RESUMEN
BACKGROUND: Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. METHODS: We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-ß42 (Aß42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. RESULTS: NP with CAA had significantly lower CSF Aß42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aß42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CONCLUSIONS: CSF Aß42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.
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Péptidos beta-Amiloides , Biomarcadores , Angiopatía Amiloide Cerebral , Imagen por Resonancia Magnética , Fragmentos de Péptidos , Tomografía de Emisión de Positrones , Humanos , Péptidos beta-Amiloides/líquido cefalorraquídeo , Angiopatía Amiloide Cerebral/diagnóstico por imagen , Angiopatía Amiloide Cerebral/líquido cefalorraquídeo , Femenino , Masculino , Anciano , Fragmentos de Péptidos/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/líquido cefalorraquídeo , Anciano de 80 o más Años , Placa Amiloide/diagnóstico por imagenRESUMEN
The diagnostic value of imaging Aß plaques in Alzheimer's disease (AD) has accelerated the development of fluorine-18 labeled radiotracers with a longer half-life for easier translation to clinical use. We have developed [18F]flotaza, which shows high binding to Aß plaques in postmortem human AD brain slices with low white matter binding. We report the binding of [18F]flotaza in postmortem AD hippocampus compared to cognitively normal (CN) brains and the evaluation of [18F]flotaza in transgenic 5xFAD mice expressing Aß plaques. [18F]Flotaza binding was assessed in well-characterized human postmortem brain tissue sections consisting of HP CA1-subiculum (HP CA1-SUB) regions in AD (n = 28; 13 male and 15 female) and CN subjects (n = 32; 16 male and 16 female). Adjacent slices were immunostained with anti-Aß and analyzed using QuPath. In vitro and in vivo [18F]flotaza PET/CT studies were carried out in 5xFAD mice. Post-mortem human brain slices from all AD subjects were positively IHC stained with anti-Aß. High [18F]flotaza binding was measured in the HP CA1-SUB grey matter (GM) regions compared to white matter (WM) of AD subjects with GM/WM > 100 in some subjects. The majority of CN subjects had no decipherable binding. Male AD exhibited greater WM than AD females (AD WMâ/WMâ > 5; p < 0.001) but no difference amongst CN WM. In vitro studies in 5xFAD mice brain slices exhibited high binding [18F]flotaza ratios (>50 versus cerebellum) in the cortex, HP, and thalamus. In vivo, PET [18F]flotaza exhibited binding to Aß plaques in 5xFAD mice with SUVR~1.4. [18F]Flotaza is a new Aß plaque PET imaging agent that exhibited high binding to Aß plaques in postmortem human AD. Along with the promising results in 5xFAD mice, the translation of [18F]flotaza to human PET studies may be worthwhile.
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Enfermedad de Alzheimer , Radioisótopos de Flúor , Hipocampo , Placa Amiloide , Tomografía Computarizada por Tomografía de Emisión de Positrones , Anciano , Anciano de 80 o más Años , Animales , Femenino , Humanos , Masculino , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/genética , Autopsia , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Ratones Transgénicos , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Placa Amiloide/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Piridinas , Pirrolidinonas , Radiofármacos/farmacocinéticaRESUMEN
The relationship between amyloidosis and vasculature in cognitive impairment and Alzheimer's disease (AD) pathogenesis is increasingly acknowledged. We conducted a quantitative and topographic assessment of retinal perivascular amyloid plaque (AP) distribution in individuals with both normal and impaired cognition. Using a retrospective dataset of scanning laser ophthalmoscopy fluorescence images from twenty-eight subjects with varying cognitive states, we developed a novel image processing method to examine retinal peri-arteriolar and peri-venular curcumin-positive AP burden. We further correlated retinal perivascular amyloidosis with neuroimaging measures and neurocognitive scores. Our study unveiled that peri-arteriolar AP counts surpassed peri-venular counts throughout the entire cohort (P < 0.0001), irrespective of the primary, secondary, or tertiary vascular branch location, with a notable increase among cognitively impaired individuals. Moreover, secondary branch peri-venular AP count was elevated in the cognitively impaired (P < 0.01). Significantly, peri-venular AP count, particularly in secondary and tertiary venules, exhibited a strong correlation with clinical dementia rating, Montreal cognitive assessment score, hippocampal volume, and white matter hyperintensity count. In conclusion, our exploratory analysis detected greater peri-arteriolar versus peri-venular amyloidosis and a marked elevation of amyloid deposition in secondary branch peri-venular regions among cognitively impaired subjects. These findings underscore the potential feasibility of retinal perivascular amyloid imaging in predicting cognitive decline and AD progression. Larger longitudinal studies encompassing diverse populations and AD-biomarker confirmation are warranted to delineate the temporal-spatial dynamics of retinal perivascular amyloid deposition in cognitive impairment and the AD continuum.
