Accumulating evidence suggests that Alzheimer's disease (AD) is heterogenous and can be classified into several subtypes. Here, we propose a robust subtyping method for AD based on cortical atrophy ...patterns and graph theory. We calculated similarities between subjects in their atrophy patterns throughout the whole brain, and clustered subjects with similar atrophy patterns using the Louvain method for modular organization extraction. We applied our method to AD patients recruited at Samsung Medical Center and externally validated our method by using the AD Neuroimaging Initiative (ADNI) dataset. Our method categorized very mild AD into three clinically distinct subtypes with high reproducibility (>90%); the parietal-predominant (P), medial temporal-predominant (MT), and diffuse (D) atrophy subtype. The P subtype showed the worst clinical presentation throughout the cognitive domains, while the MT and D subtypes exhibited relatively mild presentation. The MT subtype revealed more impaired language and executive function compared to the D subtype.
Here, we report an essentially complete genome assembly for the Ty1-less Saccharomyces paradoxus strain DG1768 (derivative of strain 337) based on PacBio and Illumina shotgun sequence data. We also ...document the genetic alterations that make this yeast strain a key resource for Ty1 mobility studies.
A novel series of melanin concentrating hormone receptor 1 (MCHr1) antagonists were the starting point for a drug discovery program that culminated in the discovery of 103 (AZD1979). The lead ...optimization program was conducted with a focus on reducing lipophilicity and understanding the physicochemical properties governing CNS exposure and undesired off-target pharmacology such as hERG interactions. An integrated approach was taken where the key assay was ex vivo receptor occupancy in mice. The candidate compound 103 displayed appropriate lipophilicity for a CNS indication and showed excellent permeability with no efflux. Preclinical GLP toxicology and safety pharmacology studies were without major findings and 103 was taken into clinical trials.
Lymphotoxin-α (LTα), lymphotoxin-β (LTβ), and tumor necrosis factor-α (TNFα) are inflammatory mediators that play crucial roles in lymphoid organ development. We demonstrate here that LTα also ...contributes to the function of lymphatic vessels and to lymphangiogenesis during inflammation. LTα−/− mice exhibited reduced lymph flow velocities and increased interstitial fluid pressure. Airways of LTβ−/− mice infected with Mycoplasma pulmonis had significantly more lymphangiogenesis than wild type (WT) or LTα−/− mice, as did the skin draining immunization sites of LTβ−/− mice. Macrophages, B cells, and T cells, known sources of LT and TNFα, were apparent in the skin surrounding the immunization sites as were LTα, LTβ, and TNFα mRNAs. Ectopic expression of LTα led to the development of LYVE-1 and Prox1-positive lymphatic vessels within tertiary lymphoid organs (TLOs). Quantification of pancreatic lymphatic vessel density in RIPLTαLTβ−/− and WT mice revealed that LTα was sufficient for inducing lymphangiogenesis and that LTβ was not required for this process. Kidneys of inducible LTα transgenic mice developed lymphatic vessels before the appearance of obvious TLOs. These data indicate that LTα plays a significant role in lymphatic vessel function and in inflammation-associated lymphangiogenesis.
In the Alzheimer's disease (AD) continuum, the prodromal state of mild cognitive impairment (MCI) precedes AD dementia and identifying MCI individuals at risk of progression is important for clinical ...management. Our goal was to develop generalizable multivariate models that integrate high-dimensional data (multimodal neuroimaging and cerebrospinal fluid biomarkers, genetic factors, and measures of cognitive resilience) for identification of MCI individuals who progress to AD within 3 years. Our main findings were i) we were able to build generalizable models with clinically relevant accuracy (~93%) for identifying MCI individuals who progress to AD within 3 years; ii) markers of AD pathophysiology (amyloid, tau, neuronal injury) accounted for large shares of the variance in predicting progression; iii) our methodology allowed us to discover that expression of CR1 (complement receptor 1), an AD susceptibility gene involved in immune pathways, uniquely added independent predictive value. This work highlights the value of optimized machine learning approaches for analyzing multimodal patient information for making predictive assessments.
To clarify associations between
ε4 allele and age on longitudinal rates of β-amyloid (Aβ) accumulation within Aβ+ and Aβ- older individuals without dementia.
We analyzed 595 older adults without ...dementia classified cross-sectionally as Aβ- (n = 325) and Aβ+ (n = 270) using longitudinal florbetapir PET. The influence of age and
genotype on longitudinal accumulation of Aβ was examined with linear mixed models.
ε4 and older age were associated with higher risk of being classified as Aβ+ at baseline. The annual rate of Aβ accumulation was significantly greater than zero for Aβ- ε3 (0.0021 ± 0.0007 standardized uptake value ratio SUVR units) and Aβ- ε4 (0.0044 ± 0.0010 SUVR units), as well as Aβ+ ε3 (0.0141 ± 0.0019 SUVR units) and Aβ+ ε4 (0.0126 ± 0.0018 SUVR units). Aβ accumulation was significantly faster in Aβ- ε4 compared to Aβ- ε3 and Aβ- ε2. Rates of Aβ accumulation did not differ significantly between Aβ+
groups. Older age was associated with higher rates of Aβ accumulation in the Aβ- group.
ε4 carriage and older age were predictors of longitudinal Aβ accumulation within the Aβ- group but not the Aβ+ group.
ε2 carriage was protective against longitudinal Aβ accumulation within the Aβ- group.
genotype in conjunction with chronologic age may aid in participant selection for primary prevention trials aimed at halting Aβ accumulation before abnormal levels are reached.
