UCB-J Positron Emission Tomography Research Articles

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

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.

Assessment of Gray Matter Microstructure and Synaptic Density in Alzheimer's Disease: A Multimodal Imaging Study With DTI and SV2A PET

Multimodal imaging techniques have furthered our understanding of how different aspects of Alzheimer's disease (AD) pathology relate to one another. Diffusion tensor imaging (DTI) measures such as mean diffusivity (MD) may be a surrogate measure of the changes in gray matter structure associated with AD. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has been used to quantify synaptic loss, which is the major pathological correlate of cognitive impairment in AD. In this study, we investigated the relationship between gray matter microstructure and synaptic density. DTI was used to measure MD and [11C]UCB-J PET to measure synaptic density in 33 amyloid-positive participants with AD and 17 amyloid-negative cognitively normal (CN) participants aged 50-83. Univariate regression analyses were used to assess the association between synaptic density and MD in both the AD and CN groups. Hippocampal MD was inversely associated with hippocampal synaptic density in participants with AD (r=-0.55, p <0.001, df=31) but not CN (r=0.13, p=0.62, df=15). Exploratory analyses across other regions known to be affected in AD suggested widespread inverse associations between synaptic density and MD in the AD group. In the setting of AD, an increase in gray matter MD is inversely associated with synaptic density. These co-occurring changes may suggest a link between synaptic loss and gray matter microstructural changes in AD. Imaging studies of gray matter microstructure and synaptic density may allow important insights into AD-related neuropathology.

Investigating synaptic changes in Essential Tremor with PET Imaging (P7-11.005)

<h3>Objective:</h3> To utilize positron emission tomography (PET) imaging with the synaptic density tracer [¹¹ C] UCB-J to characterize the distribution in the cerebellum and other brain areas in essential tremor (ET) compared to healthy controls (HC). <h3>Background:</h3> Numerous lines of evidence point to a cerebellar origins of ET, with a number of studies pointing to Purkinje cell loss. Studying potential markers of cell loss <i>in vivo</i> would be of great value. [¹¹ C] UCB-J has been found to be an excellent tracer for quantitative imaging of synaptic vesicle glycoprotein 2A (SV2A), a marker of synaptic density, in the human brain. This tracer has not been used to study the ET brain. <h3>Design/Methods:</h3> Six individuals with ET with a mean age (SD) of 65 (10); three males), and sixteen demographically matched healthy comparison controls (HC; 63 (9); six males) participated in an [¹¹ C] UCB-J PET scan. Binding potential value (<i>BP</i>_ND: binding potential of available receptors) was the primary outcome measure and using the centrum semiovale as the reference region. Muller Gartner partial volume correction (PVC) was applied to control for possible volumetric differences. T-tests were calculated for between group differences, and p values were uncorrected for multiple comparisons given the exploratory nature. <h3>Results:</h3> We observed significantly lower synaptic availability in ET compared to HC in the cerebellum (−11%, p=0.04), right cerebellum (−11%, p=0.03), vermis (−12%, p=0.04), motor cortex (−21%, p=0.001), and supplementary motor cortex (−20%, p=0.006). <h3>Conclusions:</h3> This <i>in vivo</i> investigation with [¹¹ C] UCB-J PET in ET is the first sample to date (to our knowledge) and found preliminary evidence of lower synaptic availability in key brain areas. Additional data analysis is ongoing, such as applying Iterative-Yang PVC, correlating synaptic changes with clinical scores, and exploring network-based analyses. <b>Disclosure:</b> Ms. Yang has nothing to disclose. Mika Naganawa has nothing to disclose. Nora Hernandez has nothing to disclose. Mr. Nguyen has nothing to disclose. Nabeel Nabulsi, 21953 has nothing to disclose. An immediate family member of Yiyun Huang, 8202 has stock in Pfiy. An immediate family member of Yiyun Huang, 8202 has stock in Johnson and Johnson . Yiyun Huang, 8202 has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH. Richard Carson has nothing to disclose. Dr. Matuskey has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Eleisver. The institution of Dr. Matuskey has received research support from Abbvie. Dr. Louis has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wolters Kluwer - Merritt’s Textbook of Neurology. The institution of Dr. Louis has received research support from National Institutes of Health.

