Positive Potential of Fetal Nigral Implants for Parkinson Disease
(Editorial) by Roger N. Rosenberg Archives of Neurology. 2004;61:837-838.


Abstract of article, "Reaction time and movement time after embryonic
cell implantation in Parkinson disease." follows


"In 2001, Freed et al1 reported that human embryonic dopamine-neuron
transplants survive in patients with severe Parkinson disease (PD) and do
result in some clinical benefit in younger but not in older patients,
those older than 60 years. In a similar study in 2003 with bilateral
human embryonic dopamine-neuron implants in the putamen in patients with
PD, Olanow et al2concluded that transplantation offered no significant
improvement and could not be recommended.  Both studies were unable to
achieve their primary objective of major clinical improvement despite
increased striatal F-18 fluorodopa uptake with positron emission
tomography and data showing maintenance of transplanted neurons at
postmortem examination.1-2 Freed et al1 did find improved motor function
in a subset of patients younger than 60 years; Olanow et al did not find
similar evidence but did note improvement in patients with milder disease
at baseline. Of note, both studies reported disabling dyskinesia while
not receiving medication in patients who received a transplant.  In this
issue of the ARCHIVES, Gordon et al3 provide an update from the original
Freed et al1 cohort of patients who were initially described in 2001.
They have quantitatively analyzed patients who received either sham or
embryonic nigral implants for their combined reaction time (RT) and
movement time (MT) to measure motor performance. Reaction time is a
measure of premovement central neural processing. Movement time is a
physiologic correlate of movement and is prolonged in bradykinesia.1, 3
Forty patients with levodopa-responsive Hoehn and Yahr scale stage 3 or
greater PD were randomized to receive implants or placebo (sham) surgery.
All patients underwent RT + MT measurements preoperatively and at 4 and
12 months postoperatively while not taking medication. Of considerable
interest, the difference in mean RT + MT between the sham and the implant
groups was statistically significant (P = .005) and was greatest in those
older than 60 years (P = .003). They found that there was significant
deterioration in the sham surgery group at 12 months, which was thought
to be the result of worsening in patients older than 60 years (P = .003).

Their findings are of significance even though they may be clinically
modest. I concur with Gordon et al that these observations show that
comprehensive analyses of different RT paradigms can document subtle
changes in motor performance across time. These documented changes of
physiologic benefit recorded in their article do indicate that there are
objective markers of motor behavior that were altered for the better with
embryonic tissue implantation in patients with PD.
We are at the beginning of our understanding of the neurobiological and
neurotherapeutic basis of stem cell and embryonic cell transplantation
for neurological diseases. The human genome was first sequenced and
analyzed in 2001, and of the 30 000 to 35 000 genes now known, only about
5% have been identified as to their gene product and function in the
mammalian brain. An entire issue of the Archives of Neurology was devoted
to Genomic Neurology in November 2001, and one can see in that review
issue that the era of genomic neurology has really just begun.
The therapeutic rewards from a complete analysis of the genomic and
proteomic microarrays from normal and PD brain tissue will provide
important insights as to the specificity of altered gene expression in PD
caused by inherited genetic polymorphisms or the consequence of
environmental factors and toxins. We should be very encouraged by the
studies of Freed et al,1 Olanow et al,2 and Gordon et al3 related to the
margins of improvement in embryonic neuronal implant therapy for PD.
Embryonic neuronal implants and stem cell implants provide many potential
therapeutic factors besides dopamine. These tissue implants secrete
trophic factors, cytokines, interleukins, and even potential toxic
inflammatory products.  The issue now is to define the specific factors
needed to reestablish the normal nigral-striatal, nigral-pallidal,
nigral-subthalamic, and nigral-reticular connections that the stem cell
or embryonic neuronal implant can provide. The specific genes that
synthesize these factors (gene products) responsible for forming these
circuits need to be identified from ongoing neurogenomic studies and
induced in association with the neural or stem cell implants to
reestablish a normal extrapyramidal motor circuitry to reverse the
degenerative pathologic process of PD. It is clear now that these genes
that underlie the formation of motor circuits in embryogenesis will be
found and will provide the instructions to reproduce these events again.
The current information provided by present studies1-3 provide an
important beginning and basis to design new genomic approaches.  Gordon
et al3 in this issue of the ARCHIVES build on the prior observations of
Freed et al1 and Olanow et al2 in showing that small but definite
improvements do occur with embryonic neural implants.  The challenge now
is to build on these nascent findings through genetic and genomic
studies. I believe these will provide important insights into neural
circuit patterning and formation and will lead to highly specific and
effective new genomic-based therapies. The golden age of neurology is
just beginning!
AUTHOR INFORMATION
Corresponding author: Roger N. Rosenberg, MD, Archives of Neurology,
University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd,
Dallas, TX 75235-9108 (e-mail: [log in to unmask]).

