PILRA polymorphism modifies the effect of APOE4 and GM17 on Alzheimer's disease risk.

PILRA (rs1859788 A > G) has been suggested to be a protective variant for Alzheimer's disease (AD) and is an entry co-receptor for herpes simplex virus-1. We conducted a nested case-control study of 360 1:1-matched AD subjects. Interactions between the PILRA-A allele, APOE risk variants (ε3/ε4 or ε4/ε4) and GM17 for AD risk were modelled. The associations were cross-validated using two independent whole-genome sequencing datasets. We found negative interactions between PILRA-A and GM17 (OR 0.72, 95% CI 0.52-1.00) and between PILRA-A and APOE risk variants (OR 0.56, 95% CI 0.32-0.98) in the discovery dataset. In the replication cohort, a joint effect of PILRA and PILRA × GM 17/17 was observed for the risk of developing AD (p .02). Here, we report a negative effect modification by PILRA on APOE and GM17 high-risk variants for future AD risk in two independent datasets. This highlights the complex genetics of AD.

Long-term time trends in reactivated herpes simplex infections and treatment in Sweden.

BACKGROUND: Our aim was to describe the annual prevalence of herpes simplex virus (HSV) reactivation in relation to solar ultraviolet (UV) radiation and antiviral drug use in the Swedish adult population. METHODS: The study comprised 2879 anti-HSV-1 immunoglobulin (Ig) G positive subjects from five different cohorts who had donated serum from 1988 to 2010. The sera were analyzed for anti-HSV IgM using enzyme-linked immunosorbent assay. Associations between the presence of anti-HSV IgM antibodies, the apolipoprotein E ε4 allele and the serum sampling year were assessed by logistic regression. Seasonality of anti-HSV IgM was evaluated in a UV radiation model. Data of antiviral drugs for the entire Swedish population were compiled from two different nationwide databases: the Swedish Prescribed Drug Register and the Swedish Association of the Pharmaceutical Industry. RESULTS: Cross-sectional and longitudinal analyses indicated that the prevalence of anti-HSV IgM antibodies declined between 1988 and 2010 (odds ratio [OR] = 0.912, p < .001), while the total annual use of antiviral drugs in Sweden gradually increased from 1984 to 2017. Higher UV radiation was associated with higher prevalence of anti-HSV IgM antibodies (OR = 1.071, p = .043). CONCLUSION: The declining time trend of HSV reactivation in a Swedish cohort coincides with a steady increase of antiviral drug use in the Swedish general population.

Plasma Amyloid-ß in Relation to Antibodies Against Herpes Simplex Virus, Cytomegalovirus, and Chlamydophila pneumoniae.

BACKGROUND: Amyloid-ß (Aß), the key constituent of Alzheimer's disease (AD) plaques, has antimicrobial properties. OBJECTIVE: To investigate the association between plasma Aß and antibodies against the AD-related pathogens herpes simplex virus (HSV), cytomegalovirus (CMV), and C. pneumoniae. METHODS: Plasma from 339 AD cases, obtained on average 9.4 years (±4.00) before diagnosis, and their matched controls were analyzed for Aß40 and Aß42 concentrations with Luminex xMAP technology and INNOBIA plasma Aß-form assays. Enzyme-linked immunosorbent assays were utilized for analyses of anti-HSV immunoglobulin (Ig) G, anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG. Follow-up samples were available for 150 of the cases. RESULTS: Presence and levels of anti-HSV1 IgG, anti-HSV2 IgG, anti-CMV IgG, and anti-C. pneumoniae IgG did not correlate with concentrations of Aß42 or Aß40 in cases or controls. CONCLUSION: Levels of plasma Aß were not associated with antibodies against different AD-related pathogens.

Herpesvirus infections, antiviral treatment, and the risk of dementia-a registry-based cohort study in Sweden.

INTRODUCTION: Herpesviruses, including Herpes simplex virus type 1 (HSV1) and varicella zoster-virus (VZV), have been implicated in Alzheimer's disease (AD) development. Likewise, antiviral treatment has been suggested to protect against dementia development in herpes-infected individuals. METHODS: The study enrolled 265,172 subjects aged ≥ 50 years, with diagnoses of VZV or HSV, or prescribed antiviral drugs between 31 December 2005 and 31 December 2017. Controls were matched in a 1:1 ratio by sex and birth year. RESULTS: Antiviral treatment was associated with decreased risk of dementia (adjusted hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.86 to 0.92), while herpes infection without antiviral drugs increased the risk of dementia (adjusted HR 1.50, 95% CI 1.29 to 1.74). DISCUSSION: Antiviral treatment was associated with a reduced long-term risk of dementia among individuals with overt signs of herpes infection. This is consistent with earlier findings indicating that herpesviruses are involved in the pathogenesis of AD.

Proactive Construction of an Annotated Imaging Database for Artificial Intelligence Training.

