DNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans.

Humanized mouse models can be used to explore human gene regulatory elements (REs), which frequently lie in non-coding and less conserved genomic regions. Epigenetic modifications of gene REs, also in the context of gene x environment interactions, have not yet been explored in humanized mouse models. We applied high-accuracy measurement of DNA methylation (DNAm) via targeted bisulfite sequencing (HAM-TBS) to investigate DNAm in three tissues/brain regions (blood, prefrontal cortex and hippocampus) of mice carrying the human FK506-binding protein 5 (FKBP5) gene, an important candidate gene associated with stress-related psychiatric disorders. We explored DNAm in three functional intronic glucocorticoid-responsive elements (at introns 2, 5, and 7) of FKBP5 at baseline, in cases of differing genotype (rs1360780 single nucleotide polymorphism), and following application of the synthetic glucocorticoid dexamethasone. We compared DNAm patterns in the humanized mouse (N = 58) to those in human peripheral blood (N = 447 and N = 89) and human postmortem brain prefrontal cortex (N = 86). Overall, DNAm patterns in the humanized mouse model seem to recapitulate DNAm patterns observed in human tissue. At baseline, this was to a higher extent in brain tissue. The animal model also recapitulated effects of dexamethasone on DNAm, especially in peripheral blood and to a lesser extent effects of genotype on DNAm. The humanized mouse model could thus assist in reverse translation of human findings in psychiatry that involve genetic and epigenetic regulation in non-coding elements.

Extensive evaluation of DNA methylation of functional elements in the murine Fkbp5 locus using high-accuracy DNA methylation measurement via targeted bisulfite sequencing.

FKBP5 is an important stress-regulatory gene implicated in stress-related psychiatric diseases. Single nucleotide polymorphisms of the FKBP5 gene were shown to interact with early life stress to alter the glucocorticoid-related stress response and moderate disease risk. Demethylation of cytosine-phosphate-guanine-dinucleotides (CpGs) in regulatory glucocorticoid-responsive elements was suggested to be the mediating epigenetic mechanism for long-term stress effects, but studies on Fkbp5 DNA methylation (DNAm) in rodents are so far limited. We evaluated the applicability of high-accuracy DNA methylation measurement via targeted bisulfite sequencing (HAM-TBS), a next-generation sequencing-based technology, to allow a more in-depth characterisation of the DNA methylation of the murine Fkbp5 locus in three different tissues (blood, frontal cortex and hippocampus). In this study, we not only increased the number of evaluated sites in previously described regulatory regions (in introns 1 and 5), but also extended the evaluation to novel, possibly relevant regulatory regions of the gene (in intron 8, the transcriptional start site, the proximal enhancer and CTCF-binding sites within the 5'UTR). We here describe the assessment of HAM-TBS assays for a panel of 157 CpGs with possible functional relevance in the murine Fkbp5 gene. DNAm profiles were tissue-specific, with lesser differences between the two brain regions than between the brain and blood. Moreover, we identified DNAm changes in the Fkbp5 locus after early life stress exposure in the frontal cortex and blood. Our findings indicate that HAM-TBS is a valuable tool for broader exploration of the DNAm of the murine Fkbp5 locus and its involvement in the stress response.

Multiple brain abscesses caused by Rhinocladiella mackenziei in an immunocompetent patient: a case report and literature review.

Primary cerebral phaeohyphomycosis due to Rhinocladiella mackenziei is an extremely rare infection carrying more than 80% mortality, with most cases reported from the Middle East region. This darkly pigmented black yeast is highly neurotropic, aggressive and refractory to most antifungal agents. Here we present an immunocompetent elderly male, presenting with multiple brain abscesses, with R. mackenziei confirmed by nuclear ribosomal repeat region sequencing, who was successfully treated by surgical debridement and intravenous voriconazole. To our knowledge this is the first case reported from the United Kingdom. We also present a review of all such cases so far reported in the English literature world-wide, which we believe is a step further to understanding the pathogenesis and establishing effective treatment of this rare, yet often fatal disease.

Transdiagnostic evaluation of epigenetic age acceleration and burden of psychiatric disorders.

