Redox active metals have long been implicated in neurodegenerative disorders, especially those in which protein misfolding is a major feature, including Alzheimer's (AD), Parkinson's disease, and Huntington's disease (HD). Age or disease-mediated dyshomeostasis of copper, zinc and iron promote aberrant protein aggregation through direct binding to the protein concerned or by promoting aggregation indirectly by increasing the labile metal pool or enhancing the pro- oxidative capacity of the tissue micro-environment2, 3. Oxidative modifications of disease-related proteins by metals promote their oligomerization and resistance to degradation and clearance, resulting in their accumulation4, 5. Metals, especially iron, also accumulate in these disorders, as has been demonstrated in post-mortem studies and are themselves considered targets for disease- modifying therapies6. Compounds that target metal-protein interactions are being tested in AD and HD. PBT2, an orally bioavailable metal ligand with high brain penetration reduces the accumulation of toxic aggregates in Alzheimer's disease and improves several cognitive domains7, 8. PBT2 and its older analog, clioquinol are neuroprotective in mouse models of HD and reduce huntingtin aggregation in them, preclinical evidence that metals may be a valid therapeutic target in HD and it is now being assessed in a phase II study. At present, there is no direct way to monitor the effects in brain of therapies targeting metals. Because these diseases are slowly progressive and highly variable, imaging markers that could measure metal accumulation and have the potential to measure changes with progression or treatment would be invaluable. In the current proposal, we plan to evaluate novel acquisition and analytical algorithms to measure regional concentrations of iron using a 7 Tesla MRI scanner. The higher field strength will provide the much needed sensitivity to evaluate regional changes in the Field Map signal, which measures brain iron concentrations, and may provide important information about target engagement. Hypothesis: Field Map values obtained at 7T, corresponding to alterations in iron concentrations, will be present in the striatum and in select cortical regions n gene expanded pre-manifest individuals and in patients with early Huntington's disease that are also progressive.
Specific Aim 1 : To analyze Field Map measurements of healthy control subjects, premanifest and early HD at 7T. Hypothesis 2: Select regions of human post-mortem brain tissue will reflect changes in metals and metal regulating pathways.
Specific Aim 2 : Examine regional metal levels by ex vivo scanning at 7T and by ICP-MS and selected metal homeostasis regulators using immunocytochemistry, Western analysis, HPLC, and QPCR.
We have evidence that metals are dysregulated in Huntington's disease (HD) and that this dysregulation may play a critical role in the pathophysiology of HD. We plan to use novel MRI methods at high field strengths to evaluate regional increases in metals in the brain in patients with early HD and to determine if treatment with a compound that modulates brain metals can be measured non-invasively with these novel methods.
