Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Common variants in Alzheimer's disease and risk stratification by polygenic risk scores.

Funder: Funder: Fundación bancaria ‘La Caixa’ Number: LCF/PR/PR16/51110003 Funder: Grifols SA Number: LCF/PR/PR16/51110003 Funder: European Union/EFPIA Innovative Medicines Initiative Joint Number: 115975 Funder: JPco-fuND FP-829-029 Number: 733051061Genetic discoveries of Alzheimer's disease are the drivers of our understanding, and together with polygenetic risk stratification can contribute towards planning of feasible and efficient preventive and curative clinical trials. We first perform a large genetic association study by merging all available case-control datasets and by-proxy study results (discovery n = 409,435 and validation size n = 58,190). Here, we add six variants associated with Alzheimer's disease risk (near APP, CHRNE, PRKD3/NDUFAF7, PLCG2 and two exonic variants in the SHARPIN gene). Assessment of the polygenic risk score and stratifying by APOE reveal a 4 to 5.5 years difference in median age at onset of Alzheimer's disease patients in APOE ɛ4 carriers. Because of this study, the underlying mechanisms of APP can be studied to refine the amyloid cascade and the polygenic risk score provides a tool to select individuals at high risk of Alzheimer's disease

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues

Cost-Effectiveness Analysis of 68Ga DOTA-TATE PET/CT, 111In-Pentetreotide SPECT/CT and CT for Diagnostic Workup of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are relatively rare neoplasms arising from the hormone-producing neuroendocrine system that can occur in various organs such as pancreas, small bowel, stomach and lung. As the majority of these tumors express somatostatin receptors (SSR) on their cell membrane, utilization of SSR analogs in nuclear medicine is a promising, but relatively costly approach for detection and localization. The aim of this study was to analyze the cost-effectiveness of 68Ga-DOTA-TATE PET/CT (Gallium-68 DOTA-TATE Positron emission tomography/computed tomography) compared to 111In-pentetreotide SPECT/CT (Indium-111 pentetreotide Single Photon emission computed tomography/computed tomography) and to CT (computed tomography) alone in detection of NETs. A decision model on the basis of Markov simulations evaluated lifetime costs and quality-adjusted life years (QALYs) related to either a CT, SPECT/CT or PET/CT. Model input parameters were obtained from publicized research projects. The analysis is grounded on the US healthcare system. Deterministic sensitivity analysis of diagnostic parameters and probabilistic sensitivity analysis predicated on a Monte Carlo simulation with 30,000 reiterations was executed. The willingness-to-pay (WTP) was determined to be $100,000/QALY. In the base-case investigation, PET/CT ended up with total costs of$88,003.07 with an efficacy of 4.179, whereas CT ended up with total costs of $88,894.71 with an efficacy of 4.165. SPECT/CT ended up with total costs of$89,973.34 with an efficacy of 4.158. Therefore, the strategies CT and SPECT/CT were dominated by PET/CT in the base-case scenario. In the sensitivity analyses, PET/CT remained a cost-effective strategy. This result was due to reduced therapy costs of timely detection. The additional costs of 68Ga-DOTA-TATE PET/CT when compared to CT alone are justified in the light of potential savings in therapy costs and better outcomes

Contrast-Enhanced Ultrasound (CEUS) for Follow-Up of Bosniak 2F Complex Renal Cystic Lesions-A 12-Year Retrospective Study in a Specialized European Center

Bosniak 2F renal cystic lesions feature morphologic characteristics between Bosniak I and III categories, the majority of which remain benign. However, a minor part of Bosniak 2F lesions may progress to malignancy. The purpose of this study was to assess Bosniak 2F cystic lesions during follow-up examinations by CEUS. One-hundred-and-twelve out of 364 patients with Bosniak 2F lesions underwent follow-up CEUS examinations between February 2008 and February 2020. Twelve out of 364 patients underwent renal surgery without follow-up CEUS. The progression rate of Bosniak 2F renal lesions detected by CEUS accounted for 7.1% (8/112 patients) after a mean of 12.9 months. The first follow-up CEUS revealed 75% of progressions (6/8), the remaining 25% (2/8) of progressions were detected during second follow-up CEUS. Underlying clear-cell renal cell carcinoma was histopathologically validated in 5/8 progressive complex cystic renal lesions. Stable sonomorphologic features were observed in 92.1% (104/112 patients). CEUS depicts a promising diagnostic imaging modality in the diagnostic work-up and follow-up of complex renal cystic lesions at higher spatial and temporal resolutions than CT or MRI. Its excellent safety profile, its easy and repeatable accessibility, and low financial costs render CEUS an attractive and powerful alternative imaging tool for monitoring complex renal cystic lesions

