Our primary objective is to evaluate the use of abnormal brain iron accumulations, associated with Alzheimer's disease (AD), as a non-invasive early diagnostic biomarker for Magnetic Resonance Imaging (MRI). Iron is an essential element for many processes in the human brain, but it is also known to accumulate with age. Significant accumulations of iron are observed in regions where brain cells die in many brain diseases, and are often linked to disease pathology such as the senile plaques that are seen in AD brain tissue. We know from high-resolution x-ray and electron microscopy studies of Alzheimer's that unusual forms of iron oxide particle (magnetite) form in the brain tissue, and that these particles have stronger magnetic properties than the particles in which we normally store brain iron. We suspect that these particles form under conditions where iron storage breaks down, and that they may be associated with the over-production of free radicals and subsequent cell death. It is very important that AD is diagnosed as early as possible, in order to have the option of treating and slowing disease progression before significant loss of brain cells occurs. MRI is currently being used as a diagnostic tool for AD, where both atrophy (the loss of brain cells), and senile plaques, are being imaged to assist confirmation of diagnosis. However, by the time detectable levels of atrophy and formation of senile plaques occur, clinical symptoms have usually developed. There is a substantial body of evidence to indicate that iron accumulation may precede the onset of clinical symptoms, and we propose to establish whether these iron accumulations can be used as an early diagnostic marker for AD using modified MRI scans. Regional concentrations of iron can affect MRI, as iron is magnetic and disrupts the local magnetic field at the site of the accumulation. This property is already being used to scan patients with liver iron overload disease. Although the concentrations of magnetite in Alzheimer's tissue are small, and widely dispersed, we will study autopsy tissue from twenty Alzheimer's cases and twenty healthy age-matched controls to establish whether there are detectable differences, using the outstanding MRI facilities (including the 17.6T Bruker Avance scanner) available at University of Florida. It has already been shown that senile plaques in Alzheimer's tissue contain enough iron to be detected by MRI. We will also scan the tissue sections using a recently developed high-energy microfocus x-ray beam technique that lets us determine map and characterize tiny iron accumulations in tissue sections (i.e. their chemical and structural state), working at international synchrotron facilities including the Advanced Photon Source in Chicago, and DIAMOND in the UK. We will support the findings with magnetometry measurements to quantify the distribution of magnetic iron particles in the tissue. The combination of synchrotron x-ray techniques and MRI will provide us with the key to interpret iron-induced artifacts in MRI, enabling the development of iron-specific scanning techniques that can in the future be used in non-invasive clinical early detection and diagnosis of AD and related disorders. Virtually all new treatments being evaluated for AD rely on early intervention in order to be effective, presenting doctors with a quandary as currently there are no reliable early diagnostic techniques for AD. Here we propose to develop a non-invasive, MRI-based technique for early detection of AD based on results of our work on identifying and quantifying iron compounds associated with neurodegenerative disorders. This work, if successful, will have a profound impact on the way that AD is diagnosed, the assessment of new drugs to treat AD, and the treatment options available to high-risk individuals. ? ? ?
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| House, Emily; Mold, Matthew; Collingwood, Joanna et al. (2009) Copper abolishes the beta-sheet secondary structure of preformed amyloid fibrils of amyloid-beta(42). J Alzheimers Dis 18:811-7 |
| Collingwood, Joanna F; Chong, Ryan K K; Kasama, Takeshi et al. (2008) Three-dimensional tomographic imaging and characterization of iron compounds within Alzheimer's plaque core material. J Alzheimers Dis 14:235-45 |
