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Biomedical subjects

C D Marsden

Publications and source records attributed to C D Marsden.

At least 19 recordsLinked to original sources
PubMed2001

Levodopa reversible loss of the Piper frequency oscillation component in Parkinson's disease.

OBJECTIVES: Although Parkinson's disease is typically characterised by bradykinesia, rigidity, and rest tremor, the possibility that two additional motor deficits are manifest during small hand muscle activity was explored-namely, weakness and abnormal physiological tremor. METHODS: A paradigm previously used in normal subjects reliably records the strength, tremor and surface EMG of index finger abducting contractions against a compliant (elastic) resistance. In addition to the well known physiological tremor at around 10 Hz, there are other co existing peak tremor frequencies at around 20 and 40 Hz; the last of these frequencies corresponds to the range of EMG Piper rhythm. The same technique was used to study parkinsonian patients while on and off dopaminergic medication. RESULTS: The maximum strength of finger abduction produced by first dorsal interosseous contraction was considerably lower when patients were off medication (mean (SD) 6.27 (1.49) N when off v 12.33 (3.64) N when on). There was also a marked reduction in the power of Piper frequency finger tremor (p<0.0005) and EMG (p<0.0005) oscillations that did not simply result from weaker contraction. CONCLUSION: As the components of physiological tremor at higher frequencies are thought to derive from CNS oscillations important in motor control, their loss in parkinsonism in association with severe off symptoms may represent an important pathophysiological link between dopaminergic depletion and parkinsonian motor deficits.

Electromyography↗
PubMed2000

Detailed genotyping demonstrates association between the slow acetylator genotype for N-acetyltransferase 2 (NAT2) and familial Parkinson's disease.

In a preliminary report we demonstrated an association between the slow acetylator genotype of N-acetyltransferase 2 (NAT2) and familial cases of Parkinson's disease (FPD). Using a considerably more precise NAT2 typing method, which detects all mutant NAT2 alleles with a frequency of >1% in the white population, we have now retyped all the original patients and control subjects to investigate the reliability of our initial findings. The slow acetylator genotype remained considerably more common among FPD (73%) than normal control subjects (NPC, 43%) or the disease (Huntington's disease [HD]) control group (52%) with an odds ratio (OR) of 3.58 (95% confidence interval (CI): 1.96-6.56; p = 0.00003) for FPD versus NPC and an OR of 2.50 (95% CI: 1.37-4.56, p = 0.003) for FPD versus HD. Furthermore, the wild-type allele 4 conferred a protective effect with an OR of 0.39 (95% CI: 0.23-0.64; p = 0.0025) for FPD versus NPC and an OR of 0.50 (95% CI: 0.30-0.85, p = 0.01) for FPD versus HD. The results of this study support an association between the NAT2 slow acetylator genotype and FPD in our population.

Acetylation↗
PubMed2000

Benign hereditary chorea--entity or syndrome?

The existence of "benign hereditary chorea" (BHC), a rare disorder of childhood-onset familial chorea without other neurologic features or progression, has increasingly been questioned, because many patients with this disorder were subsequently diagnosed with different conditions. We therefore analyzed all published reports of families with BHC and contacted their authors to obtain follow-up information. In addition, we reviewed all patients in whom at least one of the authors had at some stage considered a possible diagnosis of BHC. Of 42 families reported to have BHC in the literature, we obtained follow-up information on 11 families, three of which had been seen by us. An additional seven new, unreported families and four sporadic cases, in which this diagnosis was suspected by at least one of us at one point, were reviewed and videotaped. On reviewing the videotapes of the 11 families in the literature, the diagnosis of BHC was changed in nine. In the remaining two families, atypical features suggesting different diagnoses were present in the original reports. In none of our own previously unreported patients (seven familial and four sporadic) was BHC diagnosed unequivocally by all evaluators after review of their video recordings. In three of these families and all four sporadic patients the diagnosis was changed; in one family multifocal myoclonus could not be differentiated from chorea by any author, and in the remaining three families no consensus between the raters was found. Apart from the 11 families in whom we obtained follow-up information, analysis of the remaining 31 reports on families with BHC also revealed atypical features in the majority. We conclude that BHC is not a diagnosis, but a syndrome that requires further investigation. Whether there is a distinct entity "BHC" with a single gene abnormality remains to be proven.

Adolescent↗
PubMed2000

Disruption of spatial organization and interjoint coordination in Parkinson's disease, progressive supranuclear palsy, and multiple system atrophy.

