PET imaging of synaptic density in Parkinsonian disorders.

Publisher: Wiley Interscience Country of Publication: United States NLM ID: 7600111 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4547 (Electronic) Linking ISSN: 03604012 NLM ISO Abbreviation: J Neurosci Res Subsets: MEDLINE

Publication: New York, NY : Wiley Interscience
Original Publication: New York, Liss.

Parkinsonian Disorders*/diagnostic imaging ; Parkinsonian Disorders*/metabolism ; Parkinson Disease*/metabolism; Humans ; Positron-Emission Tomography/methods ; Synapses/metabolism ; Dopamine/metabolism ; Brain/metabolism

Synaptic dysfunction and altered synaptic pruning are present in people with Parkinsonian disorders. Dopamine loss and alpha-synuclein accumulation, two hallmarks of Parkinson's disease (PD) pathology, contribute to synaptic dysfunction and reduced synaptic density in PD. Atypical Parkinsonian disorders are likely to have unique spatiotemporal patterns of synaptic density, differentiating them from PD. Therefore, quantification of synaptic density has the potential to support diagnoses, monitor disease progression, and treatment efficacy. Novel radiotracers for positron emission tomography which target the presynaptic vesicle protein SV2A have been developed to quantify presynaptic density. The radiotracers have successfully investigated synaptic density in preclinical models of PD and people with Parkinsonian disorders. Therefore, this review will summarize the preclinical and clinical utilization of SV2A radiotracers in people with Parkinsonian disorders. We will evaluate how SV2A abundance is associated with other imaging modalities and the considerations for interpreting SV2A in Parkinsonian pathology.
(© 2023 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)

Andersen, K. B., Andersen, K. B., Hansen, A. K., Schacht, A. C., Horsager, J., Gottrup, H., Klit, H., Danielsen, E. H., Poston, K. L., Pavese, N., Brooks, D. J., & Borghammer, P. (2023). Synaptic density and glucose consumption in patients with Lewy body diseases: An [11C]UCB-J and [18F]FDG PET study. Movement Disorders, 38, 796-805.
Andersen, K. B., Hansen, A. K., Damholdt, M. F., Horsager, J., Skjaerbaek, C., Gottrup, H., Klit, H., Schacht, A. C., Danielsen, E. H., Brooks, D. J., & Borghammer, P. (2021). Reduced synaptic density in patients with Lewy body dementia: An [11 C]UCB-J PET imaging study. Movement Disorders, 36, 2057-2065.
Andersen, K. B., Hansen, A. K., Knudsen, K., Schacht, A. C., Damholdt, M. F., Brooks, D. J., & Borghammer, P. (2022). Healthy brain aging assessed with [18F]FDG and [11C]UCB-J PET. Nuclear Medicine and Biology, 112-113, 52-58.
Anglade, P., Mouatt-Prigent, A., Agid, Y., & Hirsch, E. C. (1996). Synaptic plasticity in the caudate nucleus of patients with Parkinson's disease. Neurodegeneration, 5, 121-128.
Bajjalieh, S. M., Peterson, K., Linial, M., & Scheller, R. H. (1993). Brain contains two forms of synaptic vesicle protein 2. Proceedings of the National Academy of Sciences, 90, 2150-2154.
Barbagallo, G., Caligiuri, M. E., Arabia, G., Cherubini, A., Lupo, A., Nisticò, R., Salsone, M., Novellino, F., Morelli, M., Cascini, G. L., Galea, D., & Quattrone, A. (2017). Structural connectivity differences in motor network between tremor-dominant and nontremor Parkinson's disease. Human Brain Mapping, 38, 4716-4729.
Bejr-kasem, H., Pagonabarraga, J., Martínez-Horta, S., Sampedro, F., Marín-Lahoz, J., Horta-Barba, A., Aracil-Bolaños, I., Pérez-Pérez, J., Ángeles Botí, M., Campolongo, A., Izquierdo, C., Pascual-Sedano, B., Gómez-Ansón, B., & Kulisevsky, J. (2019). Disruption of the default mode network and its intrinsic functional connectivity underlies minor hallucinations in Parkinson's disease. Movement Disorders, 34, 78-86.
Bellucci, A., Mercuri, N. B., Venneri, A., Faustini, G., Longhena, F., Pizzi, M., Missale, C., & Spano, P. F. (2016). Review: Parkinson's disease: From synaptic loss to connectome dysfunction. Neuropathology and Applied Neurobiology, 42, 77-94.
Bigio, E. H., Vono, M. B., Satumtira, S., Adamson, J., Sontag, E., Hynan, L. S., White, C. L., III, Baker, M., & Hutton, M. (2001). Cortical synapse loss in progressive supranuclear palsy. Journal of Neuropathology and Experimental Neurology, 60, 403-410.
Binda, K., Steinmuller, J., Glud, A., & Lillethorup, T. (2023). Reduced synaptic SV2A density in a porcine model of Parkinson's disease and its modulation by deep brain stimulation of the subthalamic nucleus. Brain Stimulation, 16, 252. https://doi.org/10.1016/j.brs.2023.01.406.
