| 1. |
- Brundin, Patrik, et al.
(författare)
-
Bilateral caudate and putamen grafts of embryonic mesencephalic tissue treated with lazaroids in Parkinson's disease
- 2000
-
Ingår i: Brain. - 1460-2156. ; 123, s. 1380-1390
-
Tidskriftsartikel (refereegranskat)abstract
- 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.
|
|
| 2. |
- Brundin, Patrik, et al.
(författare)
-
The neurobiology of cell transplantation in Parkinson's disease
- 2001
-
Ingår i: Clinical Neuroscience Research. - 1873-779X. ; 1:6, s. 507-520
-
Tidskriftsartikel (refereegranskat)abstract
- Over the past decade, neural grafting has emerged as a new treatment option for Parkinson's disease. When performed successfully, grafts of human embryonic neural tissue can give rise to major symptomatic relief in patients, However, a recent report on a double-blind placebo control study, which received worldwide attention, described less pronounced beneficial effects of the grafts, and found them to be significant only in patients younger than 60 years of age. Moreover, a subgroup of patients developed disabling dyskinesias as a result of the surgery. These findings, and great logistical problems in coordinating the harvesting of sufficient amounts of suitable human embryonic donor tissue with the transplantation surgery, have led the scientific community to question whether cell transplantation really has a future as a therapy for Parkinson's disease. In this review, we argue that the future of neural transplantation for Parkinson's disease is still bright. We relate clinical findings to observations made in experimental animals grafted with embryonic neural tissue and seek explanations for the variability in outcome seen in the clinical trials. We also briefly discuss alternative sources of donor tissue that may be applied in future clinical trials, and mention what features of cells may be crucial for them to be suitable as donor tissue for transplantation in Parkinson's disease.
|
|
| 3. |
- Hagell, Peter, et al.
(författare)
-
Apomorphine in the treatment of Parkinson's disease
- 2001
-
Ingår i: Journal of Neuroscience Nursing. - 0888-0395. ; 33:1, s. 21-38
-
Tidskriftsartikel (refereegranskat)abstract
- Apomorphine is a potent, nonselective, direct-acting dopamine-receptor agonist. Given subcutaneously, it has a rapid onset of antiparkinsonian action qualitatively comparable to that of levodopa. Despite its long history, it was not until peripheral dopaminergic side effects could be controlled by oral domperidone that the clinical usefulness of apomorphine in Parkinson's disease began to be investigated thoroughly in the mid-1980s. Although several routes have been tried, subcutaneous administration, either as intermittent injections or continuous infusion, is so far the best and most applied in the treatment of advanced, fluctuating Parkinson's disease. Clinical trials have shown stable efficacy with markedly reduced time spent in "off" phases as well as, for infusion therapy, reduced levodopa requirements. In the most successful cases, motor fluctuations disappear and the need for oral medication is eliminated. Adverse events are usually mild and dominated by cutaneous reactions. Neuropsychiatric side effects occur, but the influence of apomorphine on these remains controversial. Controlled long-term clinical trials are highly warranted to reveal the full potentials of this treatment. Careful patient selection and follow-up, where the specialized movement disorder nurse has a crucial role, are paramount for a successful long-term outcome. Apomorphine warrants a wider application in the treatment of advanced Parkinson's disease and should be tried before more invasive interventions are considered.
|
|
| 4. |
- Hagell, Peter
(författare)
-
Assessment of Graft Effects and Function in Cell Replacement Therapy for Parkinson's Disease
- 2002
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This explorative study aimed to apply, develop, and evaluate assessment methods at various levels in cell replacement therapy for Parkinson’s disease (PD). Observed motor effects in five grafted patients support that timed motor tasks and clinical ratings of parkinsonism are able to monitor motor function, but their psychometric properties need further attention. Using positron emission tomography in a unilaterally grafted PD patient, dopamine receptor binding of [11C]-raclopride was found upregulated in the non-grafted, but normal in the grafted putamen. Binding reduction was normal in the grafted putamen, but not in other striatal areas, following amphetamine administration. This supports that graft-derived dopamine release can be measured in vivo in PD. The Clinical Dyskinesia Rating Scale (CDRS) yielded reliable hyperkinesia ratings, whereas dystonia ratings were reliable within but not between raters. In grafted patients the CDRS showed that grafts can increase dyskinesias, without associated motor improvement and unrelated to the degree of dopaminergic reinnervation. Observations support the value of the CDRS, while reliability problems call for improvements. Application of the generic health status questionnaire NHP in grafted patients demonstrated effects beyond motor function, indicating the value of such questionnaires. Psychometric evaluations of the NHP and the PD-specific PDQ-39 showed ambiguities with both, emphasizing the need for further refinements and evaluations, and illustrating the importance of systematic evaluations of outcome measures. Although most methods used here require further attention before they can be considered optimal, this study illustrates the value and importance of multi-level assessments of cell replacement therapies in PD.
|
|
| 5. |
|
|
| 6. |
- Hagell, Peter, et al.
