In vivo exploration of synaptic projections in frontotemporal dementia

Salmon, Éric; Bahri, Mohamed Ali; Plenevaux, Alain; Becker, Guillaume; Seret, Alain; Delhaye, Emma; Degueldre, Christian; Balteau, Evelyne; Lemaire, Christian; Luxen, André; Bastin, Christine

doi:10.1038/s41598-021-95499-1

Cited by 16 publications

(18 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Unbiased proteomic analysis of frontal cortical tissues from postmortem tissues of FTLD-FUS and controls showed altered expression of proteins associated with synaptic communication (syntaxin subunits: STX1A, STX1B, and STXBP1, synapsin 3: SYN3, synaptotagmin I: SYT1) and those involved in cellular transport pathways (clathrin-associated adaptor proteins: AP1B1, AP2A1, AP2A2, AP2B1) (Martins-De-Souza et al, 2012 ). These findings were consistent with previously discussed changes in synaptic connectivity observed in FTLD and ALS (Henstridge et al, 2018 ; Malpetti et al, 2021 ; Salmon et al, 2021 ). Additionally, FTLD-FUS tissues had significant changes in proteins involved in signaling pathways (calcium-related proteins, CAMK2A, protein phosphatase 3, catalytic subunit, alpha isozyme: PPP3CA and neurochondrin: NCDN) (Martins-De-Souza et al, 2012 ).…”

Section: Als/ftd Models Of Diseasesupporting

confidence: 93%

“…Recent imaging techniques have been developed to study synaptic density in living FTD patients and support these histological findings. The use of [11C]UCB-J PET, a radio-ligand that selectively binds to synaptic vesicle protein 2A (SV2A), to assess the regional distribution of synaptic loss in patients with probable bvFTD and carriers of C9ORF72 hexanucleotide repeat expansions, showed that loss of synaptic densities occur in the frontotemporal region (Malpetti et al, 2021 ; Salmon et al, 2021 ). Importantly, this study showed that pre-symptomatic FTD-C9 patients had reduced synaptic density and that extensive synaptic loss was observed in patients with severe cognitive impairments (Malpetti et al, 2021 ).…”

Section: Neuropathological Features Of Als and Ftdmentioning

confidence: 99%

See 1 more Smart Citation

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Gelon

Dutchak

Sephton

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Synaptic loss is a pathological feature of all neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is a disease of the cortical and spinal motor neurons resulting in fatal paralysis due to denervation of muscles. FTD is a form of dementia that primarily affects brain regions controlling cognition, language and behavior. Once classified as two distinct diseases, ALS and FTD are now considered as part of a common disease spectrum based on overlapping clinical, pathological and genetic evidence. At the cellular level, aggregation of common proteins and overlapping gene susceptibilities are shared in both ALS and FTD. Despite the convergence of these two fields of research, the underlying disease mechanisms remain elusive. However, recent discovers from ALS and FTD patient studies and models of ALS/FTD strongly suggests that synaptic dysfunction is an early event in the disease process and a unifying hallmark of these diseases. This review provides a summary of the reported anatomical and cellular changes that occur in cortical and spinal motor neurons in ALS and FTD tissues and models of disease. We also highlight studies that identify changes in the proteome and transcriptome of ALS and FTD models and provide a conceptual overview of the processes that contribute to synaptic dysfunction in these diseases. Due to space limitations and the vast number of publications in the ALS and FTD fields, many articles have not been discussed in this review. As such, this review focuses on the three most common shared mutations in ALS and FTD, the hexanucleuotide repeat expansion within intron 1 of chromosome 9 open reading frame 72 (C9ORF72), transactive response DNA binding protein 43 (TARDBP or TDP-43) and fused in sarcoma (FUS), with the intention of highlighting common pathways that promote synaptic dysfunction in the ALS-FTD disease spectrum.

show abstract

Section: Als/ftd Models Of Diseasesupporting

confidence: 93%

Section: Neuropathological Features Of Als and Ftdmentioning

confidence: 99%

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Gelon

Dutchak

Sephton

2022

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…[ 18 F]UCB-H uptake was assessed in patients with a behavioral variant of frontotemporal dementia, showing a trend toward a decrease in the distribution volume of the tracer in the right parahippocampal region compared to healthy subjects. Comparisons between patients with the behavioral variant of frontotemporal dementia and data from a group of patients with Alzheimer’s disease did not result in significant differences ( Salmon et al, 2021 ).…”

Section: Synaptic Vesicle Glycoprotein 2a and Positron Emission Tomog...mentioning

confidence: 99%

Synaptic Vesicle Glycoprotein 2A: Features and Functions

et al. 2022

View full text Add to dashboard Cite

In recent years, the field of neuroimaging dramatically moved forward by means of the expeditious development of specific radioligands of novel targets. Among these targets, the synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein of synaptic vesicles, present in all synaptic terminals, irrespective of neurotransmitter content. It is involved in key functions of neurons, focused on the regulation of neurotransmitter release. The ubiquitous expression in gray matter regions of the brain is the basis of its candidacy as a marker of synaptic density. Following the development of molecules derived from the structure of the anti-epileptic drug levetiracetam, which selectively binds to SV2A, several radiolabeled markers have been synthetized to allow the study of SV2A distribution with positron emission tomography (PET). These radioligands permit the evaluation of in vivo changes of SV2A distribution held to be a potential measure of synaptic density in physiological and pathological conditions. The use of SV2A as a biomarker of synaptic density raises important questions. Despite numerous studies over the last decades, the biological function and the expressional properties of SV2A remain poorly understood. Some functions of SV2A were claimed, but have not been fully elucidated. While the expression of SV2A is ubiquitous, stronger associations between SV2A and Υ amino butyric acid (GABA)-ergic rather than glutamatergic synapses were observed in some brain structures. A further issue is the unclear interaction between SV2A and its tracers, which reflects a need to clarify what really is detected with neuroimaging tools. Here, we summarize the current knowledge of the SV2A protein and we discuss uncertain aspects of SV2A biology and physiology. As SV2A expression is ubiquitous, but likely more strongly related to a certain type of neurotransmission in particular circumstances, a more extensive knowledge of the protein would greatly facilitate the analysis and interpretation of neuroimaging results by allowing the evaluation not only of an increase or decrease of the protein level, but also of the type of neurotransmission involved.

show abstract

“…[ 11 C]UCB-J is not the only potential marker of synaptic health in frontotemporal dementia, and related disorders. A previous study using [ 18 F]UCB-H PET to assess synaptic loss did not identify a deficit in frontotemporal dementia vs controls, nor was there a difference between frontotemporal dementia and Alzheimer’s disease (Salmon et al ., 2021). The lower specific binding of [ 18 F]UCB-H compared to [ 11 C]UCB-J may have contributed to the null result.…”

Section: Discussionmentioning

confidence: 98%

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

Malpetti

Jones

Cope

et al. 2022

Preprint

View full text Add to dashboard Cite

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.

show abstract

In vivo exploration of synaptic projections in frontotemporal dementia

Cited by 16 publications

References 65 publications

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Synaptic Vesicle Glycoprotein 2A: Features and Functions

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

Contact Info

Product

Resources

About

In vivo exploration of synaptic projections in frontotemporal dementia

Cited by 16 publications

References 65 publications

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Synaptic dysfunction in ALS and FTD: anatomical and molecular changes provide insights into mechanisms of disease

Synaptic Vesicle Glycoprotein 2A: Features and Functions

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

Contact Info

Product

Resources

About

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