A significant, functional and replicable risk KTN1 variant block for schizophrenia.

Cortical and subcortical structural alteration has been extensively reported in schizophrenia, including the unusual expansion of gray matter volumes (GMVs) of basal ganglia (BG), especially putamen. Previous genome-wide association studies pinpointed kinectin 1 gene (KTN1) as the most significant gene regulating the GMV of putamen. In this study, the role of KTN1 variants in risk and pathogenesis of schizophrenia was explored. A dense set of SNPs (n = 849) covering entire KTN1 was analyzed in three independent European- or African-American samples (n = 6704) and one mixed European and Asian Psychiatric Genomics Consortium sample (n = 56,418 cases vs. 78,818 controls), to identify replicable SNP-schizophrenia associations. The regulatory effects of schizophrenia-associated variants on the KTN1 mRNA expression in 16 cortical or subcortical regions in two European cohorts (n = 138 and 210, respectively), the total intracranial volume (ICV) in 46 European cohorts (n = 18,713), the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258), and the surface areas (SA) and thickness (TH) of whole cortex and 34 cortical regions in 50 European cohorts (n = 33,992) and eight non-European cohorts (n = 2944) were carefully explored. We found that across entire KTN1, only 26 SNPs within the same block (r2 > 0.85) were associated with schizophrenia across ≥ 2 independent samples (7.5 × 10-5 ≤ p ≤ 0.048). The schizophrenia-risk alleles, which increased significantly risk for schizophrenia in Europeans (q < 0.05), were all minor alleles (f < 0.5), consistently increased (1) the KTN1 mRNA expression in 12 brain regions significantly (5.9 × 10-12 ≤ p ≤ 0.050; q < 0.05), (2) the ICV significantly (6.1 × 10-4 ≤ p ≤ 0.008; q < 0.05), (3) the SA of whole (9.6 × 10-3 ≤ p ≤ 0.047) and two regional cortices potentially (2.5 × 10-3 ≤ p ≤ 0.042; q > 0.05), and (4) the TH of eight regional cortices potentially (0.006 ≤ p ≤ 0.050; q > 0.05), and consistently decreased (1) the BG GMVs significantly (1.8 × 10-19 ≤ p ≤ 0.050; q < 0.05), especially putamen GMV (1.8 × 10-19 ≤ p ≤ 1.0 × 10-4; q < 0.05, (2) the SA of four regional cortices potentially (0.010 ≤ p ≤ 0.048), and (3) the TH of four regional cortices potentially (0.015 ≤ p ≤ 0.049) in Europeans. We concluded that we identified a significant, functional, and robust risk variant block covering entire KTN1 that might play a critical role in the risk and pathogenesis of schizophrenia.

Male-specific, replicable and functional roles of genetic variants and cerebral gray matter volumes in ADHD: a gene-wide association study across KTN1 and a region-wide functional validation across brain.

Attention deficit hyperactivity disorder (ADHD) is associated with reduction of cortical and subcortical gray matter volumes (GMVs). The kinectin 1 gene (KTN1) has recently been reported to significantly regulate GMVs and ADHD risk. In this study, we aimed to identify sex-specific, replicable risk KTN1 alleles for ADHD and to explore their regulatory effects on mRNA expression and cortical and subcortical GMVs. We examined a total of 1020 KTN1 SNPs in one discovery sample (ABCD cohort: 5573 males and 5082 females) and three independent replication European samples (Samples #1 and #2 each with 802/122 and 472/141 male/female offspring with ADHD; and Sample #3 with 14,154/4945 ADHD and 17,948/16,246 healthy males/females) to identify replicable associations within each sex. We examined the regulatory effects of ADHD-risk alleles on the KTN1 mRNA expression in two European brain cohorts (n = 348), total intracranial volume (TIV) in 46 European cohorts (n = 18,713) and the ABCD cohort, as well as the GMVs of seven subcortical structures in 50 European cohorts (n = 38,258) and of 118 cortical and subcortical regions in the ABCD cohort. We found that four KTN1 variants significantly regulated the risk of ADHD with the same direction of effect in males across discovery and replication samples (0.003 ≤ p ≤ 0.041), but none in females. All four ADHD-risk alleles significantly decreased KTN1 mRNA expression in all brain regions examined (1.2 × 10-5 ≤ p ≤ 0.039). The ADHD-risk alleles significantly increased basal ganglia (2.8 × 10-22 ≤ p ≤ 0.040) and hippocampus (p = 0.010) GMVs but reduced amygdala GMV (p = 0.030) and TIV (0.010 < p ≤ 0.013). The ADHD-risk alleles also significantly reduced some cortical (right superior temporal pole, right rectus) and cerebellar but increased other cortical (0.007 ≤ p ≤ 0.050) GMVs. To conclude, we identified a set of replicable and functional risk KTN1 alleles for ADHD, specifically in males. KTN1 may play a critical role in the pathogenesis of ADHD, and the reduction of specific cortical and subcortical, including amygdalar but not basal ganglia or hippocampal, GMVs may serve as a neural marker of the genetic effects.

