Synaptic Density and Glucose Consumption in Patients with <scp>Lewy Body Diseases</scp>: An [<scp><sup>11</sup>C</scp>]<scp>UCB‐J</scp> and [<scp><sup>18</sup>F</scp>]<scp>FDG PET</scp> Study

Andersen, Katrine B; Hansen, Allan K; Schacht, Anna Christina; Horsager, Jacob; Gottrup, Hanne; Klit, Henriette; Danielsen, Erik Hvid; Poston, Kathleen L.; Pavese, Nicola; Brooks, David J.; Borghammer, Per

doi:10.1002/mds.29375

Cited by 20 publications

(9 citation statements)

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“…Understanding the association between BP ND and R 1 longitudinally would help to unravel which comes first, and whether this changes as the disease progresses. Further, in our study we observed a higher magnitude of synaptic loss than losses in relative brain perfusion (compared to controls), while a previous study with [ 11 C]UCB-J and [ 18 F]FDG PET in Parkinson’s disease cohort with and without dementia observed a higher loss in metabolism 32 . This could be an example where glucose metabolism is more sensitive than blood flow but can also be caused due to dissociation between glucose metabolism and blood flow 33 .…”

Section: Discussioncontrasting

confidence: 69%

Synaptic loss and its association with symptom severity in Parkinson’s disease

Holmes,

Honhar,

Tinaz

et al. 2024

npj Parkinsons Dis.

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Parkinson’s disease (PD) is the fastest growing neurodegenerative disease, but at present there is no cure, nor any disease-modifying treatments. Synaptic biomarkers from in vivo imaging have shown promise in imaging loss of synapses in PD and other neurodegenerative disorders. Here, we provide new clinical insights from a cross-sectional, high-resolution positron emission tomography (PET) study of 30 PD individuals and 30 age- and sex-matched healthy controls (HC) with the radiotracer [11C]UCB-J, which binds to synaptic vesicle glycoprotein 2A (SV2A), and is therefore, a biomarker of synaptic density in the living brain. We also examined a measure of relative brain perfusion from the early part of the same PET scan. Our results provide evidence for synaptic density loss in the substantia nigra that had been previously reported, but also extend this to other early-Braak stage regions known to be affected in PD (brainstem, caudate, olfactory cortex). Importantly, we also found a direct association between synaptic density loss in the nigra and severity of symptoms in patients. A greater extent and wider distribution of synaptic density loss in PD patients with longer illness duration suggests that [11C]UCB-J PET can be used to measure synapse loss with disease progression. We also demonstrate lower brain perfusion in PD vs. HC groups, with a greater extent of abnormalities in those with longer duration of illness, suggesting that [11C]UCB-J PET can simultaneously provide information on changes in brain perfusion. These results implicate synaptic imaging as a useful PD biomarker for future disease-modifying interventions.

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Section: Discussioncontrasting

confidence: 69%

Synaptic loss and its association with symptom severity in Parkinson’s disease

Holmes,

Honhar,

Tinaz

et al. 2024

npj Parkinsons Dis.

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“…The SUVR1 decrease matched well with volumetric changes and the SUVR1 levels in frontal cortex correlated with cognitive function ( Andersen et al, 2021 ). However, in a follow-up study by the same groups, changes in 18F-FDG exceeded those observed in 11C-UCB-J PET ( Andersen et al, 2023 ). This discrepancy could imply that both changes represent distinct facets of the pathogenesis, rendering 11C-UCB-J PET a complementary tool in the evaluation of LBD.…”

Section: Sv2a Pet In Neurodegenerative Diseasesmentioning

confidence: 86%

SV2A PET imaging in human neurodegenerative diseases

Bavarsad,

Grinberg

2024

Front. Aging Neurosci.

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This manuscript presents a thorough review of synaptic vesicle glycoprotein 2A (SV2A) as a biomarker for synaptic integrity using Positron Emission Tomography (PET) in neurodegenerative diseases. Synaptic pathology, characterized by synaptic loss, has been linked to various brain diseases. Therefore, there is a need for a minimally invasive approach to measuring synaptic density in living human patients. Several radiotracers targeting synaptic vesicle protein 2A (SV2A) have been created and effectively adapted for use in human subjects through PET scans. SV2A is an integral glycoprotein found in the membranes of synaptic vesicles in all synaptic terminals and is widely distributed throughout the brain. The review delves into the development of SV2A-specific PET radiotracers, highlighting their advancements and limitations in neurodegenerative diseases. Among these tracers, 11C-UCB-J is the most used so far. We summarize and discuss an increasing body of research that compares measurements of synaptic density using SV2A PET with other established indicators of neurodegenerative diseases, including cognitive performance and radiological findings, thus providing a comprehensive analysis of SV2A’s effectiveness and reliability as a diagnostic tool in contrast to traditional markers. Although the literature overall suggests the promise of SV2A as a diagnostic and therapeutic monitoring tool, uncertainties persist regarding the superiority of SV2A as a biomarker compared to other available markers. The review also underscores the paucity of studies characterizing SV2A distribution and loss in human brain tissue from patients with neurodegenerative diseases, emphasizing the need to generate quantitative neuropathological maps of SV2A density in cases with neurodegenerative diseases to fully harness the potential of SV2A PET imaging in clinical settings. We conclude by outlining future research directions, stressing the importance of integrating SV2A PET imaging with other biomarkers and clinical assessments and the need for longitudinal studies to track SV2A changes throughout neurodegenerative disease progression, which could lead to breakthroughs in early diagnosis and the evaluation of new treatments.

