Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats

11C-UCB-J is a positron emission tomography (PET) radioligand that has been used in humans for synaptic vesicle glycoprotein 2A (SV2A) imaging and as a potential synaptic density marker. The centrum semiovale (CS) is a proposed reference region for noninvasive quantification of 11C-UCB-J, due to negligible concentrations of SV2A in this region in baboon brain assessed by in vitro methods. However, in displacement scans with SV2A-specific drug levetiracetam in humans, a decrease in 11C-UCB-J concentration was observed in the CS, consistent with some degree of specific binding. The current study aims to validate the CS as a reference region by (1) optimizing CS region of interest (ROI) to minimize spill-in from gray matter with high radioactivity concentrations; (2) investigating convergence of CS ROI values using ordered subset expectation maximization (OS-EM) reconstruction, and (3) comparing baseline CS volume of distribution ( VT) to nondisplaceable uptake in gray matter, VND. Improving ROI definition and increasing OS-EM iterations during reconstruction decreased the difference between CS VT and VND. However, even with these corrections, CS VT overestimated VND by ∼35–40%. These measures showed significant correlation, suggesting that, though biased, the CS may be a useful estimate of nondisplaceable uptake, allowing for noninvasive quantification for SV2A PET.

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First in Vivo Evidence of Lower Synaptic Density Marker in Obesity and the Relationship With Psychopathology

Biological Psychiatry ◽

10.1016/j.biopsych.2021.02.257 ◽

2021 ◽

Vol 89 (9) ◽

pp. S99

Author(s):

Ruth Asch ◽

Sophie Holmes ◽

Marc Potenza ◽

Stephen Baldassarri ◽

Robert Pietrzak ◽

...

Keyword(s):

Synaptic Density ◽

The Relationship ◽

Density Marker

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Berberine Alleviates Amyloid-beta Pathogenesis Via Activating LKB1/AMPK Signaling in the Brain of APP/PS1 Transgenic Mice

Current Molecular Medicine ◽

10.2174/1566524019666190315164120 ◽

2019 ◽

Vol 19 (5) ◽

pp. 342-348 ◽

Cited By ~ 2

Author(s):

Zhi-You Cai ◽

Chuan-Ling Wang ◽

Tao-Tao Lu ◽

Wen-Ming Yang

Keyword(s):

Transgenic Mice ◽

Western Blotting ◽

Amyloid Β ◽

Adenosine Monophosphate ◽

Camp Response Element Binding ◽

Enzyme Linked Immunosorbent Assay ◽

Synaptic Density ◽

Ampk Signaling ◽

The Brain ◽

Post Synaptic Density

Background:Liver kinase B1 (LKB1)/5’-adenosine monophosphate-activated protein kinase (AMPK) signaling, a metabolic checkpoint, plays a neuro-protective role in the pathogenesis of Alzheimer’s disease (AD). Amyloid-β (Aβ) acts as a classical biomarker of AD. The aim of the present study was to explore whether berberine (BBR) activates LKB1/AMPK signaling and ameliorates Aβ pathology.Methods:The Aβ levels were detected using enzyme-linked immunosorbent assay and immunohistochemistry. The following biomarkers were measured by Western blotting: phosphorylated (p-) LKB1 (Ser334 and Thr189), p-AMPK (AMPKα and AMPKβ1), synaptophysin, post-synaptic density protein 95 and p-cAMP-response element binding protein (p-CREB). The glial fibrillary acidic protein (GFAP) was determined using Western blotting and immunohistochemistry.Results:BBR inhibited Aβ expression in the brain of APP/PS1 mice. There was a strong up-regulation of both p-LKB1 (Ser334 and Thr189) and p-AMPK (AMPKα and AMPKβ1) in the brains of APP/PS1 transgenic mice after BBR-treatment (P<0.01). BBR promoted the expression of synaptophysin, post-synaptic density protein 95 and p-CREB(Ser133) in the AD brain, compared with the model mice.Conclusion:BBR alleviates Aβ pathogenesis and rescues synapse damage via activating LKB1/AMPK signaling in the brain of APP/PS1 transgenic mice.

