1985 — 1986 |
Sadun, Alfredo A |
R23Activity Code Description: Undocumented code - click on the grant title for more information. |
Neuroanatomy of the Human Visual Pathways @ University of Southern California
The present view of the neuroanatomy of the human visual system has been formulated from observations of gross pathological dissections, deductions made from clinical cases and inferences from animal studies. Further attempts to delineate the visual pathways in man have been limited by the infeasibility of contemporary neuroscience research methods for use in man. This has remained an obstacle in attempts to analyze the physiologic basis of human neuro-ophthalmic disease. We have recently developed and demonstrated the use of a staining method utilizing paraphenylene-diamine (PPD) to identify degenerated axons and axon preterminals in the human brain. The PPD method reliably stains degenerated axons even years after the neural lesion. Preliminary studies have been done on 19 post-mortem cases, 14 of these with documented optic nerve lesions. The primary visual pathways were studied with PPD conventional light microscopic methods, and EM. With this new method, degenerated retinofugal fibers and their terminals were followed to primary visual brain nuclei. Our studies confirm some previously proposed primary retinal projections, reveal neuroanatomical discrepancies between man and other species, and provide evidence for retinofugal pathways not previously described in man. The nature of the PPD stain and the long-term course of axonal degeneration will be studied by comparisons of PPD and EM in perfused experimental animal brains. With this new method, we can extend our preliminary findings by following degenerated axons and describing the terminal distribution patterns of the retinofugal fibers in human necropsy brain tissue in which previous damage to the visual system has occurred. We hope to identify other visual nuclei not previously demonstrated in man by examining brain areas suggested by experimental animal studies. It is also possible to identify various retinal fiber types by size, compare their distribution, and describe the post-synaptic changes which may follow chronic deafferentation of visual input. The ability to directly study the human visual pathways will enable us to go beyond our reliance on animal models of human visual neuroanatomy. This opportunity to learn of the human visual anatomy may lead to the appreciation of the anatomical substrates with which we can better understand neuro-ophthalmic abnormalities, such as amblyopia or cortical blindness.
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1989 — 1991 |
Sadun, Alfredo A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Aids as a Cause For Primary Optic Neuropathy
Acquired Immunodeficiency Syndrome (AIDS) is known to produce several clinical manifestations in the eye as well as in various other parts of the central nervous system. However, the optic nerves fro patients with AIDS have not been systematically evaluated either clinically or histopathologically. REcent investigations in our laboratory provide preliminary evidence that optic nerves obtained from AIDS patients have diminution of axons compared to age-matched controls. This axonal loss did not appear to correlate with the use of certain medication regimens. We will utilize the PPD method for identifying degeneration in the optic nerves of patients with AIDS on various treatment modalities and HIV+ and HIV- age-matched controls. The distribution of this degeneration could lead to insights regarding the nature of the lesion and efficacy of treatment. Additionally, the PPD method in conjunction with our computerized image enhancement system permits us to do quantitative analyses of total fiber counts, and the nerve fiber spectrum. The extent and distribution of degeneration in intracranial optic nerve can be compared to degeneration in retrobulbar optic nerve and retinal to help ascertain to what extent AIDS related degeneration in the optic nerve is primary or consequent to nerve fiber layer infarcts from retinal manifestations of the disease. The pattern and extent of degeneration of the optic nerves can then be compared with the clinical impairments associated with optic nerve disease in AIDS patients. Such clinical impairments may be detectable in AIDS Related Complex (ARC) or other HIV+ patients in the absence of obvious symptoms.
