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Cited by 13Treatment of Major DepressionNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Challenges and rewards of in vivo synaptic density imaging, and its application to the study of depression

Open access
Asch, Ruth H., Abdallah, Chadi G., Carson, Richard E., Esterlis, Irina·2025·Neuropsychopharmacology
DOI 10.1038/s41386-024-01913-3PMC PMC11525584
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Abstract

The development of novel radiotracers for Positron Emission Tomography (PET) imaging agents targeting the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system, provides a method for the in vivo quantification of synaptic density. This is of particular interest in neuropsychiatric disorders given that synaptic alterations appear to underlie disease progression and symptom severity. In this review, we briefly describe the development of these SV2A tracers and the evaluation of quantification methods. Next, we discuss application of SV2A PET imaging to the study of depression, including a review of our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms and the use of a ketamine drug challenge to examine synaptogenesis in vivo. We then highlight the importance of performing translational PET imaging in animal models in conjunction with clinical imaging. We consider the ongoing challenges, possible solutions, and present preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress. Finally, we discuss methodological improvements and future directions for SV2A imaging, potentially in conjunction with other neural markers.

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Crossref · 10.1038/s41386-024-01913-3

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Claims the paper makes

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  • Findingown data

    The authors' findings demonstrate lower SV2A synaptic density in people with significant depressive symptoms.

    “our findings demonstrating lower SV2A synaptic density in people with significant depressive symptoms”
    Quote in the paperSubstantial claim
  • Findingown data

    Preliminary findings from the authors' lab demonstrate translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress.

    “preliminary findings from our lab demonstrating the translational benefit and potential of in vivo SV2A imaging in animal models of chronic stress”
    Quote in the paperSubstantial claim
  • Findingcitation

    Work from the authors' group and others has shown that quantification of SV2A is similar to that of other markers of synaptic density in clinical samples and after drug challenge.

    “work from our group and others has shown that quantification of SV2A is similar to that of other markers of synaptic density in clinical samples and after drug challenge”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [10] Kaufman A, Salazar S, Haas L, Yang J, Kostylev M, Jeng A, et al. Fyn inhibition rescues established memory and synapse loss in Alzheimer mice. Ann Neurol 2015;77:953–71. source

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    • cites [71] Kato T, Pothula S, Liu R, Duman C, Terwilliger R, Vlasuk G, et al. Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation. J Clin Invest. 2019;129:2542–54. source

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  • Findingcitation

    Work by Ron Duman, in collaboration with the authors' group, demonstrated elevated synaptic protein expression, including SV2A, in the prefrontal cortex of rats 24 hours after a single subanesthetic dose of ketamine (10 mg/kg).

    “Work by Ron Duman, in collaboration with our group, demonstrated elevated synaptic protein expression, including SV2A, in the prefrontal cortex of rats 24-hours (time comparable to human peak antidepressant effects) after a single subanesthetic dose of ketamine (10 mg/kg)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Kato T, Pothula S, Liu R, Duman C, Terwilliger R, Vlasuk G, et al. Sestrin modulator NV-5138 produces rapid antidepressant effects via direct mTORC1 activation. J Clin Invest. 2019;129:2542–54. source

      Not checked in the free run.

  • Findingown data

    dlPFC connectivity was positively correlated with severity of depressive symptoms.

    “and positively correlated with severity of depressive symptoms”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [132] Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529. source

      Not checked in the free run.

  • May combine two claims. 47
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Findingown data

    The authors found no detectable effect of ketamine on synaptic density in healthy controls (n=9), a clinical group (MDD and/or PTSD, n=12), or non-human primates (n=4).

    “we found no detectible effect of ketamine on synaptic density in healthy controls (HC, n = 9), or in a clinical group [MDD and/or PTSD (n = 12)] or in non-human primates (Macaca malatta, n = 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [160] Holmes SE, Finnema SJ, Naganawa M, DellaGioia N, Holden D, Fowles K, et al. Imaging the effect of ketamine on synaptic density (SV2A) in the living brain. Mol Psychiatry. 2022;27:2273–81. source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisenone given

    PET imaging can quantify specific physiological functions and measure unique elements of the living brain including receptors, transporters, and enzymes.

    “The great strength of positron emission tomography (PET) imaging is its ability to quantify specific physiological functions and to measure unique elements of the living brain including receptors, transporters, and enzymes.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Synaptic alterations appear to underlie disease progression and symptom severity in neuropsychiatric disorders.

    “synaptic alterations appear to underlie disease progression and symptom severity”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    SV2A is an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system.

    “the synaptic vesicle glycoprotein 2 A (SV2A), an integral glycoprotein present in the membrane of all synaptic vesicles throughout the central nervous system”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    MR technologies enable in vivo study of the brain, with some results potentially approximating synaptic changes and function.

    “Use of magnetic resonance (MR) technologies, including structural imaging (MRI), functional imaging (fMRI) and spectroscopy (MRS), has enabled the study of the brain in vivo, with some results potentially approximating synaptic changes and function.”
    Quote in the paperSubstantial claim

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    Premisecitation

    fMRI measures of brain function are dependent on high-energy demands of cerebral signaling, with glutamatergic action potentials (71%) and neurotransmitter cycling (9%) accounting for the largest proportion of the brain's total energetic needs.

    “fMRI measures of brain function are dependent on the high-energy demands of cerebral signaling, with glutamatergic action potentials (71%) and neurotransmitter cycling (9%) accounting for the largest proportion of the brain's total energetic needs”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [14] Yu Y, Herman P, Rothman D, Agarwal D, Hyder F. Evaluating the gray and white matter energy budgets of human brain function. J Cereb Blood Flow Metab: Off J Int Soc Cereb Blood Flow Metab. 2018;38:1339–53. source

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    • cites [15] Howarth C, Gleeson P, Attwell D. Updated energy budgets for neural computation in the neocortex and cerebellum. J Cereb blood flow Metab. 2012;32:1222–32. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PET has yielded novel radiopharmaceuticals relevant to neuropsychiatric disorders and depression, leading to insights regarding molecular mechanisms contributing to symptom etiology and severity.

