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Cannabinoid receptor CB 2 (CB 2 R) is upregulated on activated microglia and astrocytes in the brain under inflammatory conditions and plays important roles in many neurological diseases, such as Alzheimer’s disease, amyotrophic lateral sclerosis, and ischemic stroke. The advent of positron emission tomography (PET) using CB 2 R radiotracers has enabled the visualization of CB 2 R distribution in vivo in animal models of central nervous system inflammation, however translation to humans has been less successful. Several novel CB 2 R radiotracers have been developed and evaluated to quantify microglial activation. In this review, we summarize the recent preclinical and clinical imaging results of CB 2 R PET tracers and discuss the prospects of CB 2 R imaging using PET.

Tauvid has been approved by the U.S. Food and Drug Administration (FDA) in 2020 for positron emission tomography (PET) imaging of adult patients with cognitive impairments undergoing evaluation for Alzheimer’s disease (AD) based on tau pathology. Abnormal aggregation of tau proteins is one of the main pathologies present in AD and is receiving increasing attention as a diagnostic and therapeutic target. In this review, we summarised the production and quality control of Tauvid, its clinical application, pharmacology and pharmacokinetics, as well as its limitation due to off-target binding. Moreover, a brief overview on the second-generation of Tau PET tracers is provided. The approval of Tauvid marks a step forward in the field of AD research and opens up opportunities for second-generation tau tracers to advance tau PET imaging in the clinic.

Mitochondrial dysfunction and accumulation of α-synuclein aggregates are hallmarks of the neurodegenerative Parkinson’s disease and may be interconnected. To investigate the interplay between α-synuclein and brain mitochondria at near atomic structural level, we apply NMR and identify α-synuclein protein interactors using limited proteolysis-coupled mass spectrometry (LiP-MS). Several of the proteins identified are related to ATP synthesis and homeostasis and include subunits of ATP synthase and the adenylate kinase AK2. Furthermore, our data suggest that α-synuclein interacts with the Parkinson’s disease-related protein DJ1. NMR analysis demonstrates that both AK2 and DJ1 bind to the C-terminus and other segments of α-synuclein. Using a functional assay for AK2, we show that monomeric α-synuclein has an activating effect, whereas C-terminally truncated α-synuclein and α-synuclein in an amyloid fibrillar state have no significant effect on AK2 activity. Our results suggest that α-synuclein modulates ATP homeostasis in a manner dependent on its conformation and its C-terminal acidic segment. Here, the authors show that physiological alpha-synuclein supports mitochondrial ATP homeostasis via interactions with ATP synthase and AK2, whereas its disease-linked mutants, truncated forms, and aggregates lose these interactions.

Background This study investigated sex differences in the associations between Alzheimer’s disease (AD) biomarkers, cognitive performance, and decline in memory clinic settings. Methods 249 participants (females/males:123/126), who underwent tau-PET, amyloid-PET, structural MRI, and plasma glial fibrillary acidic protein (GFAP) measurement were included from Geneva and Lausanne Memory Clinics. Mann-Whitney U tests investigated sex differences in clinical and biomarker data. Linear regression models estimated the moderating effect of sex on the relationship between biomarkers and cognitive performance and decline. Sex differences in cognitive decline were further evaluated using longitudinal linear mixed-effect models with three-way interaction effects. Results Women and men present similar clinical features, amyloid, and neurodegeneration. Women had higher tau load and plasma levels of GFAP than men ( p  < 0.05). Tau associations with amyloid (standardized β = 0.54, p  < 0.001), neurodegeneration (standardized β=-0.44, p  < 0.001), and cognition (standardized β=-0.48, p  < 0.001) were moderated by a significant interaction with sex. Specifically, the association between amyloid and tau was stronger among women than men (standardized β=-0.19, p  = 0.047), whereas the associations between tau and cognition and between tau and neurodegeneration were stronger among men than in women (standardized β=-0.76, p  = 0.001 and standardized β=-0.56, p  = 0.044). Women exhibited faster cognitive decline than men in the presence of severe cortical thinning ( p  < 0.001). Conclusion Women showed higher tau load and stronger association between amyloid and tau than men. In individuals with high tau burden, men exhibited greater neurodegeneration and cognitive impairment than women. These findings support that sex differences may impact tau deposition through an upstream interplay with amyloid, leading to downstream effects on neurodegeneration and cognitive outcomes.

Background Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the initial pathophysiological mechanism of Alzheimer’s disease (AD). The study aims to investigate the association between mGluR5 availability and AD’s biomarkers and cognitive function. Methods We examined 35 individuals with mGluR5 tracer [ 18 F]PSS232 to assess mGluR5 availability, and with [ 18 F]Florbetapir PET to assess global amyloid deposition, and [ 18 F]FDG PET to assess glucose metabolism. The plasma neurofilament light (NfL) and p-tau181 levels in a subset of individuals were measured ( n = 27). The difference in mGluR5 availability between the AD and normal control (NC) groups was explored. The associations of mGluR5 availability with amyloid deposition, glucose metabolism, gray matter volume (GMV), neuropsychological assessment scores, and plasma biomarkers were analyzed. Results The mGluR5 availability was significantly reduced in AD patients’ hippocampus and parahippocampal gyrus compared to NCs. Global amyloid deposition was positively associated with mGluR5 availability in the AD group and reversely associated in the NC group. The mGluR5 availability was positively correlated with regional glucose metabolism in the overall and stratified analyses. The availability of mGluR5 in the hippocampus and parahippocampal gyrus demonstrated a strong relationship with the GMV of the medial temporal lobe, plasma p-tau181 or NfL levels, and global cognitive performance. Conclusions [ 18 F]PSS232 PET can quantify the changes of mGluR5 availability in the progression of AD. mGluR5 availability correlated not only with neuropathological biomarkers of AD but also with neurodegenerative biomarkers and cognitive performance. mGluR5 may be a novel neurodegenerative biomarker, and whether mGluR5 could be a potential therapeutic target for AD needs to be further studied.

Classical benzodiazepines, which are widely used as sedatives, anxiolytics and anticonvulsants, exert their therapeutic effects through interactions with heteropentameric GABAA receptors composed of two α, two β and one γ2 subunit. Their high affinity binding site is located at the interface between the γ2 and the adjacent α subunit. The α-subunit gene family consists of six members and receptors can be homomeric or mixed with respect to the α-subunits. Previous work has suggested that benzodiazepine binding site ligands with selectivity for individual GABAA receptor subtypes, as defined by the benzodiazepine-binding α subunit, may have fewer side effects and may even be effective in diseases, such as schizophrenia, autism or chronic pain, that do not respond well to classical benzodiazepines. The distributions of the individual α subunits across the CNS have been extensively characterized. However, as GABAA receptors may contain two different α subunits, the distribution of the subunits does not necessarily reflect the distribution of receptor subtypes with respect to benzodiazepine pharmacology. In the present study, we have used in vivo [18F]flumazenil PET and in vitro [3H]flumazenil autoradiography in combination with GABAA receptor point-mutated mice to characterize the distribution of the two most prevalent GABAA receptor subtypes (α1 and α2) throughout the mouse brain. The results were in agreement with published in vitro data. High levels of α2-containing receptors were found in brain regions of the neuronal network of anxiety. The α1/α2 subunit combinations were predictable from the individual subunit levels. In additional experiments, we explored in vivo [18F]flumazenil PET to determine the degree of receptor occupancy at GABAA receptor subtypes following oral administration of diazepam. The dose to occupy 50% of sensitive receptors, independent of the receptor subtype(s), was 1–2mg/kg, in agreement with published data from ex vivo studies with wild type mice. In conclusion, we have resolved the quantitative distribution of α1- and α2-containing homomeric and mixed GABAA receptors in vivo at the millimeter scale and demonstrate that the regional drug receptor occupancy in vivo at these GABAA receptor subtypes can be determined by [18F]flumazenil PET. Such information should be valuable for drug development programs aiming for subtype-selective benzodiazepine site ligands for new therapeutic indications. [Display omitted] •[18F]Flumazenil PET with point-mutated mice to predict GABAA receptor pharmacology.•Mapping of homomeric and mixed α1 and α2 GABAA receptors in vivo in mouse brain.•In vivo regional GABAA receptor occupancy in mouse brain by [18F]flumazenil PET.

