Mapping the Central Genes in Bipolar Disorder Pathways: From Data to Diagnosis

Bipolar disorder (BD) is characterised by recurrent fluctuations of mood that span from mania to depression, contributing significantly to global disability and mortality.Emerging evidence implicates a role of both peripheral and central immuneinflammatory processes in the pathophysiology of BD.For example, elevated levels of acutephase proteins such as Creactive protein (CRP) and proinflammatory cytokines including interleukin6 (IL6) and tumour necrosis factor (TNF) have been observed in BD patients compared to healthy controls.Metanalytic work found significant elevation of IL4, IL10, sIL2R, sIL6R, TNF and sTNFR1 in BD versus controls.Meanwhile, reported that CRP and TNF were elevated in manic and depressive episodes but not euthymia, while IL6 remained consistently elevated across mood states.Despite this growing body of literature, case-control investigations of neuroinflammatory markers in BD remain limited, and the degree to which peripheral inflammatory indices reflect central nervous system (CNS) activation (for example microglial or glial markers) remains unclear.Against this backdrop, this research aims to compare selected neuroinflammatory biomarkers in BD patients and matched healthy controls, to elucidate the magnitude of neuroinflammatory disturbance and its possible traitversusstate character.The primary objectives are: 1.To quantify levels of selected biomarkers (e.g., IL6, TNF, CRP, and glial fibrillary acidic protein[GFAP] or YKL40) in BD versus controls; 2. To determine associations between biomarker levels and clinical variables including illness duration, number of mood episodes, and current mood state; and 3. To explore whether biomarker patterns differ across mood phases (mania, depression, euthymia).The central hypothesis is that BD patients will exhibit higher mean levels of neuroinflammatory markers compared to healthy controls, and that these elevations will be greater in active mood episodes relative to euthymia.By addressing this hypothesis, the study seeks to advance understanding of immune dysregulation in BD and support development of inflammationtargeted adjunctive treatment strategies.

Brain-Region Size May Be Long-Sought Biomarker

Background Bipolar disorder causes recurrent mania/hypomania and depression. According to the inflammatory idea, oxidative stress and antioxidants may be imbalanced throughout this illness. This study investigates the role of non-enzymatic antioxidants - serum uric acid, serum albumin, and serum bilirubin in different phases of bipolar disorder and compares them with healthy controls. Method Three groups were studied in this cohort research. One group had bipolar affective disorder patients with manic episodes, the second with depressed episodes, and the third with healthy controls. Serum uric acid, albumin, and bilirubin were measured before and after 4 weeks of treatment. The YRMS scale was used for manic episodes and the HAM-D scale was used for depressive episodes to assess disease severity. Results The study included 107 participants: 53 bipolar maniacs, 24 bipolar depressives, and 30 healthy controls. Bipolar mania was associated with considerably higher uric acid levels (5.40 mg/dl) compared to bipolar depression (4.09 mg/dl) and healthy controls (3.16 mg/dl) (p<0.001). Serum albumin levels were lower in bipolar depression (3.08 mg/dl) compared to mania (4.37 mg/dl) and healthy controls (4.60 mg/dl) (p<0.001). Results found no difference in serum bilirubin (p=0.367). Serum uric acid was reduced in bipolar mania (4.08 mg/dl) and depression (3.24 mg/dl) after 4 weeks (p<0.001), but albumin rose in depression (4.03 mg/dl) (p<0.001). Bipolar depression also increased serum bilirubin (0.72 mg/dl, p=0.01). Conclusion These findings suggest a potential role for serum uric acid and albumin as biomarkers in bipolar disorder, reflecting oxidative stress in these patients. This might also have a role in monitoring the progress and treatment of the patients. Recommendation Antioxidants can play a significant role in bipolar disorder but more research work is required. Further research with larger cohorts, consideration of confounding factors, and including measurement of more antioxidant molecules is essential to validate these findings.