Artificial intelligence (AI) holds much promise for enabling highly desired imaging diagnostics improvements. One of the most limiting bottlenecks for the development of useful clinical-grade AI models is the lack of training data. One aspect is the large amount of cases needed and another is the necessity of high-quality ground truth annotation. The aim of the project was to establish and describe the construction of a database with substantial amounts of detail-annotated oncology imaging data from pathology and radiology. A specific objective was to be proactive, that is, to support undefined subsequent AI training across a wide range of tasks, such as detection, quantification, segmentation, and classification, which puts particular focus on the quality and generality of the annotations. The main outcome of this project was the database as such, with a collection of labeled image data from breast, ovary, skin, colon, skeleton, and liver. In addition, this effort also served as an exploration of best practices for further scalability of high-quality image collections, and a main contribution of the study was generic lessons learned regarding how to successfully organize efforts to construct medical imaging databases for AI training, summarized as eight guiding principles covering team, process, and execution aspects.

TissueWand, a Rapid Histopathology Annotation Tool.

BACKGROUND: Recent advancements in machine learning (ML) bring great possibilities for the development of tools to assist with diagnostic tasks within histopathology. However, these approaches typically require a large amount of ground truth training data in the form of image annotations made by human experts. As such annotation work is a very time-consuming task, there is a great need for tools that can assist in this process, saving time while not sacrificing annotation quality. METHODS: In an iterative design process, we developed TissueWand - an interactive tool designed for efficient annotation of gigapixel-sized histopathological images, not being constrained to a predefined annotation task. RESULTS: Several findings regarding appropriate interaction concepts were made, where a key design component was semi-automation based on rapid interaction feedback in a local region. In a user study, the resulting tool was shown to cause substantial speed-up compared to manual work while maintaining quality. CONCLUSIONS: The TissueWand tool shows promise to replace manual methods for early stages of dataset curation where no task-specific ML model yet exists to aid the effort.

Annotations, Ontologies, and Whole Slide Images - Development of an Annotated Ontology-Driven Whole Slide Image Library of Normal and Abnormal Human Tissue.

OBJECTIVE: Digital pathology is today a widely used technology, and the digitalization of microscopic slides into whole slide images (WSIs) allows the use of machine learning algorithms as a tool in the diagnostic process. In recent years, "deep learning" algorithms for image analysis have been applied to digital pathology with great success. The training of these algorithms requires a large volume of high-quality images and image annotations. These large image collections are a potent source of information, and to use and share the information, standardization of the content through a consistent terminology is essential. The aim of this project was to develop a pilot dataset of exhaustive annotated WSI of normal and abnormal human tissue and link the annotations to appropriate ontological information. MATERIALS AND METHODS: Several biomedical ontologies and controlled vocabularies were investigated with the aim of selecting the most suitable ontology for this project. The selection criteria required an ontology that covered anatomical locations, histological subcompartments, histopathologic diagnoses, histopathologic terms, and generic terms such as normal, abnormal, and artifact. WSIs of normal and abnormal tissue from 50 colon resections and 69 skin excisions, diagnosed 2015-2016 at the Department of Clinical Pathology in Linköping, were randomly collected. These images were manually and exhaustively annotated at the level of major subcompartments, including normal or abnormal findings and artifacts. RESULTS: Systemized nomenclature of medicine clinical terms (SNOMED CT) was chosen, and the annotations were linked to its codes and terms. Two hundred WSI were collected and annotated, resulting in 17,497 annotations, covering a total area of 302.19 cm2, equivalent to 107,7 gigapixels. Ninety-five unique SNOMED CT codes were used. The time taken to annotate a WSI varied from 45 s to over 360 min, a total time of approximately 360 h. CONCLUSION: This work resulted in a dataset of 200 exhaustive annotated WSIs of normal and abnormal tissue from the colon and skin, and it has informed plans to build a comprehensive library of annotated WSIs. SNOMED CT was found to be the best ontology for annotation labeling. This project also demonstrates the need for future development of annotation tools in order to make the annotation process more efficient.

A genetic signature including apolipoprotein Eε4 potentiates the risk of herpes simplex-associated Alzheimer's disease.

INTRODUCTION: Herpes simplex virus type 1 (HSV1) in combination with genetic susceptibility has previously been implicated in Alzheimer's disease (AD) pathogenesis. METHODS: Plasma from 360 AD cases, obtained on average 9.6 years before diagnosis, and their age- and sex-matched controls, were analyzed for anti-HSV1 immunoglobulin (Ig) G with enzyme-linked immunosorbent assays (ELISAs). A POE genotype and nine other selected risk genes for AD were extracted from a genome-wide association study analysis by deCODE genetics, Reykjavik, Iceland. RESULTS: The interaction between APOEε4 heterozygosity (APOEε2/ε4 or ε3/ε4) and anti-HSV1 IgG carriage increased the risk of AD (OR 4.55, P = .02). A genetic risk score based on the nine AD risk genes also interacted with anti-HSV1 IgG for the risk of developing AD (OR 2.35, P = .01). DISCUSSION: The present findings suggest that the APOEε4 allele and other AD genetic risk factors might potentiate the risk of HSV1-associated AD.