Neuroinflammation plays an important role in the pathophysiology of Alzheimer’s disease. The cannabinoid type 2 receptor(CB2R) is an emerging target for neuroinflammation and therapeutics of Alzheimer’s disease. Here, we aim to assess the alterations in brain CB2R levels and evaluate novel CB2R imaging tracers in the arcAb mouse model of Alzheimer’s disease amyloidosis. Immunohistochemical staining for amyloid-b deposits(6E10), microgliosis(anti-Iba1 and anti-CD68 antibodies), astrocytes(GFAP) and the anti-CB2R antibody was performed on brain slices from 17-month-old arcAb mice. Autoradiography using the CB2R imaging probes [18F]RoSMA-18-d6, [11C]RSR-056 and [11C]RS-028 and mRNA analysis were performed in brain tissue from arcAb and nontransgenic littermate (NTL) mice at 6, 17, and 24 months of age. Specific increased CB2R immunofluorescence intensities on the increased number of GFAP-positive astrocytes and Iba1-positive microglia were detected in the hippocampus and cortex of 17-month-old arcAb mice compared to NTL mice. CB2R immunofluorescence was higher in glial cells inside 6E10-positive amyloid-b deposits than peri-plaque glial cells, which showed low background immunofluorescence in the hippocampus and cortex of 17-month-old arcAb mice. Ex-vivo autoradiography showed that the specific binding of [18F]RoSMA-18-d6 and [11C]RSR-056 was comparable in arcAb and NTL mice at 6, 17, and 24 months of age. The level of Cnr2 mRNA expression in the brain was not significantly different between arcAb and NTL mice at 6, 17 or 24 months of age. In conclusion, we demonstrated pronounced specific increases in microglial and astroglial CB2R expression levels in mouse model of AD-related cerebral amyloidosis, emphasizing CB2R as a suitable target for imaging neuroinflammation.

BackgroundPeptidic radiotracers are preferentially excreted through the kidneys, which often results in high persistent renal retention of radioactivity, limiting or even preventing therapeutic clinical translation of these radiotracers. Exendin-4, which targets the glucagon-like-peptide 1 receptor (GLP-1R) overexpressed in insulinomas and in congenital hyperinsulinism, is an example thereof. The use of the tripeptide MVK, which is readily cleaved between methionine and valine by neprilysin at the renal brush border membrane, already showed promising results in reducing kidney uptake as reported in the literature. Based on our previous findings we were interested how linker variants with multiple copies of the MV-motive influence renal washout of radiolabelled exendin-4.ResultsThree exendin-4 derivatives, carrying either one MVK, a MV-MVK or a MVK-MVK linker were synthesized and compared to a reference compound lacking a cleavable linker. In vivo results of a biodistribution in GLP-1R overexpressing tumour bearing mice at 24 h post-injection demonstrated a significant reduction (at least 57%) of renal retention of all 111In-labeled exendin-4 compounds equipped with a cleavable linker compared to the reference compound. While the insertion of the single linker MVK led to a reduction in kidney uptake of 70%, the dual approach with the linker MV-MVK slightly, but not significantly enhanced this effect, with 77% reduction in kidney uptake compared to the reference. In vitro IC50 and cell uptake studies were conducted and demonstrated that though the cleavable linkers negatively influenced the affinity towards the GLP-1R, cell uptake remained largely unaffected, except for the MV-MVK cleavable linker conjugate, which displayed lower cell uptake than the other compounds. Importantly, the tumour uptake in the biodistribution study was not significantly affected with 2.9, 2.5, 3.2 and 1.5% iA/g for radiolabelled Ex4, MVK-Ex4, MV-MVK-Ex4 and MVK-MVK-Ex4, respectively.ConclusionCleavable linkers are highly efficient in reducing the radioactivity burden in the kidney. Though the dual linker approach using the instillation of MV-MVK or MVK-MVK between exendin-4 and the radiometal chelator did not significantly outperform the single cleavable linker MVK, further structural optimization or the combination of different cleavable linkers could be a stepping stone in reducing radiation-induced nephrotoxicity.