Populations of marine organisms on coral reef islands (CRI) are connected in space and time by seawater that transports propagules of plants, animals, and algae. Yet, despite this reality, it is ...often assumed that routine replenishment of populations of marine organisms on CRI is supported by locally-sourced propagules (hereafter, larvae). Following large disturbances, however, distantly-sourced larvae from less disturbed CRI within a regional meta-population are likely to be important for local population recovery, but evaluating the roles of locally- versus distantly- sourced larvae remains difficult. While larval sources are relatively well known for many fishes, they remain virtually unknown for most taxa, particularly those associated with the benthos, including hermatypic corals. We make the case that CRI provide natural laboratories in which studies of connectivity can enhance understanding of community dynamics under future disturbance regimes, especially where ongoing changes have created novel systems that are functioning in ways differing from the recent past. However, this potential cannot be realized due to the limited breadth, detail, and spatio-temporal concordance of exiting research. Targeted research on the role of connectivity in mediating ecosystem resilience of CRI is required to understand how populations of marine organisms will change in a future affected by large-scale disturbances of anthropogenic origin. Using the coral reefs of Mo’orea (French Polynesia), Okinawa (Japan), and St. John (US Virgin Islands) as examples, we describe the data required to achieve this objective, and discuss why provision of these data will require new modes of multidisciplinary and collaborative research.
Cancer mortality is exacerbated by late-stage diagnosis. Liquid biopsies based on genomic biomarkers can noninvasively diagnose cancers. However, validation studies have reported ~10% sensitivity to ...detect stage I cancer in a screening population and specific types, such as brain or genitourinary tumors, remain undetectable. We investigated urine and plasma free glycosaminoglycan profiles (GAGomes) as tumor metabolism biomarkers for multi-cancer early detection (MCED) of 14 cancer types using 2,064 samples from 1,260 cancer or healthy subjects. We observed widespread cancer-specific changes in biofluidic GAGomes recapitulated in an in vivo cancer progression model. We developed three machine learning models based on urine (
= 220 cancer vs. 360 healthy) and plasma (
= 517 vs. 425) GAGomes that can detect any cancer with an area under the receiver operating characteristic curve of 0.83-0.93 with up to 62% sensitivity to stage I disease at 95% specificity. Undetected patients had a 39 to 50% lower risk of death. GAGomes predicted the putative cancer location with 89% accuracy. In a validation study on a screening-like population requiring ≥ 99% specificity, combined GAGomes predicted any cancer type with poor prognosis within 18 months with 43% sensitivity (21% in stage I;
= 121 and 49 cases). Overall, GAGomes appeared to be powerful MCED metabolic biomarkers, potentially doubling the number of stage I cancers detectable using genomic biomarkers.
Characterization of visible abnormalities in Barrett esophagus (BE) patients can be challenging, especially for unexperienced endoscopists. This results in suboptimal diagnostic accuracy and poor ...inter-observer agreement. Computer-aided diagnosis (CADx) systems may assist endoscopists. We aimed to develop, validate and benchmark a CADx system for BE neoplasia.
The CADx system received pretraining with ImageNet with consecutive domain-specific pretraining with GastroNet which includes 5 million endoscopic images. It was subsequently trained and internally validated using 1,758 narrow-band imaging (NBI) images of early BE neoplasia (352 patients) and 1,838 NBI images of non-dysplastic BE (173 patients) from 8 international centers. CADx was tested prospectively on corresponding image and video test sets with 30 cases (20 patients) of BE neoplasia and 60 cases (31 patients) of non-dysplastic BE. The test set was benchmarked by 44 general endoscopists in two phases (phase 1: no CADx assistance; phase 2: with CADx assistance). Ten international BE experts provided additional benchmark performance.
Stand-alone sensitivity and specificity of the CADx system were 100% and 98% for images and 93% and 96% for videos, respectively. CADx outperformed general endoscopists without CADx assistance in terms of sensitivity (p=0.04). Sensitivity and specificity of general endoscopist increased from 84% to 96% and 90 to 98% with CAD assistance (p<0.001), respectively. CADx assistance increased endoscopists’ confidence in characterization (p<0.001). CADx performance was similar to Barrett experts.
CADx assistance significantly increased characterization performance of BE neoplasia by general endoscopists to the level of expert endoscopists. The use of this CADx system may thereby improve daily Barrett surveillance.
Medical Image Imputation From Image Collections Dalca, Adrian V.; Bouman, Katherine L.; Freeman, William T. ...
IEEE transactions on medical imaging,
02/2019, Letnik:
38, Številka:
2
Journal Article
Odprti dostop
We present an algorithm for creating high-resolution anatomically plausible images consistent with acquired clinical brain MRI scans with large inter-slice spacing. Although large data sets of ...clinical images contain a wealth of information, time constraints during acquisition result in sparse scans that fail to capture much of the anatomy. These characteristics often render computational analysis impractical as many image analysis algorithms tend to fail when applied to such images. Highly specialized algorithms that explicitly handle sparse slice spacing do not generalize well across problem domains. In contrast, we aim to enable the application of existing algorithms that were originally developed for high-resolution research scans to significantly undersampled scans. We introduce a generative model that captures a fine-scale anatomical structure across subjects in clinical image collections and derives an algorithm for filling in the missing data in scans with large inter-slice spacing. Our experimental results demonstrate that the resulting method outperforms the state-of-the-art upsampling super-resolution techniques, and promises to facilitate subsequent analysis not previously possible with scans of this quality. Our implementation is freely available at https://github.com/adalca/papago.
PDF