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Amiloidosis , Atrofia , Disfunción Cognitiva , Hipocampo , Humanos , Masculino , Femenino , Anciano , Disfunción Cognitiva/patología , Disfunción Cognitiva/diagnóstico por imagen , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Atrofia/patología , Amiloidosis/patología , Amiloidosis/diagnóstico por imagen , Anciano de 80 o más Años , Estudios Retrospectivos , Persona de Mediana Edad , Placa Amiloide/patología , Placa Amiloide/diagnóstico por imagen , Enfermedades de la Retina/patología , Enfermedades de la Retina/diagnóstico por imagen , Vasos Retinianos/patología , Vasos Retinianos/diagnóstico por imagen , Oftalmoscopía/métodosRESUMEN
To date, earlier diagnosis of Alzheimer's disease (AD) is still challenging. Recent studies revealed the elevated expression of connective tissue growth factor (CTGF) in AD brain is an upstream regulator of amyloid-beta (Aß) plaque, thus CTGF could be an earlier diagnostic biomarker of AD than Aß plaque. Herein, we develop a peptide-coated gold nanocluster that specifically targets CTGF with high affinity (KD ~ 21.9 nM). The probe can well penetrate the blood-brain-barrier (BBB) of APP/PS1 transgenic mice at early-stage (earlier than 3-month-old) in vivo, allowing non-invasive NIR-II imaging of CTGF when there is no appearance of Aß plaque deposition. Notably, this probe can also be applied to measuring CTGF on postmortem brain sections by multimodal analysis, including fluorescence imaging, peroxidase-like chromogenic imaging, and ICP-MS quantitation, which enables distinguishment between the brains of AD patients and healthy people. This probe possesses great potential for precise diagnosis of earlier AD before Aß plaque formation.
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Enfermedad de Alzheimer , Encéfalo , Factor de Crecimiento del Tejido Conjuntivo , Ratones Transgénicos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Factor de Crecimiento del Tejido Conjuntivo/metabolismo , Animales , Humanos , Ratones , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Oro/química , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/diagnóstico por imagen , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Nanopartículas del Metal/química , Modelos Animales de Enfermedad , Péptidos beta-Amiloides/metabolismo , Femenino , Masculino , Imagen Multimodal/métodos , Biomarcadores/metabolismo , Imagen Óptica/métodosRESUMEN
QUESTION: Does neurodegenerative disease underlie the increased rate of dementia observed in older people with schizophrenia? Several studies have reported a higher prevalence of dementia in people with schizophrenia compared with the general population. This may reflect a higher risk of developing neurodegenerative diseases such as vascular dementia or Alzheimer's disease (AD). Alternatively, this may reflect non-pathological, age-related cognitive decline in a population with low cognitive reserve. STUDY SELECTION AND ANALYSIS: We reviewed papers that compared postmortem findings, hippocampal MRI volume or cerebrospinal fluid (CSF) markers of AD, between patients with schizophrenia with evidence of cognitive impairment (age ≥45 years) with controls. We subsequently performed a meta-analysis of postmortem studies that compared amyloid-ß plaques (APs) or neurofibrillary tangles (NFTs) in cognitively impaired patients with schizophrenia to normal controls or an AD group. FINDINGS: No studies found a significant increase of APs or NFTs in cognitively impaired patients with schizophrenia compared with controls. All postmortem studies that compared APs or NFTs in patients with schizophrenia to an AD group found significantly more APs or NFTs in AD. No studies found a significant differences in CSF total tau or phosphorylated tau between patients with schizophrenia and controls. The two studies which compared CSF Aß42 between patients with schizophrenia and controls found significantly decreased CSF Aß42 in schizophrenia compared with controls. Hippocampal volume findings were mixed. CONCLUSIONS: Studies have not found higher rates of AD-related pathology in cognitively impaired individuals with schizophrenia compared with controls. Higher rates of dementia identified in population studies may reflect a lack of specificity in clinical diagnostic tools used to diagnose dementia.
