Biology subjects

Carson, R. E.

Publications and source records attributed to Carson, R. E..

9 recordsLinked to original sources

bioRxiv2026

Preclinical Evaluation of Itareparib, a brain penetrant PARP1-selective radioligand, in Glioma Rat Model and Nonhuman Primate

Rationale: Poly(ADP-ribose) polymerase-1 (PARP1) is a central mediator of DNA damage response and is upregulated in glioma, supporting it as a molecular imaging biomarker. However, quantitative PET assessment of PARP1 in infiltrative tumors with a preserved blood-brain barrier remains an unmet need. In this study, we evaluated if [18F]Itareparib, a brain-penetrant, non-trapping, PARP1-selective radioligand with reversible kinetics, could improve brain tumor diagnosis and enable target occupancy studies in neurooncology. Methods: [18F]Itareparib was synthesized and evaluated in an orthotopic rat model of BT142 IDH1-mutant gliomas. Dynamic PET scans were performed with or without the administration of the PARP1-selective inhibitor AZD9574. Standardized uptake value ratios (SUVRs) for tumors were calculated using the contralateral region as reference and compared with distribution volume ratios (DVRs) calculated using kinetic modeling. PARP1-specific binding and tracer stability were assessed using autoradiography, immunofluorescence, biodistribution, and radiometabolite analysis. Brain kinetics of [18F]Itareparib were evaluated in a healthy nonhuman primate (NHP) at baseline and blocking conditions. Results: [18F]Itareparib rapidly entered the rat brains and showed 4-fold higher uptake in BT142 tumors than in the contralateral brain. AZD9574 reduced tumor uptake by 77%, supporting the PARP1-specific binding of [18F]Itareparib in the tumors. SUVR(30-60 min) showed the closest agreement with DVR. Autoradiographic tumor-to-reference mean ratio was 7.3, and AZD9574 reduced the tumor-to-reference ratio by 56%. PARP1 immunofluorescence was higher in tumor than the rest of the brain and correlated with autoradiographic results. In rats, the parent fraction of [18F]Itareparib exceeded 99% in brain through 60 min post tracer injection (p.i.) and was approximately 88% in plasma at 60 min p.i. In the NHP, [18F]Itareparib showed rapid brain uptake, and VT decreased by 21+/-6 % after blocking with AZD9574. Conclusion: [18F]Itareparib showed brain penetration, high in vivo metabolic stability, reversible binding kinetics, and PARP1-specific tumor uptake. These findings support further development of [18F]Itareparib for the quantitative PET imaging of PARP1 in brain tumors.

cancer biology↗

bioRxiv2025

Optimized reference region and the effect on test-retest reliability and detection of Parkinson's disease with UCB-J.

[11C]UCB-J is a radioligand targeting synaptic vesicle glycoprotein 2A, used to image synaptic density. For quantification, a small-volume centrum semiovale area was previously optimized as a [11C]UCB-J reference region (CS2mL); however, its high variability resulted in reduced reliability. Herin, we evaluated an alternative reference region method to assess longitudinal test-retest reliability and detection of Parkinsons disease (PD). For estimating distribution volume ratio (DVR), CS2mL and eleven white matter (WM) reference regions (range: 0.5-200 mL) were generated using the Freesurfer WM map. Same-day and longitudinal test-retest variability (TRV) were assessed (24 healthy subjects (HS); n=10 same-day and n=20 longitudinal HRRT scans, range: 7-1028 days). Each reference region was used to evaluate the substantia nigra (SN) and caudate DVRs in HS (n=25) and PD (n=20). The 10mL WM reference region yielded [11C]UCB-J DVR measurements with reduced variability in TRV (same-day: 10mL: 1.2{+/-}5.7%, same-day: CS2mL: -0.9{+/-}9.2% longitudinal: 10mL: 1.5{+/-}7.0%, CS2mL: 1.6{+/-}11.9%,) while maintaining <10% volume of distribution difference, compared to CS2mL. Further, a significant difference between PD and HS groups in SN and caudate DVRs was found using 10mL, with greater effect size (Cohens d 0.61 for SN and 0.66 for caudate) compared to CS2mL (0.38 for SN and 0.43 for caudate).

neuroscience↗

bioRxiv2025

Basal forebrain volume is associated with cortical amyloid burden in cognitively unimpaired older adults at varying genetic risk for Alzheimers disease

BackgroundIn mild cognitive impairment and dementia due to Alzheimers disease (AD), postmortem and in vivo neuroimaging studies have demonstrated significant neuronal loss in the basal forebrain cholinergic system (BFCS), which provides the primary cholinergic input to the cerebral cortex. Within this region, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a group of posteriorly clustered magnocellular neurons in the BFCS. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in the preclinical stages of AD. The current study investigates the relationship between sub-structural BFCS volume and cortical A{beta} burden in cognitively unimpaired middle-aged individuals at varying genetic risk for AD. MethodsCognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype {varepsilon}4{varepsilon}4 (n=15), {varepsilon}3{varepsilon}4 (n=15), and {varepsilon}3{varepsilon}3 (n=15), matched for age and sex. Participants underwent imaging with [11C]PiB PET and structural 3T MRI. Distribution volumes ratios (DVR) with a whole cerebellum reference region were calculated for [11C]PiB PET analyses. BFCS sub-structural volumes were obtained from the SPM8 Anatomy Toolbox (Cholinergic nuclei [Ch] 1-3, Ch4). MTL subregional volumes (entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using Freesurfer. ResultsBFCS amyloid burden was highest among APOE {varepsilon}4 homozygotes (Ch1-3, F(2, 42)=3.26, P=0.048; Ch4, F(2, 42)=3.82, P= 0.03). Ch4 (nbM), but not Ch1-3 volume, was found to be inversely associated with global A{beta} burden (Pearson r=-0.40, P=0.007). MTL subregional volumes were not associated with global A{beta} burden in the pooled sample. Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (P=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson r = -0.70, P=0.02) in A{beta}+ participants. ConclusionsWe observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, A{beta}+, middle-aged adults at varying genetic risk for AD. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.

neuroscience↗

bioRxiv2024

Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study

BackgroundThe pathological effects of amyloid {beta} oligomers (A{beta}o) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimers disease (AD). Positron emission tomography (PET) studies of mGluR5 using [18F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [11C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [18F]FPEB and [11C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD. MethodsFifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [18F]FPEB to measure mGluR5 and [11C]UCB-J to measure synaptic density. Parametric DVR images using equilibrium methods were generated from dynamic. For [18F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [11C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region. ResultA strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic in the AD group (r = 0.85, p <0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses within and between other brain regions suggested significant positive correlations between mGluR5 in the medial temporal lobe and synaptic density in a broader set of commonly AD-affected regions. ConclusionMedial temporal loss of mGluR5 in AD is associated with synaptic loss in both medial temporal regions and more broadly in association cortical regions, indicating that mGluR5 mediated A{beta}o toxicity may lead to early synaptic loss more broadly in AD-affected networks. In CN individuals, an isolated strong association between lower mGluR5 and lower synaptic density may indicate non-AD related synaptic loss.

pathology↗

bioRxiv2022

Molecular and connectomic vulnerability shape cross-disorder cortical abnormalities

Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21 000 patients and N = 26 000 controls, collected using a harmonized processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find that regional molecular vulnerability and macroscale brain network architecture interact to drive the spatial patterning of cortical abnormalities in multiple disorders. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, medial temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local biological attributes and global connectivity jointly shape cross-disorder cortical abnormalities.

neuroscience↗

bioRxiv2021

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

neuroscience↗

bioRxiv2021

A metabolically stable PET tracer for imaging synaptic vesicle protein 2A: Synthesis and preclinical characterization of SDM-16

PurposeTo investigate the synaptic vesicle glycoprotein 2A (SV2A) expression in the whole central nervous system and peripheral tissues, a metabolically stable SV2A radiotracer is desirable to minimize a potential confounding effect of radiometabolites. The aim of this study was to develop and evaluate a metabolically stable SV2A radiotracer, [18F]SDM-16, in nonhuman primate brains. MethodsThe racemic SDM-16 (4-(3,5-difluorophenyl)-1-((2-methyl-1H-imidazol-1-yl)methyl)pyrrolidin-2-one) was synthesized and assayed for in vitro SV2A binding affinity. We synthesized the enantiopure [18F]SDM-16 using the corresponding arylstannane precursor. Nonhuman primate brain PET was performed on a FOCUS 220 system. Arterial blood was drawn for metabolite analysis and construction of plasma input function. Regional time-activity curves (TACs) were evaluated with the one-tissue compartment (1TC) model to obtain the volume of distribution (VT). Binding potential (BPND) was calculated using either the nondisplaceable volume of distribution (VND) or the centrum semiovale (CS) as the reference region. ResultsRacemic SDM-16 was synthesized in 3 steps with 44% overall yield and has high affinity (Ki = 3.7 nM) to human SV2A. [18F]SDM-16 was prepared in greater than 99% radiochemical and enantiomeric purity. This radiotracer displayed high specific binding in brain and was metabolically more stable than other SV2A PET tracers. The plasma free fraction (fP) of [18F]SDM-16 was 69%, which was higher than those of [11C]UCB-J (46%), [18F]SynVesT-1 (43%), [18F]SynVesT-2 (41%), and [18F]UCB-H (43%). The TACs were well described with the 1TC. The averaged test-retest variability (TRV) was -9{+/-}8%, and averaged absolute TRV (aTRV) was 10{+/-}7% for all analyzed brain regions. ConclusionWe have successfully synthesized a metabolically stable and high affinity SV2A PET tracer, [18F]SDM-16, which showed high specific and reversible binding in the NHP brain. [18F]SDM-16 may have potential application in the visualization and quantification of SV2A beyond the brain.

neuroscience↗

bioRxiv2021

PET-BIDS, an extension to the brain imaging data structure for positron emission tomography

The Brain Imaging Data Structure (BIDS) is a standard for organizing and describing neuroimaging datasets. It serves not only to facilitate the process of data sharing and aggregation, but also to simplify the application and development of new methods and software for working with neuroimaging data. Here, we present an extension of BIDS to include positron emission tomography (PET) data (PET-BIDS). We describe the PET-BIDS standard in detail and share several open-access datasets curated following PET-BIDS. Additionally, we highlight several tools which are already available for converting, validating and analyzing PET-BIDS datasets.

neuroscience↗

bioRxiv2019

Effects of age, BMI and sex on the glial cell marker TSPO - a multicentre PBR28 HRRT PET study

PurposeTo investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [11C]PBR28. Methods[11C]PBR28 data from 140 healthy volunteers (72 males and 68 females; n=78 with HAB and n=62 MAB genotype; age range 19-80 years; BMI range 17.6 - 36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (n=53), Turku PET centre (n=62) and Yale University PET Center (n=25). The total volume of distribution (VT) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. ResultsThere were significant positive correlations between age and VT in the frontal and temporal cortex. BMI showed a significant negative correlation with VT in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher VT. A subgroup analysis revealed a positive correlation between VT and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. ConclusionThese findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies.

immunology↗