High-resolution functional MRI imaging shows where Alzheimer disease starts and how it spreads


Using high-resolution functional MRI ( fMRI ) imaging in patients with Alzheimer's disease and in mouse models of the disease, Columbia University Medical Center ( CUMC ) researchers have clarified three fundamental issues about Alzheimer's: where it starts, why it starts there, and how it spreads.
In addition to advancing understanding of Alzheimer's, the findings could improve early detection of the disease, when drugs may be most effective.
The study was published in the journal Nature Neuroscience.

It has been known for years that Alzheimer's starts in a brain region known as the entorhinal cortex. 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 has also shown 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 functionally, that is, 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 was that LEC dysfunction occurs when changes in tau and amyloid precursor protein ( APP ) co-exist.
The LEC is especially vulnerable to Alzheimer's because it normally accumulates tau, which sensitizes the LEC to the accumulation of APP. Together, these two proteins damage neurons in the LEC, setting the stage for Alzheimer's.

In the study, the researchers used a high-resolution variant of fMRI to map metabolic defects in the brains of 96 adults enrolled in the Washington Heights-Inwood Columbia Aging Project ( WHICAP ).
All of the adults were free of dementia at the time of enrollment.

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 fMRI images of those 12 individuals found significant decreases in cerebral blood volume ( CBV ), 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 APP in LEC dysfunction. While previous studies have suggested that entorhinal cortex dysfunction is associated with both tau and APP abnormalities, it was not known how these proteins interact to drive this dysfunction, particularly in preclinical Alzheimer's.

To answer this question, the team created three mouse models, one with elevated levels of tau in the LEC, one with elevated levels of APP, and one with elevated levels of both proteins.
The researchers found that the LEC dysfunction occurred only in the mice with both tau and APP. ( Xagena )

Source: Columbia University Medical Center, 2013

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