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(1) Background: The hippocampus (HP) and amygdala are essential structures in obsessive–compulsive behavior (OCB); however, the specific role of the HP in patients with behavioral variant frontotemporal dementia (bvFTD) and OCB remains unclear. (2) Objective: We investigated the alterations of hippocampal and amygdalar volumes in patients with bvFTD and OCB and assessed the correlations of clinical severity with hippocampal subfield and amygdalar nuclei volumes in bvFTD patients with OCB. (3) Materials and methods: Eight bvFTD patients with OCB were recruited and compared with eight age- and sex-matched healthy controls (HCs). Hippocampal subfield and amygdalar nuclei volumes were analyzed automatically using a 3T magnetic resonance image and FreeSurfer v7.1.1. All participants completed the Yale–Brown Obsessive–Compulsive Scale (Y-BOCS), Neuropsychiatric Inventory (NPI), and Frontal Behavioral Inventory (FBI). (4) Results: We observed remarkable reductions in bilateral total hippocampal volumes. Compared with the HCs, reductions in the left hippocampal subfield volume over the cornu ammonis (CA)1 body, CA2/3 body, CA4 body, granule cell layer, and molecular layer of the dentate gyrus (GC-ML-DG) body, molecular layer of the HP body, and hippocampal tail were more obvious in patients with bvFTD and OCB. Right subfield volumes over the CA1 body and molecular layer of the HP body were more significantly reduced in bvFTD patients with OCB than in those in HCs. We observed no significant difference in amygdalar nuclei volume between the groups. Among patients with bvFTD and OCB, Y-BOCS score was negatively correlated with left CA2/3 body volume (τb = −0.729, p < 0.001); total NPI score was negatively correlated with left GC-ML-DG body (τb = −0.648, p = 0.001) and total bilateral hippocampal volumes (left, τb = −0.629, p = 0.002; right, τb = −0.455, p = 0.023); and FBI score was negatively correlated with the left molecular layer of the HP body (τb = −0.668, p = 0.001), CA4 body (τb = −0.610, p = 0.002), and hippocampal tail volumes (τb = −0.552, p < 0.006). Mediation analysis confirmed these subfield volumes as direct biomarkers for clinical severity, independent of medial and lateral orbitofrontal volumes. (5) Conclusions: Alterations in hippocampal subfield volumes appear to be crucial in the pathophysiology of OCB development in patients with bvFTD.

Amisulpride is an atypical antipsychotic. It is also effective in treating depression. The potential antidepressant effect raises the concern that amisulpride can induce mania. However, reports of amisulpride-induced mania have been rare. Here, we present the case of a Taiwanese woman with a 22-year history of schizophrenia. At the age 57 years, she developed manic symptoms while on treatment with amisulpride for six weeks. She was immediately admitted to the psychiatric in-patient unit. The manic symptoms completely subsided within eight days without the administration of any mood stabilizer. Readministration of a single dose of 200 mg amisulpride during hospitalization induced the same manic symptoms, which remitted completely within 24 hours without any mood stabilizer administration.

Obesity is a metabolic disorder that results from complex interactions between genetic predisposition and dietary factors. Interleukin-4 (IL-4), besides its role in immunity, has metabolic effects on insulin efficacy. We studied the effects of IL-4 on metabolic abnormalities in a mice model of obesity involving leptin deficiency and leptin resistance. Leptin-deficient 145E and leptin-resistant high-fat diet (HFD) mice showed lower levels of circulating IL-4. 145E and HFD mice showed a number of abnormalities: Obesity, hyperglycemia, hyperinsulinemia, insulin resistance, dyslipidemia, liver injury, and adiposity with concurrent inflammation, decreases in Akt, signal transducer and activator of transcription 3 (STAT3), and STAT6 phosphorylation in the hypothalamus, liver, and epididymal fat. Independent of leptin-deficient obesity and dietary obesity, a course of 8-week IL-4 supplementation improved obesity and impairment in Akt, STAT3, and STAT6 signaling. Amelioration of cytokine expression, despite variable extents, was closely linked with the actions of IL-4. Additionally, the browning of white adipocytes by IL-4 was found in epididymal white adipose tissues and 3T3-L1 preadipocytes. Chronic exercise, weight management, and probiotics are recommended to overweight patients and IL-4 signaling is associated with clinical improvement. Thus, IL-4 could be a metabolic regulator and antiobesity candidate for the treatment of obesity and its complications.

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p

Objective: We aimed to identify biomarkers of Alzheimer's disease (AD) in order to improve diagnostic accuracy at mild stage. Methods: AD patients aged >50 years were included in the disease group. We evaluated the relationship between potential blood and cerebrospinal fluid inflammatory biomarkers, cognitive status, temporal lobe atrophy and disease severity. Inflammatory biomarkers including interleukin 6 (IL-6), IL-18, fractalkine and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) levels were measured. APOE genotypes were determined. Results: We enrolled 41 subjects in the disease group and 40 subjects in the normal control group. The majority (88.9%) of subjects in the disease group had mild AD. Elevated levels of plasma IL-6 and decreased levels of plasma TRAIL in the disease group were noted. Plasma levels of IL-6 and TRAIL were significantly correlated with their cerebrospinal fluid levels. Conclusion: Plasma IL-6 and TRAIL were identified as potential biomarkers of AD at an early stage.

Background: Pharmacotherapy of insomnia is prescribed often but may be complicated by drug dependence. Cognitivebehavioral therapy for insomnia is effective, but requires time to take effect. Repetitive transcranial magnetic stimulation (rTMS) is effective for depression but of uncertain benefit for insomnia. We studied low-frequency rTMS of the left dorsal medial prefrontal cortex (DMPFC) as an adjunctive therapy of insomnia. Methods: We recruited 60 patients with insomnia, of whom 49 completed the study. We applied 1 Hz rTMS to the DMPFC in the experimental group (n = 36) and sham coil for the placebo group (n = 13). Outcome measures included objective polysomnography (PSG) and subjective Pittsburgh Sleep Quality Index (PSQI). All participants were requested to continue prescribed pharmacotherapy. Results: After 10 sessions of low-frequency DMPFC-rTMS, the experimental group demonstrated a reduction of duration of wake after sleep onset (WASO) from 75.4 (±53.3) to 51.2 (±75.1) min (p = 0.011). Sleep efficiency (SE) increased from 74.6% (±15.6) to 80.8% (±13.8) (p = 0.004). The sham group experienced improved SE from 79.4% (±30.7) to 88.9% (±5.6) (p = 0.039). After controlling for baseline PSG parameters and hypnotic dosage, the sham group exhibited better effects of sleep onset latency and SE than the rTMS group but no difference on PSQI. Conclusion: Although the effects of rTMS and sham coil on insomnia were similar (which implied significant placebo effect), low-frequency DMPFC-rTMS might offer a safe, non-invasive, and useful adjunctive therapy of insomnia by reducing WASO. The DMPFC may represent a new target for future rTMS insomnia studies. [ABSTRACT FROM AUTHOR]

Aims: β-Site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a biological and positional candidate gene for Alzheimer’s disease (AD). Previous studies found that BACE1-null mice had impaired performance on cognition and neurodegeneration during the aging process. Additionally, a synonymous polymorphism of BACE1 (rs638405) in exon 5 has been reported to be associated with risk for AD. We hypothesized that this BACE1 gene variant might influence regional brain volumes and cognitive tests in normal individuals. Methods: Participants were 330 normal volunteers between 21 and 92 years of age (mean age 56.3 ± 22.0 years; 191 males, 139 females). Cognitive tests (the Mini-Mental State Examination and Digit Spans), magnetic resonance imaging, and genotyping of BACE1 rs638405 were examined for each subject. The differences in regional gray matter (GM) volumes between G homozygotes and C-allele carriers were tested using optimized voxel-based morphometry. Results: Compared to C-allele carriers, G homozygotes exhibited significantly larger GM volumes in the left cerebellar culmen and right cerebellar lingual area, but no significant differences on cognitive function tests. Conclusion: The findings suggest that the BACE1 rs638405 polymorphism may affect cerebellar morphology, but not cognitive function in healthy humans.

BACKGROUND: White matter lesions can be easily observed on T2-weighted MR images, and are termed white matter hyperintensities (WMH). Their presence may be correlated with cognitive impairment; however, the relationship between regional WMH volume and catechol-O-methyltransferase (COMT) Val158Met polymorphism in healthy populations remains unclear. METHODS: We recruited 315 ethnic Chinese adults with a mean age of 54.9 ± 21.8 years (range: 21-89 y) to examine the genetic effect of COMT on regional WMH and the manner in which they interact to affect cognitive function in a healthy adult population. Cognitive tests, structural MRI scans, and genotyping of COMT were conducted for each participant. RESULTS: Negative correlations between the Digit Span Forward (DSF) score and frontal WMH volumes (r = -.123, P = .032, uncorrected) were noted. For the genetic effect of COMT, no significant difference in cognitive performance was observed among 3 genotypic groups. However, differences in WMH volumes over the subcortical region (P = .016, uncorrected), whole brain (P = .047, uncorrected), and a trend over the frontal region (P = .050, uncorrected) were observed among 3 COMT genotypic groups. Met homozygotes and Met/Val heterozygotes exhibited larger WMH volumes in these brain regions than the Val homozygotes. Furthermore, a correlation between the DSF and regional WMH volume was observed only in Met homozygotes. The effect size (cohen's f) revealed a small effect. CONCLUSIONS: The results indicate that COMT might modulate WMH volumes and the effects of WMH on cognition.

The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2±22.0 years (range: 21-92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P

We report the first genome-wide association study of a joint analysis using 795 Han Chinese individuals with treatment-refractory schizophrenia (TRS) and 806 controls. Three loci showed suggestive significant association with TRS were identified. These loci include: rs10218843 (P = 3.04 × 10(-7)) and rs11265461 (P = 1.94 × 10(-7)) are adjacent to signaling lymphocytic activation molecule family member 1 (SLAMF1); rs4699030 (P = 1.94 × 10(-6)) and rs230529 (P = 1.74 × 10(-7)) are located in the gene nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NFKB1); and rs13049286 (P = 3.05 × 10(-5)) and rs3827219 (P = 1.66 × 10(-5)) fall in receptor-interacting serine/threonine-protein kinase 4 (RIPK4). One isolated single nucleotide polymorphism (SNP), rs739617 (P = 3.87 × 10(-5)) was also identified to be associated with TRS. The -94delATTG allele (rs28362691) located in the promoter region of NFKB1 was identified by resequencing and was found to associate with TRS (P = 4.85 × 10(-6)). The promoter assay demonstrated that the -94delATTG allele had a significant lower promoter activity than the -94insATTG allele in the SH-SY5Y cells. This study suggests that rs28362691 in NFKB1 might be involved in the development of TRS.

OBJECTIVES: The forced swim test (FST) is a commonly used model to predict antidepressant efficacy. Uncovering the genetic basis of the model may unravel the mechanism of antidepressant treatment. METHODS: FVB/NJ (FVB) and C57BL/6J (B6) were first identified as the response and non-response strains to fluoxetine (a serotonin-specific reuptake inhibitor antidepressant) treatment in the mouse FST. Simple-interval (SIM) and composite-interval (CIM) mappings were applied to map the quantitative trait loci (QTLs) of the anti-immobility effect of fluoxetine in FST (FST(FLX)) in 865 male B6×FVB-F2 mice. The brain mRNA expressions of the gene with the maximum QTL-linkage signal for FST(FLX) after the FST were compared between B6 and FVB mice and also compared between fluoxetine and saline treatment. The association of the variants in the human homologue of the mouse FST(FLX)-QTL gene with major depressive disorder (MDD) and antidepressant response were investigated in 1080 human subjects (MDD/control = 582/498). RESULTS: One linkage signal for FST(FLX)-QTL was detected at an intronic SNP (rs6215396) of the mouse Zfp326 gene (maximal CIM-LOD = 9.36). The Zfp326 mRNA expression in the FVB thalamus was significantly down-regulated by fluoxetine in the FST, and the higher FVB-to-B6 Zfp326 mRNA expressions in the frontal cortex, striatum and hypothalamus diminished after fluoxetine treatment. Two coding-synonymous SNPs (rs2816881 and rs10922744) in the human homologue of Zfp326, ZNF326, were significantly associated with the 8-week antidepressant treatment response in the MDD patients (Bonferroni-corrected p = 0.004-0.028). CONCLUSIONS: The findings suggest the involvement of the Zfp326 and ZNF326 genes in antidepressant treatment response.