    “This has yielded a plethora of novel radiopharmaceuticals relevant to the study of neuropsychiatric disorders in general, and depression more specifically, leading to unique insights regarding molecular mechanisms in the brain contributing to symptom etiology and severity”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [1] Smith DF, Jakobsen S. Molecular neurobiology of depression: PET findings on the elusive correlation with symptom severity. Front Psychiatry. 2013;4:8. source

      Not checked in the free run.

    • cites [2] Cervenka S, Frick A, Bodén R, Lubberink M. Application of positron emission tomography in psychiatry—methodological developments and future directions. Transl Psychiatry. 2022;12:248. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Synaptic density is predicted to positively correlate with both glutamate cycling and energy consumption.

    “Synaptic density is predicted to positively correlate with both glutamate cycling (V Cycle ) and energy consumption (V TCAn ).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Rothman DL, de Graaf RA, Hyder F, Mason GF, Behar KL, De Feyter HM. In vivo (13) C and (1) H-[(13) C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer. NMR Biomed. 2019;32:e4172. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Smaller hippocampal and prefrontal cortical volumes is one of the earliest and most replicated structural MRI evidence of gray matter deficits in MDD and other stress-related disorders, although there is some variability.

    “Smaller hippocampal and prefrontal cortical volumes is one of the earliest and most replicated structural MRI evidence of gray matter deficits in MDD and other stress-related disorders [24][25][26], although there is some variability in findings [27,28].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24][25][26]

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    • cites [27] Wu CJL, Mu Q, Fang Z, Hamoudi HJAS, Huang M, Hu S, et al. Altered hippocampal subfield volumes in major depressive disorder with and without anhedonia. BMC Psychiatry. 2023;23:540. source

      Not checked in the free run.

    • cites [28] Sun YHN, Wang M, Lu L, Luo C, Tang B, Yao C, et al. Hippocampal subfield alterations in schizophrenia and major depressive disorder: a systematic review and network meta-analysis of anatomic MRI studies. J Psychiatry Neurosci. 2023;48:E34–E49. source

      Not checked in the free run.

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    Premisecitation

    13C MRS can estimate overall glutamate release and cycling, neuronal energetic consumption, and energy-per-cycle ratio.

    “when MRS is combined with infusion of carbon-13 non-radioactive isotopes ( 13 C MRS), we can estimate the overall glutamate release and cycling (V Cycle ), neuronal energetic consumption (V TCAn ) and the energy-percycle ratio (V TCAn /V Cycle )”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Abdallah CG, De Feyter HM, Averill LA, Jiang L, Averill CL, Chowdhury GMI, et al. The effects of ketamine on prefrontal glutamate neurotransmission in healthy and depressed subjects. Neuropsychopharmacology. 2018;43:2154–60. source

      Not checked in the free run.

    • cites [22] Rothman DL, de Graaf RA, Hyder F, Mason GF, Behar KL, De Feyter HM. In vivo (13) C and (1) H-[(13) C] MRS studies of neuroenergetics and neurotransmitter cycling, applications to neurological and psychiatric disease and brain cancer. NMR Biomed. 2019;32:e4172. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reduced global brain connectivity in the PFC is among the most reproducible resting state fMRI findings in MDD, and is thought to reflect an underlying PFC reduction in synaptic density and strength associated with depression.

    “Reduced global brain connectivity (GBC) in the PFC is among the most reproducible resting state fMRI finding in MDD [20,[33][34][35][36][37], and is thought to reflect an underlying PFC reduction in synaptic density and strength associated with depression”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20,[33][34][35][36][37]

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    Premisecitation

    fcMRI measures have been found to be positively associated with regional cerebral blood flow and glutamate neurotransmission, supporting the notion that MRI methodologies can provide information regarding synaptic health and fidelity.

    “fcMRI measures have been found to be positively associated with regional cerebral blow flow [18,19] and glutamate neurotransmission [20], further supporting the notion that MRI methodologies can provide information regarding synaptic health and fidelity”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Liang X, Connelly A, Calamante F. Graph analysis of resting-state ASL perfusion MRI data: nonlinear correlations among CBF and network metrics. NeuroImage. 2014;87:265–75. source

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    • cites [19] Liang X, Zou Q, He Y, Yang Y. Coupling of functional connectivity and regional cerebral blood flow reveals a physiological basis for network hubs of the human brain. Proc Natl Acad Sci USA. 2013;110:1929–34. source

      Not checked in the free run.

    • cites [20] Abdallah C, Averill C, Salas R, Averill L, Baldwin P, Krystal J, et al. Prefrontal connectivity and glutamate transmission: relevance to depression pathophysiology and ketamine treatment. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2:566–74.

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  • May combine two claims.

    Interpretationreasoning

    General utility of the SV2A marker in a wide range of disorders makes it uniquely suited for translational and human imaging, with potential to aid in disease diagnosis and differentiation, as well as monitoring treatment response.

    “The general utility of this marker in a wide range of disorders makes it uniquely suited for translational and human imaging, with the potential to aid in disease diagnosis and differentiation, as well as monitoring treatment response.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    SV2 is a glycoprotein present within the membrane (with 12 transmembrane domains) of every secretory vesicle, including synaptic vesicles.

    “The pre-synaptic vesicle protein 2 (SV2) is a glycoprotein [43] present within the membrane (with 12 transmembrane domains) of every secretory vesicle, including synaptic vesicles”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [43] Bajjalieh SM, Peterson K, Shinghal R, Scheller RH. SV2, a brain synaptic vesicle protein homologous to bacterial transporters. Science. 1992;257:1271–3. source

      Not checked in the free run.

