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Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-ß (Aß) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aß and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (ß (SE)â=â-0.021(0.008), pâ=â0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (ß (SE)â=â-0.035(0.009), pâ=â0.001), inferior temporal (ß (SE)â=â-0.029(0.010), pâ=â0.012), and rhinal cortex tau(ß (SE)â=â-0.033(0.010), pâ=â0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities.
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Péptidos beta-Amiloides , Ejercicio Físico , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Masculino , Femenino , Proteínas tau/metabolismo , Persona de Mediana Edad , Péptidos beta-Amiloides/metabolismo , Ejercicio Físico/fisiología , Estudios Transversales , Anciano , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Estudios de CohortesRESUMEN
Positron emission tomography (PET) imaging employs positron-emitting radioisotopes to visualize biological processes in living subjects with high sensitivity and quantitative accuracy. As the most translational molecular imaging modality, PET can detect and image a wide range of radiotracers with minimal or no modification to parent drugs or targeting molecules. This Perspective provides a comprehensive analysis of developing PET radioligands using allosteric modulators for the metabotropic glutamate receptor subtype 4 (mGluR4) as a therapeutic target for neurological disorders. We focus on the selection of lead compounds from various chemotypes of mGluR4 positive allosteric modulators (PAMs) and discuss the challenges and systematic characterization required in developing brain-penetrant PET tracers specific for mGluR4. Through this analysis, we offer insights into the development and evaluation of PET ligands. Our review concludes that further research and development in this field hold great promise for discovering effective treatments for neurological disorders.
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Tomografía de Emisión de Positrones , Radiofármacos , Receptores de Glutamato Metabotrópico , Tomografía de Emisión de Positrones/métodos , Humanos , Receptores de Glutamato Metabotrópico/metabolismo , Animales , Radiofármacos/química , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Regulación Alostérica , LigandosRESUMEN
PURPOSE: To develop a practical method to enable 3D T1 mapping of brain metabolites. THEORY AND METHODS: Due to the high dimensionality of the imaging problem underlying metabolite T1 mapping, measurement of metabolite T1 values has been currently limited to a single voxel or slice. This work achieved 3D metabolite T1 mapping by leveraging a recent ultrafast MRSI technique called SPICE (spectroscopic imaging by exploiting spatiospectral correlation). The Ernst-angle FID MRSI data acquisition used in SPICE was extended to variable flip angles, with variable-density sparse sampling for efficient encoding of metabolite T1 information. In data processing, a novel generalized series model was used to remove water and subcutaneous lipid signals; a low-rank tensor model with prelearned subspaces was used to reconstruct the variable-flip-angle metabolite signals jointly from the noisy data. RESULTS: The proposed method was evaluated using both phantom and healthy subject data. Phantom experimental results demonstrated that high-quality 3D metabolite T1 maps could be obtained and used for correction of T1 saturation effects. In vivo experimental results showed metabolite T1 maps with a large spatial coverage of 240 × 240 × 72 mm3 and good reproducibility coefficients (< 11%) in a 14.5-min scan. The metabolite T1 times obtained ranged from 0.99 to 1.44 s in gray matter and from 1.00 to 1.35 s in white matter. CONCLUSION: We successfully demonstrated the feasibility of 3D metabolite T1 mapping within a clinically acceptable scan time. The proposed method may prove useful for both T1 mapping of brain metabolites and correcting the T1-weighting effects in quantitative metabolic imaging.
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Algoritmos , Encéfalo , Imagenología Tridimensional , Imagen por Resonancia Magnética , Fantasmas de Imagen , Humanos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Imagenología Tridimensional/métodos , Imagen por Resonancia Magnética/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Masculino , Mapeo Encefálico/métodos , Espectroscopía de Resonancia Magnética/métodos , Adulto , Reproducibilidad de los Resultados , FemeninoRESUMEN
People with human immunodeficiency virus (HIV, PWH) face an increased risk of cardiovascular disease (CVD) compared to the general population. We previously demonstrated that people with (versus without) HIV have higher macrophage-specific arterial infiltration in relation to systemic monocyte activation. We now show that select T lymphocyte subpopulations (naïve CD4+, effector memory CD4+, and central memory CD8+) are differentially associated with macrophage-specific arterial infiltration among participants with versus without HIV, with evidence of interaction by HIV status. Our results suggest that among PWH, circulating T lymphocytes associate with macrophage-specific arterial infiltration, of relevance to atherogenesis and CVD risk. CLINICAL TRIALS REGISTRATION: NCT02542371.
