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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 127 records · Page 7Linked to original sources
PubMed1997

GTP cyclohydrolase I mutations in patients with dystonia responsive to anticholinergic drugs.

OBJECTIVES: To investigate the hypothesis that GTP cyclohydrolase I (GCH1) mutations are responsible for the phenotype of highly anticholinergic responsive dystonia in patients with apparent primary torsion dystonia. METHODS: From 107 British patients with clinically diagnosed primary torsion dystonia, seven patients were identified with an excellent response to anticholinergic drugs. All six exons of the GCH1 gene were sequenced in these patients to identify mutations. RESULTS: Three novel GCH1 mutations were identified in two patients. One patient was a compound heterozygote with asymptomatic carrier parents. The clinical phenotype of patients with and without GCH1 mutations was similar. CONCLUSIONS: These findings show that a proportion of patients with apparent primary torsion dystonia and a good response to anticholinergic drugs have GCH1 mutations and therefore have a variant of dopa responsive dystonia. The difficulty in distinguishing clinically between patients with and without mutations underscores the importance of considering the diagnosis of a levodopa responsive dystonia in all such patients.

Adult↗
PubMed1997

Clinical features and natural history of axial predominant adult onset primary dystonia.

The clinical features and natural history of 18 patients with adult onset axial predominant severe truncal primary dystonia are presented. The mean age of onset was 41 (42 for men, 39 for women) and there was a higher proportion of men (10:8). Analysis of their clinical features and follow up over three to five years or more showed that these patients generally conform to the characteristics of other types of adult onset primary dystonias. They tended to remain focal although there could be an initial contiguous spread, sometimes beginning in the craniocervical region and spreading axially or, rarely, vice versa. If spread occurred, involvement of the head, neck, and arms was mild in comparison with the severe dystonia of the trunk. However, in none of the patients with craniocervical or truncal onset did the dystonia spread to involve the legs. More than a third (seven of 18) of the patients had a prior history of injury at the site subsequently affected by dystonia. Treatment response to various drugs overall was poor but a third of the patients improved on treatment either with triple therapy (a combination of tetrabenazine, pimozide, and an anticholinergic drug) or high dose anticholinergic drugs alone. Severe depression occurred in 33% of patients, mainly due to the negative personal image arising from their disfiguring dystonia. None of the patients had a family history of dystonia and at the moment it is unclear whether these patients with sporadic axial dystonia are non-genetic phenocopies or are a manifestation of one or more of the genes that cause generalised dystonia or torticollis.

Adult↗
PubMed1997

Abnormal access of axial vibrotactile input to deafferented somatosensory cortex in human upper limb amputees.

We studied two human subjects with total deafferentation of one upper limb secondary to traumatic multiple cervical root avulsions. Both subjects developed a phantom limb and underwent elective amputation of the paralyzed, deafferentated limb. Psychophysical study revealed in each subject an area of skin in the pectoral region ipsilateral to the amputation where vibrotactile stimulation (VS) elicited referred sensations (RS) in the phantom limb. Positron emission tomography was then used to measure regional cerebral blood flow changes during VS of the pectoral region ipsilateral to the amputation with RS and during VS of a homologous part of the pectoral region adjacent to the intact arm without RS. A voxel-based correlation analysis was subsequently used to study functional connectivity. VS of the pectoral region adjacent to the intact arm was associated with activation of the dorsal part of the contralateral primary somatosensory cortex (S1) in a position consistent with the S1 trunk area. In contrast, VS of the pectoral region ipsilateral to the amputation with RS was associated with activation of the contralateral S1 that extended from the level of the trunk representation ventrally over distances of 20 and 12 mm, respectively, in the two subjects. The area of S1 activated during VS of the digits in a normal control subject was coextensive with the ventral S1 region abnormally activated during VS of the ectopic phantom representation in the two amputees, suggesting that the deafferented digit or hand/arm area had been activated by sensory input from the pectoral region. Correlation analysis showed an abnormal pattern of intrinsic connectivity within the deafferented S1 hand/arm area of both amputees. In one subject, the deafferented S1 was functionally connected with 3 times as many S1 voxels as the normally afferented S1. This abnormal functional connectivity extended in both the rostrocaudal and ventrodorsal dimensions. The results demonstrate that sensory input delivered to the axial body surface may gain access to the S1 hand/arm area in some humans who have suffered extensive deafferentation of this area. The findings are consistent with the hypothesis that deafferentation of an area of S1 may result in activation of previously dormant inputs from body surfaces represented in immediately adjacent parts of S1. The results also provide evidence that changes in functional connectivity between these adjacent areas of the cortex play a role in the somatotopic reorganization.

Adult↗
PubMed1997

Cabergoline in the treatment of early Parkinson's disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa. The PKDS009 Collaborative Study Group.

Cabergoline is a potent D2 receptor agonist with a half-life of 65 hours that may provide continuous dopaminergic stimulation administered once daily. In this study, we randomized de novo Parkinson's disease (PD) patients to treatment with increasing doses of cabergoline (0.25 to 4 mg/d) or levodopa (100 to 600 mg/d) up to the optimal or maximum tolerated dose. Decreases of > 30% in motor disability (Unified Parkinson's Disease Rating Scale Factor III) versus baseline were considered indicative of clinical improvement. If 30% improvement was not achieved, levodopa/ carbidopa could be added on an open basis. Of the 208 patients entered in the cabergoline group, 175 remained in the study for 1 year at a mean dose of 2.8 mg/d; in the levodopa group, 176 of the 205 patients entered were still on study after 1 year at a mean dose of 468 mg/d. The proportion of patients requiring additional levodopa/carbidopa increased in the cabergoline group from 18% at 6 months to 38% at 1 year versus 10% (p = 0.05) at 6 months and 18% (p < 0.01) at 1 year in the levodopa group. The proportion of patients showing clinical improvement did not differ significantly between the two groups, or between the subgroups on monotherapy, at any endpoint. Irrespective of levodopa/carbidopa addition, 81% of patients in the cabergoline group and 87% of patients in the levodopa group were clinically improved at 1 year (p = 0.189); the corresponding figures for the subgroup on monotherapy were 79% in the cabergoline-treated patients and 86% in the levodopa-treated patients (p = 0.199). The mean difference versus baseline in Unified Parkinson's Disease Rating Scale Factor III scores in patients who remained on monotherapy up to 1 year was 12.6 (95% confidence interval [CI]: 10.8, 14.3) in the cabergoline group and 16.4 (95% CI: 14.8, 18.0) in the levodopa group. Adverse events occurred in 76% of patients on cabergoline and in 66% of patients on levodopa. The severity profile for reported events was similar for the two agents. The results of this study indicate that cabergoline treatment for up to 1 year is only marginally less effective than levodopa in the proportion of patients who can be treated in monotherapy. More than 60% of de novo PD patients could be managed on cabergoline alone up to 1 year. In the patients in whom levodopa/carbidopa was needed, the combination therapy provided efficacy similar to that obtained with levodopa alone, with a relevant sparing of levodopa.

Aged↗
PubMed1997

Evaluation of four candidate genes encoding proteins of the dopamine pathway in familial and sporadic Parkinson's disease: evidence for association of a DRD2 allele.

