NAF Ataxia Research Studies Currently Underway

Arnulf H Koeppen, MD

VA Medical Center
The pathogenesis of hereditary ataxia

Summary: Cerebellar ataxia is the aggregate result of disturbed connections between the cerebellum, the brain stem, and the spinal cord. One group of fiber connections constitutes the "cerebellar module". The participating nerve fibers form a precise triangle between the lower brain stem where the important inferior olive is located, and the Purkinje cells of the cerebellar cortex. In turn, Purkinje cells send their impulses to a gray matter structure in the depth of the cerebellum, the dentate nucleus. This nucleus is the main way station for information that exits the cerebellum and streams towards the forebrain. However, the dentate nucleus must also report back to the inferior olivary nucleus. The triangular module is continuously active during movement. It provides surveillance and control, and a disturbance in the module causes ataxia. In most spinocerebellar ataxias (SCA), sporadic ataxia, and Friedreich's ataxia (FRDA), at least one component of the cerebellar module is destroyed. In SCA-1, SCA-2, SCA-7, and the most common form of sporadic ataxia, multiple system atrophy (MSA), an additional problem exists in the gray matter of the pons. The pons, literally the bridge, is a bulging part of the middle brain stem. It conveys abundant impulses to the cerebellum. When its nerve cells degenerate, the patient will have olivopontocerebellar atrophy (OPCA). In SCA-3/Machado-Joseph disease (MJD) and FRDA, the disease predominantly affects the dentate nucleus. The principal investigator seeks to apply his experience with numerous tissue samples from patients with ataxia to an advanced study of the disturbed cerebellar module. The focus is on connections between nerve cells. When a nerve cell dies, it can no longer receive or issue signals. It can also not provide the normal nutrients that travel up and down nerve connections. However, in SCA-6, deprived nerve fibers can seek new connections with neighboring cells and find nutrients from an alternate source. The investigator also believes that nerve cell loss in the dentate nucleus is due to an inappropriate proliferation of terminals. This phenomenon is especially prominent in the dentate nucleus of patients with SCA- 3/MJD and FRDA. If this research shows that abnormal nerve terminals proliferate and utilize an excess of an otherwise normal transmitter substance, such as glutamic acid, currently available drugs may be beneficial.