Binda, K. H., Lillethorup, T. P., Real, C. C., Baerentzen, S. L., Nielsen, M. N., Orlowski, D., Brooks, D. J., Chacur, M., & Landau, A. M. (2021). Exercise protects synaptic density in a rat model of Parkinson's disease. Experimental Neurology, 342, 113741.
Booth, R. G., & Baldessarini, R. J. (1991). (+)-6,7-benzomorphan sigma ligands stimulate dopamine synthesis in rat corpus striatum tissue. Brain Research, 557, 349-352.
Borgkvist, A., Avegno, E. M., Wong, M. Y., Kheirbek, M. A., Sonders, M. S., Hen, R., & Sulzer, D. (2015). Loss of Striatonigral GABAergic presynaptic inhibition enables motor sensitization in parkinsonian mice. Neuron, 87, 976-988.
Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., & Del Tredici, K. (2004). Stages in the development of Parkinson's disease-related pathology. Cell and Tissue Research, 318, 121-134.
Buckley, K., & Kelly, R. B. (1985). Identification of a transmembrane glycoprotein specific for secretory vesicles of neural and endocrine cells. The Journal of Cell Biology, 100, 1284-1294.
Burke, S. N., & Barnes, C. A. (2006). Neural plasticity in the ageing brain. Nature Reviews Neuroscience, 7, 30-40.
Cai, Z., Drake, L., Naganawa, M., Najafzadeh, S., Pracitto, R., Lindemann, M., Li, S., Ropchan, J., Labaree, D., Emery, P., Dias, M., Henry, S., Nabulsi, N., Matuskey, D., Hillmer, A., Carson, R., & Huang, Y. (2020). First-in-human study of [18F]SynVesT-2, a novel SV2A radioligand with fast kinetics and high specific binding signals. Journal of Nuclear Medicine, 61, 462.
Calabresi, P., Ghiglieri, V., Mazzocchetti, P., Corbelli, I., & Picconi, B. (2015). Levodopa-induced plasticity: A double-edged sword in Parkinson's disease? Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences, 370, 1-14.
Calo, L., Wegrzynowicz, M., Santivañez-Perez, J., & Grazia Spillantini, M. (2016). Synaptic failure and α-synuclein. Movement Disorders Journal, 31, 169-177.
Carson, R., Naganawa, M., Matuskey, D., Mecca, A., Pittman, B., Toyonaga, T., Lu, Y., Dias, M., Nabulsi, N., Finnema, S., Chen, M.-K., Malison, R., Esterlis, I., van Dyck, C., & Huang, Y. (2018). Age and sex effects on synaptic density in healthy humans as assessed with SV2A PET. Journal of Nuclear Medicine, 59, 541.
Chang, W.-P., & Südhof, T. C. (2009). SV2 renders primed synaptic vesicles competent for Ca2+-Induced exocytosis. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 29, 883-897.
Chen, M.-K., Mecca, A. P., Naganawa, M., Finnema, S. J., Toyonaga, T., Lin, S. F., Najafzadeh, S., Ropchan, J., Lu, Y., McDonald, J. W., Michalak, H. R., Nabulsi, N. B., Arnsten, A. F. T., Huang, Y., Carson, R. E., & van Dyck, C. H. (2018). Assessing synaptic density in Alzheimer disease with synaptic vesicle glycoprotein 2A positron emission tomographic imaging. JAMA Neurology, 75, 1215-1224.
Chen, W.-W., Zhang, X., & Huang, W.-J. (2016). Role of neuroinflammation in neurodegenerative diseases (review). Molecular Medicine Reports, 13, 3391-3396.
Chowdhury, R., Lambert, C., Dolan, R. J., & Düzel, E. (2013). Parcellation of the human substantia nigra based on anatomical connectivity to the striatum. NeuroImage, 81, 191-198.
Claassen, D. O., McDonell, K. E., Donahue, M., Rawal, S., Wylie, S. A., Neimat, J. S., Kang, H., Hedera, P., Zald, D., Landman, B., Dawant, B., & Rane, S. (2016). Cortical asymmetry in Parkinson's disease: Early susceptibility of the left hemisphere. Brain and Behavior: A Cognitive Neuroscience Perspective, 6, e00573.
Constantinescu, C., Carroll, V., Gouasmat, A., Tresse, C., Russell, D., Gunn, R., Barret, O., Rabiner, E., & Marek, K. (2019). Evaluation of [18F]MNI-1126, an18F-labeled SV2A PET tracer in healthy, Parkinson disease and Alzheimer's disease subjects. Journal of Nuclear Medicine, 60, 320.
Constantinescu, C. C., Tresse, C., Zheng, M. Q., Gouasmat, A., Carroll, V. M., Mistico, L., Alagille, D., Sandiego, C. M., Papin, C., Marek, K., Seibyl, J. P., Tamagnan, G. D., & Barret, O. (2019). Development and in vivo preclinical imaging of Fluorine-18-labeled synaptic vesicle protein 2A (SV2A) PET tracers. Molecular Imaging and Biology, 21, 509-518.
de la Fuente-Fernández, R., Kishore, A., Calne, D. B., Ruth, T. J., & Stoessl, A. J. (2000). Nigrostriatal dopamine system and motor lateralization. Behavioural Brain Research, 112, 63-68.