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Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; pâ=â0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEÉ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.
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Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Proteínas tau/sangre , Masculino , Femenino , Persona de Mediana Edad , Estudios Transversales , Anciano , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Tiazoles , Compuestos de Anilina , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Biomarcadores/sangre , CarbolinasRESUMEN
BACKGROUND: 4-Aminopyridine (4AP) is a medication for the symptomatic treatment of multiple sclerosis. Several 4AP-based PET tracers have been developed for imaging demyelination. In preclinical studies, [11C]3MeO4AP has shown promise due to its high brain permeability, high metabolic stability, high plasma availability, and high in vivo binding affinity. To prepare for the translation to human studies, we developed a cGMP-compatible automated radiosynthesis protocol and evaluated the whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP in non-human primates (NHPs). METHODS: Automated radiosynthesis was carried out using a GE TRACERlab FX-C Pro synthesis module. One male and one female adult rhesus macaques were used in the study. A high-resolution CT from cranial vertex to knee was acquired. PET data were collected using a dynamic acquisition protocol with four bed positions and 13 passes over a total scan time of ~ 150 min. Based on the CT and PET images, volumes of interest (VOIs) were manually drawn for selected organs. Non-decay corrected time-activity curves (TACs) were extracted for each VOI. Radiation dosimetry and effective dose were calculated from the integrated TACs using OLINDA software. RESULTS: Fully automated radiosynthesis of [11C]3MeO4AP was achieved with 7.3 ± 1.2% (n = 4) of non-decay corrected radiochemical yield within 38 min of synthesis and purification time. [11C]3MeO4AP distributed quickly throughout the body and into the brain. The organs with highest dose were the kidneys. The average effective dose of [11C]3MeO4AP was 4.0 ± 0.6 µSv/MBq. No significant changes in vital signs were observed during the scan. CONCLUSION: A cGMP-compatible automated radiosynthesis of [11C]3MeO4AP was developed. The whole-body biodistribution and radiation dosimetry of [11C]3MeO4AP was successfully evaluated in NHPs. [11C]3MeO4AP shows lower average effective dose than [18F]3F4AP and similar average effective dose as other carbon-11 tracers.
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Objective.Performing positron emission tomography (PET) denoising within the image space proves effective in reducing the variance in PET images. In recent years, deep learning has demonstrated superior denoising performance, but models trained on a specific noise level typically fail to generalize well on different noise levels, due to inherent distribution shifts between inputs. The distribution shift usually results in bias in the denoised images. Our goal is to tackle such a problem using a domain generalization technique.Approach.We propose to utilize the domain generalization technique with a novel feature space continuous discriminator (CD) for adversarial training, using the fraction of events as a continuous domain label. The core idea is to enforce the extraction of noise-level invariant features. Thus minimizing the distribution divergence of latent feature representation for different continuous noise levels, and making the model general for arbitrary noise levels. We created three sets of 10%, 13%-22% (uniformly randomly selected), or 25% fractions of events from 9718F-MK6240 tau PET studies of 60 subjects. For each set, we generated 20 noise realizations. Training, validation, and testing were implemented using 1400, 120, and 420 pairs of 3D image volumes from the same or different sets. We used 3D UNet as the baseline and implemented CD to the continuous noise level training data of 13%-22% set.Main results.The proposed CD improves the denoising performance of our model trained in a 13%-22% fraction set for testing in both 10% and 25% fraction sets, measured by bias and standard deviation using full-count images as references. In addition, our CD method can improve the SSIM and PSNR consistently for Alzheimer-related regions and the whole brain.Significance.To our knowledge, this is the first attempt to alleviate the performance degradation in cross-noise level denoising from the perspective of domain generalization. Our study is also a pioneer work of continuous domain generalization to utilize continuously changing source domains.
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Imagenología Tridimensional , Tomografía de Emisión de Positrones , Humanos , Relación Señal-Ruido , Tomografía de Emisión de Positrones/métodos , Imagenología Tridimensional/métodos , Encéfalo , Procesamiento de Imagen Asistido por Computador/métodos , AlgoritmosRESUMEN
Stimulation of the M4 muscarinic acetylcholine receptor reduces striatal hyperdopaminergia, suggesting its potential as a therapeutic target for schizophrenia. Emraclidine (CVL-231) is a novel, highly selective, positive allosteric modulator (PAM) of M4 muscarinic acetylcholine receptors i.e. acts as a modulator that increases the response of these receptors. First, we aimed to further characterize the positron emission tomography (PET) imaging and quantification performance of a recently developed M4 PAM radiotracer, [11C]MK-6884, in non-human primates (NHPs). Second, we applied these results to determine the receptor occupancy of CVL-231 as a function of dose. Using paired baseline-blocking PET scans, we quantified total volume of distribution, binding potential, and receptor occupancy. Both blood-based and reference region-based methods quantified M4 receptor levels across brain regions. The 2-tissue 4-parameter kinetic model best fitted regional [11C]MK-6884-time activity curves. Only the caudate nucleus and putamen displayed statistically significant [11C]MK-6884 uptake and dose-dependent blocking by CVL-231. For binding potential and receptor occupancy quantification, the simplified reference tissue model using the grey cerebellum as a reference region was employed. CVL-231 demonstrated dose-dependent M4 receptor occupancy in the striatum of the NHP brain and shows promise for further development in clinical trials.
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Macaca mulatta , Tomografía de Emisión de Positrones , Receptor Muscarínico M4 , Animales , Tomografía de Emisión de Positrones/métodos , Receptor Muscarínico M4/metabolismo , Regulación Alostérica , Masculino , Radioisótopos de Carbono , Óxidos S-Cíclicos/farmacología , Radiofármacos/farmacocinética , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Cinética , Femenino , Compuestos de Azabiciclo/farmacología , Compuestos de Azabiciclo/farmacocinéticaRESUMEN
BACKGROUND: Accurate gross tumor volume (GTV) delineation is a critical step in radiation therapy treatment planning. However, it is reader dependent and thus susceptible to intra- and inter-reader variability. GTV delineation of soft tissue sarcoma (STS) often relies on CT and MR images. PURPOSE: This study investigates the potential role of 18F-FDG PET in reducing intra- and inter-reader variability thereby improving reproducibility of GTV delineation in STS, without incurring additional costs or radiation exposure. MATERIALS AND METHODS: Three readers performed independent GTV delineation of 61 patients with STS using first CT and MR followed by CT, MR, and 18F-FDG PET images. Each reader performed a total of six delineation trials, three trials per imaging modality group. Dice Similarity Coefficient (DSC) score and Hausdorff distance (HD) were used to assess both intra- and inter-reader variability using generated simultaneous truth and performance level estimation (STAPLE) GTVs as ground truth. Statistical analysis was performed using a Wilcoxon signed-ranked test. RESULTS: There was a statistically significant decrease in both intra- and inter-reader variability in GTV delineation using CT, MR 18F-FDG PET images vs. CT and MR images. This was translated by an increase in the DSC score and a decrease in the HD for GTVs drawn from CT, MR and 18F-FDG PET images vs. GTVs drawn from CT and MR for all readers and across all three trials. CONCLUSION: Incorporation of 18F-FDG PET into CT and MR images decreased intra- and inter-reader variability and subsequently increased reproducibility of GTV delineation in STS.
