Machine Learning to Detect Alzheimer's Disease from Circulating Non-coding RNAs

Blood-borne small non-coding (sncRNAs) are among the prominent candidates for blood-based diagnostic tests. Often, high-throughput approaches are applied to discover biomarker signatures. These have to be validated in larger cohorts and evaluated by adequate statistical learning approaches. Previously, we published high-throughput sequencing based microRNA (miRNA) signatures in Alzheimer’s disease (AD) patients in the United States (US) and Germany. Here, we determined abundance levels of 21 known circulating miRNAs in 465 individuals encompassing AD patients and controls by RT-qPCR. We computed models to assess the relation between miRNA expression and phenotypes, gender, age, or disease severity (Mini-Mental State Examination; MMSE). Of the 21 miRNAs, expression levels of 20 miRNAs were consistently de-regulated in the US and German cohorts. 18 miRNAs were significantly correlated with neurodegeneration (Benjamini-Hochberg adjusted P < 0.05) with highest significance for miR-532-5p (Benjamini-Hochberg adjusted P = 4.8 × 10−30). Machine learning models reached an area under the curve (AUC) value of 87.6% in differentiating AD patients from controls. Further, ten miRNAs were significantly correlated with MMSE, in particular miR-26a/26b-5p (adjusted P = 0.0002). Interestingly, the miRNAs with lower abundance in AD were enriched in monocytes and T-helper cells, while those up-regulated in AD were enriched in serum, exosomes, cytotoxic t-cells, and B-cells. Our study represents the next important step in translational research for a miRNA-based AD test

Cholinergic Pathway SNPs and Postural Control in 477 Older Adults

Objective: To determine whether single nucleotide polymorphisms (SNPs) of the cholinergic system and quantitative parameters of postural control are associated in healthy older adults. This is a cross-sectional analysis from the TREND study.Methods: All participants performed a static postural control task for 30 s on a foam pad in semitandem stance and eyes closed. We analyzed mean power frequency (MPF), area, acceleration, jerk, and velocity from a mobile sensor worn at the lower back using a validated algorithm. Genotypes of four SNPs in genes involved in the cholinergic system (SLC5A7, CHAT, BCHE, CHRNA4) were extracted from the NeuroX chip. All participants present a normal neurological examination and a Minimental state examination score &gt;24.Results: Four hundred and seventy seven participants were included. Mean age was 69 years, 41% were female. One SNP of the cholinergic pathway was significantly associated with a quantitative postural control parameter. The minor allele of rs6542746 in SLC5A7 was associated with lower MPF (4.04 vs. 4.22 Hz; p = 3.91 × 10-4). Moreover, the following associations showed trends toward significance: minor allele of rs6542746 in SLC5A7 with higher anteroposterior acceleration (318 vs. 287 mG; p = 0.005), and minor allele of rs3810950 in CHAT with higher mediolateral acceleration [1.77 vs. 1.65 log(mG); p = 0.03] and velocity [1.83 vs. 1.74 log(mm/s); p = 0.019]. Intraindividual occurrence of rs6542746 and rs3810950 minor alleles was dose-dependently related with lower MPF (p = 0.004).Conclusion: This observational study suggests an influence of SNPs of the cholinergic pathway on postural control in older adults

Gait Is Associated with Cognitive Flexibility: A Dual-Tasking Study in Healthy Older People

Objectives: To analyze which gait parameters are primarily influenced by cognitive flexibility, and whether such an effect depends on the walking condition used. Design: Cross-sectional analysis. Setting: Tübingen evaluation of Risk factors for Early detection of Neurodegenerative Disorders. Participants: A total of 661 non-demented individuals (49-80 years). Measurements: A gait assessment with four conditions was performed: a 20 m walk at convenient speed (C), at fast speed (F), at fast speed while checking boxes (FB), and while subtracting serial 7s (FS). Seven gait parameters from a wearable sensor-unit (McRoberts, Netherlands) were compared with delta Trail-Making-Test (dTMT) values, which is a measure of cognitive flexibility. Walking strategies of good and poor dTMT performers were compared by evaluating the patterns of gait parameters across conditions. Results: Five parameters correlated significantly with the dTMT in the FS condition, two parameters in the F and FB condition, and none in the C condition. Overall correlations were relatively weak. Gait speed was the gait parameter that most strongly correlated with the dTMT (r(2) = 7.4%). In good, but not poor, dTMT performers differences between FB and FS were significantly different in variability-associated gait parameters. Conclusion: Older individuals need cognitive flexibility to perform difficult walking conditions. This association is best seen in gait speed. New and particularly relevant for recognition and training of deficits is that older individuals with poor cognitive flexibility have obviously fewer resources to adapt to challenging walking conditions. Our findings partially explain gait deficits in older adults with poor cognitive flexibility

