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PURPOSE: Alzheimer's disease (AD) dementia may not be a single disease entity. Early-onset AD (EOAD) and late-onset AD (LOAD) have been united under the same eponym of AD until now, but disentangling the heterogeneity according to the age of sonset has been a major tenet in the field of AD research. MATERIALS AND METHODS: Ninety-nine patients with AD (EOAD, n=54; LOAD, n=45) and 66 cognitively normal controls completed both [18F]THK5351 and [18F]flutemetamol (FLUTE) positron emission tomography scans along with structural magnetic resonance imaging and detailed neuropsychological tests. RESULTS: EOAD patients had higher THK retention in the precuneus, parietal, and frontal lobe, while LOAD patients had higher THK retention in the medial temporal lobe. Intravoxel correlation analyses revealed that EOAD presented narrower territory of local FLUTE-THK correlation, while LOAD presented broader territory of correlation extending to overall parieto-occipito-temporal regions. EOAD patients had broader brain areas which showed significant negative correlations between cortical thickness and THK retention, whereas in LOAD, only limited brain areas showed significant correlation with THK retention. In EOAD, most of the cognitive test results were correlated with THK retention. However, a few cognitive test results were correlated with THK retention in LOAD. CONCLUSION: LOAD seemed to show gradual increase in tau and amyloid, and those two pathologies have association to each other. On the other hand, in EOAD, tau and amyloid may develop more abruptly and independently. These findings suggest LOAD and EOAD may have different courses of pathomechanism.
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Doença de Alzheimer , Atrofia , Encéfalo , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Proteínas tau , Humanos , Doença de Alzheimer/patologia , Doença de Alzheimer/diagnóstico por imagem , Masculino , Feminino , Proteínas tau/metabolismo , Idoso , Atrofia/patologia , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos de Anilina , Idade de Início , Amiloide/metabolismo , Idoso de 80 Anos ou mais , Benzotiazóis , Aminopiridinas , QuinolinasRESUMO
Abnormal alpha-synuclein (αSyn) and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim to visualize αSyn inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. The fluorescent pyrimidoindole derivative THK-565 probe was characterized by means of recombinant fibrils and brains from 10- to 11-month-old M83 mice. Concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging were subsequently performed in vivo. Structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 T as well as scanning transmission x-ray microscopy (STXM) were performed to characterize the iron deposits in the perfused brains. Immunofluorescence and Prussian blue staining were further performed on brain slices to validate the detection of αSyn inclusions and iron deposition. THK-565 showed increased fluorescence upon binding to recombinant αSyn fibrils and αSyn inclusions in post-mortem brain slices from patients with PD and M83 mice. Administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 min post-intravenous injection by wide-field fluorescence compared to nontransgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. In conclusion, we demonstrated in vivo mapping of αSyn by means of noninvasive epifluorescence and vMSOT imaging and validated the results by targeting the THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.
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BACKGROUND AND AIM: The differentiation of isolated cortical venous thrombosis (ICVT) from cerebral amyloid angiopathy (CAA) can be difficult because both diseases share similar neurological symptoms and imaging findings. N-methyl-11C-2-(4'-methylaminophenyl)-6-hydroxybenzo-thiazole (11C-PiB) positron emission tomography (PET) functions as a diagnostic modality for CAA by detecting amyloid deposition. The present prospective study evaluated amyloid deposition using 11C-PiB-PET in consecutive patients with suspected ICVT. METHOD: This study was a prospective observational study. Patients who attended or were hospitalized between May 2019 and March 2020 were included in the analysis. Consecutive patients who met the criteria for suspicion of ICVT were enrolled in the study, and the clinical course, symptoms, imaging findings (including magnetic resonance imaging), and the 11C-PiB-PET findings of each case were analyzed. RESULTS: The study cohort included four patients (64-82 years of age, all women). In one younger patient, 11C-PiB-PET afforded no findings suggestive of CAA, whereas the remaining three patients exhibited 11C-PiB-PET findings suggestive of CAA. CONCLUSION: Although 11C-PiB-PET would be a reasonable modality for distinguishing ICVT from CAA, especially in younger patients, it might be difficult to differentiate ICVT from CAA in elderly patients because of the potential deposition of amyloid. CLINICAL TRIAL REGISTRATION: URL: https://www.umin.ac.jp/ctr/ Unique identifier: UMIN 000037101.
