamen than in the caudate. Thus, the pattern of dopaminergic denervation was similar to the one observed in idiopathic Parkinson's disease.
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PMID:PET study and neuropsychological assessment of a long-lasting post-encephalitic parkinsonism. 972 Sep 76

The herbicide paraquat, bearing structural similarity to the known dopaminergic neurotoxicant MPTP, has been suggested as a potential etiologic factor in Parkinson's disease. Consideration of paraquat as a candidate neurotoxicant requires demonstration that systemic delivery produces substantia nigra dopaminergic neuron loss and the attendant neurobehavioral syndrome reflecting depletion of dopamine terminals within the striatum. To address these issues paraquat was administered systemically into adult C57 bl/6 mice, ambulatory behavior monitored, substantia nigra dopamine neuron number and striatal dopamine terminal density quantified. The data indicate that paraquat like MPTP elicits a dose-dependent decrease in substantia nigra dopaminergic neurons assessed by a Fluoro-gold prelabeling method, a decline in striatal dopamine nerve terminal density assessed by measurement of tyrosine hydroxylase immunoreactivity; and neurobehavioral syndrome characterized by reduced ambulatory activity. Taken together, these data suggest that systemically absorbed paraquat crosses the blood-brain barrier to cause destruction of dopamine neurons in the substantia nigra, consequent reduction of dopaminergic innervation of the striatum and a neurobehavioral syndrome similar to the well characterized and bona fide dopaminergic toxin MPTP.
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PMID:Paraquat elicited neurobehavioral syndrome caused by dopaminergic neuron loss. 1009 6

The existence of a dopaminergic innervation of the subthalamic nucleus (STN) has been demonstrated in rats but has remained controversial in primates. The aim of the present study was first to demonstrate the existence of a dopaminergic innervation of the STN in monkeys using tracing methods and then to quantify the loss of dopaminergic fibers in the parkinsonian state in monkeys and humans. Following injection of Fluoro-Gold into the STN of a vervet monkey (Cercopithecus aethiops), retrogradely labeled neurons were found to be scattered in all dopaminergic areas of the mesencephalon. Injection of biotin dextran amine into dopaminergic areas A8 and A9 of two monkeys resulted in anterogradely labeled axons located throughout the whole extent of the STN. Labeled axons that also expressed tyrosine hydroxylase (TH) were reconstructed from serial sections. Some terminal axonal arborizations had profuse branching and occupied much of the STN, and others were restricted to small portions of the nucleus. In TH-immunoreactive sections, numerous sparse, fine, and varicose TH-positive fibers were observed in the STN of normal monkeys and humans. Quantification of these TH-positive fibers revealed a 51% loss of TH-positive fibers in MPTP-intoxicated monkeys and a 65% loss in Parkinson's disease patients compared with their respective controls. These findings demonstrate the existence of a dopaminergic innervation of the STN in primates. The loss of dopaminergic innervation in MPTP-intoxicated monkeys and in Parkinson's disease patients may directly affect the activity of STN neurons and could participate in the hyperactivity of the structure.
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PMID:Dopaminergic innervation of the subthalamic nucleus in the normal state, in MPTP-treated monkeys, and in Parkinson's disease patients. 1094 Sep 46

Positron emission tomography (PET) coupled to 6-[18F]Fluoro-L-Dopa (18F-Dopa) remains the gold standard for assessing dysfunctionality concerning the dopaminergic nigrostriatal pathway in Parkinson's disease and related disorders. The use of ligands of the dopamine transporters (DAT) is an attractive alternative target; consequently, the current aim was to validate one of them, 11C-PE2I, using a multiinjection modeling approach allowing accurate quantitation of DAT densities in the striatum. Experiments were performed in three controls, three MPTP-treated (parkinsonian) baboons, and one reserpine-treated baboon. 11C-PE2I B'max values obtained with this approach were compared with 18F-Dopa input rate constant values (Ki), in vitro Bmax binding of 125I-PE2I, and the number of dopaminergic neurons in the substantia nigra estimated postmortem by stereology. In the caudate nucleus and putamen, control values for 11C-PE2I B'max were 673 and 658 pmol/mL, respectively, whereas it was strongly reduced in the MPTP-treated (B'max = 26 and 36 pmol/mL) and reserpine-treated animals (B'max = 338 and 483 pmol/mL). In vivo 11C-PE2I B'max values correlated with 18F-Dopa Ki values and in vitro 125I-PE2I Bmax values in the striatum and with the number of nigral dopaminergic neurons. Altogether, these data support the use of 11C-PE2I for monitoring striatal dopaminergic disorders and the effect of potential neuroprotective strategies.
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PMID:Anatomic and biochemical correlates of the dopamine transporter ligand 11C-PE2I in normal and parkinsonian primates: comparison with 6-[18F]fluoro-L-dopa. 1143 90


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