A Neurodegenerative Vascular Burden Index and the Impact on Cognition

A wide range of vascular burden factors have been identified to impact vascular function and structure as indicated by carotid intima-media thickness (IMT). On the basis of their impact on IMT, vascular factors may be selected and clustered in a vascular burden index (VBI). Since many vascular factors increase the risk of Alzheimer's disease (AD), a multifactorial neurodegenerative VBI may be related to early pathological processes in AD and cognitive decline in its preclinical stages.We investigated an elderly cohort at risk for neurodegeneration (TREND study, n = 1102) for the multifactorial influence of vascular burden factors on IMT measured by ultrasound. To create a VBI for this cohort, vascular factors and their definitions (considering medical history, medication and/or blood marker data) were selected based on their statistical effects on IMT in multiple regressions including age and sex. The impact of the VBI on cognitive performance was assessed using the Trail-Making Test (TMT) and the CERAD neuropsychological battery.IMT was significantly predicted by age (standardized β = .26), sex (.09; males > females) and the factors included in the VBI: obesity (.18), hypertension (.14), smoking (.08), diabetes (.07), and atherosclerosis (.05), whereas other cardiovascular diseases or hypercholesterolemia were not significant. Individuals with 2 or more VBI factors compared to individuals without had an odds ratio of 3.17 regarding overly increased IMT (≥1.0 mm). The VBI showed an impact on executive control (log(TMT B-A), p = .047) and a trend towards decreased global cognitive function (CERAD total score, p = .057) independent of age, sex and education.A VBI established on the basis of IMT may help to identify individuals with overly increased vascular burden linked to decreased cognitive function indicating neurodegenerative processes. The longitudinal study of this risk cohort will reveal the value of the VBI as prodromal marker for cognitive decline and AD

Effects of phone versus mail survey methods on the measurement of health-related quality of life and emotional and behavioural problems in adolescents

<p>Abstract</p> <p>Background</p> <p>Telephone interviews have become established as an alternative to traditional mail surveys for collecting epidemiological data in public health research. However, the use of telephone and mail surveys raises the question of to what extent the results of different data collection methods deviate from one another. We therefore set out to study possible differences in using telephone and mail survey methods to measure health-related quality of life and emotional and behavioural problems in children and adolescents.</p> <p>Methods</p> <p>A total of 1700 German children aged 8-18 years and their parents were interviewed randomly either by telephone or by mail. Health-related Quality of Life (HRQoL) and mental health problems (MHP) were assessed using the KINDL-R Quality of Life instrument and the Strengths and Difficulties Questionnaire (SDQ) children's self-report and parent proxy report versions. Mean Differences ("d" effect size) and differences in Cronbach alpha were examined across modes of administration. Pearson correlation between children's and parents' scores was calculated within a multi-trait-multi-method (MTMM) analysis and compared across survey modes using Fisher-Z transformation.</p> <p>Results</p> <p>Telephone and mail survey methods resulted in similar completion rates and similar socio-demographic and socio-economic makeups of the samples. Telephone methods resulted in more positive self- and parent proxy reports of children's HRQoL (SMD ≤ 0.27) and MHP (SMD ≤ 0.32) on many scales. For the phone administered KINDL, lower Cronbach alpha values (self/proxy Total: 0.79/0.84) were observed (mail survey self/proxy Total: 0.84/0.87). KINDL MTMM results were weaker for the phone surveys: mono-trait-multi-method mean r = 0.31 (mail: r = 0.45); multi-trait-mono-method mean (self/parents) r = 0.29/0.36 (mail: r = 0.34/0.40); multi-trait-multi-method mean r = 0.14 (mail: r = 0.21). Weaker MTMM results were also observed for the phone administered SDQ: mono-trait-multi-method mean r = 0.32 (mail: r = 0.40); multi-trait-mono-method mean (self/parents) r = 0.24/0.30 (mail: r = 0.20/0.32); multi-trait-multi-method mean r = 0.14 (mail = 0.14). The SDQ classification into borderline and abnormal for some scales was affected by the method (OR = 0.36-1.55).</p> <p>Conclusions</p> <p>The observed differences between phone and mail surveys are small but should be regarded as relevant in certain settings. Therefore, while both methods are valid, some changes are necessary. The weaker reliability and MTMM validity associated with phone methods necessitates improved phone adaptations of paper and pencil questionnaires. The effects of phone versus mail survey modes are partly different across constructs/measures.</p

TMPRSS2-ERG -specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling

<p>Abstract</p> <p>Background</p> <p><it>TMPRSS2-ERG </it>gene fusions occur in about 50% of all prostate cancer cases and represent promising markers for molecular subtyping. Although <it>TMPRSS2-ERG </it>fusion seems to be a critical event in prostate cancer, the precise functional role in cancer development and progression is still unclear.</p> <p>Methods</p> <p>We studied large-scale gene expression profiles in 47 prostate tumor tissue samples and in 48 normal prostate tissue samples taken from the non-suspect area of clinical low-risk tumors using Affymetrix GeneChip Exon 1.0 ST microarrays.</p> <p>Results</p> <p>Comparison of gene expression levels among <it>TMPRSS2-ERG </it>fusion-positive and negative tumors as well as benign samples demonstrated a distinct transcriptional program induced by the gene fusion event. Well-known biomarkers for prostate cancer detection like <it>CRISP3 </it>were found to be associated with the gene fusion status. WNT and TGF-β/BMP signaling pathways were significantly associated with genes upregulated in <it>TMPRSS2-ERG </it>fusion-positive tumors.</p> <p>Conclusions</p> <p>The <it>TMPRSS2-ERG </it>gene fusion results in the modulation of transcriptional patterns and cellular pathways with potential consequences for prostate cancer progression. Well-known biomarkers for prostate cancer detection were found to be associated with the gene fusion. Our results suggest that the fusion status should be considered in retrospective and future studies to assess biomarkers for prostate cancer detection, progression and targeted therapy.</p

Hepatitis B Virus Impairs TLR9 Expression and Function in Plasmacytoid Dendritic Cells

Plasmacytoid dendritic cells (pDCs) play a key role in detecting pathogens by producing large amounts of type I interferon (IFN) by sensing the presence of viral infections through the Toll-Like Receptor (TLR) pathway. TLR9 is a sensor of viral and bacterial DNA motifs and activates the IRF7 transcription factor which leads to type I IFN secretion by pDCs. However, during chronic hepatitis B virus (HBV) infection, pDCs display an impaired ability to secrete IFN-α following ex vivo stimulation with TLR9 ligands. Here we highlight several strategies used by HBV to block IFN-α production through a specific impairment of the TLR9 signaling. Our results show that HBV particle internalisation could inhibit TLR9- but not TLR7-mediated secretion of IFN-α by pDCs. We observed that HBV down-regulated TLR9 transcriptional activity in pDCs and B cells in which TLR9 mRNA and protein levels were reduced. HBV can interfere with TLR9 activity by blocking the MyD88-IRAK4 axis and Sendai virus targeting IRF7 to block IFN-α production. Neutralising CpG motif sequences were identified within HBV DNA genome of genotypes A to H which displayed a suppressive effect on TLR9-immune activation. Moreover, TLR9 mRNA and protein were downregulated in PBMCs from patients with HBV-associated chronic hepatitis and hepatocellular carcinoma. Thus HBV has developed several escape mechanisms to avoid TLR9 activation in both pDCs and B lymphocytes, which may in turn contribute to the establishment and/or persistence of chronic infection

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms