Hereditary PrP Amyloidosis with Alzheimer Changes

Over the past thirteen years investigators of the Departments of Pathology, Neurology, Medical Genetics and Ophthalmology of Indiana University have studied a large kindred from Southern Indiana. Members of this family develop ataxia, Parkinsonism and dementia in the fifth decade of life. The disease is autosomal dominant and it has been traced back eight generations to 1796. Currently there are 164 fully at-risk individuals: they have a 50% chance to develop the disease. Two hundred and forty individuals are one-half at-risk. It is of great interest that the neuropathologic studies carried out in six individuals of this kindred have shown an Alzheimer-like pathology. Indeed neuritic plaques and neurofibrillary tangles are consistently observed. In spite of the similarity with Alzheimer disease, immunocytochemical studies have revealed that this condition is significantly different from Alzheimer disease. In fact the amyloid of the plaques is not immunolabeled by antisera against the ß-protein but it is labeled by a prion protein. The neuropathologic studies have been extended and a collaboration with Ors. Bugiani and Tagliavini of the Neurological Institute “C Beata” in Milano has allowed us to simultaneously investigate several issues, such as immunohistochemical properties of the neurofibrillary tangles and of the amyloid, nerve cell loss, iron deposition, topography of plaques and tangles . Recently, we have initiated collaborative efforts with Ors. Stanley Prusiner and Blas Frangione. In Dr. Prusiner’s laboratory, it has been found that in affected members of the Indiana kindred, there is no mutation in the open reading frame of the gene that codes for the PrP protein. In Dr. Frangione’s laboratory, the first attempt to isolate human PrP amyloid has been carried out. Having learned that there is no mutation in the PrP gene open reading frame, it becomes essential to further develop the multidisciplinary efforts in order to clarify the disease of the Indiana kindred. We are planning to extend the clinical studies in order to make possible the early identification of new patients among the individuals of the IK, who are at risk for developing the neurological signs. Neuro-ophthalmologic studies indicate that abnormal eye movement may precede the onset of ataxia by several months or even years. Sophisticated studies of the abnormal ocular movement are in progress and the data are being correlated with Nuclear Magnetic Resonance results. In the Department of Medical Genetics, investigators are collecting DNA samples and carrying out genetic linkage analysis. In Dr. Frangione’s laboratory, the characterization of the amyloid protein  proceeds. The neuropathologic studies, now proposed, will definitively reveal the neuropathologic phenotype of the disease in the Indiana Kindred. Furthermore, it will be of significant interest to carry out a neuropathologic comparison between patients of the IK, patients with familial Alzheimer disease and individuals affected by similar neurological signs and known to have a mutation of the PrP gene.

In the literature, several families characterized by a dominant disorders with ataxia and dementia have been described; neuropathologically presence of neurofibrillary tangles and plaques is most conspicuous. Such cases have been labeled as familial Alzheimer disease. Is there a link between Alzheimer disease and the IK disease? Carrying out the proposed neuropathologic investigations, in conjunction with amyloid cha- racterization and genetic linkage analysis will allow us to shed new light on this important question.