In vivo synaptic density loss is related to tau deposition in amnestic mild cognitive impairment

Abstract

ObjectiveTo investigate in vivo whether synaptic loss and neurofibrillary tangle load spatially overlap and correlate with clinical symptoms in patients with amnestic mild cognitive impairment (aMCI).MethodsIn this cross-sectional study, 10 patients with aMCI and 10 healthy controls underwent triple PET-MRI with 11C-UCB-J (synaptic vesicle protein 2A), 18F-MK-6240 (tau deposition), and 11C-Pittsburgh compound B (β-amyloid) and neuropsychological assessment. Gray matter atrophy was assessed by voxel-based morphometry with T1-weighted MRIs. Voxel-wise and volume-of-interest analyses were conducted on PET data. The interrelationship of synaptic density and tau deposition was investigated. We also investigated correlations of 18F-MK-6240 and 11C-UCB-J binding with cognitive performance.ResultsCompared to controls, patients with aMCI showed a decreased 11C-UCB-J binding mainly in substructures of the medial temporal lobe (MTL; 48%–51%, pcluster = 0.02). Increased 18F-MK6240 binding in the same region was observed (42%–44%, pcluster = 0.0003), spreading to association cortices. In the MTL, higher 18F-MK-6240 binding inversely related to lower 11C-UCB-J binding (p = 0.02, r = −0.76). Decreased performance on cognitive tests was associated with both increased 18F-MK-6240 and decreased 11C-UCB-J binding in the hippocampus (p < 0.01, r > 0.7), although in a multivariate analysis only 18F-MK-6240 binding was significantly related to cognitive performance.ConclusionsPatients with aMCI have high tau deposition and synaptic density loss mainly in key regions known to be involved in early cognitive impairment, indicating that these are interrelated in the MTL, while tau binding had already spread toward association cortices. Longitudinal data are needed to provide further insight into the temporal aspects of this relationship.

In vivo tau pathology is associated with synaptic loss and altered synaptic function

“…1). In line with a previous study from Vanhaute and others [21], the pattern of tau pathology was slightly more widespread and pronounced compared to the pattern of reduced synaptic density, which corresponds with a conceptual model that suggests tau to precede and potentially drive structural degeneration and loss of synaptic function [51].…”

“…Recent studies in patients with AD have observed strongest reductions in SV2A radiotracer-binding in the hippocampus [17][18][19], a key region for structural synaptic degeneration in AD [20]. Furthermore, a recent PET study observed an association between decreased SV2A-binding and increased tau-binding in the medial temporal lobe in patients with amnestic mild cognitive impairment [21].…”

Tau Deposition and Structural Connectivity Demonstrate Differential Association Patterns with Neurocognitive Tests

“…By comparing measures of WM connectivity obtained by dMRI (CC and Strength) to tau accumulation obtained by tau PET, the present study shows that tau accumulation is negatively correlated with structural connectivity in the early Braak stage regions. This is consistent with our recent finding that tau-related WM alterations were concentrated in early tau propagation pathways and results from postmortem studies that synaptic density loss is related to tau deposition in the spectrum of AD (Pooler et al, 2014;Vanhaute et al, 2020). When compared to neurocognitive tests, tau deposition and network metrics showed disparate patterns.…”

PET Neuroimaging of Alzheimer's Disease: Radiotracers and Their Utility in Clinical Research

“…In a more recent [ 11 C]UCB-J study with a larger cohort of 34 AD and MCI patients, the significant loss of synaptic density measured by PET in the hippocampus and entorhinal cortex followed by parahippocampal cortex, amygdala, lateral temporal cortex, pre-frontal cortex, posterior cingulate cortex/precuneus, lateral parietal cortex, and pericentral cortex was found to be generally correlated with atrophy measured by structural MRI which is in line with autopsy reports, and was more significantly correlated with CDR-SB ( r = −0.54, P = 0.00003) and episodic memory ( r = 0.56, P = 0.00001) than in the smaller sample reported earlier (de Wilde et al, 2016 ; Chen et al, 2018 ; Mecca et al, 2020 ). The relationship between cognitive performances and medial temporal (especially hippocampus and parahippocampal gyrus) synaptic density loss in aMCI was strengthened by a mutually correlated regional tau accumulation, as was revealed by a multi-tracer PET study using [ 18 F]MK-6240 and [ 11 C]UCB-J (Vanhaute et al, 2020 ).…”