Delva, A., Van Laere, K., & Vandenberghe, W. (2022). Longitudinal positron emission tomography imaging of presynaptic terminals in early Parkinson's disease. Movement Disorders, 37, 1883-1892.
Delva, A., Van Weehaeghe, D., Koole, M., Van Laere, K., & Vandenberghe, W. (2020). Loss of presynaptic terminal integrity in the substantia Nigra in early Parkinson's disease. Movement Disorders Journal, 35, 1977-1986.
Dickson, D. W., Rademakers, R., & Hutton, M. L. (2007). Progressive supranuclear palsy: Pathology and genetics. Brain Pathology, 17, 74-82.
Dickstein, D. L., Kabaso, D., Rocher, A. B., Luebke, J. I., Wearne, S. L., & Hof, P. R. (2007). Changes in the structural complexity of the aged brain. Aging Cell, 6, 275-284.
Dong, J., Hawes, S., Wu, J., Le, W., & Cai, H. (2021). Connectivity and functionality of the Globus pallidus externa under normal conditions and Parkinson's disease. Frontiers in Neural Circuits, 15, 1-19.
Dunn, A. R., Stout, K. A., Ozawa, M., Lohr, K. M., Hoffman, C. A., Bernstein, A. I., Li, Y., Wang, M., Sgobio, C., Sastry, N., Cai, H., Caudle, W. M., & Miller, G. W. (2017). Synaptic vesicle glycoprotein 2C (SV2C) modulates dopamine release and is disrupted in Parkinson disease. Proceedings of the National Academy of Sciences, 114, E2253-E2262.
Emmi, A., Antonini, A., Macchi, V., Porzionato, A., & De Caro, R. (2020). Anatomy and connectivity of the subthalamic nucleus in humans and non-human primates. Frontiers in Neuroanatomy, 14, 1-27.
Fabbrini, G., Brotchie, J. M., Grandas, F., Nomoto, M., & Goetz, C. G. (2007). Levodopa-induced dyskinesias. Movement Disorders, 22, 1379-1389.
Fang, X. T., Toyonaga, T., Hillmer, A. T., Matuskey, D., Holmes, S. E., Radhakrishnan, R., Mecca, A. P., van Dyck, C. H., D'Souza, D. C., Esterlis, I., Worhunsky, P. D., & Carson, R. E. (2021). Identifying brain networks in synaptic density PET (11C-UCB-J) with independent component analysis. Neuroimage, 237, 118167.
Finnema, S. J., Nabulsi, N. B., Eid, T., Detyniecki, K., Lin, S. F., Chen, M. K., Dhaher, R., Matuskey, D., Baum, E., Holden, D., Spencer, D. D., Mercier, J., Hannestad, J., Huang, Y., & Carson, R. E. (2016). Imaging synaptic density in the living human brain. Science Translational Medicine, 8, 348-396.
Finnema, S. J., Nabulsi, N. B., Mercier, J., Lin, S. F., Chen, M. K., Matuskey, D., Gallezot, J. D., Henry, S., Hannestad, J., Huang, Y., & Carson, R. E. (2018). Kinetic evaluation and test-retest reproducibility of [11C]UCB-J, a novel radioligand for positron emission tomography imaging of synaptic vesicle glycoprotein 2A in humans. Journal of Cerebral Blood Flow and Metabolism, 38, 2041-2052.
Fisher-Lavie, A., & Ziv, N. E. (2013). Matching dynamics of presynaptic and postsynaptic scaffolds. The Journal of Neuroscience, 33, 13094-13100.
Floor, E., & Feist, B. E. (1989). Most synaptic vesicles isolated from rat brain carry three membrane proteins, SV2, synaptophysin, and p65. Journal of Neurochemistry, 52, 1433-1437.
Fourie, C., Kim, E., Waldvogel, H., Wong, J. M., McGregor, A., Faull, R. L. M., & Montgomery, J. M. (2014). Differential changes in postsynaptic density proteins in postmortem Huntington's disease and Parkinson's disease human brains. Journal of Neurodegenerative Diseases, 2014, 1-14.
Frick, K. M., & Fernandez, S. M. (2003). Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice. Neurobiology of Aging, 24, 615-626.
González-Rodríguez, P., Zampese, E., Stout, K. A., Guzman, J. N., Ilijic, E., Yang, B., Tkatch, T., Stavarache, M. A., Wokosin, D. L., Gao, L., Kaplitt, M. G., López-Barneo, J., Schumacker, P. T., & Surmeier, D. J. (2021). Disruption of mitochondrial complex I induces progressive parkinsonism. Nature, 599, 650-656.
Hayashi, T., & Su, T.-P. (2007). Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2+) signaling and cell survival. Cell, 131, 596-610.