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Fluorodesoxiglucosa F18 , Imagen por Resonancia Magnética , Tomografía de Emisión de Positrones , Sarcoma , Carga Tumoral , Humanos , Sarcoma/diagnóstico por imagen , Sarcoma/patología , Sarcoma/radioterapia , Tomografía de Emisión de Positrones/métodos , Femenino , Masculino , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Radiofármacos , Variaciones Dependientes del Observador , Adulto , Anciano , Reproducibilidad de los Resultados , Tomografía Computarizada por Rayos X/métodos , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/radioterapia , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
BACKGROUND: Understanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps. METHODS: Across 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABAA (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography. RESULTS: Results revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies. CONCLUSIONS: Acute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in µ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD.
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BACKGROUND AND OBJECTIVES: Both short and long sleep duration were previously associated with incident dementia, but underlying mechanisms remain unclear. We evaluated how self-reported sleep duration and its change over time associate with (A)myloid, (T)au, (N)eurodegeneration, and (V)ascular neuroimaging markers of Alzheimer disease. METHODS: Two Framingham Heart Study overlapping samples were studied: participants who underwent 11C-Pittsburg Compound B amyloid and 18F-flortaucipir tau PET imaging and participants who underwent an MRI. MRI metrics estimated neurodegeneration (total brain volume) and cerebrovascular injuries (white matter hyperintensities [WMHs] volume, covert brain infarcts, free-water [FW] fraction). Self-reported sleep duration was assessed and split into categories both at the time of neuroimaging testing and approximately 13 years before: short ≤6 hours. average 7-8 hours, and long ≥9 hours. Logistic and linear regression models were used to examine sleep duration and neuroimaging metrics. RESULTS: The tested cohort was composed of 271 participants (age 53.6 ± 8.0 years; 51% male) in the PET imaging sample and 2,165 participants (age 61.3 ± 11.1 years; 45% male) in the MRI sample. No fully adjusted association was observed between cross-sectional sleep duration and neuroimaging metrics. In fully adjusted models compared with consistently sleeping 7-8 hours, groups transitioning to a longer sleep duration category over time had higher FW fraction (short to average ß [SE] 0.0062 [0.0024], p = 0.009; short to long ß [SE] 0.0164 [0.0076], p = 0.031; average to long ß [SE] 0.0083 [0.0022], p = 0.002), and those specifically going from average to long sleep duration also had higher WMH burden (ß [SE] 0.29 [0.11], p = 0.007). The opposite associations (lower WMH and FW) were observed in participants consistently sleeping ≥9 hours as compared with people consistently sleeping 7-8 hours in fully adjusted models (ß [SE] -0.43 [0.20], p = 0.028; ß [SE] -0.019 [0.004], p = 0.020). Each hour of increasing sleep (continuous, ß [SE] 0.12 [0.04], p = 0.003; ß [SE] 0.002 [0.001], p = 0.021) and extensive increase in sleep duration (≥2 hours vs 0 ± 1 hour change; ß [SE] 0.24 [0.10], p = 0.019; ß [SE] 0.0081 [0.0025], p = 0.001) over time was associated with higher WMH burden and FW fraction in fully adjusted models. Sleep duration change was not associated with PET amyloid or tau outcomes. DISCUSSION: Longer self-reported sleep duration over time was associated with neuroimaging biomarkers of cerebrovascular pathology as evidenced by higher WMH burden and FW fraction. A longer sleep duration extending over time may be an early change in the neurodegenerative trajectory.
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Proteínas Amiloidogénicas , Duración del Sueño , Masculino , Humanos , Persona de Mediana Edad , Anciano , Femenino , Estudios Transversales , Neuroimagen , BiomarcadoresRESUMEN
We and others have shown that [18F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [18F]-MK-6240 and [18F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [18F]-MK-6240 closely parallels that of [18F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [18F]-Flortaucipir, [18F]-MK-6240 and [18F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing ß-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers.