Clinical experience of photon counting breast tomosynthesis: comparison with traditional mammography.

BACKGROUND: In two-dimensional mammography, a well-known problem is over- and underlying tissue which can either obstruct a lesion or create a false-positive result. Tomosynthesis, with an ability to layer the tissue in the image, has the potential to resolve these issues. PURPOSE: To compare the diagnostic quality, sensitivity and specificity of a single tomosynthesis mammography image and a traditional two-view set of two-dimensional mammograms and to assess the comfort of the two techniques. MATERIAL AND METHODS: One hundred and forty-four women, mainly chosen because of suspicious features on standard mammograms (76 malignant), had a single tomosynthesis image taken of one breast using a novel photon counting system. On average, the dose of the tomosynthesis images was 0.63 times that of the two-view images and the compression force during the procedure was halved. The resulting images were viewed by two radiologists and assessed both individually and comparing the two techniques. RESULTS: In 56% of the cases the radiologists rated the diagnostic quality of the lesion details higher in the tomosynthesis images than in the conventional images (and in 91% equal or higher), which means there is a statistically significant preference for the tomosynthesis technique. This included the calcifications which were rated as having better quality in 41% of the cases. While sensitivity was slightly higher for traditional mammography the specificity was higher for tomosynthesis. However, neither of these two differences was large enough to be statistically significant. CONCLUSION: The overall accuracy of the two techniques was virtually equal despite the radiologist's very limited experience with tomosynthesis images and vast experience with two-dimensional mammography. As the diagnostic quality of the lesion details in the tomosynthesis images was valued considerably higher this factor should improve with experience. The patients also favored the tomosynthesis examination, rating the comfort of the procedure as much higher than regular mammography which might affect screening attendance.

Optimization of a dual-energy contrast-enhanced technique for a photon-counting digital breast tomosynthesis system: I. A theoretical model.

PURPOSE: Dual-energy (DE) iodine contrast-enhanced x-ray imaging of the breast has been shown to identify cancers that would otherwise be mammographically occult. In this article, theoretical modeling was performed to obtain optimally enhanced iodine images for a photon-counting digital breast tomosynthesis (DBT) system using a DE acquisition technique. METHODS: In the system examined, the breast is scanned with a multislit prepatient collimator aligned with a multidetector camera. Each detector collects a projection image at a unique angle during the scan. Low-energy (LE) and high-energy (HE) projection images are acquired simultaneously in a single scan by covering alternate collimator slits with Sn and Cu filters, respectively. Sn filters ranging from 0.08 to 0.22 mm thickness and Cu filters from 0.11 to 0.27 mm thickness were investigated. A tube voltage of 49 kV was selected. Tomographic images, hereafter referred to as DBT images, were reconstructed using a shift-and-add algorithm. Iodine-enhanced DBT images were acquired by performing a weighted logarithmic subtraction of the HE and LE DBT images, The DE technique was evaluated for 20-80 mm thick breasts. Weighting factors, w(t) that optimally cancel breast tissue were computed. Signal-difference-to-noise ratios (SDNRs) between iodine-enhanced and nonenhanced breast tissue normalized to the square root of the mean glandular dose (MGD) were computed as a function of the fraction of the MGD allocated to the HE images. Peak SDNR/ mean square root of MGD and optimal dose allocations were identified. SDNR/ mean square root of MGD and dose allocations were computed for several practical feasible system configurations (i.e., determined by the number of collimator slits covered by Sn and Cu). A practicalsystem configuration an d Sn-Cu filterpair that accounts for the trade-off between SDNR, tube-output, and MGD were selected. RESULTS: w(t) depends on the Sn-Cu filter combination used, as well as on the breast thickness; to optimally cancel 0% with 50% glandular breast tissue, w(t) values were found to range from 0.46 to 0.72 for all breast thicknesses and Sn-Cu filter pairs studied. The optimal w(t) values needed to cancel all possible breast tissue glandularites vary by less than 1% for 20 mm thick breasts and 18% for 80 mm breasts. The system configuration where one collimator slit covered by Sn is alternated with two collimator slits covered by Cu delivers SDNR/ mean square root of MGD nearest to the peak value. A reasonable compromise is a 0.16 mm Sn-0.23 mm Cu filter pair, resulting in SDNR values between 1.64 and 0.61 and MGD between 0.70 and 0.53 mGy for 20-80 mm thick breasts at the maximum tube current. CONCLUSIONS: A DE acquisition technique for a photon-counting DBT imaging system has been developed and optimized.