IntroductionTraumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. A growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post-traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts. We hypothesise that repeated intravenous treatment with mesenchymal stromal cells derived from Wharton’s Jelly of the umbilical cord-derived mesenchymal stromal cells ((WJ-UC-MSC) may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neurological status.Methods and analysisThe TRAUMACELL trial is a prospective, national multicentre, phase III, superiority, double-arm comparative randomised (1:1) double-blinded clinical trial. Among patients aged between 18–50, with a severe TBI defined by a Glasgow score less than 12 (within the first 48 hours) with brain traumatic lesion on CT Scan and needing intracranial pressure monitoring, with no other significant organ trauma (abbreviated injury scale<2) and unresponsive to verbal commands after 5 days of sedation discontinuation, 68 will be randomly allocated to receive either WJ-UC-MSC solution or placebo, with three intravenous injections 1 week apart. The primary outcome is the [18F]-DPA-714 signal intensity in corpus callosum measured by dynamic positron emission tomography (PET)-MRI at 6 months after the last injection, blinded to the randomisation arm, to evaluate the post-traumatic neuro-inflammation.Ethics and disseminationThe TRAUMACELL trial has been approved by an independent ethics committee (CPP SUD EST II) and French Medicines Agency (2023-504415-33-00) for all study centres. Participant recruitment will be starting in September 2024. Results will be published in international peer-reviewed medical journals.Trial registration numberNCT06146062, first posted 24 November 2023Protocol version identifierTRAUMACELL−V.2.0_20240102

BACKGROUND:The locus coeruleus (LC) and the nucleus basalis of Meynert (NBM) are altered in early stages of Alzheimer's disease (AD). Little is known about LC and NBM alteration in limbic-predominant age-related TDP-43 encephalopathy (LATE) and frontotemporal dementia (FTD). The aim of the present study is to investigate in vivo LC and NBM integrity in patients with suspected-LATE, early-amnestic AD and FTD in comparison with controls. METHODS:Seventy-two participants (23 early amnestic-AD patients, 17 suspected-LATE, 17 FTD patients, defined by a clinical-biological diagnosis reinforced by amyloid and tau PET imaging, and 15 controls) underwent neuropsychological assessment and 3T brain MRI. We analyzed the locus coeruleus signal intensity (LC-I) and the NBM volume as well as their relation with cognition and with medial temporal/cortical atrophy. RESULTS:We found significantly lower LC-I and NBM volume in amnestic-AD and suspected-LATE in comparison with controls. In FTD, we also observed lower NBM volume but a slightly less marked alteration of the LC-I, independently of the temporal or frontal phenotype. NBM volume was correlated with the global cognitive efficiency in AD patients. Strong correlations were found between NBM volume and that of medial temporal structures, particularly the amygdala in both AD and FTD patients. CONCLUSIONS:The alteration of LC and NBM in amnestic-AD, presumed-LATE and FTD suggests a common vulnerability of these structures to different proteinopathies. Targeting the noradrenergic and cholinergic systems could be effective therapeutic strategies in LATE and FTD.

We aimed to assess the effect of concomitant medication, age, sex, body mass index and 18-kDa translocator protein (TSPO) binding affinity status on the metabolism and plasma pharmacokinetics of [18F]DPA-714 and their influence on the plasma input function in a large cohort of 201 subjects who underwent brain and whole-body PET imaging to investigate the role of neuroinflammation in neurological diseases. The non-metabolized fraction of [18F]DPA-714 was estimated in venous plasma of 138 patients and 63 healthy controls (HCs; including additional arterial sampling in 16 subjects) during the 90 min brain PET acquisition using a direct solid-phase extraction method. The mean fraction between 70 and 90 min post-injection ([18F]DPA-71470–90) and corresponding normalized plasma concentration (SUV70-90) were correlated with all factors using a multiple linear regression model. Differences between groups (arterial vs venous measurements; HCs vs patients; high- (HAB), mixed- (MAB) and low-affinity binders (LAB); subjects with vs without co-medications, females vs males were also assessed using the non-parametric Mann–Whitney or Kruskal–Wallis ANOVA tests. Finally, the impact of co-medications on the brain uptake of [18F]DPA-714 at equilibrium was investigated. As no significant differences were observed between arterial and venous [18F]DPA-71470–90 and SUV70-90, venous plasma was used for correlations. [18F]DPA-71470–90 was not significantly different between patients and HCS (59.7 ± 12.3

