Transplanted allogeneic fetal dopamine neurons survive and improve motor function in idiopathic Parkinson's disease.
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Abortion, Spontaneous↗
Biomedical subjects
C D Marsden
Publications and source records attributed to C D Marsden.
Axial myoclonus of propriospinal origin.
Three patients are described with nonrhythmic repetitive axial myoclonic jerks causing symmetric flexion of the neck, trunk, hips and knees. No electrophysiological evidence of a cortical or brainstem reticular origin for the myoclonus was found. In the first patient the axial jerks only occurred spontaneously. The latencies of recruitment of spinal segments during a jerk indicated that the discharge arose in the mid thoracic cord and then slowly spread at about 5 ms-1 up and down the cord to involve rostral and caudal segments. No structural lesion was identified in this patient. In the second patient spontaneous and reflex axial jerks developed following the excision of a cervical haemangioblastoma. In the stimulus-induced jerks the relative latencies of muscles innervated by rostral and caudal spinal segments suggested that the myoclonus originated between the upper cervical and midthoracic cord. In the final patient, EMG activity during spontaneous and stimulus-induced jerks commenced in the rectus abdominis, and was followed by later activity in muscles innervated by rostral spinal segments, suggesting that the myoclonus originated in the midthoracic cord. No structural lesion was identified in this patient. Electrophysiological evidence is used to argue a spinal origin for these axial jerks in all 3 cases. There are striking features common both to this form of human myoclonus and to long propriospinal pathways identified in animals. The new concept of propriospinal myoclonus is suggested.
Adult↗
Dual task performance and processing resources in normal subjects and patients with Parkinson's disease.
In recent years, there has been a growing consensus among investigators that the presence or absence of external cues guiding behaviour and attention is an important factor in determining whether or not deficits are found in patients with Parkinson's disease (PD). In an earlier study, the authors suggested that the pattern of impaired and intact performance could be explained in terms of differential resource demands of the tasks, combined with depleted levels of central processing resources in PD patients. Two experiments are reported, both employing dual-task paradigms. The first assessed, in normal subjects, the relative processing demands of a cued and an uncued version of the Stroop task. The results supported the proposal that the noncued task made greater demands on the subject's limited processing resources. Further, performing a resource demanding secondary task concurrently with the Stroop test produced, in normal subjects, the same pattern of impaired performance as that reported previously in PD patients. In the second experiment the same dual-task paradigm was employed with a group of PD patients and normal aged-matched controls. Only the patients showed an increase in reaction time on the Stroop task when performing a resource demanding secondary task. The patients also showed an interfering effect with concurrent foot tapping but not with an articulatory suppression task. The results were taken to support the hypothesis that PD patients have depleted central processing resources. In considering the present data, alternative explanations for the results are considered, in particular the possibility that they represent a deficit in switching processing resources between two tasks as the combined demands outweigh available resources.
Adult↗
Preliminary report: activation of the cerebellum in essential tremor.
Several images of cerebral blood flow were recorded during inhalation of carbon-15-labelled carbon dioxide by positron emission tomography in four patients with essential tremor and four normal controls. Unilateral involuntary postural tremor in essential tremor patients was associated with blood flow significantly greater than that at rest in the contralateral sensorimotor cortex, both lateral premotor regions, and both cerebellar hemispheres. Of these regions, only the cerebellum was not activated in normal controls holding a posture without tremor or in essential tremor patients undergoing passive wrist movement. The increased flow in the cerebellum therefore seems to represent neural activity involved in tremor generation. It is proposed that essential tremor is due to oscillation within cerebello-olivary pathways, relayed by way of the thalamus and motor cortex to the spinal cord.
Administration, Inhalation↗
1-Methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) is less neurotoxic than MPTP in the common marmoset.
Four adult marmosets were treated with increasing doses of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in the range 0.23-4.3 mg/kg i.p. to give a cumulative dose of 11.0-11.6 mg/kg over a 6-10 day period. After 4 days of treatment, and as the dosage was gradually increased, the animals exhibited mild motor deficits. These abnormalities slowly declined over the following 1-6 week period. In contrast, similar treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 3-5 days in a cumulative dose of 6.9-9.2 mg/kg produced gross impairment of motor function which persisted throughout the 5 weeks period of observation. Administration of 2'-methyl-MPTP for 6-10 days caused some decrease in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) content in the caudate nucleus in animals 5-6 weeks after the start of treatment. There was a small decrease in [3H]dopamine uptake into putamen synaptosomes. This contrasted with the marked decreases in all these parameters observed after MPTP treatment of common marmosets. Histological examination of the substantia nigra from the four animals treated with 2'-methyl-MPTP did not show degeneration or loss of dopamine-containing cell bodies in the zona compacta. In contrast, MPTP caused severe destruction of these pigmented nigral neurones. In the common marmoset 2'-methyl-MPTP does not appear to show the same neurotoxic action as MPTP itself. This contrasts with findings in the mouse where 2'-methyl-MPTP is more toxic to dopamine-containing cells of substantia nigra than MPTP.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Parkinson's disease.
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1-Methyl-4-phenylpyridinium↗
Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease.
Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.
Brain↗
Lack of change in striatal DARPP-32 levels following nigrostriatal dopaminergic lesions in animals and in parkinsonian syndromes in man.
The present study was performed to determine the effect of a nearly complete nigrostriatal dopaminergic denervation on DARPP-32 levels in the striatum from animals and parkinsonian patients. DARPP-32 levels were estimated by in vitro phosphorylation in the presence of cAMP, or after inactivation of endogenous kinases and phosphatases, in the presence of the catalytic subunit of cAMP-dependent protein kinase. Intranigral 6-hydroxydopamine (6-OHDA) infusion in rats, or peripheral administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to common marmosets, did not change striatal DARPP-32 levels. Postmortem studies, carried out on brains obtained shortly after death, from patients with Parkinson disease, or from patients with progressive supranuclear palsy, showed that the levels of striatal DARPP-32 were not different from controls. These results indicate that dopaminergic striatal denervation did not modify the amount of DARPP-32 in the striatum, suggesting that the expression of DARPP-32, a protein which mediates some of the effects of dopamine in striatal neurons, is independent from the dopaminergic innervation.
Aged↗
Sleep spindles in torsion dystonia.
Quantitative analysis of overnight sleep spindles was performed in 14 patients with primary generalized torsion dystonia, 10 patients with secondary torsion dystonia, 10 normal subjects, and 39 patients with other neurological disorders. Only 4 patients with torsion dystonia had increased numbers of sleep spindles, and only one of these had sleep spindles of an abnormal amplitude or duration. Sleep spindle abnormalities do not appear to be common in torsion dystonia, and are unlikely to be of pathophysiological significance in this condition.
Adolescent↗
The blink reflex in patients with idiopathic torsion dystonia.
The blink reflex and its recovery cycle were examined in 57 patients with idiopathic dystonia affecting different parts of the body. The group comprised 9 patients with generalized and 15 with segmental forms, 19 with torticollis, and 14 with focal arm dystonia. None had blepharospasm. The duration and amplitude of the R2 component of the blink reflex showed only minor changes. However, its recovery cycle to paired supraorbital nerve stimuli was abnormal in all groups of patients, except those with focal arm dystonia. These findings may be interpreted as showing abnormal control of the interneuronal networks mediating the blink reflex in patients with dystonia affecting sites other than the facial muscles. The fact that the principal changes were seen in patients with torticollis, and generalized or segmental dystonia, suggests that the extent of dystonia (rather than the severity) and, therefore, the close proximity to the cranial muscles was important in determining the extent of the abnormal interneuron function.
Arm↗
Natural history of adult-onset idiopathic torticollis.
The rates of spontaneous remission and progression of dystonia to other sites were studied in 72 patients who first presented with adult-onset torticollis, and who were followed up for a mean of 7.7 years. Dystonia had progressed to sites other than the neck (mainly the face and upper limbs) in 23 patients (32%). The latter cases were not differentiated from those with isolated torticollis in terms of any of the demographic or clinical features studied, although they tended to have suffered from torticollis longer. Fifteen patients (20.8%) had experienced a spontaneous remission of their torticollis, which was sustained for a median period of 3 years in 9 cases (12.5%). Eighty-seven percent of the 15 remissions had occurred during the first 5 years of the illness. In the 9 cases with sustained remission, the duration of torticollis before spontaneous remission was significantly longer and remission had mostly occurred after 2 years of illness compared with the 6 who had relapsed. The 15 cases with spontaneous remission tended to have an earlier age of onset compared with those with no remission. Sixty-five percent of cases were correctly classified on the basis of age at onset, which emerged as the only salient variable in the discrimination of the 15 patients with spontaneous remission from the 57 without spontaneous remission. Age at onset, form of torticollis, gender, and direction of head deviation resulted in a correct classification rate of 70%, in the discrimination of the 9 cases with sustained remission from those with no remission.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Progressive myoclonic ataxia (the Ramsay Hunt syndrome).
It has been suggested from studies of patients with progressive myoclonus epilepsy that the term Ramsay Hunt syndrome should be abandoned, as its use has led to nosologic confusion, and because, in the light of modern diagnostic techniques, the majority of cases can be allocated to specific disease categories, chiefly, Unverricht-Lundborg disease (Baltic myoclonus) and mitochondrial encephalomyopathy. Review of 30 cases of this syndrome, defined as progressive ataxia and myoclonus and infrequent seizures in the absence of dementia, showed that a clinical or biochemically supported diagnosis could not be made in 43%. This low diagnostic yield probably reflects differences in ascertainment of patients; those described here were referred with a syndrome of progressive myoclonic ataxia (the Ramsay Hunt syndrome) rather than progressive myoclonus epilepsy. These two syndromes share common causes, but a smaller proportion of patients with progressive myoclonic ataxia can currently be diagnosed precisely during life.
Adolescent↗
The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease.
A group of healthy control subjects and patients with Parkinson's disease were investigated using positron emission tomography and two tracers as indicators of different specific properties of the presynaptic dopaminergic system in caudate nucleus and putamen. The first tracer, 6-L-(18F)-fluorodopa, was used as an analog of levodopa to assess its regional brain uptake, conversion into, and retention as dopamine and further metabolites. The second tracer, (11C)-nomifensine was employed as an indicator of striatal monaminergic reuptake sites that are principally dopaminergic. We have used this tracer to assess dopaminergic nerve terminal density. In patients with Parkinson's disease, striatal uptake of both tracers was decreased, putamen being significantly more affected than caudate. Side-to-side differences of uptake in putamen, but not caudate, correlated with corresponding left-right differences of scored clinical motor performance. Both 6-L(18F)-fluorodopa and (11C)-nomifensine tracer uptake in putamen was decreased on average to 40% of normal values, suggesting that a substantial part of the cellular elements of the dopaminergic nigrostriatal system is still intact in living parkinsonian patients. This is in contrast to the generally extreme depletion of endogenous dopamine in the putamen of patients found at postmortem. Our results lend support to the search for drug treatments that protect against further nigrostriatal cell loss and that could be exhibited as soon as the disease manifests clinically. If successful, a sufficient striatal nerve terminal pool would remain so that the effectiveness of levodopa as a dopamine repletor could persist.
Aged↗
Differing patterns of striatal 18F-dopa uptake in Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy.
Using positron emission tomography (PET), we studied regional striatal 18F-dopa uptake in 16 patients with L-dopa-responsive Parkinson's disease (PD), 18 patients with multiple system atrophy, and 10 patients with progressive supranuclear palsy. Results were compared with those of 30 age-matched normal volunteers. The patients with PD showed significantly reduced mean uptake of 18F-dopa in the caudate and putamen compared to controls, but while function in the posterior part of the putamen was severely impaired (45% of normal), function in the anterior part of the putamen and in the caudate was relatively spared (62% and 84% of normal). Mean 18F-dopa uptake in the posterior putamen was depressed to similar levels in all patients. Unlike patients with PD, the patients with progressive supranuclear palsy showed equally severe impairment of mean 18F-dopa uptake in the anterior and posterior putamen. Caudate 18F-dopa uptake was also significantly lower in patients with progressive supranuclear palsy than in patients with PD, being depressed to the same level as that in the putamen. Mean 18F-dopa uptake values in the anterior putamen and caudate in patients with multiple system atrophy lay between PD and progressive supranuclear palsy levels. Locomotor disability of individual patients with PD or multiple system atrophy correlated with decline in striatal 18F-dopa uptake, but this was not the case for the patients with progressive supranuclear palsy. We conclude that patients with PD have selective nigral pathological features with relative preservation of the dopaminergic function in the anterior putamen and caudate, whereas there is progressively more extensive nigral involvement in multiple system atrophy and progressive supranuclear palsy.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Striatal function in normal aging: implications for Parkinson's disease.
Central to several current theories of the etiology of Parkinson's disease is the premise that the nigrostriatal dopaminergic system degenerates with normal aging. Much of the evidence for this assertion has come from postmortem neurochemical studies. We have used L-6-[18F] fluoro-Dopa and positron emission tomography in 26 healthy volunteers (age range, 27-76 years) to examine striatal and frontal cortical tracer uptake. Data have been analyzed by using a graphical approach to calculate an influx constant (Ki) for L-6-[18F]fluoro-Dopa uptake into the caudate, putamen, and medial frontal cortex of each subject. In the population studied, there was no decline in Ki with age for any of these structures. A series of physiological measurements made on the older subjects also showed few significant changes with age. The positron emission tomographic findings demonstrate preservation of nigrostriatal dopaminergic function in normal aging. The pathological process causing Parkinson's disease may operate closer to the time of presentation than has been suggested.
Adult↗
Diaphragmatic flutter, the moving umbilicus syndrome, and "belly dancer's" dyskinesia.
Five patients presenting with focal abnormal involuntary movements of the abdominal wall are described. One was shown to have diaphragmatic flutter, which may represent a variant of the palatal myoclonus syndrome. The other four had writhing movements and contractions of the abdominal wall at frequencies of approximately 30 per minute. In two of the latter cases, these abdominal movements were profoundly influenced by respiratory manoeuvres. They were quite unlike the movements of spinal myoclonus or axial torsion dystonia. None of the patients were taking drugs that might have provoked their abnormal movements, or had any other evidence of neurological deficit. No cause was established in any of the cases.
Abdominal Muscles↗
Trunk and head tremor as isolated manifestations of dystonia.
Five patients presenting with isolated tremors of the trunk or neck are described. Their clinical features were similar to seven other patients who presented with head tremor, or arm and head tremor, but then eventually developed obvious torticollis, sometimes with arm dystonia. We conclude that isolated tremor of the trunk or head, especially of slow frequency (2-5 Hz), and in the case of the head in a "no-no" direction, may be the initial manifestation of focal dystonia.
Adult↗