Search

Despite an apparently silent imaging, some patients with mild traumatic brain injury (TBI) experience cognitive dysfunctions, which may persist chronically. Brain changes responsible for these dysfunctions are unclear and commonly overlooked. It is thus crucial to increase our understanding of the mechanisms linking the initial event to the functional deficits, and to provide objective evidence of brain tissue alterations underpinning these deficits. We first set up a murine model of closed-head controlled cortical impact, which provoked persistent cognitive and sensorimotor deficits, despite no evidence of brain contusion or bleeding on MRI, thus recapitulating features of mild TBI. Molecular MRI for P-selectin, a key adhesion molecule, detected no sign of cerebrovascular inflammation after mild TBI, as confirmed by immunostainings. By contrast, in vivo PET imaging with the TSPO ligand [18F]DPA-714 demonstrated persisting signs of neuroinflammation in the ipsilateral cortex and hippocampus after mild TBI. Interestingly, immunohistochemical analyses confirmed these spatio-temporal profiles, showing a robust parenchymal astrogliosis and microgliosis, at least up to 3 weeks post-injury in both the cortex and hippocampus. In conclusion, we show that even one single mild TBI induces long-term behavioural deficits, associated with a persistent neuro-inflammatory status that can be detected by PET imaging.

International audience; Molecular imaging is a biomedical research discipline that has quickly emerged to afford the observation, characterization, monitoring, and quantification of biomarkers and biological processes in living organism. It covers a large array of imaging techniques, each of which provides anatomical, functional, or metabolic information. Multimodality, as the combination of two or more of these techniques, has proven to be one of the best options to boost their individual properties, hence offering unprecedented tools for human health. In this review, we will focus on the combination of positron emission tomography and fluorescence imaging from the specific perspective of the chemical synthesis of dual imaging agents. Based on a detailed analysis of the literature, this review aims at giving a comprehensive overview of the chemical strategies implemented to build adequate imaging tools considering radiohalogens and radiometals as positron emitters, fluorescent dyes mostly emitting in the NIR window and all types of targeting vectors.

Considering the individual characteristics of positron emission tomography (PET) and optical imaging (OI) in terms of sensitivity, spatial resolution, and tissue penetration, the development of dual imaging agents for bimodal PET/OI imaging is a growing field. A current major breakthrough in this field is the design of monomolecular agent displaying both a radioisotope for PET and a fluorescent dye for OI. We took advantage of the multifunctionalities allowed by a clickable

Molecular imaging with PET offers an alternative method to quantify programmed-death-ligand 1 (PD-L1) to accurately select patients for immunotherapies. More and more clinical and preclinical trials involve radiolabeling of antibody fragments for their desirably fast clearance and high tumor penetration. As the radiolabeling strategy can significantly impact pharmacokinetics and biodistribution, we explored in this work a site-specific radiofluorination strategy on an anti-PD-L1 fragment antigen-binding (Fab) and compared the pharmacokinetic and biodistribution properties with the same Fab labeled using stochastic radiolabeling chemistry. We applied an enzymatic bioconjugation mediated by a variant of the lipoic acid ligase (LplA) that promotes the formation of an amide bond between a short peptide cloned onto the C terminus of the Fab. A synthetic analogue of the enzyme natural substrate, lipoic acid, was radiolabeled with fluorine-18 for site-specific conjugation by LplA. We compared the biodistribution of the site-specifically labeled Fab with a stochastically labeled Fab on lysine side chains in tumor-bearing mice. The two methods of fluorination demonstrate a comparable whole-body biodistribution. The

ObjectivesTo explore in vivo innate immune cell activation as a function of the distance from ventricular CSF in patients with multiple sclerosis (MS) using [18F]-DPA714 PET and to investigate its relationship with periventricular microstructural damage, evaluated by magnetization transfer ratio (MTR), and with trajectories of disability worsening.MethodsThirty-seven patients with MS and 19 healthy controls underwent MRI and [18F]-DPA714 TSPO dynamic PET, from which individual maps of voxels characterized by innate immune cell activation (DPA+) were generated. White matter (WM) was divided in 3-mm-thick concentric rings radiating from the ventricular surface toward the cortex, and the percentage of DPA+ voxels and mean MTR were extracted from each ring. Two-year trajectories of disability worsening were collected to identify patients with and without recent disability worsening.ResultsThe percentage of DPA+ voxels was higher in patients compared to controls in the periventricular WM (p = 6.10e-6) and declined with increasing distance from ventricular surface, with a steeper gradient in patients compared to controls (p = 0.001). This gradient was found in both periventricular lesions and normal-appearing WM. In the total WM, it correlated with a gradient of microstructural tissue damage measured by MTR (rs = −0.65, p = 1.0e-3). Compared to clinically stable patients, patients with disability worsening were characterized by a higher percentage of DPA+ voxels in the periventricular normal-appearing WM (p = 0.025).ConclusionsOur results demonstrate that in MS the innate immune cell activation predominates in periventricular regions and is associated with microstructural damage and disability worsening. This could result from the diffusion of proinflammatory CSF-derived factors into surrounding tissues.

International audience; 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 [11C]-PK11195 have provided inconclusive results. Here we assess the presence and distribution of neuroinflammatory response in PD patients using [18F]-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 [18F]-DPA714 and [11C]-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 [18F]-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 [11C]-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: [18F]-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.Trial registration: Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.

International audience; Epidermal growth factor receptor (EGFR), involved in cell proliferation and migration, is overexpressed in ~50% of glioblastomas. Anti-EGFR based strategies using monoclonal antibodies (mAb) such as cetuximab (CTX) have been proposed for central nervous system (CNS) cancer therapy. However, the blood-brain barrier (BBB) drastically restricts their brain penetration which limits their efficacy for the treatment of glioblastomas. Herein, a longitudinal PET imaging study was performed to assess the relevance and the impact of focused ultrasound (FUS)-mediated BBB permeabilization on the brain exposure to the anti-EGFR mAb CTX over time. For this purpose, FUS permeabilization process with microbubbles was applied on intact BBB mouse brain before the injection of 89 Zr-labeled CTX for longitudinal imaging monitoring. FUS induced a dramatic increase in mAb penetration to the brain, 2 times higher compared to the intact BBB. The transfer of 89 Zr-CTX from blood to the brain was rendered significant by FUS (k uptake = 1.3 ± 0.23 min −1 with FUS versus k uptake = 0 ± 0.006 min −1 without FUS). FUS allowed significant and prolonged exposure to mAb in the brain parenchyma. This study confirms the potential of FUS as a target delivery method for mAb in CNS.

Publisher: American Chemical Society; International audience; Propargylated bambus[4,6]urils were prepared by an efficient one-step condensation of dipropargylglycoluril with formaldehyde under microwave irradiation. Their functionalization by click chemistry (CuAAC) afforded new multivalent architectures decorated with 8 or 12 ligands. Grafting of glycosides provided water-soluble glycobambus[4,6]uril platforms with glucosyl12BU[6] showing good affinity toward iodide anion in aqueous medium.

Prosthetic approach for the radiolabeling of biologics with fluorine-18 is a robust strategy and has been employed for many years. It requires fast, biocompatible and selective reactions suited to these fragile molecules. Michael addition of a nucleophilic thiol moiety on α,β-unsaturated carbonyl entities is an interesting compromise between simplicity of preparation of the prosthetic reagent and control of the selectivity of the addition. The α,β-unsaturated carbonyl entity of the biologic can easily be generated by addition of a maleimide function using adequate heterobifunctional linkers or generated by selective modification of a cysteine residue leading to a dehydroalanine moiety. We report here the design, synthesis and radiosynthesis of a new fluoropyridine-based thiol [The preparation of cold reference and labeling precursor of [We have developed an original [

Drugs promoting myelin repair represent a promising therapeutic approach in multiple sclerosis and several candidate molecules are currently being evaluated, fostering the need of a quantitative method to specifically measure myelin content in vivo. PET using the benzothiazole derivative 11C-PiB has been successfully used to quantify myelin content changes in humans. Stilbene derivatives, such as 11C-MeDAS, have also been shown to bind to myelin in animals and are considered a promising radiopharmaceutical class for myelin imaging. Fluorinated compounds from both classes are now commercially available and thus should constitute clinically useful myelin radiotracers. The aim of this study is to provide a head-to-head comparison of 18F-florbetaben, 18F-florbetapir, 18F-flutemetamol, 11C-MeDAS, and 11C-PiB with regard to brain kinetics and binding in white matter (WM). Four baboons underwent a 90-min dynamic PET scan for each radioligand. Arterial blood samples were collected during the exam for each radiotracer, except for 18F-florbetapir, to obtain a radiometabolite-corrected input function. Standardized uptake value ratio between 75 at 90 min (SUVR75–90), binding potential (BP) estimated with Logan method with input function, and distribution volume ratio (DVR) estimated with Logan reference method (using cerebellar gray matter as reference region) were calculated in WM and compared between tracers using mixed effect models. In WM, 18F-florbetapir had the highest SUVR75–90 (1.38 ± 0.03), followed by 18F-flutemetamol (1.34 ± 0.02), 18F-florbetaben (1.32 ± 0.07), 11C-MeDAS (1.27 ± 0.04), and 11C-PiB (1.25 ± 0.07). With regard to BP, 18F-florbetaben had the highest value (0.32 ± 0.06) compared with 18F-flutemetamol (0.20 ± 0.03), 11C-MeDAS (0.17 ± 0.03), and 11C-PiB (0.16 ± 0.03). No difference in DVR was detected between 18F-florbetaben (1.26 ± 0.06) and 18F-florbetapir (1.27 ± 0.03), but both were significantly higher in DVR than 18F-flutemetamol (1.17 ± 0.02), 11C-MeDAS (1.16 ± 0.03), and 11C-PiB (1.14 ± 0.02). Given their higher binding and longer half-life, our study indicates that 18F-florbetapir and 18F-florbetaben are promising tracers for myelin imaging which are readily available for clinical application in demyelinating diseases.