Amyloid precursor protein (APP) mutations associated with familial Alzheimer's disease (AD) usually lead to increases in amyloid β-protein (Aβ) levels or aggregation. Here, we identified a novel APP mutation, located within the Aβ sequence (Aβ(D7H)), in a Taiwanese family with early onset AD and explored the pathogenicity of this mutation. Cellular and biochemical analysis reveal that this mutation increased Aβ production, Aβ42/40 ratio and prolonged Aβ42 oligomer state with higher neurotoxicity. Because the D7H mutant Aβ has an additional metal ion-coordinating residue, histidine, we speculate that this mutation may promote susceptibility of Aβ to ion. When co-incubated with Zn(2+) or Cu(2+), Aβ(D7H) aggregated into low molecular weight oligomers. Together, the D7H mutation could contribute to AD pathology through a "double punch" effect on elevating both Aβ production and oligomerization. Although the pathogenic nature of this mutation needs further confirmation, our findings suggest that the Aβ N-terminal region potentially modulates APP processing and Aβ aggregation, and further provides a genetic indication of the importance of Zn(2+) and Cu(2+) in the etiology of AD.

BackgroundGenetic polymorphisms in the gene encoding the β-adrenergic receptors (β-AR) have a pivotal role in the functions of the autonomic nervous system. Using heart rate variability (HRV) as an indicator of autonomic function, we present a bottom-up genotype-phenotype analysis to investigate the association between β-AR gene polymorphisms and heart rate dynamics.MethodsA total of 221 healthy Han Chinese adults (59 males and 162 females, aged 33.6 ± 10.8 years, range 19 to 63 years) were recruited and genotyped for three common β-AR polymorphisms: β(1)-AR Ser49Gly, β(2)-AR Arg16Gly and β(2)-AR Gln27Glu. Each subject underwent two hours of electrocardiogram monitoring at rest. We applied an information-based similarity (IBS) index to measure the pairwise dissimilarity of heart rate dynamics among study subjects.ResultsWith the aid of agglomerative hierarchical cluster analysis, we categorized subjects into major clusters, which were found to have significantly different distributions of β(2)-AR Arg16Gly genotype. Furthermore, the non-randomness index, a nonlinear HRV measure derived from the IBS method, was significantly lower in Arg16 homozygotes than in Gly16 carriers. The non-randomness index was negatively correlated with parasympathetic-related HRV variables and positively correlated with those HRV indices reflecting a sympathovagal shift toward sympathetic activity.ConclusionsWe demonstrate a bottom-up categorization approach combining the IBS method and hierarchical cluster analysis to detect subgroups of subjects with HRV phenotypes associated with β-AR polymorphisms. Our results provide evidence that β(2)-AR polymorphisms are significantly associated with the acceleration/deceleration pattern of heart rate oscillation, reflecting the underlying mode of autonomic nervous system control.

BACKGROUND: Reversible cerebral vasoconstriction syndrome (RCVS) could be complicated by cerebral ischemic events. Hypothetical mechanisms of RCVS involve endothelial dysfunction and sympathetic overactivity, both of which were reported to be related to brain-derived neurotrophic factor (BDNF). The study investigated the association between functional BDNF Val66Met polymorphism and RCVS. METHODS: Patients with RCVS and controls were prospectively recruited and genotyped for the BDNF Val66Met polymorphism. Magnetic resonance angiography (MRA) and transcranial color-coded Doppler sonography were employed to evaluate cerebral vasoconstriction. Genotyping results, clinical parameters, vasoconstriction scores, mean flow velocities of the middle cerebral artery (V(MCA)), and Lindegaard indices were analyzed. Split-sample approach was employed to internally validate the data. PRINCIPAL FINDINGS: Ninety Taiwanese patients with RCVS and 180 age- and gender-matched normal controls of the same ethnicity completed the study. The genotype frequencies did not differ between patients and controls. Compared to patients with Met/Met homozygosity, patients with Val allele had higher mean vasoconstriction scores of all arterial segments (1.60±0.72 vs. 0.87±0.39, p120 cm/s (p

BACKGROUND: Obesity is a multifactorial disease that arises from complex interactions between genetic predisposition and environmental factors. Leptin is central to the regulation of energy metabolism and control of body weight in mammals. METHODOLOGY/PRINCIPAL FINDINGS: To better recapitulate the complexity of human obesity syndrome, we applied N-ethyl-N-nitrosourea (ENU) mutagenesis in combination with a set of metabolic assays in screening mice for obesity. Mapping revealed linkage to the chromosome 6 within a region containing mouse Leptin gene. Sequencing on the candidate genes identified a novel T-to-A mutation in the third exon of Leptin gene, which translates to a V145E amino acid exchange in the leptin propeptide. Homozygous Leptin(145E/145E) mutant mice exhibited morbid obesity, accompanied by adipose hypertrophy, energy imbalance, and liver steatosis. This was further associated with severe insulin resistance, hyperinsulinemia, dyslipidemia, and hyperleptinemia, characteristics of human obesity syndrome. Hypothalamic leptin actions in inhibition of orexigenic peptides NPY and AgRP and induction of SOCS1 and SOCS3 were attenuated in Leptin(145E/145E) mice. Administration of exogenous wild-type leptin attenuated hyperphagia and body weight increase in Leptin(145E/145E) mice. However, mutant V145E leptin coimmunoprecipitated with leptin receptor, suggesting that the V145E mutation does not affect the binding of leptin to its receptor. Molecular modeling predicted that the mutated residue would form hydrogen bond with the adjacent residues, potentially affecting the structure and formation of an active complex with leptin receptor within that region. CONCLUSIONS/SIGNIFICANCE: Thus, our evolutionary, structural, and in vivo metabolic information suggests the residue 145 as of special function significance. The mouse model harboring leptin V145E mutation will provide new information on the current understanding of leptin biology and novel mouse model for the study of human obesity syndrome.