Free water imaging as a novel biomarker in Wilson's disease: A cross-sectional study.

BACKGROUND: The bi-tensor free water imaging may provide more specific information in detecting microstructural brain tissue alterations than conventional single tensor diffusion tensor imaging. The study aimed to investigate microstructural changes in deep gray matter (DGM) nuclei of Wilson's disease (WD) using a bi-tensor free water imaging and whether the findings correlate with the neurological impairment in WD patients. METHODS: The study included 29 WD patients and 25 controls. Free water and free water corrected fractional anisotropy (FAT) in DGM nuclei of WD patients were calculated. The correlations of free water and FAT with the Unified WD Rating Scale (UWDRS) neurological subscale of WD patients were performed. RESULTS: Free water and FAT values were significantly increased in multiple DGM nuclei of neurological WD patients compared to controls. WD patients with normal appearing on conventional MRI also had significantly higher free water and FAT values in multiple DGM nuclei than controls. Positive correlations were noted between the UWDRS neurological subscores and free water values of the putamen and pontine tegmentum as well as FAT values of the dentate nucleus, red nucleus, and globus pallidus. In addition, the measured free water and FAT values of specific structures also showed a positive correlation with specific clinical symptoms in neurological WD patients, such as dysarthria, parkinsonian signs, tremor, dystonia, and ataxia. CONCLUSIONS: Free water imaging detects microstructural changes in both normal and abnormal appearing DGM nuclei of WD patients. Free water imaging indices were correlated with the severity of neurological impairment in WD patients.

Advances in the Therapeutic Use of Non-Ergot Dopamine Agonists in the Treatment of Motor and Non-Motor Symptoms of Parkinson's Disease.

Dopamine (DA) agonists, as an excellent dopamine replacement therapy for patients with early and advanced Parkinson's disease (PD), play a vital role in controlling motor and several nonmotor symptoms. Besides, the application of DA agonists may delay levodopa therapy and the associated risk of motor complications. Indeed, each DA agonist has unique pharmacokinetic and pharmacodynamic characteristics and therefore has different therapeutic efficacy and safety profile. The comorbidities, significant non-motor manifestations, concomitant medications, and clinical features of PD individuals should guide the selection of a specific DA agonist to provide a more patient-tailored treatment option. Thorough knowledge of DA agonists helps clinicians better balance clinical efficacy and side effects. Therefore, this review refers to recent English-written articles on DA agonist therapy for PD patients and summarizes the latest findings on non-ergot DA agonists as well as the advantages and disadvantages of each compound to help clinicians in the selection of a specific DA agonist. In addition, novel D1/D5 partial agonists and new formulations of DA agonists are also discussed.

Pharmacological and Non-pharmacological Treatments of Sleep Disorders in Parkinson's Disease.