Sulfonylurea receptor 1 (SUR1) overexpression in the central nervous system is a potential biomarker for positron emission tomography (PET) imaging of brain damage and recovery. VU0071063, a selective ligand of SUR1 able to cross the blood-brain barrier, was isotopically radiolabeled with carbon-11 from a desmethyl precursor obtained quantitatively in one step. Ready-to-inject [11C]VU0071063 was obtained in 18 ± 2% radiochemical yield and 103 ± 22 GBq/μmol molar activity. PET imaging in healthy rats demonstrated a significant brain penetration and rapid elimination of the tracer in vivo, encouraging further investigation in animal models of SUR1 overexpression.

International audience; AGuIX are emerging radiosensitizing nanoparticles (NPs) for precision radiotherapy (RT) under clinical evaluation (Phase 2). Despite being accompanied by MRI thanks to the presence of gadolinium (Gd) at its surface, more sensitive and quantifiable imaging technique should further leverage the full potential of this technology. In this study, it is shown that Zr-89 can be labeled on such NPs directly for positron emission tomography (PET) imaging with a simple and scalable method. The stability of such complexes is remarkable in vitro and in vivo. Using a glioblastoma orthotopic rat model, it is shown that injected Zr-89-AGuIX is detectable inside the tumor for at least 1 week. Interestingly, the particles seem to efficiently infiltrate the tumor even in necrotic areas, which places great hope for the treatment of radioresistant tumor. Lastly, the first PET/MR whole-body imaging is performed in non-human primate (NHP), which further demonstrates the translational potential of these bimodal NP.

Recent studies in neurodegenerative conditions have increasingly highlighted that the same neuropathology can trigger different clinical phenotypes or, vice-versa, that similar phenotypes can be triggered by different neuropathologies. This evidence has called for the adoption of a pathology spectrum-based approach to study neurodegenerative proteinopathies. These conditions share brain deposition of abnormal protein aggregates, leading to aberrant biochemical, metabolic, functional, and structural changes. Positron emission tomography (PET) is a well-recognized and unique tool for the in vivo assessment of brain neuropathology, and novel PET techniques are emerging for the study of specific protein species. Today, key applications of PET range from early research and clinical diagnostic tools to their use in clinical trials for both participants screening and outcome evaluation. This position article critically reviews the role of distinct PET molecular tracers for different neurodegenerative proteinopathies, highlighting their strengths, weaknesses, and opportunities, with special emphasis on methodological challenges and future applications. (C) 2019 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Methods for the radiolabeling of biologics with fluorine-18 have been of interest for several decades. A common approach consists in the preparation of a prosthetic reagent, a small molecule bearing a fluorine-18 that is conjugated with the macromolecule to an appropriate function. Click chemistry, and more particularly cycloadditions, is an interesting approach to radiolabel molecules thanks to mild reaction conditions, high yields, low by-products formation, and strong orthogonality. Moreover, the chemical functions involved in the cycloaddition reaction are stable in the drastic radiofluorination conditions, thus allowing a simple radiosynthetic route to prepare the prosthetic reagent. We report herein the radiosynthesis of 18 F-FPyZIDE, a pyridine-based azide-bearing prosthetic reagent. We exemplified its conjugation via copper-catalyzed cycloaddition (CuAAC) and strain-promoted cycloaddition (SPAAC) with several terminal alkyne or strained alkyne model compounds.