Patients with basal ganglia diseases may exhibit ideomotor apraxia. To define the nature of the impairment of the action production system, we studied a repetitive gesture of slicing bread by three-dimensional computergraphic analysis in eight nondemented patients with Parkinson's disease in the "on" state, five with progressive supranuclear palsy and four with multiple system atrophy. Two patients with Parkinson's disease and two with progressive supranuclear palsy showed ideomotor apraxia for transitive movements on standard testing. A Selspott II system was used for kinematic analysis of wrist trajectories and angular motions of the shoulder and elbow joints. Patients with Parkinson's disease, progressive supranuclear palsy, and even some with multiple system atrophy exhibited kinematic deficits in the spatial precision of movement and velocity-curvature relationships; in addition, they failed to maintain proper angle/angle relationships and to apportion their relative joint amplitudes normally. Spatial disruption of wrist trajectories was more severe in patients with ideomotor apraxia. We posit that the basal ganglia are part of the parallel parieto-frontal circuits devoted to sensorimotor integration for object-oriented behavior. The severity and characteristics of spatial abnormalities of a transitive movement would therefore depend on the location and distribution of the pathologic process within these circuits.

Aged↗
PubMed2000

Paroxysmal dystonic choreoathetosis: clinical features and investigation of pathophysiology in a large family.

Paroxysmal dystonic choreoathetosis (PDC) is an unusual hyperkinetic movement disorder characterized by attacks of chorea, dystonia, and ballism with onset in childhood. We report a large British family with dominantly inherited PDC linked to chromosome 2q and describe the clinical features in 20 affected family members. Attacks were precipitated by a variety of factors, including caffeine, alcohol, or emotion, and could be relieved by short periods of sleep in most subjects. The clinical features in the family are compared with those of 11 other PDC families in the literature and a core phenotype for PDC suggested. CSF monoamine metabolites measured at baseline and during an attack in one subject were found to increase during the attack. Magnetic resonance spectroscopy of brain and basal ganglia performed both during and between attacks was normal. Positron emission tomography using the D2 receptor ligand, 11C-raclopride, showed no abnormalities.

Adult↗
PubMed2000

Botulinum toxin antibody testing: comparison between the mouse protection assay and the mouse lethality assay.

Conventionally, the standard test for detection of antibodies against botulinum toxin (BT-A) has been the mouse lethality assay (MLA). Because this test has a number of disadvantages, a novel mouse protection assay (MPA) was recently introduced. We sought to compare the results of both tests. Forty-three samples from 38 patients with cervical dystonia and complete or partial subjective BT-A therapy failure underwent simultaneous MPA and MLA testing. Twenty-seven samples showed concordant results in both tests. Eleven of them were MPA- and MLA-positive and 16 MPA- and MLA-negative, resulting in a significant association of the dichotomous test results (Fisher exact test, p <0.01). Sixteen samples showed discordant results. All of those were MPA-positive and MLA-negative. This excess of MPA-positive results was also significant (Wilcoxon signed-rank test, p <0.001). Of the patients with MPA-positive samples, 62% had complete and 38% had partial therapy failure. Of the patients with MLA-positive samples, 90% had complete and 10% had partial therapy failure. MPA and MLA results show significant association. Statistical analysis and predominance of partial therapy failure in MPA-positive patients demonstrate higher sensitivity of MPA. With its methodologic advantages, its test parameter being more relevant to BT-A therapy, and its higher sensitivity, the MPA appears to be superior to the MLA.

Animals↗
PubMed2000

Essential tremor: an overdiagnosed condition?

The diagnosis of essential tremor (ET) and its differentiation from other types of tremor is often difficult. In 1994 Bain et al. defined a classical phenotype by studying 20 patients with pure essential tremor and similarly affected family members in at least three generations. We assessed how many of the patients diagnosed by different neurologists at our institution as having ET conformed to this defined phenotype. We randomly selected 50 patients who were diagnosed with ET by any neurologist at the National Hospital for Neurology and Neurosurgery since the publication of the Bain et al. report, and determined the number of patients who had clinical features compatible with the phenotype that it had defined. Only 25 (50%) of these patients had ET so defined. Ten patients clearly had alternative diagnoses: four had clear additional dystonia, two neuropathic tremor, two had unilateral leg tremor, one drug-induced tremor, and one sudden onset after head trauma. The remaining 15 patients also had atypical features including myoclonus (one), onset in a body part other than the arms (six), sudden onset (two), rest tremor (seven), onset after the age of 65 years (four), a family member with an isolated head tremor (one), or reduced armswing (two). The diagnosis of ET is overused even among experienced neurologists, and other types of tremor should be considered in atypical patients before making this diagnosis.

Adolescent↗
PubMed2000

The timing of primary orthostatic tremor bursts has a task-specific plasticity.

