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Pharmacological phosphodiesterase 4D (PDE4D) inhibition shows therapeutic potential to restore memory function in Alzheimer's disease (AD), but will likely evoke adverse side effects. As PDE4D encodes multiple isoforms, targeting specific isoforms may improve treatment efficacy and safety. Here, we investigated whether PDE4D isoform expression and PDE4D DNA methylation is affected in AD and whether expression changes are associated with severity of pathology and cognitive impairment. In post-mortem temporal lobe brain material from AD patients (n = 42) and age-matched controls (n = 40), we measured PDE4D isoform expression and PDE4D DNA (hydroxy)methylation using quantitative polymerase chain reaction and Illumina 450k Beadarrays, respectively. Linear regression revealed increased PDE4D1, -D3, -D5, and -D8 expression in AD with concurrent (hydroxy)methylation changes in associated promoter regions. Moreover, increased PDE4D1 and-D3 expression was associated with higherplaque and tau pathology levels, higher Braak stages, and progressed cognitive impairment. Future studies should indicate functional roles of specific PDE4D isoforms and the efficacy and safety of their selective inhibition to restore memory function in AD. (C) 2020 The Authors. Published by Elsevier Inc. ; This work was financially supported by grants from ISAO/Alzheimer Nederland WE.03-2016-07, Young European Research Universities Network (YERUN), and the Baeter Laeve foundation. Additional funds have been provided by the Internationale Stichting Alzheimer Onderzoek (ISAO)/Alzheimer Netherlands (Award #11532; Funded by the Dorpmans-Wigmans Foundation) (DvdH), and by the Joint ProgrammeeNeurodegenerative Disease Research (JPND) for the EPI-AD consortium (http://www.neurodegenerationresearch.eu/wp-content/uploads/2015/10/Factsheet_EPI-AD.pdf).The project is supported through the following funding organizations under the aegis of JPND; The Netherlands, The Netherlands Organisation for Health Research and Development (ZonMw); United Kingdom, Medical Research Council; Germany, German Federal Ministry of Education and Research (BMBF); Luxembourg, National Research Fund (FNR). This project has received funding from the European Union's Horizon 2020 research and innovation program under Grant Agreement No. 643417. ; Prickaerts, J (corresponding author), Maastricht Univ, Dept Psychiat & Neuropsychol, Sch Mental Hlth & Neurosci, POB 616, NL-6200 MD Maastricht, Netherlands. jos.prickaerts@maastrichtuniversity.nl

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects (N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of >=|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings.

Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. Results: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10 -08 ) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. Conclusions: This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.ResultsStage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.ConclusionsThis study ...

Background Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis. Results Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 x 10(-08)) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region. Conclusions This ...

BackgroundEpigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis.ResultsStage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10-08) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region.ConclusionsThis study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.