Biology subjects

Bertoglio, D.

Publications and source records attributed to Bertoglio, D..

5 recordsLinked to original sources

bioRxiv2024

Short-term caloric restriction or resveratrol supplementation alters large-scale brain network connectivity in male and female rats

IntroductionDietary interventions such as caloric restriction (CR) exert positive effects on brain health. Unfortunately, poor compliance hinders the success of this approach. A proposed alternative is resveratrol (Rsv), a CR-mimetic known to promote brain health. Direct comparison between the effects of Rsv and CR on brain health is lacking, with limited knowledge on their sex-specific effects. Therefore, we aimed to compare and unravel the sex-specific impact of these dietary interventions on spontaneous brain activity. MethodsHere, we used resting-state fMRI to investigate functional connectivity (FC) changes in five prominent resting-state brain networks (RSNs) in healthy four month old male and female F344 rats supplemented to either 40% CR or daily Rsv supplementation (10 mg/kg, oral) for the duration of one month. ResultsOur results demonstrated a decreased body weight (BW) in CR rats, as well as an increase in body weight in male Rsv supplemented rats, compared to female Rsv supplemented rats, whereas this difference between sexes was not observed in the control or CR groups. Furthermore, we found that both CR or Rsv supplementation induce a female-specific decrease of FC between the subcortical network and hippocampal network, and between the subcortical network and lateral cortical network. Moreover, Rsv supplementation lowered FC within the hippocampal network and between the hippocampal and the default mode like network, the lateral cortical network and the sensory network - an effect not observed for the CR rats. Finally, we observed an overall lower FC in male rats compared to females, irrespective of dietary intervention, within the subcortical network and between the subcortical, the sensory and default mode like network. DiscussionOur findings reveal that both CR and Rsv induce a similar female-specific decrease of FC in RSNs associated with memory and emotion, all the while CR and Rsv induce dissimilar changes in body weight and other within- and between RSN FC measures. Altogether, this study provides insight into the effects and comparability of short-term CR and Rsv supplementation on brain connectivity within and between RSNs in both male and female F344 rats, providing a FC reference for future research of dietary effects.

neuroscience↗

bioRxiv2024

Preclinical validation and kinetic modelling of the SV2A PET ligand UCB-J in mice

Synaptic vesicle protein 2A (SV2A) is ubiquitously expressed in presynaptic terminals where it functions as a neurotransmission regulator protein. Synaptopathy has been reported during healthy ageing and in a variety of neurodegenerative diseases. Positron emission tomography (PET) imaging of SV2A can be used to evaluate synaptic density. The PET ligand [11C]UCB-J has high binding affinity and selectivity for SV2A but has a short physical half-life due to the 11C isotope. Here we report the characterization and validation of its 18F-labeled equivalent, [18F]UCB-J, in terms of specificity, reproducibility and stability in C57BL/6J mice. Plasma analysis revealed at least one polar radiometabolite. Kinetic modelling was performed using a population-based metabolite corrected image-derived input function (IDIF). [18F]UCB-J showed relatively fast kinetics and a reliable measure of the IDIF-based volume of distribution (VT(IDIF)). [18F]UCB-J specificity for SV2A was confirmed through a levetiracetam blocking assay (50 to 200 mg/kg). Reproducibility of the VT(IDIF) was determined through test-retest analysis, revealing significant correlation (r2=0.773, p<0.0001). Time-stability analyses indicate a scan duration of 60 min to be sufficient to obtain a reliable VT(IDIF). In conclusion, [18F]UCB-J is a selective SV2A ligand with optimal kinetics in mice. Further investigation is warranted for (pre)clinical applicability of [18F]UCB-J in synaptopathies.

neuroscience↗

bioRxiv2024

Preclinical evaluation of the novel CHDI-650 PET ligand for non-invasive quantification of mutant huntingtin aggregates in Huntington's disease

PurposePositron emission tomography (PET) imaging of mutant huntingtin (mHTT) aggregates is a potential tool to monitor disease progression as well as the efficacy of candidate therapeutic interventions for Huntingtons disease (HD). To date, the focus has been mainly on the investigation of 11C radioligands; however, favourable 18F radiotracers will facilitate future clinical translation. This work aimed at characterising the novel [18F]CHDI-650 PET radiotracer using a combination of in vivo and in vitro approaches in a mouse model of HD. MethodsAfter characterising [18F]CHDI-650 using in vitro autoradiography, we assessed in vivo plasma and brain radiotracer stability as well as kinetics through dynamic PET imaging in the heterozygous (HET) zQ175DN mouse model of HD and wild-type (WT) littermates at 9 months of age. Additionally, we performed a head-to-head comparison study at 3 months with the previously published [11C]CHDI-180R radioligand. ResultsPlasma and brain radiometabolite profiles indicated a suitable metabolic profile for in vivo imaging of [18F]CHDI-650. Both in vitro autoradiography and in vivo [18F]CHDI-650 PET imaging at 9 months of age demonstrated a significant genotype effect (p<0.0001) despite the poor test-retest reliability. [18F]CHDI-650 PET imaging at 3 months of age displayed higher differentiation between genotypes when compared to [11C]CHDI-180R. ConclusionOverall, [18F]CHDI-650 allows for discrimination between HET and WT zQ175DN mice at 9 and 3 months of age. [18F]CHDI-650 represents the first suitable 18F radioligand to image mHTT aggregates in mice and its clinical evaluation is underway.

neuroscience↗

bioRxiv2022

Identification of pre-synaptic density networks using SV2A PET imaging and ICA in healthy and diseased 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 Huntingtons disease, HD). 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 ({beta}) 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.

neuroscience↗

bioRxiv2021

A novel imaging ligand as a biomarker for mutant huntingtin-lowering in Huntington's disease

Huntingtons disease (HD) is a dominantly inherited neurodegenerative disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene that encodes the pathologic mutant HTT (mHTT) protein with an expanded polyglutamine (PolyQ) tract. While several therapeutic programs targeting mHTT expression have advanced to clinical evaluation, no method is currently available to visualize mHTT levels in the living brain. Here we demonstrate the development of a positron emission tomography (PET) imaging radioligand with high affinity and selectivity for mHTT aggregates. This small molecule radiolabeled with 11C ([11C]CHDI-180R) enables non-invasive monitoring of mHTT pathology in the brain and can track region-and time-dependent suppression of mHTT in response to therapeutic interventions targeting mHTT expression. We further show that therapeutic agents that lower mHTT in the striatum have a functional restorative effect that can be measured by preservation of striatal imaging markers, enabling a translational path to assess the functional effect of mHTT lowering.

neuroscience↗