| 1. |
|
|
| 2. |
- Lindvall, O, et al.
(author)
-
Evidence for long-term survival and function of dopaminergic grafts in progressive Parkinson's disease
- 1994
-
In: Annals of Neurology. - : Wiley. - 0364-5134. ; 35:2, s. 80-172
-
Journal article (peer-reviewed)abstract
- Two patients with idiopathic Parkinson's disease (Patients 3 and 4 in our series) were followed up to 3 years after grafting of human embryonic dopamine-rich mesencephalic tissue unilaterally into the putamen. During the first postoperative year both patients showed significant amelioration of parkinsonian symptoms and increased 6-L-[18F]-fluorodopa uptake in the grafted putamen, as assessed with positron emission tomography. Three years after grafting the patients still exhibited increased fluorodopa uptake in the grafted putamen and significant clinical improvements, evidenced by a reduction of the severity of symptoms and of the time spent in the "off" phase, and by a prolongation of the effect of a single dose of L-dopa. Between 1 and 3 years after surgery, Patient 3 showed only minor changes of parkinsonian symptoms on the side contralateral to the graft, whereas there was a worsening on the ipsilateral side. Fluorodopa uptake decreased in the nongrafted putamen but was unchanged in the grafted putamen. Patient 4 continued to improve after the first postoperative year and L-dopa was withdrawn after 32 months. The reduction of parkinsonian symptoms on the side contralateral to the graft became more pronounced between 1 and 3 years after surgery. Fluorodopa uptake further increased in the grafted putamen, whereas no change was detected on the non-grafted side. These results indicate that grafts of embryonic dopamine neurons can survive, grow, and exert functional effects up to at least 3 years after surgery in the parkinsonian brain, despite an ongoing disease process leading to degeneration of the intrinsic dopamine system.
|
|
| 3. |
- Sawle, G V, et al.
(author)
-
Transplantation of fetal dopamine neurons in Parkinson's disease : PET [18F]6-L-fluorodopa studies in two patients with putaminal implants
- 1992
-
In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 31:2, s. 73-166
-
Journal article (peer-reviewed)abstract
- Two patients with Parkinson's disease who underwent implantation of fetal mesencephalic tissue into the putamen were serially studied using positron emission tomography and [18F]6-L-fluorodopa ([18F]dopa). The uptake of [18F]dopa is related to the functional integrity of the presynaptic dopaminergic system. Preoperative studies revealed a marked decrease in putamen [18F]dopa uptake, with lesser involvement of the caudate. Two and 4 months, respectively, after operation, both patients demonstrated functional improvement, as described elsewhere. One patient was scanned 5, 8, and 13 months after the operation and the other was scanned 7 and 12 months after the operation. In both patients, [18F]dopa uptake increased within the operated putamen despite a progressive decrease in tracer uptake in the unoperated striatal structures. We believe that this increased uptake of [18F]dopa at the implantation site represents functional integrity within a surviving neural graft. While there has been little further clinical improvement beyond the fifth postoperative month, the uptake of [18F]dopa at the operation site in both patients has progressively increased. The kinetic data provide evidence of disease progression in the unoperated striatum, which, balanced against increasing graft function, may explain why clinical improvement reached a plateau within months after surgery.
|
|
| 4. |
- Clarke, D J, et al.
