Brain Transplant:Brain Transplant:1994 NOVA Documentary1994 NOVA Documentary

Follow upFollow up

List of MethodsList of MethodsBehavioralBehavioralVarious tests of motor function - pupillary reflex, walking, sitting, standing, Various tests of motor function - pupillary reflex, walking, sitting, standing, talking, finger touching, balance (from a push), blinking (tap of forehead), talking, finger touching, balance (from a push), blinking (tap of forehead), rigidity (movement of wrist or limb)rigidity (movement of wrist or limb)

Nervous systemNervous systemL-DOPA and other drug treatments (e.g., neuroprotection)L-DOPA and other drug treatments (e.g., neuroprotection)Chemical identification of MPTPChemical identification of MPTPAdrenal tissue to brain transplantAdrenal tissue to brain transplantAnimal model of PD using MPTPAnimal model of PD using MPTPNerve graft tissue transplantNerve graft tissue transplant in monkeys and humans in monkeys and humans

DissectingDissecting fresh fetal nerve cells from substantia nigra fresh fetal nerve cells from substantia nigraStereotaxic surgeryStereotaxic surgery – –

intracerebral injectionintracerebral injection of fresh tissue suspension of fresh tissue suspension into caudate and putamen (striatum)into caudate and putamen (striatum)

postoperative care (baseball game)postoperative care (baseball game)immunosuppression therapy immunosuppression therapy PET PET scan of flora-dopa uptake in striatum and scan of flora-dopa uptake in striatum and Estimation of percentage of graft secreting dopamine Estimation of percentage of graft secreting dopamine

Follow-up questionsFollow-up questions

Given that it took George and Juanita two Given that it took George and Juanita two years to show miraculous recovery, what years to show miraculous recovery, what was the status of Connie at this time point was the status of Connie at this time point following surgery?following surgery?

Are there any more recent reports of her Are there any more recent reports of her progress, or lack thereof?progress, or lack thereof?

What is her present condition?What is her present condition?

Why didn’t NOVA report on her progress as Why didn’t NOVA report on her progress as promised in the documentary?promised in the documentary?

JOURNEY OUT OF HOPELESSNESS   GREENFIELD JOURNEY OUT OF HOPELESSNESS   GREENFIELD WOMAN THANKS READERS WHOSE DONATIONS WOMAN THANKS READERS WHOSE DONATIONS

RESTORED HER HUMANITY RESTORED HER HUMANITY from PARKINSN Archives: Sun, 28 May 1995   from PARKINSN Archives: Sun, 28 May 1995  

Langston, the renowned Parkinson's disease Langston, the renowned Parkinson's disease scientist, described the essence of Connie's scientist, described the essence of Connie's improvement this way: improvement this way:

''What makes you human is the ability to interact ''What makes you human is the ability to interact with other humans. If you lose that, and Connie with other humans. If you lose that, and Connie had, you lose the essence of life. It takes away had, you lose the essence of life. It takes away what makes you a person. Connie is still very what makes you a person. Connie is still very disabled, but she has regained her humanity. disabled, but she has regained her humanity. She is no longer a statue in the corner.'' She is no longer a statue in the corner.''

Local news report from 1995, a year after Local news report from 1995, a year after Connie’s transplantConnie’s transplant

Writer Writer Jim Trotter Jim Trotter at the Mercury Newsat the Mercury News

Two years agoTwo years ago, when I drove down with Langston from the Parkinson's , when I drove down with Langston from the Parkinson's Institute to visit Connie in Greenfield, the scene was far different. Institute to visit Connie in Greenfield, the scene was far different. Sophisticated computer testing indicated that Sophisticated computer testing indicated that she was still cognitive, she was still cognitive, that her brain comprehended, beyond the frozen maskthat her brain comprehended, beyond the frozen mask. But even . But even with the aid of elaborate computer switches, with the aid of elaborate computer switches, she couldn't she couldn't communicatecommunicate.   .  

Now she is a smiling human being who can walk a bit and respond to Now she is a smiling human being who can walk a bit and respond to questions. questions. Surgery to reattach her ankle ligaments will greatly Surgery to reattach her ankle ligaments will greatly enhance her mobility. But enhance her mobility. But Langston said overcoming language Langston said overcoming language ''ignition failure'' -- the inability to talk spontaneously in expressing ''ignition failure'' -- the inability to talk spontaneously in expressing one's thoughts -- will take more time.one's thoughts -- will take more time.   ''But when that happens, she   ''But when that happens, she will really be back,'' he said.   will really be back,'' he said.  

I could not resist sitting down next to Connie and telling her how much I 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.''   admired her courage. She turned her eyes and said, ''Thank you.''   Don't give up, I said.   Painstakingly, but clearly, she responded.   ''I Don't give up, I said.   Painstakingly, but clearly, she responded.   ''I won't.'' won't.''

Symptoms of PDSymptoms of PD

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

L-DOPA treatmentL-DOPA treatment

Reversed symptoms but the therapeutic window closed as Reversed symptoms but the therapeutic window closed as severe side effects set in – hallucinations, dyskinesia, and severe side effects set in – hallucinations, dyskinesia, and uncontrollable movementuncontrollable 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.

Normal PD

ModerateMPTP

SevereMPTP

Radiolabeled FD uptake in the striatum

PD – reduced uptake in the putamen

MPTP – uniform reductions in both the caudate nucleus and putamen

NIH-sponsored placebo controlled trials

Winkler et al, 2005Winkler et al, 2005

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

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

Winkler et al, 2005Winkler et al, 2005

variability in individual outcomes in the open label variability in individual outcomes in the open label studies suggest that other factors might contribute studies suggest that other factors might contribute to the success of the treatment.to the success of the treatment.

1)1) preparation and composition of the graft tissuepreparation and composition of the graft tissue - prolonged - prolonged cold storage and use of solid grafts are not as goodcold storage and use of solid grafts are not as good

2)2) selection of patientsselection of patients - older patients do not tend to benefit as - older patients do not tend to benefit as much as young patients due to less confined damage and much as young patients due to less confined damage and reduced ability to accept to graftreduced ability to accept to graft

3)3) pre-graft medicationpre-graft medication – low-dose patients tend to benefit more – low-dose patients tend to benefit more from graft. In fact, one of the controlled studies with older from graft. In fact, one of the controlled studies with older patients with no significant group improvement there was a patients with no significant group improvement there was a correlation between the magnitude of the response to dose of correlation between the magnitude of the response to dose of L-dopa and the magnitude of the postsurgical improvement.L-dopa and the magnitude of the postsurgical improvement.

4)4) graft placementgraft placement – grafts only innervate tissue 2-3 mm from the – grafts only innervate tissue 2-3 mm from the graft site so benefits will depend on the location of the graft site so benefits will depend on the location of the placement and whether there is limited damage outside of the placement and whether there is limited damage outside of the striatum.striatum.

The authors conclude that standardized procedures for The authors conclude that standardized procedures for selection of patients, graft preparation and selection of patients, graft preparation and immunosuppresion, combined with tailoring the placement immunosuppresion, combined with tailoring the placement of grafts may improve the outcome of this promising of grafts may improve the outcome of this promising therapy for PD.therapy for PD.

MPTP exposure initiates long-term neurodegeneration

Practice questionsPractice questions

Where was the fetal tissue taken from and where Where was the fetal tissue taken from and where was it transplanted to?was it transplanted to?

Immunosuppresion is important for post-surgical Immunosuppresion is important for post-surgical improvement to occur in the first 6 months or after improvement to occur in the first 6 months or after that time.that time.

What was shown to be a misconception regarding What was shown to be a misconception regarding MPTP exposure and why?MPTP exposure and why?

What data suggests that MPTP does not induce What data suggests that MPTP does not induce PD?PD?