Bipolar disorder (BD) is a common and debilitating mental disorder. However, there are no biomarkers available to aid in the diagnosis of this disorder. Here, we used a gas chromatography-mass spectrometry (GC-MS) based metabonomic method to characterize the urinary metabolic profiling of BD subjects and healthy controls to identify and validate urinary metabolite biomarkers for BD. Multivariate statistical analysis was used to visualize group discrimination and identify differentially expressed urinary metabolites in BD subjects relative to the healthy controls. Multivariate statistical analysis showed that the BD group was significantly distinguishable from the healthy control. Totally, 37 urinary metabolites responsible for discriminating BD subjects from healthy controls were identified. Interestingly, of 37 differential metabolites, 2,4-dihydroxypyrimidine was identified as an effective diagnostic biomarker for BD, yielding an area under the receiver operating characteristic curve (AUC) of 0.889 in the training samples (45 BD subjects and 61 healthy controls) and 0.805 in the test samples (26 BD subjects and 33 healthy controls). Our findings suggest that 2,4-dihydroxypyrimidine is a promising candidate urinary biomarker for BD, which may facilitate development of a urine-based diagnostic test for BD.

BackgroundFractional anisotropy (FA) in the uncinate fasciculus and the cingulum may be biomarkers for bipolar disorder and may even be distinctly affected in different subtypes of bipolar disorder, an area in need of further research.AimThis study aims to establish if FA in the uncinate fasciculus and cingulum shows differences between healthy controls (HC), patients with bipolar disorder type I (BD-I) and type II (BD-II), and their unaffected siblings.MethodsFA measures from the uncinate fasciculus, cingulum body and parahippocampal cingulum were compared through tractography methods in 40 HC, 32 BD-I, 34 BD-II, 17 siblings of BD-I and 14 siblings of BD-II.ResultsThe main effects were found in both the right and left uncinate with BD-I showing significantly lower FA than both BD-II and HC. BD-II participants did not differ from HC. Siblings showed similar effects in the left UF. In a subsequent complementary analysis, we investigated the association between FA in the uncinate fasciculus and polygenic risk for bipolar and psychosis in a large cohort (n= 570) of healthy subjects. However, we found no significant association.ConclusionsFA in the uncinate fasciculus differs significantly between BD-I compared to BD-II and HC. This supports the hypothesis of differences in the physiological sub-tract between BD subtypes. Similar results were found in unaffected siblings, suggesting the potential for this biomarker to represent an endophenotype for BD-I. However FA in the uncinate fasciculus seems unrelated to polygenic risk for BD or psychosis.

The interplay between state- and trait-related disruptions in structural networks remains unclear in bipolar disorder (BD), but graph theory can offer insights into global and local network changes. We sought to use diffusion-tensor imaging (DTI) and graph theory approaches to analyze structural topological properties across distinct mood states and identify high-risk individuals by examining state- and trait-related impairments in BD. We studied changes in white matter network among patients with BD and healthy controls, exploring relationships with clinical variables. Secondary analysis involved comparing patients with BD with unaffected people at high genetic risk for BD. We included 152 patients with BD, including 52 with depressive BD (DBD), 64 with euthymic BD (EBD) and 36 with manic BD (MBD); we also included 75 healthy controls. Secondary analyses involved 27 unaffected people at high genetic risk for BD. Patients with DBD and MBD exhibited significantly lower global efficiencies than those with EBD and healthy controls, with patients with DBD showing the lowest global efficiencies. In addition, patients with DBD displayed impaired local efficiency and normalized clustering coefficient (γ). At a global level, γ correlated negatively with depression and anxiety. Compared with healthy controls, and across mood states, patients with BD showed abnormal shortest path lengths in the frontolimbic circuit, a trend mirrored among those at high genetic risk for BD. Considerations include medication effects, absence of recorded BD episode counts and the cross-sectional nature of the study. Mood-specific whole-brain network metrics could serve as potential biomarkers in BD for transitions between mood states. Moreover, these findings contribute to evidence of trait-related frontolimbic circuit irregularities, shedding light on underlying pathophysiological mechanisms in BD.

Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease that leads to the motor neurons depletion in the spinal cord anterior horn and pyramidal tract. Several evaluations have been proposed in order to provide a better follow-up and management of secondary complications. However, the biggest difficulty is to select a single instrument to objectively assess the neurological deficit, the

Bipolar disorder (BD) is a serious mental disorder that globally affected 40 million people in 2019. According to the National Alliance on Mental Illness (NAMI), the present state of scientific knowledge only permits psychiatrists to diagnose BD using subjective and imprecise questionnaires. Therefore, developing a diagnostic tool with objective and precise biomarkers should be a major focus of research in this field. Among the potential biomarkers for BD, electroencephalogram (EEG)-based signatures of BD are considered to be the most optimal marker due to their strong links with behavioural symptoms and also their non-invasiveness. The goal of this review is to give a detailed summary of current techniques for investigating the traces of BD through EEG abnormalities. In this review, 13 studies from databases such as ScienceDirect and PubMed seeking to utilize EEG characteristics to diagnose BD were selected. The search keywords were “EEG in BD diagnosis”, “EEG microstates in BD”, and “EEG features for BD patients”. The publication date was set from 2007 to 2021. From these studies, we synthesize the effects of BD on each EEG feature, as well as detail the pros and cons when using each feature as a biomarker for BD. Results showed that EEG microstates demonstrate their potential among the seven EEG properties discussed in this article, as shown by several studies. By definition, EEG microstates are a dynamic representation of the spatial distribution of the scalp's electric potential as it varies over time. Specifically, four microstate classes recorded in different brain regions are classified into A (right-frontal left-posterior), B (left-frontal right-posterior), C (midline frontal-occipital), and D (midline frontal topographies). Greater presence of microstate class B in BD patients during task-free resting states are a distinctive characteristic of BD patients from which BD can be differentiated from other psychiatric illnesses. Besides microstates, EEG resting states are also considered to have a bright future in BD diagnosis. Specifically, by investigating brain frequency bands, researchers have discovered that BD patients exhibit abnormal delta and alpha signals as compared to healthy controls (HCs). The abnormalities of microstate B in EEG microstate characteristics would be the most promising biomarker for detecting BD. In addition, anomalies in delta and alpha signals during resting EEG states are possible BD diagnostic indicators.

The relation of optical coherence tomography findings with oxidative stress parameters in patients with bipolar disorder and unaffected first-degree relatives

ObjectivesIn this study, we horizontally compared olfactory function and interleukin-6 levels in bipolar disorder (BD) patients with manic and depressive episodes with those in healthy controls. We also compared these variables longitudinally between patients in the acute versus euthymic phase, and assessed the correlation between olfactory function and interleukin-6 in BD patients overall. The purpose of this study was to search potential biomarkers for early diagnosis and efficacy evaluation of BD, and to provide more clinical evidence for exploring the hypothesis of neuroimmune pathways in BD.MethodsThe study included 50 manic BD patients, 31 depressive BD patients, and 59 healthy controls, and all patients were followed until they entered the euthymic phase. Olfactory sensitivity (OS) and olfactory identification (OI) were evaluated via the Sniffin’ Sticks test. We collected blood samples and measured serum interleukin-6 levels.ResultsThe results showed that the OS and OI in manic BD group and depressive BD group were significantly lower than those in healthy controls (P < 0.05, Cohen’s d = 0.657, 0.446, η2 = 0.744, 0.676, respectively), and the OI in euthymic manic BD group and euthymic depressive BD group were significantly lower than those in healthy controls (P < 0.0167, η2 = 0.72, 0.653, respectively). OS returned to normal levels with remission of the disease (P < 0.0167, η2 = 12.106), while OI was continuously impaired. Serum interleukin-6 decreased with remission in manic BD (P = 0.038, η2 = 12.118), but did not return to normal levels (P = 0.006, η2 = 0.719). OS was negatively correlated with serum interleukin-6 in manic BD patients (r = -0.386, P = 0.006).ConclusionThe dynamic recovery of OS (impaired in acute phase, restored in euthymia) suggests its potential as a disease-activity biomarker in BD, while persistent OI deficits may reflect trait-related neurobiological features. However, their specificity and clinical utility require rigorous validation. There is a potential correlation between inflammatory activity and olfactory dysfunction in manic BD patients, but its causal relationship and specific mechanism need to be further verified.

Reported structural abnormalities of patients with bipolar disorder (BD) are inconsistent and the use of psychotropic medication is one of the sources of heterogeneity. A fairly small number of morphometric studies have involved comparison of BD on different mood stabilizers. Here in this study, we aimed to investigate the cortical thickness and subcortical volumes in euthymic BD patients on lithium and valproate and healthy controls (HC), and to elucidate the relationship between the use of medication and brain structure variations. We acquired structural magnetic resonance imaging data from 35 BD patients (19/valproate;16/lithium) and 30 HC subjects. Cortical thickness was compared in multiple locations across the continuous cortical surface, and subcortical volumes were compared on a structure-by-structure basis. Group analyses revealed widespread thinning of the prefrontal cortex in BD. Compared with BD on valproate, BD on lithium showed significant increased cortical thickness of the left rostral middle frontal cortex and right superior frontal cortex, while cortical thickness was not significantly different between BD on lithium and HC in the bilateral rostral middle frontal cortex. Moreover, no significant difference was observed in subcortical volume. Limitations of this study comprise the possible effect of other psychotropic drugs, small sample size and the cross-sectional design. Therefore, the results suggest medication-related neurobiological difference between BD patients on different mood stabilizers, but no casual role can be proposed. Our findings provided new evidence about the effects of psychotropic medication upon neuroanatomy in BD, and could help to explain the inconsistency of existing studies as well as contribute to the extraction of reliable neuroimaging biomarkers in BD.

A reliable biomarker signature for bipolar disorder sensitive to illness phase would be of considerable clinical benefit. Among circulating blood-derived markers there has been a significant amount of research into inflammatory markers, neurotrophins and oxidative stress markers.AimsTo synthesise and interpret existing evidence of inflammatory markers, neurotrophins and oxidative stress markers in bipolar disorder focusing on the mood phase of illness. Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, a systematic review was conducted for studies investigating peripheral biomarkers in bipolar disorder compared with healthy controls. We searched Medline, Embase, PsycINFO, SciELO and Web of Science, and separated studies by bipolar mood phase (mania, depression and euthymia). Extracted data on each biomarker in separate mood phases were synthesised using random-effects model meta-analyses. In total, 53 studies were included, comprising 2467 cases and 2360 controls. Fourteen biomarkers were identified from meta-analyses of three or more studies. No biomarker differentiated mood phase in bipolar disorder individually. Biomarker meta-analyses suggest a combination of high-sensitivity C-reactive protein/interleukin-6, brain derived neurotrophic factor/tumour necrosis factor (TNF)-α and soluble TNF-α receptor 1 can differentiate specific mood phase in bipolar disorder. Several other biomarkers of interest were identified. Combining biomarker results could differentiate individuals with bipolar disorder from healthy controls and indicate a specific mood-phase signature. Future research should seek to test these combinations of biomarkers in longitudinal studies.Declaration of interestNone.

BackgroundThe purine system represented by uric acid may be involved in the pathogenesis of bipolar disorder, This study intends to explore the association of serum uric acid levels with bipolar disorder in Chinese patients through meta-analysis.MethodsElectronic databases, including PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI), searching from inception to December 2022. Randomized Controlled Trials that reported serum uric acid levels and bipolar disorder were included. Two investigators independently extracted data and RevMan5.4 and Stata14.2 were used for statistical analyses.ResultsTwenty-eight studies with 4482 bipolar disorder, 1568 depression, 785 schizophrenia, and 2876 healthy control subjects were included in this meta-analysis. The results of the meta-analysis showed that serum uric acid levels in the bipolar disorder group were significantly higher than those in depression [SMD 0.53 (0.37, 0.70), p < 0.00001], schizophrenia [SMD 0.27 (0.05, 0.49), p = 0.02] and healthy control group [SMD 0.87 (0.67, 1.06), p < 0.00001]. Subgroup-analysis showed that in Chinese people with bipolar disorder, uric acid levels of the manic episode were higher than the depressed episode [SMD 0.31 (0.22, 0.41), p < 0.00001].ConclusionOur results indicated a strong association between serum uric acid levels and bipolar disorder in Chinese patients, but further studies about whether uric acid levels can be a biomarker for bipolar disorder still need to investigate.

CSF neuroinflammatory biomarkers in bipolar disorder are associated with cognitive impairment

Data-driven learning to identify biomarkers in bipolar disorder