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Bayesian latent time joint mixed-effects model of progression in the Alzheimer's Disease Neuroimaging Initiative.
IntroductionWe characterize long-term disease dynamics from cognitively healthy to dementia using data from the Alzheimer's Disease Neuroimaging Initiative.MethodsWe apply a latent time joint mixed-effects model to 16 cognitive, functional, biomarker, and imaging outcomes in Alzheimer's Disease Neuroimaging Initiative. Markov chain Monte Carlo methods are used for estimation and inference.ResultsWe find good concordance between latent time and diagnosis. Change in amyloid positron emission tomography shows a moderate correlation with change in cerebrospinal fluid tau (ρ = 0.310) and phosphorylated tau (ρ = 0.294) and weaker correlation with amyloid-β 42 (ρ = 0.176). In comparison to amyloid positron emission tomography, change in volumetric magnetic resonance imaging summaries is more strongly correlated with cognitive measures (e.g., ρ = 0.731 for ventricles and Alzheimer's Disease Assessment Scale). The average disease trends are consistent with the amyloid cascade hypothesis.DiscussionThe latent time joint mixed-effects model can (1) uncover long-term disease trends; (2) estimate the sequence of pathological abnormalities; and (3) provide subject-specific prognostic estimates of the time until onset of symptoms
FDG-PET imaging, EEG and sleep phenotypes as translational biomarkers for research in Alzheimer's disease
Peer reviewedPublisher PD
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Time-course of effects of external beam radiation on [18F]FDG uptake in healthy tissue and bone marrow.
The utility of PET for monitoring responses to radiation therapy have been complicated by metabolically active processes in surrounding normal tissues. We examined the time-course of [18F]FDG uptake in normal tissues using small animal-dedicated PET during the 2 month period following external beam radiation. Four mice received 12 Gy of external beam radiation, in a single fraction to the left half of the body. Small animal [18F]FDG-PET scans were acquired for each mouse at 0 (pre-radiation), 1, 2, 3, 4, 5, 8, 12, 19, 24, and 38 days following irradiation. [18F]FDG activity in various tissues was compared between irradiated and non-irradiated body halves before, and at each time point after irradiation. Radiation had a significant impact on [18F]FDG uptake in previously healthy tissues, and time-course of effects differed in different types of tissues. For example, liver tissue demonstrated increased uptake, particularly over days 3-12, with the mean left to right uptake ratio increasing 52% over mean baseline values (p < 0.0001). In contrast, femoral bone marrow uptake demonstrated decreased uptake, particularly over days 2-8, with the mean left to right uptake ratio decreasing 26% below mean baseline values (p = 0.0005). Significant effects were also seen in lung and brain tissue. Radiation had diverse effects on [18F]FDG uptake in previously healthy tissues. These kinds of data may help lay groundwork for a systematically acquired database of the time-course of effects of radiation on healthy tissues, useful for animal models of cancer therapy imminently, as well as interspecies extrapolations pertinent to clinical application eventually
Measuring cortical connectivity in Alzheimer's disease as a brain neural network pathology: Toward clinical applications
Objectives: The objective was to review the literature on diffusion tensor imaging as well as resting-state functional magnetic
resonance imaging and electroencephalography (EEG) to unveil neuroanatomical and neurophysiological substrates of
Alzheimer’s disease (AD) as a brain neural network pathology affecting structural and functional cortical connectivity
underlying human cognition. Methods: We reviewed papers registered in PubMed and other scientific repositories on the
use of these techniques in amnesic mild cognitive impairment (MCI) and clinically mild AD dementia patients compared to
cognitively intact elderly individuals (Controls). Results: Hundreds of peer-reviewed (cross-sectional and longitudinal) papers
have shown in patients with MCI and mild AD compared to Controls (1) impairment of callosal (splenium), thalamic,
and anterior–posterior white matter bundles; (2) reduced correlation of resting state blood oxygen level-dependent activity
across several intrinsic brain circuits including default mode and attention-related networks; and (3) abnormal power
and functional coupling of resting state cortical EEG rhythms. Clinical applications of these measures are still limited.
Conclusions: Structural and functional (in vivo) cortical connectivity measures represent a reliable marker of cerebral
reserve capacity and should be used to predict and monitor the evolution of AD and its relative impact on cognitive domains
in pre-clinical, prodromal, and dementia stages of AD. (JINS, 2016, 22, 138–163
Generation of orthotopic patient-derived xenografts from gastrointestinal stromal tumor.
BackgroundGastrointestinal stromal tumor (GIST) is the most common sarcoma and its treatment with imatinib has served as the paradigm for developing targeted anti-cancer therapies. Despite this success, imatinib-resistance has emerged as a major problem and therefore, the clinical efficacy of other drugs has been investigated. Unfortunately, most clinical trials have failed to identify efficacious drugs despite promising in vitro data and pathological responses in subcutaneous xenografts. We hypothesized that it was feasible to develop orthotopic patient-derived xenografts (PDXs) from resected GIST that could recapitulate the genetic heterogeneity and biology of the human disease.MethodsFresh tumor tissue from three patients with pathologically confirmed GISTs was obtained immediately following tumor resection. Tumor fragments (4.2-mm3) were surgically xenografted into the liver, gastric wall, renal capsule, and pancreas of immunodeficient mice. Tumor growth was serially assessed with ultrasonography (US) every 3-4 weeks. Tumors were also evaluated with positron emission tomography (PET). Animals were sacrificed when they became moribund or their tumors reached a threshold size of 2500-mm3. Tumors were subsequently passaged, as well as immunohistochemically and histologically analyzed.ResultsHerein, we describe the first model for generating orthotopic GIST PDXs. We have successfully xenografted three unique KIT-mutated tumors into a total of 25 mice with an overall success rate of 84% (21/25). We serially followed tumor growth with US to describe the natural history of PDX growth. Successful PDXs resulted in 12 primary xenografts in NOD-scid gamma or NOD-scid mice while subsequent successful passages resulted in 9 tumors. At a median of 7.9 weeks (range 2.9-33.1 weeks), tumor size averaged 473 ± 695-mm³ (median 199-mm3, range 12.6-2682.5-mm³) by US. Furthermore, tumor size on US within 14 days of death correlated with gross tumor size on necropsy. We also demonstrated that these tumors are FDG-avid on PET imaging, while immunohistochemically and histologically the PDXs resembled the primary tumors.ConclusionsWe report the first orthotopic model of human GIST using patient-derived tumor tissue. This novel, reproducible in vivo model of human GIST may enhance the study of GIST biology, biomarkers, personalized cancer treatments, and provide a preclinical platform to evaluate new therapeutic agents for GIST
Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1
Peer reviewedPublisher PD
Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.
Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD
Preclinical Applications of 3'-Deoxy-3'-[18F]Fluorothymidine in Oncology - A Systematic Review
The positron emission tomography (PET) tracer 3'-deoxy-3'-[18F]fluorothymidine ([18F]FLT) has been proposed to measure cell proliferation non-invasively in vivo. Hence, it should provide valuable information for response assessment to tumor therapies. To date, [18F]FLT uptake has found limited use as a response biomarker in clinical trials in part because a better understanding is needed of the determinants of [18F]FLT uptake and therapy-induced changes of its retention in the tumor. In this systematic review of preclinical [18F]FLT studies, comprising 174 reports, we identify the factors governing [18F]FLT uptake in tumors, among which thymidine kinase 1 plays a primary role. The majority of publications (83 %) report that decreased [18F]FLT uptake reflects the effects of anticancer therapies. 144 times [18F]FLT uptake was related to changes in proliferation as determined by ex vivo analyses. Of these approaches, 77 % describe a positive relation, implying a good concordance of tracer accumulation and tumor biology. These preclinical data indicate that [18F]FLT uptake holds promise as an imaging biomarker for response assessment in clinical studies. Understanding of the parameters which influence cellular [18F]FLT uptake and retention as well as the mechanism of changes induced by therapy is essential for successful implementation of this PET tracer. Hence, our systematic review provides the background for the use of [18F]FLT in future clinical studies
Learning Optimal Deep Projection of F-FDG PET Imaging for Early Differential Diagnosis of Parkinsonian Syndromes
Several diseases of parkinsonian syndromes present similar symptoms at early
stage and no objective widely used diagnostic methods have been approved until
now. Positron emission tomography (PET) with F-FDG was shown to be able
to assess early neuronal dysfunction of synucleinopathies and tauopathies.
Tensor factorization (TF) based approaches have been applied to identify
characteristic metabolic patterns for differential diagnosis. However, these
conventional dimension-reduction strategies assume linear or multi-linear
relationships inside data, and are therefore insufficient to distinguish
nonlinear metabolic differences between various parkinsonian syndromes. In this
paper, we propose a Deep Projection Neural Network (DPNN) to identify
characteristic metabolic pattern for early differential diagnosis of
parkinsonian syndromes. We draw our inspiration from the existing TF methods.
The network consists of a (i) compression part: which uses a deep network to
learn optimal 2D projections of 3D scans, and a (ii) classification part: which
maps the 2D projections to labels. The compression part can be pre-trained
using surplus unlabelled datasets. Also, as the classification part operates on
these 2D projections, it can be trained end-to-end effectively with limited
labelled data, in contrast to 3D approaches. We show that DPNN is more
effective in comparison to existing state-of-the-art and plausible baselines.Comment: 8 pages, 3 figures, conference, MICCAI DLMIA, 201
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