Noninvasive Quantitation of Early Biochemical Changes in Alzheimer’s Disease

Lay Summary

Developing an MRI Method for Indirectly Detecting Amyloid Early in Alzheimer’s Disease

A form of MRI imaging may provide a non-invasive indirect method to identify and quantify brain amyloid deposits in Alzheimer’s disease.  Investigators at the University of Pennsylvania will try to validate this approach using a “humanized” mouse model of the disease.  If successful, this non-invasive method could be easily applied to human diagnosis and assessment of experimental therapies designed to reduce amyloid plaques or prevent their further accumulation.

First, investigators will see whether use of high resolution “T_1r-weighted” MRI in a mouse model of Alzheimer’s disease provides direct evidence of amyloid accumulation.  To do this, they first will take brain images of the animals’ brains over time as amyloid deposits increase.  The investigators also will generate computerized maps of water in the brain that is displaced around the amyloid plaques.  The researchers hypothesize that the extent of water displacement in the brain will provide an accurate indirect measure of amyloid accumulation and changes in this accumulation over time.

The investigators then will see whether the high resolution images of amyloid plaques and the maps of water displacement indicating amyloid accumulation reflect the actual sites of amyloid that are found when the animals’ brains are autopsied. If the high resolution images and maps accurately reflect amyloid deposits, the researchers then will see whether a low resolution form of this T_1r-weighted MRI, which can be used in humans, provides a valid indirect measure of amyloid.

To validate this low-resolution form of MRI, the investigators will use a “humanized” mouse model, in which a human gene has been inserted in mice of various ages. This age span of the animals corresponds to the increasing levels of amyloid deposits that occur in humans as they age. If the low resolution and high resolution imaging techniques generate similar maps of water displacement in the brain that are presumably produced by amyloid build-up, the low resolution technique will prove to be a valid, indirect method for imaging human amyloid and changes in its accumulation over time.

Investigators propose to further validate this technique to ensure that changes in maps of water displacement seen over time solely reflect the build-up of amyloid.  They will determine whether this is the case by comparing water displacement maps generated from the animal disease model to those generated by healthy mice.  Only diseased animals should show water displacement associated with build-up of amyloid.

Finally, the researchers will test the hypothesis that amyloid accumulation similarly alters cerebral blood flow patterns, by computing cerebral blood flow maps.  They will confirm at autopsy that altered cerebral blood flow is correlated with the presence of amyloid.  If investigators prove that both water displacement and alterations in cerebral blood flow are indirect measures of the extent of amyloid accumulation, this T_1r-imaging technique would provide a way to non-invasively diagnose brain amyloid accumulation in humans.

Significance:  Currently, definitive confirmation of amyloid accumulation associated with Alzheimer’s disease is possible only at autopsy.  If this non-invasive MRI imaging technology can be validated as an accurate indirect measure of brain amyloid accumulation, including changes in amyloid build-up over time, the technology could be easily used in humans.  The technique also could be used to assess the effectiveness of experimental therapies in reducing amyloid early in the disease process, when they are most likely to be effective.

Abstract

Noninvasive Quantitation of Early Biochemical Changes in Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia in the elderly. Classic symptoms of the disease include memory loss, confusion, and biological features such as the formation of neurofibrilary tangles, senile plaques (SP) of Amyloid-b (Ab) depositions and neuronal atrophy in the brain. Early detection of the disease provides greater understanding of the underlying pathobiology, contribute to presymptomatic diagnosis and, eventually, to the development of disease-modifying therapies for use in the presymptomatic stage.

This proposal deals with the development and optimization of novel magnetic resonance imaging (MRI) methods to detect and quantify early biochemical changes due to Alzheimer's disease in a transgenic (tg) mouse model. Specifically, T1r-weighted MRI will be optimized to obtain high-resolution images of normal brains in vivo and relaxation maps will be calculated from these images. These methods will then be used to match SP from T1r-weighted images of tg mice in vivo with immuno-stained histology sections of the brain. Then the MRI methodology will be used to measure changes in T1r relaxation time (from calculated T1r maps) in plaque-rich regions as determined from both high-resolution T1r-weighted images and histology. T1r maps will also be calculated in several age groups of animals to determine if there exist any plaque burden-dependent changes in T1r values. Finally, we will optimize a previously developed MRI method to map cerebral blood flow (CBF) distribution and determine any changes in flow resulting from the presence of SP.

The accomplishment of the proposed aims will result in a non-invasive MRI method for visualizing (via T1r-weighted imaging) and quantifying (via T1r and CBF mapping) the early degenerative changes in AD in the form of senile plaques. Since the methodology is completely non-invasive, it can be translated into human studies and implemented in a clinical setting.