This application addresses Challenge Area (03) Biomarker Discovery and Validation. (RFA-OD-09-003) 03- MH-101, Biomarkers in mental disorders. The goal of the proposal is to develop biomarkers for the detection of amyloid plaques in living humans. Successful development of these biomarkers would allow for detection of amyloid burden in subjects with Alzheimer's disease (AD) and also would allow for specific and accurate early diagnosis and disease progression and disease modifying treatments. This is significant at a time when a number of therapies for AD are in clinical trial including the use of antioxidants, BACE and gamma secratase inhibitors and metal chelators. Elevated levels of metals (Cu, Zn and Fe) in amyloid plaque are targets for development of therapeutic and diagnostic agents. Metal chelators are showing promise for the treatment of AD. We plan to develop F-18 labeled analogs of 8-hydroxyquinoline (HQ), a weak metal (Zn, Cu) chelator, as PET imaging agents for early diagnosis of AD. These agents would be unique in targeting metal-protein aggregates in amyloid plaques. Toxicity issues associated with clioquinol are not likely to be problems with diagnostic agents'8- hydroxyquinoline based derivative, since the amount of these compounds administered for diagnostic purpose are sub-pharmacological levels, several orders of magnitude lower than the amounts used for therapeutic purpose. Alzheimer's disease (AD) is a debilitating neurodegenerative disorder that largely affects the elderly. The most significant pathological characteristic in the post-mortem AD brain is the presence of extracellular plaque deposits and intracellular neurofibrillar tangles. Believed to be pathogenesis of AD, the process of plaque deposition commences decades before the clinical diagnosis is possible. Plaque is comprised of aggregated fibrils of beta amyloid (A?) collocated with transition metal ions such as Zn, Cu, and Fe, that are present in the brain. These metal-protein aggregates are thought to be toxic, involved in generation of H2O2 and free radicals causing neuronal damage. Recent studies indicated that at an early stage of the disease it may be possible to disaggregate the plaque, reverse neuronal loss, and treat AD. Early diagnosis of AD pathogenesis at a molecular level would allow for these other interventional approaches to preempting AD. The goal of the project is to develop novel [18F] labeled imaging agents targeting amyloid protein-metal complex aggregates in Alzheimer's disease. Ante-mortem diagnosis of Alzheimer's based on neuropsychological tests are inconclusive at early stages of the disease and clinical PET imaging with [18F]FDG is suboptimal for differentiating various dementias. Ongoing efforts have led to the development f PET imaging agents, as [11C]PIB, [18F]FDDNP, [124]IMP, [18F]AV-45, [11C]SB-13, all of which are promising for labeling A? amyloid protein. They bind to varying hydrophobic binding pockets within A? proteins. However, all agents displayed significant weaknesses in in vivo imaging studies. They bind to varying hydrophobic binding pockets within A? proteins. However, all agents displayed significant weaknesses in in vivo imaging studies either with respect to high non-specific uptake, slow clearance from non-amyloid centers, or an inability to distinguish the various forms of plaque, which compromised their ability to unequivocally distinguish and quantify plaque. We plan to synthesize a number of fluorinated analogs of 8-hydroxy quinoline, characterize them and test them for their affinity for Zn-Abeta peptide aggregates. Selective compounds with high amyloid binding affinity will be labeled with F-18. We will test for their lipophilicity and perform ex vivo and in vivo studies. We have successfully prepared [18F]2F-HQ and initial micro PET/CT imaging studies in mice with this compound have shown desirable properties;high initial brain uptake (5-8 %ID/g) and rapid washout from normal mouse brain. These preliminary results are quite encouraging and warrant further development of this class of molecules as potential AD imaging agents. A successful [18F]HQ analog with desirable in vivo properties with high amyloid binding affinity, will be highly useful invention for the early diagnosis of AD pathogenesis. An accurate, noninvasive, molecular imaging method to assist in the early diagnosis of Alzheimer's plaque would be highly useful not only for early detection but also for following disease progression and as a biomarker for assessing new disease-modifying treatments for AD.
It would be desirable to develop a test that will identify the biological markers of Alzheimer's disease, much like cholesterol now serving as a biomarker of heart disease. Researchers are working on the development of vaccines and other treatment options. Such developments would be a huge breakthrough for a disease that has no cure and can only be diagnosed after death when a patients'brain is autopsied. Experts in the field stress the importance of diagnosing the disease at an early stage, since patients would do better if they are identified earlier. Alzheimer's is the most common form of dementia afflicting more than 5 million Americans. As the population ages, the Alzheimer's Association expects half a million new cases a year, with 10 million baby boomers eventually the degenerative disease that is fatal. According to some estimates collateral loss of productivity and associated annual costs for diagnosis, treatment, and short-and long term care totaling nearly 100 billion dollars annually to the US economy. In the next 20 years, this figure is projected to double and the costs rise to $380 billion annually. With increasing life expectancy and aging baby-boomer generation, the estimated future costs of treatment and elderly patient care, and its socio-economic implications are staggering. Two pronged early detection and early treatment is the required approach in averting this looming social and financial crisis. Amyloid is the dangerous brain plaque and tau protein tangles with in the brain cells tend to prevent neurons from communicating each other leading to loss of memory. Positron emission tomography (PET scan) can create image of the harmful beta amyoid plaque in the brains of living Alzheimer's patients. Currently used dye has very short life time (requiring an onsite cyclotron machine to produce it) limits its accessibility. It would be desirable to develop a longer lasting new radioactive agent that can be injected into patients to be scanned. We plan to develop such an agent. We plan to synthesize a number of molecules and screen them for their ability to bind to the amyloid plaque. Promising candidate molecules will be tagged with a radioisotope [18F] will be tested in using laboratory assays and imaging the animals with Alzheimer's disease with a (micro) PET scanner. A successful agent will be highly useful invention not only for early detection of but also for following disease progression and as biomarker for assessing disease-modifying treatments for Alzheimer's disease.
| Slavine, Nikolai V; Kulkarni, Padmakar V; McColl, Roderick W (2017) Iterative Image Processing for Early Diagnostic of Beta-Amyloid Plaque Deposition in Pre-Clinical Alzheimer's Disease Studies. J Appl Bioinforma Comput Biol 6: |
