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

Malpetti, Maura; Holland, Negin; Jones, P. Simon; Ye, Rong; Cope, Thomas E.; Fryer, Tim D.; Hong, Young T.; Savulich, George; Rittman, Timothy; Passamonti, Luca; Mak, Elijah; Aigbirhio, Franklin I.; O’Brien, John; Rowe, James B.

doi:10.1002/acn3.51407

Cited by 34 publications

(42 citation statements)

References 39 publications

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“…The aim of this study was to measure brain synaptic density in vivo using synaptic vesicle protein 2A-PET in patients with bvFTD 13 – 15 . SV2A-PET has been recently used to assess synaptopathy in different neuropsychiatric conditions 13 – 15 , and frontotemporal involvement was recently reported in a patient with C9orf72 mutation 16 . We anticipated loss of synaptic density in the frontal and temporal poles and we searched for precise regional loss of synaptic projections.…”

Section: Introductionmentioning

confidence: 99%

In vivo exploration of synaptic projections in frontotemporal dementia

Salmon

Bahri

Plenevaux

et al. 2021

Sci Rep

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The purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer’s disease (AD). Loss of synaptic projections was assessed with [18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, [18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in [18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes.

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Section: Introductionmentioning

confidence: 99%

In vivo exploration of synaptic projections in frontotemporal dementia

Salmon

Bahri

Plenevaux

et al. 2021

Sci Rep

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“…The distinctive distribution of synaptic loss in bvFTD across frontotemporal, insula and cingulate cortex is consistent with the typical distribution of its molecular pathologies, and its neurocognitive and behavioural profile. In this study, all of our cases were symptomatic (CDR ≥ 1), although we note that behavioural and cognitive changes can emerge in the presymptomatic and prodromal stages of bvFTD, many years before dementia and diagnosis (Rohrer et al ., 2015; Malpetti et al ., 2020; Staffaroni et al ., 2020); and synaptic loss has been identified in the presymptomatic stage of those with highly penetrant mutations such as C9orf72 expansions (Malpetti et al ., 2021). Early synaptic dysfunction in these regions may explain the subtle pre-symptomatic behavioural change and executive dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…Third, with a critical role for synaptic health in mediating between the molecular pathology and cognitive-physiological impairment of frontotemporal dementia, the ability to quantify the degree and distribution of synaptic loss can enhance novel experimental medicine studies (Cope et al, 2021). The degree and distribution of loss may be used either for stratification in inclusion or analytical stages of an early-phase clinical trial.…”

Section: Discussionmentioning

confidence: 99%

“…Full details of the protocol for [ 11 C]UCB-J synthesis, data acquisition, image reconstruction and kinetic analysis have been published elsewhere (Holland et al ., 2020; Milicevic Sephton et al ., 2020; Malpetti et al ., 2021). In brief, dynamic PET data acquisition was performed on a GE SIGNA PET/MR (GE Healthcare, Waukesha, USA) for 90 minutes following [ 11 C]UCB-J injection, with attenuation correction including the use of a multi-subject atlas method (Burgos et al ., 2014) and improvements to the brain MRI coil component (Manavaki et al ., 2019).…”

Section: Methodsmentioning

confidence: 99%

“…Previous evidence for synaptic loss in frontotemporal dementia has been indirect, including reduced synaptic density in carriers of mutations associated with frontotemporal dementia (Malpetti et al ., 2021), abnormal synaptic markers in cerebrospinal fluid (Goetzl et al ., 2016; Van Der Ende et al ., 2020; Bergström et al ., 2021), and progressive frontotemporal hypometabolism that is disproportionate to atrophy, indicated by [ 18 F]FDG PET (Diehl-Schmid et al ., 2007; Malpetti et al ., 2019; Bejanin et al ., 2020; see Chételat et al ., 2020 for review). 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).…”

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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Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia

Winchester,

Harshfield,

Shi

et al. 2023

Alzheimer's & Dementia

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With the increase in large multimodal cohorts and high‐throughput technologies, the potential for discovering novel biomarkers is no longer limited by data set size. Artificial intelligence (AI) and machine learning approaches have been developed to detect novel biomarkers and interactions in complex data sets. We discuss exemplar uses and evaluate current applications and limitations of AI to discover novel biomarkers. Remaining challenges include a lack of diversity in the data sets available, the sheer complexity of investigating interactions, the invasiveness and cost of some biomarkers, and poor reporting in some studies. Overcoming these challenges will involve collecting data from underrepresented populations, developing more powerful AI approaches, validating the use of noninvasive biomarkers, and adhering to reporting guidelines. By harnessing rich multimodal data through AI approaches and international collaborative innovation, we are well positioned to identify clinically useful biomarkers that are accurate, generalizable, unbiased, and acceptable in clinical practice.Highlights Artificial intelligence and machine learning approaches may accelerate dementia biomarker discovery. Remaining challenges include data set suitability due to size and bias in cohort selection. Multimodal data, diverse data sets, improved machine learning approaches, real‐world validation, and interdisciplinary collaboration are required.

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

Abstract: Istituto di Bioimmagini e Fisiologia Molecolare (IBFM), Consiglio Nazionale delle Ricerche (CNR), Milano, Italy Open access funding enabled and organized by ProjektDEAL.

Cited by 34 publications

References 39 publications

In vivo exploration of synaptic projections in frontotemporal dementia

In vivo exploration of synaptic projections in frontotemporal dementia

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

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia

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

Abstract: Istituto di Bioimmagini e Fisiologia Molecolare (IBFM), Consiglio Nazionale delle Ricerche (CNR), Milano, Italy Open access funding enabled and organized by ProjektDEAL.

Cited by 34 publications

References 39 publications

In vivo exploration of synaptic projections in frontotemporal dementia

In vivo exploration of synaptic projections in frontotemporal dementia

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

Artificial intelligence for biomarker discovery in Alzheimer's disease and dementia

Contact Info

Product

Resources

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

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