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Angiopatia Amiloide Cerebral , Humanos , Feminino , Idoso , Estudos Prospectivos , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Angiopatia Amiloide Cerebral/patologia , Amiloide , Tomografia por Emissão de Pósitrons/métodos , Tiazóis , Imageamento por Ressonância Magnética , Hemorragia CerebralRESUMO
A monoamine oxidase B (MAO-B) selective positron emission tomography (PET) tracer [11C]-deuterium-l-deprenyl holds promise for imaging reactive astrogliosis in neurodegenerative diseases, such as Alzheimer's disease (AD). Two novel PET tracers ([11C]-BU99008 and [18F]-SMBT-1) have recently been developed to assess the complexity of reactive astrogliosis in the AD continuum. We have investigated the binding properties of SMBT-1, l-deprenyl, and BU99008 in AD and cognitively normal control (CN) brains. Competition binding assays with [3H]-l-deprenyl and [3H]-BU99008 versus unlabeled SMBT-1 in postmortem AD and CN temporal and frontal cortex brains demonstrated that SMBT-1 interacted with [3H]-deprenyl at a single binding site (nM range) and with [3H]-BU99008 at multiple binding sites (from nM to µM). Autoradiography studies on large frozen postmortem AD and CN hemisphere brain sections demonstrated that 1 µM SMBT-1 almost completely displaced the [3H]-l-deprenyl binding (>90%), while SMBT-1 only partly displaced the [3H]-BU99008 binding (50-60% displacement) in cortical regions. In conclusion, SMBT-1, l-deprenyl, and BU99008 interact at the same MAO-B binding site, while BU99008 shows an additional independent binding site in AD and CN brains. The high translational power of our studies in human AD and CN brains suggests that the multitracer approach with SMBT-1, l-deprenyl, and BU99008 could be useful for imaging reactive astrogliosis.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Selegilina , Gliose/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Monoaminoxidase/metabolismo , Inflamação/metabolismoRESUMO
We aimed to elucidate the distribution pattern of the positron emission tomography probe [18F]THK 5351, a marker for astrogliosis and tau accumulation, in healthy aging. We also assessed the relationship between THK5351 retention and resting state networks. We enrolled 62 healthy participants in this study. All participants underwent magnetic resonance imaging/positron emission tomography scanning consisting of T1-weighted images, resting state functional magnetic resonance imaging, Pittsburgh Compound-B and THK positron emission tomography. The preprocessed THK images were entered into a scaled subprofile modeling/principal component analysis to extract THK distribution patterns. Using the most significant THK pattern, we generated regions of interest, and performed seed-based functional connectivity analyses. We also evaluated the functional connectivity overlap ratio to identify regions with high between-network connectivity. The most significant THK distributions were observed in the medial prefrontal cortex and bilateral putamen. The seed regions of interest in the medial prefrontal cortex had a functional connectivity map that significantly overlapped with regions of the dorsal default mode network. The seed regions of interest in the putamen showed strong overlap with the basal ganglia and anterior salience networks. The functional connectivity overlap ratio also showed that three peak regions had the characteristics of connector hubs. We have identified an age-related spatial distribution of THK in the medial prefrontal cortex and basal ganglia in normal aging. Interestingly, the distribution's peaks are located in regions of connector hubs that are strongly connected to large-scale resting state networks associated with higher cognitive function.