Holland, N., Jones, P. S., Savulich, G., Wiggins, J. K., Hong, Y. T., Fryer, T. D., Manavaki, R., Sephton, S. M., Boros, I., Malpetti, M., Hezemans, F. H., Aigbirhio, F. I., Coles, J. P., O'Brien, J., & Rowe, J. B. (2020). Synaptic loss in primary tauopathies revealed by [11C]UCB-J positron emission tomography. Movement Disorders, 35, 1834-1842.
Hou, Y., Luo, C., Yang, J., Ou, R., Liu, W., Song, W., Gong, Q., & Shang, H. (2017). Default-mode network connectivity in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson's disease. Journal of Neurology, 264, 152-160.
Hui, W., Xu, X., Xu, X., Gao, J., & Zhang, T. (2020). Enriched environment and social isolation affect cognition ability via altering excitatory and inhibitory synaptic density in mice hippocampus. Neurochemical Research, 45, 1-16.
Hurley, M. J., Jackson, M. J., Smith, L. A., Rose, S., & Jenner, P. (2005). Immunoautoradiographic analysis of NMDA receptor subunits and associated postsynaptic density proteins in the brain of dyskinetic MPTP-treated common marmosets. The European Journal of Neuroscience, 21, 3240-3250.
Janz, R., & Südhof, T. C. (1999). SV2C is a synaptic vesicle protein with an unusually restricted localization: Anatomy of a synaptic vesicle protein family. Neuroscience, 94, 1279-1290.
Jay, T. M. (2003). Dopamine: A potential substrate for synaptic plasticity and memory mechanisms. Progress in Neurobiology, 69, 375-390.
Karunanayaka, P. R., Lee, E. Y., Lewis, M. M., Sen, S., Eslinger, P. J., Yang, Q. X., & Huang, X. (2016). Default mode network differences between rigidity- and tremor-predominant Parkinson's disease. Cortex, 81, 239-250.
Kochubey, O., Lou, X., & Schneggenburger, R. (2011). Regulation of transmitter release by Ca2+ and synaptotagmin: Insights from a large CNS synapse. Trends in Neurosciences, 34, 237-246.
Koole, M., van Aalst, J., Devrome, M., Mertens, N., Serdons, K., Lacroix, B., Mercier, J., Sciberras, D., Maguire, P., & van Laere, K. (2019). Quantifying SV2A density and drug occupancy in the human brain using [11C]UCB-J PET imaging and subcortical white matter as reference tissue. European Journal of Nuclear Medicine and Molecular Imaging, 46, 396-406.
Kramer, M. L., & Schulz-Schaeffer, W. J. (2007). Presynaptic α-synuclein aggregates, not Lewy bodies, cause neurodegeneration in dementia with Lewy bodies. The Journal of Neuroscience, 27, 1405-1410.
Kuhlmann, N., & Milnerwood, A. J. (2020). A critical LRRK at the synapse? The neurobiological function and pathophysiological dysfunction of LRRK2. Frontiers in Molecular Neuroscience, 13, 1-19.
Kwon, H. S., & Koh, S.-H. (2020). Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes. Translational Neurodegeneration, 9, 42.
Kwon, S. E., & Chapman, E. R. (2012). Glycosylation is dispensable for sorting of synaptotagmin 1 but is critical for targeting of SV2 and synaptophysin to recycling synaptic vesicles. The Journal of Biological Chemistry, 287, 35658-35668.
Lee, H. J., Gallagher, M., & Holland, P. C. (2010). The central amygdala projection to the substantia nigra reflects prediction error information in appetitive conditioning. Learning & Memory, 17, 531-538.
Lee, H. J., Youn, J. M., Mary, J. O., Gallagher, M., & Holland, P. C. (2006). Role of substantia Nigra-amygdala connections in surprise-induced enhancement of attention. The Journal of Neuroscience, 26, 6077-6081.
Li, B., Mao, Q., Zhao, N., Xia, J., Zhao, Y., & Xu, B. (2021). Treadmill exercise overcomes memory deficits related to synaptic plasticity through modulating ionic glutamate receptors. Behavioural Brain Research, 414, 113502.
Li, S., Cai, Z., Wu, X., Holden, D., Pracitto, R., Kapinos, M., Gao, H., Labaree, D., Nabulsi, N., Carson, R. E., & Huang, Y. (2019). Synthesis and in vivo evaluation of a novel PET radiotracer for imaging of synaptic vesicle glycoprotein 2A (SV2A) in nonhuman primates. ACS Chemical Neuroscience, 10, 1544-1554.
Lynch, B. A., Lambeng, N., Nocka, K., Kensel-Hammes, P., Bajjalieh, S. M., Matagne, A., & Fuks, B. (2004). The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proceedings of the National Academy of Sciences of the United States of America, 101, 9861-9866.
Mak, E., Holland, N., Jones, P. S., Savulich, G., Low, A., Malpetti, M., Kaalund, S. S., Passamonti, L., Rittman, T., Romero-Garcia, R., Manavaki, R., Williams, G. B., Hong, Y. T., Fryer, T. D., Aigbirhio, F. I., O'Brien, J. T., & Rowe, J. B. (2021). In vivo coupling of dendritic complexity with presynaptic density in primary tauopathies. Neurobiology of Aging, 101, 187-198.
Marella, M., Seo, B. B., Yagi, T., & Matsuno-Yagi, A. (2009). Parkinson's disease and mitochondrial complex I: A perspective on the Ndi1 therapy. Journal of Bioenergetics and Biomembranes, 41, 493-497.
Matuskey, D., Tinaz, S., Wilcox, K. C., Naganawa, M., Toyonaga, T., Dias, M., Henry, S., Pittman, B., Ropchan, J., Nabulsi, N., Suridjan, I., Comley, R. A., Huang, Y., Finnema, S. J., & Carson, R. E. (2020). Synaptic changes in Parkinson disease assessed with in vivo imaging. Annals of Neurology, 87, 329-338.
Mavlyutov, T. A., Guo, L.-W., Epstein, M. L., & Ruoho, A. E. (2015). Role of the Sigma-1 receptor in amyotrophic lateral sclerosis (ALS). Journal of Pharmacological Sciences, 127, 10-16.
May, A. (2011). Experience-dependent structural plasticity in the adult human brain. Trends in Cognitive Sciences, 15, 475-482.
McManus, R. M., & Heneka, M. T. (2017). Role of neuroinflammation in neurodegeneration: New insights. Alzheimer's Research & Therapy, 9, 14.
Mesulam, M. M., Mash, D., Hersh, L., Bothwell, M., & Geula, C. (1992). Cholinergic innervation of the human striatum, globus pallidus, subthalamic nucleus, substantia nigra, and red nucleus. The Journal of Comparative Neurology, 323, 252-268.
Michiels, L., Delva, A., van Aalst, J., Ceccarini, J., Vandenberghe, W., Vandenbulcke, M., Koole, M., Lemmens, R., & Laere, K. V. (2021). Synaptic density in healthy human aging is not influenced by age or sex: A 11C-UCB-J PET study. NeuroImage, 232, 117877.
Mishina, M., Ishiwata, K., Ishii, K., Kitamura, S., Kimura, Y., Kawamura, K., Oda, K., Sasaki, T., Sakayori, O., Hamamoto, M., Kobayashi, S., & Katayama, Y. (2005). Function of sigma1 receptors in Parkinson's disease. Acta Neurologica Scandinavica, 112, 103-107.
Morais, V. A., Verstreken, P., Roethig, A., Smet, J., Snellinx, A., Vanbrabant, M., Haddad, D., Frezza, C., Mandemakers, W., Vogt-Weisenhorn, D., van Coster, R., Wurst, W., Scorrano, L., & de Strooper, B. (2009). Parkinson's disease mutations in PINK1 result in decreased complex I activity and deficient synaptic function. EMBO Molecular Medicine, 1, 99-111.
Nabulsi, N. B., Mercier, J., Holden, D., Carré, S., Najafzadeh, S., Vandergeten, M.-C., Lin, S.-F., Deo, A., Price, N., Wood, M., Lara-Jaime, T., Montel, F., Laruelle, M., Carson, R. E., Hannestad, J., & Huang, Y. (2016). Synthesis and preclinical evaluation of 11C-UCB-J as a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the brain. The Journal of Nuclear Medicine, 57, 777-784.
Naganawa, M., Gallezot, J. D., Finnema, S. J., Matuskey, D., Mecca, A., Nabulsi, N. B., Labaree, D., Ropchan, J., Malison, R. T., D'Souza, D. C., & Esterlis, I. (2021). Simplified quantification of 11C-UCB-J PET evaluated in a large human cohort. The Journal of Nuclear Medicine, 62, 418-421.
Naganawa, M., Gallezot, J.-D., Li, S., Nabulsi, N., Henry, S., Zheng, M. Q., Cai, Z. (. J.)., Gao, H., Kapinos, M., Labaree, D., Ropchan, J., Matuskey, D., Huang, Y., & Carson, R. (2022). Noninvasive quantification of 18F-SynVesT-1 binding using simplified reference tissue model 2. Journal of Nuclear Medicine, 63, 2432.
Nicastro, N., Holland, N., Savulich, G., Carter, S. F., Mak, E., Hong, Y. T., Milicevic Sephton, S., Fryer, T. D., Aigbirhio, F. I., Rowe, J. B., & O'Brien, J. T. (2020). 11C-UCB-J synaptic PET and multimodal imaging in dementia with Lewy bodies. European Journal of Hybrid Imaging, 4, 25.
Nowack, A., Yao, J., Custer, K. L., & Bajjalieh, S. M. (2010). SV2 regulates neurotransmitter release via multiple mechanisms. American Journal of Physiology-Cell Physiology, 299, 960-967.
Onwordi, E. C., Halff, E. F., Whitehurst, T., Mansur, A., Cotel, M. C., Wells, L., Creeney, H., Bonsall, D., Rogdaki, M., Shatalina, E., Reis Marques, T., Rabiner, E. A., Gunn, R. N., Natesan, S., Vernon, A. C., & Howes, O. D. (2020). Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats. Nature Communications, 11, 246.
