Comparison of Magnetic Resonance Imaging and Serum Biomarkers for Detection of Human Pluripotent Stem Cell-Derived Teratomas.

The use of cells derived from pluripotent stem cells (PSCs) for regenerative therapies confers a considerable risk for neoplastic growth and teratoma formation. Preclinical and clinical assessment of such therapies will require suitable monitoring strategies to understand and mitigate these risks. Here we generated human-induced pluripotent stem cells (iPSCs), selected clones that continued to express reprogramming factors after differentiation into cardiomyocytes, and transplanted these cardiomyocytes into immunocompromised rat hearts post-myocardial infarction. We compared magnetic resonance imaging (MRI), cardiac ultrasound, and serum biomarkers for their ability to delineate teratoma formation and growth. MRI enabled the detection of teratomas with a volume >8 mm(3). A combination of three plasma biomarkers (CEA, AFP, and HCG) was able to detect teratomas with a volume >17 mm(3) and with a sensitivity of more than 87%. Based on our findings, a combination of serum biomarkers with MRI screening may offer the highest sensitivity for teratoma detection and tracking

Airspace Technology Demonstration 2 (ATD-2) Technology Description Document (TDD)

This Technology Description Document (TDD) provides an overview of the technology for the Phase 1 Baseline Integrated Arrival, Departure, and Surface (IADS) prototype system of the National Aeronautics and Space Administration's (NASA) Airspace Technology Demonstration 2 (ATD-2) project, to be demonstrated beginning in 2017 at Charlotte Douglas International Airport (CLT). Development, integration, and field demonstration of relevant technologies of the IADS system directly address recommendations made by the Next Generation Air Transportation System (NextGen) Integration Working Group (NIWG) on Surface and Data Sharing and the Surface Collaborative Decision Making (Surface CDM) concept of operations developed jointly by the Federal Aviation Administration (FAA) and aviation industry partners. NASA is developing the IADS traffic management system under the ATD-2 project in coordination with the FAA, flight operators, CLT airport, and the National Air Traffic Controllers Association (NATCA). The primary goal of ATD-2 is to improve the predictability and operational efficiency of the air traffic system in metroplex environments, through the enhancement, development, and integration of the nation's most advanced and sophisticated arrival, departure, and surface prediction, scheduling, and management systems. The ATD-2 project is a 5-year research activity beginning in 2015 and extending through 2020. The Phase 1 Baseline IADS capability resulting from the ATD-2 research will be demonstrated at the CLT airport beginning in 2017. Phase 1 will provide the initial demonstration of the integrated system with strategic and tactical scheduling, tactical departure scheduling to an en route meter point, and an early implementation prototype of a Terminal Flight Data Manager (TFDM) Electronic Flight Data (EFD) system. The strategic surface scheduling element of the capability is consistent with the Surface CDM Concept of Operations published in 2014 by the FAA Surface Operations Directorate

International Space Station (ISS) Plasma Contactor Unit (PCU) Utilization Plan Assessment Update

The NASA Engineering and Safety Center (NESC) received a request to support the Assessment of the International Space Station (ISS) Plasma Contactor Unit (PCU) Utilization Update. The NESC conducted an earlier assessment of the use of the PCU in 2009. This document contains the outcome of the assessment update

International Space Station (ISS) Plasma Contactor Unit (PCU) Utilization Plan Assessment Update

