PET imaging of microtubules in cognitively normal and impaired older adults

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Project Summary/Abstract Microtubule (MT) integrity is critical for cell function and viability. Its disruption in Alzheimer’s disease (AD) is commonly attributed to hyperphosphorylation of the MT-associated protein, tau. However, the time course of MT instability in neurodegenerative cascade of the disease progression remains unknown. In vivo MT imaging offers an opportunity to gain this critical information on MT changes in relation to staging of AD. As MT destabilization is a common factor in both Aβ and tau-based AD pathologies, we hypothesize that a targeted MT PET radiotracer can be used as an early indicator of neuronal health and brain functions prior to onset of AD symptoms. Our lab reported the first brain-penetrant MT PET ligand, [11C]MPC-6827, and evaluated its imaging potential in vivo in rodent and non-human primate (NHP) models of AD. We evaluated its safety and radiation dosimetry profile in six healthy male and female volunteers and its imaging efficacy in two cognitively normal and two impaired older adults. Our mechanistic studies showed that [11C]MPC-6827 is selective for destabilized tubulins, and uptake increases with Aβ/tau burden in AD brain. The proposed trial will the first to measure the efficacy of an MT-based PET ligand as an early imaging biomarker in cognitively normal and mildly cognitively impaired/early AD subjects. We propose to conduct a clinical PET imaging study of [11C]MPC-6827. In Aim 1, we will determine the metabolic, pharmacokinetic, and imaging distribution parameters of [11C]MPC-6827 in three groups (n=75, 25/group) of participants, to be enrolled from the Wake Forest AD Research Center: 1) cognitively normal adults who are amyloid PET negative; 2) cognitively normal adults who are amyloid PET positive; and 3) adults with MCI or early AD who are amyloid PET positive. All the groups will be matched for age and sex. In Aim 2, [11C]MPC-6827 imaging parameters will be compared among the three groups and correlated with individual amyloid and tau PET measures, cerebrospinal fluid (CSF) measures, age, and cognitive scores. In Aim 3, we will perform longitudinal PET/CT scans with [11C]MPC-6827 in all the subjects (n=25/group) from Aim 1, 24 months after their first scan. Relationship of MT destabilization and disease progression will be established by correlating the radiotracer uptake with their associated amyloid and tau burdens. All the imaging analyses will be performed blinded to subject diagnosis. This study will provide rich imaging data source to validate MT destabilizations as an early neurodegenerative biomarker for AD pathogenesis.