Inflammatory and synaptic PET imaging in behavioural variant frontotemporal dementia caused by a repeat expansion in C9orf72 (C9orf72‐FTD)

Abstract

AbstractBackgroundPathophysiological mechanisms associated with neurodegeneration include chronic neuroinflammation and synaptic dysfunction/loss. Radiotracer [11C]PBR28 is a marker of inflammation which binds to a translocator protein expressed by activated microglia. [11C]UCB‐J is a marker of synaptic density which binds to synaptic vesicle protein 2A. We evaluated both tracers as biomarkers of C9orf72‐FTD.MethodThree individuals with C9orf72‐FTD (mean age 62.7 years) underwent two PET scans between 3 and 13 months apart using [11C]PBR28 and [11C]UCB‐J. Dynamic PET data were acquired for 90 minutes following injection of each tracer. Arterial plasma input functions were generated from arterial blood samples. Participants also had volumetric MRI scans for each PET scan. Age‐matched controls from different cohorts underwent the same procedures (n = 5 for [11C]PBR28; n = 17 for [11C]UCB‐J).Regions of interest (ROIs) were defined on co‐registered T1‐weighted MR images using the CIC anatomical atlas. [11C]PBR28 BPND values were generated using a simplified reference tissue model with a cerebellar reference region. [11C]UCB‐J DVR‐1 values were generated using regional VT normalised to the VT in the centrum semiovale. ROI volumes were expressed as a percentage of total intracranial volume. W‐scores computed from each control cohort, using age and gender as covariates, illustrated the magnitude of differences between cases and controls. W‐scores >1.65 were considered abnormal for [11C]PBR28 and ←1.65 for [11C]UCB‐J and MRI.Result[11C]PBR28 w‐scores indicated significant neuroinflammation in FTD but varied between cases. Differences in BPND were greater than in volume in frontal/temporal/cingulate cortices in the individual with the longest disease duration (DD) (16‐17 years). Inversely, in the individual with the shortest DD (1‐2 years), there were greater differences in volume than BPND in most ROIs.[11C]UCB‐J w‐scores indicated significant synaptic dysfunction/loss and were lower than w‐scores of volume in all cortical ROIs. In the individual with the longest DD, differences in [11C]PBR28 were greater than in [11C]UCB‐J in most ROIs. An inverse pattern again observed in the individual with the shortest DD suggests synaptic dysfunction/loss may precede significant neuroinflammation.ConclusionInflammatory and synaptic PET may provide more sensitive biomarkers of C9orf72‐FTD than MRI. Variability in PET signal within this genotype may be explained by DD.