Different psychiatric disorders as well as exposure to adverse life events have individually been associated with multiple age-related diseases and mortality. Age acceleration in different epigenetic clocks can serve as biomarker for such risk and could help to disentangle the interplay of psychiatric comorbidity and early adversity on age-related diseases and mortality. We evaluated five epigenetic clocks (Horvath, Hannum, PhenoAge, GrimAge and DunedinPoAm) in a transdiagnostic psychiatric sample using epigenome-wide DNA methylation data from peripheral blood of 429 subjects from two studies at the Max Planck Institute of Psychiatry. Burden of psychiatric disease, represented by a weighted score, was significantly associated with biological age acceleration as measured by GrimAge and DunedinPoAm (R2-adj. 0.22 and 0.33 for GrimAge and DunedinPoAm, respectively), but not the other investigated clocks. The relation of burden of psychiatric disease appeared independent of differences in socioeconomic status and medication. Our findings indicate that increased burden of psychiatric disease may associate with accelerated biological aging. This highlights the importance of medical management of patients with multiple psychiatric comorbidities and the potential usefulness of specific epigenetic clocks for early detection of risk and targeted intervention to reduce mortality in psychiatric patients.

Epigenetic age acceleration as a biomarker for impaired cognitive abilities in adulthood following early life adversity and psychiatric disorders.

Background: Early life adversity and psychiatric disorders are associated with earlier declines in neurocognitive abilities during adulthood. These declines may be preceded by changes in biological aging, specifically epigenetic age acceleration, providing an opportunity to uncover genome-wide biomarkers that identify individuals most likely to benefit from early screening and prevention. Methods: Five unique epigenetic age acceleration clocks derived from peripheral blood were examined in relation to latent variables of general and speeded cognitive abilities across two independent cohorts: 1) the Female Growth and Development Study (FGDS; n = 86), a 30-year prospective cohort study of substantiated child sexual abuse and non-abused controls, and 2) the Biological Classification of Mental Disorders study (BeCOME; n = 313), an adult community cohort established based on psychiatric disorders. Results: A faster pace of biological aging (DunedinPoAm) was associated with lower general cognitive abilities in both cohorts and slower speeded abilities in the BeCOME cohort. Acceleration in the Horvath clock was significantly associated with slower speeded abilities in the BeCOME cohort but not the FGDS. Acceleration in the Hannum clock and the GrimAge clock were not significantly associated with either cognitive ability. Accelerated PhenoAge was associated with slower speeded abilities in the FGDS but not the BeCOME cohort. Conclusions: The present results suggest that epigenetic age acceleration has the potential to serve as a biomarker for neurocognitive decline in adults with a history of early life adversity or psychiatric disorders. Estimates of epigenetic aging may identify adults at risk of cognitive decline that could benefit from early neurocognitive screening.

Early adversity as the prototype gene × environment interaction in mental disorders?

Childhood adversity (CA) as a significant stressor has consistently been associated with the development of mental disorders. The interaction between CA and genetic variants has been proposed to play a substantial role in disease etiology. In this review, we focus on the gene by environment (GxE) paradigm, its background and interpretation and stress the necessity of its implementation in psychiatric research. Further, we discuss the findings supporting GxCA interactions, ranging from candidate gene studies to polygenic and genome-wide approaches, their strengths and limitations. To illustrate potential underlying epigenetic mechanisms by which GxE effects are translated, we focus on results from FKBP5 × CA studies and discuss how molecular evidence can supplement previous GxE findings. In conclusion, while GxE studies constitute a valuable line of investigation, more harmonized GxE studies in large, deep-phenotyped, longitudinal cohorts, and across different developmental stages are necessary to further substantiate and understand reported GxE findings.

Vertebral Body Replacement With an Anchored Expandable Titanium Cage in the Cervical Spine: A Clinical and Radiological Evaluation.

BACKGROUND: Expandable cervical cages have been used successfully to reconstruct the anterior spinal column. OBJECTIVE: To perform clinical and radiological evaluation of vertebral body replacement with an anchored expandable titanium cage in the cervical spine after single-level and 2-level corpectomies. METHODS: Between 2011 and 2017, 40 patients underwent a single-level (N = 32) or 2-level (N = 8) anterior corpectomy and fusion using an anchored expandable vertebral body replacement cage. Clinical and radiological data at admission, postoperatively, and at 3- and 12-mo follow-up were retrospectively analyzed. Clinical assessment was performed via standardized neurological evaluation, Odom score, and McCormick classification. Radiological assessment was performed via evaluation of sagittal profile, postoperative position, fusion, and subsidence rates. RESULTS: Mean last follow-up was 14.8 ± 7 mo. Overall clinical and myelopathy-related improvements were shown directly after operation and at last follow-up. A stable centralized positioning of cages was achieved in 37 patients (93%). A mild ventral (>1.5 mm) malplacement was noted in 3 patients (7%) without clinical consequences. Sagittal alignment and preoperative cervical kyphosis improved significantly (7.8° gain of lordosis) and remained stable. Mean preoperative height of operated segments increased by 10 mm postoperatively and remained stable. Fusion rate in non-neoplastic patients and subsidence rate at last follow-up comprised 87.5% and 17.8%. With exception of 1 patient suffering from severe osteoporosis and cage subsidence, no patient needed additional secondary stabilization. CONCLUSION: Anterior corpectomy and fusion by an expandable anchored titanium cage with anchor screws without additional instrumentation resulted in overall clinical improvement and radiological anterior column support, achieving significant and reliable restoration of the physiological sagittal cervical profile.

Predictors of Epileptic Seizures and Ability to Work in Supratentorial Cavernous Angioma Located Within Eloquent Brain Areas.

BACKGROUND: The postoperative outcomes and the predictors of seizure control are poorly studied for supratentorial cavernous angiomas (CA) within or close to the eloquent brain area. OBJECTIVE: To assess the predictors of preoperative seizure control, postoperative seizure control, and postoperative ability to work, and the safety of the surgery. METHODS: Multicenter international retrospective cohort analysis of adult patients benefitting from a functional-based surgical resection with intraoperative functional brain mapping for a supratentorial CA within or close to eloquent brain areas. RESULTS: A total of 109 patients (66.1% women; mean age 38.4 ± 12.5 yr), were studied. Age >38 yr (odds ratio [OR], 7.33; 95% confidence interval [CI], 1.53-35.19; P = .013) and time to surgery > 12 mo (OR, 18.21; 95% CI, 1.11-296.55; P = .042) are independent predictors of uncontrolled seizures at the time of surgery. Focal deficit (OR, 10.25; 95% CI, 3.16-33.28; P < .001) is an independent predictor of inability to work at the time of surgery. History of epileptic seizures at the time of surgery (OR, 7.61; 95% CI, 1.67-85.42; P = .003) and partial resection of the CA and/or of the hemosiderin rim (OR, 12.02; 95% CI, 3.01-48.13; P < .001) are independent predictors of uncontrolled seizures postoperatively. Inability to work at the time of surgery (OR, 19.54; 95% CI, 1.90-425.48; P = .050), Karnofsky Performance Status ≤ 70 (OR, 51.20; 95% CI, 1.20-2175.37; P = .039), uncontrolled seizures postoperatively (OR, 105.33; 95% CI, 4.32-2566.27; P = .004), and worsening of cognitive functions postoperatively (OR, 13.71; 95% CI, 1.06-176.66; P = .045) are independent predictors of inability to work postoperatively. CONCLUSION: The functional-based resection using intraoperative functional brain mapping allows safe resection of CA and the peripheral hemosiderin rim located within or close to eloquent brain areas.

Surgical resection of cavernous angioma located within eloquent brain areas: International survey of the practical management among 19 specialized centers.

PURPOSE: The practical management of cavernous angioma located within eloquent brain area before, during and after surgical resection is poorly documented. We assessed the practical pre-operative, intra-operative, and post-operative management of cavernous angioma located within eloquent brain area. METHOD: An online survey composed of 61 items was sent to 26 centers to establish a multicenter international retrospective cohort of adult patients who underwent a surgical resection as the first-line treatment of a supratentorial cavernous angioma located within or close to eloquent brain area. RESULTS: 272 patients from 19 centers (mean 13.6 ± 16.7 per center) from eight countries were included. The pre-operative management varied significantly between centers and countries regarding the pre-operative functional assessment, the pre-operative epileptological assessment, the first given antiepileptic drug, and the time to surgery. The intra-operative environment varied significantly between centers and countries regarding the use of imaging systems, the use of functional mapping with direct electrostimulations, the extent of resection of the hemosiderin rim, the realization of a post-operative functional assessment, and the time to post-operative functional assessment. The present survey found a post-operative improvement, as compared to pre-operative evaluations, of the functional status, the ability to work, and the seizure control. CONCLUSIONS: We observed a variety of practice between centers and countries regarding the management of cavernous angioma located within eloquent regions. Multicentric prospective studies are required to solve relevant questions regarding the management of cavernous angioma-related seizures, the timing of surgery, and the optimal extent of hemosiderin rim resection.