Background Monitoring the progression of Tau pathology makes it possible to study the clinical diversity of Alzheimer’s disease. In this 2-year longitudinal PET study, we aimed to determine the progression of [ 18 F]-flortaucipir binding and of cortical atrophy, and their relationships with cognitive decline. Methods Twenty-seven AD patients at the mild cognitive impairment/mild dementia stages and twelve amyloid-negative controls underwent a neuropsychological assessment, 3 T brain MRI, and [ 18 F]-flortaucipir PET imaging (Tau1) and were monitored annually over 2 years with a second brain MRI and tau-PET imaging after 2 years (Tau2). We analyzed the progression of tau standardized uptake value ratio (SUVr) and grey matter atrophy both at the regional and voxelwise levels. We used mixed effects models to explore the relations between the progression of SUVr values, cortical atrophy, and cognitive decline. Results We found an average longitudinal increase in tau SUVr values, except for the lateral temporoparietal cortex where the average SUVr values decreased. Individual analyses revealed distinct profiles of SUVr progression according to temporoparietal Tau1 uptake: high-Tau1 patients demonstrated an increase in SUVr values over time in the frontal lobe, but a decrease in the temporoparietal cortex and a rapid clinical decline, while low-Tau1 patients displayed an increase in SUVr values in all cortical regions and a slower clinical decline. Cognitive decline was strongly associated with the progression of regional cortical atrophy, but only weakly associated with SUVr progression. Conclusions Despite a relatively small sample size, our results suggest that tau-PET imaging could identify patients with a potentially “more aggressive” clinical course characterized by high temporoparietal Tau1 SUVr values and a rapid clinical progression. In these patients, the paradoxical decrease in temporoparietal SUVr values over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. They could particularly benefit from future therapeutic trials, the neuroimaging outcome measures of which deserve to be discussed.

Positron emission tomography (PET) imaging enables the in vivo detection of amyloid and tau pathologies. The longitudinal progression of [ 18 F]-flortaucipir PET imaging could be of interest to better understand the spatial and temporal relationships between tauopathy, cortical atrophy, and the cognitive decline. We explored the longitudinal progression of the tau radiotracer binding and of cortical atrophy over 2 years in a cohort of 27 prodromal/mild AD patients (positive CSF biomarkers and amyloid-PET) compared with twelve amyloid-negative controls. All subjects underwent a complete neuropsychological assessment, 3T brain MRI, [ 11 C]-PiB and [ 18 F]-flortaucipir PET imaging (Tau1), and were monitored annually over 2 years, with a second brain MRI and tau PET imaging (Tau2) after 2 years. We studied the longitudinal progression of tau radiotracer binding (Tau2-Tau1) in AD patients and used mixed effects models to explore the relations between the progression of tau binding or cortical atrophy and cognitive decline. We found an average longitudinal increase in tau radiotracer binding in most cortical regions, especially in the frontal cortex, but an average decrease in the lateral temporoparietal cortex. In this region, individual analyses revealed two distinct evolutions of tau radiotracer binding according to Tau1 uptake: low-Tau1 AD patients (SUVr<1.6) demonstrated an increase in tau radiotracer uptake in all cortical regions and a slow clinical progression, whereas high-Tau1 patients demonstrated a paradoxical plateauing or decrease of tau tracer uptake in the temporoparietal cortex and a faster clinical progression. Cognitive decline was weakly associated with Tau2-Tau1, but strongly associated with the regional cortical atrophy progression. Our results suggest that tau PET imaging could detect patients with a “more aggressive” biological form of AD characterized by high temporo-parietal Tau1 binding. In these patients, the decrease of temporo-parietal tau tracer binding over time could be due to the rapid transition to ghost tangles, for which the affinity of the radiotracer is lower. This information may be considered to improve the design of clinical trials and the definition of the neuroimaging outcomes (choice of the tau-PET regions of interest, consideration of the evolution of cortical atrophy as a reliable reflection of the clinical progression).