BACKGROUND:It is unclear whether the loss of physiological complexity during the aging process is due to genetic variations. The APOE gene has been studied extensively in regard to its relationship with aging-associated medical illness. We hypothesize that diminished physiological complexity, as measured by heart rate variability, is influenced by polymorphisms in the APOE allele among elderly individuals. METHODOLOGY/PRINCIPAL FINDINGS:A total of 102 robust, non-demented, elderly subjects with normal functions of daily activities participated in this study (97 males and 5 females, aged 79.2+/-4.4 years, range 72-92 years). Among these individuals, the following two APOE genotypes were represented: epsilon4 non-carriers (n = 87, 85.3%) and epsilon4 carriers (n = 15, 14.7%). Multi-scale entropy (MSE), an analysis used in quantifying complexity for nonlinear time series, was employed to analyze heart-rate dynamics. Reduced physiological complexity, as measured by MSE, was significantly associated with the presence of the APOE epsilon4 allele in healthy elderly subjects, as compared to APOE epsilon4 allele non-carriers (24.6+/-5.5 versus 28.9+/-5.2, F = 9.429, p = 0.003, respectively). CONCLUSIONS/SIGNIFICANCE:This finding suggests a role for the APOE gene in the diminished physiological complexity seen in elderly populations.

Background: Genetic polymorphisms in the gene encoding the β-adrenergic receptors (β-AR) have a pivotal role in the functions of the autonomic nervous system. Using heart rate variability (HRV) as an indicator of autonomic function, we present a bottom-up genotype-phenotype analysis to investigate the association between β-AR gene polymorphisms and heart rate dynamics. Methods: A total of 221 healthy Han Chinese adults (59 males and 162 females, aged 33.6±10.8 years, range 19 to 63 years) were recruited and genotyped for three common β-AR polymorphisms: β1-AR Ser49Gly, β2-AR Arg16Gly and β2-AR Gln27Glu. Each subject underwent two hours of electrocardiogram monitoring at rest. We applied an information-based similarity (IBS) index to measure the pairwise dissimilarity of heart rate dynamics among study subjects. Results: With the aid of agglomerative hierarchical cluster analysis, we categorized subjects into major clusters, which were found to have significantly different distributions of β2-AR Arg16Gly genotype. Furthermore, the non-randomness index, a nonlinear HRV measure derived from the IBS method, was significantly lower in Arg16 homozygotes than in Gly16 carriers. The non-randomness index was negatively correlated with parasympathetic-related HRV variables and positively correlated with those HRV indices reflecting a sympathovagal shift toward sympathetic activity. Conclusions: We demonstrate a bottom-up categorization approach combining the IBS method and hierarchical cluster analysis to detect subgroups of subjects with HRV phenotypes associated with β-AR polymorphisms. Our results provide evidence that β2-AR polymorphisms are significantly associated with the acceleration/deceleration pattern of heart rate oscillation, reflecting the underlying mode of autonomic nervous system control. [ABSTRACT FROM AUTHOR]

Background: The serotonin transporter gene (5-HTT) is a key regulator of serotonergic neurotransmission and has been linked to various psychiatric disorders. Among the genetic variants, polymorphisms in the 5-HTT gene-linked polymorphic region (5-HTTLPR) and variable-number-of-tandem-repeat in the second intron (5-HTTVNTR) have functional consequences. However, their genetic impact on cortical oscillation remains unclear. This study examined the modulatory effects of 5-HTTLPR (L-allele carriers vs. non-carriers) and 5-HTTVNTR (10-repeat allele carriers vs. non-carriers) polymorphism on regional neural activity in a young female population. Methods: Blood samples and resting state eyes-closed electroencephalography (EEG) signals were collected from 195 healthy women and stratified into 2 sets of comparisons of 2 groups each: L-allele carriers (N = 91) vs. noncarriers for 5-HTTLPR and 10-repeat allele carriers (N = 25) vs. non-carriers for 5-HTTVNTR. The mean power of 18 electrodes across theta, alpha, beta, gamma, gamma1, and gamma2 frequencies was analyzed. Between-group statistics were performed by an independent t-test, and global trends of regional power were quantified by nonparametric analyses. Results: Among 5-HTTVNTR genotypes, 10-repeat allele carriers showed significantly low regional power at gamma frequencies across the brain. We noticed a consistent global trend that carriers with low transcription efficiency of 5-HTT possessed low regional powers, regardless of frequency bands. The non-parametric analyses confirmed this observation, with P values of 3.071 x 10-8 and 1.459 x 10-12 for 5-HTTLPR and 5-HTTVNTR, respectively. Conclusions and Limitations: Our analyses showed that genotypes with low 5-HTT activity are associated with less local neural synchronization during relaxation. The implication with respect to genetic vulnerability of 5-HTT across a broad range of psychiatric disorders is discussed. Given the low frequency of 10-repeat allele of 5-HTTVNTR in our research sample, the possibility of false positive findings should also be considered. [ABSTRACT FROM AUTHOR]

AbstractBrain-derived neurotrophic-factor (BDNF) and its receptor neurotrophic tyrosine kinase receptor 2 (NTRK2) have been implicated in both major depression and cognitive function. This study examines the main effects of single loci and multilocus interactions to test the hypothesis that the BDNFand NTRK2genes may contribute to the etiology of geriatric depression independently and/or through complex interactions. We genotyped the BDNFgene Val66Met (rs6265) polymorphism and four single-nucleotide polymorphisms (SNPs) (including rs1187323, rs1187329, rs1778929, and rs1545285) in the NTRK2gene in 155 elderly inpatients diagnosed with major depression and 195 age- and sex-similar control subjects. All patients were assessed with the Hamilton Rating Scale for Depression (HAM-D) for depression severity and the Mini-Mental Status Examination (MMSE) for cognitive function after admission. The genotype distributions of all five SNPs tested were significantly different between depressed patients and control subjects. BDNFrs6265, NTRK2rs1187323, and NTRK2rs1778929 (p= 0.0031, 0.002, and 0.0014, respectively) also displayed statistically significant differences in the genotypic tests after Bonferroni correction (p< 0.05/5 = 0.01). In addition, the 2-marker haplotype derived from the rs1187323 and rs1187329 polymorphisms demonstrated a significant difference between geriatric depression and control groups according to haplotype distribution (global p= 0.003). Furthermore, BDNFand NTRK2interactions were found in the significant 2-locus, 3-locus, 4-locus, and 5-locus gene–gene interaction models (p= 0.014, <0.001, 0.007, and 0.032, respectively) using a generalized multifactor dimensionality reduction (GMDR) method. Analyses using logistic regression models confirmed the gene–gene interactions. The results suggest that the BDNFand NTRK2genes may contribute to the risk of geriatric depression independently and in an interactive manner. [ABSTRACT FROM AUTHOR]

The neurotrophin hypothesis of depression and antidepressant drug action postulates that reduced activity of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF), plays an important role in the pathogenesis of major depression, and that its restoration may represent a critical mechanism underlying antidepressant therapeutic effect. This hypothesis is supported by numerous animal studies; however, evidence from clinical studies is lacking. This study is the first to use both single-marker as well as haplotype analysis to test the effect of genetic variants of BDNF on the therapeutic effects of antidepressant treatment in mood disorder. Among eight BDNF TagSNPs tested, one allele (rs908867) is associated with antidepressant response, with heterozygote carriers showing a better response than homozygous analog. The authors also identified a haplotype associated with the therapeutic response. This study provides clinical evidence to support the role of BDNF in antidepressant therapeutic mechanisms. However, further work is needed to confirm the findings, for several reasons. First, the study included not only major depression but also bipolar disorder patients; second, various antidepressants were used in this study, which could affect patients' responses; third, the frequency of the haplotype associated with treatment response is rare; and fourth, previous studies of the effects of single BDNF polymorphisms on antidepressant action have reported conflicting findings. Several suggestions for further work are discussed below. [ABSTRACT FROM AUTHOR]

Survival time and mortality risk factors in patients with Alzheimer's disease (AD) have been documented in Western countries, but comparable information on the ethnic Chinese is scarce. We consecutively recruited 159 AD patients and 145 control subjects from the Memory Clinic of Taipei Veterans General Hospital. After admission to the study, each subject received clinical, neuropsychological, and psychiatric evaluation and apolipoprotein E genotyping. Survival status was followed for 5 years. Forty-six AD patients (28.9%) and 3 control subjects (2.1%) died during the 5-year follow-up period. The mean survival time for AD patients was 4.48 years (SD = 0.1 years) after the time of enrollment. Among individuals with AD, those with severe disease, older patients, and those experiencing hallucinations were at greater risk for increased mortality. As expected, AD shortened life expectancy in these patients. The factors found to correlate with a shorter life span may suggest effective health care strategies for AD patients. [ABSTRACT FROM AUTHOR]

We investigated the conversion rate and the risk factors for conversion to dementia from questionable dementia in 124 ethnic Chinese subjects with questionable dementia at a memory clinic of a university hospital. They were evaluated annually based on cognitive testing, the clinical dementia rating scale, and a psychiatrist's interview for depression and anxiety. Apolipoprotein E genotyping was performed on 111 of these questionable dementia subjects. All subjects were evaluated at least twice during the follow-up period of 20.4 ± 12.4 months. During that period, 42 questionable dementia subjects were diagnosed as having Alzheimer's disease, with an annual conversion rate to dementia of 19.9%. Compared with the 82 nonconverters, the 42 converters were significantly older, had lower cognitive, depression, and anxiety scores, and a higher frequency of the apolipoprotein E ε4 allele. Cox regression analysis revealed that the Alzheimer's disease converters had lower scores for orientation, short-term memory, and anxiety, and a higher frequency of the apolipoprotein E ε4 allele than the nonconverters. [ABSTRACT FROM AUTHOR]

This study analyzed whether platelet amyloid β-protein precursor (AβPP) isoform ratio correlates with cognition or cognitive decline in patients with Alzheimer's disease (AD). Platelet AβPP isoform ratio was measured, and cognitive assessment was performed using the Mini-Mental State Examination (MMSE) in 66 AD patients at baseline (T0) and in 29 of these patients in a one-year follow-up (T1). There was a significant correlation between the AβPP isoform ratios and MMSE scores in the 66 AD patients at T0. The T1 subjects were divided into two groups: 12 "no decliners" (MMSE score, T1–T0 &ges; 0) and 17 "decliners" (MMSE score, T1–T0 < 0). The decliners group showed a significantly greater reduction of AβPP isoform ratio from T0 to T1 than the no decliners group. However, the decline of the ratio did not correlate with the decline of MMSE score. These findings indicate that AβPP isoform ratio correlates with cognition, and reduction in this ratio may be a marker for cognitive decline in AD patients. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, may represent a candidate gene conferring susceptibility to Alzheimer’s disease (AD). This is because it has an important role in neuronal survival, and a decreased central level of BDNF is observed in AD. Some previous studies, though not all, have demonstrated that BDNF C270T polymorphisms might be associated with AD susceptibility. We examined the association of the C270T polymorphisms with sporadic AD in a Chinese cohort of 175 AD patients and 189 controls. We also tested BDNF Val66Met-C270T haplotypes for an interaction with the apolipoprotein E υ4 (APOE4) allele in AD. The results showed that the frequency of the 66Val allele was significantly lower in AD than controls (p = 0.031), but no significant difference in C270T allele or genotype frequencies was observed between AD cases and controls. Global case-control haplotype analysis showed that there is significant difference in haplotype distribution between both groups (p = 0.033). Stratification of the data according to the APOE status showed that in APOE4 allele bearers there was no significant difference in the frequency of haplotype 66Val-270C between AD and controls (p = 0.125), although there was a significant difference between the two groups in non-APOE4 carriers (p = 0.002). These results suggest that BDNF genetic variation may possibly affect the risk for AD, particularly in subjects who are negative for APOE4. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: It has been reported that serum concentrations of interleukin-6 (IL-6), a pro-inflammatory cytokine, were significantly higher in major depressive disorder (MDD). Objectives: The aim of the present study was to examine whether the IL-6 genetic variant confers susceptibility to MDD. Methods: We genotyped a functional polymorphism in the promoter region (position –634) of the IL-6 gene in a sample of 257 MDD patients and 105 normal controls. Results: No significant differences were demonstrated for the genotype or allele frequency of the IL-6 polymorphism when comparing the MDD and control groups. Conclusions: Our findings suggested that the investigated IL-6 polymorphism does not affect MDD susceptibility. We propose that other genetic variations of IL-6, relating either to MDD or to the clinical manifestations of MDD, may need further investigation. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Monoamine oxidase A (MAOA), a mitochondrial outer membrane enzyme, degrades biogenic amines including norepinephrine, dopamine and serotonin, which have been implicated in the expression ofpersonality traits. We tested the associations between functional MAOA-uVNTR genetic variants and personality traits in a cohort of 370 healthy young Chinese females. Subjects who were homozygous for the 4-repeat allele of the MAOA-uVNTR gene tended to have a higher total score on the Harm Avoidance (HA) dimension of the Tridimensional Personality Questionnaire (TPQ) (p = 0.056), and had a significantly higher score on subdimension 4 of HA (p = 0.020) compared with the 3-repeat carriers. No significant association was demonstrated for MAOA-uVNTR polymorphism and the other two dimensions (Novelty Seeking and Reward Dependence) of TPQ. These results suggest that genetic variants of the MAOA gene may play a role in HA, but not in Novelty Seeking or Reward Dependence. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Monoamine oxidase A (MAOA), a mitochondrial enzyme involved in the degradation of biogenic amines, may be implicated in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied a variable-number-tandem-repeat (VNTR) polymorphism in the promoter region of the MAOA gene in a Chinese population of 230 MDD patients and 217 controls. We also examined the association of this polymorphism and antidepressant therapeutic response in the MDD patients who underwent a 4-week fluoxetine treatment. Our results showed a significantly increased frequency of 4-repeat (4R) allele in MDD patients, especially in the female population. Furthermore, MDD female patents who were 3R homozygotes had a significantly better response to 4-week fluoxetine treatment when compared to 4R carriers (p = 0.024), but there was a nonsignificant difference found in male patients (p = 0.081). Since the 4R allele transcribed 2-10 times more efficiently than those with 3R allele, our findings suggest that the MAOA-uVNTR may be involved in the pathogenesis of MDD and the antidepressant therapeutic mechanisms in Chinese population, and that there may be a gender effect in this association. [ABSTRACT FROM AUTHOR]

Monoamine oxidase A (MAOA) is a mitochondrial enzyme involved in the degradation of dopamine, serotonin and norepinephrine and these neurotransmitters are hypothesized to be involved in the cognitive function of humans. This study of a cohort of 191 healthy young Chinese females attempts to utilize the intelligence quotient (IQ), Wisconsin Card Sorting Test (WCST) and P300 event-related potentials as cognitive assessments for testing the relationship between the polymorphism with a variable number of tandem repeats (VNTR) in the upstream regulatory region (MAOA-uVNTR) and cognition. The results demonstrate that subjects bearing the 4/4-repeat genotype have a significantly higher full IQ than subjects bearing the 3/3-repeat genotype. However, there is no significant association between this MAOA-uVNTR polymorphism and the WCST and P300. Our study shows that the MAOA-uVNTR genetic polymorphism plays a role in the IQ; however, this may be a chance finding as the result was negative after using the Bonferroni adjustment. Therefore, we suggest that our study should be replicated and that the testing method, sex, disease and ethnicity should also be considered in future studies. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

In the ongoing search to reveal the pathophysiology of Alzheimer’s disease (AD), the cholinergic system is important due to its role in cognitive function and its significance with respect to the results of postmortem pathology and animal model studies. For this investigation, we tested the hypothesis that the allelic variant (C267A) of the cholinergic receptor muscarinic 1 (CHRM1) confers susceptibility to AD or is related to its age of onset, in a sample population of 232 AD patients and 169 normal controls. The distribution of the CHRM1 genotypes (p = 0.919) and alleles (p = 0.327) did not differ significantly comparing AD patients and controls, even after stratification according to apolipoprotein E genotype. The onset age was not significantly different comparing the CHRM1 genotype groups. Our negative findings suggest that it is unlikely that the CHRM1 C267A polymorphism plays a substantial role in conferring susceptibility to AD. We propose that other genetic variations of CHRM1, relating either to AD or to the therapeutic response for AD, may need further investigation. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect monoamine metabolism, is possibly associated with specific personality traits. In addition, a polymorphism in the dopamine D4 receptor (DRD4) gene exon 3 has been associated in some, but not all, studies with the novelty seeking personality trait, as evaluated by the Tridimensional Personality Questionnaire (TPQ). In this study, associations between these two polymorphisms and TPQ personality traits were investigated in a sample population of 120 healthy young Chinese females. The results of this analysis reveal that the COMT Val158Met polymorphism was significantly associated with novelty seeking (p = 0.017) and reward dependence scores (p = 0.015) in our sample. However, no significant differences were demonstrated comparing TPQ-specific scores for subjects bearing different DRD4 genotypes. The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence. Similar to the results of a recent meta-analytic review, however, no association was demonstrated between this DRD4 polymorphism and novelty seeking in our young Chinese female sample population. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The gene coding for catechol-O-methyltransferase (COMT), which is involved in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia.This study aimed to assess the relationship between a functional polymorphism (Val158Met) of the COMT gene and age of onset (AOO), symptomatology, global cognitive function and prognosis in patients with schizophrenia. The study enrolled 154 patients with schizophrenia from chronic wards. Results failed to show a significant association between the Vall58Met polymorphism and the Brief Psychiatric Rating Scale scores, Mini-Mental State Examination scores, and Social and Occupational Functioning Assessment Scale scores, but COMT Val158Met heterozygotes had a later AOO than homozygous patients. However, by further expanding the number of patients to 228 patients, the differences in AOO among thethree COMT genotypicgroupswas not significant. The COMTVaI158Met polymorphism did not appearto significantly affect susceptibility, symptomatology, global cognitive function and prognosis in Chinese patients with schizophrenia, but the possible association with AOO merits further investigation. [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, plays an important role in the development, maintenance and function of several neuronal systems. Recent studies have demonstrated that antidepressants, commonly used for panic disorder treatment, can increase central BDNF. In addition, animals with BDNF deficits have higher levels of anxiety when exposed to stressors in comparison to normal controls. The present study tested the hypothesis that the BDNF gene Val66Met polymorphism is associated with panic disorder. In this study, therefore, the incidence of this polymorphism was compared in 103 panic disorder patients and 180 normal controls. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing the two groups. Further- more, no association was demonstrated between this BDNF polymorphism and either mitral valve prolapse or agoraphobia in panic disorder patients. These findings suggest that the investigated BDNF polymorphism does not play a major role in the pathogenesis of panic disorder in this Chinese population. Further studies exploring the relationship between genetic variations of BDNF and the cerebral atrophy associated with, and antidepressant treatment response in, panic disorder may be appropriate. [ABSTRACT FROM AUTHOR]

Located on the presynaptic and postsynaptic terminals of serotonergic neurons, serotonin 1B receptors (5-HT1B) are involved in the modulation of serotonergic activity. The implications of 5-HT1B study of animal models of schizophrenia and antipsychotic activity involving defective sensory processes suggest that this receptor may be involved in the pathogenesis of schizophrenic disorders. In a population-based association study, we tested the hypothesis that the allelic variant, A-161T, of the 5-HT1B gene confers susceptibility to schizophrenic disorders and is associated with age of onset, aggressive behavior and attempted suicide. We genotyped the A-161T polymorphism in 110 patients with schizophrenic disorders and in 215 normal controls. No association was demonstrated between 5-HT1B genotype or allele frequencies and schizophrenic disorders, except for a trend for later age at disease onset in A/A homozygote schizophrenics in comparison with A/T heterozygote patients (p = 0.071). No significant difference in genotype distribution was determined comparing patients with and without aggressive behavior, and those with and without a history of suicide attempt. These findings suggest that the investigated 5-HT1B genetic polymorphism does not play a major role in the pathogenesis of schizophrenic disorders. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF), a member of the nerve-growth-factor family, plays an important role in neuronal survival and development, and it can modulate serotonergic activity. Further, BDNF has been implicated in the expression of personality traits and in cognitive function. We tested the associations between functional BDNF Val66Met genetic variants, and personality trait and intelligence in a cohort of 114 healthy young Chinese females. Subjects with the Val/Val genotype had a significantly higher mean performance IQ than Val/Met carriers, especially for the Object Assembly subtest. No significant association was demonstrated for the BDNF polymorphism and any of the Tridimensional Personality Questionnaire personality-factor scores, including harm avoidance. These results suggest that genetic variants of the BDNF gene may play a role in specific cognitive functions, but not in overall intelligence. In contrast to a recent report, however, this polymorphism does not appear to be associated with the neuroticism-related personality trait. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin growth factor family, has been implicated in both mood disorders and suicidal behavior. This study has examined the association between the BDNF gene Val66Met polymorphism and mood disorders, age of onset and suicidal behavior in a Chinese sample population. The genotype and allele frequencies for the BDNF gene Val66Met polymorphism did not differ comparing depression groups (total, bipolar disorder or major depression) and control subjects. Furthermore, it was not demonstrated that this BDNF polymorphism was associated with age of onset or suicidal history in our mood disorder patients. Based on these results, it seems reasonable to suggest that this polymorphism is unlikely to play a major role in the genetic susceptibility to mood disorders. Given the fact that the positive association between BDNF gene Val66Met polymorphism and bipolar disorder has only been demonstrated for a Caucasian population but not for a Japanese analog or our Chinese sample, it appears likely that this association is ethnicity dependent. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Antidepressants usually take weeks to exert significant therapeutic effects. This lag phase is suggested to be due to neural plasticity, which may be mediated by the coupling of receptors to their respective intracellular signal transduction pathways. Phosphorylated cAMP response element-binding protein (CREB), a downstream target of the cAMP signaling pathway, has been reported to be a molecular state marker for the response to antidepressant treatment in patients with major depressive disorder (MDD). In order to explore the role of CREB expression in MDD, we used quantitative reverse transcriptase-polymerase chain reaction to quantify CREB messenger RNA of the peripheral lymphocytes obtained from 21 MDD patients, before and after antidepressant treatment, and 21 normal controls. The results revealed no significant difference of CREB expression between untreated MDD patients and normal controls. However, after 8 weeks of antidepressant treatment, CREB expression was significantly decreased in MDD patients (p = 0.025). The CREB change is not associated with the types of antidepressants and therapeutic response. Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines, including interleukin (IL)-1beta, are suggested to have a role in the pathogenesis of major depressive disorder (MDD) and be related to the therapeutic effects of antidepressants. To elucidate a genetic predisposition of MDD, we studied biallelic polymorphism in the promoter region (position -511) of the IL-1beta gene in 157 patients with MDD and in 112 controls. We also examined the association of this polymorphism and fluoxetine therapeutic response in 119 MDD patients who received a 4-week fluoxetine treatment. No significant difference was found in the genetic polymorphism between MDD patients and controls. However, MDD patients who were homozygous for the -511T allele of the IL-1beta gene had a trend of less severity of depressive symptoms and more favorable fluoxetine therapeutic response than -511C carriers. Further study with a larger sample is needed to clarify the role of the IL-1beta genetic polymorphisms in the symptoms and treatment effects in MDD. [ABSTRACT FROM AUTHOR]

Objectives: The correlation between anxiety and interstitial cystitis has, as best we know, not yet been reported on. The present study investigated the psychological profile, including anxiety and depression, of patients suffering from interstitial cystitis (IC). Methods: A total of 47 IC patients, all of whom met National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases (NIDDK) criteria, plus a group of 31 age-matched, asymptomatic women received a structured interview on depression (Hamilton Rating Scale for Depression) and also on anxiety symptoms (Hamilton Rating Scale for Anxiety). IC patients also completed questionnaires relating to IC symptom severity, including urgency and frequency (visual analog scale) and O'Leary Sant index. Results: A total of 85% of our IC patients featured significant affective symptoms. The average depression scores were 16.6. Fifteen patients (31.9%) featured mild depressive symptoms, five (10.6%) had mild to moderate and 20 (42.6%) had moderate to severe depression symptoms. The mean anxiety score was 21.0, with 21 (44.7%), nine (19.1%) and 17 (36.2%) patients revealing mild, mild to moderate, and moderate to severe anxiety symptoms, respectively. Further, IC patients reported a significantly greater extent of depression and anxiety than was the case for controls. Pain scale and O'Leary Sant index were significantly correlated to anxiety and depression score. Conclusions: Most of our IC patients feature significant depression and anxiety. The extent of affective symptoms would appear to correlate well with IC symptom severity. [ABSTRACT FROM AUTHOR]

Because of a decrease in central brain-derived neurotrophic factor (BDNF) levels in Alzheimer’s disease (AD) and the important role of BDNF in neuronal survival, BDNF may represent a candidate gene conferring susceptibility to AD. Recently, a functional BDNF Val66Met polymorphism has been associated with AD in an Italian population. In the present study, we investigated a possible role of this BDNF polymorphism in the susceptibility of AD or AD onset in a Chinese population. Comparing AD patients and controls, the distribution of the BDNF genotypes and alleles did not differ significantly. The onset age was not significantly different comparing the three BDNF genotype groups. Our negative findings suggest that it is unlikely that the BDNF Val66Met polymorphism plays a major role in the pathogenesis of AD in the Chinese population and do not support previous findings that homozygosity for the 66Val allele confers an increased risk for AD. Further studies with genetic variations in BDNF relating either to AD-associated depression or to the AD treatment response are suggested. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article discusses Alzheimer's disease. Adenosine, a purine nucleoside, functions as a neuromodulator in the brain and is widely distributed throughout the central nervous system, with the highest densities in the hippocampus, the neocortex and the striatum. There is considerable evidence supporting the involvement of adenosine A2a receptor (A2aAR) in the pathogenesis of Alzheimer's disease (AD). Studies found that the intake of caffeine, an antagonist for the adenosine receptors, was inversely associated with AD risk, and the A2aAR may be the molecular target responsible for the observed beneficial effects of caffeine consumption in the development of AD.

Background: It is unclear whether the loss of physiological complexity during the aging process is due to genetic variations. The APOE gene has been studied extensively in regard to its relationship with aging-associated medical illness. We hypothesize that diminished physiological complexity, as measured by heart rate variability, is influenced by polymorphisms in the APOE allele among elderly individuals. Methodology/Principal Findings: A total of 102 robust, non-demented, elderly subjects with normal functions of daily activities participated in this study (97 males and 5 females, aged 79.2±4.4 years, range 72–92 years). Among these individuals, the following two APOE genotypes were represented: ε4 non-carriers (n = 87, 85.3%) and ε4 carriers (n = 15, 14.7%). Multi-scale entropy (MSE), an analysis used in quantifying complexity for nonlinear time series, was employed to analyze heart-rate dynamics. Reduced physiological complexity, as measured by MSE, was significantly associated with the presence of the APOE ε4 allele in healthy elderly subjects, as compared to APOE ε4 allele non-carriers (24.6±5.5 versus 28.9±5.2, F = 9.429, p = 0.003, respectively). Conclusions/Significance: This finding suggests a role for the APOE gene in the diminished physiological complexity seen in elderly populations. [ABSTRACT FROM AUTHOR]

Objective Panic disorder (PD) is characterized by panic attacks accompanied with respiratory symptoms. Internal jugular vein (IJV) alters its hemodynamics in response to respiration and which might cause cerebral blood flow (CBF) changes. In the present study, we compared (1) respiratory-related IJV hemodynamics and (2) CBF changes during Valsalva maneuver (VM) between PD and normal subjects. Methods 42 PD patients and age/gender-matched controls (14 men; 52.3 ± 11.4 years) were recruited. Duplex ultrasonography measured time-averaged mean velocity (TAMV) and lumen in IJV at baseline and deep inspiration. Lumen area <0.10 cm2 at deep inspiration was defined as IJV collapse. CBF changes during VM were recorded by transcranial Doppler (TCD). Results Compared with normal group, PD patients had significantly higher frequency of IJV collapse at deep inspiration (Left: 40.0% vs. 7.0%, p = 0.0003, Right: 17.0% vs. 0%, p = 0.0119). IJV collapse was associated with symptoms of respiratory subtype in our PD patients. PD group also had smaller lumen (Left: 0.53 ± 0.29 vs. 0.55 ± 0.26 cm2, p = 0.8296, Right: 0.63 ± 0.36 vs. 0.93 ± 0.45 cm2, p = 0.0014) and slower TAMV of IJV at baseline (Left: 11.8 ± 8.43 vs. 20.6 ± 16.5 cm/s, p = 0.0003, Right: 15.9 ± 9.19 vs. 24.1 ± 15.7 cm/s, p = 0.0062). PD patients with inspiration-induced IJV collapse had more decreased CBF during VM compared with the other PD patients and normal individuals respectively. Interpretation We are the first to show that PD have less IJV flow at baseline and more frequent collapse at deep inspiration. Inspiration-induced IJV collapsed was associated with CBF decrement during VM in PD patients. These results suggest that venous drainage impairment might play a role in the pathophysiology of PD by influencing CBF. [ABSTRACT FROM AUTHOR]