Abstract Alzheimer's disease and its related dementia (ADRD) is incurable, chronic, and long-term disabling. In the US, it is already a leading cause of death and enormous human suffering and economic loss. As the population ages, the disease burden due to ADRD continues to climb sharply. Positron emission tomography (PET) and magnetic resonance imaging (MRI) of the brain are proven vital for combating ADRD. The goal of this research is to develop the core instrumentation and image reconstruction technologies that can enable the development of a practical device for adding simultaneous high-resolution and high-sensitivity PET/MR imaging of the brain to pre-existing clinical MRI systems. This “PET head coil” is a compact but complete PET system integrated with a Philips 3.0T Tx/Rx head coil in such a way that it can be similarly used in an MRI scanner as the Philips coil while providing the same field-of-view (~30 cm in diameter and 20 cm in length) that is clinically proven as appropriate for most adult brain. For achieving superior performance in PET brain imaging and addressing issues relating to MR compatibility, space, heat dissipation and others, PET detector is based on 2.25x2.25x20mm3 lutetium yttrium orthosilicate (LYSO) crystals and size-matched silicon photomultipliers (SiPMs) in one-to-one coupling to minimize light loss, with double-end light coupling for DOI detection. A time-based multiplexing method that reads SiPMs in rows and columns and a high-density sampling data acquisition technology are employed to simplify the design of the detector and remove most electronics from the insertable part of the device. The proposed device aims to achieve a detector resolution of 2.25 mm, an energy resolution of ≲12%, a peak sensitivity of ~15%, a depth-of-interaction (DOI) resolution of ≲5 mm, and a time-of-flight (TOF) resolution of ≲300 picoseconds. Dedicated PET brain systems capable of such superb imaging performance are not in existence, let alone compact PET inserts integrated with MRI head coils. This project has two specific aims (SA). In SA1, a 9.4T small-animal MRI scanner will be used as a research platform to develop and validate two partially populated detector units of the device and a sampling DAQ unit. In SA2, realistic simulation data will be generated and used to develop and validate an optimization-based TOF PET image reconstruction algorithm that can handle detector gaps. Successful completion of these aims will validate the key enabling technologies for the proposed PET head coil to pave way for its eventual development and use for advancing ADRD research and clinical care.