A combination of fecal calprotectin and human beta-defensin 2 facilitates diagnosis and monitoring of inflammatory bowel disease

Inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) show a large overlap in clinical presentation, which presents diagnostic challenges. As a consequence, invasive and burdensome endoscopies are often used to distinguish between IBD and IBS. Here, we aimed to develop a noninvasive fecal test that can distinguish between IBD and IBS and reduce the number of endoscopies. We used shotgun metagenomic sequencing to analyze the composition and function of gut microbiota of 169 IBS patients, 447 IBD patients and 1044 population controls and measured fecal Calprotectin (FCal), human beta defensin 2 (HBD2), and chromogranin A (CgA) in these samples. These measurements were used to construct training sets (75% of data) for logistic regression and machine learning models to differentiate IBS from IBD and inactive from active IBD. The results were replicated on test sets (remaining 25% of the data) and microbiome data obtained using 16S sequencing. Fecal HBD2 showed high sensitivity and specificity for differentiating between IBD and IBS (sensitivity = 0.89, specificity = 0.76), while the inclusion of microbiome data with biomarkers (HBD2 and FCal) showed a potential for improvement in predictive power (optimal sensitivity = 0.87, specificity = 0.93). Shotgun sequencing-based models produced comparable results using 16S-sequencing data. HBD2 and FCal were found to have predictive power for IBD disease activity (AUC approximate to 0.7). HBD2 is a novel biomarker for IBD in patients with gastro-intestinal complaints, especially when used in combination with FCal and potentially in combination with gut microbiome data

White matter microstructure disruption in early stage amyloid pathology.

Introduction: Amyloid beta (Aβ) accumulation is the first pathological hallmark of Alzheimer's disease (AD), and it is associated with altered white matter (WM) microstructure. We aimed to investigate this relationship at a regional level in a cognitively unimpaired cohort. Methods: We included 179 individuals from the European Medical Information Framework for AD (EMIF‐AD) preclinAD study, who underwent diffusion magnetic resonance (MR) to determine tract‐level fractional anisotropy (FA); mean, radial, and axial diffusivity (MD/RD/AxD); and dynamic [18F]flutemetamol) positron emission tomography (PET) imaging to assess amyloid burden. Results: Regression analyses showed a non‐linear relationship between regional amyloid burden and WM microstructure. Low amyloid burden was associated with increased FA and decreased MD/RD/AxD, followed by decreased FA and increased MD/RD/AxD upon higher amyloid burden. The strongest association was observed between amyloid burden in the precuneus and body of the corpus callosum (CC) FA and diffusivity (MD/RD) measures. In addition, amyloid burden in the anterior cingulate cortex strongly related to AxD and RD measures in the genu CC. Discussion: Early amyloid deposition is associated with changes in WM microstructure. The non‐linear relationship might reflect multiple stages of axonal damage

Multi-tracer model for staging cortical amyloid deposition using PET imaging

OBJECTIVE: To develop and evaluate a model for staging cortical amyloid deposition using PET with high generalizability. METHODS: 3027 subjects (1763 Cognitively Unimpaired (CU), 658 Impaired, 467 Alzheimer's disease (AD) dementia, 111 non-AD dementia, and 28 with missing diagnosis) from six cohorts (EMIF-AD, ALFA, ABIDE, ADC, OASIS-3, ADNI) who underwent amyloid PET were retrospectively included; 1049 subjects had follow-up scans. Applying dataset-specific cut-offs to global Standard Uptake Value ratio (SUVr) values from 27 regions, single-tracer and pooled multi-tracer regional rankings were constructed from the frequency of abnormality across 400 CU subjects (100 per tracer). The pooled multi-tracer ranking was used to create a staging model consisting of four clusters of regions as it displayed a high and consistent correlation with each single-tracer ranking. Relationships between amyloid stage, clinical variables and longitudinal cognitive decline were investigated. RESULTS: SUVr abnormality was most frequently observed in cingulate, followed by orbitofrontal, precuneal, and insular cortices, then the associative, temporal and occipital regions. Abnormal amyloid levels based on binary global SUVr classification were observed in 1.0%, 5.5%, 17.9%, 90.0%, and 100.0% of stage 0-4 subjects, respectively. Baseline stage predicted decline in MMSE (ADNI: N=867, F=67.37, p3000 subjects across cohorts and radiotracers, and detects pre-global amyloid burden and distinct risk profiles of cognitive decline within globally amyloid-positive subjects

