Hypomethylating agents in the treatment of acute myeloid leukemia: A guide to optimal use

The hypomethylating agents (HMAs), decitabine and azacitidine, are valuable treatment options in acute myeloid leukemia patients who are not eligible for intensive chemotherapy. Both agents are generally well tolerated, and complications most commonly relate to myelosuppression. Antibiotic / antifungal use, regular monitoring, and proactive patient education are important to minimize these events, and reduce the need for dose delay. Responses to HMAs are often not evident for up to 6 cycles, and there is currently no validated clinical marker for predicting response. Hence, treatment should be continued for at least 4–6 cycles to ensure that patients have sufficient opportunity to respond. Delivery of insufficient numbers of cycles is a key reason for HMA failure, and premature discontinuation must be avoided. Genetic factors offer potential for better predicting responders to HMAs in future, but require further study

Differential associations of APOE-epsilon 2 and APOE-epsilon 4 alleles with PET-measured amyloid-beta and tau deposition in older individuals without dementia

Purpose: To examine associations between the APOE-ε2 and APOE-ε4 alleles and core Alzheimer’s disease (AD) pathological hallmarks as measured by amyloid-β (Aβ) and tau PET in older individuals without dementia. Methods: We analyzed data from 462 ADNI participants without dementia who underwent Aβ ([18F]florbetapir or [18F]florbetaben) and tau ([18F]flortaucipir) PET, structural MRI, and cognitive testing. Employing APOE-ε3 homozygotes as the reference group, associations between APOE-ε2 and APOE-ε4 carriership with global Aβ PET and regional tau PET measures (entorhinal cortex (ERC), inferior temporal cortex, and Braak-V/VI neocortical composite regions) were investigated using linear regression models. In a subset of 156 participants, we also investigated associations between APOE genotype and regional tau accumulation over time using linear mixed models. Finally, we assessed whether Aβ mediated the cross-sectional and longitudinal associations between APOE genotype and tau. Results: Compared to APOE-ε3 homozygotes, APOE-ε2 carriers had lower global Aβ burden (βstd [95% confidence interval (CI)]: − 0.31 [− 0.45, − 0.16], p = 0.034) but did not differ on regional tau burden or tau accumulation over time. APOE-ε4 participants showed higher Aβ (βstd [95%CI]: 0.64 [0.42, 0.82], p < 0.001) and tau burden (βstd range: 0.27-0.51, all p < 0.006). In mediation analyses, APOE-ε4 only retained an Aβ-independent effect on tau in the ERC. APOE-ε4 showed a trend towards increased tau accumulation over time in Braak-V/VI compared to APOE-ε3 homozygotes (βstd [95%CI]: 0.10 [− 0.02, 0.18], p = 0.11), and this association was fully mediated by baseline Aβ. Conclusion: Our data suggest that the established protective effect of the APOE-ε2 allele against developing clinical AD is primarily linked to resistance against Aβ deposition rather than tau pathology

An Ultrasound Matrix Transducer for High-Frame-Rate 3-D Intra-cardiac Echocardiography

Objective: Described here is the development of an ultrasound matrix transducer prototype for high-frame-rate 3-D intra-cardiac echocardiography. Methods: The matrix array consists of 16 × 18 lead zirconate titanate elements with a pitch of 160 µm × 160 µm built on top of an application-specific integrated circuit that generates transmission signals and digitizes the received signals. To reduce the number of cables in the catheter to a feasible number, we implement subarray beamforming and digitization in receive and use a combination of time-division multiplexing and pulse amplitude modulation data transmission, achieving an 18-fold reduction. The proposed imaging scheme employs seven fan-shaped diverging transmit beams operating at a pulse repetition frequency of 7.7 kHz to obtain a high frame rate. The performance of the prototype is characterized, and its functionality is fully verified. Results: The transducer exhibits a transmit efficiency of 28 Pa/V at 5 cm per element and a bandwidth of 60% in transmission. In receive, a dynamic range of 80 dB is measured with a minimum detectable pressure of 10 Pa per element. The element yield of the prototype is 98%, indicating the efficacy of the manufacturing process. The transducer is capable of imaging at a frame rate of up to 1000 volumes/s and is intended to cover a volume of 70° × 70° × 10 cm. Conclusion: These advanced imaging capabilities have the potential to support complex interventional procedures and enable full-volumetric flow, tissue, and electromechanical wave tracking in the heart.</p

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Tau-PET is superior to phospho-tau when predicting cognitive decline in symptomatic AD patients

Introduction: Biomarkers for the prediction of cognitive decline in patients with amnestic mild cognitive impairment (MCI) and amnestic mild dementia are needed for both clinical practice and clinical trials. Methods: We evaluated the ability of tau-PET (positron emission tomography), cortical atrophy on magnetic resonance imaging (MRI), baseline cognition, apolipoprotein E gene (APOE) status, plasma and cerebrospinal fluid (CSF) levels of phosphorylated tau-217, neurofilament light (NfL), and amyloid beta (Aβ)42/40 ratio (individually and in combination) to predict cognitive decline over 2 years in BioFINDER-2 and Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Baseline tau-PET and a composite baseline cognitive score were the strongest independent predictors of cognitive decline. Cortical thickness and NfL provided some additional information. Using a predictive algorithm to enrich patient selection in a theoretical clinical trial led to a significantly lower required sample size. Discussion: Models including baseline tau-PET and cognition consistently provided the best prediction of change in cognitive function over 2 years in patients with amnestic MCI or mild dementia

Identifying a task-invariant cognitive reserve network using task potency

Cognitive reserve (CR) is thought to protect against the consequence of age- or disease-related structural brain changes across multiple cognitive domains. The neural basis of CR may therefore comprise a functional network that is actively involved in many different cognitive processes. To investigate the existence of such a “task-invariant” CR network, we measured functional connectivity in a cognitively normal sample between 20 and 80 years old (N ​= ​265), both at rest and during the performance of 11 separate tasks that aim to capture four latent cognitive abilities (i.e. vocabulary, episodic memory, processing speed, and fluid reasoning). For each individual, we determined the change in functional connectivity from the resting state to each task state, which is referred to as “task potency” (Chauvin et al., 2018, 2019). Task potency was calculated for each pair among 264 nodes (Power et al., 2012) and then summarized across tasks reflecting the same cognitive ability. Subsequently, we established the correlation between task potency and IQ or education (i.e. CR factors). We identified a set of 57 pairs in which task potency showed significant correlations with IQ, but not education, across all four cognitive abilities. These pairs were included in a principal component analysis, from which we extracted the first component to obtain a latent variable reflecting task potency in this task-invariant CR network. This task potency variable was associated with better episodic memory (β ​= ​0.19, p ​< ​.01) and fluid reasoning performance (β ​= ​0.17, p ​< ​.01) above and beyond the effects of cortical thickness (range [absolute] β ​= ​0.28-0.32, p ​< ​.001). Our identification of this task-invariant network contributes to a better understanding of the mechanism underlying CR, which may facilitate the development of CR-enhancing treatments. Our work also offers a useful alternative operational measure of CR for future studies