REFERENCES
1.      Freed CR, Greene PE, Breeze RE, et al. Transplantation of embryonic
dopamine neurons for severe Parkinson disease. N Engl J Med.
2001;344:710-719. ABSTRACT/FULL TEXT
2.      Olanow CW, Goetz CG, Kordower JH, et al. Double-blind controlled trial
of bilateral fetal nigral transplantation in Parkinson disease. Ann
Neurol. 2003;54:403-414. CrossRef | ISI | MEDLINE
3.      Gordon PH, Yu Q, Qualls C, et al. Reaction time and movement time
after embryonic cell implantation in Parkinson disease. Arch Neurol.
2004;61:858-861. ABSTRACT/FULL TEXT

Abstract:

Reaction Time and Movement Time After Embryonic Cell Implantation in
Parkinson Disease Paul H. Gordon, Qiping Yu, Clifford Qualls, Hal
Winfield, Sandra Dillon, Paul E. Greene, Stanley Fahn, Robert E. Breeze,
Curt R. Freed, and Seth L. Pullman Arch Neurol. 2004;61:858-861.

Background :
 Embryonic nigral cell implants are a novel treatment for Parkinson
disease (PD). Reaction time (RT) and movement time (MT) analysis,
validated quantitative measures of premovement neural processing and
motor execution, can be used as objective physiological markers of motor
performance in PD.  Objectives  To gauge the change in motor performance
in patients with PD who received implants, and to determine whether the
physiological findings correlate with clinical outcome measures after
transplantation.

Design:
  Double-blind, placebo-controlled trial.  Patients  Forty patients with
levodopa-responsive, Hoehn and Yahr stage III or greater PD.

Interventions:
  Random assignment to embryonic tissue implants or placebo (sham)
operation.
Main Outcome Measures  Combined RT + MT scores measured preoperatively
and at 4 and 12 months postoperatively in the “off” state.

Results:  The difference in mean RT + MT scores between the sham and
implant groups was statistically significant (P = .005) and was greatest
in those 60 years or older (P = .003). Changes correlated with Unified
Parkinson’s Disease Rating Scale off scores at 4 (r = 0.87, P = .001) and
12 (r = 0.75, P = .01) months in those younger than 60 years. There was a
significant deterioration in the sham surgery group at 12 months (P =
.03) that was thought to be due to worsening in subjects 60 years and
older (P<.001).

Conclusions:
  The physiological measures detected significant changes in patients
undergoing embryonic nigral cell implants and correlated directly with
clinical outcome measures. Comprehensive analyses of RT paradigms can
document subtle changes in motor performance over time, making them
useful outcome measures in therapeutic trials of PD. These findings
support further research into nigral cell implantation for PD.

From the Department of Neurology and Clinical Motor Physiology
Laboratory, Columbia-Presbyterian Medical Center, New York, NY (Drs
Gordon, Yu, Greene, Fahn and Pullman; Mr Winfield; and Ms Dillon);
Department of Biostatistics, University of New Mexico, Albuquerque (Dr
Qualls); and Departments of Neurosurgery (Dr Breeze), Medicine (Dr
Freed), and Pharmacology (Dr Freed), University of Colorado, Denver (Drs
Breeze and Freed).

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