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Enfermedad de Alzheimer , Carbolinas , Isoquinolinas , Enfermedades Neurodegenerativas , Piridinas , Tauopatías , Humanos , Enfermedades Neurodegenerativas/patología , Melaninas/metabolismo , Encéfalo/patología , Tauopatías/patología , Monoaminooxidasa/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones/métodos , Enfermedad de Alzheimer/patologíaRESUMEN
PURPOSE: Due to various physical degradation factors and limited counts received, PET image quality needs further improvements. The denoising diffusion probabilistic model (DDPM) was a distribution learning-based model, which tried to transform a normal distribution into a specific data distribution based on iterative refinements. In this work, we proposed and evaluated different DDPM-based methods for PET image denoising. METHODS: Under the DDPM framework, one way to perform PET image denoising was to provide the PET image and/or the prior image as the input. Another way was to supply the prior image as the network input with the PET image included in the refinement steps, which could fit for scenarios of different noise levels. 150 brain [[Formula: see text]F]FDG datasets and 140 brain [[Formula: see text]F]MK-6240 (imaging neurofibrillary tangles deposition) datasets were utilized to evaluate the proposed DDPM-based methods. RESULTS: Quantification showed that the DDPM-based frameworks with PET information included generated better results than the nonlocal mean, Unet and generative adversarial network (GAN)-based denoising methods. Adding additional MR prior in the model helped achieved better performance and further reduced the uncertainty during image denoising. Solely relying on MR prior while ignoring the PET information resulted in large bias. Regional and surface quantification showed that employing MR prior as the network input while embedding PET image as a data-consistency constraint during inference achieved the best performance. CONCLUSION: DDPM-based PET image denoising is a flexible framework, which can efficiently utilize prior information and achieve better performance than the nonlocal mean, Unet and GAN-based denoising methods.
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Procesamiento de Imagen Asistido por Computador , Tomografía de Emisión de Positrones , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Tomografía de Emisión de Positrones/métodos , Relación Señal-Ruido , Modelos Estadísticos , AlgoritmosRESUMEN
Cardiac cine magnetic resonance imaging (MRI) has been used to characterize cardiovascular diseases (CVD), often providing a noninvasive phenotyping tool. While recently flourished deep learning based approaches using cine MRI yield accurate characterization results, the performance is often degraded by small training samples. In addition, many deep learning models are deemed a "black box," for which models remain largely elusive in how models yield a prediction and how reliable they are. To alleviate this, this work proposes a lightweight successive subspace learning (SSL) framework for CVD classification, based on an interpretable feedforward design, in conjunction with a cardiac atlas. Specifically, our hierarchical SSL model is based on (i) neighborhood voxel expansion, (ii) unsupervised subspace approximation, (iii) supervised regression, and (iv) multi-level feature integration. In addition, using two-phase 3D deformation fields, including end-diastolic and end-systolic phases, derived between the atlas and individual subjects as input offers objective means of assessing CVD, even with small training samples. We evaluate our framework on the ACDC2017 database, comprising one healthy group and four disease groups. Compared with 3D CNN-based approaches, our framework achieves superior classification performance with 140× fewer parameters, which supports its potential value in clinical use.
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Gabapentin, a selective ligand for the α2δ subunit of voltage-dependent calcium channels, is an anticonvulsant medication used in the treatment of neuropathic pain, epilepsy, and other neurological conditions. We recently described two radiofluorinated derivatives of gabapentin (trans-4-[18F]fluorogabapentin, [18F]tGBP4F, and cis-4-[18F]fluorogabapentin, [18F]cGBP4F) and showed that these compounds accumulate in the injured nerves in a rodent model of neuropathic pain. Given the use of gabapentin in brain diseases, here we investigate whether these radiofluorinated derivatives of gabapentin can be used for imaging α2δ receptors in the brain. Specifically, we developed automated radiosynthesis methods for [18F]tGBP4F and [18F]cGBP4F and conducted dynamic PET imaging in adult rhesus macaques with and without preadministration of pharmacological doses of gabapentin. Both radiotracers showed very high metabolic stability, negligible plasma protein binding, and slow accumulation in the brain. [18F]tGBP4F, the isomer with higher binding affinity, showed low brain uptake and could not be displaced, whereas [18F]cGBP4F showed moderate brain uptake and could be partially displaced. Kinetic modeling of brain regional time-activity curves using a metabolite-corrected arterial input function shows that a one-tissue compartment model accurately fits the data. Graphical analysis using Logan or multilinear analysis 1 produced similar results as compartmental modeling, indicating robust quantification. This study advances our understanding of how gabapentinoids work and provides an important advancement toward imaging α2δ receptors in the brain.
