臺灣博碩士論文加值系統

背景：近年來，多方證據顯示精神疾病的發生，可能與腦部發生發炎反應相關。其中，腦組織中，由星形膠細胞、動、靜脈及淋巴組織所組成的大腦血液屏障，負責帶動物質從周邊血管到中樞的流動。其中，位處於星形膠細胞終足上的AQP4水通道被認為是負責調控大腦血液屏障的通透性及影響精神疾病形成的重要關鍵。然而，在思覺失調症中這方面的研究有限。過往我們的研究顯示AQP4基因多型性與臨床抗精神病藥物劑量相關。因此，AQP4基因多型性的角色在大腦血液腦屏障和不同的神經保護作用需要進一步的研究。我們研究目的在了解思覺失調症受試者及健康受試者，兩者在AQP4基因多型性的差異。以及，AQP4基因多型性對於思覺失調症受試者，在藥物治療下的臨床症狀，及血中S100B數值變化的影響。
方法：在第一個研究中，我們招募了190位思覺失調症受試者，這些受試者提供了人口統計學的相關資料及。同時，我們採集受試者血液樣本來進行3種AQP4單核苷酸多型性（SNP）和8種單倍型(haplotype)分析。在抗精神病藥物治療期間，我們分別在收案時、收案後3週、6週及9週，進行正性與負性症狀量表（PANSS），個人與社會功能量表（PSP），整體功能性評估（GAF），臨床整體評估表（CGI）的評分，並重複4次測量血清S100B濃度。使用廣義估計方程式（GEE）分析，探討重複4次測量的對數轉換後的S100B (logS100B)數值、AQP4基因多型性和量表分數的關聯性。在第二個研究中，我們收集了292名思覺失調症受試者和100名健康受試者。為了研究AQP4基因多型性和發生思覺失調症風險的關係，我們將100名健康對照組和100名配對後罹患思覺失調症的某一南方漢民族受試者進行分析。使用卡方檢測來比較對照組和疾病組之間的等位基因和基因型分佈。
結果：經由觀察190位思覺失調症的血液數值常態分布狀況，我們認為logS100B數值1.78具有最佳的鑑別性，並將受試者分為兩組。進而發現9週藥物治療後，血清S100B數值會逐漸降低。AQP4基因多型性中的TAA單倍型與血清S100B數值升高具相關性（p = 0.006）。PANSS負性分項（PANSS-N）（p = 0.001）和臨床整體評估表-改善（CGI-1）（p = 0.003）數值與S100B數值呈現正相關。在第二個研究中，我們選取了三個相同的單核甘酸多型性。與健康對照組相比，受試者在rs1058424處的T等位基因出現頻率較高，在rs3763043處的G等位基因出現頻率較高（分別為p = 0.043和p = 0.045）。此外，rs1058424（p = 0.021，OR = 2.04）和rs3763043（p = 0.018，OR = 2.25）帶有AA基因型時，出現罹患思覺失調症的風險降低。TCG單倍型（p = 0.036）罹患思覺失調症的風險較高，而ACA單倍型（p = 0.0007）與罹患思覺失調症的風險較低，並且ACA單倍型在經過Bonferroni校正後仍具有統計學意義（p = 0.006）。
結論：AQP4的基因多型性可能與罹患思覺失調症的風險相關。藥物治療下，帶有AQP4基因多型性中的TAA單倍型的受試者，可能具有較高的血清S100B數值、較高的負性分項數值及控制不良的神經發炎反應。對數S100B數值1.78可能可以做為預測受試者負性分項嚴重程度的的指標。

Background: Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. The blood-brain barrier (BBB) with the “glymphatic” drainage formation in the central nervous system (CNS) through perivascular processes involves astrocytes. The aquaporin 4 (AQP4) gene, which is found primarily at the end-feet of astrocytes, has been suspected to play putative roles in the clearance of the glymphatic system as well as the development of psychiatric disorders. However, the limited research on AQP4 leaves many uncertainties of the gene. The influence the AQP4 polymorphism may have on the required dosage of antipsychotic drugs has been shown in previous research. We aim to determine whether an association remains between the gene polymorphisms and haplotype of AQP4, and clinical symptoms in patients with schizophrenia (SCZ) and serum S100 calcium-binding protein B (S100B). in the Southern Chinese Han population.
Methods: 190 patients with SCZ were recruited in the first study. These candidates submitted samples to test for four AQP4 tag single nucleotide polymorphisms (SNPs) along with eight haplotypes, provided demographic data and also completed relevant questionnaires. We repeatedly measured their serum S100B levels during antipsychotic treatment at weeks 0 (baseline), 3, 6, and 9, and also assessed rating scales of Positive and Negative Syndrome Scale (PANSS), Personal and Social Performance (PSP), the Global Assessment of Functioning (GAF), Clinical Global Impression (CGI). Log-transformed S100B (logS100B) level was tested for associations with haplotype and other dependent variables using generalized estimating equation (GEE) analyses. We enrolled 100 healthy individuals and 292 patients in the second study. Genetic information was drawn from a cohort of 100 patients with SCZ and 100 matched healthy controls of Southern Han Chinese descent to investigate the relationship between SCZ and APQ4 gene polymorphisms. We used the X2 test to make comparisons of the genotype and allele distributions between case and control groups. Assessments of the haplotype and the linkage equilibrium were made with two-group comparisons.
Results: The one that had the best discriminant validity for stratifying patients into two groups was logS100B level >1.78 or ≤1.78 when doing discretization via the median split procedure. Serum S100B level decreased after 9 weeks of treatment. There is an association between increased serum S100B level (p = 0.006) and the TAA haplotype of AQP4 SNPs. A positive association between S100B level and scores of the Clinical Global Impression-Improvement (CGI-I) (p = 0.003) and the PANSS negative subscale (PANSS-N) (p = 0.001). Three SNPs were found in the second study. Patients had higher G-allele frequencies at rs3763043 and T-allele frequencies at rs1058424 (p = 0.045 and p = 0.043, respectively) when compared to healthy controls. In addition, the AA genotype at both rs1058424 (p = 0.021, OR = 2.04) and rs3763043 (p = 0.018, OR = 2.25) are associated with decreased risk of SCZ. Potential risk of SCZ was found to be associated with the TCG haplotype (p = 0.036) while the ACA haplotype (p = 0.0007) associated with decreased risk of SCZ, after Bonferroni correction, retained its statistical significance (p = 0.006).
Conclusion: Patients are more likely to have negative symptoms, poor control of neuroinflammation and increased serum S100B level if they have the TAA haplotype of the APQ4 polymorphism. A logS100B level >1.78 may be sufficiently specific to predict a higher severity of negative symptoms. Association between risk of SCZ and AQP4 gene polymorphisms was shown in the second study which included patients and matched healthy controls.

Index of Contents ........................................................................................................I
List of Tables .............................................................................................................IV
List of Figures .............................................................................................................V
Chinese Abstract .......................................................................................................VI
English Abstract .....................................................................................................VIII
List of abbreviations ..............................................................................................XIII
1. Introduction .............................................................................................................1
1.1. Background ............................................................................................................1
1.1.1. The haploview concept………………………………………………………….3
1.2. The neuroinflammation hypothesis of psychiatric disorders .................................5
1.2.1. The role of blood brain barrier ............................................................................5
1.2.2. Neuroinflammation .............................................................................................6
