Quantitative UTE MR Imaging of Myelin: Novel Biomarkers for Alzheimer's Disease

7. Abstract Alzheimer’s Disease (AD) is typically considered to be a Gray Matter (GM) disease and is characterized by pathological changes including extracellular Amyloid β (Aβ) plaques and NeuroFibrillary Tangles (NFTs). However, recent studies have shown oligodendroglial degeneration and myelin impairment in White Matter (WM) in preclinical AD before Aβ plaques and NFTs appear. Intracortical myelin loss is also among the earliest events in AD. Myelin can increase brain “connectivity” by ~3000-fold. Myelin impairment can disrupt axonal transport, integrity, and plasticity, leading to a massive reduction in signal transduction. Given its indispensable role in the development and maintenance of elaborate cognitive functions, loss of myelin could play a key role in the pathogenesis of AD. A non-invasive MR imaging technique that can accurately evaluate myelin could therefore be of critical importance for precise diagnosis of AD and monitoring the effectiveness of treatment. MRI has been widely used in the diagnosis of AD. Structural MRI is an integral component of the clinical assessment of AD patients in which atrophy is the key finding. More advanced techniques such as Diffusion Tensor Imaging (DTI), quantitative Magnetization Transfer (MT), multi-component T2, multicomponent-Driven Equilibrium Single Pulse Observation of T1 and T2 (mcDESPOT), have been proposed for quantitative imaging of GM and WM in AD. However, all these techniques are based on conventional data acquisitions with Echo Times (TEs) on the order of several to tens of milliseconds. These TEs can detect signal from long T2 water components (intra/extracellular water, CSF, and/or myelin water), but are too long to detect signal from myelin with extremely short T2s (< 1 ms). It is highly desirable to develop MRI techniques to directly image myelin, quantify myelin content, and map its T1 and T2. Ultrashort Echo Time (UTE) sequences with TEs <0.1 ms allow direct detection of signal from ultrashort T2 species. The main challenge is selectivity, because long T2 water components demonstrate far higher signal than myelin. Adiabatic Inversion Recovery (IR) pulses provide uniform inversion and nulling of the longitudinal magnetizations of water components, making it possible to selectively image myelin. The initial goal of this study is to further develop, validate, and compare 3D Double Echo Sliding Inversion REcovery UTE (DESIRE-UTE) and Short TR Adiabatic Inversion Recovery UTE (STAIR-UTE) sequences for direct imaging of myelin in phantoms, specimens, and AD mice. The final goal is to evaluate the two 3D UTE sequences in a cross-sectional study of healthy volunteers and patients with Mild Cognitive Impairment (MCI) and AD. Our central hypothesis is that the 3D DESIRE-UTE and STAIR-UTE sequences will robustly detect changes in myelin in GM and WM of the brain, and that greater loss of myelin will be associated with poorer cognitive performance. The 3D DESIRE-UTE and STAIR-UTE biomarkers may improve the diagnostic capability of MRI for identifying dementia at an early stage within a window where disease-modifying therapy is effective, and allow monitoring the effectiveness of therapy.