Advanced Fusion Imaging and Contrast-Enhanced Imaging (CT/MRI-CEUS) in Oncology

Simple Summary Fusion imaging depicts an innovative technique by which previously performed computed tomography/magnetic resonance imaging can be integrated and reconstructed with advanced contrast-enhanced ultrasound using modern ultrasound devices in a real-time manner. Fusion imaging allows for complementing strengths and reducing restrictions of the combined imaging modalities. The visualization of parenchymal and tumoral microperfusion by contrast-enhanced ultrasound can be dynamically fused and assessed with images from previous cross-sectional studies and may help to decipher underlying entities of indeterminate lesions or validate suspicious morphology. The findings from our study demonstrate the benefits of fusion imaging for evaluating focal hepatic and renal lesions. The excellent safety profile, accessibility, repeatability and cost-effectiveness are advantages of fusion imaging which make it a powerful diagnostic tool for the modern radiologist. Fusion imaging depicts an innovative technique that facilitates combining assets and reducing restrictions of advanced ultrasound and cross-sectional imaging. The purpose of the present retrospective study was to evaluate the role of fusion imaging for assessing hepatic and renal lesions. Between 02/2011-08/2020, 92 patients in total were included in the study, of which 32 patients had hepatic lesions, 60 patients had renal lesions. Fusion imaging was technically successful in all patients. No adverse side effects upon intravenous (i.v.) application of SonoVue (R) (Bracco, Milan, Italy) were registered. Fusion imaging could clarify all 11 (100%) initially as indeterminate described hepatic lesions by computed tomography/magnetic resonance imaging (CT/MRI). Moreover, 5/14 (36%) initially suspicious hepatic lesions could be validated by fusion imaging, whereas in 8/14 (57%), malignant morphology was disproved. Moreover, fusion imaging allowed for the clarification of 29/30 (97%) renal lesions initially characterized as suspicious by CT/MRI, of which 19/30 (63%) underwent renal surgery, histopathology revealed malignancy in 16/19 (84%), and benignity in 3/19 (16%). Indeterminate findings could be elucidated by fusion imaging in 20/20 (100%) renal lesions. Its accessibility and repeatability, even during pregnancy and in childhood, its cost-effectiveness, and its excellent safety profile, make fusion imaging a promising instrument for the thorough evaluation of hepatic and renal lesions in the future

Structured Reporting of Head and Neck Sonography Achieves Substantial Interrater Reliability

Purpose Ultrasound examinations are often criticized for having higher examiner dependency compared to other imaging techniques. Compared to free-text reporting, structured reporting (SR) of head and neck sonography (HNS) achieves superior time efficiency as well as report quality. However, there are no findings concerning the influence of SR on the interrater reliability (IRR) of HNS

Cost-Effectiveness Analysis of Ga-68 DOTA-TATE PET/CT, In-111-Pentetreotide SPECT/CT and CT for Diagnostic Workup of Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are relatively rare neoplasms arising from the hormone-producing neuroendocrine system that can occur in various organs such as pancreas, small bowel, stomach and lung. As the majority of these tumors express somatostatin receptors (SSR) on their cell membrane, utilization of SSR analogs in nuclear medicine is a promising, but relatively costly approach for detection and localization. The aim of this study was to analyze the cost-effectiveness of Ga-68-DOTA-TATE PET/CT (Gallium-68 DOTA-TATE Positron emission tomography/computed tomography) compared to In-111-pentetreotide SPECT/CT (Indium-111 pentetreotide Single Photon emission computed tomography/computed tomography) and to CT (computed tomography) alone in detection of NETs. A decision model on the basis of Markov simulations evaluated lifetime costs and quality-adjusted life years (QALYs) related to either a CT, SPECT/CT or PET/CT. Model input parameters were obtained from publicized research projects. The analysis is grounded on the US healthcare system. Deterministic sensitivity analysis of diagnostic parameters and probabilistic sensitivity analysis predicated on a Monte Carlo simulation with 30,000 reiterations was executed. The willingness-to-pay (WTP) was determined to be $100,000/QALY. In the base-case investigation, PET/CT ended up with total costs of$88,003.07 with an efficacy of 4.179, whereas CT ended up with total costs of $88,894.71 with an efficacy of 4.165. SPECT/CT ended up with total costs of$89,973.34 with an efficacy of 4.158. Therefore, the strategies CT and SPECT/CT were dominated by PET/CT in the base-case scenario. In the sensitivity analyses, PET/CT remained a cost-effective strategy. This result was due to reduced therapy costs of timely detection. The additional costs of Ga-68-DOTA-TATE PET/CT when compared to CT alone are justified in the light of potential savings in therapy costs and better outcomes

Performance variability of radiomics machine learning models for the detection of clinically significant prostate cancer in heterogeneous MRI datasets

Background: Radiomics promises to enhance the discriminative performance for clinically significant prostate cancer (csPCa), but still lacks validation in real-life scenarios. This study investigates the classification performance and robustness of machine learning radiomics models in heterogeneous MRI datasets to characterize suspicious prostate lesions for non-invasive prediction of prostate cancer (PCa) aggressiveness compared to conventional imaging biomarkers. Methods: A total of 142 patients with clinical suspicion of PCa underwent 1.5T or 3T biparametric MRI (7 scanner types, 14 institutions) and exhibited suspicious lesions [prostate Imaging Reporting and Data System (PI-RADS) score >= 3] in peripheral or transitional zones. Whole-gland and index-lesion segmentations were performed semi-automatically. A total of 1,482 quantitative morphologic, shape, texture, and intensity-based radiomics features were extracted from T2-weighted and apparent diffusion coefficient (ADC)-images and assessed using random forest and logistic regression models. Five-fold cross-validation performance in terms of area under the ROC curve was compared to mean ADC (mADC), PI-RADS and prostate-specific antigen density (PSAD). Bias mitigation techniques targeting the high-dimensional feature space and inherent class imbalance were applied and robustness of results was systematically evaluated. Results: Trained models showed mean area under the curves (AUCs) ranging from 0.78 to 0.83 in csPCa classification. Despite using mitigation techniques, high performance variability of results could be demonstrated. Trained models achieved on average numerically higher classification performance compared to clinical parameters PI-RADS (AUC =0.78), mADC (AUC =0.71) and PSAD (AUC =0.63). Conclusions: Radiomics models' classification performance of csPCa was numerically but not significantly higher than PI-RADS scoring. Overall, clinical applicability in heterogeneous MRI datasets is limited because of high variability of results. Performance variability, robustness and reproducibility of radiomics-based measures should be addressed more transparently in future research to enable broad clinical application