1.3. The association of S100B, neuroinflammation and AQP4 ....................................6
1.3.1. The introduction of AQP4 ...................................................................................6
1.3.2. The noncoding regions of AQP4 gene ................................................................7
1.3.3. The introduction of S100 and S100B protein.......................................................7
1.3.4 Association between genetic variants and treatment response to antipsychotics10
1.4. The aims ...............................................................................................................11
2. Materials and Methods .........................................................................................12
2.1. Participants............................................................................................................12
2.1.1. Patients with SCZ ..............................................................................................13
2.1.2. Healthy controls ................................................................................................14
2.1.3. Demographic variables ......................................................................................15
2.2. The Psychometric Assessment .............................................................................15
2.2.1. PANSS ..............................................................................................................15
2.2.2. PSP ....................................................................................................................16
2.2.3. GAF ...................................................................................................................17
2.2.4. CGI ....................................................................................................................17
2.2.4.1 Severity scale ...................................................................................................17
2.2.4.2 Improvement scale……...................................................................................18
2.3. Blood sampling for genotyping ............................................................................19
2.3.1 Segment selection and primer design…………………………………………..19
2.3.2. Polymerase chain reaction (PCR) amplification………………………………20
2.3.3 DNA sequencing, SNP selection, and genotyping……………………………..20
2.3.4 Haplotype reconstruction…………………………………...………………….21
2.3.5 Human S100B ELISA detection ........................................................................21
2.4. Statistical Analyses ..............................................................................................22
2.4.1. Data processing and statistical analyses ............................................................23
3. Results…………………………………………………………………………….24
3.1. Demographic data ................................................................................................24
3.2. Repeated measurements of psychometric assessment and serum S100B level…25
3.3. Single marker analysis for AQP4 variants and SCZ…………………………….26
3.4. Linkage disequilibrium and Haplotype analysis for AQP4 variants and SCZ......26
3.5. Association between AQP4 variants, S100B and the psychometric assessment..27
4. Discussion…………………………………………………………………………28
4.1. The association S100B level and neuroinflammation in SCZ .............................28
4.1.1 The association of S100B level and the assessment ..........................................30
4.1.2 The role of AQP4 variants to affect S100B level and neuroinflammation in patients with SCZ…………………………………………………………….....31
4.2 The association of AQP4 gene and neuroinflammation in case-control study.....32
4.2.1 Polymorphisms of AQP4 genes in neuropsychiatry disease ..............................34
4.2.2 Polymorphisms of AQP4 genes and SCZ vulnerability..................................... 35
4.3 Limitations.............................................................................................................36
5. Conclusion………………………………………………………………………...38
References ..................................................................................................................40
Tables ..........................................................................................................................49
Figures ........................................................................................................................52
Appendix ....................................................................................................................67

References

Akdeniz, C., Tost, H., & Meyer-Lindenberg, A. (2014). The neurobiology of social environmental risk for schizophrenia: an evolving research field. Soc Psychiatry Psychiatr Epidemiol, 49(4), 507-517. doi:10.1007/s00127-014-0858-4
Aleksovska, K., Leoncini, E., Bonassi, S., Cesario, A., Boccia, S., & Frustaci, A. (2014). Systematic review and meta-analysis of circulating S100B blood levels in schizophrenia. PLoS One, 9(9), e106342. doi:10.1371/journal.pone.0106342
Amiry-Moghaddam, M., Frydenlund, D. S., & Ottersen, O. P. (2004). Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience, 129(4), 999-1010. doi:10.1016/j.neuroscience.2004.08.049
Astrand, R., & Unden, J. (2019). Clinical Use of the Calcium-Binding S100B Protein, a Biomarker for Head Injury. Methods Mol Biol, 1929, 679-690. doi:10.1007/978-1-4939-9030-6_42
Bacyinski, A., Xu, M., Wang, W., & Hu, J. (2017). The Paravascular Pathway for Brain Waste Clearance: Current Understanding, Significance and Controversy. Front Neuroanat, 11, 101. doi:10.3389/fnana.2017.00101
Badaut, J., Lasbennes, F., Magistretti, P. J., & Regli, L. (2002). Aquaporins in brain: distribution, physiology, and pathophysiology. J Cereb Blood Flow Metab, 22(4), 367-378. doi:10.1097/00004647-200204000-00001
Barrett, J. C. (2009). Haploview: Visualization and analysis of SNP genotype data. Cold Spring Harb Protoc, 2009(10), pdb ip71. doi:10.1101/pdb.ip71
Bonomini, F., & Rezzani, R. (2010). Aquaporin and blood brain barrier. Curr Neuropharmacol, 8(2), 92-96. doi:10.2174/157015910791233132
Burfeind, K. G., Murchison, C. F., Westaway, S. K., Simon, M. J., Erten-Lyons, D., Kaye, J. A., . . . Iliff, J. J. (2017). The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease. Alzheimers Dement (N Y), 3(3), 348-359. doi:10.1016/j.trci.2017.05.001
Catts, V. S., Wong, J., Fillman, S. G., Fung, S. J., & Shannon Weickert, C. (2014). Increased expression of astrocyte markers in schizophrenia: Association with neuroinflammation. Aust N Z J Psychiatry, 48(8), 722-734. doi:10.1177/0004867414531078
Cavazzin, C., Ferrari, D., Facchetti, F., Russignan, A., Vescovi, A. L., La Porta, C. A., & Gritti, A. (2006). Unique expression and localization of aquaporin-4 and aquaporin-9 in murine and human neural stem cells and in their glial progeny. Glia, 53(2), 167-181. doi:10.1002/glia.20256
Chen, C. H., Yang, J. H., Chiang, C. W. K., Hsiung, C. N., Wu, P. E., Chang, L. C., . . . Shen, C. Y. (2016). Population structure of Han Chinese in the modern Taiwanese population based on 10,000 participants in the Taiwan Biobank project. Hum Mol Genet, 25(24), 5321-5331. doi:10.1093/hmg/ddw346
Chung, T. S., & Lung, F. W. (2012). Different impacts of aquaporin 4 and MAOA allele variation among olanzapine, risperidone, and paliperidone in schizophrenia. J Clin Psychopharmacol, 32(3), 394-397. doi:10.1097/JCP.0b013e31825370f4
Daly, M. J., Rioux, J. D., Schaffner, S. F., Hudson, T. J., & Lander, E. S. (2001). High-resolution haplotype structure in the human genome. Nat Genet, 29(2), 229-232. doi:10.1038/ng1001-229
Dardiotis, E., Paterakis, K., Tsivgoulis, G., Tsintou, M., Hadjigeorgiou, G. F., Dardioti, M., . . . Hadjigeorgiou, G. M. (2014). AQP4 tag single nucleotide polymorphisms in patients with traumatic brain injury. J Neurotrauma, 31(23), 1920-1926. doi:10.1089/neu.2014.3347
Dassan, P., Keir, G., & Brown, M. M. (2009). Criteria for a clinically informative serum biomarker in acute ischaemic stroke: a review of S100B. Cerebrovasc Dis, 27(3), 295-302. doi:10.1159/000199468
Di Benedetto, B., Malik, V. A., Begum, S., Jablonowski, L., Gomez-Gonzalez, G. B., Neumann, I. D., & Rupprecht, R. (2016). Fluoxetine Requires the Endfeet Protein Aquaporin-4 to Enhance Plasticity of Astrocyte Processes. Front Cell Neurosci, 10, 8. doi:10.3389/fncel.2016.00008
Esposito, G., De Filippis, D., Cirillo, C., Sarnelli, G., Cuomo, R., & Iuvone, T. (2006). The astroglial-derived S100beta protein stimulates the expression of nitric oxide synthase in rodent macrophages through p38 MAP kinase activation. Life Sci, 78(23), 2707-2715. doi:10.1016/j.lfs.2005.10.023
Esposito, G., Imitola, J., Lu, J., De Filippis, D., Scuderi, C., Ganesh, V. S., . . . Sheen, V. (2008). Genomic and functional profiling of human Down syndrome neural progenitors implicates S100B and aquaporin 4 in cell injury. Hum Mol Genet, 17(3), 440-457. doi:10.1093/hmg/ddm322
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., . . . Altshuler, D. (2002). The structure of haplotype blocks in the human genome. Science, 296(5576), 2225-2229. doi:10.1126/science.1069424
Geesaman, B. J., Benson, E., Brewster, S. J., Kunkel, L. M., Blanche, H., Thomas, G., . . . Puca, A. A. (2003). Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A, 100(24), 14115-14120. doi:10.1073/pnas.1936249100
Hassager, C., Risteli, J., Risteli, L., Jensen, S. B., & Christiansen, C. (1992). Diurnal variation in serum markers of type I collagen synthesis and degradation in healthy premenopausal women. J Bone Miner Res, 7(11), 1307-1311. doi:10.1002/jbmr.5650071110
Henriksen, M. G., Nordgaard, J., & Jansson, L. B. (2017). Genetics of Schizophrenia: Overview of Methods, Findings and Limitations. Front Hum Neurosci, 11, 322. doi:10.3389/fnhum.2017.00322
Herbener, E. S., & Harrow, M. (2004). Are negative symptoms associated with functioning deficits in both schizophrenia and nonschizophrenia patients? A 10-year longitudinal analysis. Schizophr Bull, 30(4), 813-825. doi:10.1093/oxfordjournals.schbul.a007134
Heuser, K., Nagelhus, E. A., Tauboll, E., Indahl, U., Berg, P. R., Lien, S., . . . Ottersen, O. P. (2010). Variants of the genes encoding AQP4 and Kir4.1 are associated with subgroups of patients with temporal lobe epilepsy. Epilepsy Res, 88(1), 55-64. doi:10.1016/j.eplepsyres.2009.09.023
Holla, F. K., Postma, T. J., Blankenstein, M. A., van Mierlo, T. J. M., Vos, M. J., Sizoo, E. M., . . . Heimans, J. J. (2016). Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis. J Neurooncol, 129(3), 525-532. doi:10.1007/s11060-016-2204-z
Hsu, Y., Tran, M., & Linninger, A. A. (2015). Dynamic regulation of aquaporin-4 water channels in neurological disorders. Croat Med J, 56(5), 401-421. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26526878
Hubbard, J. A., Szu, J. I., & Binder, D. K. (2018). The role of aquaporin-4 in synaptic plasticity, memory and disease. Brain Res Bull, 136, 118-129. doi:10.1016/j.brainresbull.2017.02.011
Iacovetta, C., Rudloff, E., & Kirby, R. (2012). The role of aquaporin 4 in the brain. Vet Clin Pathol, 41(1), 32-44. doi:10.1111/j.1939-165X.2011.00390.x
Iliff, J., & Simon, M. (2019). CrossTalk proposal: The glymphatic system supports convective exchange of cerebrospinal fluid and brain interstitial fluid that is mediated by perivascular aquaporin-4. J Physiol, 597(17), 4417-4419. doi:10.1113/JP277635
The International HapMap Project. (2003). Nature, 426(6968), 789-796. doi:10.1038/nature02168
Jackson, D., Kirkbride, J., Croudace, T., Morgan, C., Boydell, J., Errazuriz, A., . . . Jones, P. B. (2013). Meta-analytic approaches to determine gender differences in the age-incidence characteristics of schizophrenia and related psychoses. Int J Methods Psychiatr Res, 22(1), 36-45. doi:10.1002/mpr.1376
Kooy, R. F. (2010). Distinct disorders affecting the brain share common genetic origins. F1000 Biol Rep, 2. doi:10.3410/B2-11
Lan, Y. L., Fang, D. Y., Zhao, J., Ma, T. H., & Li, S. (2016). A research update on the potential roles of aquaporin 4 in neuroinflammation. Acta Neurol Belg, 116(2), 127-134. doi:10.1007/s13760-015-0520-2
Lichtenstein, P., Yip, B. H., Bjork, C., Pawitan, Y., Cannon, T. D., Sullivan, P. F., & Hultman, C. M. (2009). Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet, 373(9659), 234-239. doi:10.1016/S0140-6736(09)60072-6
Ling, S. H., Tang, Y. L., Jiang, F., Wiste, A., Guo, S. S., Weng, Y. Z., & Yang, T. S. (2007). Plasma S-100B protein in Chinese patients with schizophrenia: comparison with healthy controls and effect of antipsychotics treatment. J Psychiatr Res, 41(1-2), 36-42. doi:10.1016/j.jpsychires.2005.11.006
Liu, E., Zhang, Y. X., Sun, L. L., Teng, Z., Wang, A. B., Han, H. B., & Yan, J. H. (2018). [Role of aquaporin-4 in the change of interstitial fluid drainage in Alzheimer's disease]. Beijing Da Xue Xue Bao Yi Xue Ban, 50(2), 203-206. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/29643515
Long, J., Huang, G., Liang, W., Liang, B., Chen, Q., Xie, J., . . . Su, L. (2014). The prevalence of schizophrenia in mainland China: evidence from epidemiological surveys. Acta Psychiatr Scand, 130(4), 244-256. doi:10.1111/acps.12296
Lu, M., Lee, M. D., Smith, B. L., Jung, J. S., Agre, P., Verdijk, M. A., . . . Deen, P. M. (1996). The human AQP4 gene: definition of the locus encoding two water channel polypeptides in brain. Proc Natl Acad Sci U S A, 93(20), 10908-10912. doi:10.1073/pnas.93.20.10908
Mader, S., & Brimberg, L. (2019). Aquaporin-4 Water Channel in the Brain and Its Implication for Health and Disease. Cells, 8(2). doi:10.3390/cells8020090
Marenholz, I., Lovering, R. C., & Heizmann, C. W. (2006). An update of the S100 nomenclature. Biochim Biophys Acta, 1763(11), 1282-1283. doi:10.1016/j.bbamcr.2006.07.013
McGurk, S. R., Moriarty, P. J., Harvey, P. D., Parrella, M., White, L., Friedman, J., & Davis, K. L. (2000). Relationship of cognitive functioning, adaptive life skills, and negative symptom severity in poor-outcome geriatric schizophrenia patients. J Neuropsychiatry Clin Neurosci, 12(2), 257-264. doi:10.1176/jnp.12.2.257
Meyer, U. (2013). Developmental neuroinflammation and schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 42, 20-34. doi:10.1016/j.pnpbp.2011.11.003
Monji, A., Kato, T. A., Mizoguchi, Y., Horikawa, H., Seki, Y., Kasai, M., . . . Kanba, S. (2013). Neuroinflammation in schizophrenia especially focused on the role of microglia. Prog Neuropsychopharmacol Biol Psychiatry, 42, 115-121. doi:10.1016/j.pnpbp.2011.12.002
Moore, B. W. (1965). A soluble protein characteristic of the nervous system. Biochem Biophys Res Commun, 19(6), 739-744. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4953930
Morera-Fumero, A. L., Diaz-Mesa, E., Abreu-Gonzalez, P., Fernandez-Lopez, L., & Cejas-Mendez, M. D. R. (2017). Day/night changes in serum S100B protein concentrations in acute paranoid schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 75, 207-212. doi:10.1016/j.pnpbp.2017.02.007
Muratake, T., Fukui, N., Kaneko, N., Amagane, H., & Someya, T. (2005). Linkage disequilibrium in aquaporin 4 gene and association study with schizophrenia. Psychiatry Clin Neurosci, 59(5), 595-598. doi:10.1111/j.1440-1819.2005.01420.x
Nagelhus, E. A., Mathiisen, T. M., & Ottersen, O. P. (2004). Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience, 129(4), 905-913. doi:10.1016/j.neuroscience.2004.08.053
Nagelhus, E. A., & Ottersen, O. P. (2013). Physiological roles of aquaporin-4 in brain. Physiol Rev, 93(4), 1543-1562. doi:10.1152/physrev.00011.2013
Nesic, O., Lee, J., Ye, Z., Unabia, G. C., Rafati, D., Hulsebosch, C. E., & Perez-Polo, J. R. (2006). Acute and chronic changes in aquaporin 4 expression after spinal cord injury. Neuroscience, 143(3), 779-792. doi:10.1016/j.neuroscience.2006.08.079
Nicchia, G. P., Nico, B., Camassa, L. M., Mola, M. G., Loh, N., Dermietzel, R., . . . Frigeri, A. (2004). The role of aquaporin-4 in the blood-brain barrier development and integrity: studies in animal and cell culture models. Neuroscience, 129(4), 935-945. doi:10.1016/j.neuroscience.2004.07.055
Oshio, K., Binder, D. K., Yang, B., Schecter, S., Verkman, A. S., & Manley, G. T. (2004). Expression of aquaporin water channels in mouse spinal cord. Neuroscience, 127(3), 685-693. doi:10.1016/j.neuroscience.2004.03.016
Pasternak, O., Kubicki, M., & Shenton, M. E. (2016). In vivo imaging of neuroinflammation in schizophrenia. Schizophr Res, 173(3), 200-212. doi:10.1016/j.schres.2015.05.034
Patrick, D. L., Burns, T., Morosini, P., Gagnon, D. D., Rothman, M., & Adriaenssen, I. (2010). Measuring social functioning with the personal and social performance scale in patients with acute symptoms of schizophrenia: interpretation of results of a pooled analysis of three Phase III trials of paliperidone extended-release tablets. Clin Ther, 32(2), 275-292. doi:10.1016/j.clinthera.2010.02.003
Pedersen, A., Diedrich, M., Kaestner, F., Koelkebeck, K., Ohrmann, P., Ponath, G., . . . Rothermundt, M. (2008). Memory impairment correlates with increased S100B serum concentrations in patients with chronic schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry, 32(8), 1789-1792. doi:10.1016/j.pnpbp.2008.07.017
Pisani, F., Sparaneo, A., Tortorella, C., Ruggieri, M., Trojano, M., Mola, M. G., . . . Svelto, M. (2013). Aquaporin-4 autoantibodies in Neuromyelitis Optica: AQP4 isoform-dependent sensitivity and specificity. PLoS One, 8(11), e79185. doi:10.1371/journal.pone.0079185
Pollak, T. A., Drndarski, S., Stone, J. M., David, A. S., McGuire, P., & Abbott, N. J. (2018). The blood-brain barrier in psychosis. Lancet Psychiatry, 5(1), 79-92. doi:10.1016/S2215-0366(17)30293-6
Practice guideline for the treatment of patients with schizophrenia. American Psychiatric Association. (1997). Am J Psychiatry, 154(4 Suppl), 1-63. doi:10.1176/ajp.154.4.1
Quincozes-Santos, A., Abib, R. T., Leite, M. C., Bobermin, D., Bambini-Junior, V., Goncalves, C. A., . . . Gottfried, C. (2008). Effect of the atypical neuroleptic risperidone on morphology and S100B secretion in C6 astroglial lineage cells. Mol Cell Biochem, 314(1-2), 59-63. doi:10.1007/s11010-008-9765-x
Ramiro, L., Simats, A., Penalba, A., Garcia-Tornel, A., Rovira, A., Mancha, F., . . . Montaner, J. (2020). Circulating Aquaporin-4 as A biomarker of early neurological improvement in stroke patients: A pilot study. Neurosci Lett, 714, 134580. doi:10.1016/j.neulet.2019.134580
Redant, S., Beretta-Piccoli, X., Mugisha, A., Attou, R., Kaefer, K., De Bels, D., . . . Honore, P. M. (2019). Hyperammonemia, the Last Indication of High-Volume Hemodiafiltration in Adult and Children: A Structured Review. Blood Purif, 48(4), 330-335. doi:10.1159/000501390
Rothermundt, M., Ahn, J. N., & Jorgens, S. (2009). S100B in schizophrenia: an update. Gen Physiol Biophys, 28 Spec No Focus, F76-81. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/20093730
Rothermundt, M., Falkai, P., Ponath, G., Abel, S., Burkle, H., Diedrich, M., . . . Arolt, V. (2004). Glial cell dysfunction in schizophrenia indicated by increased S100B in the CSF. Mol Psychiatry, 9(10), 897-899. doi:10.1038/sj.mp.4001548
Rothermundt, M., Missler, U., Arolt, V., Peters, M., Leadbeater, J., Wiesmann, M., . . . Kirchner, H. (2001). Increased S100B blood levels in unmedicated and treated schizophrenic patients are correlated with negative symptomatology. Mol Psychiatry, 6(4), 445-449. doi:10.1038/sj.mp.4000889
Rothermundt, M., Ponath, G., Glaser, T., Hetzel, G., & Arolt, V. (2004). S100B serum levels and long-term improvement of negative symptoms in patients with schizophrenia. Neuropsychopharmacology, 29(5), 1004-1011. doi:10.1038/sj.npp.1300403
Schaid, D. J., McDonnell, S. K., Sinnwell, J. P., & Thibodeau, S. N. (2013). Multiple genetic variant association testing by collapsing and kernel methods with pedigree or population structured data. Genet Epidemiol, 37(5), 409-418. doi:10.1002/gepi.21727
Schroeter, M. L., & Steiner, J. (2009). Elevated serum levels of the glial marker protein S100B are not specific for schizophrenia or mood disorders. Mol Psychiatry, 14(3), 235-237. doi:10.1038/mp.2008.85
Sedaghat, F., & Notopoulos, A. (2008). S100 protein family and its application in clinical practice. Hippokratia, 12(4), 198-204. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/19158963
Sepramaniam, S., Ying, L. K., Armugam, A., Wintour, E. M., & Jeyaseelan, K. (2012). MicroRNA-130a represses transcriptional activity of aquaporin 4 M1 promoter. J Biol Chem, 287(15), 12006-12015. doi:10.1074/jbc.M111.280701
Sorani, M. D., Zador, Z., Hurowitz, E., Yan, D., Giacomini, K. M., & Manley, G. T. (2008). Novel variants in human Aquaporin-4 reduce cellular water permeability. Hum Mol Genet, 17(15), 2379-2389. doi:10.1093/hmg/ddn138
