DEMENTIA PLATFORM U.K. EXPERIMENTAL MEDICINE: HUMAN IN VIVO ASTROGLIAL ACTIVATION IN EARLY ALZHEIMER’S DISEASE

Abstract

Astrocyte activation and atrophy influence the synaptic health and progression of Alzheimer's disease(AD). A novel PET radioligand at Imperial College London (in collaboration with GlaxoSmithKline and Imanova, Ltd.) has shown favourable characteristics in preclinical models. [11C]BU99008 is selective for I2-imidazoline binding sites (I2BS) expressed on the mitochondrial membranes of astrocytes. These I2 imidazoline binding sites (I2BS) increase with astroglial activation in the brain. The primary objective is to assess the uptake of [11C]BU99008 in mild to moderate AD compared to healthy volunteers (HV). We also are exploring the relationship between increased uptake, brain amyloid load and glucose metabolism. Thus far, in two separate cohorts, we have completed analysis of a total of 18 HVs. Non-linear registration of the CIC atlas into native space for each subject's dynamic PET data and generation of regional time-activity data, time-activity curves for frontal, temporal, parietal occipital and hippocampus are being modelled using two-tissue (2TCM) compartmental models using MIAKATTM. Cohort 1 consists of 13 subjects age (54±7yr; mean±SD), data previously presented (Tyacke et al, NRM 2016). The new Cohort 2 consists of a significantly more elderly group of 5 subjects (70±7yr). They showed uptake (VT, ml.cm-3) highest in: nucleus accumbens (152±24), globus pallidus (141±45) and striatum (119±33); intermediate in the insular cortex (87±10), and cingulate cortex (76±12); and lowest in the occipital cortex (63±5) and cerebellum (57±3). These data are in good agreement with those in Cohort 1. However, in cohort 2 there was significantly greater (Student t-test; P<0.05) increase in the regions showing lowest binding in both cohorts. A correlation using all 18 subjects for whole brain binding showed a trend towards a significant increase with age (P=0.06; Spearmans). The [11C]BU99008 PET tracer has demonstrated that the tracer has good brain uptake in humans. More AD, MCI and healthy control subjects are being scanned to evaluate its possible use as a marker of pathology progression in AD. The Medical Research Council Dementias Platform UK (DPUK) is a multi-million pound public-private partnership developed by the MRC. This study was conducted as a component of a developing DPUK Imaging Network experimental medicine programme.