Biomarkers in Neuropsychiatry最新文献

Introduction

Optical coherence tomography (OCT) is used to study retinal structure in schizophrenia. Changes in retinal structure, especially the retinal nerve fiber layer (RNFL) has been correlated with psychotic disorders. Measurement variability is a concern since there are various generations of OCT devices. We investigated the inter- and intra-device agreement of macular thickness between spectral domain (SD−OCT) and swept source−OCT (SS−OCT), and compared macula and peripapillary group differences in schizophrenia using SS−OCT.

Methods

Macular OCT thickness was obtained for schizophrenia (SZ, n = 30) and healthy controls (HC, n = 22) subjects using SD−OCT (Heidelberg Spectralis) and SS−OCT (DRI Topcon Triton). Peripapillary thickness was obtained using SS−OCT. RNFL, ganglion cell-inner plexiform complex (GCL+), RNFL plus GCL+ (GCL++), and macular thickness were collected. Clinical and cognitive data were gathered. All statistical analyses were performed using R software.

Results

There was excellent inter-scanner agreement for GCL + and GCL++ with ICC’s between r = 0.92−0.99. Good-to-excellent intra-scanner (OD vs OS) agreement was present except for macular RNFL in the SS−OCT device. No significant peripapillary group differences were identified. Poorer GAF scores were correlated with thinner macular layers and thinner overall peripapillary retinal layer. Greater mania symptoms were associated with smaller peripapillary GCL + thickness (r=-0.43, p = 0.03). Poor overall cognition (Brief Assessment of Cognition in Schizophrenia) was associated with smaller overall peripapillary retinal thickness (r = 0.36, p = 0.02).

Conclusion

While there is RNFL variability, GCL + and GCL++ are comparable between scanners SD−OCT and SS−OCT. Given that RNFL thinning is strongly implicated in psychotic disorders, the use of OCT scanners should not be interchanged due to increased RNFL measurement variability.

First-episode psychosis refers to individuals early in the course of psychotic illness. Identifying the underlying biological processes, including biomarkers, is essential for improving diagnosis and treatment. We performed metabolomics profiling of plasma from a group of first-episode psychosis patients and matched neurotypical controls. Using global metabolomics profiling, we identified antipsychotic or antidepressant medication in 22 individuals diagnosed with first-episode psychosis, closely matching the drug prescription history. There were significant differences in levels of amino acids or their derivatives, including decreases in DL-arginine, L-histidine, DL-serine and threonine as well as increases in L-glutamic acid, ornithine, and proline. Using targeted metabolomics profiling of 408 compounds in plasma samples we identified significant differences in six compounds including decreases in serotonin and arginine as well as increased levels of sarcosine, proline, cis-4-hydroxyproline and trans-4-hydroxyproline. Platelet-activating factor levels were significantly elevated in the FEP cohort. These findings suggest potential biomarkers that require validation in independent cohorts, and in several cases provide supporting evidence for previously reported observations.

Background

The hippocampus (HP) is affected across psychoses, including schizophrenia (SZ), bipolar type 1 (BDP) and schizoaffective (SAD) disorders. We examined HP subfield volumetric abnormalities along the anterior-posterior (ventral-dorsal) axis of the HP in psychosis probands, defined by traditional (DSM) diagnoses and biologically defined subtypes (biotypes, based on cognition and electrophysiology). We hypothesized that biotypes would be better discriminated by HP longitudinal axis subfields abnormalities than DSM.

Methods

The sample included 455 probands from the Bipolar Schizophrenia Network for intermediate Phenotypes (BSNIP) dataset (age 35 ± 12.0): 124 unaffected (age 40.4 ± 15.8) and 299 healthy controls (HC; 37 ± 12.0). Probands were: SZ (190), BDP (151), SAD (114). Probands according to B-SNIP defined biotypes were: biotype-1 (BT1; 120), biotype-2 (BT2; 145), biotype-3 (BT3, 190). 3 T MRI scans were processed with FreeSurfer6.0. The anterior (aHP) and posterior (pHP) HP and aHP and pHP subfields were extracted. Cognitive and clinical data were collected.

Results

All biotypes had smaller aHP subfields compared to HC. BT1 had smaller aHP than both BT2 and BT3. pHP subfields were also smaller in BT1 compared to HC and BT3, while the granule cells layer of the dentate gyrus distinguished BT2 from HC. DSM: aHP subfields were smaller in all DSM types compared to HC and did not differ among DSM categories. A few pHP subfields were affected in SAD and SZ compared to HC and distinguished SAD and SZ from BDP. Probands had smaller aHP compared to unaffected relatives.

Conclusions

Differences in subfield volumetric abnormalities along the anterior- posterior axis of the HP exist across psychoses. aHP abnormalities differ between psychosis probands and HC but do not discriminate among DSM categories. In contrast, biotypes can be differentiated from HC and from each other according to aHP-pHP subfields volumetric abnormalities. Thus, biotype typology may better reflect underlying neurobiology.