We assessed the role of four candidate genes encoding proteins involved in dopaminergic transmission, the dopamine transporter (DAT), the dopamine receptor D2 (DRD2), and the main catabolic enzymes of dopamine, monoamine oxidase A (MAOA) and B (MAOB), through allelic association studies in a population of familial and sporadic Parkinson's disease (PD). Using intronic polymorphisms of the four candidate genes, we studied the allelic distributions of the polymorphic markers in 18 affected members, one patient was chosen randomly from each PD family; 60 sporadic PD and 60 healthy unrelated control subjects were matched for sex and for country of origin. All subjects were white. To complete the study of the DRD2, we subsequently tested 40 additional sporadic PD and 40 control patients, who were recruited using a similar procedure. For DAT, MAOA, MAOB polymorphisms, similar allelic frequencies were present in familial, sporadic PD and control patients. In contrast, at the DRD2 locus, the overall allelic distribution was significantly different in the sporadic PD (p < 0.01) and in the familial PD groups (p < 0.05), each was compared with the controls. The odd ratios were significant (p < 0.01) in sporadic PD and in familial PD for allele 3 with respective values of 1.84 (95% CI, 1.23-2.74) and 2.83 (95% CI, 1.32-6.08). Individuals who were homozygous for allele 3 were 2.3 times more frequent in the sporadic PD than in controls. Results suggest that DRD2, but not DAT, MAOA and MAOB, might be a genetic determinant of PD in the population tested.

Alleles↗
PubMed1997

Multiple-system atrophy is genetically distinct from identified inherited causes of spinocerebellar degeneration.

Multiple system atrophy (MSA) is a neurodegenerative disorder of unknown cause. The only case-control study conducted in MSA patients to date suggested a possible contributory genetic component in the pathogenesis of this disorder. The aim of this study was to evaluate a possible overlap between clinically or pathologically well-defined MSA and other conditions with an identified genetic defect causing spinocerebellar degeneration in humans or mutant mice strains. The spinocerebellar ataxia type 1 and 3 genes (SCA1 and SCA3) were analyzed for a pathologic expansion in 80 patients with MSA to evaluate a possible overlap between MSA and SCA1 or SCA3. Weaver mice and lurcher mice are animal models for spinocerebellar degeneration; both share pathologic features with MSA. We sequenced the H5 pore region of the human homologue of the weaver mouse gene, hiGIRK2, in all our patients. In lurcher mice, previous biochemical studies have shown a decreased intracellular response to insulin-like growth factor 1 (IGF-1) in the cerebellar cortex, and we thus investigated the possibility of an allelic association between MSA and the receptor for IGF-1. In addition, we evaluated a possible involvement of the ciliary neurotrophic factor gene (CNTF) and examined the role of HLA-A32 to clarify the conflicting data from previous studies. No changes were detected in any of the analyzed genes. Our studies strongly suggest that MSA is an autonomous syndrome distinct from identified genetic causes for spinocerebellar degeneration.

Alleles↗
PubMed1996

Dopamine D3 receptors are not involved in the induction of c-fos mRNA by neuroleptic drugs: comparison of the dopamine D3 receptor antagonist GR103691 with typical and atypical neuroleptics.

The effect of acute and chronic administration of dopamine receptor antagonists on the expression of mRNA encoding the cellular immediate-early gene c-fos was investigated in rat brain by in situ hybridization using 35S-labelled oligonucleotide probes. The selective dopamine D3 receptor antagonist GR103691 had no effect on the level of c-fos mRNA after acute or chronic treatment. Acute treatment with haloperidol increased the level of c-fos mRNA in the caudate-putamen, nucleus accumbens shell and core, olfactory tubercle and parietal cortex. After chronic treatment with haloperidol increases in the level of c-fos mRNA in the caudate-putamen and nucleus accumbens core were no longer observed. The increase in the level of c-fos mRNA in the nucleus accumbens shell was attenuated but still significantly elevated above the level measured in vehicle-treated animals. In the olfactory tubercle, parietal cortex, frontal cortex and cingulate cortex the level of c-fos mRNA was decreased after chronic haloperidol treatment. Acute sulpiride treatment reduced the level of c-fos mRNA in the olfactory tubercle, parietal cortex and cingulate cortex. After chronic treatment with sulpiride the level of c-fos mRNA was reduced in the dorsal caudate-putamen only. Acute clozapine treatment increased the level of c-fos mRNA in the nucleus accumbens shell and islands of Calleja. After chronic treatment with clozapine the level of c-fos mRNA remained elevated in the islands of Calleja but not in the nucleus accumbens shell. These results indicate that acute and chronic blockade of dopamine D3 receptors does not cause induction of c-fos transcription in limbic, striatal or cortical regions of rat brain. This study also demonstrated that acute blockade of dopamine receptors with haloperidol, sulpiride and clozapine induced different regionally specific patterns of c-fos expression which were altered after chronic blockade.

