Sy Jye Leu

Immunologic variables in acute mania of bipolar disorder

Macrophages, lymphocytes and their products, may be involved in the pathophysiology of psychiatric disorders. The cell-mediated immune activation response of manic patients during pre-medication and medication stages remains unclear. The purpose of this case-control study was to investigate the plasma levels of immunologic variables, including interleukin (IL)-1 receptor antagonist (IL-1RA), soluble CD 4 (sCD4) and sCD8, and TH1 (interferon [IFN]-gamma and IL-2) and TH2 (IL-4 and IL-10) cytokines in patients with pre-medicated, medicated bipolar mania. The study subjects, aged 16-44 years, were physically healthy patients with Young Mania Rating Scale (YMRS) scores > or =26, and normal controls, aged 19-40 years, were matched for sex. The immune variables were measured in acute mania and in consequent remission (YMRS scores < or =12) among bipolar patients. The plasma levels of IL-1RA, sCD4, and sCD8 were found significantly increased in pre-medicated acute manic patients as compared to normal controls. But only IL-1RA and sCD8 were found different in remitted bipolar patients as compared to normal controls. For TH1 cytokines, culture supernatant level of IFN-gamma was found significantly lower in manic patients of both acute and remission stages as compared to normal controls. No significant difference was found in IL-2 level in pre-medicated acute manic patients compared to controls. For TH2 cytokines, no significant differences in IL-4 and IL-10 levels were observed. We showed that cell-mediated immune response was activated in patients with bipolar disorder during the pre-medication, medication, and the remission stages. Our study findings suggest that the immune-modulation in patients with bipolar disorder may be abnormal.

Effects of symptomatic severity on elevation of plasma soluble interleukin-2 receptor in bipolar mania

BACKGROUND Circulating soluble interleukin-2 receptors (sIL-2Rs) and soluble interleukin-6 receptors (sIL-6Rs) are stable immune measures. Elevated plasma sIL-2R levels are present in patients with schizophrenia, major depression, and bipolar mania, but not with minor psychiatric disorders. The increased plasma sIL-2R levels are state-dependent in bipolar mania. However, altered production of plasma sIL-6R and the effects of clinical characteristics on plasma sIL-6R and sIL-2R levels in bipolar disorder remains uncertain. METHODS Plasma sIL-2R and sIL-6R levels were measured in 31 Taiwanese bipolar manic (DSM-IV) patients with Young Mania Rating Scale (YMRS) scores of > or =26 as well as during the subsequent remission (YMRS< or =12), and equal numbers of age- and gender-matched healthy controls. The relationships of clinical variables such as age, age of onset, smoking, medication status, coexisting psychotic features, number of prior episodes, duration of illness, presence of depression before or following the manic episode, and manic severity to plasma sIL-2R and sIL-6R levels in acute mania along with remission were examined. RESULTS Plasma sIL-2R but not sIL-6R levels were significantly higher in acute mania than in subsequent remission (P<0.05) and controls (P<0.0005). In acute mania, the plasma sIL-2R levels were significantly correlated to YMRS scores (r=0.34, P<0.05). The remaining clinical variables had no effect on plasma sIL-2R and sIL-6R levels in acute mania or remission. There was a significantly positive relationship between the reduction of plasma sIL-2R levels from the acute to follow-up measurements (DeltasIL-2R) and symptomatic improvement of acute mania (DeltaYMRS) (r=0.61, P<0.001). LIMITATIONS Our sample included medicated and unmedicated patients in acute mania. The psychotropic medication may have divergent effects on the plasma sIL-2R levels in acute mania and subsequent remission. CONCLUSIONS Elevation of plasma sIL-2R but not sIL-6R levels in bipolar mania supports the idea that the immunomodulatory mechanism may vary in different psychotic disorders. In contrast to being a trait marker in schizophrenia and depressive disorder, plasma sIL-2R levels may be considered a biological indicator of manic severity in a group of bipolar affective patients.

Proteomic Identification of Lower Apolipoprotein A-I in Alzheimer’s Disease

Many researches have been trying to find the potential biomarkers for Alzheimer’s disease (AD). We hereby used the proteomics method to search for protein expression differences in the serum between AD patients and controls. We enrolled 59 AD patients and 74 age- and sex-matched controls in this study. Ten AD patients and 10 controls were selected for proteomic analysis. Apolipoprotein A-I (ApoA-I) was found to have a lower expression in the AD group by a proteomics two-dimensional gel electrophoresis study. We further measured the serum ApoA-I level which was significantly lower in the AD patients (112.29 ± 21.33 mg/dl) in comparison to the controls (144.53 ± 19.91 mg/dl; p < 0.0002). Lower serum ApoA-I levels might be a potential biomarker for AD.

Alterations of serum brain-derived neurotrophic factor levels in early alcohol withdrawal

AIMS Alcohol withdrawal-enhanced neurotoxicity contributes to the addictive process. Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal plasticity and learning. In this study, we explored the changes of serum BDNF levels in alcoholic patients at baseline and after one-week alcohol withdrawal. METHODS Twenty-five alcoholic patients were admitted for alcohol detoxification treatment, and 22 healthy control subjects were also enrolled. We collected blood samples of the patient group on the first and seventh day of alcohol withdrawal, and measured serum BDNF level with sandwich enzyme-linked immunosorbent assay. The severity of withdrawal symptoms was evaluated by the Clinical Institute Withdrawal Assessment-Alcohol, Revised every eight hours. RESULTS Serum BDNF levels did not differ significantly between alcoholic patients and control subjects. But BDNF levels were found to be significantly increased one week after alcohol withdrawal (from 13.9 +/- 3.8 ng/ml to 15.4 +/- 3.8 ng/ml, P = 0.03). A significant positive correlation was found between baseline BDNF level and baseline withdrawal severity (r = 0.45, P = 0.03). CONCLUSIONS The present study suggests that elevated serum BDNF levels were found in early alcohol withdrawal, implying that BDNF may involve in neuroadaptation during the period.

Reduced Expression of Circadian Clock Genes in Male Alcoholic Patients

BACKGROUND  There are clear interactions between chronic alcohol consumption and circadian rhythmicity that is regulated by several circadian clock genes. The altered expressions of these genes have been mainly described in animals. The mammalian master clock in the suprachiasmatic nuclei orchestrates the biological rhythms in peripheral tissues. As peripheral blood mononuclear cells (PBMCs) are the most accessible tissue clinically, we assessed the mRNA levels of these genes in patients with alcohol dependence (AD) undergoing alcohol-withdrawal (AW) treatment. METHODS  Twenty-two male patients fulfilled the DSM-IV diagnostic criteria of AD, and 12 comparison healthy control subjects were recruited. The patients with AD were further divided by the presence of delirium tremens (DTs), the most severe form of AW syndrome, into DT group and non-DT group. All the participants received blood withdrawal at 9 am, while the patients with AD had blood collection twice: on the next morning of admission (baseline) and on the seventh day. PBMCs were isolated from whole blood, and the mRNA expression profiles of hClock1, hBmal1, hPer1, hPer2, hCry1, and hCry2 were determined by quantitative real-time PCR. RESULTS The baseline mRNA levels of the target circadian clock genes were markedly lower in patients with AD than in control subjects. After 1 week of alcohol detoxification, there were very limited restorations of discrete circadian gene expressions. DT group did not differ in the expression patterns of circadian clock genes from non-DT group. CONCLUSIONS This is the first study demonstrating the overall lowering of circadian clock genes among patients with AD. The expression pattern is comparable between patients with and without DTs. Although preliminary with data at only one single time point, the observation of strikingly reduced mRNA levels supports the association between circadian clock gene dysregulation and chronic alcohol intake.

Reduced production of interferon-gamma but not interleukin-10 in bipolar mania and subsequent remission

BACKGROUND Activation of inflammatory response system (IRS) is suggested by increased levels of plasma soluble interleukin-2 receptor (sIL-2R) in patients with bipolar mania. The reasons for changes in stimulated interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) production in bipolar mania along with subsequent remission remain unclear. METHODS We measured phytohemagglutinin (PHA)-stimulated IFN-gamma and IL-10 production in 20 physically healthy inpatients aged between 18 and 45 years with bipolar mania (DSM-IV) using Young Mania Rating Scale (YMRS) scores > or = 26 and in subsequent remission (YMRS < or = 12), as well as in 15 age- and sex-matched healthy normal controls. RESULTS The mean values of IFN-gamma production in patients in acute mania and in subsequent remission were significantly lower than those of healthy controls (P=0.0004, P=0.0005, respectively). There was no significant difference in IL-10 production between bipolar patients in acute mania as well as in subsequent remission and healthy controls. In acute mania, the mean values of IFN-gamma and IL-10 production in medicated patients (n = 13) did not differ from those of drug-free patients (n = 7). Other clinical variables had no effect on IFN-gamma and IL-10 production. LIMITATION The uncontrolled medication, small sample size of the bipolar individuals, and some immune re-measurements prior to full remission periods, limit generalization from the data in this study. CONCLUSION Reduced production of IFN-gamma without alternation of IL-10 in bipolar mania and subsequent remission suggest that the immune modulation may vary in patients with different major psychiatric disorders.

Immune-inflammatory markers in patients with seasonal affective disorder: effects of light therapy.

BACKGROUND There is increasing evidence that an activation of the immune-inflammatory system is involved in the pathophysiology of depressive disorders. The purposes of this study were to (1) compare immune-inflammatory markers in patients with seasonal affective disorder (SAD) with those in matched normal controls; and (2) examine the effects of light therapy on the immune-inflammatory markers in patients with SAD. METHODS Plasma concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R) and soluble IL-2 receptor (sIL-2R) were measured in 15 patients with SAD and 15 age- and sex-matched normal controls. Of the 15 patients, 14 had repeated blood sampling for these variables following 2 weeks of light therapy. RESULTS We found that patients with SAD had significantly increased IL-6 levels compared to normal controls (P<0.0005). There was a trend toward increased sIL-2R in patients with SAD (P=0.09). There was no significant difference in sIL-6R level between the two diagnostic groups (P=0.18), but the product term (IL-6xsIL-6R) was significantly higher in patients with SAD than that in normal control controls (P<0.0003). Furthermore, all 14 patients who completed the study improved with 2 weeks of light therapy and nine of them (64%) had 50% reduction in score of the Hamilton Depression Rating Scale-SAD version post-treatment compared to baseline. However, the initially increased immune markers in SAD patients were not significantly altered by the therapeutic light therapy. LIMITATIONS This study was limited to a small sample size and other immune inflammatory markers should be measured for further evidence of immune activation in seasonal depression. CONCLUSIONS Our results of increased IL-6, IL-6xsIL-6R, and sIL-2R in patients with SAD suggest an activation of the immune-inflammatory system in winter depression, which is not altered by 2 weeks of successful light therapy.

Differential Patterns of Serum Brain-Derived Neurotrophic Factor Levels in Alcoholic Patients With and Without Delirium Tremens During Acute Withdrawal