Sleep disorders are one of the most common non-motor symptoms in Parkinson's disease (PD). It can cause a notable decrease in quality of life and functioning in PD patients, as well as place a huge burden on both patients and caregivers. The most cited sleep disorders in PD included insomnia, restless legs syndrome (RLS), rapid eye movement (REM), sleep behavior disorders (RBD), excessive daytime sleepiness (EDS) and sleep disordered breathing (SDB), which can appear alone or several at the same time. In this review, we listed the recommended pharmacological treatments for common sleep disorders in PD, and discussed the recommended dosages, benefits and side effects of relative drugs. We also discussed non-pharmacological treatments to improve sleep quality, including sleep hygiene education, exercise, deep brain stimulation, cognitive behavior therapy and complementary therapies. We tried to find proper interventions for different types of sleep disorders in PD, while minimizing relative side effects.

Comparing the Clinical and Neuropsychological Characteristics of Parkinson's Disease With and Without Freezing of Gait.

INTRODUCTION: Freezing of gait (FOG) is one of the most common walking problems in Parkinson's disease (PD). Impaired cognitive function is believed to play an important role in developing and aggravating FOG in PD. But some evidence suggests that motor function discrepancy may affect testing results. Therefore, we think it is necessary for PD-FOG(+) and PD-FOG(-) patients to complete neuropsychological tests under similar motor conditions. METHODS: This study recruited 44 idiopathic PD patients [PD-FOG(+) n = 22, PD-FOG(-) n = 22] and 20 age-matched healthy controls (HC). PD-FOG(+) and PD-FOG(-) patients were matched for age, year of education, and Hoehn and Yahr score (H&Y). All participants underwent a comprehensive battery of neuropsychological assessment, and demographical and clinical information was also collected. RESULTS: PD patients showed poorer cognitive function, higher risks of depression and anxiety, and more neuropsychiatric symptoms compared with HC. When controlling for age, years of education, and H&Y, there were no statistical differences in cognitive function between PD-FOG(+) and PD-FOG(-) patients. But PD-FOG(+) patients had worse motor and non-motor symptoms than PD-FOG(-) patients. PD patients whose motor symptoms initiated with rigidity and initiated unilaterally were more likely to experience FOG. CONCLUSION: Traditional neuropsychological testing may not be sensitive enough to detect cognitive impairment in PD. Motor symptoms initiated with rigidity and initiated unilaterally might be an important predictor of FOG.

Transverse Strips Instead of Wearable Laser Lights Alleviate the Sequence Effect Toward a Destination in Parkinson's Disease Patients With Freezing of Gait.

Background: The sequence effect (SE), referring to step-to-step reduction in amplitude, is considered to lead to freezing of gait (FOG) in Parkinson's disease (PD). Visual cues may alleviate SE and help reduce freezing episodes. FOG patients show significant SE prior to turning or toward a doorway, but the SE toward a destination has not been clearly studied. Objectives: To examine the SE when approaching a destination in PD patients with FOG, and to further explore the effects of different types of visual cues on destination SE. Methods: Thirty-five PD patients were divided into a freezing (PD+FOG, n = 15) group and a non-freezing (PD-FOG, n = 20) group. Walking trials were tested under three conditions, including without cues (no-cue condition), with wearable laser lights (laser condition), and with transverse strips placed on the floor (strip condition). Kinematic data was recorded by a portable Inertial Measurement Unit (IMU) system. The destination SE and some key gait parameters were evaluated. Results: The PD+FOG group showed greater destination SE in the no-cue and laser conditions when compared to the PD-FOG group. There were no significant differences in the strip condition when comparing destination SE of the two groups. The destination SE was alleviated only by using the transverse strips on the floor. In contrast, transverse strips and wearable laser lights could increase the step length. Conclusions: The significant destination SE may explain why FOG patients are prone to freezing when heading toward their destination. Visual cues using transverse strips on the floor may be a more effective strategy for FOG rehabilitation in PD patients.

MUL1 gene polymorphisms and Parkinson's disease risk.