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

Patients with Lewy body diseases exhibit variable degrees of cortical and subcortical hypometabolism. However, the underlying causes behind this progressive hypometabolism remain unresolved. Generalized synaptic degeneration may be one key contributor. The objective of this study was to investigate whether local cortical synaptic loss is proportionally linked to the magnitude of hypometabolism in Lewy body disease. Using in vivo positron emission tomography (PET) we investigated cerebral glucose metabolism and quantified the density of cerebral synapses, as measured with [18 F]fluorodeoxyglucose ([18 F]FDG) PET and [11 C]UCB-J, respectively. Volumes-of-interest were defined on magnetic resonance T1 scans and regional standard uptake value ratios-1 values were obtained for 14 pre-selected brain regions. Between-group comparisons were conducted at voxel-level. We observed regional differences in both synaptic density and cerebral glucose consumption in our cohorts of non-demented and demented patients with Parkinson's disease or dementia with Lewy bodies compared to healthy subjects. Additionally, voxel-wise comparisons showed a clear difference in cortical regions between demented patients and controls for both tracers. Importantly, our findings strongly suggested that the magnitude of reduced glucose uptake exceeded the magnitude of reduced cortical synaptic density. Here, we investigated the relationship between in vivo glucose uptake and the magnitude of synaptic density as measured using [18 F]FDG PET and [11 C]UCB-J PET in Lewy body patients. The magnitude of reduced [18 F]FDG uptake was greater than the corresponding decline in [11 C]UCB-J binding. Therefore, the progressive hypometabolism seen in Lewy body disorders cannot be fully explained by generalized synaptic degeneration. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Identification of pre-synaptic density networks using [11C]UCB-J PET imaging and ICA in mice

BackgroundSynaptic vesicle glycoprotein 2A (SV2A) is a vesicle glycoprotein involved in neurotransmitter release. SV2A is located on the pre-synaptic terminals of neurons and visualized using the radioligand [11C]UCB-J and positron emission tomography (PET) imaging. Thus, SV2A PET imaging can provide a proxy for pre-synaptic density in health and disease. This study aims to apply independent component analysis (ICA) to SV2A PET data acquired in mice to identify pre-synaptic density networks (pSDNs), explore how ageing affects these pSDNs, and determine the impact of a neurological disorder on these networks. MethodsWe used [11C]UCB-J PET imaging data (n = 135) available at different ages (3, 7, 10, and 16 months) in wild-type (WT) C57BL/6J mice and in diseased mice (mouse model of Huntington's disease, HD) with reported synaptic deficits. First, ICA was performed on a healthy dataset after it was split into two equal-sized samples (n = 36 each) and the analysis was repeated 50 times in different partitions. We tested different model orders (8, 12, and 16) and identified the pSDNs. Next, we investigated the effect of age on the loading weights of the identified pSDNs. Additionally, the identified pSDNs were compared to those of diseased mice to assess the impact of disease on each pSDNs. ResultsModel order 12 resulted in the preferred choice to provide six reliable and reproducible independent components (ICs) as supported by the cluster-quality index (IQ) and regression coefficients (β) values. Temporal analysis showed age-related statistically significant changes on the loading weights in four ICs. ICA in an HD model revealed a statistically significant disease-related effect on the loading weights in several pSDNs in line with the progression of the disease. ConclusionThis study validated the use of ICA on SV2A PET data acquired with [11C]UCB-J for the identification of cerebral pre-synaptic density networks in mice in a rigorous and reproducible manner. Furthermore, we showed that different pSDNs change with age and are affected in a disease condition. These findings highlight the potential value of ICA in understanding pre-synaptic density networks in the mouse brain.

Synaptic Loss in Frontotemporal Dementia Revealed by [11 C]UCB-J Positron Emission Tomography.

Synaptic loss is an early feature of neurodegenerative disease models, and is severe in post mortem clinical studies, including frontotemporal dementia. Positron emission tomography (PET) with radiotracers that bind to synaptic vesicle glycoprotein 2A enables quantification of synaptic density in vivo. This study used [11 C]UCB-J PET in participants with behavioral variant frontotemporal dementia (bvFTD), testing the hypothesis that synaptic loss is severe and related to clinical severity. Eleven participants with clinically probable bvFTD and 25 age- and sex-matched healthy controls were included. Participants underwent dynamic [11 C]UCB-J PET, structural magnetic resonance imaging, and a neuropsychological battery, including the revised Addenbrooke Cognitive Examination, and INECO frontal screening. General linear models compared [11 C]UCB-J binding potential maps and gray matter volume between groups, and assessed associations between synaptic density and clinical severity in patients. Analyses were also performed using partial volume corrected [11 C]UCB-J binding potential from regions of interest (ROIs). Patients with bvFTD showed severe synaptic loss compared to controls. [11 C]UCB-J binding was reduced bilaterally in medial and dorsolateral frontal regions, inferior frontal gyri, anterior and posterior cingulate gyrus, insular cortex, and medial temporal lobe. Synaptic loss in the frontal and cingulate regions correlated significantly with cognitive impairments. Synaptic loss was more severe than atrophy. Results from ROI-based analyses mirrored the voxelwise results. In accordance with preclinical models, and human postmortem evidence, there is widespread frontotemporal loss of synapses in symptomatic bvFTD, in proportion to severity. [11 C]UCB-J PET could support translational studies and experimental medicine strategies for new disease-modifying treatments for neurodegeneration. ANN NEUROL 2023;93:142-154.

Synaptic density and cognitive performance in Alzheimer's disease: A PET imaging study with [11 C]UCB-J.

For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD). However, this statement is based on remarkably few patients studied by autopsy or biopsy. With the recent advent of synaptic vesicle glycoprotein 2A (SV2A) positron emission tomography (PET) imaging, we have begun to evaluate the consequences of synaptic alterations in vivo. We examined the relationship between synaptic density measured by [11 C]UCB-J PET and neuropsychological test performance in 45 participants with early AD. Global synaptic density showed a significant positive association with global cognition and performance on five individual cognitive domains in participants with early AD. Synaptic density was a stronger predictor of cognitive performance than gray matter volume. These results confirm neuropathologic studies demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the early stages of AD.

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

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

In vivo imaging of synaptic density with [11C]UCB-J PET in two mouse models of neurodegenerative disease

The positron emission tomography (PET) radioligand [11C]UCB-J binds to synaptic vesicle protein 2A (SV2A) and is used to investigate synaptic density in the living brain. Clinical studies have indicated reduced [11C]UCB-J binding in Alzheimer's disease (AD) and Parkinson's disease (PD) brains compared to healthy controls. Still, it is unknown whether [11C]UCB-J PET can visualise synaptic loss in mouse models of these disorders. Such models are essential for understanding disease pathology and for evaluating the effects of novel disease-modifying drug candidates. In the present study, synaptic density in transgenic models of AD (ArcSwe) and PD (L61) was studied using [11C]UCB-J PET. Data were acquired during 60 min after injection, and time-activity curves (TACs) in different brain regions and the left ventricle of the heart were generated based on the dynamic PET images. The [11C]UCB-J brain concentrations were expressed as standardised uptake value (SUV) over time. The area under the SUV curve (AUC), the ratio of AUC in the brain to that in the heart (AUCbrain/blood), and the volume of distribution (VT) obtained by kinetic modelling using the heart TAC as input were compared between transgenic and age-matched wild type (WT) mice. The L61 mice displayed 11–13% lower AUCbrain/blood ratio and brain VT generated by kinetic modeling compared to the control WT mice. In general, also transgenic ArcSwe mice tended to show lower [11C]UCB-J brain exposure than age-matched WT controls, but variation within the different animal groups was high. Older WT mice (18–20 months) showed lower [11C]UCB-J brain exposure than younger WT mice (8–9 months). Together, these data imply that [11C]UCB-J PET reflects synaptic density in mouse models of neurodegeneration and that inter-subject variation is large. In addition, the study suggested that model-independent AUCbrain/blood ratio can be used to evaluate [11C]UCB-J binding as an alternative to full pharmacokinetic modelling.

In vivo evidence of lower synaptic vesicle density in schizophrenia.

Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [11C]UCB-J is a proxy measure of synaptic density. In this study wedetermined whether[11C]UCB-J binding,an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using [11C]UCB-J and high-resolution research tomography (HRRT). [11C]UCB-J distribution volume (VT) and binding potential (BPND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [11C]UCB-J BPND with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen'sd = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85)and temporal cortex (-11%, Cohen'sd = 1.23). These differences remained significant after partial volume correction. [11C]UCB-J BPND did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that [11C]UCB-J PET is a sensitive tool to detect lowersynaptic density in SCZ and holds promise for future studies of early detection and disease progression.

Synaptic density is associated with cognitive performance in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