OBJECTIVE:To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa-translocator-protein-positron emission tomography (PET) -based classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years.METHODS:Thirty-six people with MS (disease duration 9 ± 6 years; 12 with relapsing-remitting, 13 with secondary-progressive, and 11 with primary-progressive) and 19 healthy controls (HCs) underwent a dynamic [18 F]-DPA-714-PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of [18 F]-DPA-714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim-active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration.RESULTS:Patients with MS had higher innate inflammation in normal-appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non-gadolinium-enhancing lesions, 53% were classified as homogeneously-active (median = 17 per patient with MS), 6% rim-active (median = 1 per patient with MS), and 41% non-active (median = 14 per patient with MS). The number of homogenously-active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (β = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (β = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes.INTERPRETATION:The [18 F]-DPA-714-PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366-383.

La demande en radiopharmaceutiques pour la recherche translationnelle en imagerie, ainsi que pour la médecine de précision, ne cesse de croître. Le SHFJ dispose d’une nouvelle plateforme de fabrication de MRPexp, CaOR, afin de répondre à cette demande. La plateforme CaOR est équipé de deux automates All-in-One Trasis® pour le radiomarquage au fluor-18 et deux automates C11-pro2 IPhase® pour le radiomarquage au carbone-11, installés dans des enceintes blindées, situées dans une salle blanche afin de travailler dans des conditions d’hygiène et de radioprotection appropriées. La plateforme possède également un laboratoire de contrôle qualité radiophysico-chimique et microbiologique. Les MRPexp produits sont distribués à des partenaires académiques, hospitaliers et industriels. CaOR dispose de 2,5 équivalents temps-plein (ETP) pharmaciens et 3 ETP techniciens pour une production d’une centaine de MRPexp la première année (2022). Tous les lots produits en 2022 ont été conformes. Le portefeuille comporte 7 MRPexp marqués au 18F : [18F]DPA-714, [18F]AV1451, [18F]MK6240, [18F]Fludarabine, [18F]LBT-999, [18F]MNI659 et [18F]RO948 (rendements moyens corrigés de la décroissance de 30,8 ± 16,6 %) avec une activité molaire (Am) moyenne de 199,2 ± 144,7 GBq/μmol (à fin de d’irradiation EOB) et de 4 MRPe marqués au 11C : [11C]PIB, [11C]Métoclopramide, [11C]Flumazénil et [11C]UCBJ (rendements moyens corrigés de la décroissance de 29,7 ± 20,5 %) avec une Am moyenne de 108,6 ± 41,0 GBq/μmol EOB. La production de MRPexp couvre actuellement 17 protocoles d’essais cliniques pour des patients inclus au SHFJ et dans les hôpitaux partenaires. CaOR, dont la mise en place a été un défi technique et humain, est aujourd’hui en mesure de répondre à la demande croissante de MRPexp originaux et de nouvelles molécules enrichiront le portefeuille dans les mois à venir.