The 1000IBD project:multi-omics data of 1000 inflammatory bowel disease patients; data release 1

BackgroundInflammatory bowel disease (IBD) is a chronic complex disease of the gastrointestinal tract. Patients with IBD can experience a wide range of symptoms, but the pathophysiological mechanisms that cause these individual differences in clinical presentation remain largely unknown. In consequence, IBD is currently classified into subtypes using clinical characteristics. If we are to develop a more targeted treatment approach, molecular subtypes of IBD need to be discovered that can be used as new drug targets. To achieve this, we need multiple layers of molecular data generated from the same IBD patients.Construction and contentWe initiated the 1000IBD project (https://1000ibd.org) to prospectively follow more than 1000 IBD patients from the Northern provinces of the Netherlands. For these patients, we have collected a uniquely large number of phenotypes and generated multi-omics profiles. To date, 1215 participants have been enrolled in the project and enrolment is on-going. Phenotype data collected for these participants includes information on dietary and environmental factors, drug responses and adverse drug events. Genome information has been generated using genotyping (ImmunoChip, Global Screening Array and HumanExomeChip) and sequencing (whole exome sequencing and targeted resequencing of IBD susceptibility loci), transcriptome information generated using RNA-sequencing of intestinal biopsies and microbiome information generated using both sequencing of the 16S rRNA gene and whole genome shotgun metagenomic sequencing.Utility and discussionAll molecular data generated within the 1000IBD project will be shared on the European Genome-Phenome Archive (https://ega-archive.org, accession no: EGAS00001002702). The first data release, detailed in this announcement and released simultaneously with this publication, will contain basic phenotypes for 1215 participants, genotypes of 314 participants and gut microbiome data from stool samples (315 participants) and biopsies (107 participants) generated by tag sequencing the 16S gene. Future releases will comprise many more additional phenotypes and -omics data layers. 1000IBD data can be used by other researchers as a replication cohort, a dataset to test new software tools, or a dataset for applying new statistical models.ConclusionsWe report on the establishment and future development of the 1000IBD project: the first comprehensive multi-omics dataset aimed at discovering IBD biomarker profiles and treatment targets

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Correction to: A nonsynonymous mutation in PLCG2 reduces the risk of Alzheimer’s disease, dementia with Lewy bodies and frontotemporal dementia, and increases the likelihood of longevity

The IPDGC (The International Parkinson Disease Genomics Consortium) and EADB (Alzheimer Disease European DNA biobank) are listed correctly as an author to the article, however, they were incorrectly listed more than once

Gut feelings:the relations between depression, anxiety, psychotropic drugs and the gut microbiome