Animals↗
PubMed1996

Selective localisation of P450 enzymes and NADPH-P450 oxidoreductase in rat basal ganglia using anti-peptide antisera.

Environmental or endogenous toxins may cause nigral cell death in Parkinson's disease (PD) due to altered expression of P450 enzymes. In rat brain, immunohistochemistry using anti-peptide antisera showed NADPH-P450 oxidoreductase and CYP2B1/2 in various hypothalamic nuclei and CYP1A1 in the globus pallidus, but neither enzyme was expressed in substantia nigra. No specific immunoreactivity to CYP2D1 or CYP3A1 was found in any brain region examined. In contrast, CYP2E1 was expressed in substantia nigra and in striatal blood vessels. Since CYP2E1 is associated with free radical production, it may contribute to the oxidative stress believed to underlie nigral degeneration.

Alleles↗
PubMed1996

Mitochondrial respiratory enzyme function and superoxide dismutase activity following brain glutathione depletion in the rat.

In substantia nigra from patients with Parkinson's disease, there are decreased levels of reduced glutathione (GSH) and diminished activities of mitochondrial complex I and alpha-ketoglutarate dehydrogenase (alpha-KGDH), along with increased activity of superoxide dismutase (SOD). However, the interrelationship among these events is uncertain. We now report the effect of decreased brain GSH levels on SOD and mitochondrial respiratory enzyme activity in rat brain. In addition, we have investigated the ability of thioctic acid, an endogenous antioxidant, to alter these parameters. Unilateral or bilateral intracerebroventricular (ICV) administration of buthionine sulphoximine (BSO; 1 x 3.2 mg or 2 x 1.6 mg) over a 48-hr period reduced cortical GSH by 55-70%. There was no change in the activity of complex I, II/III, or IV or of citrate synthase in cortex. Similarly, there was no alteration of mitochondrial or cytosolic SOD activity. Thioctic acid (50 or 100 mg/kg IP) alone had no effect on cortical GSH levels in control animals and did not reverse the decrease in GSH levels produced by unilateral or bilateral ICV BSO administration. Thioctic acid (50 or 100 mg/kg IP) had no overall effect on complex I, II/III, or IV or on citrate synthase activity in control animals. Thioctic acid also did not alter cortical mitochondrial respiratory enzyme activity in BSO-treated rats. At the lower dose, thioctic acid tended to increase mitochondrial and cytosolic SOD activity in control animals and in BSO-treated rats. However, at the higher dose, thioctic acid tended to decrease mitochondrial SOD activity. Overall, there was no consistent effect of thioctic acid (50 or 100 mg/kg IP) on SOD activity in control or BSO-treated animals. This study shows that BSO-induced glutathione deficiency does not lead to alterations in mitochondrial respiratory enzyme activity or to changes in SOD activity. GSH depletion in Parkinson's disease therefore may not account for the alterations occurring in complex I and mitochondrial SOD in substantia nigra. Thioctic acid did not alter brain GSH levels or mitochondrial function. Interestingly, however, it did produce some alterations in SOD activity, which may reflect either its antioxidant activity or its ability to act as a thiol-disulphide redox couple.

Animals↗
PubMed1996

The GTP-cyclohydrolase I gene in atypical parkinsonian patients: a clinico-genetic study.

GTP cyclohydrolase I (GTPCH) has recently been identified as the first causative gene for Dopa-responsive dystonia (DRD). DRD typically presents with dystonia in the lower limbs in childhood, but may produce an akinetic-rigid syndrome in middle and old age. We have sequenced the GTPCH gene in 29 Parkinsonian patients without a positive family history for DRD, but who shared at least one feature of the akinetic-rigid presentation of DRD: 23 patients had at least one living relative who also suffered from an akinetic-rigid syndrome; 2 patients had an abnormally mild course of their parkinsonism which was extremely dopa-responsive. DNA was also analysed from 4 brain samples of patients who were clinically diagnosed as suffering from Parkinson's disease, but then did not show any pathological findings at post mortem. No changes in the sequence of the GTPCH gene were detected. We conclude that so far there is no evidence that mutations of the GTPCH gene are responsible for the development of parkinsonism in patients without a positive family history of DRD.

Aged↗
PubMed1996

D3 receptor expression within the basal ganglia is not affected by Parkinson's disease.

Quantitative receptor autoradiography and in situ hybridization were used to investigate the expression of dopamine D3 receptors in sections of human brain containing limbic (nucleus accumbens) and striatal (caudate nucleus, putamen) regions. High levels of dopamine D3 receptor mRNA and specific [3H](+/-)7-hydroxy-N,N-di-N-propyl-2-aminotetralin ([3H]7-OH-DPAT) binding sites were detected in the nucleus accumbens with lower levels in the caudate nucleus and putamen. No difference in D3 receptor expression was observed between normal and parkinsonian brain. These results indicate that D3 receptor expression is not altered in Parkinson's disease. In addition, they suggest that dopamine release in striatal and limbic areas is not necessary for maintenance of D3 receptor expression.

Aged↗
PubMed1996

Inhibition of [3H]dopamine uptake into striatal synaptosomes by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary isoquinoline derivatives (7 isoquinolines, 2 dihydroisoquinolines and 5 1,2,3,4-tetrahydroisoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, isoquinoline derivatives may be necessary to cause neurodegeneration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Oxidative stress and Parkinson's disease.

The underlying mechanism of cell death in substantia nigra of Parkinson's disease patients remains unknown. Biochemical changes occurring in substantia nigra in Parkinson's disease (increased iron levels, inhibition of complex I activity and decreased reduced glutathione levels; GSH) suggest that oxidative stress and free radical species may be involved. In particular, a decrease in GSH levels may be an early component of the process, since this also occurs in incidental Lewy body disease (presymptomatic Parkinson's disease). GSH is lost only from the substantia nigra in Parkinson's disease and this does not occur in other neurodegenerative disorders of the basal ganglia. GSH loss appears to be global throughout the substantia nigra and not localized to either the glia or neuronal elements. The activity of enzymes involved in the glutathione cycle are normal with the exception of gamma-glutamyltranspeptidase, the activity of which is increased. This could result in increased removal and degradation of glutathione from cells. Depletion of GSH in rat using L-buthionine-[S, R]-sulfoxamine (BSO) potentiates 6-hydroxydopamine (6-OHDA) toxicity but does not in itself produce degeneration of the nigrostriatal pathway. Oxidative stress may be a potentially important factor in the degeneration of the substantia nigra in Parkinson's disease and warrants further investigation into its role in this process.

Animals↗
PubMed1996

Effects of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on mitochondrial respiration.