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PURPOSE: Noninvasive imaging of protein aggregates in the brain is critical for the early diagnosis, disease monitoring, and evaluation of the effectiveness of novel therapies for Alzheimer's disease (AD). Near-infrared fluorescence (NIRF) imaging with specific probes is a promising technique for the in vivo detection of protein deposits without radiation exposure. Comprehensive screening of fluorescent compounds identified a novel compound, THK-565, for the in vivo imaging of amyloid-ß (Aß) deposits in the mouse brain. This study assessed whether THK-565 could detect amyloid-ß deposits in vivo in the AD mouse model. PROCEDURES: The fluorescent properties of THK-565 were evaluated in the presence and absence of Aß fibrils. APP knock-in (APP-KI) mice were used as an animal model of AD. In vivo NIRF images were acquired after the intravenous administration of THK-565 and THK-265 in mice. The binding selectivity of THK-565 to Aß was evaluated using brain slices obtained from these mouse models. RESULTS: The fluorescence intensity of the THK-565 solution substantially increased by mixing with Aß fibrils. The maximum emission wavelength of the complex of THK-565 and Aß fibrils was 704 nm, which was within the optical window range. THK-565 selectively bound to amyloid deposits in brain sections of APP-KI mice After the intravenous administration of THK-565, the fluorescence signal in the head of APP-KI mice was significantly higher than that of wild-type mice and higher than that after administration of THK-265. Ex vivo analysis confirmed that the THK-565 signal corresponded to Aß immunostaining in the brain sections of these mice. CONCLUSIONS: A novel NIRF probe, THK-565, enabled the in vivo detection of Aß deposits in the brains of the AD mouse model, suggesting that NIRF imaging with THK-565 could non-invasively assess disease-specific pathology in AD.
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Doença de Alzheimer , Camundongos , Animais , Doença de Alzheimer/metabolismo , Placa Amiloide/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Modelos Animais de Doenças , Corantes Fluorescentes/química , Camundongos TransgênicosRESUMO
Background: Abnormal alpha-synuclein and iron accumulation in the brain play an important role in Parkinson's disease (PD). Herein, we aim at visualizing alpha-synuclein inclusions and iron deposition in the brains of M83 (A53T) mouse models of PD in vivo. Methods: Fluorescently labelled pyrimidoindole-derivative THK-565 was characterized by using recombinant fibrils and brains from 10-11 months old M83 mice, which subsequently underwent in vivo concurrent wide-field fluorescence and volumetric multispectral optoacoustic tomography (vMSOT) imaging. The in vivo results were verified against structural and susceptibility weighted imaging (SWI) magnetic resonance imaging (MRI) at 9.4 Tesla and scanning transmission X-ray microscopy (STXM) of perfused brains. Brain slice immunofluorescence and Prussian blue staining were further performed to validate the detection of alpha-synuclein inclusions and iron deposition in the brain, respectively. Results: THK-565 showed increased fluorescence upon binding to recombinant alpha-synuclein fibrils and alpha-synuclein inclusions in post-mortem brain slices from patients with Parkinson's disease and M83 mice. i.v. administration of THK-565 in M83 mice showed higher cerebral retention at 20 and 40 minutes post-injection by wide-field fluorescence compared to non-transgenic littermate mice, in congruence with the vMSOT findings. SWI/phase images and Prussian blue indicated the accumulation of iron deposits in the brains of M83 mice, presumably in the Fe3+ form, as evinced by the STXM results. Conclusion: We demonstrated in vivo mapping of alpha-synuclein by means of non-invasive epifluorescence and vMSOT imaging assisted with a targeted THK-565 label and SWI/STXM identification of iron deposits in M83 mouse brains ex vivo.
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BACKGROUND: Little is known regarding the differential effects of the apolipoprotein E (APOE) É4 on the regional topography of amyloid and tau in patients with both early-onset (EOAD) and late-onset Alzheimer's disease (LOAD). OBJECTIVE: To compare the distribution and association of tau, amyloid, and cortical thickness among groups classified by the presence of APOEÉ4 allele and onset age. METHODS: A total of 165 participants including 54 EOAD patients (29 É4-; 25 É4+), 45 LOAD patients (21 É4-; 24 É4+), and 66 age-matched controls underwent 3T MRI, 18F-THK5351 (THK) and 18F-flutemetamol (FLUTE) PET scans, APOE genotyping, and neuropsychological tests. Data for voxel-wise and standardized uptake values from PET scans were analyzed in the context of APOE and age at onset. RESULTS: EOAD É4- patients showed greater THK retention in the association cortices, whereas their EOAD É4+ counterparts had more retention in medial temporal areas. THK topography of LOAD É4+ was similar to EOAD É4â+â. THK correlated positively with FLUTE and conversely with mean cortical thickness, being lowest in EOAD É4-, highest in LOAD É4-, and modest in É4+ groups. Even in the APOEÉ4+ groups, THK tended to correlate with FLUTE and mean cortical thickness in the inferior parietal region in EOAD and in the medial temporal region in LOAD. LOAD É4- manifested with prevalent small vessel disease markers and the lowest correlation between THK retention and cognition. CONCLUSION: Our observations suggest the differential effects of the APOEÉ4 on the relationship between tau and amyloid in EOAD and LOAD.