The gut microbiome is involved in the bi-directional relationship of the gut – brain axis. As most studies of this relationship are small and do not account for use of psychotropic drugs (PTDs), we explored the relations of the gut microbiome with several internalizing disorders, while adjusting for PTDs and other relevant medications, in 7,656 Lifelines participants from the Northern Netherlands (5,522 controls and 491 participants with at least one internalizing disorder). Disorders included dysthymia, major depressive disorder (MDD), any depressive disorder (AnyDep: dysthymia or MDD), generalized anxiety disorder (GAD) and any anxiety disorder (AnyAnx: GAD, social phobia and panic disorder). Compared to controls, 17 species were associated with depressive disorders and 3 were associated with anxiety disorders. Around 90% of these associations remained significant (FDR <0.05) after adjustment for PTD use, suggesting that the disorders, not PTD use, drove these associations. Negative associations were observed for the butyrate-producing bacteria Ruminococcus bromii in participants with AnyDep and for Bifidobacterium bifidum in AnyAnx participants, along with many others. Tryptophan and glutamate synthesis modules and the 3,4-Dihydroxyphenylacetic acid synthesis module (related to dopamine metabolism) were negatively associated with MDD and/or dysthymia. After additional adjustment for functional gastrointestinal disorders and irritable bowel syndrome, these relations remained either statistically (FDR <0.05) or nominally (P < 0.05) significant. Overall, multiple bacterial species and functional modules were associated with internalizing disorders, including gut – brain relevant components, while associations to PTD use were moderate. These findings suggest that internalizing disorders rather than PTDs are associated with gut microbiome differences relative to controls

Correction to: The 1000IBD project: multi-omics data of 1000 inflammatory bowel disease patients; data release 1

Following publication of the original article [1], the authors

Genetically identical twins show comparable tau PET load and spatial distribution

Tau accumulation starts during the preclinical phase of Alzheimer's disease and is closely associated with cognitive decline. For preventive purposes, it is important to identify factors associated with tau accumulation and spread. Studying genetically identical twin-pairs may give insight into genetic and environmental contributions to tau pathology, as similarities in identical twin-pairs largely result from genetic factors, while differences in identical twin-pairs can largely be attributed to non-shared, environmental factors. This study aimed to examine similarities and dissimilarities in a cohort of genetically identical older twin-pairs in 1) tau load and 2) spatial distribution of tau, measured with [18F]flortaucipir PET. We selected 78 genetically identical twins (39 pairs; average age 73 ± 6), enriched for amyloid-β pathology and APOE ε4 carriership, who underwent dynamic [18F]flortaucipir PET. We extracted binding potentials (BPND) in entorhinal, temporal, widespread neocortical and global regions, and examined within-pair similarities in BPND using age and sex corrected intra-class correlations. Furthermore, we tested whether twin-pairs showed a more similar spatial [18F]flortaucipir distribution compared to non-twin pairs, and whether the participant's co-twin could be identified solely based on the spatial [18F]flortaucipir distribution. Last, we explored whether environmental (e.g. physical activity, obesity) factors could explain observed differences in twins of a pair in [18F]flortaucipir BPND. On visual inspection, Alzheimer's disease-like [18F]flortaucipir PET patterns were observed, and although we mainly identified similarities in twin-pairs, some pairs showed strong dissimilarities. [18F]flortaucipir BPND was correlated in twins in the entorhinal (r = 0.40; p = 0.01), neocortical (r = 0.59; p < 0.01) and global (r = 0.56; p < 0.01) regions, but not in the temporal region (r = 0.20; p = 0.10). The [18F]flortaucipir distribution pattern was significantly more similar between twins of the same pair (mean r = 0.27; SD = 0.09) than between non-twin pairings of participants (mean r = 0.01; SD = 0.10) (p < 0.01), also after correcting for proxies of off-target binding. Based on the spatial [18F]flortaucipir distribution, we could identify with an accuracy of 86% which twins belonged to the same pair. Finally, within-pair differences in [18F]flortaucipir BPND were associated with within-pair differences in depressive symptoms (0.37<β<0.56), physical activity (-0.41<β<-0.42) and social activity (-0.32<β<-0.36) (all p < 0.05). Overall, identical twin-pairs were comparable in tau load and spatial distribution, highlighting the important role of genetic factors in the accumulation and spreading of tau pathology. Considering also the presence of dissimilarities in tau pathology in identical twin-pairs, our results additionally support a role for (potentially modifiable) environmental factors in the onset of Alzheimer's disease pathological processes, which may be of interest for future prevention strategies