The end-stage of amyotrophic lateral sclerosis (ALS) is commonly regarded as a complete Locked-In Syndrome (cLIS). Shifting the perspective from cLIS (assumed consciousness) to Cognitive Motor Dissociation (potentially demonstrable consciousness), we aimed to assess the preservation of covert awareness (internally preserved but externally inaccessible) using a multimodal battery. We evaluate two end-stage ALS patients using neurophysiological testing, passive and active auditory oddball paradigms, an auditory Brain-Computer Interface (BCI), functional activation-task imaging, long-term EEG, brain morphology, and resting-state metabolism to characterize underlying brain function. Patient 1 initially follows simple commands but fails twice at BCI control. At follow-up, command following is no longer observed and his oddball cognitive responses disappear. Patient 2, at a single evaluation, is unable to follow commands or control the BCI. Both patients exhibit altered wakefulness, brain atrophy, and a global cortico–subcortical hypometabolism pattern consistent with a disorder of consciousness, regarded as an extreme manifestation of ALS-associated fronto-temporal dementia. Although it is not possible to firmly prove the absence of awareness, each independent measure concurred with suggesting that a “degenerative disorder of consciousness” rather than a cLIS may constitute the final stage of ALS. This condition appears pathophysiologically distinct from typical tetraplegia and anarthria, in which behavioural communication and BCI use persist to enhance quality of life. Identifying the neuroimaging signatures of this condition represents a substantial milestone in understanding end-stage ALS. Large-scale longitudinal investigations are warranted to determine the prevalence of this profile among patients whose communication appears impossible. Some patients with amyotrophic lateral sclerosis become progressively paralyzed to the extent that they can no longer communicate. This raises a critical question: does consciousness remain despite a complete loss of interaction? To address this issue, we analysed brain activity in two patients at the late stage of this disease. Our findings indicate that no reliable signs of awareness could be detected, even when employing advanced methods to assess brain function, including approaches designed to enable communication without movement. Two hypotheses may account for this outcome: either prolonged paralysis progressively leads to the disappearance of consciousness, or the degeneration of brain function itself directly underlies its loss. However, our conclusions ultimately depend on the reliability of consciousness assessment tools, even when used in combination. Gobert et al. investigate whether consciousness persists in end-stage Amyotrophic Lateral Sclerosis, traditionally assumed as being fully aware but unable to communicate. Multimodal assessments, including Brain-Computer Interface, suggest some individuals may show degenerative disorder of consciousness rather than a complete Locked-In Syndrome.

Degeneration of the noradrenergic system is now considered a pathological hallmark of Parkinson's disease, but little is known about its consequences in terms of parkinsonian manifestations. Here, we evaluated two aspects of the noradrenergic system using multimodal in vivo imaging in patients with Parkinson's disease and healthy controls: the pigmented cell bodies of the locus coeruleus with neuromelanin sensitive MRI; and the density of α2-adrenergic receptors (ARs) with PET using 11C-yohimbine. Thirty patients with Parkinson's disease and 30 age- and sex-matched healthy control subjects were included. The characteristics of the patients' symptoms were assessed using the Movement Disorder Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Patients showed reduced neuromelanin signal intensity in the locus coeruleus compared with controls and diminished 11C-yohimbine binding in widespread cortical regions, including the motor cortex, as well as in the insula, thalamus and putamen. Clinically, locus coeruleus neuronal loss was correlated with motor (bradykinesia, motor fluctuations, tremor) and non-motor (fatigue, apathy, constipation) symptoms. A reduction of α2-AR availability in the thalamus was associated with tremor, while a reduction in the putamen, the insula and the superior temporal gyrus was associated with anxiety. These results highlight a multifaceted alteration of the noradrenergic system in Parkinson's disease since locus coeruleus and α2-AR degeneration were found to be partly uncoupled. These findings raise important issues about noradrenergic dysfunction that may encourage the search for new drugs targeting this system, including α2-ARs, for the treatment of Parkinson's disease.

The end-stage of amyotrophic lateral sclerosis [ALS] is presumed to be a complete Locked-In Syndrome [cLIS], assuming an internally preserved consciousness that would not be accessible anymore from the outside. However, whether consciousness persists at this stage of ALS remains to be demonstrated. Shifting the perspective from cLIS (presupposed consciousness) to Cognitive Motor Dissociation (to-be-demonstrated consciousness), we attempted to demonstrate consciousness and communication with two cLIS-ALS patients using a multimodal awareness assessment battery. It involved complete neurophysiological assessments, passive and active auditory oddball paradigm (Subject-Own-Name/P300), an auditory-based Brain-Computer-Interface [BCI] and activation-task imaging using functional MRI or [15O]H2O PET. Wakefulness (long-term EEG), brain morphology (CT or MRI scans) and resting brain metabolism ([18F]fluoro-deoxy-glucose PET) were used to describe the underlying cLIS brain function. While Patient 1 could initially follow simple commands, he failed twice to control the BCI. At follow-up, he showed no more evidence of command following and his oddball (Own Name - P300) cognitive responses has disappeared. At his unique evaluation, Patient 2 was neither able to follow simple commands nor to control the BCI. Both patients had altered wakefulness, brain atrophy, and a global cortico-sub-cortical hypometabolism pattern compatible with a disorder of consciousness, regarded as an extreme form of an ALS-associated fronto-temporal dementia. While it is not possible to firmly demonstrate the absence of awareness, each independent measure concurred with suggesting that a degenerative disorder of consciousness rather than a cLIS might be the final stage of ALS. In future cass, this dramatic cognitive decline should be anticipated before communication disappears to enable precise advance directives regarding end-of-life issues in case complete, and neurophysiologically confirmed, unresponsiveness occurs. Altogether, the neuroimaging features distinguishing the mechanisms in this rare condition is a significant milestone to understand end-stage ALS. The present clinical study calls for further exploration of this terminal stage to determine the prevalence of this profile in whom communication seems hopeless. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement AO was funded by the Fondation pour la Recherche Medicale (FRM, ING20121226307). PS, JM, EM were funded by one grant from the Fondation pour la Recherche Medicale (FRM, FDM201906008524). JM, EM and PS were funded by ANR-17-CE40-0005, MindMadeClear & ANR-20-CE17-0023, ANR HiFi. PS was funded by Perce-Neige Fondation. The teams of the Lyon Neurocience Research Center are funded by the Labex cortex. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Hospices Civils de LYON CSE-HCL - IRB 00013204; Pr Cyrille Confavreux gave ethical approval for this work (approval N. 24-310). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript.

Alterations of serotonin type 4 receptor levels are linked to mood disorders and cognitive deficits in several conditions. However, few studies have investigated 5-HT4R alterations in movement disorders. We wondered whether striatal 5-HT4R expression is altered in experimental parkinsonism. We used a brain bank tissue from a rat and a macaque model of Parkinson's disease (PD). We then investigated its in vivo PET imaging regulation in a cohort of macaques. Dopaminergic depletion increases striatal 5-HT4R in the two models, further augmented after dyskinesia-inducing L-Dopa. Pending confirmation in PD patients, the 5-HT4R might offer a therapeutic target for dampening PD's symptoms.

Prone position decreases acute lung macrophage inflammation quantified in vivo with [11C](R)-PK11195 positron emission tomography in an experimental acute respiratory distress syndrome. Regional macrophage inflammation is maximal in the most anterior and posterior lung section of supine animals, in relation with increased regional tidal strain and hyperinflation, and reduced regional lung compliance.

The neurofunctional basis of the noradrenergic (NA) system and its associated disorders is still very incomplete because in vivo imaging tools in humans have been missing up to now. Here, for the first time, we use [11C]yohimbine in a large sample of subjects (46 healthy volunteers, 23 females, 23 males; aged 20–50) to perform direct quantification of regional alpha 2 adrenergic receptors’ (α2-ARs) availability in the living human brain. The global map shows the highest [11C]yohimbine binding in the hippocampus, the occipital lobe, the cingulate gyrus, and the frontal lobe. Moderate binding was found in the parietal lobe, thalamus, parahippocampus, insula, and temporal lobe. Low levels of binding were found in the basal ganglia, the amygdala, the cerebellum, and the raphe nucleus. Parcellation of the brain into anatomical subregions revealed important variations in [11C]yohimbine binding within most structures. Strong heterogeneity was found in the occipital lobe, the frontal lobe, and the basal ganglia, with substantial gender effects. Mapping the distribution of α2-ARs in the living human brain may prove useful not only for understanding the role of the NA system in many brain functions, but also for understanding neurodegenerative diseases in which altered NA transmission with specific loss of α2-ARs is suspected.

F13640 (a.k.a. befiradol, NLX-112) is a highly selective 5-HT1A receptor ligand that was selected as a PET radiopharmaceutical-candidate based on animal studies. Due to its high efficacy agonist properties, [18F]F13640 binds preferentially to functional 5-HT1A receptors, which are coupled to intracellular G-proteins. Here, we characterize brain labeling of 5-HT1A receptors by [18F]F13640 in humans and describe a simplified model for its quantification. PET/CT and PET-MRI scans were conducted in a total of 13 healthy male volunteers (29 ± 9 years old), with arterial input functions (AIF) (n = 9) and test–retest protocol (n = 8). Several kinetic models were compared (one tissue compartment model, two-tissue compartment model, and Logan); two models with reference region were also evaluated: simplified reference tissue model (SRTM) and the logan reference model (LREF). [18F]F13640 showed high uptake values in raphe nuclei and cortical regions. SRTM and LREF models showed a very high correlation with kinetic models using AIF. As concerns test–retest parameters and the prolonged binding kinetics of [18F]F13640, better reproducibility, and reliability were found with the LREF method. Cerebellum white matter and frontal lobe white matter stand out as suitable reference regions. The favorable brain labeling and kinetic profile of [18F]F13640, its high receptor specificity and its high efficacy agonist properties open new perspectives for studying functionally active 5-HT1A receptors, unlike previous radiopharmaceuticals that act as antagonists. [18F]F13640’s kinetic properties allow injection outside of the PET scanner with delayed acquisitions, facilitating the design of innovative longitudinal protocols in neurology and psychiatry. Trial Registration EudraCT 2017–002,722-21.

Reperfusion therapies in acute ischemic stroke have demonstrated their efficacy in promoting clinical recovery. However, ischemia/reperfusion injury and related inflammation remain a major challenge in patient clinical management. We evaluated the spatio-temporal evolution of inflammation using sequential clinical [11C]PK11195 PET-MRI in a non-human primate (NHP) stroke model mimicking endovascular thrombectomy (EVT) with a neuroprotective cyclosporine A (CsA) treatment. The NHP underwent a 110-min transient endovascular middle cerebral artery occlusion. We acquired [11C]PK11195 dynamic PET-MR imaging at baseline, 7 and 30 days after intervention. Individual voxel-wise analysis was performed thanks to a baseline scan database. We quantified [11C]PK11195 in anatomical regions and in lesioned areas defined on per-occlusion MR diffusion-weighted imaging and perfusion [15O2]H2OPET imaging. [11C]PK11195 parametric maps showed a clear uptake overlapping the lesion core at D7, which further increased at D30. Voxel-wise analysis identified individuals with significant inflammation at D30, with voxels located within the most severe diffusion reduction area during occlusion, mainly in the putamen. The quantitative analysis revealed that thalamic inflammation lasted until D30 and was significantly reduced in the CsA-treated group compared to the placebo. In conclusion, we showed that chronic inflammation matched ADC decrease at occlusion time, a region exposed to an initial burst of damage-associated molecular patterns, in an NHP stroke model mimicking EVT. We described secondary thalamic inflammation and the protective effect of CsA in this region. We propose that major ADC drop in the putamen during occlusion may identify individuals who could benefit from early personalized treatment targeting inflammation.

Imaging of acute lung inflammation is pivotal to evaluate innovative ventilation strategies. We aimed to develop and validate a three-tissue compartment kinetic model (3TCM) of [11C](R)-PK11195 lung uptake in experimental acute respiratory distress syndrome (ARDS) to help quantify macrophagic inflammation, while accounting for the impact of its non-specific and irreversible uptake in lung tissues. We analyzed the data of 38 positron emission tomography (PET) studies performed in 21 swine with or without experimental ARDS, receiving general anesthesia and mechanical ventilation. Model input function was a plasma, metabolite-corrected, image-derived input function measured in the main pulmonary artery. Regional lung analysis consisted in applying both the 3TCM and the two-tissue compartment model (2TCM); in each region, the best model was selected using a selection algorithm with a goodness-of-fit criterion. Regional best model binding potentials (BPND) were compared to lung macrophage presence, semi-quantified in pathology. The 3TCM was preferred in 142 lung regions (62%, 95% confidence interval: 56 to 69%). BPND determined by the 2TCM was significantly higher than the value computed with the 3TCM (overall median with interquartile range: 0.81 [0.44–1.33] vs. 0.60 [0.34–0.94], p < 0.02). Regional macrophage score was significantly associated with the best model BPND (p = 0.03). Regional BPND was significantly increased in the hyperinflated lung compartment, compared to the normally aerated one (median with interquartile range: 0.8 [0.6–1.7] vs. 0.6 [0.3–0.8], p = 0.03). To assess the intensity and spatial distribution of acute macrophagic lung inflammation in the context of experimental ARDS with mechanical ventilation, PET quantification of [11C](R)-PK11195 lung uptake was significantly improved in most lung regions using the 3TCM. This new methodology offers the opportunity to non-invasively evaluate innovative ventilatory strategies aiming at controlling acute lung inflammation.

Abstract Atherosclerosis is a chronic systemic inflammatory disease, inducing cardiovascular and cerebrovascular acute events. A role of neuroinflammation is suspected, but not yet investigated in the gyrencephalic brain and the related activity at blood−brain interfaces is unknown. A non-human primate model of advanced atherosclerosis was first established using longitudinal blood samples, multimodal imaging and gene analysis in aged animals. Non-human primate carotid lesions were compared with human carotid endarterectomy samples. During the whole-body imaging session, imaging of neuroinflammation and choroid plexus function was performed. Advanced plaques were present in multiple sites, premature deaths occurred and downstream lesions (myocardial fibrosis, lacunar stroke) were present in this model. Vascular lesions were similar to in humans: high plaque activity on PET and MRI imaging and systemic inflammation (high plasma C-reactive protein levels: 42 ± 14 µg/ml). We also found the same gene association (metabolic, inflammatory and anti-inflammatory markers) as in patients with similar histological features. Metabolic imaging localized abnormal brain glucose metabolism in the frontal cortex. It corresponded to cortical neuro-inflammation (PET imaging) that correlated with C-reactive protein level. Multimodal imaging also revealed pronounced choroid plexus function impairment in aging atherosclerotic non-human primates. In conclusion, multimodal whole-body inflammation exploration at the vascular level and blood−brain interfaces identified high-risk aging atherosclerosis. These results open the way for systemic and central inflammation targeting in atherosclerosis in the new era of immunotherapy.

BACKGROUND:Parkinson's disease (PD) is characterized by heterogeneous motor and nonmotor manifestations related to alterations in monoaminergic neurotransmission systems. Nevertheless, the characterization of concomitant dopaminergic and serotonergic dysfunction after different durations of Parkinson's disease, as well as their respective involvement in the expression and severity of neuropsychiatric signs, has gained little attention so far. METHODS:To fill this gap, we conducted a cross-sectional study combining clinical and dual-tracer positron emission tomography (PET) neuroimaging approaches, using radioligands of dopamine ([11 C]-N-(3-iodoprop-2E-enyl)-2-beta-carbomethoxy-3-beta-(4-methylphenyl)-nortropane) ([11 C]PE2I) and serotonin ([11 C]-N,N-dimethyl-2-(-2-amino-4-cyanophenylthio)-benzylamine) ([11 C]DASB) reuptake, after different durations of Parkinson's disease (ie, in short-disease duration drug-naive de novo (n = 27, 0-2 years-duration), suffering from apathy (n = 14) or not (n = 13); intermediate-disease duration (n = 15, 4-7 years-duration) and long-disease duration, non-demented (n = 15, 8-10 years-duration) patients). Fifteen age-matched healthy subjects were also enrolled. RESULTS:The main findings are threefold: (1) both dopaminergic and serotonergic lesions worsen with the duration of Parkinson's disease, spreading from midbrain/subcortical to cortical regions; (2) the presence of apathy at PD onset is associated with more severe cortical and subcortical serotonergic and dopaminergic disruption, similar to the denervation pattern observed in intermediate-disease duration patients; and (3) the severity of parkinsonian apathy, depression, and trait-anxiety appears primarily related to serotonergic alteration within corticostriatal limbic areas. CONCLUSIONS:Altogether, these findings highlight the prominent role of serotonergic degeneration in the expression of several neuropsychiatric symptoms occurring after different durations of Parkinson's disease. © 2021 International Parkinson and Movement Disorder Society.

Previous work introduced the [11C]yohimbine as a suitable ligand of central α2-adrenoreceptors (α2-ARs) for PET imaging. However, reproducibility of [11C]yohimbine PET measurements in healthy humans estimated with a simplified modeling method with reference region, as well as sensitivity of [11C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap.METHODS:Thirteen healthy humans underwent two [11C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested.RESULTS:We showed high test-retest reproducibility of DVR estimation with LREF and SRTM regardless of reference region (CC, CERWM, FLWM). The best fit was obtained with SRTMCC (r2=0.94). Test-retest showed that the SRTMCC is highly reproducible (mean ICC>0.7), with a slight bias (-1.8%), whereas SRTMCERWM had lower bias (-0.1%), and excellent ICC (mean>0.8). Using SRTMCC, regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis.CONCLUSION:The results add experimental support for the suitability of [11C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.

Previous studies have suggested the role of microcalcifications in plaque vulnerability. This exploratory study sought to assess the potential of hybrid positron-emission tomography (PET)/magnetic resonance imaging (MRI) using 18F-sodium fluoride (18F-NaF) to check simultaneously 18F-NaF uptake, a marker of microcalcifications, and morphological criteria of vulnerability. We included 12 patients with either recently symptomatic or asymptomatic carotid stenosis. All patients underwent 18F-NaF PET/MRI. 18F-NaF target-to-background ratio (TBR) was measured in culprit and nonculprit (including contralateral plaques of symptomatic patients) plaques as well as in other arterial walls. Morphological criteria of vulnerability were assessed on MRI. Mineral metabolism markers were also collected. 18F-NaF uptake was higher in culprit compared to nonculprit plaques (median TBR 2.6 [2.2-2.8] vs 1.7 [1.3-2.2]; P = 0.03) but was not associated with morphological criteria of vulnerability on MRI. We found a positive correlation between 18F-NaF uptake and calcium plaque volume and ratio but not with circulating tissue-nonspecific alkaline phosphatase (TNAP) activity and inorganic pyrophosphate (PPi) levels. 18F-NaF uptake in the other arterial walls did not differ between symptomatic and asymptomatic patients. 18F-NaF PET/MRI may be a promising tool for providing additional insights into the plaque vulnerability.

Purpose: The opioid system role in anorexia nervosa (AN) pathophysiology is still unclear since conflicting results were reported on peripheral and cerebrospinal fluid opioids levels. The study main aim was to evaluate cerebral AN opiate receptor availability by using [C-11] diprenorphine, a ligand with non-selective binding. Methods: In vivo [C-11] diprenorphine cerebral non-displaceable binding potential (BPND) evaluated by PET imaging was compared between three groups : 17 undernourished restrictive-type AN patients (LeanAN), 15 AN patients having regained normal weight (RecAN) and 15 controls. A lower BPND may account for an increased opioid tone and vice versa. Serum hormones and endogenous opioids levels, eating-related and unspecific psychological traits were also evaluated. Results: Compared to controls, LeanAN and RecAN patients had decreased [C-11]diprenorphine BPND in middle frontal gyrus, temporo-parietal cortices, anterior cingulate cortex and in left accumbens nucleus. Hypothalamopituitary (H-P), left amygdala and insula BPND was found decreased only in LeanAN and that of putamen only in RecAN. LeanAN presented higher dynorphin A and enkephalin serum levels than in controls or RecAN. Inverse correlations were found in total group between : 24 h mean serum cortisol levels and anterior cingulate gyrus or insula BPND; eating concern score and left amygdala BPND. Positive correlation were found between leptin and hypothamus BPND; LH and pituitary BPND. Conclusions: Low opiate receptor availability may be interpreted as an increased opioid tone in areas associated with both reward/aversive system in both AN groups. The relationship between the opioid receptors activity and hypercorticism or specific psychometric scores in some of these regions suggests adaptive mechanisms facing anxiety but also may play a role in the disease perpetuation.

In an acute ischaemic stroke, understanding the dynamics of blood-brain barrier injury is of particular importance for the prevention of symptomatic haemorrhagic transformation. However, the available techniques assessing blood-brain barrier permeability are not quantitative and are little used in the context of acute reperfusion therapy. Nanoparticles cross the healthy or impaired blood-brain barrier through combined passive and active processes. Imaging and quantifying their transfer rate could better characterize blood-brain barrier damage and refine the delivery of neuroprotective agents. We previously developed an original endovascular stroke model of acute ischaemic stroke treated by mechanical thrombectomy followed by positron emission tomography-magnetic resonance imaging. Cerebral capillary permeability was quantified for two molecule sizes: small clinical gadolinium Gd-DOTA (<1 nm) and AGuIX® nanoparticles (∼5 nm) used for brain theranostics. On dynamic contrast-enhanced magnetic resonance imaging, the baseline transfer constant K trans was 0.94 [0.48, 1.72] and 0.16 [0.08, 0.33] ×10-3 min-1, respectively, in the normal brain parenchyma, consistent with their respective sizes, and 1.90 [1.23, 3.95] and 2.86 [1.39, 4.52] ×10-3 min-1 in choroid plexus, confirming higher permeability than brain parenchyma. At early reperfusion, K trans for both Gd-DOTA and AGuIX® nanoparticles was significantly higher within the ischaemic area compared to the contralateral hemisphere; 2.23 [1.17, 4.13] and 0.82 [0.46, 1.87] ×10-3 min-1 for Gd-DOTA and AGuIX® nanoparticles, respectively. With AGuIX® nanoparticles, K trans also increased within the ischaemic growth areas, suggesting added value for AGuIX®. Finally, K trans was significantly lower in both the lesion and the choroid plexus in a drug-treated group (ciclosporin A, n = 7) compared to placebo (n = 5). K trans quantification with AGuIX® nanoparticles can monitor early blood-brain barrier damage and treatment effect in ischaemic stroke after reperfusion.

Stroke is a devastating disease. Endovascular mechanical thrombectomy is dramatically changing the management of acute ischemic stroke, raising new challenges regarding brain outcome and opening up new avenues for brain protection. In this context, relevant experiment models are required for testing new therapies and addressing important questions about infarct progression despite successful recanalization, reversibility of ischemic lesions, blood-brain barrier disruption and reperfusion damage. Here, we developed a minimally invasive non-human primate model of cerebral ischemia (Macaca fascicularis) based on an endovascular transient occlusion and recanalization of the middle cerebral artery (MCA). We evaluated per-occlusion and post-recanalization impairment on PET-MRI, in addition to acute and chronic neuro-functional assessment. Voxel-based analyses between per-occlusion PET-MRI and day-7 MRI showed two different patterns of lesion evolution: "symptomatic salvaged tissue" (SST) and "asymptomatic infarcted tissue" (AIT). Extended SST was present in all cases. AIT, remote from the area at risk, represented 45% of the final lesion. This model also expresses both worsening of fine motor skills and dysexecutive behavior over the chronic post-stroke period, a result in agreement with cortical-subcortical lesions. We thus fully characterized an original translational model of ischemia-reperfusion damage after stroke, with consistent ischemia time, and thrombus retrieval for effective recanalization.

Rationale: Renal positron emission tomography (PET) functional imaging allows non-invasive and dynamic measurements of functional and metabolic parameters. [O-15]H2O is used as a perfusion tracer, and [C-11]acetate as an oxidative metabolism in this purpose, requiring two injections to assess those fundamental parameters. Yet, in cardiac physiology study, the high first-pass myocardial extraction fraction of [C-11]acetate allowed to use its influx rate as a blood flow marker too. Since [C-11]acetate has been characterized by a 20-25% single pass renal extraction in dogs, it could be used as a potential tracer for renal perfusion. The aim of this study was to determine whether [C-11]acetate influx rate can be used as quantitative in vivo marker of kidney perfusion in human. Methods: In 10 healthy subjects, dynamic PET acquisitions were performed after [O-15]H2O and [C-11]acetate injections spaced by a 15-minute interval. As previously validated, with compartmental modeling of kinetics, renal perfusion and oxidative metabolism were estimated respectively with influx rate of [O-15]H2O and efflux rate of [C-11]acetate. Additionally, influx rate of [C-11]acetate was regressed to influx rate of [O-15]H2O. Results: Renal time activity curves of [C-11]-acetate was best fitted with a mono compartmental model compared to a bi-compartmental model (p < 0.0001). [C-11]acetate influx rate was significantly correlated with perfusion quantified with [O-15]H2O (r(2) = 0.37, p < 0.001) at baseline. This regression allowed the computation of a renal [C-11]acetate extraction fraction (EF), and further the computation of renal blood flow from its influx rate. Conclusion: In healthy subjects, over a wide range of renal perfusion, direct estimates of renal oxygen consumption as well as tissue perfusion can be obtained by PET with a single tracer [C-11]acetate. This approach needs to be validated in CKD patients, and would be of great interest to design clinical protocol aiming at evaluating ischemic nephropathies candidate to revascularization. (C) 2019 Elsevier Inc. All rights reserved.

Macrophagic lung infiltration is pivotal in the development of lung biotrauma because of ventilation-induced lung injury (VILI). We assessed the performance of [11C](R)-PK11195, a positron emission tomography (PET) radiotracer binding the translocator protein, to quantify macrophage lung recruitment during experimental VILI. Pigs ( n = 6) were mechanically ventilated under general anesthesia, using protective ventilation settings (baseline). Experimental VILI was performed by titrating tidal volume to reach a transpulmonary end-inspiratory pressure (∆PL) of 35–40 cmH2O. We acquired PET/computed tomography (CT) lung images at baseline and after 4 h of VILI. Lung macrophages were quantified in vivo by the standardized uptake value (SUV) of [11C](R)-PK11195 measured in PET on the whole lung and in six lung regions and ex vivo on lung pathology at the end of experiment. Lung mechanics were extracted from CT images to assess their association with the PET signal. ∆PL increased from 9 ± 1 cmH2O under protective ventilation, to 36 ± 6 cmH2O during experimental VILI. Compared with baseline, whole-lung [11C](R)-PK11195 SUV significantly increased from 1.8 ± 0.5 to 2.9 ± 0.5 after experimental VILI. Regional [11C](R)-PK11195 SUV was positively associated with the magnitude of macrophage recruitment in pathology ( P = 0.03). Compared with baseline, whole-lung CT-derived dynamic strain and tidal hyperinflation increased significantly after experimental VILI, from 0.6 ± 0 to 2.0 ± 0.4, and 1 ± 1 to 43 ± 19%, respectively. On multivariate analysis, both were significantly associated with regional [11C](R)-PK11195 SUV. [11C](R)-PK11195 lung uptake (a proxy of lung inflammation) was increased by experimental VILI and was associated with the magnitude of dynamic strain and tidal hyperinflation. NEW & NOTEWORTHY We assessed the performance of [11C](R)-PK11195, a translocator protein-specific positron emission tomography (PET) radiotracer, to quantify macrophage lung recruitment during experimental ventilation-induced lung injury (VILI). In this proof-of-concept study, we showed that the in vivo quantification of [11C](R)-PK11195 lung uptake in PET reflected the magnitude of macrophage lung recruitment after VILI. Furthermore, increased [11C](R)-PK11195 lung uptake was associated with harmful levels of dynamic strain and tidal hyperinflation applied to the lungs.