New Form Of Inherited Dementia Identified

INDIANAPOLIS-- Researchers at the Indiana University School of Medicine and the Medical Research Council of Great Britain have identified an autosomal dominant inherited dementia which first appears in individuals in their forties and fifties and is both pathologically and clinically different from Alzheimer disease. They report their findings in a paper published in the April 15 issue of the Proceedings of National Academy of Sciences.

These findings also will be presented at the American Academy of Neurology meeting in Boston on April 17 by Bernardino Ghetti M.D., a neuropathologist and senior author of the PNAS paper. Two of the papers co-authors will also make presentations at the AAN meeting. Martin R Farlow, M.D. will discuss the clinical aspects of the disease. Jill R. Murrell Ph.D. will describe the search for the gene causing this type of dementia. All three are members of the IUSM faculty.

The researchers have named the newly identified brain disorder familial multiple system tauopathy with presenile dementia. The name reflects the characteristics of the disease. It has an early onset, is inherited, and involves both the cortical and subcortical systems of the brain In addition, tau, a microtubule associated protein found in the brain, is abnormal in these patients.

The cortex is the outer layer of gray matter of the cerebrum and cerebellum of the brain. The subcortical system is the part of the brain beneath the cortex. Tau is responsible for the maintenance of the microtubules that in turn are important for transport within brain cells.

Dr. Ghetti noted that the study of tau had led to the discovery of the new dementia. "We don't yet know why tau becomes abnormal in patients with this disease, but we do know that it becomes abnormal in a different way than it does in patients with other types of dementia including Alzheimer disease."

This is the first hereditary disease in which the tau abnormality is present in glial cells as well as nerve cells. Examining the brains of nine affected members of an extended family, Dr. Ghetti found that this disease is characterized by abundant filaments of tau protein in the neurons and glial cells. The filaments in the neurons are twisted. These tau deposits differ in diameter and spacing from the paired filaments found in the nerve cells of Alzheimer disease patients. No detectable amyloid plaque deposits were found in the brains of individuals with this newly identified dementia. Amyloid plaque deposits are characteristic of Alzheimer disease-affected brains.

Using electrophoresis to isolate the protein, the researchers noted 3 bands of biological markers in this disease, unlike the 4 bands which characterize Alzheimer disease.

"We now have in front of us a challenge to find a new gene that may have an extremely important role in the maintenance of the central nervous system," said Dr. Ghetti. The IU researchers have localized the gene to chromosome 17, the same chromosome on which the tau gene is found. Clinical symptoms of the newly identified disease include short term memory deficit, eye movement alterations, disequilibrium, and Parkinson disease-like neurological characteristics including rigidity and gait problems. These symptoms are reflected in the wide spectrum of changes in brain structure affecting both the cortical and subcortical regions seen during post-mortuary examination.

Affected individuals live an average eleven years after onset of the disease.

Other members of the research team are molecular biologists Maria Grazia Spillantini, Michel Goedert and electron microscopist R. Anthony Crowther. Al1 are with the Medical Research Council of Great Britain and have studied tau for many years.

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