(author)
-
Synaptic connections formed by grafts of different types of cholinergic neurons in the host hippocampus
- 1990
-
In: Experimental Neurology. - : Elsevier BV. - 0014-4886. ; 107:1, s. 11-22
-
Journal article (peer-reviewed)abstract
- The present experiment was performed to determine whether different types of grafted central cholinergic neurons are able to form synaptic contacts with host hippocampal neurons. Grafts from the septal-diagonal band area, which contain the neurons that normally innervate the hippocampal formation, were compared to those from the nucleus basalis magnocellularis region (NBM), the striatum, the pontomesencephalic tegmentum of the brain stem, and the spinal cord. The regions were dissected from 14- to 16-day-old rat fetuses, and the same number of viable cells (35 x 10(4] from each of the different regions was stereotaxically injected as a cell suspension into the hippocampus of rats subjected to a complete fimbria-fornix lesion, transecting the intrinsic septohippocampal pathways. At 14 to 17 weeks after transplantation, the brains were processed for choline acetyltransferase (ChAT) immunocytochemistry at the light and electron microscopic levels and acetylcholinesterase (AChE) histochemistry at the light microscopic level. There was a great variation in the number of surviving ChAT-positive cells among the different graft types. The septal grafts contained the highest number of ChAT-positive cells, and the striatal grafts showed the lowest numbers. The NBM, brain stem, and spinal cord grafts were in between. The differences in the number of ChAT-positive neurons between the groups matched, in general, the differences found in the magnitude of graft-derived AChE-positive fiber growth into the host hippocampal formation. At the electron microscopical level, all types of grafts were capable of forming synaptic contacts with host elements, however, with vast differences in the number of synapses found. The septal grafts produced the highest number of contacts, whereas the striatal and spinal cord grafts produced very few contacts. The ultrastructure of the cholinergic fibers from grafts obtained from the forebrain areas, i.e., septum, NBM, and striatum all appeared normal, whereas brain stem and spinal cord grafts produced different types of anomalies. The results show that grafted cholinergic neurons, that normally do not innervate the hippocampus, can send axons and form synaptic contacts in the host hippocampus. The ability to reinnervate the denervated hippocampal target appears to be shared by the embryologically closely related forebrain cholinergic neuron types, i.e., the septal, NBM, and striatal neurons. The marked differences in overall fiber ingrowth and number of synapses observed between these different types of grafts could be explained largely on the basis of differences in survivability of each grafted neuron type. By contrast, the reinnervation obtained from the grafted brain stem and spinal cord neurons were both quantitatively and qualitatively abnormal.(ABSTRACT TRUNCATED AT 400 WORDS)
|
|
| 5. |
- Duan, W M, et al.
(author)
-
Sequential intrastriatal grafting of allogeneic embryonic dopamine-rich neuronal tissue in adult rats : will the second graft be rejected?
- 1993
-
In: Neuroscience. - 0306-4522. ; 57:2, s. 74-261
-
Journal article (peer-reviewed)abstract
- An important issue in clinical neural grafting is whether a second instriatial allograft can survive well in a patient who has received an allograft before. In this study, the survival, immunogenicity and function of intrastriatal grafts of allogeneic or syngeneic embryonic dopamine-rich tissue in rats which had previously received either an intrastriatal allo- or syn-graft or sham injections were examined. The first graft tissue was taken from inbred Lewis or Sprague-Dawley rat embryos and grafted into an intact striatum of adult Sprague-Dawley rats subjected to a unilateral 6-hydroxydopamine lesion on the contralateral side. Eight weeks after the first transplantation, either allogeneic or syngeneic tissue was grafted as dissociated tissue into the dopamine depleted striatum. The function of the second grafts was assessed by rotational asymmetry at two different time points, i.e. eight and 14 weeks after the second transplantation. There were significant reductions of rotational asymmetry in all groups over time, but no significant difference between groups. Tyrosine hydroxylase immunocytochemistry was used to assess dopamine cell survival and graft size. Statistical analysis revealed no significant differnce in the mean number of tyrosine hydroxylase immunoreactive cells or the mean volume of the second grafts placed on the right side (lesioned side) between groups. Monoclonal antibodies were used to evaluate cellular immune reactions and the major histocompatibility complex class I and class II expression in and around grafts. No major histocompatibility complex class I expression was seen in any of the graft combinations. The expression of the major histocompatibility complex class II antigens was generally higher in patches in and around the second allograft of rats which had previously received an allograft than that in and around any other type of grafts. However, the expression of the major histocompatibility complex class II antigens was low throughout the grafts and did not appear as marked perivascular infiltrates. All the major histocompatibility complex class II positive cells displayed a microglia-like morphology, supported by the parallel microglia and macrophage-specific OX-42 immunostaining. The results show that there is no marked on-going immune reactions in or around the implantation site in any group fourteen weeks after a second transplantation. It may be concluded, therefore, that sequential allografting, using stereotaxic implantation of dissociated embryonic neural tissue into the striatal parenchyma, is possible to perform without a major risk of graft rejection, provided that an atraumatic technique is used.