Neuropathological studies have shown alterations in both locus coeruleus (LC) and basal forebrain in frontotemporal degeneration (FTD) and corticobasal syndrome (CBS) particularly in progressive supranuclear palsy (PSP). We aimed to investigate in vivo the LC and nucleus basalis of Meynert (NBM) integrity in patients with FTD and CBS. We compared the LC signal intensity (LC-I), which reflects the LC integrity, and the NBM volume on 3T MRI in i) FTD patients (n = 17) ii) CBS patients (n = 8;) iii) prodromal/mild AD (n = 34) and iv) amyloid-negative controls (n = 15). PiB-PET and/or AD CSF biomarkers were negative in all FTD and CBS patients, and positive in all AD patients. All subjects underwent a complete neuropsychological assessment and 3T brain MRI performed on the same scan. The four groups were age-matched. The MMSE score did not differ significantly between the 3 groups of patients. Compared to controls, LC-I and NBM volume were significantly decreased in FTD (p = 0.05 and 0.00015, respectively) and AD patients (p = 0.0005 and 0.002, respectively). LC-I and NBM volume were also decreased in CBS in comparison with controls but the difference was not statistically significant. In addition, we found no statistically significant difference in LC-I and NBM volume between the three groups of patients. We observed no correlation between LC-I or NBM volume and amyloid load, either when considering the whole group of patients or AD and FTD/CBS patients separately. Our results are in line with neuropathological data and suggest that both cholinergic and noradrenergic systems are altered in AD and FTD. Post mortem data have suggested that, in FTD, both structures were more impaired in tau than in TDP-43 proteinopathy, which cannot be explored in our study. In CBS, our results are less clear-cut, probably due to the small sample size. Taken together, our data support the pathophysiological model in which both LC and NBM play a critical role not only in AD but also in other diseases and proteinopathies like FTD.

La maladie d'Alzheimer (MA) est caractérisée par l'accumulation anormale dans le cerveau des protéines tau et amyloïde et est souvent révélée par des troubles de la mémoire. Cependant, ceux-ci peuvent aussi se rencontrer dans d'autres maladies et conduire à des diagnostics par excès. L'objectif de l'étude est de définir l'apport de l'imagerie moléculaire par TEP pour le diagnostic étiologique chez des patients amnésiques bien caractérisés. Trente-six patients consultant pour un syndrome amnésique progressif évocateur de maladie d'Alzheimer ainsi que trente sujets sains ont été inclus dans l'étude. Tous les sujets ont bénéficié d'un bilan neuropsychologique et de neuro-imagerie : IRM à 3 T (atrophie) et deux examens TEP : [11 C]-PIB (332 ± 61 MBq ; dépôts amyloïdes) et [18F]-Flortaucipir (376 ± 21 MBq ; protéine tau) réalisés sur un tomographe à haute résolution (HRRT ; Siemens). Les sujets ont bénéficié d'un suivi clinique et IRM à 2 ans ainsi que d'une seconde TEP Tau (n = 20). La signature moléculaire de la MA était définie par une rétention amyloïde corticale positive (PIB index > 1,45) et une TEP tau positive dans les régions temporales médianes (z-score > 1,96). Les patients ne remplissant pas ces critères étant considérés comme présentant une pathologie non-MA. Selon ces critères, 21/36 patients ont été classés comme MA (PIB index : 2,9 ± 0,6 ; Tau 1,8 ± 0,7) et 15 comme non-MA (PIB index : 1,3 ± 0,2 ; Tau 1,2 ± 0,1). Les déficits neuropsychologiques et l'atrophie des hippocampes étaient similaires dans les deux groupes. Parmi les patients non-MA : 3 avaient une fixation PIB élevée mais pas de fixation Tau et 5 avaient une fixation Tau circonscrite au cortex entorhinal ou à l'amygdale mais étaient PIB négatifs. Le suivi longitudinal a montré une évolution plus importante du déclin cognitif et de l'atrophie temporale médiane dans le groupe MA vs non-MA. De même, à 2 ans, la fixation du traceur tau a augmenté chez les patients MA. (n = 12), mais est restée stable chez les non-MA. (n = 8). Le couplage de l'imagerie TEP amyloïde et tau a permis d'affiner le diagnostic étiologique chez des patients présentant des troubles mnésiques évocateurs de MA, pour lesquels cette maladie a néanmoins été éliminée chez environ 40 % d'entre eux. Chez les patients non-MA, l'imagerie TEP-tau a parfois permis de détecter une possible tauopathie limitée aux lobes temporaux médians, qui pourrait correspondre à une tauopathie primaire liée à l'âge.