Ouchi, Y., Yoshikawa, E., Sekine, Y., Futatsubashi, M., Kanno, T., Ogusu, T., & Torizuka, T. (2005). Microglial activation and dopamine terminal loss in early Parkinson's disease. Annals of Neurology, 57, 168-175.
Peterson, D. S., Fling, B. W., Mancini, M., Cohen, R. G., Nutt, J. G., & Horak, F. B. (2015). Dual-task interference and brain structural connectivity in people with Parkinson's disease who freeze. Journal of Neurology, Neurosurgery, and Psychiatry, 86, 786-792.
Petralia, R. S., Mattson, M. P., & Yao, P. J. (2014). Communication breakdown: The impact of ageing on synapse structure. Ageing Research Reviews, 14, 31-42.
Pettigrew, C., & Soldan, A. (2019). Defining cognitive reserve and implications for cognitive aging. Current Neurology and Neuroscience Reports, 19, 1.
Piccoli, G., Condliffe, S. B., Bauer, M., Giesert, F., Boldt, K., de Astis, S., Meixner, A., Sarioglu, H., Vogt-Weisenhorn, D. M., Wurst, W., Gloeckner, C. J., Matteoli, M., Sala, C., & Ueffing, M. (2011). LRRK2 controls synaptic vesicle storage and mobilization within the recycling Pool. The Journal of Neuroscience, 31, 2225-2237.
Putcha, D., Ross, R. S., Cronin-Golomb, A., Janes, A. C., & Stern, C. E. (2016). Salience and default mode network coupling predicts cognition in aging and Parkinson's disease. Journal of the International Neuropsychological Society, 22, 205-215.
Raval, N. R., Gudmundsen, F., Juhl, M., Andersen, I. V., Speth, N., Videbaek, A., Petersen, I. N., Mikkelsen, J. D., Fisher, P. M. D., Herth, M. M., Plavén-Sigray, P., Knudsen, G. M., & Palner, M. (2021). Synaptic density and neuronal metabolic function measured by positron emission tomography in the unilateral 6-OHDA rat model of Parkinson's disease. Frontiers in Synaptic Neuroscience, 13, 715811.
Renaudo, A., L'Hoste, S., Guizouarn, H., Borgèse, F., & Soriani, O. (2007). Cancer cell cycle modulated by a functional coupling between sigma-1 receptors and Cl-channels. The Journal of Biological Chemistry, 282, 2259-2267.
Saito, S., Kobayashi, S., Ohashi, Y., Igarashi, M., Komiya, Y., & Ando, S. (1994). Decreased synaptic density in aged brains and its prevention by rearing under enriched environment as revealed by synaptophysin contents. Journal of Neuroscience Research, 39, 57-62.
Salardini, E., Silva-Rudberg, J. A., O'Dell, R. S., Chen, M. K., Ra, J., Georgelos, J. K., Morehouse, M. R., Melino, K. P., Nabulsi, N. B., Huang, Y., Carson, R. E., van Dyck, C. H., & Mecca, A. P. (2022). Assessment of gray matter microstructure and synaptic density in Alzheimer's disease: A multimodal imaging study with DWI and SV2A PET. Alzheimer's & Dementia, 18, e065064.
Sambo, D. O., Lebowitz, J. J., & Khoshbouei, H. (2018). The sigma-1 receptor as a regulator of dopamine neurotransmission: A potential therapeutic target for methamphetamine addiction. Pharmacology & Therapeutics, 186, 152-167.
Sanchez-Catasus, C. A., Bohnen, N. I., Yeh, F. C., D'Cruz, N., Kanel, P., & Müller, M. L. T. M. (2021). Dopaminergic nigrostriatal connectivity in early Parkinson disease: In vivo neuroimaging study of 11C-DTBZ PET combined with correlational tractography. Journal of Nuclear Medicine, 62, 545-552.
Sassone, J., Serratto, G. M., Valtorta, F., Silani, V., Passafaro, M., & Ciammola, A. (2017). The synaptic function of parkin. Brain: A Journal of Neurology, 140, 2265-2272.
Schindlbeck, K. A., Vo, A., Mattis, P. J., Villringer, K., Marzinzik, F., Fiebach, J. B., & Eidelberg, D. (2021). Cognition-related functional topographies in Parkinson's disease: Localized loss of the ventral default mode network. Cerebral Cortex, 31, 5139-5150.
Schirinzi, T., Madeo, G., Martella, G., Maltese, M., Picconi, B., Calabresi, P., & Pisani, A. (2016). Early synaptic dysfunction in Parkinson's disease: Insights from animal models. Movement Disorders, 31, 802-813.
Schulz-Schaeffer, W. J. (2010). The synaptic pathology of alpha-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia. Acta Neuropathologica (Berl.), 120, 131-143.