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“…In patients with DLB, synaptic loss was observed in substantia nigra, occipital, parietal and frontal cortices but not in medial temporal regions such as hippocampus and amygdala [ 48 ]. In a direct comparison of 11 C-UCB-J and 18 F-FDG in DLB patients, the magnitude as well as spatial extent of hypometabolism exceeded that of synaptic loss [ 75 ]. As for FTD, decreased synaptic density was most prominent in frontal regions and to a somewhat lesser extent also in temporal regions, insula and anterior cingulate [ 44 ].…”

Section: Discussionmentioning

confidence: 99%

In vivo PET of synaptic density as potential diagnostic marker for cognitive disorders: prospective comparison with current imaging markers for neuronal dysfunction and relation to symptomatology - study protocol

Vanderlinden,

Carron,

Vandenberghe

et al. 2024

BMC Med Imaging

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Background 18F-FDG brain PET is clinically used for differential diagnosis in cognitive dysfunction of unclear etiology and for exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. 18F-FDG PET measures regional glucose metabolism, which represents a combination of neuronal/synaptic activity but also astrocytic activity and neuroinflammation. Recently, imaging of synaptic vesicle protein 2 A (SV2A) has become available and was shown to be a proxy of synaptic density. This prospective study will investigate the use of 18F-SynVesT-1 for imaging SV2A and its discriminative power for differential diagnosis in cognitive disorders in a head-to-head comparison to 18F-FDG PET. In addition, simultaneous PET/MR allows an evaluation of contributing factors and the additional value of advanced MRI imaging to FDG/SV2A PET imaging will be investigated. In this work, the study design and protocol are depicted. Methods In this prospective, multimodal imaging study, 110 patients with uncertain diagnosis of cognitive impairment who are referred for 18F-FDG PET brain imaging in their diagnostic work-up in a tertiary memory clinic will be recruited. In addition, 40 healthy volunteers (HV) between 18 and 85 years (M/F) will be included. All study participants will undergo simultaneous 18F-SynVesT-1 PET/MR and an extensive neuropsychological evaluation. Amyloid status will be measured by PET using 18FNAV4694, in HV above 50 years of age. Structural T1-weighted and T2-weighted fluid-attenuated inversion recovery MR images, triple-tagging arterial spin labeling (ASL) and resting-state functional MRI (rs-fMRI) will be obtained. The study has been registered on ClinicalTrials.gov (NCT05384353) and is approved by the local Research Ethics Committee. Discussion The main endpoint of the study will be the comparison of the diagnostic accuracy between 18F-SynVesT-1 and 18F-FDG PET in cognitive disorders with uncertain etiology and in exclusion of a neurodegenerative cause in patients with cognitive impairment in late-life psychiatric disorders. The strength of the relationship between cognition and imaging data will be assessed, as well as the potential incremental diagnostic value of including MR volumetry, ASL perfusion and rs-fMRI.

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Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [¹¹C]UCB‐J and [¹⁸F]FDG PET Study

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 20 publications

References 58 publications

Synaptic loss and its association with symptom severity in Parkinson’s disease

Synaptic loss and its association with symptom severity in Parkinson’s disease

SV2A PET imaging in human neurodegenerative diseases

In vivo PET of synaptic density as potential diagnostic marker for cognitive disorders: prospective comparison with current imaging markers for neuronal dysfunction and relation to symptomatology - study protocol

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Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [11C]UCB‐J and [18F]FDG PET Study

Abstract: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 20 publications

References 58 publications

Synaptic loss and its association with symptom severity in Parkinson’s disease

Synaptic loss and its association with symptom severity in Parkinson’s disease

SV2A PET imaging in human neurodegenerative diseases

In vivo PET of synaptic density as potential diagnostic marker for cognitive disorders: prospective comparison with current imaging markers for neuronal dysfunction and relation to symptomatology - study protocol

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Synaptic Density and Glucose Consumption in Patients with Lewy Body Diseases: An [¹¹C]UCB‐J and [¹⁸F]FDG PET Study