The International Space Station (ISS) vehicle undergoes spacecraft charging as it interacts with Earth's ionosphere and magnetic field. The interaction can result in a large potential difference developing between the ISS metal chassis and the local ionosphere plasma environment. If an astronaut conducting extravehicular activities (EVA) is exposed to the potential difference, then a possible electrical shock hazard arises. The control of this hazard was addressed by a number of documents within the ISS Program (ISSP) including Catastrophic Safety Hazard for Astronauts on EVA (ISS-EVA-312-4A_revE). The safety hazard identified the risk for an astronaut to experience an electrical shock in the event an arc was generated on an extravehicular mobility unit (EMU) surface. A catastrophic safety hazard, by the ISS requirements, necessitates mitigation by a two-fault tolerant system of hazard controls. Traditionally, the plasma contactor units (PCUs) on the ISS have been used to limit the charging and serve as a "ground strap" between the ISS structure and the surrounding ionospheric plasma. In 2009, a previous NASA Engineering and Safety Center (NESC) team evaluated the PCU utilization plan (NESC Request #07-054-E) with the objective to assess whether leaving PCUs off during non-EVA time periods presented risk to the ISS through assembly completion. For this study, in situ measurements of ISS charging, covering the installation of three of the four photovoltaic arrays, and laboratory testing results provided key data to underpin the assessment. The conclusion stated, "there appears to be no significant risk of damage to critical equipment nor excessive ISS thermal coating damage as a result of eliminating PCU operations during non- EVA times." In 2013, the ISSP was presented with recommendations from Boeing Space Environments for the "Conditional" Marginalization of Plasma Hazard. These recommendations include a plan that would keep the PCUs off during EVAs when the space environment forecast input to the ISS charging model indicates floating potentials (FP) within specified limits. These recommendations were based on the persistence of conditions in the space environment due to the current low solar cycle and belief in the accuracy and completeness of the ISS charging model. Subsequently, a Noncompliance Report (NCR), ISS-NCR-232G, Lack of Two-fault Tolerance to EVA Crew Shock in the Low Earth Orbit Plasma Environment, was signed in September 2013 specifying new guidelines for the use of shock hazard controls based on a forecast of the space environment from ISS plasma measurements taken prior to the EVA [ISS-EVA-312-AC, 2012]. This NESC assessment re-evaluates EVA charging hazards through a process that is based on over 14 years of ISS operations, charging measurements, laboratory tests, EMU studies and modifications, and safety reports. The assessment seeks an objective review of the plasma charging hazards associated with EVA operations to determine if any of the present hazard controls can safely change the PCU utilization plan to allow more flexibility in ISS operations during EVA preparation and execution

An exploration of cognitive subgroups in Alzheimer's disease

Heterogeneity is observed in the patterns of cognition in Alzheimer's disease (AD). Such heterogeneity might suggest the involvement of different etiological pathways or different host responses to pathology. A total of 627 subjects with mild/moderate AD underwent cognitive assessment with the Mini-Mental State Examination (MMSE) and the Dementia Rating Scale-2 (DRS-2). Latent class analysis (LCA) was performed on cognition subscale data to identify and characterize cognitive subgroups. Clinical, demographic, and genetic factors were explored for association with class membership. LCA suggested the existence of four subgroups; one group with mild and another with severe global impairment across the cognitive domains, one group with primary impairments in attention and construction, and another group with primary deficits in memory and orientation. Education, disease duration, age, Apolipoprotein E-ε4 (APOE ε4) status, gender, presence of grasp reflex, white matter changes, and early or prominent visuospatial impairment were all associated with class membership. Our results support the existence of heterogeneity in patterns of cognitive impairment in AD. Our observation of classes characterized by predominant deficits in attention/construction and memory respectively deserves further exploration as does the association between membership in the attention/construction class and APOE ε4 negative status. (JINS, 2010, 16, 233-243.

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BackgroundThe Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.MethodsThe COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.ResultsThe CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.ConclusionAvailability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years

Avoid or Embrace? Practice Effects in Alzheimer's Disease Prevention Trials

Demonstrating a slowing in the rate of cognitive decline is a common outcome measure in clinical trials in Alzheimer’s disease (AD). Selection of cognitive endpoints typically includes modeling candidate outcome measures in the many, richly phenotyped observational cohort studies available. An important part of choosing cognitive endpoints is a consideration of improvements in performance due to repeated cognitive testing (termed “practice effects”). As primary and secondary AD prevention trials are comprised predominantly of cognitively unimpaired participants, practice effects may be substantial and may have considerable impact on detecting cognitive change. The extent to which practice effects in AD prevention trials are similar to those from observational studies and how these potential differences impact trials is unknown. In the current study, we analyzed data from the recently completed DIAN-TU-001 clinical trial (TU) and the associated DIAN-Observational (OBS) study. Results indicated that asymptomatic mutation carriers in the TU exhibited persistent practice effects on several key outcomes spanning the entire trial duration. Critically, these practice related improvements were larger on certain tests in the TU relative to matched participants from the OBS study. Our results suggest that the magnitude of practice effects may not be captured by modeling potential endpoints in observational studies where assessments are typically less frequent and drug expectancy effects are absent. Using alternate instrument forms (represented in our study by computerized tasks) may partly mitigate practice effects in clinical trials but incorporating practice effects as outcomes may also be viable. Thus, investigators must carefully consider practice effects (either by minimizing them or modeling them directly) when designing cognitive endpoint AD prevention trials by utilizing trial data with similar assessment frequencies

Genome-wide analyses as part of the international FTLD-TDP whole-genome sequencing consortium reveals novel disease risk factors and increases support for immune dysfunction in FTLD

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) represents the most common pathological subtype of FTLD. We established the international FTLD-TDP whole genome sequencing consortium to thoroughly characterize the known genetic causes of FTLD-TDP and identify novel genetic risk factors. Through the study of 1,131 unrelated Caucasian patients, we estimated that C9orf72 repeat expansions and GRN loss-of-function mutations account for 25.5% and 13.9% of FTLD-TDP patients, respectively. Mutations in TBK1 (1.5%) and other known FTLD genes (1.4%) were rare, and the disease in 57.7% of FTLD-TDP patients was unexplained by the known FTLD genes. To unravel the contribution of common genetic factors to the FTLD-TDP etiology in these patients, we conducted a two-stage association study comprising the analysis of whole-genome sequencing data from 517 FTLD-TDP patients and 838 controls, followed by targeted genotyping of the most associated genomic loci in 119 additional FTLD-TDP patients and 1653 controls. We identified three genome-wide significant FTLD-TDP risk loci: one new locus at chromosome 7q36 within the DPP6 gene led by rs118113626 (pvalue=4.82e-08, OR=2.12), and two known loci: UNC13A, led by rs1297319 (pvalue=1.27e-08, OR=1.50) and HLA-DQA2 led by rs17219281 (pvalue=3.22e-08, OR=1.98). While HLA represents a locus previously implicated in clinical FTLD and related neurodegenerative disorders, the association signal in our study is independent from previously reported associations. Through inspection of our whole genome sequence data for genes with an excess of rare loss-of-function variants in FTLD-TDP patients (n≥3) as compared to controls (n=0), we further discovered a possible role for genes functioning within the TBK1-related immune pathway (e.g. DHX58, TRIM21, IRF7) in the genetic etiology of FTLD-TDP. Together, our study based on the largest cohort of unrelated FTLD-TDP patients assembled to date provides a comprehensive view of the genetic landscape of FTLD-TDP, nominates novel FTLD-TDP risk loci, and strongly implicates the immune pathway in FTLD-TDP pathogenesis

Frontotemporal dementia and its subtypes: a genome-wide association study

SummaryBackground Frontotemporal dementia (FTD) is a complex disorder characterised by a broad range of clinical manifestations, differential pathological signatures, and genetic variability. Mutations in three genes—MAPT, GRN, and C9orf72—have been associated with FTD. We sought to identify novel genetic risk loci associated with the disorder. Methods We did a two-stage genome-wide association study on clinical FTD, analysing samples from 3526 patients with {FTD} and 9402 healthy controls. To reduce genetic heterogeneity, all participants were of European ancestry. In the discovery phase (samples from 2154 patients with {FTD} and 4308 controls), we did separate association analyses for each {FTD} subtype (behavioural variant FTD, semantic dementia, progressive non-fluent aphasia, and {FTD} overlapping with motor neuron disease FTD-MND), followed by a meta-analysis of the entire dataset. We carried forward replication of the novel suggestive loci in an independent sample series (samples from 1372 patients and 5094 controls) and then did joint phase and brain expression and methylation quantitative trait loci analyses for the associated (p<5 × 10−8) single-nucleotide polymorphisms. Findings We identified novel associations exceeding the genome-wide significance threshold (p<5 × 10−8). Combined (joint) analyses of discovery and replication phases showed genome-wide significant association at 6p21.3, \{HLA\} locus (immune system), for rs9268877 (p=1·05 × 10−8; odds ratio=1·204 95% \{CI\} 1·11–1·30), rs9268856 (p=5·51 × 10−9; 0·809 0·76–0·86) and rs1980493 (p value=1·57 × 10−8, 0·775 0·69–0·86) in the entire cohort. We also identified a potential novel locus at 11q14, encompassing RAB38/CTSC (the transcripts of which are related to lysosomal biology), for the behavioural \{FTD\} subtype for which joint analyses showed suggestive association for rs302668 (p=2·44 × 10−7; 0·814 0·71–0·92). Analysis of expression and methylation quantitative trait loci data suggested that these loci might affect expression and methylation in cis. Interpretation Our findings suggest that immune system processes (link to 6p21.3) and possibly lysosomal and autophagy pathways (link to 11q14) are potentially involved in FTD. Our findings need to be replicated to better define the association of the newly identified loci with disease and to shed light on the pathomechanisms contributing to FTD. Funding The National Institute of Neurological Disorders and Stroke and National Institute on Aging, the Wellcome/MRC Centre on Parkinson's disease, Alzheimer's Research UK, and Texas Tech University Health Sciences Center

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder