A[18F]3F4AP PET measure of myelin/axonal integrity in aging and Alzheimer's disease - Project Summary/Abstract Myelin integrity is a fundamental component to brain health and cognition. This study investigates the additive benefits [18F]3F4AP positron emission tomography (PET) to standard magnetic resonance imaging (MRI) metrics in understanding the relationship of myelin integrity with aging, cerebrovascular disease (CVD), and Alzheimer’s disease (AD) pathology (amyloid plaques and hyperphosphorylated tau neurofibrillary tangles). Although change in myelin integrity is not specific to AD, animal models and MRI studies have shown myelin involvement at various stages of AD pathology. Soluble oligomeric forms of amyloid are toxic to myelin-producing oligodendrocytes, and demyelination can lead to amyloid accumulation, highlighting a potential feedback loop in the early stages of AD pathology. Subjects with lower myelin density are at a higher risk of tau spreading. After tau has spread, tau- related neurodegeneration results in further demyelination (Wallerian degeneration). Such myelin changes can range from subtle within normal appearing white matter to white matter lesions. Location matters, parietal white matter lesions are associated with AD pathology, whereas frontal white matter are associated with both AD and CVD. PET can be a highly sensitive and specific method for measuring pathology. A novel PET tracer, [18F]3F4AP, binds to voltage-gated potassium channels (Kv1 family) exposed during demyelination, making it a surrogate marker for myelin integrity. In our preliminary data, [18F]3F4AP provides additive information to MRI measures of myelin and axonal integrity (myelin water fraction, MWF, and diffusion tensor imaging fractional anisotropy, DTI-FA) in participants with multiple sclerosis. As an example, within a MS participant, there were 3 white matter lesions that appeared homogenous in MWF and DTI-FA, however [18F]3F4AP PET yielded clearly heterogenous signal. In this project, we will evaluate and compare [18F]3F4AP PET to MRI DTI-FA in aging, AD and CVD. We will study a cohort of 28 participants, including young, older unimpaired, and older adults with mild cognitive impairment (MCI) or dementia due to AD and varying levels of CVD. Participants will undergo 90-minute dynamic [18F]3F4AP PET scans, standard MRI battery including DTI and cognitive testing. The older participants will also undergo amyloid and tau PET scans. The study aims to optimize [18F]3F4AP quantification based on arterial sampling dynamic acquisition. If a suitable reference region is not identified, we will use a carotid image-derived input function with parent fraction calculated from venous sampling, a method that has been successful with this tracer in MS participants. Using DTI-FA and [18F]3F4AP PET quantification in white matter lesions, normal appearing white matter, and gray matter, subsequent aims will seek to identify when in the spectrum of AD and CVD pathology changes in myelin integrity occur and where myelin changes are occurring relative to the presence of AD and CVD pathology. The results of this study have the potential to inform preventative and restorative therapeutics to support current amyloid and tau lowering therapies.