La buprénorphine est un agoniste partiel des récepteurs opioïdes μ, utilisé dans l’antalgie ou comme substitut dans l’addiction aux opiacés. L’imagerie PET permet l’étude non-invasive de sa biodistribution et de sa pharmacocinétique cérébrale et tissulaire. Nous présentons ici la première administration à l’homme de la 11C-buprénorphine chez des volontaires sains dans le cadre d’un essai clinique (EudraCT n°2017-001897-41). La buprénorphine (qualité pharmaceutique) a été obtenue par radiomarquage au carbone 11 en position O-méthyl. 3 sujets sains (hommes, âge moyen = 27 ans) ont reçu un bolus iv de 11C-buprénorphine (208 ± 72 MBq) puis subit une imagerie corps entier de 90 min sur TEP-IRM. GE Signa. La reconstruction permit d’obtenir des images TEP dynamiques superposées à l’IRM (séquences de 2 à 16 min). Les courbes temps-activités d’organes cibles (corrigées de la décroissance) ont été déterminées à partir des volumes d’intérêt issus du logiciel Pmod. La concentration radioactive par organe est exprimée en pourcentage de la dose injectée par volume ( %ID.cm-3 ± écart-type). Les sites majeurs de biodistribution étaient le foie (0,0108 ± 0,0040 %ID.cm-3), la vésicule et les canaux biliaires (0,1652 ± 0,1873 %ID cm3) en accord avec le métabolisme hépatique connu de la buprénorphine. Les séquences tardives montraient une sécrétion duodénale évoluant vers le jéjunum. Peu de radioactivité a été observée au niveau urinaire (dernière séquence 0,0353 ± 0,0184 %ID cm-3) suggérant une faible élimination par ce biais. la distribution cérébrale était importante et cohérente avec la localisation connue des récepteurs μ. Une discrète fixation myocardique (0,0021 ± 0,0002 %ID cm3) fut également observée. Aucun volontaire n’a rapporté d’effet indésirable. Cette étude first-in-man d’imagerie TEP-IRM de la 11C-buprénorphine a permis d’observer la biodistribution et est cohérente avec son profil pharmacocinétique. La fixation cérébrale est également jugée satisfaisante pour l’imagerie des récepteurs opioïdes μ et témoigne d’une sécurité d’utilisation appropriée. la localisation myocardique de la buprénorphine est possiblement liée à l’expression de récepteurs opioïdes impliqués dans la régulation cardiovasculaire et la résistance myocardique au stress [1]. De futures études pourront être menées pour étudier les récepteurs aux opiacées hors du système nerveux central.

ObjectivesTo explore whether regional tau binding measured at baseline is associated with the rapidity of Alzheimer’s disease (AD) progression over 2 years, as assessed by the decline in specified cognitive domains, and the progression of regional brain atrophy, in comparison with amyloid-positron emission tomography (PET), MRI and cerebrospinal fluid (CSF) biomarkers.MethodsThirty-six patients with AD (positive CSF biomarkers and amyloid-PET) and 15 controls underwent a complete neuropsychological assessment, 3T brain MRI, [11C]-PiB and [18F]-flortaucipir PET imaging, and were monitored annually over 2 years, with a second brain MRI after 2 years. We used mixed effects models to explore the relations between tau-PET, amyloid-PET, CSF biomarkers and MRI at baseline and cognitive decline and the progression of brain atrophy over 2 years in patients with AD.ResultsBaseline tau-PET was strongly associated with the subsequent cognitive decline in regions that are usually associated with each cognitive domain. No significant relationship was observed between the cognitive decline and initial amyloid load, regional cortical atrophy or CSF biomarkers. Baseline tau tracer binding in the superior temporal gyrus was associated with subsequent atrophy in an inferomedial temporal volume of interest, as was the voxelwise tau tracer binding with subsequent cortical atrophy in the superior temporal, parietal and frontal association cortices.ConclusionsThese results suggest that tau tracer binding is predictive of cognitive decline in AD in domain-specific brain areas, which provides important insights into the interaction between tau burden and neurodegeneration, and is of the utmost importance to develop new prognostic markers that will help improve the design of therapeutic trials.

Organic Anion-Transporting Polypeptides (OATPs) are known to control the liver uptake of many drugs. Non-hepatic expression of OATPs has been reported although functional importance for whole-body pharmacokinetics (WBPK) remains unknown. Glyburide is a well described substrate of several hepatic and non-hepatic OATPs. Dynamic whole-body positron emission tomography (DWB-PET) with [11C]glyburide was performed in humans for determination of the importance of OATPs for liver uptake and WBPK. Seven healthy male subjects (24.7 ± 3.2 years) underwent [11C]glyburide PET scan with concomitant blood sampling. All subjects underwent baseline [11C]glyburide PET scan. Five subjects underwent a subsequent [11C]glyburide PET scan after infusion of the potent OATP inhibitor rifampicin (9 mg/kg i.v.). The transfer constant (kuptake) of [11C]glyburide from blood to the liver was estimated using the integration plot method. The tissue exposure of [11C]glyburide was described by the area under the time-activity curve (AUC) and corresponding tissue/blood ratio (AUCR). [11C]glyburide was barely metabolized in both the baseline and rifampicin conditions. Parent (unmetabolized) [11C]glyburide accounted for > 90 % of the plasma radioactivity. Excellent correlation was found between radioactive counting in arterial blood samples and in the image-derived input function, in both the baseline and rifampicin conditions (R2 = 97.9 %, p < 0.01). [11C]glyburide predominantly accumulated in the liver. Rifampicin decreased liver kuptake by 77.3 ± 7.3 %, which increased exposure in blood, kidneys, spleen, myocardium and brain (p < 0.05). No significant change in AUCR was observed except in the liver (p < 0.01). [11C]glyburide benefits from metabolic stability and high sensitivity to OATP inhibition which enables quantitative determination of OATP function. DWB-PET suggests negligible role for non-hepatic OATPs in controlling the tissue distribution of [11C]glyburide.

BACKGROUND AND PURPOSE:Lesion remyelination preserves axonal integrity in animal models of multiple sclerosis (MS), but an in vivo demonstration of its protective effect on surrounding tissues in humans is lacking.METHODS:Nineteen persons with MS were enrolled in a cohort study and underwent two positron emission tomography (PET)/magnetic resonance imaging (MRI) scans 1-4 months apart. Voxelwise maps of Pittsburgh compound B distribution volume ratio, reflecting myelin content, were used to calculate an index of baseline demyelination, and of dynamic demyelination and remyelination over the follow-up in 549 single white matter lesions. Changes in fractional anisotropy and mean diffusivity, reflecting microstructural damage, were calculated in the proximal and distal 3-mm-thick rings surrounding each lesion, and used to classify perilesional microstructure as "preserved" or "worsening" over the follow-up. Mixed-effect linear models and logistic regressions were employed to investigate whether PET-derived lesional indices were associated with changes in MRI metrics in perilesions, and to identify which of them best predicted the microstructural evolution of perilesions over time.RESULTS:A higher index of remyelination, and a lower index of baseline and dynamic demyelination in lesions were associated with a less severe microstructural deterioration of the corresponding proximal and distal perilesions over time (p-value range: <0.001-0.012), but the index of remyelination was the best predicting variable of perilesional fate. For every extra 1% of remyelination within each lesion, the probability of the corresponding perilesional microstructure remaining preserved over time increased by 39% (odds ratio = 6.62, 95% confidence interval = 2.16-20.32, p < 0.001).CONCLUSIONS:Intralesional remyelination is associated with the microstructural preservation of surrounding tissues, possibly preventing neuroaxonal damage resulting from Wallerian degeneration.

Introduction: Increasing evidence suggests that neuroinflammation is active in Parkinson disease (PD) and contributes to neurodegeneration. This process can be studied in vivo with PET and radioligands targeting TSPO, upregulated in activated microglia. Initial PET studies investigating microglial activation in PD with the [C-11]PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [F-18]-DPA714 and to correlate imaging biomarkers to dopamine transporter imaging and clinical status. Methods: PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [F-18]-DPA714 and [C-11]-PE2I and analyzed. They were all genotyped for TSPO polymorphism. Regional binding parameters were estimated (reference Logan graphical approach with supervised cluster analysis). Impact of TSPO genotype was analyzed using Wilcoxon signed-rank test. Differences between groups were investigated using a two-way ANOVA and Tukey post hoc tests. Results: PD patients showed significantly higher [F-18]-DPA714 binding compared to healthy controls bilaterally in the midbrain (p < 0.001), the frontal cortex (p = 0.001), and the putamen contralateral to the more clinically affected hemibody (p = 0.038). Microglial activation in these regions did not correlate with the severity of motor symptoms, disease duration nor putaminal [C-11]-PE2I uptake. However, there was a trend toward a correlation between cortical TSPO binding and disease duration (p = 0.015 uncorrected, p = 0.07 after Bonferroni correction). Conclusion: [F-18]-DPA714 binding confirmed that there is a specific topographic pattern of microglial activation in the nigro-striatal pathway and the frontal cortex of PD patients.

We aimed to investigate the amyloid and tau PET imaging signatures of patients with amnestic syndrome of the hippocampal type (ASHT) and study their clinical and imaging progression according to their initial PET imaging status. Thirty-six patients with a progressive ASHT and 30 controls underwent a complete neuropsychological assessment, 3 T brain MRI, [11C]-PiB and [18F]-Flortaucipir PET imaging. Subjects were clinically followed-up annually over 2 years, with a second 3 T MRI (n = 27 ASHT patients, n = 28 controls) and tau-PET (n = 20 ASHT patients) at the last visit. At baseline, in accordance with the recent biological definition of Alzheimer’s disease (AD), the AD PET signature was defined as the combination of (i) positive cortical amyloid load, and (ii) increased tau tracer binding in the entorhinal cortices and at least one of the following regions: amygdala, parahippocampal gyri, fusiform gyri. Patients who did not meet these criteria were considered to have a non-AD pathology (SNAP). Twenty-one patients were classified as AD and 15 as SNAP. We found a circumscribed tau tracer retention in the entorhinal cortices and/or amygdala in 5 amyloid-negative SNAP patients. At baseline, the SNAP patients were older and had lower ApoE ε4 allele frequency than the AD patients, but both groups did not differ regarding the neuropsychological testing and medial temporal lobe atrophy. During the 2-year follow-up, the episodic memory and language decline, as well as the temporo-parietal atrophy progression, were more pronounced in the AD sub-group, while the SNAP patients had a more pronounced progression of atrophy in the frontal lobes. Longitudinal tau tracer binding increased in AD patients but remained stable in SNAP patients. At baseline, distinct amyloid and tau PET signatures differentiated early AD and SNAP patients despite identical cognitive profiles characterized by an isolated ASHT and a similar degree of medial temporal atrophy. During the longitudinal follow-up, AD and SNAP patients diverged regarding clinical and imaging progression. Among SNAP patients, tau PET imaging could detect a tauopathy restricted to the medial temporal lobes, which was possibly explained by primary age-related tauopathy.