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Doença de Alzheimer , Humanos , Alelos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides , Apolipoproteína E4/genética , Apolipoproteínas E/genética , Cognição , Tomografia por Emissão de PósitronsRESUMO
Astrogliosis is a crucial feature of neuroinflammation and is characterized by the significant upregulation of glial fibrillary acidic protein (GFAP) expression. Hence, visualizing GFAP in the living brain of patients with damaged central nervous system using positron emission tomography (PET) is of great importance, and it is expected to depict neuroinflammation more directly than existing neuroinflammation imaging markers. However, no PET radiotracers for GFAP are currently available. Therefore, neuroimaging with antibody-like affinity proteins could be a viable strategy for visualizing imaging targets that small molecules rarely recognize, such as GFAP, while we need to overcome the challenges of slow clearance and low brain permeability. The E9 nanobody, a small-affinity protein with high affinity and selectivity for GFAP, was utilized in this study. E9 was engineered by fusing a brain shuttle peptide that facilitates blood-brain barrier permeation via two different types of linker domains: E9-GS-ApoE (EGA) and E9-EAK-ApoE (EEA). E9, EGA and EEA were radiolabeled with fluorine-18 using cell-free protein radiosynthesis. In vitro autoradiography showed that all radiolabeled proteins exhibited a significant difference in neuroinflammation in the brain sections created from a rat model constructed by injecting lipopolysaccharide (LPS) into the unilateral striatum of wildtype rats, and an excess competitor displaced their binding. However, exploratory in vivo PET imaging and ex vivo biodistribution studies in the rat model failed to distinguish neuroinflammatory lesions within 3 h of 18F-EEA intravenous injection. This study contributes to a better understanding of the characteristics of small-affinity proteins fused with a brain shuttle peptide for further research into the use of protein molecules as PET tracers for imaging neuropathology.
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Doenças Neuroinflamatórias , Tomografia Computadorizada por Raios X , Animais , Ratos , Apolipoproteínas E , Encéfalo/diagnóstico por imagem , Proteína Glial Fibrilar Ácida , Peptídeos , Distribuição Tecidual , Anticorpos de Domínio ÚnicoRESUMO
Tau PET tracers are expected to be sufficiently sensitive to track the progression of age-related tau pathology in the medial temporal cortex. The tau PET tracer N-(4-[18F]fluoro-5-methylpyridin-2-yl)-7-aminoimidazo[1,2-a]pyridine ([18F]SNFT-1) has been successfully developed by optimizing imidazo[1,2-a]pyridine derivatives. We characterized the binding properties of [18F]SNFT-1 using a head-to-head comparison with other reported 18F-labeled tau tracers. Methods: The binding affinity of SNFT-1 to tau, amyloid, and monoamine oxidase A and B was compared with that of the second-generation tau tracers MK-6240, PM-PBB3, PI-2620, RO6958948, JNJ-64326067, and flortaucipir. In vitro binding properties of 18F-labeled tau tracers were evaluated through the autoradiography of frozen human brain tissues from patients with diverse neurodegenerative disease spectra. Pharmacokinetics, metabolism, and radiation dosimetry were assessed in normal mice after intravenous administration of [18F]SNFT-1. Results: In vitro binding assays demonstrated that [18F]SNFT-1 possesses high selectivity and high affinity for tau aggregates in Alzheimer disease (AD) brains. Autoradiographic analysis of tau deposits in medial temporal brain sections from patients with AD showed a higher signal-to-background ratio for [18F]SNFT-1 than for the other tau PET tracers and no significant binding with non-AD tau, α-synuclein, transactiviation response DNA-binding protein-43, and transmembrane protein 106B aggregates in human brain sections. Furthermore, [18F]SNFT-1 did not bind significantly to various receptors, ion channels, or transporters. [18F]SNFT-1 showed a high initial brain uptake and rapid washout from the brains of normal mice without radiolabeled metabolites. Conclusion: These preclinical data suggest that [18F]SNFT-1 is a promising and selective tau radiotracer candidate that allows the quantitative monitoring of age-related accumulation of tau aggregates in the human brain.
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Doença de Alzheimer , Doenças Neurodegenerativas , Humanos , Camundongos , Animais , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Piridinas/farmacocinética , Encéfalo/metabolismo , Proteínas tau/metabolismo , Tomografia por Emissão de PósitronsRESUMO
Quantification of in vivo reactive astrogliosis, which represents neural inflammation and remodeling in the brain, is an emerging methodology for the evaluation of patients with neurodegenerative diseases. [18F]THK-5351 is a positron emission tomography (PET) tracer for monoamine oxidase B (MAO-B), a molecular marker of reactive astrogliosis. We performed in vivo [18F]THK-5351 PET in a patient who at autopsy was found to have argyrophilic grain disease (AGD) with comorbid pathology to visualize reactive astrogliosis for the first time. We aimed to validate an imaging-pathology correlation using [18F]THK-5351 PET and the autopsy brain. The patient, a 78-year-old man, was pathologically diagnosed with AGD combined with limbic-predominant age-related transactive response DNA-binding protein of 43 kDa encephalopathy and Lewy body disease without Alzheimer disease-related neuropathological changes. Reactive astrogliosis in the postmortem brain was abundant in the inferior temporal gyrus, insular gyrus, entorhinal cortex, and ambient gyrus where premortem [18F]THK-5351 signals were high. We found a proportional correlation between the amount of reactive astrogliosis in the postmortem brain and the in vivo [18F]THK-5351 standardized uptake value ratio (r = 0.8535, p = 0.0004). These results indicated that reactive astrogliosis in AGD with comorbid pathology could be identified and quantified by in vivo MAO-B imaging.
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Doença de Alzheimer , Doenças Neurodegenerativas , Masculino , Humanos , Idoso , Gliose/patologia , Doença de Alzheimer/patologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/metabolismo , Encéfalo/patologia , Tomografia por Emissão de Pósitrons , Monoaminoxidase/metabolismo , Proteínas tau/metabolismoRESUMO
Glial cells are non-neuronal cells that make up the central nervous system, including astrocytes, oligodendrocytes, microglia, and ependymal cells, which play an important role in brain homeostasis. However, activated microglia and reactive astrocytes cause neuroinflammation, which is closely related to neurodegeneration. Neuronal loss, gliosis, and accumulation of misfolded proteins are commonly observed in the brain of many neurodegenerative diseases at autopsy. Therefore, in vivo imaging of glial cell responses by positron emission tomography (PET) would be useful not only for understanding pathological processes, but also for differential diagnosis and evaluation of disease-modifying therapeutics targeting glial cells. The gold standard marker for reactive astrocytes is glial fibrillary acidic protein (GFAP), but no specific ligands are available. To date, there are two targets of reactive astrocytes that are under intense investigation: Monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS). PET radiopharmaceuticals for MAO-B and I2BS have been developed and are under clinical investigation. In this chapter, we review the MAO-B and I2BS as molecular targets for imaging reactive astrocytes and introduce the PET tracers and their clinical studies.
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Gliose , Tomografia por Emissão de Pósitrons , Humanos , Gliose/diagnóstico por imagem , Gliose/metabolismo , Gliose/patologia , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Astrócitos/metabolismo , Monoaminoxidase/metabolismoRESUMO
OBJECTIVE: Monoamine oxidase B (MAO-B) is highly abundant in reactive astrocytes and upregulated in neuroinflammatory processes. However, the age-related change of MAO-B in amyloid-negative cognitively unimpaired elderly subjects has not yet been sufficiently evaluated on positron emission tomography (PET). 18F-THK5351 is a radiotracer with high affinity to MAO-B, which may potentially serve as an imaging biomarker for detecting neuroinflammation. The purpose of this study was to investigate the age-related topographic change of 18F-THK5351 PET in amyloid-negative cognitively unimpaired elderly subjects. METHODS: The age-related change of 18F-THK5351 retention was evaluated on the visual analysis, voxel and region of interest (ROI)-based analyses using Statistical Parametric Mapping and PETSurfer tool of FreeSurfer in 31 amyloid-negative cognitively unimpaired elderly subjects. RESULTS: On visual inspection, elderly groups showed the spread of 18F-THK5351 accumulation from the medial to inferolateral temporal and basal frontal lobes, and cingulate gyrus. Additionally, voxel- and ROI-based analysis demonstrated the correlation between 18F-THK5351 accumulation and participants' age, especially in the inferior temporal lobes. CONCLUSIONS: This study demonstrated age-dependent increase of 18F-THK5351 retention in amyloid-negative cognitively unimpaired subjects, which suggests an increase in MAO-B positive reactive astrocytes with aging.
