Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study

Michiels, Laura; Delva, Aline; Aalst, June van; Ceccarini, Jenny; Vandenberghe, Wim; Vandenbulcke, Mathieu; Lemmens, Robin; Laere, Koen Van

doi:10.1016/j.neuroimage.2021.117877

Cited by 36 publications

(35 citation statements)

References 46 publications

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“…The synaptic density in frontal and cingulate regions as quantified with [ 11 C]UCB-J BP ND correlates with patients’ cognitive performance. [ 11 C]UCB-J BP ND was not related to the estimated symptom duration or age, in line with previous evidence (Michiels et al ., 2021). These principal results were observed with and without partial volume correction, and using both voxel-wise and regional analysis.…”

Section: Discussionsupporting

confidence: 89%

“…Recently, new tools to quantify synaptic density in vivo have been developed, including radioligands that bind selectively to synaptic vesicle protein 2A (SV2A) as an assay of synaptic density (Finnema et al ., 2016; Heurling et al ., 2019). Synaptic density changes only slightly in mid- and later-life (Finnema et al ., 2016; Michiels et al ., 2021), providing a stable background against which to assess the effect of disease and disease-severity.…”

Section: Introductionmentioning

confidence: 99%

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

Malpetti

Jones

Cope

et al. 2022

Preprint

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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: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

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

Malpetti

Jones

Cope

et al. 2022

Preprint

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“…We have previously demonstrated that there is no major influence of age on synaptic density with SUVR as measure and therefore we included the full set of healthy controls instead of limiting the control cohort to age-matched subjects as this would decrease the power of the study. 69 To confirm this hypothesis we conducted a post hoc analysis with an age-matched control cohort (data not shown) which revealed comparable results. Another difference we observed between patients and controls was the lower injected 11 C-UCB-J activity which was inevitable as patients will receive follow-up scans, necessitating a lower injected dose to not exceed the legally allowed yearly radiation dose (as this study is part of a multimodal, multitracer imaging study).…”

Section: Discussionmentioning

confidence: 81%

Changes in synaptic density in the subacute phase after ischemic stroke: A¹¹C-UCB-J PET/MR study

Michiels

Mertens

Thijs

et al. 2021

J Cereb Blood Flow Metab

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Functional alterations after ischemic stroke have been described with Magnetic Resonance Imaging (MRI) and perfusion Positron Emission Tomography (PET), but no data on in vivo synaptic changes exist. Recently, imaging of synaptic density became available by targeting synaptic vesicle protein 2 A, a protein ubiquitously expressed in all presynaptic nerve terminals. We hypothesized that in subacute ischemic stroke loss of synaptic density can be evaluated with 11C-UCB-J PET in the ischemic tissue and that alterations in synaptic density can be present in brain regions beyond the ischemic core. We recruited ischemic stroke patients to undergo 11C-UCB-J PET/MR imaging 21 ± 8 days after stroke onset to investigate regional 11C-UCB-J SUVR (standardized uptake value ratio). There was a decrease (but residual signal) of 11C-UCB-J SUVR within the lesion of 16 stroke patients compared to 40 healthy controls (ratiolesion/controls = 0.67 ± 0.28, p = 0.00023). Moreover, 11C-UCB-J SUVR was lower in the non-lesioned tissue of the affected hemisphere compared to the unaffected hemisphere (ΔSUVR = −0.17, p = 0.0035). The contralesional cerebellar hemisphere showed a lower 11C-UCB-J SUVR compared to the ipsilesional cerebellar hemisphere (ΔSUVR = −0.14, p = 0.0048). In 8 out of 16 patients, the asymmetry index suggested crossed cerebellar diaschisis. Future research is required to longitudinally study these changes in synaptic density and their association with outcome.

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“…Despite age differences between carriers and controls, previous evidence suggests that [ 11 C]UCB‐J binding reflecting synaptic density does not decline with age. 22 In familial FTD, thalamic atrophy has been commonly reported in C9orf72 mutation carriers, 9 , 10 , 23 , 24 , 25 , 26 early in the pre‐symptomatic stage before the age of 40 11 and decades prior to symptom onset. 8 Thalamic neurodegeneration may not be specific to C9orf72 mutations.…”

Section: Discussionmentioning

confidence: 99%

Synaptic density in carriers of C9orf72 mutations: a [¹¹C]UCB‐J PET study

Malpetti

Holland

Jones

et al. 2021

Ann Clin Transl Neurol

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Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study

Cited by 36 publications

References 46 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

Changes in synaptic density in the subacute phase after ischemic stroke: A¹¹C-UCB-J PET/MR study

Synaptic density in carriers of C9orf72 mutations: a [¹¹C]UCB‐J PET study

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Synaptic density in healthy human aging is not influenced by age or sex: a 11C-UCB-J PET study

Cited by 36 publications

References 46 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

Changes in synaptic density in the subacute phase after ischemic stroke: A11C-UCB-J PET/MR study

Synaptic density in carriers of C9orf72 mutations: a [11C]UCB‐J PET study

Contact Info

Product

Resources

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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

Changes in synaptic density in the subacute phase after ischemic stroke: A¹¹C-UCB-J PET/MR study

Synaptic density in carriers of C9orf72 mutations: a [¹¹C]UCB‐J PET study