Background Choroid plexuses (CPs) have been suggested as a key gateway for inflammation in experimental autoimmune encephalitis, but in vivo evidence of their involvement in multiple sclerosis (MS) is lacking. Purpose To assess CP volumetric and inflammatory changes in patients with MS versus healthy control participants. Materials and Methods This was a secondary analysis of 97 patients (61 with relapsing-remitting MS [RRMS] and 36 with progressive MS) and 44 healthy control participants who participated in three prospective 3.0-T brain MRI studies between May 2009 and September 2017. A subgroup of 37 patients and 19 healthy control participants also underwent translocator protein fluorine 18 (18F)-DPA-714 PET for neuroinflammation. Relapses and disability scores were collected at baseline and over 2 years. CPs were manually segmented on three-dimensional T1-weighted images; other brain volumes were additionally segmented. Volumes were expressed as a ratio of intracranial volume. The 18F-DPA-714 distribution volume ratio was quantified in parenchymal regions, whereas standardized uptake value was used for CP inflammation. Multivariable linear regression analyses were performed to assess CP volumetric and inflammatory differences between patients with MS and healthy control participants and correlations between CP volume and lesion load, brain volumes, 18F-DPA-714 uptake, and annualized relapse rate. Results Ninety-seven patients with MS (mean age, 42 years ± 12 [standard deviation]; 49 women) and 44 healthy control participants (mean age, 39 years ± 14; 23 women) underwent MRI. Thirty-seven patients with MS and 19 healthy control participants underwent PET. CPs were 35% larger in patients with MS (mean value, 15.9 × 10-4 ± 4.5) than in healthy control participants (mean value, 11.8 × 10-4 ± 3.8; P = .004). Subgroup analysis confirmed greater CP volume in patients with RRMS (mean value, 15.5 × 10-4 ± 4.6; P = .008) than in healthy control participants. CP enlargement was greater in patients with active lesions at MRI (mean volume, 18.2 × 10-4 ± 4.9 in patients with lesions that enhanced with gadolinium vs 14.9 × 10-4 ± 4 in patients with lesions that did not enhance with gadolinium; P < .001) and correlated with white matter lesion load (r = 0.39; 95% CI: 0.20, 0.55; P < .001) and 18F-DPA-714 binding in the thalami (r = 0.44; 95% CI: 0.22, 0.72; P = .04) and normal-appearing white matter (r = 0.5; 95% CI: 0.20, 0.71; P = .005). Moreover, it correlated with annualized relapse rate in patients with RRMS (r = 0.37; 95% CI: 0.1, 0.55; P = .005). Finally, patients with MS showed 18.5% higher CP 18F-DPA-714 uptake than control participants (mean value, 0.778 ± 0.23 vs 0.635 ± 0.15, respectively; P = .01). CP volume in patients with RRMS (r = 0.57; 95% CI: 0.37, 0.73; P = .009) correlated with higher 18F-DPA-714 uptake. Conclusion Choroid plexuses (CPs) are enlarged and inflamed in patients with multiple sclerosis (MS), particularly in those with relapsing-remitting MS with inflammatory profiles; CP volumetric analysis could represent an MS imaging marker. © RSNA, 2021 EudraCT no. 2008-004174-40; clinical trial registration nos. NCT02305264 and NCT01651520 Online supplemental material is available for this article.

Introduction: Glyburide is an approved anti-diabetes drug binding to the sulfonylurea receptors-1 (SUR-1) and substrate of solute carrier (SLC) transporters, which can be isotopically rad iolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [C-11]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [C-11]glyburide in PET imaging clinical trials. Methods: Different conditions were explored to afford non-radioactive glyburide by one or two-step methylation. These experiments were monitored by UPLC-MS. The optimized process was applied to the automated radiosynthesis of [C-11]glyburide using a TRACERIab (R) FX C Pro. A complete quality control according to Pharmacopeia guidelines was realized. Results: One-step methylation revealed regioselectivity issues as methylation occurred preferentially on the sulfonylurea moiety. Two-step approach by methylation followed by reaction with cyclohexyl isocyanate afforded glyburide without formation of methylated side products. Ready-to-inject [C-11]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 +/- 20 GBq/mu mol molar activity within 40 min (n = 8). [C-11] Glyburide quality control was compliant with the Pharmacopeia requirements. Conclusions: We have described a highly reproducible and automated two-step radiosynthesis of [C-11]glyburide which was qualified as a radiopharmaceutical for human injection. This whole manufacturing process is currently being used to conduct a clinical trial to elucidate the hepatic transport of drugs. Advances in knowledge: Compared to previously reported radiosynthesis of [C-11]glyburide, this work provides an original and reproducible approach which can be transferred to any PET centre interested in using this radiotracer for preclinical or clinical imaging. Implication for patient care: This work provides a method to manufacture [C-11]glyburide for human PET imaging. This radiopharmaceutical could be used to elucidate the role of transporters in drug exposure of different organs or to monitor brain recovery after central nervous system (CNS) injuries. (C) 2020 Elsevier Inc. All rights reserved.