OBJECTIVES: Parkinson's disease (PD) is afflicting millions of patients worldwide, and gene therapy may be a hope for cure. Recent researches have shown that MUL1 may play a key role in PD pathogenesis, but no specific genetic variants have been identified. This study was aimed to verify the hypothesis that variants in MUL1 gene were associated with PD risk in a Chinese cohort. METHODS: Ten single nucleotide polymorphisms of the MUL1 gene were genotyped through Sanger sequencing in a case-control study containing 100 PD patients and 100 controls matched for age and gender. RESULTS: Our results showed that rs529974 in MUL1 gene was significantly associated with the risk of PD. The allele T in rs529974(+) caused an additional PD tendency (OR = 0.353, 95% CI: [0.179-0.712], P = 0.003), which was independent of gender, clinical features, and severity of PD symptom. CONCLUSION: The allele T in the rs529974(+) MUL1 gene was susceptible to PD. The present findings may provide valuable information for early diagnose of PD and individualized pharmacological therapy, but still requires large-scale studies to confirm.

Expression of AMHR2 and C-KIT in cervical lesions in Uyghur Women of Xinjiang, China.

BACKGROUND: Cervical cancer is one of the most common malignant tumors in women. Anti-Müllerian hormone receptor 2 (AMHR2) and C-Kit were two members of protein kinase which were reported increased in some cancers like ovarian carcinoma and breast cancer. The present study aimed to assess the expression of AMHR2 and c-Kit in cervical cancer of different differentiated degrees as well as in cervicitis sections. METHODS: All the lesions were collected randomly during clinical observations in hospitals located in Xinjiang, China. Polymerase chain reaction (PCR) and immunohistochemical staining were used to detect AMHR2 and c-Kit expression in cervical samples from women who had been infected with human papilloma virus (HPV)16. The expression rate was compared between cervical cancer of well, moderately and poorly differentiated and cervicitis. RESULTS: The average age of the patients was 45 years; ranged from 23 to 80. For AMHR2, all 17 cervicitis samples ranged from (++) to (++++), while cervical cancer showed 11 (+), 9 (++), 15 (+++),9 (++++), and 8 (-), which showed AMHR2 expression was lessen with the poorer of differentiation degree of cervical cancer (P < .05). For c-Kit, 18 cervicitis samples mainly expressed as (-) with none showed (+++) or (++++), while cervical cancer samples showed 7 (-), 6 (+), 1 (++), 2 (+++), and 8 (++++), which indicated c-Kit's expression increased with the reduction of cervical cancer's differentiation degree (P < .05). CONCLUSION: AMHR2 might have some correlation with self defense of our body, while c-Kit might link with the potential invasive capacity of cervical cancer.

Elevated Expression of Ox2R in Cervical Cancers and Placentas of Uyghur Women in Xinjiang, China

Objective:Cervical cancer is one of the major causes of mortality of Uyghur women in Xinjiang, China. Although increased expression of orexin receptor (OxR), known to be strongly expressed in human placenta, has a proven relation to some cancers , there have been few studies of cervical cancer. Thus, we explored this question by evaluating the expression of orexin receptor as a biomarker for screening early stage of cervical cancer in Uyghur women with highest occurrence rate of cervical cancer in China. Study Design: We used polymerase chain reaction (PCR) and immunohistochemical staining to determine the expression of both Ox1R and Ox2R in cervical cancer and cervicitis biopsies collected from Uyghur women infected with human papilloma virus (HPV)16. The expression rate was compared between cervical cancers of low, intermediate and high differentiation and cervicitis. Results:Although there was no significant difference in the expression rate of Ox1R between groups, Ox2R was significantly overexpressed in cervical cancer patients when compared to the cervicitis group. Ox1R was negative in normal human placenta while Ox2R was positive. Conclusions: While expression of Ox1R had no correlation with invasion or metastatic potential, Ox2R demonstrated elevation in cervical cancer with heterogeneity in groups with different metastatic potential, in the human placenta as well, implying that it might serve as an indicator of invasive capacity along with other indices.