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Biomarcadores , Esquizofrenia , Humanos , Esquizofrenia/líquido cefalorraquídeo , Esquizofrenia/patología , Biomarcadores/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/líquido cefalorraquídeo , Enfermedades Neurodegenerativas/patología , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Ovillos Neurofibrilares/patología , Placa Amiloide/patología , Placa Amiloide/diagnóstico por imagenRESUMEN
Background: Amyloid-ß (Aß) plaques play a pivotal role in Alzheimer's disease. The current positron emission tomography (PET) is expensive and limited in availability. In contrast, blood-based biomarkers (BBBMs) show potential for characterizing Aß plaques more affordably. We have previously proposed an MRI-based hippocampal morphometry measure to be an indicator of Aß plaques. Objective: To develop and validate an integrated model to predict brain amyloid PET positivity combining MRI feature and plasma Aß42/40 ratio. Methods: We extracted hippocampal multivariate morphometry statistics from MR images and together with plasma Aß42/40 trained a random forest classifier to perform a binary classification of participant brain amyloid PET positivity. We evaluated the model performance using two distinct cohorts, one from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the other from the Banner Alzheimer's Institute (BAI), including prediction accuracy, precision, recall rate, F1 score, and AUC score. Results: Results from ADNI (mean age 72.6, Aß+ârate 49.5%) and BAI (mean age 66.2, Aß+ârate 36.9%) datasets revealed the integrated multimodal (IMM) model's superior performance over unimodal models. The IMM model achieved prediction accuracies of 0.86 in ADNI and 0.92 in BAI, surpassing unimodal models based solely on structural MRI (0.81 and 0.87) or plasma Aß42/40 (0.73 and 0.81) predictors. CONCLUSIONS: Our IMM model, combining MRI and BBBM data, offers a highly accurate approach to predict brain amyloid PET positivity. This innovative multiplex biomarker strategy presents an accessible and cost-effective avenue for advancing Alzheimer's disease diagnostics, leveraging diverse pathologic features related to Aß plaques and structural MRI.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Placa Amiloide/diagnóstico por imagen , Péptidos beta-Amiloides , Amiloide , Tomografía de Emisión de Positrones , Imagen por Resonancia Magnética , Biomarcadores , Disfunción Cognitiva/diagnóstico por imagen , Proteínas tauRESUMEN
This study presents the synthesis and characterization of two fluorescent norbornadiene (NBD) photoswitches, each incorporating two conjugated pyrene units. Expanding on the limited repertoire of reported photoswitchable fluorescent NBDs, we explore their properties with a focus on applications in bioimaging of amyloid beta (Aß) plaques. While the fluorescence emission of the NBD decreases upon photoisomerization, aligning with what has been previously reported, for the first time we observed luminescence after irradiation of the quadricyclane (QC) isomer. We deduce how the observed emission is induced by photoisomerization to the excited state of the parent isomer (NBD) which is then the emitting species. Thorough characterizations including NMR, UV-Vis, fluorescence, X-ray structural analysis and density functional theory (DFT) calculations provide a comprehensive understanding of these systems. Notably, one NBD-QC system exhibits exceptional durability. Additionally, these molecules serve as effective fluorescent stains targeting Aß plaques inâ situ, with observed NBD/QC switching within the plaques. Molecular docking simulations explore NBD interactions with amyloid, unveiling novel binding modes. These insights mark a crucial advancement in the comprehension and design of future photochromic NBDs for bioimaging applications and beyond, emphasizing their potential in studying and addressing protein aggregates.
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Péptidos beta-Amiloides , Colorantes Fluorescentes , Pirenos , Colorantes Fluorescentes/química , Pirenos/química , Péptidos beta-Amiloides/química , Péptidos beta-Amiloides/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Norbornanos/química , Placa Amiloide/química , Placa Amiloide/diagnóstico por imagen , Teoría Funcional de la Densidad , Isomerismo , Espectrometría de FluorescenciaRESUMEN
Alzheimer's disease is pathologically featured by the accumulation of amyloid-beta (Aß) plaque and neurofibrillary tangles. Compared to small animal positron emission tomography, optical imaging features nonionizing radiation, low cost, and logistic convenience. Optical detection of Aß deposits is typically implemented by 2D macroscopic imaging and various microscopic techniques assisted with Aß-targeted contrast agents. Here, we introduce fluorescence molecular tomography (FMT), a macroscopic 3D fluorescence imaging technique, convenient for in vivo longitudinal monitoring of the animal brain without the involvement of cranial window opening operation. This chapter aims to provide the protocols for FMT in vivo imaging of Aß deposits in the brain of rodent model of Alzheimer's disease. The materials, stepwise method, notes, limitations of FMT, and emerging opportunities for FMT techniques are presented.