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Improved synthesis of SV2A targeting radiotracer [11C]UCB-J

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-019-0080-5 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Johanna Rokka ◽

Eva Schlein ◽

Jonas Eriksson

Keyword(s):

Methyl Iodide ◽

Water Solution ◽

Synthesis Method ◽

Radiochemical Yield ◽

Preparative Hplc ◽

Step Method ◽

Synaptic Density ◽

Excellent Starting Point ◽

Starting Point

Abstract Introduction [11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases. The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J. Results After semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium. Conclusions A robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications.

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Acute and chronic synaptic pathology in multiple sclerosis gray matter

Multiple Sclerosis Journal ◽

10.1177/13524585211022174 ◽

2021 ◽

pp. 135245852110221

Author(s):

Marco Vercellino ◽

Stella Marasciulo ◽

Silvia Grifoni ◽

Elena Vallino-Costassa ◽

Chiara Bosa ◽

...

Keyword(s):

Multiple Sclerosis ◽

Brain Tissue ◽

Gray Matter ◽

Axonal Loss ◽

Strong Indication ◽

Synaptic Loss ◽

Synaptic Density ◽

Synaptic Pathology ◽

Gabaergic Synapses ◽

And Control

Objectives: To investigate the extent of synaptic loss, and the contribution of gray matter (GM) inflammation and demyelination to synaptic loss, in multiple sclerosis (MS) brain tissue. Methods: This study was performed on two different post-mortem series of MS and control brains, including deep GM and cortical GM. MS brain samples had been specifically selected for the presence of active demyelinating GM lesions. Over 1,000,000 individual synapses were identified and counted using confocal microscopy, and further characterized as glutamatergic/GABAergic. Synaptic counts were also correlated with neuronal/axonal loss. Results: Important synaptic loss was observed in active demyelinating GM lesions (−58.9%), while in chronic inactive GM lesions, synaptic density was only mildly reduced compared to adjacent non-lesional gray matter (NLGM) (−12.6%). Synaptic loss equally affected glutamatergic and GABAergic synapses. Diffuse synaptic loss was observed in MS NLGM compared to control GM (−21.2% overall). Conclusion: This study provides evidence, in MS brain tissue, of acute synaptic damage/loss during active GM inflammatory demyelination and of synaptic reorganization in chronically demyelinated GM, affecting equally glutamatergic and GABAergic synapses. Furthermore, this study provides a strong indication of widespread synaptic loss in MS NLGM also independently from focal GM demyelination.

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Principal component analysis of synaptic density measured with [11C]UCB-J PET in Alzheimer's disease

American Journal of Geriatric Psychiatry ◽

10.1016/j.jagp.2021.01.041 ◽

2021 ◽

Vol 29 (4) ◽

pp. S47-S48

Author(s):

Ryan O'Dell ◽

Albert Higgins-Chen ◽

Dhruva Gupta ◽

Ming-Kai Chen ◽

Mika Naganawa ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Principal Component Analysis ◽

Principal Component ◽

Component Analysis ◽

Synaptic Density

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In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20981502 ◽

2021 ◽

pp. 0271678X2098150

Author(s):

June van Aalst ◽

Jenny Ceccarini ◽

Stefan Sunaert ◽

Patrick Dupont ◽

Michel Koole ◽

...

Keyword(s):

Glucose Metabolism ◽

Medial Temporal Lobe ◽

Regional Differences ◽

Specific Binding ◽

Aerobic Glycolysis ◽

Glucose Consumption ◽

Brain Regions ◽

Synaptic Density ◽

Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

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Identifying brain networks in synaptic density PET (11C-UCB-J) with independent component analysis

NeuroImage ◽

10.1016/j.neuroimage.2021.118167 ◽

2021 ◽

pp. 118167

Author(s):

Xiaotian T. Fang ◽

Takuya Toyonaga ◽

Ansel T. Hillmer ◽

David Matuskey ◽

Sophie E. Holmes ◽

...

Keyword(s):

Independent Component Analysis ◽

Brain Networks ◽

Component Analysis ◽

Independent Component ◽

Synaptic Density

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In vivo exploration of synaptic projections in frontotemporal dementia

Scientific Reports ◽

10.1038/s41598-021-95499-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eric Salmon ◽

Mohamed Ali Bahri ◽

Alain Plenevaux ◽

Guillaume Becker ◽

Alain Seret ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Input Function ◽

Parahippocampal Gyrus ◽

Exploratory Research ◽

Social Brain ◽

Synaptic Density ◽

Clinical Disorder ◽

Significant Difference ◽

The Right

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

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