Synaptic loss in behavioural variant frontotemporal dementia revealed by [¹¹C]UCB-J PET

Abstract

Synaptic loss is an early feature of neurodegenerative disease models, and is often severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) imaging with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synapses in vivo. This study used [11C]UCB-J PET in people with behavioural variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. We performed a cross-sectional observational study of bvFTD, versus healthy controls, in which participants underwent neurological examination, neuropsychological assessment, magnetic resonance imaging (MRI) and [11C]UCB-J PET. Patients were recruited from the Cambridge Centre for Frontotemporal Dementia at the University of Cambridge, and healthy volunteers from the UK National Institute for Health Research Join Dementia Research register. Eleven people with a clinical diagnosis of probable bvFTD and 25 age- and sex-matched healthy controls were included. All participants underwent dynamic [11C]UCB-J PET imaging, structural MRI and a neuropsychological battery, including the Addenbrooke's cognitive examination (ACE-R), and INECO frontal screening (IFS). General linear models were used to compare [11C]UCB-J binding potential maps between groups, and correlate synaptic density with cognitive performance and clinical features in patients. Group-comparison and correlation analyses were also performed using partial-volume corrected [11C]UCB-J binding potential from regions of interest (ROIs). Patients with bvFTD showed severe synaptic loss compared to controls. In particular, [11C]UCB-J binding was significantly reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex and medial temporal lobe. Synaptic loss in the left frontal and cingulate regions correlated significantly with cognitive impairments as assessed with ACE-R and IFS. Results from ROI-based analyses mirrored the voxel-wise results. In keeping with preclinical models, and human post mortem data, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to disease severity. [11C]UCB-J PET could support translational studies and experimental medicines strategies for new disease-modifying treatments for neurodegeneration.

Neurophysiological consequences of synapse loss in progressive supranuclear palsy

“…The relationship between synaptic density and functional change has been examined previously through correlational methods. For example, in Alzheimer's disease 6,36 , progressive supranuclear palsy 10 , and frontotemporal dementia 12 synaptic density correlates with cognitive function. Magnetoencephalographic evidence of abnormal oscillatory dynamics has been linked to lower [11C]UCB-J uptake in the occipital cortex 7 , while tauopathies have been correlated with spectral differences and spectrally-constrained changes in connectivity in a range of neurodegenerative disorders; including Alzheimer's disease and frontotemporal dementia 21,[37][38][39][40][41] .…”

“…We focus on synapse loss as the neuropathology, which is common across many neurodegenerative diseases, and closely related to the severity of dementia [5][6][7][8][9][10][11][12] . This kind of synapse loss is a consequence of protein misfolding, aggregation and inflammation in multiple disorders, and begins before cell death 13 .…”

“…Post-mortem studies have identified celland region-specific changes in synaptic density [14][15][16] . Quantification of region-specific synaptic density is now possible in vivo with PET, using ligands for the presynaptic vesicle protein 2A (SV2A PET) 12,17,18 . However, less is known about the impact of this synaptic loss on the neurophysiological function of local cortical networks 7 .…”

The neurophysiological effect of NMDA-R antagonism of frontotemporal lobar degeneration is conditional on individual GABA concentration

“…Neurophysiological changes can occur prior to atrophy, or in the absence of atrophy. This is in part because of the loss of synapses [78,79] and reductions in critical neurotransmitters [6] in bvFTD, PSP [32,33,80,81] but the distribution was wide. This variation in GABA, not atrophy, correlated with the effect of memantine on the cortical MMN response.…”

Synaptic proteomics reveal distinct molecular signatures of cognitive change andC9ORF72repeat expansion in the human ALS cortex

“…This was the first evidence that synapse loss was associated with cognitive change in ALS. Interestingly, recent PET studies in FTD patients revealed synapse loss in frontotemporal cortices that correlated with lower cognitive scores, thus highlighting overlapping synaptic vulnerability between ALSci and FTD [13].…”