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Adult, female cynomolgus monkey (Macaca fasciculata)

SIGNALMENT: Adult, female cynomolgus monkey (Macaca fasciculata)

TREATMENT PROTOCOL

This animal received test compound 6 µg/day rhNGF (recombinant human Nerve Growth Factor) for 6 months by continuous infusion directly into the lateral ventricle of the brain.

GROSS PATHOLOGY: No gross lesions.

LABORATORY RESULTS:
There were no effects on body weight or other in-life effects, and no changes in clinical pathology parameters.

What's Your Diagnosis? Provide your possible etiologies in the comment section below. Member login is required to comment.

R113a. Treated. Scanning power. H&E. Cervical spinal cord. Note the thick layer of abnormal tissue overlying the spinal cord on the dorsal and dorsolateral surfaces.	R113b. Treated 10x obj, H&E stain. Cervical spinal cord. Same section as Figure 113a but rotated 90 degrees counterclockwise. The abnormal tissue is very cellular and forms rather haphazard bundles of cells (left).
R113c.Treated 40x obj, H&E stain. Same area as Figure 113b. Nuclei in the abnormal tissue are spindle-shaped. The matrix looks rather fibrillar.	R113d. Treated, 60x obj, Holmes Silver Nitrate/Luxol Fast Blue stain. In this section was taken from the same area dorsal to the cervical spinal cord in R113a above. Some of the linear structures are probably nerve fibers, but good myelin staining is not seen.
R113e. Treated 40x obj, Type 4 collagen immunostain. Same area as R113d above. Intensely positive staining. This is the type of collagen found in basement membranes.	R11f. Treated, 40x obj, Same area as above. Neurofilament immunostain. Not as profound as the previous stain, but still clearly positive for this intermediate filament found in cells of neural origin.
R113g. Treated, 4200x, TEM. Same area as above. Tissue was not well preserved for EM, but both myelinated and unmyelinated axons are evident.	R113h. Treated 21000x, TEM. Same area as above. Note the beautifully laminated myelin sheath and the basement membrane around the outside.

MORPHOLOGIC DIAGNOSI(E)S AND ETIOLOGY:

Cervical spinal cord: Nervous tissue proliferation, intraleptomeningeal, chronic, dorsal and dorsolateral, marked

Etiology: Chronic exposure to recombinant human Nerve Growth Factor via the intracerebroventricular route

Neuroproliferative response to Nerve Growth Factor (NGF) within the leptomeninges of the cervical spinal cord. H&E stained sections show the thick layer of new tissue overlying the cervical spinal cord under the dura. The Holmes Silver Nitrate/Luxol Fast Blue stain for nerve fibers and myelin is suggestive of a nervous origin for the tissue. Positive Neurofilament stain (intermediate filament in cells of neural origin) supports that conclusion. Positive Type IV collagen (component of basement membrane) suggests a support cell network.

Electron microscopy is less than optimal, being done on tissue that was immersion fixed in formalin for 6 month prior to processing. However, scattered myelinated fibers, Schwann cell-like cells and nerve fibers are identifiable.

CONTRIBUTOR: Roche Bioscience, Palo Alto, CA, USA.

CONTRIBUTOR'S COMMENTS:

Six-month ICV (IntraCerebroVentricular) studies with rhNGF were run in rats and monkeys. A similar neuroproliferative response within the leptomeninges of the hindbrain and spinal cord occurred in both species at all doses tested. Immunohistochemical staining and electron microscopy indicated that the proliferative tissue consisted of nerve fibers and support cells (1). Reversibility of the effect was shown in rats on a seven-week ICV study (2).

Nerve Growth Factor was discovered in the early 1950s and has been the subject of much research interest in the subsequent decades. Its use in the treatment of Alzheimer s disease was proposed because of its known role in supporting the differentiation, growth and survival of cholinergic neurons in the basal forebrain. Loss of these neurons is part of the constellation of changes associated with Alzheimer s disease.

Syntex and Synergen formed a joint venture to evaluate the use of NGF for Alzheimer s disease. The ICV route was chosen to bypass the blood brain barrier and place the agent as close to the target area as possible. Evaluation of the 6-month rat and monkey studies showed no pathology in the basal forebrain or the ventricular system, but a significant effect (proliferation of nerve fibers and support cells) around the caudal-ventral brain and the dorsal-lateral spinal cord in both species, as shown in the slides seen below.

That NGF should cause such a change should not be surprising; it is just living up to its name. What is surprising is that in 40 years the effect was not reported despite very active research. The take-home message from this case is never focus too tightly on the area of interest, there may be something important going on elsewhere .

After reporting the pathology findings to the FDA, the joint venture elected to discontinue the development of rhNGF for Alzheimer s disease based in part on the difficulties of monitoring for the neuroproliferative effect.

REFERENCES:

1. 1. "Hyperplastic Changes within the Leptomeninges of the Rat and Monkey in Response to Chronic Intracerebroventricular Infusion of Nerve Growth Factor", P. A. Day-Lollini, G. R. Stewart, M. J. Taylor, R. M. Johnson and G. J. Chellman, Experimental Neurology 145, PP 24-37 (1997).
   2. "Reversible Schwann Cell Hyperplasia and Sprouting of Sensory and Sympathetic Neurites after Intraventricular Administration of Nerve Growth Factor", J. Winkler, G. A. Ramirez, H. G. Kuhn, D. A. Peterson, P. A. Day-Lollini, G. R. Stewart, M. A. Tuszynski, F. H. Gage, and L. J. Thal, Annals of Neurology, Vol. 1, No. 1, PP 82-93, 1997.