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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 343 records · Page 19Linked to original sources
PubMed1992

Brain muscarinic cholinergic receptors in Huntington's disease.

Muscarinic cholinergic receptors and choline acetyltransferase (ChAT) activity were studied in postmortem brain tissue from patients with Huntington's disease and matched control subjects. In comparison with controls, reductions in ChAT activity were found in the hippocampus, but not in the temporal cortex in Huntington's disease. Patients with Huntington's disease showed reduced densities of the total number of muscarinic receptors and of M-2 receptors in the hippocampus while the density of M-1 receptors was unaltered. Muscarinic receptor binding was unchanged in the temporal cortex. These results indicate a degeneration in Huntington's disease of the septo-hippocampal cholinergic pathway, but no impairment of the innominato-cortical cholinergic system.

Brain Chemistry↗
PubMed1992

L-dopa withdrawal in Parkinson's disease selectively impairs cognitive performance in tests sensitive to frontal lobe dysfunction.

A group of ten patients with idiopathic Parkinson's disease (PD) was tested on a series of automated tests of learning, memory, planning and attention whilst either on or off L-dopa medication. Controlled withdrawal of L-dopa interfered with aspects of performance on three of the tests that had previously been shown to be sensitive to frontal lobe dysfunction; a spatial working memory task, the Tower of London planning test, and a visual discrimination paradigm that also included intra- and extra-dimensional shift tests of selective attention. More specifically, errors were increased in the spatial working memory test, and both the accuracy and latency of thinking were impaired. Thinking time was significantly slowed following L-dopa withdrawal, even though the possible contaminating effects on motor slowing were fully controlled by a yoked control procedure. Nine out of ten patients reached a further stage of the visual discrimination, set-shifting paradigm when on, rather than off, L-dopa medication. Spatial span was also impaired off medication, but there were no effects of L-dopa withdrawal on tests of pattern and spatial recognition memory, simultaneous and delayed matching to sample or visuospatial conditional associative learning. Comparisons with a large control group confirmed previous findings that PD is associated with deficits on the majority of these tests. The results are discussed in terms of the fronto-striatal, dopamine dependent nature of some of the cognitive deficits found in PD, but the apparent dopamine-independent nature of deficits in other aspects of cognitive functioning, notably in tests of visual recognition memory and associative learning.

Brain Diseases↗
PubMed1992

Motor activity following the administration of selective D-1 and D-2 dopaminergic drugs to MPTP-treated common marmosets.

The ability of selective D-1 agonist and antagonist drugs to alter motor deficits and locomotor activity was studied in MPTP-treated common marmosets. Both the D-2 agonist quinpirole and the mixed D-1/D-2 agonist apomorphine reversed the motor impairments and induced locomotor activity. The D-1 antagonist SCH 23390 and the D-2 antagonist raclopride given alone further reduced motor function in MPTP-treated animals. The actions of quinpirole were potently and completely inhibited by raclopride but only partially and inconsistently by SCH 23390. In contrast, the effects of apomorphine were markedly but incompletely inhibited by both raclopride and SCH 23390. The D-1 agonist SKF 38393 alone caused a dose related reduction in motor activity. SKF 38393 weakly and partially inhibited the improvements in motor function produced by quinpirole but had a more pronounced effect on apomorphine induced motor activity. The induction of motor activity in MPTP treated common marmosets may separately involve both D-1 and D-2 receptors. Comparison with our previous data on the effect of the same drugs in normal common marmosets provides some evidence for a breakdown of linkage between D-1 and D-2 systems following MPTP treatment. The actions of SKF 38393 in MPTP-treated common marmosets contrasts with its ability to induce behavioural activation and a facilitation of D-2 mediated behaviour in rodents. SKF 38393 may not be the compound with which to delineate the role of D-1 receptors in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1992

Motor function, graft survival and gliosis in rats with 6-OHDA lesions and foetal ventral mesencephalic grafts chronically treated with L-dopa and carbidopa.

In rats with a unilateral 6-OHDA lesion of the nigrostriatal pathway, foetal ventral mesencephalic grafts implanted into the 6-OHDA-lesioned striatum produced a reduction in apomorphine-induced contralateral rotation, and complete abolition of (+)-amphetamine-induced ipsilateral rotation. The graft-induced reduction of apomorphine and (+)-amphetamine-induced rotation was not affected by chronic 27 week administration of L-DOPA and carbidopa to rats receiving foetal grafts. TH-immunohistochemistry revealed greater than 96% loss of dopamine cells in the substantia nigra ipsilateral to the 6-OHDA lesion in all animals, but cell loss in the ipsilateral ventral tegmental area was more variable (21-46% of the intact side). TH-positive cells in the intact substantia nigra and ventral tegmental area were not affected by chronic treatment with L-DOPA and carbidopa. In the lesioned striatum of rats receiving sham grafts, no TH-positive cells or fibres were seen. In the 6-OHDA-lesioned striatum of animals receiving foetal grafts, many TH-positive cells were seen in the grafts and chronic treatment with L-DOPA and carbidopa did not reduce cell survival. GFA-P immunohistochemistry revealed that a unilateral 6-OHDA lesion followed by a sham graft was not associated with a reactive gliosis reaction in the striatum at the time of study (38 weeks after lesion surgery and 30 weeks after sham-graft), and treatment of such rats with L-DOPA and carbidopa was also without effect on glia. In contrast there was a marked gliosis in the striatum surrounding foetal grafts which was unaffected by chronic treatment with L-DOPA and carbidopa. The grafts themselves were surrounded by a rim of glial cells, and the glial density within the grafts was higher in animals receiving chronic L-DOPA and carbidopa treatment. However, there was no obvious relationship between the number of TH-positive cells within the grafts, or graft volume, and glial cell density within the grafts. These results suggest that long-term treatment with L-DOPA and carbidopa does not impair either the behavioural recovery produced by foetal ventral mesencephalic grafts in rats or the long-term survival of grafts as revealed by TH-immunohistochemistry. The presence of a foetal graft is associated with a reactive gliosis in the implanted striatum, which was not altered by long-term treatment with L-DOPA and carbidopa. However such treatment did result in an increase in glial density within the grafts themselves.

Animals↗
PubMed1992

Cognitive performance in multiple system atrophy.

The cognitive performance of a group of patients with multiple system atrophy (MSA) of striato-nigral predominance was compared with that of age and IQ matched control subjects, using three tests sensitive to frontal lobe dysfunction and a battery sensitive to memory and learning deficits in Parkinson's disease and dementia of the Alzheimer type. The MSA group showed significant deficits in all three of the tests previously shown to be sensitive to frontal lobe dysfunction. Thus, a significant proportion of patients from the MSA group failed an attentional set-shifting test, specifically at the stage when an extra-dimensional shift was required. They were also impaired in a subject-ordered test of spatial working memory. The MSA group showed deficits mostly confined to measures of speed of thinking, rather than accuracy, on the Tower of London task. These deficits were seen in the absence of consistent impairments in language or visual perception. Moreover, the MSA group showed no significant deficits in tests of spatial and pattern recognition previously shown to be sensitive to patients early in the course of probable Alzheimer's disease and only a few patients exhibited impairment on the Warrington Recognition Memory Test. There were impairments on other tests of visual memory and learning relative to matched controls, but these could not easily be related to fundamental deficits of memory or learning. Thus, on a matching-to-sample task the patients were impaired at simultaneous but not delayed matching to sample, whereas difficulties in a pattern-location learning task were more evident at its initial, easier stages. The MSA group showed no consistent evidence of intellectual deterioration as assessed from their performance on subtests of the Wechsler Adult Intelligence Scale (WAIS) and the National Adult Reading Test (NART). Consideration of individual cases showed that there was some heterogeneity in the pattern of deficits in the MSA group, with one patient showing no impairment, even in the face of considerable physical disability. The results show a distinctive pattern of cognitive deficits, unlike those previously seen using the same tests in patients with Parkinson's and Alzheimer's diseases, and suggesting a prominent frontal-lobe-like component. The implications for concepts of 'subcortical' dementia and 'fronto-striatal' cognitive dysfunction are considered.

Adult↗
PubMed1992

Brain, skeletal muscle and platelet homogenate mitochondrial function in Parkinson's disease.

The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with idiopathic Parkinson's disease has provided new understanding into the possible mechanisms that may underlie this neurodegenerative disorder. The biochemical defect is identical to that induced in humans, primates and mice exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We have studied mitochondrial respiratory chain function in various brain regions, in skeletal muscle and in blood platelets from patients with idiopathic Parkinson's disease and from matched controls. We provide evidence suggesting that the complex I deficiency in Parkinson's disease is limited to the brain and that this defect is specific for the substantia nigra. The tissue specificity of the complex I deficiency in Parkinson's disease and its localization to the substantia nigra support the proposition that complex I deficiency may be directly involved in the cause of dopaminergic cell death in Parkinson's disease. An understanding of the molecular basis of this biochemical defect will provide valuable insight into the cause of Parkinson's disease. Our findings of normal mitochondrial function in platelet homogenates suggests that this tissue cannot be used to develop a 'diagnostic test' for Parkinson's disease.

Aged↗
PubMed1992

Simple and choice reaction time and the use of advance information for motor preparation in Parkinson's disease.

The effects of different types of advance information (warning signal, temporal cue, movement parameter cue), presented at different intervals before an imperative stimulus on reaction time (RT) were examined. Sixteen patients with Parkinson's disease and 16 age-matched normal controls performed a simple reaction time (SRT) task, an uncued, two partially cued (cueing of direction of movement or hand) and a fully cued visual four choice reaction time (CRT) tasks. An S1-S2 paradigm was used, where a warning signal/precue (S1) preceded the imperative signal (S2) by 0 (uncued and unwarned conditions), 200 ms, 800 ms, 1600 ms or 3200 ms. When the unwarned SRT and uncued CRT conditions were compared, the patients were slower than the controls in both conditions, with the group differences being larger for the CRT than the SRT task. Both patients and controls benefited from a warning signal presented before the imperative stimulus (S2), especially when it occurred 200 ms prior to S2. Advance information about the parameters of the required response was used by both patients and controls to preprogramme responses before the onset of S2. In both groups, RTs were generally faster for longer S1-S2 intervals. With an S1-S2 interval of 3200 ms, advance information about two movement parameters was 'fully' used by the patients to preprogramme responses such that their fully cued CRT was reduced to the level of SRT. In the controls, this process was complete by 800 ms. The most parsimonious explanation of the pattern of results across the SRT, fully cued CRT and uncued CRT conditions would be in terms of a slowness in response initiation in Parkinson's disease, which is a stage of processing common to all RT conditions. Deficits at one or more of the stages of processing unique to CRT are, however, necessary to explain the differentially greater slowness of uncued CRT in Parkinson's disease.

Aged↗
PubMed1992

The auditory startle response in the Steele-Richardson-Olszewski syndrome and Parkinson's disease.

The startle response to an unexpected auditory stimulus was studied in eight patients with a clinical diagnosis of the Steele-Richardson-Olszewski syndrome (SRO), 11 patients with idiopathic Parkinson's disease (PD) and 12 normal subjects. The patients with PD were studied 'on' at the time of maximal effect of their treatment; five of these patients were also studied in their 'off' state without treatment. The auditory startle response was absent in three patients with SRO: in the remaining five the latency to onset of earliest electromyography activity (EMG) of the auditory startle response was delayed and few muscles (orbicularis oculi, sternocleidomastoid and rectus abdominis) were recruited in the response. In PD the auditory startle response was similar to that recorded in normal subjects, both in terms of the pattern of muscles recruited and the amplitude of the EMG responses, but the latency of responses in orbicularis oculi and sternocleidomastoid muscles were significantly delayed. This result was not influenced by treatment with L-dopa. In patients with SRO the finding of an abnormal startle response is consistent with loss of neurons in the lower pontine reticular formation. This region is intimately involved in the startle response in animal studies. In patients with PD the late auditory startle response might be related to withdrawal of facilitatory input to brainstem centres and reticulospinal pathways from basal ganglia. The similarity of the responses in patients when 'on' and 'off' suggests these pathways are not under potent dopaminergic control.

Adult↗
PubMed1992

Fronto-striatal cognitive deficits at different stages of Parkinson's disease.

Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the 'Tower of London' test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and 'early in the course' of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage. These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's disease.

Aged↗
PubMed1992

Debrisoquine hydroxylation in Parkinson's disease.

Debrisoquine (DBQ) metabolism was studied in 80 Parkinson's disease (PD) patients, 26 of whom had young onset Parkinson's disease (YOPD), and in 143 controls. There was no significant difference between the proportion of poor metabolisers of DBQ among YOPD patients compared either to other parkinsonians, or to controls. Nor was there a significant correlation between the age of disease onset and DBQ metabolic ratio (MR). The results do not support the suggestion that impairment of DBQ metabolism (and hence cytochrome P450) is a primary defect in YOPD. However, in comparison with controls, MR values were modestly but significantly higher in PD patients, even in those not treated with drugs known to affect DBQ metabolism.

Adolescent↗
PubMed1992

Effect of digital nerve stimuli on responses to electrical or magnetic stimulation of the human brain.

1. Reflexes were elicited in the first dorsal interosseous muscle of seven normal subjects by electrical stimulation of the digital nerves of the index finger at 3 times perceptual threshold while subjects maintained a constant voluntary contraction of the muscle. The average response in the surface-rectified electromyogram (EMG) consisted of an early inhibitory (I1) component followed by a later excitation (E2). 2. Low intensity anodal electrical or magnetic scalp stimuli were given over the motor cortex in order to elicit muscle responses within the period of the I1 and E2 reflex components. 3. Compared with control responses elicited in the absence of digital nerve stimulation, responses to electrical cortex stimulation were suppressed in the I1 period and facilitated during the E2 period of the reflex. In contrast, responses evoked by magnetic stimulation were suppressed during I1 and also for the first 10 ms or so of the E2 response. Magnetically evoked responses were facilitated during the later part of the E2 reflex. 4. Similar effects were seen when the probability of firing of single motor units was studied. 5. In three subjects, small taps were given to the abducted index finger in order to stretch the first dorsal interosseous muscle and evoke reflexes which were of comparable size to the E2 reflex evoked by digital nerve stimulation. In contrast to the experiments in which digital nerve stimuli were given, responses evoked by magnetic stimulation over motor cortex were facilitated at all times during the course of the reflex evoked when the muscle was stretched. 6. We conclude that single electrical stimuli applied to the digital nerves can reduce for a short period the excitability of motor cortex to magnetic stimulation. This occurs at a time when the same stimulus is evoking an excitatory (E2) reflex in the average surface-rectified EMG.

Adult↗
PubMed1992

Interhemispheric inhibition of the human motor cortex.

1. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus over the motor cortex of one hemisphere on the size of EMG responses evoked in the first dorsal interosseous (FDI) muscle by a magnetic test stimulus given over the opposite hemisphere. 2. A single conditioning shock to one hemisphere produced inhibition of the test response evoked from the opposite hemisphere when the conditioning-test interval was 5-6 ms or longer. We shall refer to this as interhemispheric inhibition. However, the minimum latency of inhibition observed using surface EMG responses may have underestimated the true interhemispheric conduction time. Single motor unit studies suggested values 4-7 ms longer than the minimum interval observed with surface EMG. 3. Interhemispheric inhibition was seen when the test muscle was active or relaxed. Increasing the intensity of the conditioning stimulus increased the duration of inhibition: increasing the intensity of the test stimulus reduced the depth of inhibition. 4. The conditioning coil had to be placed on the appropriate area of scalp for inhibition to occur. The effect of the conditioning stimulus was maximal when it was applied over the hand area of motor cortex, and decreased when the stimulus was moved medial or lateral to that point. 5. The inhibitory effect on the test stimulus probably occurred at the level of the cerebral cortex. In contrast to the inhibition of test responses evoked by magnetic test stimuli, test responses evoked in active FDI by a small anodal electric shock were not significantly inhibited by a contralateral magnetic conditioning stimulus. Similarly, H reflexes in relaxed forearm flexor muscles were unaffected by conditioning stimuli to the ipsilateral hemisphere. However, inhibition was observed if the experiment was repeated with the muscles active.

Adult↗
PubMed1992

"Isolated" postinfectious myoclonus.

Two cases are reported who developed myoclonus as the only manifestation of a post-infectious syndrome without evidence of encephalitis or the opsoclonus-myoclonus syndrome. Case 1 had generalised myoclonus following an influenza-like illness, while case 2 had right upper limb segmental myoclonus following uncomplicated chicken pox. Neither had any localising neurological signs or abnormality on investigation. Both recovered completely within six months of the onset. Similar cases are reviewed from the literature and it is suggested that such cases be called "isolated" post-infectious myoclonus.

Adolescent↗
PubMed1992

The effect of withdrawal of dopaminergic medication on simple and choice reaction time and the use of advance information in Parkinson's disease.

Eight patients with Parkinson's disease performed simple reaction time (SRT), uncued, partially and fully cued four choice (CRT) tasks. They were tested on two occasions; on their normal dose of dopaminergic medication and following withdrawal of such medication for an average of 14.4 hours. Disability as rated on the Webster scale was greater in the drug reduced state. Although RTs were generally slower when tested in the drug reduced state than when on medication, few differences emerged. Withdrawal of dopaminergic medication had no effect on unwarned SRT and unwarned and uncued CRT performance. Both on and off medication, the patients benefited from a warning signal presented before the imperative stimulus. In both medication states, the speeding up of RT was greatest with a warning signal presented 200 ms before S2. When the imperative stimulus was unwarned, the temporal predictability of its occurrence speeded RT more when on medication than when off. Advance movement parameter information was used by patients to pre-programme responses both on and off medication. In both medication states, the fully cued CRT was the same as SRT only with the 3200 ms S1-S2 interval. Medication state had no effect on movement time or the number of errors. It is suggested that slowness in motor readiness and motor programming may not be specific to striatal dopamine deficiency but rather a nonspecific concomitant of brain damage.

Adult↗
PubMed1992

Psychological functioning before and after treatment of torticollis with botulinum toxin.

The impact of botulinum toxin injection on psychological function was assessed in 26 patients with idiopathic torticollis. Eighty five per cent of the patients and 88% of the relatives considered torticollis to be better following the injections. Symptomatic improvement with the injections was associated with significant reduction of depression and disability, but non-significant improvement in body concept, and self-esteem. This concordant pattern of change in symptoms and psychological function with the injections supports the proposal that in torticollis depression and disability are consequences of the postural abnormality of the head.

Adult↗
PubMed1992

Effect of practice on performance of a skilled motor task in patients with Parkinson's disease.

Parkinson's disease leads to a breakdown in the execution of highly practised, skilled movements such as walking and handwriting. The improved execution of skilled movements with practice can be understood as a process of schema learning, the determining of the relevant parameters of the specific movement. The ability of patients with Parkinson's disease and age matched normal control subjects to improve their performance, with practice, on a skilled motor task, doing up buttons, was assessed. The task was assessed on its own and with simultaneous foot tapping. Both groups showed an initial improvement in the task on its own and deterioration in performance when buttoning with foot tapping. The amount of interference, however, decreased with practice, particularly in the patients with a 2 Hz tapping rate. The results suggest that patients with Parkinson's disease are capable of schema learning but require more practice than control subjects to achieve comparable levels of performance. This may be a reflection of the fundamental motor dysfunction of the disease rather than a specific learning deficit.

Adult↗
PubMed1992

Parkinson's disease in twins studied with 18F-dopa and positron emission tomography.

We used 18F-dopa PET to examine concordance for dysfunction of the nigrostriatal dopaminergic system in 18 co-twins of patients with Parkinson's disease (PD) and scanned one clinically concordant monozygotic (MZ) twin pair, 17 asymptomatic co-twins (10 MZ, 7 dizygotic [DZ]), and 13 twins with PD (8 MZ, 5 DZ). Mean 18F-dopa uptake of the twins with PD was significantly reduced in putamen to 38% and in caudate to 66% of normal. Mean putamen 18F-dopa uptake for the 17 asymptomatic co-twins was also significantly reduced (86% of normal), as was putamen tracer uptake for the 10 MZ (87% of normal) and seven DZ (83% of normal) asymptomatic co-twin subgroups. Four of 10 MZ and two of seven DZ asymptomatic co-twins had putamen 18F-dopa uptake reduced more than 2 SDs below the normal mean. Three of these four asymptomatic MZ co-twins had tremor on examination at the time of PET and one has now developed PD 2 years later. Our PET findings give concordances for nigral dysfunction of 45% in the MZ pairs and 29% in the DZ pairs at a 2-SD threshold, and 18% in MZ and 0% in DZ pairs at a 3-SD threshold of significance. These data suggest that the concordance for nigral pathology in PD twins may be higher than previously realized and that the presence of an isolated postural or rest tremor may be a phenotypic expression of PD.

Adult↗