Shi, H., Ge, X., Ma, X., Zheng, M., Cui, X., Pan, W., Zheng, P., Yang, X., Zhang, P., Hu, M., Hu, T., Tang, R., Zheng, K., Huang, X. F., & Yu, Y. (2021). A fiber-deprived diet causes cognitive impairment and hippocampal microglia-mediated synaptic loss through the gut microbiota and metabolites. Microbiome, 9, 223.
Smart, K., Uribe, C., Desmond, K. L., Martin, S. L., Vasdev, N., & Strafella, A. P. (2023). Preliminary assessment of reference region quantification and reduced scanning times for [18F]SynVesT-1 PET in Parkinson's disease. Molecular Imaging, 2023, 1-9.
Smart, K., Uribe, C., Desmond, K. L., Martin, S. L., Vasdev, N., & Strafella, A. P. (2023). Non-invasive quantification and time stability of [18F]SynVesT-1 in patients with Parkinson's disease. Journal of Nuclear Medicine, 8.
Sonne, J., Reddy, V., & Beato, M. R. (2022). Neuroanatomy, Substantia Nigra. StatPearls [Internet]. StatPearls Publishing.
Stephenson, D. T., Childs, M. A., Li, Q., Carvajal-Gonzalez, S., Opsahl, A., Tengowski, M., Meglasson, M. D., Merchant, K., & Emborg, M. E. (2007). Differential loss of presynaptic dopaminergic markers in parkinsonian monkeys. Cell Transplantation, 16, 229-244.
Stern, Y. (2012). Cognitive reserve in ageing and Alzheimer's disease. Lancet Neurology, 11, 1006-1012.
Stokholm, K., Thomsen, M. B., Phan, J. A., Møller, L. K., Bay-Richter, C., Christiansen, S. H., Woldbye, D. P. D., Romero-Ramos, M., & Landau, A. M. (2021). α-Synuclein overexpression increases dopamine D2/3 receptor binding and immune activation in a model of early Parkinson's disease. Biomedicine, 9, 1876.
Tan, W.-Q., Yeoh, C. S., Rumpel, H., Nadkarni, N., Lye, W. K., Tan, E. K., & Chan, L. L. (2015). Deterministic tractography of the nigrostriatal-Nigropallidal pathway in Parkinson's disease. Scientific Reports, 5, 17283.
Teleanu, D. M., Niculescu, A. G., Lungu, I. I., Radu, C. I., Vladâcenco, O., Roza, E., Costăchescu, B., Grumezescu, A. M., & Teleanu, R. I. (2022). An overview of oxidative stress, neuroinflammation, and neurodegenerative diseases. International Journal of Molecular Sciences, 23, 5938.
Tessitore, A., Esposito, F., Vitale, C., Santangelo, G., Amboni, M., Russo, A., Corbo, D., Cirillo, G., Barone, P., & Tedeschi, G. (2012). Default-mode network connectivity in cognitively unimpaired patients with Parkinson disease. Neurology, 79, 2226-2232.
Tessitore, A., Giordano, A., Russo, A., & Tedeschi, G. (2016). Structural connectivity in Parkinson's disease. Parkinsonism & Related Disorders, 22, S56-S59.
Thanvi, B., Lo, N., & Robinson, T. (2007). Levodopa-induced dyskinesia in Parkinson's disease: Clinical features, pathogenesis, prevention and treatment. Postgraduate Medical Journal, 83, 384-388.
Theisen, F., Leda, R., Pozorski, V., Oh, J. M., Adluru, N., Wong, R., Okonkwo, O., Dean, D. C., III, Bendlin, B. B., Johnson, S. C., Alexander, A. L., & Gallagher, C. L. (2017). Evaluation of striatonigral connectivity using probabilistic tractography in Parkinson's disease. NeuroImage: Clinical, 16, 557-563.
Thomsen, M. B., Jacobsen, J., Lillethorup, T. P., Schacht, A. C., Simonsen, M., Romero-Ramos, M., Brooks, D. J., & Landau, A. M. (2021). In vivo imaging of synaptic SV2A protein density in healthy and striatal-lesioned rats with [11C]UCB-J PET. Journal of Cerebral Blood Flow & Metabolism, 41, 819-830.
Tokudome, K., Okumura, T., Shimizu, S., Mashimo, T., Takizawa, A., Serikawa, T., Terada, R., Ishihara, S., Kunisawa, N., Sasa, M., & Ohno, Y. (2016). Synaptic vesicle glycoprotein 2A (SV2A) regulates kindling epileptogenesis via GABAergic neurotransmission. Scientific Reports, 6, 27420.
Tsai, S.-Y. A., Pokrass, M. J., Klauer, N. R., De Credico, N. E., & Su, T.-P. (2014). Sigma-1 receptor chaperones in neurodegenerative and psychiatric disorders. Expert Opinion on Therapeutic Targets, 18, 1461-1476.
Tucsek, Z., Toth, P., Sosnowska, D., Gautam, T., Mitschelen, M., Koller, A., Szalai, G., Sonntag, W. E., Ungvari, Z., & Csiszar, A. (2014). Obesity in aging exacerbates blood-brain barrier disruption, neuroinflammation, and oxidative stress in the mouse hippocampus: Effects on expression of genes involved in beta-amyloid generation and Alzheimer's disease. The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 69, 1212-1226.