International audience; To fully exploit the potential of positron emission tomography (PET) imaging to assess drug distribution and pharmacokinetics in the central nervous system, the contribution of radiometabolites to the PET signal has to be determined for correct interpretation of data. However, radiosynthesis and extensive study of radiometabolites are rarely investigated and very challenging for complex drugs. Therefore, an original radio-biomimetic (RBM) approach was developed to rapidly synthesize radiometabolites and non-invasively investigate their kinetics with PET imaging. This method enabled the challenging radiosynthesis of [11C]nor-buprenorphine ([11C]nor-BUP), the main metabolite of buprenorphine (BUP) which has been identified as a substrate of the P-glycoprotein (P-gp) transport function at the blood-brain barrier (BBB). Biomimetic conditions using cytochromes P450 3A4 to convert BUP into nor-BUP were optimized taking into account the short half-life of carbon-11 (t1/2 = 20.4 min). Those conditions afforded 32% of conversion within 20 min and were applied to the biomimetic radiosynthesis of [11C]nor-BUP from [11C]BUP. Automated radiosynthesis of [11C]BUP according to a procedure described in the literature followed by optimized RBM conditions afforded [11C]nor-BUP in 1.5% decay-corrected radiochemical yield within 90 min and 90 ± 15 GBq/μmol molar activity. HPLC quality control showed chemical and radiochemical purities above 98%. To demonstrate the applicability of the RBM approach to preclinical studies, brain PET images in rats showed a drastic lower uptake of [11C]nor-BUP (0.067 ± 0.023%ID/cm-3) compared to [11C]BUP (0.436 ± 0.054%ID/cm-3). P-gp inhibition using Tariquidar increased the brain uptake of [11C]nor-BUP (0.557 ± 0.077%ID/cm-3).

International audience; 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 radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [ 11 C]glyburide and a full European Pharmacopeia 9.7 compliant quality control to use [ 11 C]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 [ 11 C]glyburide using a TRACERlab® 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 [ 11 C]glyburide was obtained in 5% non-decay corrected radiochemical yield and 110 ± 20 GBq/μmol molar activity within 40 min (n = 8). [ 11 C] Glyburide quality control was compliant with the Pharmacopeia requirements.Conclusions: We have described a highly reproducible and automated two-step radiosynthesis of [ 11 C]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 [ 11 C]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 [ 11 C]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.

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 [PD patients (n = 24, Hoehn and Yahr I-III) and 28 healthy controls were scanned with [PD patients showed significantly higher [[Trial registration: INFLAPARK, NCT02319382. Registered 18 December 2014- Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02319382.

Radiolabeling of peptides with fluorine-18 is hurdled by their chemical sensitivity and complicated processes. Original triflyl-pyridine intermediates afforded ammonium precursors that were radiolabeled at low temperature. From that study, a generic tag has been designed to allow a simple one-step/late-stage radiolabelling of peptides. The strategy has been transposed to an automated “on-resin” radiolabelling.

Our objective was to develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using (18)F-DPA-714 translocator protein PET and to explore the relationship between these maps and individual trajectories of worsening disability in patients with multiple sclerosis (MS). Methods: Patients with MS (n = 37), whose trajectories of worsening disability over the 2 y preceding study entry were calculated, and healthy controls (n = 19) underwent MRI and (18)F-DPA-714 PET. A threshold for significant activation of (18)F-DPA-714 binding was calculated with a voxelwise randomized permutation-based comparison between patients and controls and used to classify each WM voxel in all subjects as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were used to calculate the extent of activation in WM regions of interests and to classify each WM lesion as DPA-active, DPA-inactive, or unclassified. Results: Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM (NAWM) (NAWM in patients, 24.6% ± 1.4%; WM in controls, 14.6% ± 2.0%; P < 0.001). In patients with MS, the percentage of DPA+ voxels increased significantly from the NAWM to the perilesional areas, T2 hyperintense lesions, and T1 hypointense lesions (38.1% ± 2.6%, 45.0% ± 2.6%, 51.8% ± 2.6%, respectively; P < 0.001). Among the 1,379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (odds ratio, 1.13; P = 0.009), a higher percentage of DPA+ voxels in the NAWM (odds ratio, 1.16; P = 0.009), and a higher percentage of DPA+ voxels in T1 spin-echo lesions (odds ratio, 1.06; P = 0.036) were significantly associated with a retrospectively more severe clinical trajectory in patients with MS. Conclusion: A more severe trajectory of disability worsening in MS is associated with innate immune cell activation inside and around WM lesions. (18)F-DPA-714 PET may provide a promising biomarker to identify patients at risk of a severe clinical trajectory.

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 radiolabelled with carbon-11 for PET imaging. The aim of this work is to present an original and reproducible automated radiosynthesis of [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 [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 [We have described a highly reproducible and automated two-step radiosynthesis of [Compared to previously reported radiosynthesis of [This work provides a method to manufacture [

International audience; A robust, click chemistry inspired procedure for radiolabeling of cyclic ureas was developed. This protocol, suitable for all carbon isotopes (11C, 13C, 14C), is based on the direct functionalization of carbon dioxide: the universal building block for carbon radiolabeling. The strategy is operationally simple, reproducible in different radiochemistry centers, exhibits a remarkably wide substrate scope with short reaction times, and demonstrates superior reactivity compared to previously reported systems. With this procedure, a variety of pharmaceuticals and an unprotected peptide were labeled with high radiochemical efficiency.

Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA-714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty-four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages.