Brain Transplant: 1994 NOVA Documentary Follow up

List of Methods Behavioral Nervous system Various tests of motor function - pupillary reflex, walking, sitting, standing, talking, finger touching, balance (from a push), blinking (tap of forehead), rigidity (movement of wrist or limb) Nervous system L-DOPA and other drug treatments (e.g., neuroprotection) Chemical identification of MPTP Adrenal tissue to brain transplant Animal model of PD using MPTP Nerve graft tissue transplant in monkeys and humans Dissecting fresh fetal nerve cells from substantia nigra Stereotaxic surgery – intracerebral injection of fresh tissue suspension into caudate and putamen (striatum) postoperative care (baseball game) immunosuppression therapy PET scan of flora-dopa uptake in striatum and Estimation of percentage of graft secreting dopamine

Follow-up questions Given that it took George and Juanita two years to show miraculous recovery, what was the status of Connie at this time point following surgery? Are there any more recent reports of her progress, or lack thereof? What is her present condition? Why didn’t NOVA report on her progress as promised in the documentary?

JOURNEY OUT OF HOPELESSNESS   GREENFIELD WOMAN THANKS READERS WHOSE DONATIONS RESTORED HER HUMANITY from PARKINSN Archives: Sun, 28 May 1995   Langston, the renowned Parkinson's disease scientist, described the essence of Connie's improvement this way: ''What makes you human is the ability to interact with other humans. If you lose that, and Connie had, you lose the essence of life. It takes away what makes you a person. Connie is still very disabled, but she has regained her humanity. She is no longer a statue in the corner.''

Local news report from 1995, a year after Connie’s transplant Writer Jim Trotter at the Mercury News Two years ago, when I drove down with Langston from the Parkinson's Institute to visit Connie in Greenfield, the scene was far different. Sophisticated computer testing indicated that she was still cognitive, that her brain comprehended, beyond the frozen mask. But even with the aid of elaborate computer switches, she couldn't communicate. Now she is a smiling human being who can walk a bit and respond to questions. Surgery to reattach her ankle ligaments will greatly enhance her mobility. But Langston said overcoming language ''ignition failure'' -- the inability to talk spontaneously in expressing one's thoughts -- will take more time. ''But when that happens, she will really be back,'' he said. I could not resist sitting down next to Connie and telling her how much I admired her courage. She turned her eyes and said, ''Thank you.'' Don't give up, I said. Painstakingly, but clearly, she responded. ''I won't.''

Symptoms of PD 1) resting tremor (rhythmic shaking of an extremity), 2) slowness of movement (hypokinesia or bradykinesia) - movements take much longer to execute and there is also a general lack of movement (akinesia), 3) cogwheel rigidity (arms and legs become stiff with a ratchet or jerky quality of movement - almost no other disease produces this symptom), 4) slow shuffling gait, short steps with the patient bent or flexed over (very characteristic of PD) and 5) loss of facial expression and lack of spontaneous blinking which gives the appearance staring.

L-DOPA treatment Reversed symptoms but the therapeutic window closed as severe side effects set in – hallucinations, dyskinesia, and uncontrollable movement

“Parkinson’s disease is not caused by transient exposure to MPTP” That is, only f you use a strict neurobiological marker as the criterion. The similarities in behavioral changes suggests strongly that MPTP exposure replicates virtually all the behavioral symptoms of PD.

PD – reduced uptake in the putamen Radiolabeled FD uptake in the striatum Normal PD PD – reduced uptake in the putamen MPTP – uniform reductions in both the caudate nucleus and putamen Moderate MPTP Severe MPTP

NIH-sponsored placebo controlled trials

Winkler et al, 2005 Figure 1. Functional recovery after neural transplantation in Parkinson’s disease (PD). Recovery is suggested to occur in two phases: phase one is characterized by functional changes limited to the striatum, whereas in phase two changes of cortical activation can also be detected.

Winkler et al, 2005 Figure 2. Allografts of fetal dopaminergic neurons are accompanied by a delayed immune/ inflammatory response, which could affect long-term survival and functional efficacy of the transplanted dopaminergic neurons.

variability in individual outcomes in the open label studies suggest that other factors might contribute to the success of the treatment. preparation and composition of the graft tissue - prolonged cold storage and use of solid grafts are not as good selection of patients - older patients do not tend to benefit as much as young patients due to less confined damage and reduced ability to accept to graft pre-graft medication – low-dose patients tend to benefit more from graft. In fact, one of the controlled studies with older patients with no significant group improvement there was a correlation between the magnitude of the response to dose of L-dopa and the magnitude of the postsurgical improvement. graft placement – grafts only innervate tissue 2-3 mm from the graft site so benefits will depend on the location of the placement and whether there is limited damage outside of the striatum. The authors conclude that standardized procedures for selection of patients, graft preparation and immunosuppresion, combined with tailoring the placement of grafts may improve the outcome of this promising therapy for PD.

MPTP exposure initiates long-term neurodegeneration

Practice questions Where was the fetal tissue taken from and where was it transplanted to? Immunosuppresion is important for post-surgical improvement to occur in the first 6 months or after that time. What was shown to be a misconception regarding MPTP exposure and why? What data suggests that MPTP does not induce PD?