    • cites [44][45][46]

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    Interpretationreasoning

    MRI measures described are related to synaptic density and strength, but the relationship is often indirect and other non-synaptic factors may affect these measures.

    “While the MRI measures described above are related to synaptic density and strength, it is important to underscore the often indirect nature of this relationship and the possibility that other non-synaptic factors may affect these measures.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    SV2A is the most broadly expressed isoform, observed in all gray matter structures, with peak expression in subcortical areas such as basal ganglia and thalamus.

    “SV2A is the most broadly expressed isoform, observed in all gray matter structures, but with peak expression in subcortical areas such as the basal ganglia and thalamus”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47,[57][58][59]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Evidence from structural and functional studies suggests SV2 proteins play multiple roles in the life cycle of a synaptic vesicle to promote proper vesicular function.

    “evidence from structural and functional studies suggests SV2 proteins play multiple roles in the “life cycle” of a synaptic vesicle to promote proper vesicular function”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Stout KA, Dunn AR, Hoffman C, Miller GW. The synaptic vesicle glycoprotein 2: structure, function, and disease relevance. ACS Chem Neurosci. 2019;10:3927–38. source

      Not checked in the free run.

    • cites [49] Mendoza-Torreblanca JG, Vanoye-Carlo A, Phillips-Farfan BV, Carmona-Aparicio L, Gomez-Lira G. Synaptic vesicle protein 2A: basic facts and role in synaptic function. Eur J Neurosci. 2013;38:3529–39. source

      Not checked in the free run.

    • cites [50] Bartholome O, Van den Ackerveken P, Sanchez Gil J, de la Brassinne Bonardeaux O, Leprince P, Franzen R, et al. Puzzling out synaptic vesicle 2 family members functions. Front Mol Neurosci. 2017;10:148. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The SV2 family has three isoforms: SV2A, SV2B, and SV2C.

    “The SV2 family has three isoforms: SV2A, SV2B, and SV2C”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46][47][48]

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    There is evidence of preferential SV2A expression in GABAergic neuronal subtypes relative to glutamatergic neuronal populations in both rodent and human brain.

    “there is evidence of preferential SV2A expression in GABergic (inhibitory) neuronal subtypes relative to glutmateric (excitatory) neuronal populations in both rodent [60] and human (The Human Protein Atlas, version 15; www.proteinatlas.org)[61] brain”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Mendoza-Torreblanca JG, García-Cruz ME, Sánchez-Cruz I, Gomez-Gonzalez B, Juárez-Méndez S, Gómez-Lira G. Analysis of differential expression of synaptic vesicle protein 2A in the adult rat brain. Neuroscience. 2019;419:108–20. source

      Not checked in the free run.

    • cites [61] Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SV2A is a promising biomarker of synaptic density as it is ubiquitously and mostly homogeneously present in synaptic vesicles with low variation in copy number per vesicle.

    “SV2A is a promising biomarker of synaptic density as it is ubiquitously and, for the most part, homogeneously present in synaptic vesicles [47] with low variation in copy number per vesicle [66].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Bajjalieh SM, Frantz GD, Weimann JM, McConnell SK, Scheller RH. Differential expression of synaptic vesicle protein 2 (SV2) isoforms. J Neurosci: Off J Soc Neurosci. 1994;14:5223–35. source

      Not checked in the free run.

    • cites [66] Mutch SA, Kensel-Hammes P, Gadd JC, Fujimoto BS, Allen RW, Schiro PG, et al. Protein quantification at the single vesicle level reveals that a subset of synaptic vesicle proteins are trafficked with high precision. J Neurosci : Off J Soc Neurosci. 2011;31:1461–70. source

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  • May combine two claims.

    Interpretationcitation

    Differences in SV2A expression or tracer binding could represent alterations in number of presynaptic terminals, number of synaptic vesicles within each terminal, or how many molecules of SV2A are expressed per individual synaptic vesicle.

    “Differences in SV2A expression or tracer binding could represent alterations in: (1) the number of presynaptic terminals, (2) the number of synaptic vesicles within each synaptic terminal; or (3) how many molecules of SV2A are expressed by each individual synaptic vesicle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Rossi R, Arjmand S, Bærentzen SL, Gjedde A, Landau AM. Synaptic vesicle glycoprotein 2A: features and functions. Front Neurosci. 2022;16:864514. source

      Not checked in the free run.

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    Interpretationnone given

    Despite SV2A quantification showing good agreement with other synaptic proteins, there is still uncertainty of the biological interpretation of altered SV2A density.

    “there is still uncertainty of the biological interpretation of altered SV2A density”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Quantification of radiotracer binding to SV2A does correlate with measures of synaptic vesicle number and expression of other pre-synaptic proteins classically used in postmortem and in vitro work.

    “quantification of radiotracer binding to SV2A does correlate with measures of synaptic vesicle number [8,9,69,70] and expression of other pre-synaptic proteins classically used in postmortem and in vitro work (e.g., synaptophysin, synapsin).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [8] Kang H, Voleti B, Hajszan T, Rajkowska G, Stockmeier C, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7. source

      Not checked in the free run.

    • cites [9] Finnema S, Nabulsi N, Eid T, Detyniecki K, Lin S, Chen M, et al. Imaging synaptic density in the living human brain by positron emission tomography. Sci Transl Med. 2016;8:348ra396. source

      Not checked in the free run.

    • cites [69] Cai Z, Li S, Matuskey D, Nabulsi N, Huang Y. PET imaging of synaptic density: a new tool for investigation of neuropsychiatric diseases. Neurosci Lett. 2018;691:44–50. source

      Not checked in the free run.

    • cites [70] Chen M, Mecca A, Naganawa M, Finnema S, Toyonaga T, Lin S, et al. Assessing synaptic density in alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurol. 2018;75:1215–24. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    SV2A expression is slightly enriched at inhibitory synapses, such that SV2A PET imaging may be more or less sensitive to synaptic alterations induced by disease states or treatments preferentially targeting certain neuronal populations.

    “SV2A expression is slightly enriched at inhibitory synapses [60,61], such that SV2A PET imaging may be more or less sensitive to synaptic alterations induced by disease states or treatments preferentially tagetting certain neuronal populations.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [60] Mendoza-Torreblanca JG, García-Cruz ME, Sánchez-Cruz I, Gomez-Gonzalez B, Juárez-Méndez S, Gómez-Lira G. Analysis of differential expression of synaptic vesicle protein 2A in the adult rat brain. Neuroscience. 2019;419:108–20. source

      Not checked in the free run.

    • cites [61] Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postmortem human studies have revealed cell atrophy, loss of glia, and decreased PFC volume in depression.

    “Postmortem human studies have also revealed cell atrophy, loss of glia, and decreased PFC volume in depression”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75][76][77][78]

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    Interpretationcitation

    Scifo and colleagues did not observe differences in protein expression within the MDD groups, suggesting that synapse-related changes may persist in stress-related disorders.

    “they did not observe differences in protein expression within the MDD groups, suggesting that synapse-related changes may persist in stress-related disorders”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Scifo E, Pabba M, Kapadia F, Ma T, Lewis D, Tseng G, et al. Sustained molecular pathology across episodes and remission in major depressive disorder. Biol Psychiatry. 2018;83:81–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vesicle number is stable across neurons and has been shown to change in accordance with alterations in synaptic density at the same rate.

    “vesicle number is stable across neurons [92][93][94] and has been shown to change in accordance with alterations in synaptic density at the same rate [95,96].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [92][93][94]

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    • cites [95] Li N, Lee B, Liu R, Banasr M, Dwyer J, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source

      Not checked in the free run.

    • cites [96] Nava N, Treccani G, Liebenberg N, Chen F, Popoli M, Wegener G, et al. Chronic desipramine prevents acute stress-induced reorganization of medial prefrontal cortex architecture by blocking glutamate vesicle accumulation and excitatory synapse increase. Int J Neuropsychopharmacol. 2014;18:pyu085. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Electron microscopic stereology and microarray gene profiling in brain tissue of individuals with MDD have shown a lower number of quantified synapses in the dlPFC relative to matched controls, with correspondingly lower expression of synaptic vesicle function related genes.

    “Electron microscopic stereology and microarray gene profiling conducted in brain tissue of individuals with MDD have shown a lower number of quantified synapses in the dlPFC relative to matched controls [8] with a correspondingly lower expression of synaptic vesicle function related genes (e.g., synapsin I).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Kang H, Voleti B, Hajszan T, Rajkowska G, Stockmeier C, Licznerski P, et al. Decreased expression of synapse-related genes and loss of synapses in major depressive disorder. Nat Med. 2012;18:1413–7. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ketamine, a glutamate NMDA receptor antagonist, can rapidly (within a few hours) reduce depressive symptoms, an effect that can last for a week, or in some cases, longer.

    “ketamine, a glutamate N-methyl-daspartate (NMDA) receptor antagonist, can rapidly (within a few hours) reduce depressive symptoms, an effect that can last for a week, or in some cases, longer”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97][98][99][100]

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    Premisecitation

    Reductions in PFC and HIP dendritic arborization and spine density often develop as a consequence of stress and can be observed as early as after 7 days of restraint stress.

    “Reductions in PFC and HIP dendritic arborization and spine density often develop as a consequence of stress [88] and can be observed as early as after 7 days of restraint stress [89].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [88] Bogoch Y, Biala Y, Linial M, Weinstock M. Anxiety induced by prenatal stress is associated with suppression of hippocampal genes involved in synaptic function. J Neurochem. 2007;101:1018–30. source

      Not checked in the free run.

    • cites [89] Liu R, Aghajanian G. Stress blunts serotonin- and hypocretin-evoked EPSCs in prefrontal cortex: role of corticosterone-mediated apical dendritic atrophy. Proc Natl Acad Sci. 2008;105:359–64. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The first attempt to develop a SV2A-PET radioligand was [11C]levetiracetam.

    “the first attempt to develop a SV2A-PET radioligand was [ 11 C]levetiracetam”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [108] Cai H, Mangner TJ, Muzik O, Wang M-W, Chugani DC, Chugani HT. Radiosynthesis of 11C-levetiracetam: a potential marker for PET imaging of SV2A expression. ACS Med Chem Lett. 2014;5:1152–5. source

      Not checked in the free run.

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    Premisecitation

    [11C]levetiracetam did not progress, probably due to its low binding affinity to SV2A (Ki = 1.74 μM).

    “Ultimately, this tracer did not progress, probably due to its low binding affinity to SV2A (K i = 1.74 µM)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [109] Danish A, Namasivayam V, Schiedel AC, Muller CE. Interaction of approved drugs with synaptic vesicle protein 2A. Arch Pharm (Weinh). 2017;350:1700003. source

      Not checked in the free run.

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    Premisecitation

    A single administration of ketamine significantly increases the number of synaptic vesicles as well as important synaptic structural proteins within hours of drug administration, persisting for about 7 days.

    “a single administration of ketamine significantly increases the number of synaptic vesicles [101] as well as important synaptic structural proteins within hours of drug administration that persisted for about 7 days [30,95,101].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [101] Müller HK, Wegener G, Liebenberg N, Zarate CA Jr, Popoli M, Elfving B. Ketamine regulates the presynaptic release machinery in the hippocampus. J Psychiatr Res. 2013;47:892–9. source

      Not checked in the free run.

    • cites [30] Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61. source

      Not checked in the free run.

    • cites [95] Li N, Lee B, Liu R, Banasr M, Dwyer J, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rodent stress models of depression, the formation of new synapses can be observed within 24 hours of ketamine administration and can last for a week, which is also the time course of ketamine's antidepressant response in individuals with depression.