Background Presentations and outcomes of acute myocardial infarction (MI) differ between women and men, with the worst outcomes being reported in younger women. Mental stress induced ischemia and sympathetic activation have been suggested to play a prominent role in the pathogenesis of MI in younger women, however, the impact of sex hormones on these parameters remains unknown. Methods The effect of sex hormones and age on myocardial infarct size and myocardial sympathetic activity (MSA) was assessed in male and female, as well as young (4–6 months) and aged (20–22 months) FVB/N mice ( n  = 106, 60 gonadectomized and 46 sham-operated animals) who underwent in vivo [ 11 C]meta-hydroxyephedrine ([ 11 C]mHED) positron emission tomography (PET) and cardiac magnetic resonance (CMR) imaging 24 h after a 30 min myocardial ischemic injury. Results MSA and catecholamine levels following myocardial injury were highest in young males ( p  = 0.008 and p  = 0.043 vs. young females, respectively) and were reduced by orchiectomy. Accordingly, testosterone serum levels correlated positively with MSA ( r  = 0.66, p  < 0.001). Males had a larger average infarct size and lower left ventricular contractility following myocardial injury than females ( p  < 0.05 vs. females). These sex differences were no longer evident in gonadectomized animals (p = NS vs. females). In female animals, estrogen depletion did not affect MSA (ovariectomy effect, p  = 0.892). Female animals showed an age-dependent increase in MSA ( p  = 0.011), which was absent in males. Conclusion Testosterone associates with an increase in sympathetic tone, contributing to adverse cardiac remodeling following MI. Conversely, females maintain sympathetic integrity, independent of sex hormones. Our results suggest a biological advantage of female sex in post MI recovery. Further research is warranted to confirm these findings in humans. Plain English Summary Heart attacks affect men and women differently, with younger women often experiencing worse outcomes than men. One reason for this difference might be how stress and heart nerve activity are influenced by sex hormones, though this has not been well understood to date. In this study, we investigated how sex hormones and age affect heart damage and nerve activity in male and female mice. We used advanced imaging techniques to look at the hearts of young and older mice, some of which had their sex organs removed to study the hormone effects. Our results showed that young male mice had higher nerve activity and stress hormone levels after a heart attack compared to young female mice. Removing the male sex hormone (testosterone) reduced this activity, suggesting testosterone worsens heart damage. In contrast, removing female sex hormones (oestrogen and progesterone) did not affect nerve activity in female mice. Females also maintained better heart function after a heart attack, regardless of their hormones. In summary, male sex hormones may worsen early heart attack recovery by increasing stress on the heart, while female hearts were more resilient in our study. This information could help refine risk stratification and treatment of heart attack in men and women. Highlights In a validated murine model of acute myocardial infarction (MI), young males show higher myocardial sympathetic activity (MSA) and stress hormone levels compared to their female counterparts. Circulating testosterone levels correlated with an enhanced MSA post MI in males. Female mice maintain better heart function after a heart attack, regardless of estrogen levels. Sex differences in MI outcomes are eliminated when sex hormones are removed. These findings highlight a potential protective role of female sex in post MI recovery.

The ATN model represents a research framework used to describe in subjects the presence or absence of Alzheimer's disease (AD) pathology through biomarkers. The aim of this study was to describe the prevalence of different ATN profiles using quantitative imaging biomarkers in two independent cohorts, and to evaluate the pertinence of ATN biomarkers to identify comparable populations across independent cohorts. A total of 172 subjects from the Geneva Memory Clinic and 113 volunteers from a study on healthy aging at the University Hospital of Zurich underwent amyloid (A) and tau (T) PET, as well as T1-weigthed MRI scans using site-specific protocols. Subjects were classified by cognition (cognitively unimpaired, CU, or impaired, CI) based on clinical assessment by experts. Amyloid data converted into the standardized centiloid scale, tau PET data normalized to cerebellar uptake, and hippocampal volume expressed as a ratio over total intracranial volume ratio were considered as biomarkers for A, T, and neurodegeneration (N), respectively. Positivity for each biomarker was defined based on previously published thresholds. Subjects were then classified according to the ATN model. Differences among profiles were tested using Kruskal-Wallis ANOVA, and between cohorts using Wilcoxon tests. Twenty-nine percent of subjects from the Geneva cohorts were classified with a normal (A-T-N-) profile, while the Zurich cohort included 64% of subjects in the same category. Meanwhile, 63% of the Geneva and 16% of the Zurich cohort were classified within the AD continuum (being A+ regardless of other biomarkers' statuses). Within cohorts, ATN profiles were significantly different for age and mini-mental state examination scores, but not for years of education. Age was not significantly different between cohorts. In general, imaging A and T biomarkers were significantly different between cohorts, but they were no longer significantly different when stratifying the cohorts by ATN profile. N was not significantly different between cohorts. Stratifying subjects into ATN profiles provides comparable groups of subjects even when individual recruitment followed different criteria.