Isoquinoline derivatives exert 1-methyl-4-phenylpyridinium (MPP+)-like activity as inhibitors of complex I and alpha-ketoglutarate dehydrogenase activity in rat brain mitochondrial fragments. We now examine the ability of 19 isoquinoline derivatives and MPP+ to accumulate and inhibit respiration in intact rat liver mitochondria, assessed using polarographic techniques. None of the compounds examined inhibited respiration supported by either succinate + rotenone or tetramethylparaphenylenediamine (TMPD) + ascorbate. However, with glutamate + malate as substrates, 15 isoquinoline derivatives and MPP+ inhibited state 3 and, to a lesser extent, state 4 respiration in a time-dependent manner. None of the isoquinoline derivatives were more potent than MPP+. 6,7-Dimethoxy-1-styryl-3,4-dihydroisoquinoline uncoupled mitochondrial respiration. Qualitative structure-activity relationship studies revealed that isoquinolinium cations were more active than isoquinolines in inhibiting mitochondrial respiration; these, in turn, were more active than dihydroisoquinolines and 1,2,3,4-tetrahydroisoquinolines. Three-dimensional quantitative structure-activity relationship studies using Comparative Molecular Field Analysis showed that the inhibitory potency of isoquinoline derivatives was determined by steric, rather than electrostatic, properties of the compounds. A hypothetical binding site was identified that may be related to a rate-limiting transport process, rather than to enzyme inhibition. In conclusion, isoquinoline derivatives are less potent in inhibiting respiration in intact mitochondria than impairing complex I activity in mitochondrial fragments. This suggests that isoquinoline derivatives are not accumulated by mitochondria as avidly as MPP+. The activity of charged and neutral isoquinoline derivatives implicates both active and passive processes by which these compounds enter mitochondria, although the quaternary nitrogen moiety of the isoquinolinium cations favours mitochondrial accumulation and inhibition of respiration. These findings suggest that isoquinoline derivatives may exert mitochondrial toxicity in vivo similar to that of MPTP/MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

The isomers of thioctic acid alter C-deoxyglucose incorporation in rat basal ganglia.

Nigral cell death in Parkinson's disease is associated with decreased reduced glutathione (GSH) levels, impaired complex I activity and inhibition of alpha-ketoglutarate dehydrogenase (alpha-KGDH) in substantia nigra. Thioctic acid exerts antioxidant activity through a thiol-disulphide redox couple and is an essential cofactor for alpha-KGDH. However, it is not known whether or not thioctic acid enters basal ganglia or exerts beneficial effects in Parkinson's disease. As a global measure of altered cerebral function, the effect of R- and S-thioctic acid on 14C-2-deoxyglucose (14C-2DG) incorporation was investigated in rats. Rats were treated with either R- or S-thioctic acid (50 mg/kg IP) or 0.9% saline acutely or for 5 days and 14C-2DG incorporation in basal ganglia was assessed. Following acute administration, R- but not S-thioctic acid caused an overall increase in 14C-2DG incorporation that was significant in both substantia nigra zona compacta and zona reticulata. R-thioctic acid also increased the incorporation of 14C-2DG in the medial forebrain bundle, thalamus, and red nucleus. S-thioctic acid decreased 14C-2DG incorporation in the subthalamic nucleus, but increased it in the red nucleus. Following repeated administration, R-thioctic acid no longer increased 14C-2DG incorporation in either zona compacta or zona reticulata of substantia nigra. However, both R- and S-thioctic acid now decreased 14C-2DG incorporation in the subthalamic nucleus. The data suggest that thioctic acid does enter the brain can alter neuronal activity in areas of the basal ganglia intimately associated with the motor deficits exhibited in Parkinson's disease.

Animals↗
PubMed1996

Toxicity to PC12 cells of isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 1-methyl-4-phenylpyridinium (MPP+) are inhibitors of mitochondrial function and substrates for the dopamine re-uptake system, but their neuronal toxicity is unclear. In this study, the effects of exposing PC12 cells to four isoquinoline derivatives (isoquinoline, N-methylisoquinolinium, 6,7-methylenedioxyisoquinoline and 1,2,3,4-tetrahydroisoquinoline) and MPP+ (100-1000 microM) were examined. All compounds exhibited concentration-dependent toxicity as determined by lactate dehydrogenase release, but none of the isoquinoline derivatives were more toxic than MPP+. Cytotoxicity of these compounds appears to be directly correlated with their substrate affinity for the dopamine reuptake system, but not mitochondrial inhibition. Thus, the low toxicity of isoquinoline derivatives towards PC12 cells suggests that high concentrations of or prolonged exposure to these compounds may be necessary to cause the neurodegenerative changes related to Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