The Burrill Report

Using high-resolution functional MRI imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center researchers have clarified three fundamental issues about Alzheimer's disease: where it starts, why it starts there, and how it spreads. Besides advancing understanding of the debilitating neurodegenerative disease, the findings could improve early detection when drugs may be most effective.

“It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex,” says co-senior author Scott Small, professor of neurology, professor of radiology, and director of the Alzheimer's Disease Research Center. “But this study is the first to show in living patients that it begins specifically in the lateral entorhinal cortex, or LEC. The LEC is considered to be a gateway to the hippocampus, which plays a key role in the consolidation of long-term memory, among other functions. If the LEC is affected, other aspects of the hippocampus will also be affected.”

The study, which was just published in the online edition of Nature Neuroscience, also shows that, over time, Alzheimer's spreads from the LEC directly to other areas of the cerebral cortex, in particular, the parietal cortex, a brain region involved in various functions, including spatial orientation and navigation. The researchers suspect that Alzheimer's spreads by compromising the function of neurons in the LEC, which then compromises the integrity of neurons in adjoining areas.

A third major finding of the study is that LEC dysfunction occurs when changes in tau and amyloid precursor protein co-exist. “The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of amyloid precursor protein. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's,” says co-senior author Karen Duff, professor of pathology and cell biology in psychiatry and in the Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University Medical Center and at the New York State Psychiatric Institute.

The researchers used a high-resolution variant of functional MRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project, a longitudinal study of aging and dementia among elderly, urban-dwelling residents that began enrolling patients in 1989 and has followed more than 5,900 residents over 65 years of age. All of the adults in the study were free of dementia at the time of enrollment, allowing researchers to image and characterize patients with Alzheimer’s in its earliest, preclinical stage.

The 96 adults were followed for an average of 3.5 years, at which time 12 individuals were found to have progressed to mild Alzheimer's disease. An analysis of the baseline functional MRI images of those 12 individuals found significant decreases in cerebral blood volume—a measure of metabolic activity—in the LEC compared with that of the 84 adults who were free of dementia.

A second part of the study addressed the role of tau and amyloid precursor protein in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and amyloid precursor protein abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

The researchers created three mouse models to answer this question, one with elevated levels of tau in the LEC, one with elevated levels of amyloid precursor protein, and one with elevated levels of both proteins. The researchers found that the LEC dysfunction occurred only in the mice with both tau and amyloid precursor protein.

The study has implications for both research and treatment. “Now that we've pinpointed where Alzheimer's starts, and shown that those changes are observable using functional MRI, we may be able to detect Alzheimer's at its earliest preclinical stage, when the disease might be more treatable and before it spreads to other brain regions,” says Small.

The researchers also note that the new imaging method could also be used to assess the efficacy of promising Alzheimer's drugs during the disease’s early stages.

The study was supported by several grants from National Institutes of Health.

December 26, 2013
http://www.burrillreport.com/article-alzheimer%e2%80%99s_disease_unraveled.html