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Doença de Alzheimer , Monoaminoxidase , Idoso , Envelhecimento , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Monoaminoxidase/metabolismo , Tomografia por Emissão de Pósitrons , Proteínas tau/metabolismoRESUMO
Alzheimer's disease (AD) is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of neurofibrillary tangles (NFT). Amyloid beta (Aß) and tau imaging are widely used for diagnosing and monitoring AD in clinical settings. We evaluated the pathology of a recently developed 6 × Tg - AD (6 × Tg) mouse model by crossbreeding 5 × FAD mice with mice expressing mutant (P301L) tau protein using micro-positron emission tomography (PET) image analysis. PET studies were performed in these 6 × Tg mice using [18F]Flutemetamol, which is an amyloid PET radiotracer; [18F]THK5351 and [18F]MK6240, which are tau PET radiotracers; moreover, [18F]DPA714, which is a translocator protein (TSPO) radiotracer, and comparisons were made with age-matched mice of their respective parental strains. We compared group differences in standardized uptake value ratio (SUVR), kinetic parameters, biodistribution, and histopathology. [18F]Flutemetamol images showed prominent cortical uptake and matched well with 6E10 staining images from 2-month-old 6 × Tg mice. [18F]Flutemetamol images showed a significant correlation with [18F]DPA714 in the cortex and hippocampus. [18F]THK5351 images revealed prominent hippocampal uptake and matched well with AT8 immunostaining images in 4-month-old 6 × Tg mice. Moreover, [18F]THK5351 images were confirmed using [18F]MK6240, which revealed significant correlations in the cortex and hippocampus. Uptake of [18F]THK5351 or [18F]MK6240 was highly correlated with [18F]Flutemetamol in 4-month-old 6 × Tg mice. In conclusion, PET imaging revealed significant age-related uptake of Aß, tau, and TSPO in 6 × Tg mice, which was highly correlated with age-dependent pathology.
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Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Compostos de Anilina/farmacocinética , Animais , Benzotiazóis/farmacocinética , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Camundongos , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
OBJECTIVE: To examine the effect of apolipoprotein E (APOE) É4 dose on blood-brain barrier (BBB) clearance function, evaluated using an advanced MRI technique and analyse its correlation with brain iron and ß-amyloid accumulation in the early stages of the Alzheimer's continuum. METHODS: In this single-centre observational prospective cohort study, 24 APOE É4 non-carriers, 22 heterozygotes and 20 homozygotes in the early stages of the Alzheimer's continuum were scanned with diffusion-prepared arterial spin labelling, which estimates the water exchange rate across the BBB (kw). Participants also underwent quantitative susceptibility mapping, [11C]Pittsburgh compound B-positron emission tomography and neuropsychological testing. Using an atlas-based approach, we compared the regional kw of the whole brain among the groups and analysed its correlation with the neuroradiological and neuropsychological findings. RESULTS: The BBB kw values in the neocortices differed significantly among the groups (APOE É4 non-carriers>heterozygotes>homozygotes). These values correlated with brain iron levels (frontal lobe: r=-0.476, 95% CI=-0.644 to -0.264, p=0.011; medial temporal lobe: r=-0.455, 95% CI=-0.628 to -0.239, p=0.017), ß-amyloid loads (frontal lobe: r=-0.504, 95% CI=-0.731 to -0.176, p=0.015; medial temporal lobe: r=-0.452, 95% CI=-0.699 to -0.110, p=0.036) and neuropsychological scores, after adjusting for age, sex and APOE É4 dose. INTERPRETATION: Our results suggest that an increased APOE É4 dose is associated with decreased effective brain-waste clearance, such as iron and ß-amyloid, through the BBB.
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BACKGROUND: In sporadic Alzheimer's disease (AD), brain amyloid-beta (Aß) deposition is believed to be a consequence of impaired Aß clearance, but this relationship is not well established in living humans. CSF clearance, a major feature of brain glymphatic clearance (BGC), has been shown to be abnormal in AD murine models. MRI phase contrast and intrathecally delivered contrast studies have reported reduced CSF flow in AD. Using PET and tau tracer 18F-THK5117, we previously reported that the ventricular CSF clearance of the PET tracer was reduced in AD and associated with elevated brain Aß levels. METHODS: In the present study, we use two PET tracers, 18F-THK5351 and 11C-PiB to estimate CSF clearance calculated from early dynamic PET frames in 9 normal controls and 15 AD participants. RESULTS: we observed that the ventricular CSF clearance measures were correlated (r = 0.66, p < 0.01), with reductions in AD of 18 and 27%, respectively. We also replicated a significant relationship between ventricular CSF clearance (18F-THK5351) and brain Aß load (r = - 0.64, n = 24, p < 0.01). With a larger sample size, we extended our observations to show that reduced CSF clearance is associated with reductions in cortical thickness and cognitive performance. CONCLUSIONS: Overall, the findings support the hypothesis that failed CSF clearance is a feature of AD that is related to Aß deposition and to the pathology of AD. Longitudinal studies are needed to determine whether failed CSF clearance is a predictor of progressive amyloidosis or its consequence.
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Doença de Alzheimer , Amiloidose , Doença de Alzheimer/complicações , Peptídeos beta-Amiloides , Amiloidose/complicações , Amiloidose/patologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Humanos , Imageamento por Ressonância Magnética , CamundongosRESUMO
Many neurodegenerative diseases are neuropathologically characterized by neuronal loss, gliosis, and the deposition of misfolded proteins such as ß-amyloid (Aß) plaques and tau tangles in Alzheimer's disease (AD). In postmortem AD brains, reactive astrocytes and activated microglia are observed surrounding Aß plaques and tau tangles. These activated glial cells secrete pro-inflammatory cytokines and reactive oxygen species, which may contribute to neurodegeneration. Therefore, in vivo imaging of glial response by positron emission tomography (PET) combined with Aß and tau PET would provide new insights to better understand the disease process, as well as aid in the differential diagnosis, and monitoring glial response disease-specific therapeutics. There are two promising targets proposed for imaging reactive astrogliosis: monoamine oxidase-B (MAO-B) and imidazoline2 binding site (I2BS), which are predominantly expressed in the mitochondrial membranes of astrocytes and are upregulated in various neurodegenerative conditions. PET tracers targeting these two MAO-B and I2BS have been evaluated in humans. [18F]THK-5351, which was originally designed to target tau aggregates in AD, showed high affinity for MAO-B and clearly visualized reactive astrocytes in progressive supranuclear palsy (PSP). However, the lack of selectivity of [18F]THK-5351 binding to both MAO-B and tau, severely limits its clinical utility as a biomarker. Recently, [18F]SMBT-1 was developed as a selective and reversible MAO-B PET tracer via compound optimization of [18F]THK-5351. In this review, we summarize the strategy underlying molecular imaging of reactive astrogliosis and clinical studies using MAO-B and I2BS PET tracers.
RESUMO
(S)-(2-Methylpyrid-5-yl)-6-[(3-[18F]fluoro-2-hydroxy)propoxy]quinoline ([18F]SMBT-1) was recently developed as a novel class of selective and reversible monoamine oxidase-B (MAO-B) tracers for in vivo imaging of reactive astrogliosis via positron emission tomography. To investigate the effect of the chirality of [18F]SMBT-1 on tracer performance, we synthesized (S)-[18F]6 ([18F]SMBT-1) and (R)-[18F]6 and compared their binding properties, pharmacokinetics, and metabolism. (S)-6 showed higher binding affinity to MAO-B and lower binding affinity to MAO-A than (R)-6, demonstrating a higher selectivity ratio (MAO-B/MAO-A). A pharmacokinetic study in mice demonstrated that both (S)-[18F]6 and (R)-[18F]6 showed sufficient initial brain uptake. However, (S)-[18F]6 was cleared significantly faster from the body. An abundant sulfoconjugate metabolite M2 was observed in plasma for (S)-[18F]6 but not for (R)-[18F]6. In vitro sulfation assays confirmed that (S)-6 was more reactive than (R)-6, consistent with the in vivo findings. Mefenamic acid, a selective sulfotransferase 1A1 (SULT1A1) inhibitor, strongly inhibited the in vitro sulfation of (S)-6 by mouse liver fractions, human liver cytosol fractions, and human recombinant SULT1A1 enzyme. Genetic polymorphisms of SULT1A1 did not affect the sulfation of (S)-6 in vitro. In conclusion, (S)-[18F]6 had a more favorable binding affinity and binding selectivity for MAO-B than (R)-[18F]6. Additionally, (S)-[18F]6 also possessed better pharmacological and metabolic properties than (R)-[18F]6. These results suggest that (S)-[18F]6 ([18F]SMBT-1) is a promising candidate for application in the imaging of MAO-B in vivo.
Assuntos
Monoaminoxidase , Tomografia por Emissão de Pósitrons , Animais , Encéfalo , Gliose , Camundongos , Monoaminoxidase/metabolismo , Inibidores da Monoaminoxidase/química , Tomografia por Emissão de Pósitrons/métodosRESUMO
A neuroinflammatory reaction in Alzheimer disease (AD) brains involves reactive astrocytes that overexpress monoamine oxidase-B (MAO-B). 18F-(S)-(2-methylpyrid-5-yl)-6-[(3-fluoro-2-hydroxy)propoxy]quinoline (18F-SMBT-1) is a novel 18F PET tracer highly selective for MAO-B. We characterized the clinical performance of 18F-SMBT-1 PET across the AD continuum as a potential surrogate marker of reactive astrogliosis. Methods: We assessed 18F-SMBT-1 PET regional binding in 77 volunteers (76 ± 5.5 y old; 41 women, 36 men) across the AD continuum: 57 who were cognitively normal (CN) (44 amyloid-ß [Aß]-negative [Aß-] and 13 Aß-positive [Aß+]), 12 who had mild cognitive impairment (9 Aß- and 3 Aß+), and 8 who had AD dementia (6 Aß+ and 2 Aß-). All participants also underwent Aß and tau PET imaging, 3-T MRI, and neuropsychologic evaluation. Tau imaging results were expressed in SUV ratios using the cerebellar cortex as a reference region, whereas Aß burden was expressed in centiloids. 18F-SMBT-1 outcomes were expressed as SUV ratio using the subcortical white matter as a reference region. Results: 18F-SMBT-1 yielded high-contrast images at steady state (60-80 min after injection). When compared with the Aß- CN group, there were no significant differences in 18F-SMBT-1 binding in the group with Aß- mild cognitive impairment. Conversely, 18F-SMBT-1 binding was significantly higher in several cortical regions in the Aß+ AD group but also was significantly lower in the mesial temporal lobe and basal ganglia. Most importantly, 18F-SMBT-1 binding was significantly higher in the same regions in the Aß+ CN group as in the Aß- CN group. When all clinical groups were considered together, 18F-SMBT-1 correlated strongly with Aß burden and much less with tau burden. Although in most cortical regions 18F-SMBT-1 did not correlate with brain volumetrics, regions known for high MAO-B concentrations presented a direct association with hippocampal and gray matter volumes, whereas the occipital lobe was directly associated with white matter hyperintensity. 18F-SMBT-1 binding was inversely correlated with Mini Mental State Examination and the Australian Imaging Biomarkers and Lifestyle's Preclinical Alzheimer Cognitive Composite in some neocortical regions such as the frontal cortex, lateral temporal lobe, and supramarginal gyrus. Conclusion: Cross-sectional human PET studies with 18F-SMBT-1 showed that Aß+ AD patients, but most importantly, Aß+ CN individuals, had significantly higher regional 18F-SMBT-1 binding than Aß- CN individuals. Moreover, in several regions in the brain, 18F-SMBT-1 retention was highly associated with Aß load. These findings suggest that increased 18F-SMBT-1 binding is detectable at the preclinical stages of Aß accumulation, providing strong support for its use as a surrogate marker of astrogliosis in the AD continuum.