    “In the rodent stress models of depression, the formation of new synapses can be observed within 24 hours of ketamine administration and can last for a week [30], which, likely not coincidentally, is also the time course of ketamine's antidepressant response in individuals with depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A single dose of ketamine increases the total number of spines and pre-synaptic vesicle proteins in the PFC within 2 hours of ketamine administration, with increases in spine density occurring in parallel to increases in pre-synaptic vesicle protein expression.

    “a single dose of ketamine increases the total number of spines and pre-synaptic vesicle proteins in the PFC within 2 hours of ketamine administration (Fig. 1, middle row, right panel) [30,95], with increases in spine density occurring in parallel to increases in pre-synaptic vesicle protein expression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [30] Li N, Liu R-J, Dwyer JM, Banasr M, Lee B, Son H, et al. Glutamate N-methyl-D-aspartate receptor antagonists rapidly reverse behavioral and synaptic deficits caused by chronic stress exposure. Biol Psychiatry. 2011;69:754–61. source

      Not checked in the free run.

    • cites [95] Li N, Lee B, Liu R, Banasr M, Dwyer J, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 2004, Lynch et al. demonstrated that SV2A is the target of antiepileptic drug levetiracetam.

    “In 2004, Lynch et al. demonstrated that SV2A is the target of antiepileptic drug levetiracetam”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [106] Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA. 2004;101:9861–6. source

      Not checked in the free run.

    • cites [107] Gillard M, Chatelain P, Fuks B. Binding characteristics of levetiracetam to synaptic vesicle protein 2A (SV2A) in human brain and in CHO cells expressing the human recombinant protein. Eur J Pharm. 2006;536:102–8. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent human scans with [18F]SynVesT-2 demonstrate slightly lower binding potential but faster kinetics than [18F]SynVesT-1.

    “Recent human scans with [ 18 F] SynVesT-2 demonstrate slightly lower binding potential but faster kinetics than [ 18 F]SynVesT-1”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Drake LR, Wu Y, Naganawa M, Asch R, Zheng C, Najafzadeh S, et al. First-in-Human Study of 18F-SynVesT-2: An SV2A PET imaging probe with fast brain kinetics and high specific binding. J Nucl Med. 2024;65:462–9. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Of these, [11C]UCB-J possessed the most suitable pharmacokinetics: rapid and high brain uptake, reversible binding kinetics, and relatively low nonspecific binding in white matter.

    “Of these, [ 11 C]UCB-J possessed the most suitable pharmacokinetics, i.e., rapid and high brain uptake, reversible binding kinetics, and relatively low nonspecific binding in white matter”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the Brain. J Nucl Med. 2016;57:777–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subsequent SV2A human imaging data were highly consistent with preclinical data, i.e., [11C]UCB-J has ideal imaging characteristics, higher binding kinetics and specific binding in the brain.

    “Subsequent SV2A human imaging data were highly consistent with preclinical data, i.e., [ 11 C]UCB-J has ideal imaging characteristics [67], possessing higher binding kinetics [118] and specific binding in the brain [119].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [67] Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra396. source

      Not checked in the free run.

    • cites [118] Lubberink M, Appel L, Daging J, Lindskog K, Danfors T, Larsson E-M, et al. Tracer kinetic analysis of the SV2A ligand 11C-UCBA as a PET marker for synaptic density in humans. J Nucl Med. 2017;58:631.

      Not checked in the free run.

    • cites [119] Bahri MA, Plenevaux A, Aerts J, Bastin C, Becker G, Mercier J, et al. Measuring brain synaptic vesicle protein 2A with positron emission tomography and [(18)F]UCB-H. Alzheimers Dement (N. Y) 2017;3:481–6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Three of the SV2A ligands were radiolabeled as [11C]UCB-A, [18F]UCB-H, and [11C]UCB-J, and all were evaluated in nonhuman primates.

    “Three of the SV2A ligands were radiolabeled as [ 11 C] UCB-A [112], [ 18 F]UCB-H [113-116], and [ 11 C]UCB-J [117], and all were evaluated in nonhuman primates (NHP).”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [112] Estrada S, Lubberink M, Thibblin A, Sprycha M, Buchanan T, Mestdagh N, et al. 11C]UCB-A, a novel PET tracer for synaptic vesicle protein 2 A. Nucl Med Biol. 2016;43:325–32. source

      Not checked in the free run.

    • cites [113] Warnock GI, Aerts J, Bahri MA, Bretin F, Lemaire C, Giacomelli F, et al. Evaluation of 18F-UCB-H as a novel PET tracer for synaptic vesicle protein 2A in the brain. J Nucl Med. 2014;55:1336–41. source

      Not checked in the free run.

    • cites [114] Becker G, Warnier C, Serrano ME, Bahri MA, Mercier J, Lemaire C, et al. Pharmacokinetic Characterization of [18F]UCB-H PET Radiopharmaceutical in the Rat Brain. Mol Pharm. 2017;14:2719–25. source

      Not checked in the free run.

    • cites [115] Warnier C, Lemaire C, Becker G, Zaragoza G, Giacomelli F, Aerts J, et al. Enabling efficient positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) with a robust and one-step radiosynthesis of a highly potent 18F-labeled ligand ([18F]UCB-H). J Med Chem. 2016;59:8955–66. source

      Not checked in the free run.

    • cites [116] Bretin F, Warnock G, Bahri MA, Aerts J, Mestdagh N, Buchanan T, et al. Preclinical radiation dosimetry for the novel SV2A radiotracer [18F]UCB-H. EJNMMI Res. 2013;3:35. source

      Not checked in the free run.

    • cites [117] Nabulsi NB, Mercier J, Holden D, Carre S, Najafzadeh S, Vandergeten MC, et al. Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the Brain. J Nucl Med. 2016;57:777–84. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In humans, [18F]SynVesT-1 displayed outstanding characteristics: very high brain uptake, fast and reversible kinetics, excellent test-retest reproducibility and binding specificity to SV2A.

