In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

Mak, Elijah; Holland, Negin; Jones, P. Simon; Savulich, George; Low, Audrey; Malpetti, Maura; Kaalund, Sanne S; Passamonti, Luca; Rittman, Timothy; Romero-García, Rafael; Manavaki, Roido; Williams, Guy B.; Hong, Young T.; Fryer, Tim D.; Aigbirhio, Franklin I.; O’Brien, John; Rowe, James B.

doi:10.1016/j.neurobiolaging.2021.01.016

Cited by 24 publications

(54 citation statements)

References 69 publications

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“…In preclinical models, [ 11 C]UCB-J may now be used in autoradiography or in vivo PET (Finnema et al ., 2016; Nabulsi et al ., 2016; Bertoglio et al ., 2020; Varnäs et al ., 2020; Thomsen et al ., 2021; Xiong et al ., 2021) to quantify synapse density, where it is highly correlated with better established markers such as synaptophysin (Finnema et al ., 2016). [ 11 C]UCB-J therefore offers a bridge between preclinical and clinical models, where quantitative whole-brain models of pathogenesis in dementia, including frontotemporal dementia, can be improved by the inclusion of synaptic density estimates in addition to structural connectivity (Raj et al ., 2012) and post-synaptic structural integrity (Mak et al ., 2021). In addition, it is possible that tau and TDP-43 mediated bvFTD have distinct spatiotemporal profiles of synaptic loss.…”

Section: Discussionmentioning

confidence: 99%

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

Malpetti

Jones

Cope

et al. 2022

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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.

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Section: Discussionmentioning

confidence: 99%

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

Malpetti

Jones

Cope

et al. 2022

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“…Third, we note that in PET studies of neurodegeneration with atrophy, grey matter volume loss can affect the interpretation of PET signals. However, synaptic loss in PSP and CBD occurs even in areas of the brain without discernible atrophy on MRI 7,8 . Nonetheless, we used a stringent partial volume correction method (GTM) to minimise the effect of atrophy on our ligand cross-correlations.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we use the term CBD to refer to patients with CBS in whom Alzheimer's disease is excluded by [ 11 C]PiB PET, whereby in the absence of amyloid pathology there is a high clinicopathological correlation with 4R-tauopathy at post mortem. Both PSP and CBD demonstrate synaptic loss in vivo 7,8 and at post-mortem 1,2 . The distribution of tau pathology in both diseases is well characterised with cortical and subcortical involvement 21,22 .…”

Section: Introductionmentioning

confidence: 97%

“…It is closely related to cognitive decline in symptomatic stages of disease 4,5 , but can begin long before symptom onset and neuronal loss 6 . Synaptic loss and dysfunction may be an important mediator of decline even where atrophy is minimal or absent 7,8 . Conversely, synaptic connectivity may facilitate the spread of oligomeric mis-folded proteins such as tau 9,10 .…”

Section: Introductionmentioning

confidence: 99%

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Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Holland

Malpetti

Rittman

et al. 2021

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The relationship between in vivo synaptic density and tau burden in primary tauopathies is key to understanding the impact of tauopathy on functional decline and in informing new early therapeutic strategies. In this cross-sectional observational study, we determine the in vivo relationship between synaptic density and molecular pathology, in the primary tauopathies of Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD), as a function of disease severity. Twenty three patients with PSP, and twelve patients with Corticobasal Syndrome (CBS) were recruited from a tertiary referral centre. Nineteen education, sex and gender–matched control participants were recruited from the National Institute for Health Research Join Dementia Research platform. Cerebral synaptic density and molecular pathology, in all participants, were estimated using PET imaging with the radioligands [11C]UCB–J and [18F]AV–1451, respectively. Patients with CBS also underwent amyloid PET imaging with [11C]PiB to exclude those with likely Alzheimer's pathology – we refer to the amyloid negative cohort as having CBD although acknowledge other pathologies exist. Disease severity was assessed with the PSP rating scale; regional non-displaceable binding potentials (BPND) of [11C]UCB–J and [18F]AV–1451 were estimated in regions of interest from the Hammersmith Atlas, excluding those with known off-target binding for [18F]AV–1451. As an exploratory analysis, we also investigated the relationship between molecular pathology in cortical brain regions, and synaptic density in connected subcortical areas. Across brain regions, there was a positive correlation between [11C]UCB–J and [18F]AV–1451 BPND (β=0.4, t=4.7, p<0.0001). However, the direction of this correlation became less positive as a function of disease severity in patients (β = -0.03, T = -4.0, p = 0.002). Between brain regions, cortical [18F]AV-1451 binding was negatively correlated with synaptic density in subcortical areas (caudate nucleus, putamen, and substantia nigra). Brain regions with higher synaptic density are associated with a higher [18F]AV–1451 binding in PSP/CBD, but this association diminishes with disease severity. Moreover, higher cortical [18F]AV–1451 binding correlates with lower subcortical synaptic density. Longitudinal imaging is required to confirm the mediation of synaptic loss by molecular pathology. However, the effect of disease severity suggests a biphasic relationship between synaptic density and tauopathy, with synapse rich regions vulnerable to accrual of pathology, followed by a loss of synapses in response to pathology. Given the importance of synaptic function for cognition, our study elucidates the pathophysiology of primary tauopathies and may inform the design of future clinical trials.

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“…Informative and clinically practical measures of microstructural changes and synaptic loss promises earlier diagnosis and improved monitoring of disease progression and responses to new disease modifying therapies. [15] Neurite Orientation Dispersion and Density Imaging (NODDI) is an advanced approach to in vivo diffusion-weighted MRI based on a multi-compartment diffusion model which allows a more precise characterisation of water diffusion than diffusion tensor imaging (DTI). [16] When applied to brain grey matter, NODDI provides measures related to the extracellular free water volume fraction (FISO), neurite density (NDI) (the intracellular volume fraction), and the local diffusion tensor orientation dispersion (ODI) (interpretated in this context as a measure of neurite branching).…”

Section: Introductionmentioning

confidence: 99%

Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease

Venkataraman

Bishop

Mansur

et al. 2021

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1.ABSTRACTBackgroundSynaptic loss and neurite dystrophy are early events in Alzheimer’s Disease (AD). We aimed to characterise early synaptic microstructural changes in vivo.MethodsMRI neurite orientation dispersion and density imaging (NODDI) and diffusion tensor imaging (DTI) were used to image cortical microstructure in both sporadic, late onset, amyloid PET positive AD patients and healthy controls (total n = 28). We derived NODDI measures of grey matter extracellular free water (FISO), neurite density (NDI) and orientation dispersion (ODI), which provides an index of neurite branching and orientation, as well as more conventional DTI measures of fractional anisotropy (FA), mean/axial/radial diffusivity (MD, AD, RD, respectively). We also performed [11C]UCB-J PET, which provides a specific measure of the density of pre-synaptic vesicular protein SV2A. Both sets of measures were compared to regional brain volumes.ResultsThe AD patients showed expected relative decreases in regional brain volumes (range, -6 to - 23%) and regional [11C]UCB-J densities (range, -2 to -25%). Differences between AD and controls were greatest in the hippocampus. NODDI microstructural measures showed greater FISO (range, +26 to +44%) in AD, with little difference in NDI (range, -1 to +7%) and mild focal changes in ODI (range, -4 to +3%). Regionally greater FISO and lower [11C]UCB-J binding were correlated across grey matter in patients (most strongly in the caudate, r2 = 0.37, p = 0.001). FISO and DTI RD were strongly positively associated, particularly in the hippocampus (r2 = 0.98, p < 7.4 × 10−9). After 12-18 months we found a 5% increase in FISO in the temporal lobe, but little change across all ROIs in NDI and ODI. An exploratory analysis showed higher parietal lobe FISO was associated with lower language scores in people with AD.ConclusionsWe interpreted the increased extracellular free water as a possible consequence of glial activation. The dynamic range of disease-associated differences and the feasibility of measuring FISO on commercially available imaging systems makes it a potential surrogate for pathology related to synapse loss that could be used to support early-stage evaluations of novel therapeutics for AD.

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In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

Cited by 24 publications

References 69 publications

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

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

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study

Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease

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In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies

Cited by 24 publications

References 69 publications

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

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

Molecular pathology and synaptic loss in primary tauopathies: [18F]AV-1451 and [11C]UCB-J PET study

Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer’s Disease

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

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

Molecular pathology and synaptic loss in primary tauopathies: [¹⁸F]AV-1451 and [¹¹C]UCB-J PET study