D1 and D2 receptor imaging may also provide a dopamin-ergic molecular basis of functional recovery in the nigrostriatal system after neural transplantation. An increase in the number of functional D1 and D2 DA receptors is likely to indicate a more extensive integration of the graft with the host brain. PET with [11C]SCH 23390 and RAC has been used to examine the effect of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain (94). The grafts from the youngest donors showed a significant increase in D1 and D2
receptor binding when compared with the lesion-alone group. This increase was correlated with the improved motor function in the rats. Striatal grafts from younger donors produced greater behavioral recovery than grafts prepared from older embryos due to the increased proportion of viable tissue within the grafts.
PET with RAC is capable of measuring synaptic DA release from embryonic nigral transplants. This was performed in a PD patient demonstrating the sustained and marked clinical improvement, as well as gradual increase of FDOPA uptake to normal during a period of 10 yr after grafting in the unilateral putamen (95). RAC binding to DA D2 receptors was measured with saline or methamphetamine infusion. Binding at baseline was normal in the grafted putamen but upregulated in the nongrafted putamen and caudate. Drug-induced binding reduction was also restored to the normal level in the grafted putamen. These results suggest that graft has successfully normalized DA storage and D2 receptor occupancy in the den-ervated striatum.
H2 15O with PET can be a useful tool to study the recovery of striatocortical functional systems in patients treated with fetal cell implantation. It is reported that recovery of movement-related cortical function has been delayed in PD after striatal dopaminergic grafting (96). The cortical activation was still impaired at 6.5 mo after transplantation, although motor symptoms and mean striatal DA storage capacity had significantly improved. At 18 mo after surgery, there was further significant clinical improvement without any more increase in striatal FDOPA uptake. The surgery significantly improved rostral supplementary motor and dorsal prefrontal cortical activation during performance of joystick movements, in agreement with the results of subthalamic nucleus DBS (63,65). These data suggest that it is not enough for the graft to simply deliver DA and that functional integration of the grafted neurons within the host brain is necessary to produce substantial clinical recovery in PD.
Presently, this type of study can also be performed using functional magnetic resonance imaging to measure alternation in regional cerebral blood volume (rCBV). rCBV is an indicator of neuronal metabolism as it is linked to the cerebral oxygen consumption varying in response to motor tasks. Two PD patients with clinically excellent outcome after transplantation were examined this way with a repetitive motor task (97). Activation was recorded consistently in the part of the putamen receiving the graft, suggesting that the formation of neural connections between host and transplanted tissues as the same paradigm also activates the putamen in normal volunteers.
It is known that DA release in response to amphetamine challenge induces a significant increase in rCBV in specific parts of the corticostriatal circuitry. One double-blind study in a unilateral rat model of PD reported complete absence of rCBV activation to amphetamine in striatum and cortex ipsilateral to the lesion (98). Cell graft in the lesioned striatum resulted in appreciable amphetamine-induced activation in the striatum and sensorimotor cortex, similar in magnitudes to those in the contralateral intact hemisphere. No response was evident in control rats with sham surgery. This study demonstrates that behavioral restoration in animal models parallels observation from functional MRI data.
FDG/PET imaging can be very useful in mapping the metabolic brain response to neuronal cell implantation in the human trials of PD patients. This has been proven repeatedly with other neurosurgical therapies summarized earlier. In the first open-label human trial for stroke ( 99), 12 patients with chronic basal ganglia infarction and motor impairment were investigated before and 6 and 12 mo after stereotactic implantation of cultured human neuronal cells. Alterations in glucose metabolism in the stroke area at 6 and 12 mo after implantation correlated positively with motor performance measures. The results suggest improved local cellular function or engraftment of implanted cells in some of these patients.
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