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Neuralgia , Tomografía de Emisión de Positrones , Animales , Gabapentina/farmacología , Gabapentina/metabolismo , Macaca mulatta , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Neuralgia/metabolismoRESUMEN
BACKGROUND AND OBJECTIVES: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with ß-amyloid (Aß) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aß, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aß and tau. METHODS: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aß imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aß, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. RESULTS: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aß burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aß and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. DISCUSSION: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aß or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Masculino , Humanos , Femenino , Anciano , Persona de Mediana Edad , Anciano de 80 o más Años , Proteínas tau , Estudios Prospectivos , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides , Disfunción Cognitiva/diagnóstico por imagen , Biomarcadores , Atrofia , Tomografía de Emisión de PositronesRESUMEN
Background: Multidisciplinary management is crucial in cancer diagnosis and treatment. Multidisciplinary teams include specialists in surgery, medical therapies, and radiation therapy (RT), each playing unique roles in oncology care. One significant aspect is RT, guided by radiation oncologists (ROs). This paper serves as a detailed primer for non-oncologists, medical students, or non-clinical investigators, educating them on contemporary RT practices. Methods: This report follows the process of RT planning and execution. Starting from the decision-making in multidisciplinary teams to the completion of RT and subsequent patient follow-up, it aims to offer non-oncologists an understanding of the RO's work in a comprehensive manner. Results: The first step in RT is a planning session that includes obtaining a CT scan of the area to be treated, known as the CT simulation. The patients are imaged in the exact position in which they will receive treatment. The second step, which is the primary source of uncertainty, involves the delineation of treatment targets and organs at risk (OAR). The objective is to ensure precise irradiation of the target volume while sparing the OARs as much as possible. Various radiation modalities, such as external beam therapy with electrons, photons, or particles (including protons and carbon ions), as well as brachytherapy, are utilized. Within these modalities, several techniques, such as three-dimensional conformal RT, intensity-modulated RT, volumetric modulated arc therapy, scattering beam proton therapy, and intensity-modulated proton therapy, are employed to achieve optimal treatment outcomes. The RT plan development is an iterative process involving medical physicists, dosimetrists, and ROs. The complexity and time required vary, ranging from an hour to a week. Once approved, RT begins, with image-guided RT being standard practice for patient alignment. The RO manages acute toxicities during treatment and prepares a summary upon completion. There is a considerable variance in practices, with some ROs offering lifelong follow-up and managing potential late effects of treatment. Conclusions: Comprehension of RT clinical effects by non-oncologists providers significantly elevates long-term patient care quality. Hence, educating non-oncologists enhances care for RT patients, underlining this report's importance.
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Alzheimer's disease can be detected early through biomarkers such as tau positron emission tomography (PET) imaging, which shows abnormal protein accumulations in the brain. The standardized uptake value ratio (SUVR) is often used to quantify tau-PET imaging, but topological information from multiple brain regions is also linked to tau pathology. Here a new method was developed to investigate the correlations between brain regions using subject-level tau networks. Participants with cognitive normal (74), early mild cognitive impairment (35), late mild cognitive impairment (32), and Alzheimer's disease (40) were included. The abnormality network from each scan was constructed to extract topological features, and 7 functional clusters were further analyzed for connectivity strengths. Results showed that the proposed method performed better than conventional SUVR measures for disease staging and prodromal sign detection. For example, when to differ healthy subjects with and without amyloid deposition, topological biomarker is significant with P < 0.01, SUVR is not with P > 0.05. Functionally significant clusters, i.e. medial temporal lobe, default mode network, and visual-related regions, were identified as critical hubs vulnerable to early disease conversion before mild cognitive impairment. These findings were replicated in an independent data cohort, demonstrating the potential to monitor the early sign and progression of Alzheimer's disease from a topological perspective for individual.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/metabolismo , Péptidos beta-Amiloides/metabolismo , Disfunción Cognitiva/patología , Encéfalo/patología , Biomarcadores , Tomografía de Emisión de Positrones/métodosRESUMEN
New developments in dynamic magnetic resonance imaging (MRI) facilitate high-quality data acquisition of human velopharyngeal deformations in real-time speech. With recently established speech motion atlases, group analysis is made possible via spatially and temporally aligned datasets in the atlas space from a desired population of interest. In practice, when analyzing motion characteristics from various subjects performing a designated speech task, it is observed that different subjects' velopharyngeal deformation patterns could vary during the pronunciation of the same utterance, regardless of the spatial and temporal alignment of their MRI. Since such variation can be subtle, identification and extraction of unique patterns out of these high-dimensional datasets is a challenging task. In this work, we present a method that computes and visualizes subtle deformation variation patterns as principal components of a subject group's dynamic motion fields in the atlas space. Coupled with the real-time speech audio recordings during image acquisition, the key time frames that contain maximum speech variations are identified by the principal components of temporally aligned audio waveforms, which in turn inform the temporal location of the maximum spatial deformation variation. Henceforth, the motion fields between the key frames and the reference frame for each subject are computed and warped into the common atlas space, enabling a direct extraction of motion variation patterns via quantitative analysis. The method was evaluated on a dataset of twelve healthy subjects. Subtle velopharyngeal motion differences were visualized quantitatively to reveal pronunciation-specific patterns among different subjects.
RESUMEN
PURPOSE: To introduce a method of inducing Bloch-Siegert shift and magnetization Transfer Simultaneously (BTS) and demonstrate its utilization for measuring binary spin-bath model parameters free pool spin-lattice relaxation ( T 1 F $$ {T}_1^{\mathrm{F}} $$ ), macromolecular fraction ( f $$ f $$ ), magnetization exchange rate ( k F $$ {k}_{\mathrm{F}} $$ ) and local transmit field ( B 1 + $$ {B}_1^{+} $$ ). THEORY AND METHODS: Bloch-Siegert shift and magnetization transfer is simultaneously induced through the application of off-resonance irradiation in between excitation and acquisition of an RF-spoiled gradient-echo scheme. Applying the binary spin-bath model, an analytical signal equation is derived and verified through Bloch simulations. Monte Carlo simulations were performed to analyze the method's performance. The estimation of the binary spin-bath parameters with B 1 + $$ {B}_1^{+} $$ compensation was further investigated through experiments, both ex vivo and in vivo. RESULTS: Comparing BTS with existing methods, simulations showed that existing methods can significantly bias T 1 $$ {T}_1 $$ estimation when not accounting for transmit B 1 $$ {B}_1 $$ heterogeneity and MT effects that are present. Phantom experiments further showed that the degree of this bias increases with increasing macromolecular proton fraction. Multi-parameter fit results from an in vivo brain study generated values in agreement with previous literature. Based on these studies, we confirmed that BTS is a robust method for estimating the binary spin-bath parameters in macromolecule-rich environments, even in the presence of B 1 + $$ {B}_1^{+} $$ inhomogeneity. CONCLUSION: A method of estimating Bloch-Siegert shift and magnetization transfer effect has been developed and validated. Both simulations and experiments confirmed that BTS can estimate spin-bath parameters ( T 1 F $$ {T}_1^{\mathrm{F}} $$ , f $$ f $$ , k F $$ {k}_{\mathrm{F}} $$ ) that are free from B 1 + $$ {B}_1^{+} $$ bias.