Conference Coverage of 54th Annual Meeting of the American Academy of Neurology
Rohit Bakshi, MD
Neuroimager and Associate Professor of Neurology, University at Buffalo, State University of New York, Buffalo, New York
The Mystery of the Multiple Sclerosis (MS) Lesion
Claudia F. Lucchinetti, MD,[9-11] from the Mayo Clinic, Rochester, Minnesota, presented her work on the neuropathology of MS white matter lesions. Current therapies for MS are only partially effective. Many patients will continue to experience relapses and progression of disease despite the most aggressive immunotherapy. Dr. Lucchinetti speculated that the inflammation is a key factor in the pathogenesis of MS. Yet, current therapies that suppress autoimmunity may not completely suppress inflammation. She pointed out that MS is a heterogeneous disease from the standpoint of clinical, neuroimaging, and pathologic features. Recent studies suggest heterogeneity in the patterns of inflammation, demyelination, oligodendrocyte damage, axonal injury, and remyelination among MS patients. These findings raise the possibility that different mechanisms of tissue injury may occur across a spectrum of patients and, thus, multifactorial therapeutic approaches may be necessary.
Dr. Lucchinetti described the pathologic findings from a database of 83 patients with MS, including acute lesions studied by biopsy or autopsy. Four patterns of lesion morphology emerged from this database:
Type I -- Macrophage mediated
Type II -- Antibody mediated
Type III -- Diffuse lesions with loss of myelin-associated glycoprotein
Type IV -- Oligodendrocyte loss, lack of repair
One of these patterns usually predominates in a particular patient. The type I lesion, seen in about 20% of cases, is characterized by marked T-lymphocyte and macrophage infiltration, oligodendrocyte preservation, and evidence of remyelination and repair. The lesions show perivascular inflammation and have well-defined borders. The type II lesion is seen in about 53% of cases and has several of the features of type I lesions. However, type II lesions also have marked immunoglobulin deposition and complement activation. Type III lesions are seen in about 25% of patients. Poorly defined borders and inflammation that is diffuse rather than perivascular characterize these plaques. The myelin-associated glycoprotein is selectively lost and there is little evidence of remyelination. Type IV lesions are typified by loss of oligodendrocytes and the lack of repair. This pattern is only seen in 2% of patients.
Dr. Lucchinetti remarked that the link between specific lesion types and clinical patterns of disease are not yet clear. Preliminary data suggest that patients with Devic disease (neuromyelitis optica) have type II lesions. Balo concentric sclerosis is associated with the type III pattern. Primary progressive MS is related to type IV lesions. However, no definite pattern has been linked to the most common forms of MS, the relapsing-remitting and secondary progressive subtypes.
The next steps are to determine if these histologic lesion types are responsive to specific and possibly different therapeutic strategies. Patients with pattern II lesions have shown the best response to plasma exchange, supporting the concept of antibody-mediated damage. Dr. Lucchinetti's work will continue to unravel these pathologic clues under support from the National MS Society's Lesion Project. This $1.8 million grant over 5 years has been instrumental in continuing the work of this scientist and her international collaborators.
Learning About Human Neurodegenerative Diseases From Flies
Mel B. Feany, MD, PhD,[6-8] from Harvard University Medical School, Boston, Massachusetts, reviewed her work developing insect models of neurodegenerative diseases. As an example, she focused on a model similar to Parkinson's disease in Drosophila fruit flies. Why are fruit flies useful in the study of neurologic diseases? Dr. Feany described 3 main reasons:
Fruit flies are remarkably similar, genetically, to humans, with a 50% overlap in genetic code.
The basic mechanisms of cell injury, death, and regeneration are present in fruit flies and appear to be similar to human cellular biology.
Flies are attractive to study due to their small size, inexpensiveness, and relatively rapid life cycle (60 days).
She then discussed the pathophysiology of Parkinson's disease, including striatonigral depigmentation and deposition of Lewy bodies, the neuropathologic hallmark of Parkinson's disease. Lewy (inclusion) bodies are composed of a protein, alpha-synuclein (ASN). Although the direct role of ASN in the pathogenesis of Parkinson's disease is not clear, familial forms of the disorder are associated with a mutation leading to an aggregation of ASN. Administration of ASN to the brains of flies leads to the selective death of dopaminergic cells. Similarly, humans with Parkinson's disease experience a selective loss of dopaminergic cells in the substantia nigra. The flies also develop Lewy body-like inclusions in the brain. Approximately 30 days into their life cycle, the ASN-treated flies begin to lose motor ability more rapidly than predicted by normal aging.
Dr. Feany remarked at how such an animal model could have important applications to developing better treatments for Parkinson's disease, improving the understanding of the mechanisms behind dopaminergic cell death and repair, and the testing of new pharmacologic agents. Other fly models of human neurodegenerative disease have already been developed to study Huntington's disease, spinocerebellar ataxia, and tauopathies.
From Stem Cells to Circuits: Differentiation and Neurodevelopment
Ronald McKay, PhD,[12-18] from the National Institutes of Health, Bethesda, Maryland, spoke about stem cell research and its potential effect on neurologic disorders. Dr. McKay described his research, which is just beginning to disentangle the complexities of stem cell differentiation and neurodevelopment. He explained that neural stem cells can be induced to become either central nervous system or peripheral nervous system cells, indicating that these are truly undifferentiated. The fate of stem cell maturation can be controlled and directed in vitro. When stem cells are induced to form neurons in the laboratory or through implantation, they form functioning synapses.
One of the great challenges in this field is to develop the methods
for properly incorporating stem cells into complex in vivo neural networks.
This involves understanding how cell-to-cell signaling occurs as neural
circuits develop. Neuronal differentiation is a complex process involving
the release of trophic (growth) factors. During the development of neuronal
pathways, a delicate balance must be maintained between excitatory and
inhibitory connections to assure that the resulting networks function properly.
His studies have shown some of the important events leading to the birth
and death of nerve cells. He believes that, ultimately, this line of research
will have an effect on a variety of chronic neurologic diseases including
Parkinson's, Alzheimer's, and demyelinating diseases.
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