<h3>Introduction</h3> For 30 years synapse loss has been referred to as the major pathological correlate of cognitive impairment in Alzheimer's disease (AD; Terry, et al. 1991; DeKosky and Scheff. 1990). However, this statement is based on remarkably few patients studied by autopsy or biopsy in limited brain regions, largely at the moderate to severe stages of disease. With the recent advent of synaptic positron emission tomography (PET) imaging, we have begun to evaluate synaptic alterations <i>in vivo</i>. Synaptic vesicle glycoprotein 2A (SV2A) is expressed in virtually all synapses and is located in synaptic vesicles at presynaptic terminals (Bajjalieh, et al. 1993). [¹¹C]UCB-J was recently developed as a PET tracer for SV2A and advanced for human studies (Finnema, et al. 2016). In our recent study of [¹¹C]UCB-J PET, we observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants (Mecca, et al. 2020). However, initial attempts using PET imaging to associate synaptic density with cognitive performance have been hindered by the use of limited cognitive measures. In this study we examined the relationship between synaptic density and cognitive performance in early AD using [¹¹C]UCB-J PET and an extensive neuropsychological test battery. <h3>Methods</h3> Using [¹¹C]UCB-J binding to SV2A, synaptic density was measured in 45 amyloid positive participants with AD (17 amnestic mild cognitive impairment and 28 mild dementia) and 20 amyloid negative cognitively normal (CN) participants aged 50-85 years. Synaptic density was calculated as the distribution volume ratio (<i>DVR</i>) in a composite region of interest (ROI) of AD-affected regions (prefrontal, lateral temporal, medial temporal, lateral parietal, anterior cingulate, posterior cingulate, precuneus, and lateral occipital) using cerebellum as reference region. A neuropsychological test battery was administered to assess performance in five cognitive domains: Verbal Memory (Logical Memory II, Rey Auditory Verbal Learning Test [RAVLT] total words recalled across trials 1-5, RAVLT delayed recall), Language (Boston Naming Test, Category Fluency), Executive Function (Stroop Color Word, Trails B, Letter Fluency), Processing Speed (Stroop Word, Trails A, WAIS-3 Digit Symbol Substitution), and Visuospatial Ability (Rey-Osterrieth Complex Figure, WAIS-3 Block Design, WAIS-3 Picture Completion). Neuropsychological test raw scores were converted to z-scores using the means and SDs from the pooled AD and CN sample), and cognitive domain scores were generated for each AD participant by averaging z-scores within the domain. Global cognitive scores were then generated for each participant by averaging the five domain scores. <h3>Results</h3> In a multiple linear regression model controlling for age, sex, and education, synaptic density ([¹¹C]UCB-J <i>DVR</i>) was a significant predictor of global cognitive performance in participants with AD (β=3.21, η²=0.29, <i>P</i>=0.0001; Figure 1A). Synaptic density was also a significant predictor of performance in all five cognitive domains: Verbal Memory (β=1.35, η²=0.11, <i>P</i>=0.022; Figure 1B), Language (β=3.82, η²=0.25, <i>P</i>=0.001; Figure 1C), Executive Function (β=3.28, η²=0.20, <i>P</i>=0.001; Figure 1D), Processing Speed (β=4.03, η²=0.23, <i>P</i>=0.001; Figure 1E), and Visuospatial Ability (β=3.58, η²=0.22, <i>P</i>=0.001; Figure 1F). The relatively weak association with verbal memory may have resulted from floor effects on the measures that comprised this domain. The observed associations between synaptic density and global cognition remained significant after correction for partial volume effects (β=2.16, η²=0.23, <i>P</i>=0.001), and synaptic density was a stronger predictor of cognitive performance than gray matter volume (β=0.01, η²=0.17, <i>P</i>=0.005). <h3>Conclusions</h3> These results confirm neuropathologic studies, demonstrating a significant association between synaptic density and cognitive performance, and suggest that this correlation extends to the mild and prodromal stages of AD. They further support the use of synaptic imaging as a potential surrogate biomarker outcome for therapeutic trials that is well-correlated with clinical measures. Longitudinal studies are needed to relate change in synaptic density as measured by [¹¹C]UCB-J PET with change in cognitive performance. <h3>Funding</h3> R01-AG052560 [REC, CHvD], R01-AG062276 [CHvD], RF1-AG057553 [REC, CHvD], Dana Foundation [MKC]), P50-AG047270 [CHvD, MKC], P30-AG066508 [CHvD], K23-AG057784 [APM], R25-MH071584 (RSO), T32-MH019961 [RSO], and Thomas P. Detre Fellowship [RSO].

Association of Aß deposition and regional synaptic density in early Alzheimer's disease: a PET imaging study with [11C]UCB-J

<h3>Introduction</h3> Synaptic loss is an early pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. We have recently demonstrated extensive synaptic loss in the medial temporal and neocortical regions of participants with AD, using <i>in vivo</i> positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A), a promising biomarker of synaptic density. Attempts to associate amyloid-β (Aβ) pathogenesis with synaptic loss in AD however, have thus far been limited to small numbers of postmortem studies. Aβ plaque burden is not well-correlated with indices of clinical severity or neurodegeneration—at least in the dementia stage—as deposition of Aβ reaches a ceiling. In this study, we examined in vivothe association between fibrillar Aβ deposition and synaptic density in early AD using [¹¹C]PiB and [¹¹C]UCB-J PET. We hypothesized that global Aβ deposition would be more strongly inversely associated with hippocampal synaptic density in participants with amnestic mild cognitive impairment (aMCI, a stage of continued Aβ accumulation) compared to those with dementia (a stage of relative Aβ plateau). <h3>Methods</h3> [¹¹C]UCB-J (for SV2A) and [¹¹C]PiB (Aβ deposition) binding were measured in 14 participants with aMCI due to AD, 24 participants with mild AD dementia, and 19 cognitively normal (CN) participants aged 55-85 years. For [¹¹C]PiB data analysis, parametric images of binding potential (<i>BP</i>_ND) were generated using SRTM2 with cerebellum as a reference region and converted to distribution volume ratios (<i>DVR</i>). For [¹¹C]UCB-J, <i>BP</i>_NDwas computed using SRTM2 with a shrunken centrum semiovale reference region and converted to <i>DVR</i> with a cerebellum reference region. For the primary analysis of the association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI and dementia, separate univariate regression analyses were performed for each diagnostic group with Pearson <i>r</i> and associated two-tailed <i>P</i> values reported for each model. Fisher <i>z</i>-transformation assessed significant differences in correlation coefficients between the aMCI and dementia groups, with one-tailed <i>P</i> values reported. Exploratory analyses examined correlations between both global and regional Aβ deposition and SV2A binding across a broad range of brain regions using both ROI- and surface-based approaches. Global Aβ deposition was determined for a composite of regions commonly affected by Aβ deposition in AD which included: prefrontal, lateral temporal, posterior cingulate/precuneus, and lateral parietal ROIs. <h3>Results</h3> The AD group showed significant widespread reductions in cortical and subcortical synaptic density, most pronounced in the medial temporal lobe, and significantly elevated cortical amyloid in regions commonly affected by AD pathology (Figure 1). We observed a significant inverse association between global Aβ deposition and hippocampal SV2A binding in participants with aMCI (r = -0.55, <i>P</i> = 0.04), but not mild dementia (r = 0.05, <i>P</i> = 0.82; difference statistically significant by Fisher <i>z</i>= -1.80, <i>P</i> = 0.04; Figure 2).This stronger association was observed to survive partial volume correction (aMCI <i>r</i>= -0.56, <i>P</i>= 0.04; dementia <i>r</i>= -0.01, <i>P</i>= 0.96; Fisher <i>z</i>= -1.67, <i>P</i>= 0.047). Exploratory analyses across other ROIs and whole brain analyses demonstrated no broad or consistent associations between global Aβ deposition and regional SV2A binding in either diagnostic group. ROI-based analyses of the association between regional Aβ deposition and SV2A binding also revealed no consistent pattern but suggested a nominal inverse association in the dementia group between local Aβ deposition and SV2A binding in medial occipital cortex and a more compelling, larger positive correlation between local Aβ accumulation and synaptic density in hippocampus (Table 1). <h3>Conclusions</h3> To our knowledge, we have conducted the first <i>in vivo</i> study investigating the relationship between Aβ deposition and synaptic alterations in participants with AD. We observed significant inverse associations between measures of global Aβ deposition and hippocampal synaptic density within participants with aMCI but not with dementia. Our findings lend support to a model in which fibrillar Aβ may still accumulating in the early stages of clinical disease but approaching a relative plateau, a point at which Aβ may uncouple from neurodegenerative processes including synaptic loss. Future research shouldinvestigate the relationship between Aβ deposition and synaptic loss in larger cohorts beginning preclinically and followed longitudinally in conjunction with other biomarkers. <h3>Funding</h3> P50-AG047270 (CHvD), P30-AG066508 [CHvD], K23-AG057794 (APM), R01-AG052560 (REC, CHV), R01-AG062276 (CHvD), Dana Foundation (MKC), T32-MH019961 (RSO), and Thomas P. Detre Fellowship (RSO).

In vivo tau pathology is associated with synaptic loss and altered synaptic function

BackgroundThe mechanism of synaptic loss in Alzheimer’s disease is poorly understood and may be associated with tau pathology. In this combined positron emission tomography (PET) and magnetoencephalography (MEG) study, we aimed to investigate spatial associations between regional tau pathology ([18F]flortaucipir PET), synaptic density (synaptic vesicle 2A [11C]UCB-J PET) and synaptic function (MEG) in Alzheimer’s disease.MethodsSeven amyloid-positive Alzheimer’s disease subjects from the Amsterdam Dementia Cohort underwent dynamic 130-min [18F]flortaucipir PET, dynamic 60-min [11C]UCB-J PET with arterial sampling and 2 × 5-min resting-state MEG measurement. [18F]flortaucipir- and [11C]UCB-J-specific binding (binding potential, BPND) and MEG spectral measures (relative delta, theta and alpha power; broadband power; and peak frequency) were assessed in cortical brain regions of interest. Associations between regional [18F]flortaucipir BPND, [11C]UCB-J BPND and MEG spectral measures were assessed using Spearman correlations and generalized estimating equation models.ResultsAcross subjects, higher regional [18F]flortaucipir uptake was associated with lower [11C]UCB-J uptake. Within subjects, the association between [11C]UCB-J and [18F]flortaucipir depended on within-subject neocortical tau load; negative associations were observed when neocortical tau load was high, gradually changing into opposite patterns with decreasing neocortical tau burden. Both higher [18F]flortaucipir and lower [11C]UCB-J uptake were associated with altered synaptic function, indicative of slowing of oscillatory activity, most pronounced in the occipital lobe.ConclusionsThese results indicate that in Alzheimer’s disease, tau pathology is closely associated with reduced synaptic density and synaptic dysfunction.

Sapap3 deletion causes dynamic synaptic density abnormalities: a longitudinal [11C]UCB-J PET study in a model of obsessive\u2013compulsive disorder-like behaviour

BackgroundCurrently, the evidence on synaptic abnormalities in neuropsychiatric disorders—including obsessive–compulsive disorder (OCD)—is emerging. The newly established positron emission tomography (PET) ligand ((R)-1-((3-((11)C-methyl-(11)C)pyridin-4-yl)methyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-2-one) ([11C]UCB-J) provides the opportunity to visualize synaptic density changes in vivo, by targeting the synaptic vesicle protein 2A (SV2A). Here, we aim to evaluate such alterations in the brain of the SAP90/PSD-95-associated protein 3 (Sapap3) knockout (ko) mouse model, showing an abnormal corticostriatal neurotransmission resulting in OCD-like behaviour.MethodsLongitudinal [11C]UCB-J µPET/CT scans were acquired in Sapap3 ko and wildtype (wt) control mice (n = 9/group) to study SV2A availability. Based on the Logan reference method, we calculated the volume of distribution (VT(IDIF)) for [11C]UCB-J. Both cross-sectional (wt vs. ko) and longitudinal (3 vs. 9 months) volume-of-interest-based statistical analysis and voxel-based statistical parametric mapping were performed. Both [11C]UCB-J ex vivo autoradiography and [3H]UCB-J in vitro autoradiography were used for the validation of the µPET data.ResultsAt the age of 3 months, Sapap3 ko mice are already characterized by a significantly lower SV2A availability compared to wt littermates (i.a. cortex − 12.69%, p < 0.01; striatum − 14.12%, p < 0.001, thalamus − 13.11%, p < 0.001, and hippocampus − 12.99%, p < 0.001). Healthy ageing in control mice was associated with a diffuse and significant (p < 0.001) decline throughout the brain, whereas in Sapap3 ko mice this decline was more confined to the corticostriatal level. A strong linear relationship (p < 0.0001) was established between the outcome parameters of [11C]UCB-J µPET and [11C]UCB-J ex vivo autoradiography, while such relationship was absent for [3H]UCB-J in vitro autoradiography.Conclusions[11C]UCB-J PET is a potential marker for synaptic density deficits in the Sapap3 ko mouse model for OCD, parallel to disease progression. Our data suggest that [11C]UCB-J ex vivo autoradiography is a suitable proxy for [11C]UCB-J PET data in mice.

Kinetics and 28-day test–retest repeatability and reproducibility of [11C]UCB-J PET brain imaging

[11C]UCB-J is a novel radioligand that binds to synaptic vesicle glycoprotein 2A (SV2A). The main objective of this study was to determine the 28-day test–retest repeatability (TRT) of quantitative [11C]UCB-J brain positron emission tomography (PET) imaging in Alzheimer’s disease (AD) patients and healthy controls (HCs). Nine HCs and eight AD patients underwent two 60 min dynamic [11C]UCB-J PET scans with arterial sampling with an interval of 28 days. The optimal tracer kinetic model was assessed using the Akaike criteria (AIC). Micro-/macro-parameters such as tracer delivery (K1) and volume of distribution (VT) were estimated using the optimal model. Data were also analysed for simplified reference tissue model (SRTM) with centrum semi-ovale (white matter) as reference region. Based on AIC, both 1T2k_VB and 2T4k_VB described the [11C]UCB-J kinetics equally well. Analysis showed that whole-brain grey matter TRT for VT, DVR and SRTM BPND were –2.2% ± 8.5, 0.4% ± 12.0 and –8.0% ± 10.2, averaged over all subjects. [11C]UCB-J kinetics can be well described by a 1T2k_VB model, and a 60 min scan duration was sufficient to obtain reliable estimates for both plasma input and reference tissue models. TRT for VT, DVR and BPND was <15% (1SD) averaged over all subjects and indicates adequate quantitative repeatability of [11C]UCB-J PET.

Preclinical PET Studies of [11C]UCB-J Binding in Minipig Brain.

Loss of neuronal synapse function is associated with a number of brain disorders. The [11C]UCB-J positron emission tomography (PET) tracer allows for in vivo examination of synaptic density, as it binds to synaptic vesicle glycoprotein 2A (SV2A) expressed in presynaptic terminals. Here, we characterise [11C]UCB-J imaging in Göttingen minipigs. Using PET imaging, we examined tracer specificity and compared kinetic models. We explored the use of a standard blood curve and centrum semiovale white matter as a reference region. We compared in vivo [11C]UCB-J PET imaging to in vitro autoradiography, Western blotting and real-time quantitative polymerase chain reaction. The uptake kinetics of [11C]UCB-J could be described using a 1-tissue compartment model and blocking of SV2A availability with levetiracetam showed dose-dependent specific binding. Population-based blood curves resulted in reliable [11C]UCB-J binding estimates, while it was not possible to use centrum semiovale white matter as a non-specific reference region. Brain [11C]UCB-J PET signals correlated well with [3H]UCB-J autoradiography and SV2A protein levels. [11C]UCB-J PET is a valid in vivo marker of synaptic density in the minipig brain, with binding values close to those reported for humans. Minipig models of disease could be valuable for investigating the efficacy of putative neuroprotective agents for preserving synaptic function in future non-invasive, longitudinal studies.

O11.3. SYNAPTIC MARKER PROTEIN SV2A IS REDUCED IN SCHIZOPHRENIA IN VIVO AND UNAFFECTED BY ANTIPSYCHOTICS IN RATS

BackgroundThe synaptic dysfunction hypothesis of schizophrenia is supported by multiple lines of evidence. However, in vivo evidence is lacking. Moreover, it is not known if antipsychotics alter synaptic protein levels. We addressed this in a combined clinical study using [11C]UCB-J, a positron emission tomography (PET) radioligand specific for synaptic vesicle glycoprotein 2A (SV2A), and rodent study of clinically relevant antipsychotic drug exposure.MethodsWe scanned 18 subjects with schizophrenia (SCZ) and 18 healthy volunteers (HV) with [11C]UCB-J PET and T1-weighted MRI, estimating grey matter volumes of distribution (VT) and corrected grey matter volumes (GMV) for the frontal cortex (FC), anterior cingulate cortex (ACC) and hippocampus. In addition, we estimated the [11C]UCB-J distribution volume ratio (DVR) in these regions, using the centrum semiovale (CS) as a pseudoreference region. We collected clinical data including PANSS score, chlorpromazine-equivalent antipsychotic dose (CPZ) and duration of illness (DOI). In parallel, we investigated the effects of olanzapine and haloperidol administration on SV2A levels in the Sprague-Dawley rat frontal cortex using western blotting, [3H]UCB-J autoradiography and immunostaining with confocal microscopy. We used two-way analysis of variance (ANOVA) to test effects of group, ROI and group-by-ROI interaction on VT and DVR. We used planned post hoc t-tests to test group effects at each ROI, with false discovery-rate adjustment for multiple comparisons. We used two-way ANOVA with Bonferroni’s post-hoc test to analyse autoradiography and SV2A immunostaining data, and the Kruskal-Wallis test, with alpha=0.05, to analyse western blot data.ResultsClinical study: We found significant group-by-region interaction (F2, 68=7.472, p=0.001), group (F1, 34=6.170, p=0.02) and ROI (F2, 68=426.0, p<0.0001) effects on VT, with significant reductions in mean [SEM] VT of large effect size in the SCZ group in the FC (SCZ=16.93 [0.80]; HV=19.50 [0.64]; t=2.51, df=34.0, p=0.03, Cohen’s d=0.8) and ACC (SCZ=19.55 [0.75]; HV=22.49 [0.72]; t=2.83, df=34.0, p=0.02, Cohen’s d=0.9), but not in the hippocampus (SCZ=14.09 [0.59]; HV=15.44 [0.50]; t=1.75, df=34.0, p=0.09, Cohen’s d=0.6). Furthermore, we found significant group-by-region interaction (F2, 68=7.97, p=0.0008), group (F1, 34=8.1, p=0.007) and ROI (F2, 68=510.9, p<0.0001) effects on DVR, with significant reductions of large effect size in the FC (SCZ=2.93 [0.17]; HV=3.48 [0.09]; t=2.89, df=34.0, p=0.01, Cohen’s d=1.0), ACC (SCZ=3.39 [0.17]; HV=3.99 [0.09]; t=3.05, df=34.0, p=0.01, Cohen’s d=1.0) and, additionally, hippocampus (SCZ=2.40 [0.12]; HV=2.74 [0.07]; t=2.32, df=34.0, p=0.03, Cohen’s d=0.8). There were no significant relationships (p>0.05) between VT and GMV, PANSS score, DOI and CPZ.Preclinical study: Chronic olanzapine or haloperidol exposure did not significantly affect total SV2A immunostaining intensity (p=0.97 and p=0.71 respectively) in the rat frontal cortex as compared to vehicle-exposed controls. Moreover, chronic haloperidol exposure did not significantly affect [3H]UCB-J specific binding (p=0.27) or SV2A protein levels (relative to GAPDH, p=0.71).DiscussionThese findings provide evidence for the first time that presynaptic marker protein levels are reduced in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for this, consistent with the synaptic dysfunction hypothesis.

In vivo measurement of widespread synaptic loss in Alzheimer's disease with SV2A PET.

IntroductionSynaptic loss is a robust and consistent pathology in Alzheimer's disease (AD) and the major structural correlate of cognitive impairment. Positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a promising biomarker of synaptic density.MethodsWe measured SV2A binding in 34 participants with early AD and 19 cognitively normal (CN) participants using [11C]UCB‐J PET and a cerebellar reference region for calculation of the distribution volume ratio.ResultsWe observed widespread reductions of SV2A binding in medial temporal and neocortical brain regions in early AD compared to CN participants. These reductions were largely maintained after correction for volume loss and were more extensive than decreases in gray matter volume.ConclusionWe were able to measure widespread synaptic loss due to AD using [11C]UCB‐J PET. Future studies will continue to evaluate the utility of SV2A PET for tracking AD progression and for monitoring potential therapies.

Autoradiographic mapping of synaptic vesicle glycoprotein 2A in non-human primate and human brain.

Synaptic vesicle glycoprotein 2A (SV2A) has been previously characterized as an imaging biomarker for assessment of synaptic density in positron emission tomography (PET) studies of patients with neurological conditions. To provide detailed maps of the brain localization of SV2A autoradiography studies were carried out using the SV2A radioligand [11 C]UCB-J and whole hemisphere sections of non-human primate (NHP) and human brain. Binding of [11 C]UCB-J was observed in all evaluated grey matter structures of the primate brain, with highest density in the caudate nucleus and cortex and lowest density in pons and globus pallidus. The density of [11 C]UCB-J binding sites in human brain showed a good correlation with that in NHP brain. Binding of [11 C]UCB-J in the white matter was very low relative to that in grey matter containing structures and was only inhibited to a minor extent by co-incubation with a saturating concentration of unlabelled UCB-J. The high-resolution images obtained in the present study may aid the interpretation of data acquired in human subjects examined using [11 C]UCB-J in PET studies. In addition, observation of low binding for [11 C]UCB-J in white matter (centrum semiovale) supports that this structure can be used as a reference region for quantitative analysis of [11 C]UCB-J PET data.

ASSOCIATION BETWEEN CEREBRAL AMYLOID ACCUMULATION AND SYNAPTIC DENSITY IN ALZHEIMER'S DISEASE: A MULTITRACER PET STUDY

Introduction Alzheimer's Disease (AD) pathology is traditionally characterized by the accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles comprised of hyperphosphorylated tau. However, an equally important pathology, synaptic loss, has been demonstrated to be an early event in the disease process and a major structural correlate of cognitive impairment. Recently, positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A) has emerged as a novel biomarker of synaptic density. We have previously demonstrated extensive synaptic loss that is more widespread than reductions in gray matter volume in cortical and subcortical brain regions of participants with AD. The current study further investigates the association of local and global cortical amyloid burden with synaptic density. Methods [11C]UCB-J binding to SV2A and [11C]PiB binding to amyloid were measured in 38 participants with AD (14 amnestic MCI and 24 mild dementia) and 20 cognitively normal (CN) participants aged 55-85?years. For [11C]PiB image analysis, parametric images of the binding potential (BPND) were generated using SRTM2 with whole cerebellum as a reference region and converted to distribution volume ratios (DVR). For [11C]UCB-J, parametric images of BPND were first computed using SRTM2 with a shrunken (2 mL) centrum semiovale (CS) reference region. BPND was then converted to DVR with a cerebellum reference region. Brain amyloid and synaptic density were measured in frontal, posterior cingulate/precuneus, lateral parietal, lateral temporal, medial temporal, lateral occipital, medial occipital, and pericentral regions of interest (ROIs). For [11C]PiB parametric images, a composite cortical DVR (representative of global amyloid burden) was calculated by combining the frontal, posterior cingulate/precuneus, lateral parietal, and lateral temporal regions. Results The study sample consisted of 58 participants (38 AD and 20 CN) with no group differences observed in sex (p=0.85), age (p=0.46), or education (p=0.06). AD participants had clinical characteristics typical of amnestic MCI and mild AD with CDR-global = 0.74±0.25 (p Conclusions Using [11C]UCB-J PET, widespread reductions of synaptic density in cortical and subcortical regions were observed in AD compared to CN participants. This included regions not traditionally associated with fibrillar amyloid pathology, such as the pericentral cortex. Interestingly, the cortical regions associated with the least robust accumulation of fibrillar amyloid (medial temporal cortex) were associated with the most pronounced reductions in synaptic density. Although significant negative associations between both global and local amyloid burden and regional synaptic density were observed for the pooled sample, this was driven by differences between diagnostic groups and was not significant within the AD group alone. Our findings are therefore consistent with previous postmortem studies describing the patterns of fibrillar amyloid burden and synaptic loss in AD. This research was funded by: NIA (P50AG047270 [CHvD], K23AG057784 [APM], R01AG052560 [REC, CHV], R01AG062276 [CHvD], and The Dana Foundation [MKC]), NIMH R25MH071584 and T32MH019961 (RSO), and the Detre T. Memorial Fellowship (RSO).