    “In humans, [ 18 F]SynVesT-1 displayed outstanding characteristics, i.e., very high brain uptake, fast and reversible kinetics, excellent test-retest reproducibility and binding specificity to SV2A”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [124] Li S, Naganawa M, Pracitto R, Najafzadeh S, Holden D, Henry S, et al. Assessment of test-retest reproducibility of [(18)F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A. Eur J Nucl Med Mol Imaging. 2021;48:1327–38. source

      Not checked in the free run.

    • cites [125] Naganawa M, Li S, Nabulsi N, Henry S, Zheng MQ, Pracitto R, et al. First-in-human evaluation of (18)F-SynVesT-1, a radioligand for PET imaging of synaptic vesicle glycoprotein 2A. J Nucl Med. 2021;62:561–7. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The availability of these fluorine-18 labeled SV2A-PET radioligands provides the opportunity for multicenter clinical studies within neuropsychiatry, neurology, and beyond.

    “The availability of these fluorine-18 labeled SV2A-PET radioligands provides the opportunity for multicenter clinical studies within the context of neuropsychiatry, neurology, and beyond.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Postmortem findings from animal models consistently demonstrate that stress induces synaptic dysfunction, including reductions in synaptic density, as measured by quantification of synaptic structure and assessments of synaptic protein expression.

    “Postmortem findings from these animal models consistently demostrate that stress induces synaptic dysfunction [5,6,135], including reductions in synaptic density, as measured by both quantification of synaptic structure and assessments of synaptic protein expression”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Duman CH, Duman RS. Spine synapse remodeling in the pathophysiology and treatment of depression. Neurosci Lett. 2015;601:20–29. source

      Not checked in the free run.

    • cites [6] Duman RS, Aghajanian GK. Synaptic dysfunction in depression: potential therapeutic targets. Science. 2012;338:68–72. source

      Not checked in the free run.

    • cites [135] Krystal JH, Abdallah CG, Averill LA, Kelmendi B, Harpaz-Rotem I, Sanacora G, et al. Synaptic loss and the pathophysiology of PTSD: implications for ketamine as a prototype novel therapeutic. Curr Psychiatry Rep. 2017;19:74. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatments targeting synaptic plasticity and synaptogenesis, such as ketamine and psilocybin, have both been shown to result in upregulation of SV2A.

    “treatments targeting synaptic plasticity and synaptogenesis, such as ketamine and the psychedelic psilocybin, have both been shown to result in upregulation of SV2A”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    Excellent test-retest reproducibility and low noise VT images can be obtained.

    “Excellent test-retest reproducibility and low noise V T images can be obtained”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [124] Li S, Naganawa M, Pracitto R, Najafzadeh S, Holden D, Henry S, et al. Assessment of test-retest reproducibility of [(18)F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A. Eur J Nucl Med Mol Imaging. 2021;48:1327–38. source

      Not checked in the free run.

    • cites [125] Naganawa M, Li S, Nabulsi N, Henry S, Zheng MQ, Pracitto R, et al. First-in-human evaluation of (18)F-SynVesT-1, a radioligand for PET imaging of synaptic vesicle glycoprotein 2A. J Nucl Med. 2021;62:561–7. source

      Not checked in the free run.

    • The authors state this as an assumption: For VT quantification, nonspecific binding of the radiotracer is not significantly different between groups.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    All brain gray matter contains synapses and SV2A.

    “Given that all of the brain gray matter contains synapses and SV2A”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Repeated restraint stress resulted in dendritic spine loss by decreasing spine formation and enhancing spine elimination, while ketamine prevented spine elimination and promoted reformation of stress-eliminated spines.

    “Ng and colleagues [146] found that repeated restraint stress resulted in dendritic spine loss by decreasing spine formation and enhancing spine elimination, while ketamine prevented spine elimination and promoted reformation of stress-eliminated spines.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [146] Ng LHL, Huang Y, Han L, Chang RC-C, Chan YS, Lai CSW. Ketamine and selective activation of parvalbumin interneurons inhibit stress-induced dendritic spine elimination. Transl psychiatry. 2018;8:272. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The null findings and discrepancy from the authors' report in younger individuals could be due in part to differences in PET methodology, including the use of CS as a reference region.

    “the null findings and discrepancy from our report in younger individuals could also be, in part, due to differences in the PET methodology, including the use of CS as a reference region.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [159] Vande Casteele T, Laroy M, Van Cauwenberge M, Koole M, Dupont P, Sunaert S, et al. Preliminary evidence for preserved synaptic density in late-life depression. Transl psychiatry. 2024;14:145. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent work by Vande Casteele and colleagues did not observe a synaptic deficit in older individuals (73.0 ± 6.2 years) with depression or correlations with clinical outcomes.

    “recent work by Vande Casteele and colegues [159] did not observe a synaptic deficit in older individuals (73.0 ± 6.2 years) with depression or corelations with clinical outcomes.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [159] Vande Casteele T, Laroy M, Van Cauwenberge M, Koole M, Dupont P, Sunaert S, et al. Preliminary evidence for preserved synaptic density in late-life depression. Transl psychiatry. 2024;14:145. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Catheterization of a major artery is needed for blood sampling, and the total blood volume required means small-animal studies would be terminal.

    “catheterization of a major artery would be needed for blood sampling and the total volume of blood required ultimately means these studies in small animals would be terminal.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Population-based metabolite correction could be a solution for radiometabolites, but ideally this should be established for each tracer and validated in each animal model.

    “For the case of radiometabolites, a population-based metabolite correction could be a solution [157,158], but ideally this should be established for each tracer and validated in each animal model [152].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [157] Bertoglio D, Verhaeghe J, Miranda A, Kertesz I, Cybulska K, Korat Š, et al. Validation and noninvasive kinetic modeling of [(11)C]UCB-J PET imaging in mice. J Cereb Blood Flow Metab. 2020;40:1351–62. source

      Not checked in the free run.

    • cites [158] Bertoglio D, Zajicek F, Lombaerde S, Miranda A, Stroobants S, Wang Y, et al. Validation, kinetic modeling, and test-retest reproducibility of [(18)F]SynVesT-1 for PET imaging of synaptic vesicle glycoprotein 2A in mice. J Cereb Blood Flow Metab. 2022;42:1867–78. source

      Not checked in the free run.

    • cites [152] Toyonaga T, Fesharaki-Zadeh A, Strittmatter SM, Carson RE, Cai Z. PET imaging of synaptic density: challenges and opportunities of synaptic vesicle glycoprotein 2A PET in small animal imaging. Front Neurosci. 2022;16:787404. source

      Not checked in the free run.

    • Rests on an assumption: Caveats of the IDIF approach include PVE, cardiac motion artifact, and inability to perform radiometabolite correction at the individual level.

  • May combine two claims.

    Premisecitation

    To detect a 20% lower SV2A in the hippocampus, assuming a standard deviation of 10%, type I error of 0.05, and type II error of 0.20, a study would require 25 mice per group but only 14 rats per group due to PVE.

    “to detect a 20% lower SV2A in the hippocampus, assuming a standard deviation of 10%, type I error (α) of 0.05, and type II error (β) of 0.20, a study would require 25 per group for mice, but only 14 rats per group, simply due to PVE [152].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Toyonaga T, Fesharaki-Zadeh A, Strittmatter SM, Carson RE, Cai Z. PET imaging of synaptic density: challenges and opportunities of synaptic vesicle glycoprotein 2A PET in small animal imaging. Front Neurosci. 2022;16:787404. source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    The IDIF approach avoids blood sampling but has limitations.

    “While this method avoids blood sampling and may be very useful, it is not without limitations.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Caveats of the IDIF approach include PVE, cardiac motion artifact, and inability to perform radiometabolite correction at the individual level.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mGlu5 receptor is thought to be implicated in stress disorders including unipolar and bipolar depression and anxiety.

    “mGlu5 receptor -located primarily postsynaptically -plays a key role in synaptic plasticity and is thought to be implicated in stress disorders including unipolar and bipolar depression and anxiety, as previously reviewed [162,163].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Asch RH, Hillmer AT, Baldassarri SR, Esterlis I. The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders. Int Rev Neurobiol. 2022;168:265–310. source

      Not checked in the free run.

    • cites [163] Esterlis I, Holmes SE, Sharma P, Krystal JH, DeLorenzo C. Metabotropic glutamatergic receptor 5 and stress disorders: Knowledge gained from receptor imaging studies. Biol psychiatry. 2018;84:95–105. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mGlu5 receptor plays a key role in synaptic plasticity.

    “mGlu5 receptor -located primarily postsynaptically -plays a key role in synaptic plasticity and is thought to be implicated in stress disorders including unipolar and bipolar depression and anxiety, as previously reviewed [162,163].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Asch RH, Hillmer AT, Baldassarri SR, Esterlis I. The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders. Int Rev Neurobiol. 2022;168:265–310. source

      Not checked in the free run.

    • cites [163] Esterlis I, Holmes SE, Sharma P, Krystal JH, DeLorenzo C. Metabotropic glutamatergic receptor 5 and stress disorders: Knowledge gained from receptor imaging studies. Biol psychiatry. 2018;84:95–105. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    mGlu5 receptor is located primarily postsynaptically.

    “mGlu5 receptor -located primarily postsynaptically -plays a key role in synaptic plasticity and is thought to be implicated in stress disorders including unipolar and bipolar depression and anxiety, as previously reviewed [162,163].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [162] Asch RH, Hillmer AT, Baldassarri SR, Esterlis I. The metabotropic glutamate receptor 5 as a biomarker for psychiatric disorders. Int Rev Neurobiol. 2022;168:265–310. source

      Not checked in the free run.

    • cites [163] Esterlis I, Holmes SE, Sharma P, Krystal JH, DeLorenzo C. Metabotropic glutamatergic receptor 5 and stress disorders: Knowledge gained from receptor imaging studies. Biol psychiatry. 2018;84:95–105. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    PET imaging of SV2A provides a direct measure of synaptic vesicles and is a proxy for synaptic density.

    “PET imaging of SV2A provides a direct measure of synaptic vesicles and is a proxy for synaptic density.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The regional pattern of synaptic loss and associations with clinical outcomes could potentially provide insights for differentiating various types of neuropsychiatric, neurodevelopmental, and neurodegenerative disorders.

    “the regional pattern of synaptic loss and associations with clinica outcomes could potentially provide insights for differentiating various types of neuropsychiatric, neurodevelopmental, and neurodegenerative disorders.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Loss of synaptic density is not specific to depression.

    “Although the loss of synaptic density is not specific to depression”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Although mGlu5 may not be altered in MDD, it may still be an important target for symptom modulation.

    “suggesting that although mGlu5 may not be altered in MDD, it may still be an important target for symptom modulation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11 C] ABP688 and PET imaging study in depression. Mol psychiatry. 2018;23:824–32. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    These PET studies generally indicate SV2A deficit to be widespread.

    “These PET studies generally indicate SV2A deficit to be widespread.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clinical studies have been performed in epilepsy, schizophrenia, post-traumatic stress disorder, stroke, cocaine use disorder, and cannabis use disorder, as well as in normal aging.

    “[173], schizophrenia [174, 175], post-traumatic stress disorder [132], stroke [176], cocaine use disorder [133], and cannabis use disorder [177], as well as in normal aging [178].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [173] Finnema SJ, Toyonaga T, Detyniecki K, Chen MK, Dias M, Wang Q, et al. Reduced synaptic vesicle protein 2A binding in temporal lobe epilepsy: A [(11) C]UCB-J positron emission tomography study. Epilepsia. 2020;61:2183–93. source

      Not checked in the free run.