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1994 — 1997 |
Sadun, Alfredo A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Cytokines in Aids-Associated Optic Neuropathy @ University of Southern California
Acquired immunodeficiency syndrome (AIDS) carries a high morbidity rate, with a high incidence of neurological and opthalmogical expressions. Recently, we described the clinical and histopathological features of an AIDS-associated optic neuropathy. The histopathology of these optic nerves resembles progressive diffuse leukoencephalopathy (PDL) characteristic of the brain pathology seen in AIDS. Dramatic morphologic evidence of activated neuroglia and macrophages was seen in association with axons at varying stages of degeneration. We hypothesize that the macrophages associated with degeneration may mediate axon degeneration via the release of various cytokines, particularly tumor necrosis factor (TNF). We are studying the association of TNF with the primary optic neuropathy of AIDS in humans and investigating causality and (to some extent) mechanics, through animal models. The incidence of the primary optic neuropathy of AIDS is now established by psychophysical assessments in AIDS patients and by postmortem optic nerve pathology. We have also succeeded in establishing an animal model of optic nerve axonal degeneration, produced by intravitreal injection of TNF in rabbits. We are continuing to refine and develop this animal model by establishing dose/response curves, following the time course of injury, and looking for different stages of cellular response in the rabbit optic nerve with light microscopy, morphometry, and electron microscopy. TNF levels will be obtained in AIDS patients and controls and correlated with the clinical manifestations of the disease as measured by several ophthalmological and neurological tests. Histopathology and ultrastructure of postmortem AIDS optic nerve will be compared to ur rabbit model. Comparison will also be made to simian AIDS using the monkey model maintained at the California Primate Research Center. This combined clinical/psychophysical, histopathological and immunochemical approach in both human an animal models will contribute to an understanding of the mechanisms of axonal death and may provide a means to test TNF suppressive effects as a potential treatment for AIDS and other conditions.
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1997 — 1999 |
Sadun, Alfredo A |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Optic Neuropathy From Mitochondrial Derangement @ University of Southern California
DESCRIPTION: A recent epidemic of optic nerve blindness affecting 50,000 people in Cuba was successfully treated through vitamin therapy. The clinical features of the Cuban epidemic of optic neuropathy (CEON) were similar to both tobacco-alcohol-amblyopia and Leber's hereditary optic neuropathy (Leber's). In each case, there is evidence that singular or combined insults to mitochondrial oxidative phosphorylation impair ATP production, however, this does not explain why other metabolically active tissues such as liver or heart are spared. Therefore, the questions remain: why nerves, why the optic nerve, why the papillo macular bundle? The PI hypothesizes that a common pathophysiological mechanism involving impaired mitochondria and the ATP expensive mitochondrial axonal transportation underlies genetic optic nerve diseases such as Leber s metabolic and nutritional diseases such as CEON, and a variety of toxic optic neuropathies as well. Total ATP depletion due to blockage of mitochondrial transportation may trigger cell death although conventional wisdom suggests that partial optic nerve axonal stasis (e.g. papilledema) does not usually lead to degeneration. The PI is studying the association between the compromise of mitochondrial function and optic neuropathies and investigating causality and mechanism. Four trips to Cuba have given the investigator unparalleled access to examine patients and obtain tissues (150 sera and CSF samples, sural nerve biopsies, and an eye with optic nerve all secured at the height of the epidemic) from CEON patients. The pathophysiology of CEON, as revealed by clinical, pathological, and blood biochemical correlations suggests that deranged oxidative phosphorylation may be the source of this disease. He has succeeded in developing an analogous animal model of deranged oxidative phosphorylation by administering chronic, low doses of methanol to folic acid deficient rats. With parallels to CEON, the animal model has elevated serum formate levels and optic nerve axonal vacuolation, reflecting blocked transport, found only at the lamina cribrosa. The PI is continuing to refine and characterize this model by following the time course of injury. The animal model will permit us to examine the relationship between elevated formate, the inhibition of oxidative phosphorylation as measured by ATP level, mitochondrial transport, and neuronal injury (assessed via morphological, ultrastructural, and biochemical analysis). These findings will permit to test the hypothesis that in susceptible neuronal tissues, mitochondrial derangement leads to ATP depletion, hence to decreased mitochondrial transportation which results in even further ATP depletion as part of a vicious cycle that collapses the system. By modulating and trying to prevent this vicious cycle, he will gain better understanding of the kinetics of the mitochondrial pathways. He expects this to lead to new treatments for a variety of genetic and acquired optic neuropathies.
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