Uribe, C., Desmond, K. L., Raymond, R., Smart, K., Reilhac, A., Mena, A., Lang, A. E., Kovacs, G., Vasdev, N., & Strafella, A. P. (2022). In vivo synaptic density in parkinsonism [abstract]. Movement Disorders, 37(suppl 2). https://www.mdsabstracts.org/abstract/in-vivo-synaptic-density-in-parkinsonism/.
Uribe, C., Martin, S. L., Smart, K., Desmond, K. L., Lang, A. E., Vasdev, N., & Strafella, A. P. (2023). Imaging presynaptic terminal integrity in parkinsonism: New findings from the 18F-SynVesT-1 tracer.
Usami, Y., Hatano, T., Imai, S., Kubo, S. I., Sato, S., Saiki, S., Fujioka, Y., Ohba, Y., Sato, F., Funayama, M., Eguchi, H., Shiba, K., Ariga, H., Shen, J., & Hattori, N. (2011). DJ-1 associates with synaptic membranes. Neurobiology of Disease, 43, 651-662.
Venkataraman, A. V., Bishop, C., Mansur, A., Rizzo, G., Lewis, Y., Kocagoncu, E., Lingford-Hughes, A., Huiban, M., Passchier, J., Rowe, J. B., Tsukada, H., Brooks, D. J., Martarello, L., Comley, R. A., Chen, L., Hargreaves, R., Schwarz, A. J., Gunn, R. N., Rabiner, E. A., & Matthews, P. M. (2021). Imaging synaptic microstructure and synaptic loss in vivo in early Alzheimer's disease. 2021.11.23.21266746 Preprint at https://doi.org/10.1101/2021.11.23.21266746.
Wang, M., Jiang, S., Yuan, Y., Zhang, L., Ding, J., Wang, J., Zhang, J., Zhang, K., & Wang, J. (2016). Alterations of functional and structural connectivity of freezing of gait in Parkinson's disease. Journal of Neurology, 263, 1583-1592.
Ward, R. J., Dexter, D. T., & Crichton, R. R. (2022). Iron, neuroinflammation and neurodegeneration. International Journal of Molecular Sciences, 23, 7267.
Wilson, H., Pagano, G., de Natale, E. R., Mansur, A., Caminiti, S. P., Polychronis, S., Middleton, L. T., Price, G., Schmidt, K. F., Gunn, R. N., Rabiner, E. A., & Politis, M. (2020). Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson's disease. Movement Disorders, 35, 1416-1427.
Xiong, M., Roshanbin, S., Rokka, J., Schlein, E., Ingelsson, M., Sehlin, D., Eriksson, J., & Syvänen, S. (2021). In vivo imaging of synaptic density with [11C]UCB-J PET in two mouse models of neurodegenerative disease. NeuroImage, 239, 118302.
Yang, L., Wu, C., Li, Y., Dong, Y., Wu, C. Y. C., Lee, R. H. C., Brann, D. W., Lin, H. W., & Zhang, Q. (2022). Long-term exercise pre-training attenuates Alzheimer's disease-related pathology in a transgenic rat model of Alzheimer's disease. GeroScience, 44, 1457-1477.
Yao, J., Nowack, A., Kensel-Hammes, P., Gardner, R. G., & Bajjalieh, S. M. (2010). Cotrafficking of SV2 and synaptotagmin at the synapse. Journal of Neuroscience: The Official Journal of the Society for Neuroscience, 30, 5569-5578.
Yao, N., Shek-Kwan Chang, R., Cheung, C., Pang, S., Lau, K. K., Suckling, J., Rowe, J. B., Yu, K., Ka-Fung Mak, H., Chua, S. E., Ho, S. L., & McAlonan, G. M. (2014). The default mode network is disrupted in parkinson's disease with visual hallucinations. Human Brain Mapping, 35, 5658-5666.
Zarifkar, P., Kim, J., La, C., Zhang, K., YorkWilliams, S., Levine, T. F., Tian, L., Borghammer, P., & Poston, K. L. (2021). Cognitive impairment in Parkinson's disease is associated with default mode network subsystem connectivity and cerebrospinal fluid Aβ. Parkinsonism & Related Disorders, 83, 71-78.
Zhang, Y., Wu, I. W., Buckley, S., Coffey, C. S., Foster, E., Mendick, S., Seibyl, J., & Schuff, N. (2015). Diffusion tensor imaging of the nigrostriatal fibers in Parkinson's disease. Movement Disorders, 30, 1229-1236.

Canada CIHR

Keywords: Parkinson's disease; SV2A; SynVesT-1; UCB-J; corticobasal degeneration; multiple systems atrophy; progressive supranuclear palsy

VTD58H1Z2X (Dopamine)

Date Created: 20231010 Date Completed: 20240321 Latest Revision: 20241206

20241209

10.1002/jnr.25253

37814917