Hsing Cheng Liu

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.

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.

Polymorphisms of the Parkin Gene in Sporadic Parkinson’s Disease among Chinese in Taiwan

The role of genetics in Parkinson’s disease (PD), previously controversial, is now documented by several studies. A major breakthrough has been the discovery of two single-gene defects in familial PD. A single base pair change at position 209 from G to A (G209A) in the fourth exon of the α-synuclein gene has been identified in cases of autosomal dominant familial PD. Mutations in the Parkin gene can induce autosomal recessive juvenile parkinsonism. A polymorphism of R/W366 in the Parkin gene was found to be associated with a protective factor for sporadic PD. We surveyed the polymorphisms of the Parkin gene, including S/N167, R/W366 and V/L380, in 92 cases of sporadic PD and 98 nonaffected individuals in Taiwanese Chinese. The allele frequencies of these polymorphisms are not significantly different between PD and nonaffected controls. We conclude that polymorphisms of the Parkin gene, S/N167, R/W366, V/L380, are not genetic factors for sporadic PD among Chinese in Taiwan.

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.

Genetic risk factors of sporadic Alzheimer's disease among Chinese in Taiwan.

To evaluate the genetic factors for AD among a Chinese population in Taiwan, we studied the polymorphisms of six candidate genes of Alzheimers disease (AD), including the regulatory region of apolipoprotein E (Apo-E, G-186T), the promoter of apolipoprotein E (Apo-E, A-491T), the bleomycin hydrolase gene (BH, A1450G), a mutation of alpha(2)-macroglobulin gene (A2M G2998A), low-density lipoprotein receptor-related protein gene (LRP, C766T), and alpha(1)-antichymotrypsin gene (ACT, -15Ala/Thr) in AD patients and non-affected elder individuals among Taiwanese Chinese. Eighty-two AD patients and 110 non-affected individuals were recruited for this study. We used polymerase chain reaction (PCR) and restriction enzyme digestion to identify their genotypes. The statistical examination was performed by combining the results of our previous reports - apolipoprotein E epsilon4 (ApoE-4), presenilin-1 intronic polymorphism (PS-1, allele 1/2), and the five-nucleotide deletion of alpha(2)-macroglobulin gene (A2M). Among these nine candidate genes of AD, the ApoE-4 allele is the only independent genetic risk factor for AD. The other candidate genes in this study were not associated with the occurrence of AD. In addition, there are no gene-gene interactions.

No Mutation of G209A in the Alpha-Synuclein Gene in Sporadic Parkinson’s Disease among Taiwan Chinese

The role of genetics in Parkinson’s disease (PD), previously controversial, is now supported by several studies. A major breakthrough has been the discovery of a single gene defect in familial Parkinson’s disease. A single base pair change at position 209 from G to A (G209A) in the fourth exon of the α-synuclein gene has been identified in cases of familial PD. We looked for this mutation in 65 cases of sporadic PD in Taiwan Chinese patients but found none of these patients with this mutation. We conclude that mutation of G209A in the α-synuclein gene plays no role in sporadic PD among Taiwan Chinese.

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.

A pilot study for circadian gene disturbance in dementia patients

Disturbance of circadian gene regulation might contribute to behavioral and psychological symptoms in dementia patients. This study was to evaluate the CpG island methylation status on the circadian gene promoters in dementia patients. We conducted a set of methylation specific polymerase chain reaction (mPCR) followed by nucleotide sequencing to analyze the methylation status within the promoters of nine circadian-related genes, including PER1, PER2, PER3, CRY1, CRY2, CLOCK, BMAL1, TIM and CK1epsilon, in the genomic DNA from the peripheral blood leukocytes of 80 dementia patients and 80 age- and gender-matched controls. A total of seven dementia patients (7/80) had CpG island methylation in the circadian genes and none of the controls had methylation. There were three and four patients had CpG island methylation on the promoters of PER1 and CRY1, respectively. Dementia with Lewy body (DLB) patients had the significantly highest frequency of circadian gene CpG island methylation (35.7%). It suggested that epigenetic methylation of circadian gene was more prevalent in dementia patients, especially for the DLB patients. The significance of circadian gene methylation in clinical behavior/sleep disturbance in dementia patients needs further study.

Identification of TLR downstream pathways in stroke patients

OBJECTIVE Toll-like receptors (TLRs) are important molecules for detecting both pathogen invasion and tissue damage. The expression of TLR4 is upregulated in ischemic stroke, at least in the subacute stage. However, the TLR downstream pathways in the context of stroke have not been well studied in previous research. The purpose of this study is to elucidate the TLR4 downstream pathways following ischemic stroke. DESIGN AND METHODS In this study, 12 ischemic stroke patients and 12 controls were selected from among 89 ischemic stroke patients and 166 controls. The chosen subjects had the highest levels of TLR4 mRNA in the peripheral blood. The differences in the TLR downstream signaling pathways, which were studied by using an RT2 Profiler TM PCR array system (Qiagen), were analyzed. The differentially expressed genes were analyzed by using GeneSpring GX and visualized based on the TLR pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG). RESULTS The genes upregulated in stroke patients were found to be involved in the MyD88-independent pathway and in UBE2V1-TRAF6 ubiquitin-mediated proteolysis. The genes were more expressed in extracellular space, receptor binding, and cytokine receptor binding by use of gene ontology (GO) terms than in control patients. CONCLUSIONS We found that the MyD88-independent pathway and the ubiquitin-mediated proteolysis pathway, especially TRAF6, may be the most vital molecules among TLR downstream pathways in incidences of ischemic stroke.

Low Sleep Efficiency in Patients with Cognitive Impairment

Alzheimers disease (AD) is the most common cause of dementias. Mild cognitive impairment (MCI) indicates the situation that a person has memory complaints and mild objective cognitive impairment but no evidence of dementia. Sleep disturbance, one of the behavioral and psychological symptoms of dementia (BPSD), frequently occurs in patients with AD or MCI. The alteration of sleep architectures in AD patients remains inconclusive. In this study, we conducted the polysomnography. (PSG) examination among patients with mild AD with cholinesterase inhibitors (N=10) or MCI (N=12) and age-matched nondemented controls (N=13). The results showed sleep efficiency, which was one of the important parameters for sleep quality was significantly lower in patients with MCI and AD (N=22), 79.14 +/- 11.06 % vs. 67.07 +/- 19.10 %, p=0.046. There were no statistic differences of sleep architecture but a trend of REM insufficiency in patients with MCI or AD. The mean scores of geriatric depression score (GDS) and Epworth sleepiness scale (ESS) did not differ among the three groups. Our study implicated maintenance of sleep was impaired in patients with cognitive impairment and it was independent with depressive symptoms.