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Effect of nerve growth factor in adrenal autografts in parkinsonism.

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{2-51, whereas risk estimates less than 40% were obtained
in two other studies [l, 67. Resolution of these apparent
differences will be an important step toward understanding
the genetic component in AD.
‘Department of Neurology
tSchool of Public Health
Boston University School of Medicine
$Department of Neurology
Massachusetts General Hospital
Harvard University School of Medicine
Boston, M A
1. Farrer LA, OSullivan DM, Cupples LA, et al. Assessment of
genetic risk for Alzheimer’s disease among first-degree relatives.
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2. BreitnerJCS, Folstein MF. Familial Alzheimer dementia: a prevalent disorder with specific clinical features. Psycho1 Med 1984;
3. Mohs RC, Breitner JCS, Silverman JM, Davis KL. Alzheimer’s
disease: morbid risk among first degree relatives approximates
50% by age 90. Arch Gen Psychiatry 1987;44:405-408
4. Huff FJ, Auerbach BA, Chakravani A, Boiler F. Risk of dementia in relatives of patients with Alzheimer’s disease. Neurology
5. Martin RL, Gerteis G, Gabrielli WF. A family-genetic study of
dementia of the Alzheimer type. Arch Gen Psychiatry 1988;45:
6. Irwin ME, Sadovnick AD, Baird PA, Beattie BL. Familial risks in
Alzheimer’s disease: data for an unselected population. Alzheimer Dis Assoc Dis 1989;3(suppl 1):lO
Effect of Nerve
Growth Factor in Adrenal
Autogrts in Parkrnsonism
obtained during autograft procedures, and normal adrenals
were supplied by 10 kidney donors in the transplantation
Adrenal medulla was carefully dissected and cells were
dissociated, essentially as described by Tischler and colleagues 141. Thirty 60-mm dishes were plated for each experiment. 7s-NGF (100 ng/ml) was added to 15 dishes and
untreated sister cultures were used as a control. Observation
of single cell morphology and cell counting were performed
every other day. Adrenal cells were plated at low density
(total cell recovery was about 500 cells per dish) to reduce
the effects of reciprocal cellular conditioning. Cultures were
fed twice a week and pictures were taken every other day.
After staining for tyrosine hydroxylase (TH), 92% ( +- 6 SD)
of the attached cells were found to be catecholaminergic
independently of NGF treatment. A morphological change
occurred spontaneously in both NGF-treated and untreated
chromaffin cells (both from control and parkinsonian medulla) after a delay of 4 to 5 days; cells shifted from a round
shape to a polygonal appearance, showing initial neurite extensions ending in growth cones. The number of process-
Vincenzo Silani, MD, Andrea Falini, MD,
Ornella Strada, MD, Antonio Pizzuti, MD,
Gianni Pezzoli, MD, Enrico D. F. Motti, MD,
Antonio Vegeto, MD, and Guglielmo Scarlato, MD
Controversial clinical results of autografts in pharmacologically intractable parkinsonian patients have renewed interest
in the basic study of the human adrenal medulla as a putative
catecholaminergic graft donor {IJ. The value of the donor
tissue itself has been questioned after decreased catecholaminergic content was reported in the parkinsonian adrenals
[2}, which were already known to contain Lewy bodies 131.
Assessment of the cell capacity to respond to identified
neurotrophic factors would aid further evaluation of the use
of adrenomedullary tissue for grafting and the design of new
surgical strategies.
We report here on the effects of Nerve Growth Factor
(NGF) on adrenal medullary cells in culture from 3 patients
(45-51 years of age) with Parkinson’s disease (Hoehn and
Yahr, stage 3-5) and from patients without parkinsonism
(ranging in age from 9 to 60 years). Parkinsonian glands were
Cultured chromafin cells fmm an adrenal autograft in a 52year-oldparkinsonianpatient at day 15 in vitro. (A) Nerve
growth factor-treated cells show extensive neurite outgrowths
with growth cones. (Phase-contrastphotomicroscopy.) (B) Immunojuorescence-positivestain for tyrosine hydroxykzse is denonstrated in the soma and along the neurites. (A and B, x 500
before 8% reduction.)
Annals of Neurology Yo1 27 No 3 March 1990 341
bearing, polygonal cells was significantly greater in NGFtreated (75 t 4.5% SD of total cells) than in untreated cells
(8 + 2% SD). The same ratio of process-bearing to total
cells was observed in control and parkinsonian chromaffin
cultures. Even the rate of neurite outgrowth from parkinsonian medullary cells was comparable to that of age-matched
donor adrenals.
At day 15 of NGF treatment, 1 or 2 neurites per cell
extended over 1 mm of length (40 5 5.5% SD of the cells
exceeded 3 mm of length), with diffuse staining along neurites and growth cones when tested with antibody against TH
enzyme (Fig). NGF significantly increased survival in both
control and parkinsonian cells, with 88% ( k 7 . 2 SD) cell
viability observed after 30 days in vitro compared to 42%
(+6 SD) survival in untreated cultures.
These data demonstrate that aged parkinsonian adrenal
medullary cells from autograft recipients are able to maintain
the capacity to respond to epigenetic influences such as
NGF. In this respect parkinsonian medullary cells are comparable to normal control cells [5}. The evidence also suggests that the use of NGF, together with surgical strategies
such as implanted infusion pumps or in vitro pretreatment
of the adrenal cells prior to implantation, could influence
342 Annals of Neurology Vol 27 No 3 March 1990
neuronal phenotype expression and improve the effectiveness of the graft in parkinsonian patients.
Institutes of Neurology, Neurosurgery,
and Transplantation Surgery
University of Milan Medical School
Milan, Italy
1. Madrazo I, Drucker-Colin R, Diaz V, et al. Open microsurgicd
autograft of adrenal medulla to the right caudate nucleus in two
patients with intractable Parkinson’s disease. N Engl J Med
2. Carmichael SW, Wilson RJ, Brimijoin WS, et al. Decreased catecholamines in the adrenal medulla of patients with parkinsonism.
N Engl J Med 1988;318:254
3. Den Hartog Jager WA. Histochemistry of adrenal bodies in Parkinson’s disease. Arch Neurol 1970;23:528-533
4. Tischler AS, DeLellis RA, Biales B, et al. Nerve Growth Factorinduced neurite outgrowth from normal human chromaffin cells.
Lab Invest 1980;43:399-408
5. HansenJT, Notter MFD, Okawara SH, Gash DM. Organization,
fine structure, and viability of the human adrenal medulla: considerations for neural transplantation. Ann Neurol 1988;24:599609
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factors, autograft, effect, growth, nerve, adrenal, parkinsonism
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