Primary orthostatic tremor is characterized by unsteadiness and shakiness of the legs while standing. It is due to a remarkably strong and regular EMG modulation at approximately 16 Hz that is thought to be of CNS origin. Previous studies have shown that the tremor frequency is the same in all involved muscles and that the time relation between bursts of activity in different muscles may be fixed (e.g. always co-contracting or always contracting in an alternating pattern). Here we have used frequency domain analysis of postural muscle EMG signals in five primary orthostatic tremor patients and in two normal controls to explore the nature of such fixed timing patterns. The timing is found not to relate simply to the relative conduction times for passage of rhythmic bursts from a central oscillation to different muscles. Indeed, although the timing pattern (expressed as phase) of the 16-Hz EMG bursts in different postural muscles remains constant while the subject adopts a certain steady posture, it is different for different subjects and also changes when the same subject adopts a different posture. It seems unlikely that such complex task-dependent timing relations of rhythmic postural muscle activity are due to the primary pathology of primary orthostatic tremor. Instead, we suggest that the abnormally strong peripheral manifestation of a 16-Hz CNS oscillation merely unmasks normal central processes so that the timing patterns may provide a clue to the nature of postural motor control.

Aged↗
PubMed2000

Limb apraxias: higher-order disorders of sensorimotor integration.

Limb apraxia comprises a wide spectrum of higher-order motor disorders that result from acquired brain disease affecting the performance of skilled, learned movements. At present, limb apraxia is primarily classified by the nature of the errors made by the patient and the pathways through which these errors are elicited, based on a two-system model for the organization of action: a conceptual system and a production system. Dysfunction of the former would cause ideational (or conceptual) apraxia, whereas impairment of the latter would induce ideomotor and limb-kinetic apraxia. Currently, it is possible to approach several types of limb apraxia within the framework of our knowledge of the modular organization of the brain. Multiple parallel parietofrontal circuits, devoted to specific sensorimotor transformations, have been described in monkeys: visual and somatosensory transformations for reaching; transformation of information about the location of body parts necessary for the control of movements; somatosensory transformation for posture; visual transformation for grasping; and internal representation of actions. Evidence from anatomical and functional brain imaging studies suggests that the organization of the cortical motor system in humans is based on the same principles. Imitation of postures and movements also seems to be subserved by dedicated neural systems, according to the content of the gesture (meaningful versus meaningless) to be imitated. Damage to these systems would produce different types of ideomotor and limb-kinetic praxic deficits depending on the context in which the movement is performed and the cognitive demands of the action. On the other hand, ideational (or conceptual) apraxia would reflect an inability to select and use objects due to the disruption of normal integration between systems subserving the functional knowledge of actions and those involved in object knowledge.

Apraxia, Ideomotor↗
PubMed2000

Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease.

Five parkinsonian patients were transplanted bilaterally into the putamen and caudate nucleus with human embryonic mesencephalic tissue from between seven and nine donors. To increase graft survival, the lipid peroxidation inhibitor tirilazad mesylate was administered to the tissue before implantation and intravenously to the patients for 3 days thereafter. During the second postoperative year, the mean daily L-dopa dose was reduced by 54% and the UPDRS (Unified Parkinson's Disease Rating Scale) motor score in 'off' phase was reduced by a mean of 40%. At 10-23 months after grafting, PET showed a mean 61% increase of 6-L-[(18)F]fluorodopa uptake in the putamen, and 24% increase in the caudate nucleus, compared with preoperative values. No obvious differences in the pattern of motor recovery were observed between these and other previously studied cases with putamen grafts alone. The amount of mesencephalic tissue implanted in each putamen and caudate nucleus was 42 and 50% lower, respectively, compared with previously transplanted patients from our centre. Despite this reduction in grafted tissue, the magnitudes of symptomatic relief and graft survival were very similar. These findings suggest that tirilazad mesylate may improve survival of grafted dopamine neurons in patients, which is in agreement with observations in experimental animals.

Adult↗
PubMed2000

Physiological and pathological tremors and rhythmic central motor control.

In recent years there has been increasing interest in oscillatory neural activity in the CNS and in the role that such activity may have in motor control. It is thought that physiological tremor may be a manifestation in the periphery of such central oscillatory activity and that some pathological tremors are the result of derangement of these oscillators. This review re-evaluates both early and recent studies on physiological and pathological tremors and other peripheral oscillations in order to gain a new perspective on the nature and function of their central progenitors. This approach, namely using tremor as a 'window' into the function of central oscillations, is particularly suited to human investigations because of the obvious limitations of direct central recording. It is argued that physiological tremor is likely to be multifactorial in origin, with contributions not only from CNS 10-Hz range oscillatory activity, but also from motor unit firing properties, mechanical resonances and reflex loop resonances. Different origins are likely to dominate under different conditions. While some pathological tremors appear to arise as a distortion of central or peripheral components of physiological tremor, others arise de novo, such as the pathological oscillation of 3- to 6-Hz parkinsonian tremor. CNS oscillations outside the 10-Hz range are also found to modulate limb activity in normal individuals, and oscillatory activity exists in other motor systems such as eye movements. Finally, it is shown how studies of peripheral oscillations may help develop hypotheses on the role of CNS oscillations in motor control, including the proposed 'binding' function of synchronized oscillations and the possibility that motor signals could be coded by frequency of modulating oscillation as well as by synaptic connectivity.

Animals↗
PubMed2000

Unilateral lesions of the globus pallidus: report of four patients presenting with focal or segmental dystonia.

OBJECTIVES: To interpret clinical features after unilateral lesions of the globus pallidus on the basis of physiology of the basal ganglia. METHODS: Four patients with unilateral lesions in the globus pallidus (GP) were clinically examined and the literature on patients with pallidal lesions was reviewed. RESULTS: Three patients presented with contralateral dystonia largely confined to one arm in one case and one leg in two cases. One patient had predominant contralateral hemiparkinsonism manifested mainly as micrographia and mild dystonia in one arm. The cause of the lesions was unknown in two patients. In the other two symptoms had developed after head trauma and after anoxia. All lesions involved the internal segment of the GP. Two patients, including the patient with hemiparkinsonism, had additional involvement of the external segment of the GP. In the literature reports on 26 patients with bilateral lesions restricted to the GP only two with unilateral lesions were found. The patients with bilateral pallidal lesions manifested with dystonia, parkinsonism, or abulia. One of the patients with unilateral GP lesions had contralateral hemidystonia, the other contralateral arm tremor. CONCLUSION: These cases emphasise the importance of the GP, particularly its internal segment, in the pathophysiology of dystonia.

Adult↗
PubMed2000

The pedunculopontine nucleus: its role in the genesis of movement disorders.

The pedunculopontine nucleus (PPN) is located in the dorso-lateral part of the ponto-mesencephalic tegmentum. The PPN is composed of two groups of neurons: one containing acetylcholine, and the other containing non-cholinergic neurotransmitters (GABA, glutamate). The PPN is connected reciprocally with the limbic system, the basal ganglia nuclei (globus pallidus, substantia nigra, subthalamic nucleus), and the brainstem reticular formation. The caudally directed corticolimbic-ventral striatal-ventral pallidal-PPN-pontomedullary reticular nuclei-spinal cord pathway seems to be involved in the initiation, acceleration, deceleration, and termination of locomotion. This pathway is under the control of the deep cerebellar and basal ganglia nuclei at the level of the PPN, particularly via potent inputs from the medial globus pallidus, substantia nigra pars reticulata and subthalamic nucleus. The PPN sends profuse ascending cholinergic efferent fibers to almost all the thalamic nuclei, to mediate phasic events in rapid-eye-movement sleep. Experimental evidence suggests that the PPN, along with other brain stem nuclei, is also involved in anti-nociception and startle reactions. In idiopathic Parkinson's disease (IPD) and parkinson plus syndrome, overactive pallidal and nigral inhibitory inputs to the PPN may cause sequential occurrences of PPN hypofunction, decreased excitatory PPN input to the substantia nigra, and aggravation of striatal dopamine deficiency. In addition, neuronal loss in the PPN itself may cause dopamine-resistant parkinsonian deficits, including gait disorders, postural instability and sleep disturbances. In patients with IPD, such deficits may improve after posteroventral pallidotomy, but not after thalamotomy. One of the possible explanations for such differences is that dopamine-resistant parkinsonian deficits are mediated to the PPN by the descending pallido-PPN inhibitory fibers, which leave the pallido-thalamic pathways before they reach the thalamic targets.

Animals↗
PubMed1999

Expression and localisation of CYP2D enzymes in rat basal ganglia.

P450 enzymes in the CYP2D subfamily have been suggested to contribute to the susceptibility of individuals in developing Parkinson's disease. We have used specific anti-peptide antisera and peroxidase immunohistochemistry to investigate the expression of CYP2D enzymes in the rat brain and some possible factors that may affect their regulation. In male Wistar rats, CYP2D1 was not detected in the basal ganglia or in any other brain region. CYP2D2 was weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gyrus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from the basal ganglia, although moderate amounts of CYP2D3 were detected within fibres of the oculomotor root, and very low levels of CYP2D4 were present in white matter tracts. In contrast, CYP2D5 was extensively expressed in the basal ganglia, including neurones in the subthalamic nucleus, substantia nigra and interpeduncular nucleus, as well as other areas of the brain, including the ventral tegmental area, piriform cortex, hippocampus, dentate gyrus, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesioning of the nigro-striatal tract to cause almost a complete loss of tyrosine hydroxylase containing neurones in the substantia nigra, also reduced the number of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expressed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar rats had no effect on the number of CYP2D5-positive neurones in the substantia nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the midbrain was similar to that of Wistar rats; furthermore, there was no difference in expression or distribution between male and female rats. In contrast to naive rats, extensive expression of CYP2D4 was found throughout the basal ganglia and in other brain nuclei in Wistar rats treated with not only clozapine, but also saline, suggesting that CYP2D4 may be induced as a result of mild stress. The function of CYP2D enzymes in the brain remains unknown, but their selective localisation suggests a physiological role in neuronal activity and in adaptation to abnormal situations.

Animals↗
PubMed1999

Common 3 and 10 Hz oscillations modulate human eye and finger movements while they simultaneously track a visual target.

1. A 10 Hz range centrally originating oscillation has been found to modulate slow finger movements and anticipatory smooth eye movements. To determine if an interaction or linkage occurs between these two central oscillations during combined visuo-manual tracking, frequency and coherence analysis were performed on finger and eye movements while they simultaneously tracked a visual target moving in intermittently visible sinusoidal patterns. 2. Two different frequencies of common or linked oscillation were found. The first, at 2-3 Hz, was dependent on visual feedback of target and finger tracking positions. The second, at around 10 Hz, still occurred when both target and finger positions were largely obscured, indicating that this common oscillation was generated internally by the motor system independent of visual feedback. Both 3 and 10 Hz oscillation frequencies were also shared by the right and left fingers if subjects used these together to track a visual target. 3. The linking of the 10 Hz range oscillations between the eyes and finger was task specific; it never occurred when eye and finger movements were made simultaneously and independently, but only when they moved simultaneously and followed the target together. However, although specific for tracking by the eyes and fingers together, the linking behaviour did not appear to be a prerequisite for such tracking, since significant coherence in the 10 Hz range was only present in a proportion of trials where these combined movements were made. 4. The experiments show that common oscillations may modulate anatomically very distinct structures, indicating that single central oscillations may have a widespread distribution in the central nervous system. The task-specific manifestation of the common oscillation in the eye and finger suggests that such mechanisms may have a functional role in hand-eye co-ordination.

Adult↗
PubMed1999

The vulnerability of nigral neurons to Parkinson's disease is unrelated to their intrinsic capacity for dopamine synthesis: an in situ hybridization study.

The contribution of the dopamine-synthetic capacity of nigral neuronal subregions to their vulnerability to degeneration in idiopathic Parkinson's disease (IPD) was explored using semiquantitative in situ hybridization to study expression of mRNA encoding the rate-limiting dopamine synthetic enzyme, tyrosine hydroxylase (TH). Expression of mRNA, the structural protein, beta-tubulin, and the glycolytic enzyme, fructose-1,6, biphosphate aldolase (aldolase C) was studied in parallel in individual neurons of the substantia nigra pars compacta (SNc) in matched groups of IPD and control subjects. TH mRNA expression was found to be heterogeneously expressed in nigral neurons in control and IPD subjects. There was no significant difference in mean values for TH mRNA expression between control and IPD cases and none between nigral subregions, either in control subjects or in established IPD subjects in this study, but there was evidence for a selective upregulation of TH mRNA expression in non-melanized neurons in IPD. There was no relationship between TH mRNA expression disease duration or L-dopa dosage in the IPD group. Mean TH mRNA values for two additional 40-year-old control subjects fell within the range of values of the aged-control group. Aldolase C and beta-tubulin expression did not differ between control and IPD groups or between nigral subregions. These findings suggest that regulation of dopamine synthesis at the level of the cell body does not play a part in determining the pattern of nigral cell vulnerability in IPD. The heterogeneous pattern of TH synthesis was not age-dependent and may be of physiological significance in nigral function. There was no evidence for compensatory upregulation of TH synthesis in surviving melanized neurons in IPD but non-melanized neurons may be involved in this process. Surviving nigral neurons in IPD appear to retain the capacity for normal aldolase C and beta-tubulin peptide synthesis. Long-term L-dopa treatment does not appear to compromise normal function of nigral dopaminergic neurons.

Aged↗