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Enfermedad de Alzheimer , Amiloidosis , Ratones , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Medios de Contraste , Fluorescencia , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Tomografía de Emisión de Positrones/métodos , Placa Amiloide/diagnóstico por imagen , Ratones Transgénicos , Modelos Animales de EnfermedadRESUMEN
OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Femenino , Masculino , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Anciano de 80 o más Años , Estudios Transversales , Factores de Tiempo , Edad de Inicio , Estudios de Cohortes , Progresión de la Enfermedad , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/patologíaRESUMEN
In vivo imaging and accurate identification of amyloid-ß (Aß) plaque are crucial in Alzheimer's disease (AD) research. In this work, we propose to combine the coherent anti-Stokes Raman scattering (CARS) microscopy, a powerful detection technology for providing Raman spectra and label-free imaging, with deep learning to distinguish Aß from non-Aß regions in AD mice brains in vivo. The 1D CARS spectra is firstly converted to 2D CARS figures by using two different methods: spectral recurrence plot (SRP) and spectral Gramian angular field (SGAF). This can provide more learnable information to the network, improving the classification precision. We then devise a cross-stage attention network (CSAN) that automatically learns the features of Aß plaques and non-Aß regions by taking advantage of the computational advances in deep learning. Our algorithm yields higher accuracy, precision, sensitivity and specificity than the results of conventional multivariate statistical analysis method and 1D CARS spectra combined with deep learning, demonstrating its competence in identifying Aß plaques. Last but not least, the CSAN framework requires no prior information on the imaging modality and may be applicable to other spectroscopy analytical fields.
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Enfermedad de Alzheimer , Aprendizaje Profundo , Ratones , Animales , Espectrometría Raman , Péptidos beta-Amiloides/análisis , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Microscopía Óptica no Lineal , Placa Amiloide/diagnóstico por imagen , EncéfaloRESUMEN
Amyloid-ß (Aß) peptide deposition, hyperphosphorylated tau proteins, reactive astrocytes, high levels of metal ions, and upregulated monoamine oxidases are considered to be the primary pathological markers of Alzheimer's disease (AD). Among them, Aß peptide deposition or Aß plaques, is regarded as the initial factor in the pathogenesis of AD and a critical pathological hallmark in AD. This review highlights recently Aß-specific fluorescent probes for two-photon imaging of Aß plaques in vivo. It includes the synthesis and detection mechanism of probes, as well as their application to two-photon imaging of Aß plaques in vivo.
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Enfermedad de Alzheimer , Colorantes Fluorescentes , Humanos , Péptidos beta-Amiloides , Placa Amiloide/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico por imagen , Diagnóstico por ImagenRESUMEN
Real-time studies of biomarkers for neurological disorders present significant opportunities for diagnosing and treating related diseases, and fluorescent probes offer a promising approach to brain imaging. However, intracerebral fluorescence imaging is often limited by blood-brain barrier permeability and penetration depth. Moreover, only very few probes have rapid intracerebral metabolic properties, which are critical for in vivo imaging. Here, we developed a novel class of fluorescent dyes with two-photon excitation and near-infrared (NIR) emission (920/705 nm). The representative WAPP-4 probe exhibits a large Stokes shift (Δλ = 324 nm in ethanol) and excellent blood-brain barrier permeability. Notably, using WAPP-4, we achieved in vivo 3D dynamic imaging of Aß plaques in the brains of living mice with Alzheimer's disease (AD). In addition, super-resolution imaging showed that WAPP-4 could effectively characterize the distribution and shape of Aß plaques in isolated brain slices. This study demonstrates that newly developed fluorescent dyes with large Stokes shifts and blood-brain barrier permeability enable real-time imaging of amyloid plaques, which will contribute to the development of other valuable tools for near-infrared imaging and super-resolution imaging in the brain.
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Técnicas Biosensibles , Colorantes Fluorescentes , Animales , Ratones , Placa Amiloide/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Barrera Hematoencefálica , Cloruro de PoliviniloRESUMEN
Amyloid-ß (Aß) plaques from Alzheimer's Disease (AD) can be visualized ex vivo in label-free brain samples using synchrotron X-ray phase-contrast tomography (XPCT). However, for XPCT to be useful as a screening method for amyloid pathology, it is essential to understand which factors drive the detection of Aß plaques. The current study was designed to test the hypothesis that Aß-related contrast in XPCT could be caused by Aß fibrils and/or by metals trapped in the plaques. Fibrillar and elemental compositions of Aß plaques were probed in brain samples from different types of AD patients and AD models to establish a relationship between XPCT contrast and Aß plaque characteristics. XPCT, micro-Fourier-Transform Infrared spectroscopy and micro-X-Ray Fluorescence spectroscopy were conducted on human samples (one genetic and one sporadic case) and on four transgenic rodent strains (mouse: APPPS1, ArcAß, J20; rat: TgF344). Aß plaques from the genetic AD patient were visible using XPCT, and had higher ß-sheet content and higher metal levels than those from the sporadic AD patient, which remained undetected by XPCT. Aß plaques in J20 mice and TgF344 rats appeared hyperdense on XPCT images, while they were hypodense with a hyperdense core in the case of APPPS1 and ArcAß mice. In all four transgenic strains, ß-sheet content was similar, while metal levels were highly variable: J20 (zinc and iron) and TgF344 (copper) strains showed greater metal accumulation than APPPS1 and ArcAß mice. Hence, a hyperdense contrast formation of Aß plaques in XPCT images was associated with biometal entrapment within plaques. STATEMENT OF SIGNIFICANCE: The role of metals in Alzheimer's disease (AD) has been a subject of continuous interest. It was already known that amyloid-ß plaques (Aß), the earliest hallmark of AD, tend to trap endogenous biometals like zinc, iron and copper. Here we show that this metal accumulation is the main reason why Aß plaques are detected with a new technique called X-ray phase contrast tomography (XPCT). XPCT enables to map the distribution of Aß plaques in the whole excised brain without labeling. In this work we describe a unique collection of four transgenic models of AD, together with a human sporadic and a rare genetic case of AD, thus exploring the full spectrum of amyloid contrast in XPCT.
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Enfermedad de Alzheimer , Oligoelementos , Humanos , Ratones , Animales , Ratas , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Cobre/química , Rayos X , Ratones Transgénicos , Péptidos beta-Amiloides/metabolismo , Metales , Zinc/química , Hierro , Encéfalo/metabolismo , Amiloide , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/química , Modelos Animales de EnfermedadRESUMEN
Alzheimer's disease (AD), with incurable neurodegenerative damage, has attracted growing interest in exploration of better AD biomarkers in its early diagnosis. Among various biomarkers, amyloid-ß (Aß) aggregates and mitochondrial viscosity are closely related to AD and their dual imaging might provide a potential and feasible strategy. In this work, five GFP-based red-emissive fluorescent probes were rationally designed and synthesized for selective detection of ß-amyloid plaques and viscosity, among which C25e exhibited superior properties and could successfully image ß-amyloid plaques and mitochondrial viscosity with different fluorescence wavelength signals "turn-on" at around 624 and 640 nm, respectively. Moreover, the staining of brain sections from a transgenic AD mouse showed that probe C25e showed higher selectivity and signal-to-noise ratio towards Aß plaques than commercially-available Thio-S. In addition, the probe C25e was, for the first time, employed for monitoring amyloid-ß induced mitochondrial viscosity changes. Therefore, this GFP-based red-emissive fluorescent probe C25e could serve as a dual-functional tool for imaging ß-amyloid plaques and mitochondrial viscosity, which might provide a unique strategy for the early diagnosis of Alzheimer's disease.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Ratones , Animales , Péptidos beta-Amiloides/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Colorantes Fluorescentes , Placa Amiloide/diagnóstico por imagen , Viscosidad , Ratones Transgénicos , Encéfalo/metabolismoRESUMEN
Natural products often provide a pool of pharmacologically relevant precursors for the development of various drug-related molecules. In this review, the research performed on some radiolabeled chalcone derivatives characterized by the presence of the α-ß unsaturated carbonyl functional group as potential radiotracers for the imaging of ß-amyloids plaques will be summarized. Chalcones' structural modifications and chemical approaches which allow their radiolabeling with the most common SPECT (Single Photon Emission Computed Tomography) and PET (Positron Emission Tomography) radionuclides will be described, as well as the state of the art regarding their in vitro binding affinity and in vivo biodistribution and pharmacokinetics in preclinical studies. Moreover, an explanation of the rationale behind their potential utilization as probes for Alzheimer's disease in nuclear medicine applications will be provided.
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Enfermedad de Alzheimer , Chalcona , Chalconas , Humanos , Péptidos beta-Amiloides/metabolismo , Chalcona/metabolismo , Chalconas/química , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Distribución Tisular , Encéfalo/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Tomografía de Emisión de Positrones , Tomografía Computarizada de Emisión de Fotón ÚnicoRESUMEN
Beta-amyloid (Aß) plaque pathology is one of the most prominent histopathological feature of Alzheimer's disease (AD). The exact pathogenic mechanisms linking Aß to AD pathogenesis remain however not fully understood. Recent advances in amyloid-targeting pharmacotherapies highlight the critical relevance of Aß aggregation for understanding the molecular basis of AD pathogenesis. We developed a novel, integrated, tetramodal chemical imaging paradigm for acquisition of trimodal mass spectrometry imaging (MSI) and interlaced fluorescent microscopy from a single tissue section. We used this approach to comprehensively investigate lipid-Aß correlates at single plaques in two different mouse models of AD (tgAPPSwe and tgAPPArcSwe) with varying degrees of intrinsic properties affecting amyloid aggregation. Integration of the multimodal imaging data and multivariate data analysis identified characteristic patterns of plaque-associated lipid- and peptide localizations across both mouse models. Correlative fluorescence microscopy using structure-sensitive amyloid probes identified intra-plaque structure-specific lipid- and Aß patterns, including Aß 1-40 and Aß 1-42 along with gangliosides (GM), phosphoinositols (PI), conjugated ceramides (CerP and PE-Cer), and lysophospholipids (LPC, LPA, and LPI). Single plaque correlation analysis across all modalities further revealed how these distinct lipid species were associated with Aß peptide deposition across plaque heterogeneity, indicating different roles for those lipids in plaque growth and amyloid fibrillation, respectively. Here, conjugated ceramide species correlated with Aß core formation indicating their involvement in initial plaque seeding or amyloid maturation. In contrast, LPI and PI were solely correlated with general plaque growth. In addition, GM1 and LPC correlated with continuous Aß deposition and maturation. The results highlight the potential of this comprehensive multimodal imaging approach and implement distinct lipids in amyloidogenic proteinopathy.
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Enfermedad de Alzheimer , Ratones , Animales , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Ratones Transgénicos , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Péptidos beta-Amiloides/química , Modelos Animales de Enfermedad , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/patología , Lípidos , Encéfalo/metabolismoRESUMEN
BACKGROUND: The amyloid probability score (APS) is the model read-out of the analytically validated mass spectrometry-based PrecivityAD® blood test that incorporates the plasma Aß42/40 ratio, ApoE proteotype, and age to identify the likelihood of brain amyloid plaques among cognitively impaired individuals being evaluated for Alzheimer's disease. PURPOSE: This study aimed to provide additional independent evidence that the pre-established APS algorithm, along with its cutoff values, discriminates between amyloid positive and negative individuals. METHODS: The diagnostic performance of the PrecivityAD test was analyzed in a cohort of 200 nonrandomly selected Australian Imaging, Biomarker & Lifestyle Flagship Study of Aging (AIBL) study participants, who were either cognitively impaired or healthy controls, and for whom a blood sample and amyloid PET imaging were available. RESULTS: In a subset of the dataset aligned with the Intended Use population (patients aged 60 and older with CDR ≥0.5), the pre-established APS algorithm predicted amyloid PET with a sensitivity of 84.9% (CI: 72.9-92.1%) and specificity of 96% (CI: 80.5-99.3%), exclusive of 13 individuals for whom the test was inconclusive. INTERPRETATION: The study shows individuals with a high APS are more likely than those with a low APS to have abnormal amounts of amyloid plaques and be on an amyloid accumulation trajectory, a dynamic and evolving process characteristic of progressive AD pathology. Exploratory data suggest APS retains its diagnostic performance in healthy individuals, supporting further screening studies in the cognitively unimpaired.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Persona de Mediana Edad , Anciano , Placa Amiloide/diagnóstico por imagen , Australia , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Envejecimiento/patología , AmiloideRESUMEN
Accurate quantification of amyloid beta (Aß) plaques is an important indicator for Alzheimer's disease diagnosis and treatment. For this purpose, new highly sensitive Aß tracers were designed by regulating the position and number of nitrogen atoms. A series of derivatives of florbetapir (AV45) containing different numbers and positions of N atoms were synthesized and evaluated for in vitro affinity and in vivo biodistribution. Preliminary study results showed that [18F]BIBD-124 and [18F]BIBD-127 had better clearance rates and less in vivo defluorination than AV45 in ICR (ICR = Institute of Cancer Research) mice. Autoradiography and molecular docking indicated that the binding sites of [18F]BIBD-124/127 were similar to that of [18F]AV45. Micro-positron emission tomography-computed tomography imaging further demonstrated that [18F]BIBD-124 could monitor Aß plaques similar to [18F]AV45. Besides, the imaging contrast of [18F]BIBD-124 is better than that of [18F]AV45. Mass spectrometric metabolic analysis showed that BIBD-124 was less demethylated than AV45 without subsequent acetylation, which might explain its less non-specific uptake and higher imaging contrast. Gauss calculations further confirmed that the introduction of N5 in [18F]BIBD-124 decreased demethylation. Considering imaging contrast and in vivo defluorination, [18F]BIBD-124 is expected to be a promising radiotracer of Aß plaques for further clinical trials.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales , Ratones , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Ratones Endogámicos ICR , Simulación del Acoplamiento Molecular , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Distribución Tisular , Radioisótopos de FlúorRESUMEN
Radioiodinated imaging agents for Aß amyloid plaque imaging in Alzheimer's disease (AD) patients have not been actively pursued. Our previous studies employed the "diaza" derivatives [11C]TAZA and [18F]flotaza in order to develop successful positron emission tomography (PET) imaging agents for Aß plaques. There is a need for radioiodinated imaging agents for Aß plaques for single photon emission computed tomography (SPECT) and PET imaging. We report our findings on the preparation of [124/125I]IAZA, a "diaza" analog of [11C]TAZA and [18F]flotaza, and the evaluation of binding to Aß plaques in the postmortem human AD brain. The binding affinity of IAZA for Aß plaques was Ki = 10.9 nM with weak binding affinity for neurofibrillary tangles (Ki = 3.71 µM). Both [125I]IAZA and [124I]IAZA were produced in >25% radiochemical yield and >90% radiochemical purity. In vitro binding of [125I]IAZA and [124I]IAZA in postmortem human AD brains was higher in gray matter containing Aß plaques compared to white matter (ratio of gray to white matter was >7). Anti-Aß immunostaining strongly correlated with [124/125I]IAZA in postmortem AD human brains. The binding of [124/125I]IAZA in postmortem human AD brains was displaced by the known Aß plaque imaging agents. Thus, radiolabeled [124/123I]IAZA may potentially be a useful PET or SPECT radioligand for Aß plaques in brain imaging studies.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Radioisótopos de Yodo/metabolismo , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/metabolismo , Péptidos beta-Amiloides/metabolismoRESUMEN
Fibrillar aggregates of the amyloid-ß protein (Aß) are the main component of the senile plaques found in brains of patients with Alzheimer's disease (AD). Development of probes allowing the noninvasive and high-fidelity mapping of Aß plaques in vivo is critical for AD early detection, drug screening and biomedical research. QM-FN-SO3 (quinoline-malononitrile-thiophene-(dimethylamino)phenylsulfonate) is a near-infrared aggregation-induced-emission-active fluorescent probe capable of crossing the blood-brain barrier (BBB) and ultrasensitively lighting up Aß plaques in living mice. Herein, we describe detailed procedures for the two-stage synthesis of QM-FN-SO3 and its applications for mapping Aß plaques in brain tissues and living mice. Compared with commercial thioflavin (Th) derivatives ThT and ThS (the gold standard for detection of Aß aggregates) and other reported Aß plaque fluorescent probes, QM-FN-SO3 confers several advantages, such as long emission wavelength, large Stokes shift, ultrahigh sensitivity, good BBB penetrability and miscibility in aqueous biological media. The preparation of QM-FN-SO3 takes ~2 d, and the confocal imaging experiments for Aß plaque visualization, including the preparation for mouse brain sections, take ~7 d. Notably, acquisition and analyses for in vivo visualization of Aß plaques in mice can be completed within 1 h and require only a basic knowledge of spectroscopy and chemistry.