BACKGROUND Brain-derived neurotrophic factor (BDNF) is associated with alcohol addiction and withdrawal-related neurotoxicity. Delirium tremens (DT) is the most serious complication of alcohol withdrawal syndrome (AWS). In this study, we explored the differences in serum BDNF levels, measured at baseline and 1 week after alcohol withdrawal among alcoholic patients with and without DT. METHODS Sixty-five inpatients, fulfilling the DSM-IV criteria of alcohol dependence and admitted for alcohol detoxification, as well as 39 healthy control subjects were enrolled. The alcoholic patients were divided by the appearance of DTs into the DT group (n = 25) and non-DT group (n = 40). We collected blood samples of the patient groups on the first and seventh days of alcohol withdrawal and measured serum BDNF levels by sandwich enzyme-linked immunosorbent assay. RESULTS Serum BDNF levels differed significantly among the three groups: (i) control group 14.8 ± 4.7 ng/ml; (ii) non-DT group 12.3 ± 3.3 ng/ml; (iii) DT group 6.2 ± 2.6 ng/ml (p < 0.001). One week after alcohol withdrawal, the BDNF levels increased significantly for both alcoholic groups. While non-DT group had comparable BDNF levels (13.4 ± 3.5 ng/ml) with controls, the DT group still exhibited lower levels (8.9 ± 4.4 ng/ml). CONCLUSIONS This study suggests chronic drinking leads to a reduction in BDNF levels, and patients with more deficient BDNF expression are vulnerable to the development of DTs. Additionally, BDNF levels elevated after prompt alcohol detoxification treatment. These findings indicate that BDNF could involve modifying the phenotypes of AWS as well as the pertinent neuroadaptive processes of alcohol dependence.

Inflammatory mediators of cerebrospinal fluid from patients with spinal cord injury

BACKGROUND The guidelines of MP treatment for acute SCI are still under debate. We examined the inflammatory mediators of CSF in patients with SCI and assessed the effect of MP treatment. METHODS We studied 7 patients with acute SCI at the cervical level and examined the mediators of CSF in patients by cytokine antibody array, ELISA and gelatin zymography. RESULTS We found that levels of IL-6, IL-8, monocyte chemoattractant protein-1, neutrophil-activating peptide 2, intracellular adhesion molecule-1, soluble Fas, tissue inhibitors of metalloproteinase 1, and matrix metalloproteinases-2 and -9 were upregulated in patients with complete SCI without MP treatment as compared to patients with MP treatments, incomplete SCI, or controls. Nerve growth factor was upregulated in patients with MP treatment. CONCLUSIONS We suggest that a neuroinflammatory CSF profile after complete SCI could be suppressed with MP treatment via downregulating the expression of various cytokines.

Modulation of the development of human monocyte-derived dendritic cells by lithium chloride.

Lithium has been used or explored to treat psychiatric and neurodegenerative diseases that are frequently associated with an abnormal immune status. It is likely that lithium may work through modulation of immune responses in these patients. Because dendritic cells (DC) play a central role in regulating immune responses, this study investigated the influence of lithium chloride (LiCl) on the development and function of DC. Exposure to LiCl during the differentiation of human monocyte‐derived immature DCs (iDC) enhances CD86 and CD83 expression and increases the production of IL‐1β, IL‐6, IL‐8, IL‐10, and TNF‐α. However, the presence of LiCl during LPS‐induced maturation of iDC has the opposite effect. During iDC differentiation, LiCl suppresses the activity of glycogen synthase kinase (GSK)‐3β, and activates PI3K and MEK. In addition, LiCl activates peroxisome proliferator‐activated receptor γ (PPARγ) during iDC differentiation, a pathway not described before. Each of these signaling pathways appears to have distinct impact on the differentiating iDC. The enhanced CD86 expression by LiCl involves the PI3K/AKT and GSK‐3β pathway. LiCl modulates the expression of CD83 in iDC mainly through MEK/ERK, PI3K/AKT, and PPARγ pathways, while the increased production of IL‐1β and TNF‐α mainly involves the MEK/ERK pathway. The effect of LiCl on IL‐6/IL‐8/IL‐10 secretion in iDC is mediated through inhibition of GSK‐3β. We have also demonstrated that PPARγ is downstream of GSK‐3β and is responsible for the LiCl‐mediated modulation of CD86/83 and CD1 expression, but not IL‐6/8/10 secretion. The combined influence of these molecular signaling pathways may account for certain clinical effect of lithium. J. Cell. Physiol. 226: 424–433, 2011.