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Lindvall, O, et al.
(author)
-
Transplantation of fetal dopamine neurons in Parkinson's disease : one-year clinical and neurophysiological observations in two patients with putaminal implants
- 1992
-
In: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 31:2, s. 65-155
-
Journal article (peer-reviewed)abstract
- Ventral mesencephalic tissue from aborted human fetuses (age, 6-7 weeks' postconception) was implanted unilaterally into the putamen using stereotaxic surgery in 2 immunosuppressed patients (Patients 3 and 4 in our series) with advanced idiopathic Parkinson's disease. Tissue from 4 fetuses was grafted to each patient. Compared with our previous 2 patients, the following changes in the grafting procedure were introduced: the implantation instrument was thinner, more tissue was placed in the operated structure, and the time between abortion and grafting was shorter. There were no postoperative complications. Both patients showed a gradual and significant amelioration of parkinsonian symptoms (most marked in Patient 3) starting at 6 and 12 weeks after grafting, respectively, reaching maximum stability at approximately 4 to 5 months; patients remained relatively stable thereafter during the 1-year follow-up period. Clinical improvement was observed as a reduction of the time spent in the "off" phase and the number of daily "off" periods; a lessening of bradykinesia and rigidity during the "off" phase, mainly but not solely on the side contralateral to the graft; and a prolongation and change in the pattern of the effect of a single dose of L-dopa. Neurophysiological measurements revealed a more rapid performance of simple and complex arm and hand movements bilaterally, but primarily contralateral to the graft. The results indicate that patients with Parkinson's disease can show significant and sustained improvement of motor function after intrastriatal implantation of fetal dopamine-rich mesencephalic tissue. The accompanying paper by Sawle and colleagues describes the results of repeated positron emission tomography scans in these patients.
|
|
| 9. |
- Nakao, Naoyuki, et al.
(author)
-
Lazaroids improve the survival of grafted rat embryonic dopamine neurons
- 1994
-
In: Proceedings of the National Academy of Sciences of the United States of America. - 0027-8424. ; 91:26, s. 12-12408
-
Journal article (peer-reviewed)abstract
- In rodent models of Parkinson disease in which transplants of dissociated rodent and human embryonic mesencephalic tissue, rich in dopamine neurons, have been studied, only 5-20% of the dopamine neurons survive the implantation procedure. We have investigated the effects of inhibiting free radical generation with two lazaroids, U-74389G and U-83836E, on the survival of embryonic rat dopamine neurons. U-74389G is a 21-aminosteroid, and U-83836E combines the piperazinyl pyrimidine portion of 21-aminosteroids with the antioxidant ring of alpha-tocopherol. In an initial study, we found that the lazaroids markedly prolonged the period after tissue dissociation that an embryonic mesencephalic cell suspension exhibits high cell viability in vitro, as assessed by using a dye exclusion method. In a second series of experiments, addition of lazaroids to dissociated mesencephalic graft tissue increased the yield of surviving rat dopamine neurons 2.6-fold after implantation in the dopamine-denervated rat striatum. The improved survival correlated with an earlier onset of graft-induced functional effects in the amphetamine-induced rotation test. Thus, inhibition of free radical generation can significantly increase the yield of grafted embryonic dopamine neurons. Addition of lazaroids to the graft preparation is a relatively simple modification of the transplantation protocol and could readily be applied in a clinical setting. Moreover, since iron-dependent lipid peroxidation has been suggested to play a role in the death of nigral dopamine neurons in Parkinson disease and lazaroids are particularly potent inhibitors of such processes, the findings may have implications for the pathogenesis of this disease.
|
|
| 10. |
- Nilsson, O G, et al.
(author)
-
Amelioration of spatial memory impairment by intrahippocampal grafts of mixed septal and raphe tissue in rats with combined cholinergic and serotonergic denervation of the forebrain
- 1990
-
In: Brain Research. - : Elsevier BV. - 0006-8993. ; 515:1-2, s. 193-206
-
Journal article (peer-reviewed)abstract
- Previous studies in the rat have shown that a serotonergic depletion greatly potentiates the learning and memory impairments produced by pharmacological or lesion-induced cholinergic blockade in the forebrain. The impairment produced by combined serotonergic-cholinergic lesions is reminiscent of that seen in memory-impaired aged rats. In the present experiment, we investigated whether grafts of cholinergic septal tissue and serotonergic mesencephalic raphe tissue, placed in the hippocampus, could reverse the severe memory impairment produced by combined cholinergic-serotonergic lesions. Adult rats were given an intraventricular injection of 5,7-dihydroxytryptamine followed by a radiofrequency lesion of the septum 1-2 weeks later. Three weeks after lesion surgery, the rats were given bilateral intrahippocampal cell suspension grafts of either fetal septal or mesencephalic raphe tissue, or both. The rats were tested for spatial learning and memory in the Morris water maze task at 4 and 10 months after grafting. At 4 months, lesioned and grafted groups were all impaired compared to the normal controls in their swim time and distance swum to find the platform, and they did not show any spatially focussed search strategy in the spatial probe trial when the platform was removed from the tank. At 10 months, the rats with mixed cholinergic and serotonergic grafts were no longer impaired compared to normals in their swim time and distance to find the platform, and they were significantly improved compared to the other grafted groups. Moreover, in the spatial probe trial, the rats with mixed cholinergic and serotonergic grafts displayed a spatially focussed search behaviour over the previous platform site, which was not seen in the lesioned control rats or in the other graft groups. Morphological analysis of the hippocampus revealed that the septal grafts produced an acetylcholinesterase-positive innervation but were totally devoid of serotonin innervation. The raphe grafts produced mainly a serotonin innervation, of both acetylcholinesterase- and serotonin-positive fibres. The results suggest that a mixture of septal and raphe tissue is required when grafted to the hippocampal formation in order to ameliorate the severe spatial learning and memory impairments produced by a combined cholinergic and serotonergic denervation, and that each of these graft types separately are not sufficient to ameliorate such deficits.
|
|
| 11. |
- Widner, H, et al.
(author)
-
Sequential intracerebral transplantation of allogeneic and syngeneic fetal dopamine-rich neuronal tissue in adult rats : will the first graft be rejected?
- 1993
-
In: Cell Transplantation. - 0963-6897. ; 2:4, s. 17-307
-
Journal article (peer-reviewed)abstract
- The immune response against intracerebral grafts of allogeneic fetal dopamine-rich tissue was assessed in adult rats. Sprague-Dawley rats, now outbred, but originating from an inbred stock, were given unilateral 6-hydroxy-dopamine lesions of the mesostriatal pathway, and grafted intrastriatally with mechanically dissociated ventral mesencephalic tissue (embryonic day 13-15) obtained from an inbred Lewis strain. Graft survival was assessed by functional recovery of amphetamine-induced rotational behavior on four different occasions postsurgery, and histologically using catecholamine histofluorescence and tyrosine hydroxylase immunohistochemistry. The following groups were analysed: long-term survival of a single allogeneic graft; survival of a first allogeneic graft with a syngeneic second graft; survival of a first allograft combined with a second allogeneic graft; the survival of bilateral allogeneic grafts following a subsequent orthotopic allogeneic skin graft. Evidence for recipient immunization was obtained using an indirect fluorescent antibody detection technique, Simonsen's Spleen Index (S I) test. Viable grafts, giving rise to behavioral compensation, were present after 40 wk in rats from all groups. The "first" allograft always displayed good survival and function, even following a second intracerebral allograft. However, five of nine "second" allogeneic intracerebral grafts survived poorly. In contrast, all secondary syngeneic grafts survived well. Following the application of a subsequent orthotopic allogeneic skin graft in a subgroup of rats, there was a significantly lower survival of grafted dopamine neurons in the "first" graft.
|
|
| 12. |
|
|