    • cites [174] Onwordi EC, Whitehurst T, Mansur A, Statton B, Berry A, Quinlan M, et al. The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study. Transl psychiatry. 2021;11:393. source

      Not checked in the free run.

    • cites [175] Radhakrishnan R, Skosnik PD, Ranganathan M, Naganawa M, Toyonaga T, Finnema S, et al. In vivo evidence of lower synaptic vesicle density in schizophrenia. Mol Psychiatry. 2021;26:7690–8. source

      Not checked in the free run.

    • cites [132] Holmes SE, Scheinost D, Finnema SJ, Naganawa M, Davis MT, DellaGioia N, et al. Lower synaptic density is associated with depression severity and network alterations. Nat Commun. 2019;10:1529. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This increase in synaptic density has been observed in animal models using post mortem synaptic measures and in humans with depression associated with a pre-treatment synaptic deficit using in vivo SV2A PET.

    “This has been observed in animal models using post mortem synaptic measures (middle, right panel), and in humans with depression associated with a pre-treatment synaptic deficit using in vivo SV2A PET (bottm, right panel).”
    Quote in the paperSubstantial claim
63 of 63

  • The authors state this as an assumption.

    For VT quantification, nonspecific binding of the radiotracer is not significantly different between groups.

    “which assumes that nonspecific binding of the radiotracer is not significantly different between groups”

  • The paper relies on this without support.

    Image reconstruction smoothing further degrades spatial resolution.

    “This resolution is further degraded by smoothing performed during image reconstruction.”

  • The paper relies on this without support.

    SV2A imaging in models of neuropsychiatric disorders typically hypothesizes lower synaptic density and SV2A levels relative to healthy/control animals or less impacted brain regions.

    “SV2A imaging in models of neuropsychiatric disorders typically hypothesize lower synaptic density and SV2A levels (and thus, lower radiotracer uptake) relative to healthy/ control animals or as compaired with brain regions anticipated to be less impacted by stress.”

  • The paper relies on this without support.

    It is impossible to completely avoid PVE in small animals.

    “While it is impossible to completely avoid a PVE in small animals”

  • The paper relies on this without support.

    Relative to postmortem evaluations, there is comparatively limited in vivo evidence of synaptic alterations in animal models of stress.

    “Relative to postmortem evaluations, there is comparatively limited in vivo evidence of synaptic alterations in animal models of stress.”

  • The paper relies on this without support.

    None of the in vivo studies, to date, have used SV2A PET.

    “Notably, none of the in vivo studies, to date, have used SV2A PET.”

  • The paper relies on this without support.

    Caveats of the IDIF approach include PVE, cardiac motion artifact, and inability to perform radiometabolite correction at the individual level.

    “Caveats of the IDIF approach include the PVE, cardiac motion artifact, and the inability to perform radiometabolite correction at the individual level.”

  • The paper relies on this without support.

    Arterial blood sampling is a practical challenge in rodent imaging studies.

    “Another practical challenge is arterial blood sampling in rodent imaging studies.”

  • The paper relies on this without support.

    Several studies examining mGlu5 receptor in vivo in depression have been published with mixed results.

    “Several studies examining mGlu5 receptor in vivo in depression have been published with mixed results.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Distribution volume is described both as specific binding and as total binding

    Minor

    The quantification section presents obtaining distribution volume as one way to isolate specific binding by subtracting nonspecific binding. It later defines distribution volume as the sum of specific and nonspecific binding, which is not that isolated measure.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 5

  1. Finnema SJ, Nabulsi NB, Eid T, Detyniecki K, Lin SF, Chen MK, et al. Imaging synaptic density in the living human brain. Sci Transl Med. 2016;8:348ra396. · DOI · Paper page
  2. Carson RE. Tracer kinetic modeling. In Positron Emission Tomography: Basic Science and Clinical Practice. Edited by E. VP, L. BD, W. TD, N. MM. London, Springer-Verlag; 2003. pp. 147–179.
  3. Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11C] ABP688 and PET imaging study in depression. Mol psychiatry. 2018;23:824–32. · DOI · Paper page
  4. Abdallah C, Mason G, DellaGioia N, Sanacora G, Jiang L, Matuskey D, et al. mGluR5 and glutamate involvement in MDD: a multimodal imaging study. Biol Psychiatry: Cogn Neurosci Neuroimaging. 2017;2:449–56.
  5. Esterlis I, DellaGioia N, Pietrzak RH, Matuskey D, Nabulsi N, Abdallah CG, et al. Ketamine-induced reduction in mGluR5 availability is associated with an antidepressant response: an [11 C] ABP688 and PET imaging study in depression. Mol psychiatry. 2018;23:824–32. · DOI · Paper page

Cited by

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Related

Authors
Asch, R. H., Abdallah, C. G., Carson, R. E., & Esterlis, I.
Affiliations
  • Yale University (US)
  • Baylor College of Medicine (US)
Corresponding author
Esterlis, Irina
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2024-07-22
Volume
50
Issue
1
Pages
153-163
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-024-01913-3
PMC
PMC11525584
OpenAlex
W4400873088
Cited by
13
References
176
Citations by year
2026: 5 · 2025: 7 · 2024: 1
FWCI
0.81
Type
journal article
Language
en
Update notices
correction (2025-03-19)
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (KL2TR001862, R01MH132137, R01 MH118728, R01 MH116657)
  • the Beth K and Stuart Yudofsky Chair in the Neuropsychiatry of Military Post Traumatic Stress Syndrome
Topics
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
synaptic density, SV2A, PET radiotracer, depression, synaptogenesis, chronic stress, animal models
MeSH terms
Animals, Brain, Depression, Humans, Membrane Glycoproteins, Nerve Tissue Proteins, Synapses, Positron-Emission Tomography

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