PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is the leading cause of dementia characterized by progressive cognitive decline. The underlying causes remain poorly understood after decades of efforts, and the disease still cannot be cured, prevented, or significantly delayed. Myelin impairment can disrupt axonal transport, integrity, and plasticity, leading to a massive reduction in signal transduction. Given its essential role in development and maintenance of higher 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. Synthetic MRI (SyMRI) has been proposed to indirectly map myelin by assessing brain parenchymal fraction (BPF) and myelin parenchymal fraction (MyPF). However, myelin has a very short T2 (<<1 ms) and is invisible with conventional sequences such as those used with SyMRI. As a result, SyMRI only indirectly evaluates myelin via measuring water signals, and cannot evaluate myelin quality using the T1 and T2* relaxation times. Ultrashort echo time (UTE) sequences with echo times (TEs) of ~8µs, which are 100-1000 times shorter than the TEs of conventional sequences, make it possible to directly detect signal from myelin protons and so circumvent problems associated with SyMRI. The major challenge with UTE approach is the concurrent detection of high signal from various water components. The 3D short TR adiabatic inversion recovery UTE (STAIR-UTE) sequence employs an adiabatic inversion pulse for uniform inversion of long-T2 tissues, which together with a short TR and a high flip angle allow robust suppression of all water components with a wide range of T1 values, thereby selective myelin mapping. The first aim of this study is to validate and compare 3D STAIR-UTE and SyMRI sequences for myelin imaging in phantoms and brain specimens from donors without (n=20), and with AD (n=20) using histology as reference standard. The second aim is to evaluate STAIR-UTE and SyMRI sequences for myelin mapping in patients with mild cognitive impairment (MCI) (n=40) and AD (n=40) as well as healthy controls (n=40). The participants are part of Dr. Du’s newly funded R01 grant. We will correlate SyMRI metrics (BPF, MyPF) and STAIR-UTE metrics (myelin PD, T1, T2*) with cognitive assessments including Mini-Mental State Examination (MMSE), Consortium to Establish a Registry of Dementia (CERAD), and Clinical Dementia Rating (CDR) scales. Our central hypothesis is that 3D STAIR-UTE sequence will robustly detect changes in myelin, and that mapping of myelin quantity with myelin PD and quality with myelin T1 and T2* will provide more specific evaluation of myelin damage and correlate better with disability and disease progression in AD than metrics derived from the SyMRI approach. Dr. Athertya and her mentor, Dr Du, have designed a detailed training plan and assembled a strong researc...