Some of the biochemical abnormalities underlying schizophrenia, involve differences in methylation and methylating enzymes, as well as other related target genes. We present results of a study of differences in mRNA expression in peripheral blood lymphocytes (PBLs) and post-mortem brains of chronic schizophrenics (CSZ) and non-psychotic controls (NPC), emphasizing the differential effects of sex and antipsychotic drug treatment on mRNA findings. We studied mRNA expression in lymphocytes of 61 CSZ and 49 NPC subjects using qPCR assays with TaqMan probes to assess levels of DNMT, TET, GABAergic, NR3C1, BDNF mRNAs, and several additional targets identified in a recent RNA sequence analysis. In parallel we studied DNMT1 and GAD67 in samples of brain tissues from 19 CSZ, 26 NPC. In PBLs DNMT1 and DNMT3A mRNA levels were significantly higher in male CSZ vs NPC No significant differences were detected in females. The GAD1, NR3C1 and CNTNAP2 mRNA levels were significantly higher in CSZ than NPC. In CSZ patients treated with clozapine, GAD-1 related, CNTNAP2, and IMPA2 mRNAs were significantly higher than in CSZ subjects not treated with clozapine. Differences between CSZ vs NPC in these mRNAs was primarily attributable to the clozapine treatment. In the brain samples, DNMT1 was significantly higher and GAD67 was significantly lower in CSZ than in NPC, but there were no significant sex differences in diagnostic effects. These findings highlight the importance of considering sex and drug treatment effects in assessing the substantive significance of differences in mRNAs between CSZ and NPC.

Prader-Willi syndrome is a complex endocrinological and developmental disorder characterized by hyperphagic, autistic, and obsessive behaviors, which have been considered to primarily originate from hypothalamus-pituitary axis system alterations in the brain. While the pituitary gland has been demonstrated to contribute to behavioral phenotypes associated with neuropeptide, e.g., arginine-vasopressin, the relevant alterations in Prader-Willi syndrome remain unknown. This study aimed to investigate developmental abnormalities in the pituitary gland structures and determine whether the structural abnormalities are associated with behavioral characteristics in Prader-Willi syndrome. In total, 21 Japanese individuals with Prader-Willi syndrome and 31 healthy controls with typical development were included. Compared with the control group, the Prader-Willi syndrome group showed reduced anterior and posterior pituitary volume ratios per total intracranial volume with relative T₁ shortening in an age-associated manner. Moreover, altered volume ratios and signal intensities were negatively correlated with hyperphagia and autistic questionnaire scores but positively correlated with obsessive scores. The findings suggest that structural and functional alterations, in part due to altered hypothalamus-pituitary function, may contribute to the behavior in Prader-Willi syndrome. The imaging-behavior correlates and in vivo neurochemical visualization of the pituitary gland might be potential intrinsic biomarkers for behavioral phenotypes in Prader-Willi syndrome and other neurodevelopmental disorders.

Background

Childhood adversity is a global health problem affecting 25–50% of children worldwide. Few prior studies have examined the underlying neurochemistry of adversity in adolescents. This cross-sectional study examined spectroscopic markers of trauma in a cohort of adolescents with major depressive disorder (MDD) and healthy controls. We hypothesized that historical adversity would have a negative relationship with spectroscopic measures of glutamate metabolites in anterior cingulate cortex.

Methods

Adolescent participants (aged 13–21) underwent a semi-structured diagnostic interview and clinical assessment, which included the self-report Childhood Trauma Questionnaire (CTQ), a 28-item assessment of childhood adversity. Proton magnetic resonance spectroscopy (¹H-MRS) scans at 3 Tesla of an anterior cingulate cortex (ACC) voxel (8 cm³) encompassing both hemispheres were collected using a 2-dimensional J-averaged sequence to assess N-acetylaspartate (NAA), Glx (glutamate+glutamine) and [NAA]/[Glx] concentrations. Generalized linear models assessed the relationships between CTQ scores and metabolite levels in ACC.

Results

Thirty-nine participants (17 healthy controls, 22 depressed participants) underwent ¹H-MRS and completed the CTQ measures. There were decrements in [NAA]/[Glx] ratio in the ACC of participants with childhood adversity while no significant relationship between CTQ total score and any of the ACC metabolites was found in the combined sample. Exploratory results revealed a positive association between Glx levels and CTQ scores in depressed participants. Conversely the [NAA]/[Glx] ratio had a negative association with total CTQ scores in the depressed participants. Emotional Abuse Scale showed a significant negative relationship with [NAA]/[Glx] ratio in the combined sample when adjusted for depression severity.

Conclusions

Our findings suggest that childhood adversity may impact brain neurochemical profiles. Further longitudinal studies should examine neurochemical correlates of childhood adversity throughout development and in populations with other psychiatric disorders.

Major affective disorder are common and disabling conditions linked to significant psychosocial impairment as well as negative outcome (e.g., suicidal behaviors) . According to a molecular perspective, major depressive disorder and suicidal behavior have been associated with structural and synaptic plasticity disturbances. Small non-coding RNAs, such as microRNAs (miRNAs), may play a significant role in the translational regulation of the synapse. This comprehensive overview is aimed to carefully review the preclinical and clinical literature results regarding the involvement of miRNAs in the pathophysiology and pharmacotherapy of major psychiatric conditions . MiRNAs may act as gene expression regulators critically affecting brain development. The alteration of some intracellular mechanisms together with impaired assembly, localization, and translational regulation of specific RNA binding proteins may affect important functions such as learning and memory contributing to the pathophysiology of major depressive disorder and suicidal behavior. Based on the main findings, most of the miRNAs which have been identified to date are expressed in human brain, where they regulate prominent neurobiological processes, such as neurogenesis and neuroplasticity. The main implications of the present findings are critically discussed.

Introduction

Multiple Sclerosis (MS) is a chronic neuro inflammatory disease which leads to progressive disability. Recent evidence suggests that vascular impairment may contribute to MS onset and progression. Optical Coherence Tomography Angiography (OCT-A) has emerged as an important imaging tool which should allow further exploration of the vessel changes in the pathogenesis and prognosis of MS.

Purpose

To quantify the vascular density (VD) of the choroid (CH) and choriocapillaris (CC) in patients with MS, comparing with normal eyes.

Materials and Methods

45 eyes of 45 MS patients [31 female; mean age (years ± SD) 41,87 ± 11.04; axial length (AL) (AL ± SD) 23.68 ± 0.90) and 45 aged-matched control subjects (33 female; mean age 39,.6 ± 8,93; AL 23.36 ± 0.75] were enrolled in this prospective study. We obtained OCT-A images based on a full-spectrum amplitude de-correlation angiography (FSADA) algorithm. The OCT-A images of the CH and CC were used for quantitative assessment in three regions of the fovea, namely, Region 1 (0–500 μm) Region 2 (500–1000 μm) and Region 3 (1000−1500 μm). Relationships of VD between MS patients with and without optic neuritis (ON) and controls were investigated by binary vessel maps generated from OCT-A slabs and analyzed using ImageJ software.

Results

Compared to controls, in eyes with MS, CH VD was significantly decreased in Region 2 (p = 0.01) and Region 3 (p < 0.01). CCVD was not different between the groups although showing a decreasing tendency in the MS group. Between eyes with and without ON there were a tendency to reduced VD in the ON group in all regions analyzed for both CH and CC layer. All the layers analyzed revealed a positive correlation between CH VD and CC VD and a negative correlation between CC VD and AL.

Conclusions

Although studies have assessed retinal VD in MS using OCT-A, the choroidal vasculature in MS remains understudied. Our results cautiously suggest a functional circulatory disturbance of choroidal vasculatures in MS patients, mainly in those who have previous ON history.

Experiencing traumatic events is unfortunately commonplace and, in some cases, may lead to the onset of debilitating mental health disorders, such as post-traumatic stress disorder (PTSD). Current diagnostic criteria for PTSD results in high depression and anxiety comorbidity. Better understanding of biological mechanisms and pathways underlying PTSD could aid in more accurate case identification and stratification of treatments. Recent meta-analysis has identified chronic PTSD to be associated with increased expression of pro-inflammatory cytokines and alterations in neuronal structures which contribute to an overall reduction in brain volume. Despite this, there are currently no biological markers in clinical use to identify PTSD or monitor treatment. This case-control study (n = 40) aimed to identify differences in peripheral blood biomarkers, and biomarker combinations, able to distinguish PTSD participants from controls, and examine in a biopsychosocial framework. The levels of 5/37 biomarkers investigated were significantly altered in the serum of PTSD participants: HDL and LDL cholesterol, tPA, IL-8 and EGF. Biomarkers could be used in combination with psychological criteria, in a biopsychosocial model, to support clinical management decisions and ensure appropriate individual treatment pathways.

Background

Neurofilament Light (NFL) is a promising biomarker of neuroaxonal injury. Its utility may be improved by expression relative to age-matched controls and by adjusting for other covariates, such as body mass index. It has recently been suggested that renal function may modulate the rate of clearance of NFL from circulation, which if confirmed would make renal function an important additional covariate to take into account when interpreting NFL data in research or clinical settings. Here we explore the relationship between renal function and NFL in a cohort of patients with secondary progressive multiple sclerosis (SPMS).

Methods

We examined data from patients with SPMS who took part in the MS-STAT randomised controlled trial. We use multivariable linear regression to explore the relationship between serum NFL and renal function, and additionally to examine whether including renal function as a covariate improves the ability of NFL to predict the subsequent rate of whole brain atrophy.

Results

Data on renal function and serum NFL was available for 122 patients. Mean eGFR 88 ml/min/1.73 m² (range 38.2–121.9). We found no evidence to support a relationship between renal function and serum NFL in this cohort. Furthermore, the inclusion of eGFR as a covariate in models assessing the relationship between NFL and the rate of whole brain atrophy had no significant effect upon the relationships observed.

Conclusions

We find no evidence for a relationship between renal function and NFL in a cohort of patients with secondary progressive multiple sclerosis. We hypothesise that the previously observed relationships between NFL and renal function related to associations between renal function and subclinical neuropathology, rather than due to modulating clearance of NFL from the circulation, but further research would be required to confirm such mechanisms.