(författare)
-
Cell survival and clinical outcome following intrastriatal transplantation in Parkinson disease
- 2001
-
Ingår i: Journal of Neuropathology and Experimental Neurology. - 1554-6578. ; 60:8, s. 741-752
-
Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal transplantation of embryonic dopaminergic neurons is currently explored as a restorative cell therapy for Parkinson disease (PD). Clinical results have varied, probably due to differences in transplantation methodology and patient selection. In this review, we assess clinical trials and autopsy findings in grafted PD patients and suggest that a minimum number of surviving dopaminergic neurons is required for a favorable outcome. Restoration of [F-18]-fluorodopa uptake in the putamen to about 50% of the normal mean seems necessary for moderate to marked clinical benefit to occur. Some studies indicate that this may require mesencephalic tissue from 3-5 human embryos implanted into each hemisphere. The volume, density and pattern of fiber outgrowth and reinnervation, as well as functional integration and dopamine release, are postulated as additional important factors for an optimal clinical outcome. For neural transplantation to become a feasible therapeutic alternative in PD, graft survival must be increased and the need for multiple donors of human embryonic tissue substantially decreased or alternate sources of donor tissue developed. Donor cells derived from alternative sources should demonstrate features comparable to those associated with successful implantation of human embryonic tissue before clinical trials are considered.
|
|
| 7. |
- Hagell, Peter
(författare)
-
Compliance and noncompliance in neuroscience
- 2000
-
Ingår i: Journal of Neuroscience Nursing. - 0888-0395. ; 32:3, s. 182-182
-
Tidskriftsartikel (refereegranskat)abstract
- Among the responses to this month's question, the most common strategy for motivating compliance is providing information. This finding is also supported with the example from Australia, where stoke sufferers are highly compliant with any intervention aimed at prevention of future strokes. In this case, the high level of compliance and (probably) motivation can be explained by the fact that stroke is potentially fatal and highly disabling. Other important issues also were identified in the responses: (a) patients' trust and belief in healthcare professionals in terms of providing information and motivation, and (b) a lack of motivation in some patients who simply do not want to comply and prefer a certain level of seizure activity or other impairments and disabilities over the potential side effects of the treatment. This raises another question that goes beyond the concept of compliance and noncompliance: How does the system comply to the patient? I will leave this topic open, and I welcome comments for a future round of discussion here at Global Views.
|
|
| 8. |
- Hagell, Peter, et al.
(författare)
-
Dyskinesias following neural transplantation in Parkinson's disease.
- 2002
-
Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1546-1726 .- 1097-6256. ; 5:7, s. 627-628
-
Tidskriftsartikel (refereegranskat)abstract
- Severe dyskinesias during the 'off' phases (periods of increased Parkinson's disease (PD) disability) have been observed following intrastriatal transplantation of human embryonic mesencephalic tissue. Here we retrospectively analyzed 14 patients who were followed for up to 11 years after grafting, and found that dyskinesias (abnormal involuntary movements and postures) increased during postoperative off phases, but were generally of mild to moderate severity. Dyskinesia severity was not related to the magnitude of graft-derived dopaminergic re-innervation, as judged by (18)F-labeled 6-L-fluorodopa (FD) positron emission tomography (PET), indicating that off-phase dyskinesias probably did not result from excessive growth of grafted dopaminergic neurons.
|
|
| 9. |
- Hagell, Peter, et al.
(författare)
-
Health-related quality of life following bilateral intrastriatal transplantation in Parkinson's disease
- 2000
-
Ingår i: Movement Disorders. - 0885-3185. ; 15:2, s. 224-229
-
Tidskriftsartikel (refereegranskat)abstract
- Intrastriatal transplantation of embryonic dopaminergic tissue is a new, experimental approach for the treatment of Parkinson's disease (PD). Clinical trials have shown longterm graft survival and therapeutically valuable improvements with decreased L-dopa dose and time spent in the "off"-phase, and reduced rigidity and hypokinesia. We have measured health-related quality of life (HRQoL) using the Nottingham Health Profile (NHP) in five patients subjected to bilateral transplantation in the caudate and putamen to explore the influence of intrastriatal grafts on HRQoL and the value of such measures in trials of restorative therapies. The results demonstrate improved HRQoL following transplantation, with individual patients showing striking improvements within different dimensions of the NHP as well as the NHP distress index (NHPD). The most pronounced improvements after grafting were observed for physical mobility along with emotional reactions and energy. These results indicate that intrastriatal transplantation of embryonic dopaminergic tissue can give rise to improvements within most areas of HRQoL, and that HRQoL measurements provide important information additional to that obtained by traditional, symptom-oriented assessment protocols. However, the optimal approach to HRQoL measurement in PD remains to be determined.
|
|
| 10. |
|
|