Sorci, G., Riuzzi, F., Arcuri, C., Tubaro, C., Bianchi, R., Giambanco, I., & Donato, R. (2013). S100B protein in tissue development, repair and regeneration. World J Biol Chem, 4(1), 1-12. doi:10.4331/wjbc.v4.i1.1
Steiner, J., Bernstein, H. G., Bielau, H., Berndt, A., Brisch, R., Mawrin, C., . . . Bogerts, B. (2007). Evidence for a wide extra-astrocytic distribution of S100B in human brain. BMC Neurosci, 8, 2. doi:10.1186/1471-2202-8-2
Steiner, J., Bernstein, H. G., Bogerts, B., Gos, T., Richter-Landsberg, C., Wunderlich, M. T., & Keilhoff, G. (2008). S100B is expressed in, and released from, OLN-93 oligodendrocytes: Influence of serum and glucose deprivation. Neuroscience, 154(2), 496-503. doi:10.1016/j.neuroscience.2008.03.060
Steiner, J., Bielau, H., Bernstein, H. G., Bogerts, B., & Wunderlich, M. T. (2006). Increased cerebrospinal fluid and serum levels of S100B in first-onset schizophrenia are not related to a degenerative release of glial fibrillar acidic protein, myelin basic protein and neurone-specific enolase from glia or neurones. J Neurol Neurosurg Psychiatry, 77(11), 1284-1287. doi:10.1136/jnnp.2006.093427
Steiner, J., Myint, A. M., Schiltz, K., Westphal, S., Bernstein, H. G., Walter, M., . . . Bogerts, B. (2010). S100B Serum Levels in Schizophrenia Are Presumably Related to Visceral Obesity and Insulin Resistance. Cardiovasc Psychiatry Neurol, 2010, 480707. doi:10.1155/2010/480707
Steiner, J., Walter, M., Wunderlich, M. T., Bernstein, H. G., Panteli, B., Brauner, M., . . . Bogerts, B. (2009). A new pathophysiological aspect of S100B in schizophrenia: potential regulation of S100B by its scavenger soluble RAGE. Biol Psychiatry, 65(12), 1107-1110. doi:10.1016/j.biopsych.2008.10.044
Stepniak, B., Papiol, S., Hammer, C., Ramin, A., Everts, S., Hennig, L., . . . Ehrenreich, H. (2014). Accumulated environmental risk determining age at schizophrenia onset: a deep phenotyping-based study. Lancet Psychiatry, 1(6), 444-453. doi:10.1016/S2215-0366(14)70379-7
Steullet, P., Cabungcal, J. H., Monin, A., Dwir, D., O'Donnell, P., Cuenod, M., & Do, K. Q. (2016). Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology? Schizophr Res, 176(1), 41-51. doi:10.1016/j.schres.2014.06.021
Szu, J. I., & Binder, D. K. (2016). The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory. Front Integr Neurosci, 10, 8. doi:10.3389/fnint.2016.00008
Tamtaji, O. R., Behnam, M., Pourattar, M. A., Jafarpour, H., & Asemi, Z. (2019). Aquaporin 4: A key player in Parkinson's disease. J Cell Physiol, 234(12), 21471-21478. doi:10.1002/jcp.28871
Verkman, A. S., Anderson, M. O., & Papadopoulos, M. C. (2014). Aquaporins: important but elusive drug targets. Nat Rev Drug Discov, 13(4), 259-277. doi:10.1038/nrd4226
Verkman, A. S., Binder, D. K., Bloch, O., Auguste, K., & Papadopoulos, M. C. (2006). Three distinct roles of aquaporin-4 in brain function revealed by knockout mice. Biochim Biophys Acta, 1758(8), 1085-1093. doi:10.1016/j.bbamem.2006.02.018
Wiesmann, M., Wandinger, K. P., Missler, U., Eckhoff, D., Rothermundt, M., Arolt, V., & Kirchner, H. (1999). Elevated plasma levels of S-100b protein in schizophrenic patients. Biol Psychiatry, 45(11), 1508-1511. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10356634
Wu, X., & Gao, J. F. (2017). [Involvement of aquaporin-4 in synaptic plasticity, learning and memory]. Sheng Li Xue Bao, 69(3), 335-343. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/28638927
Wu, Y. F., Sytwu, H. K., & Lung, F. W. (2018). Human Aquaporin 4 Gene Polymorphisms and Haplotypes Are Associated With Serum S100B Level and Negative Symptoms of Schizophrenia in a Southern Chinese Han Population. Front Psychiatry, 9, 657. doi:10.3389/fpsyt.2018.00657
Xiao, M., & Hu, G. (2014). Involvement of aquaporin 4 in astrocyte function and neuropsychiatric disorders. CNS Neurosci Ther, 20(5), 385-390. doi:10.1111/cns.12267
Yang, C., Huang, X., Mai, H., Li, J., Jiang, T., Wang, X., & Lu, T. (2016). Aquaporin-4 and Alzheimer's Disease. J Alzheimers Dis, 52(2), 391-402. doi:10.3233/JAD-150949
Zamanpoor, M. (2020). Schizophrenia in a genomic era: a review from the pathogenesis, genetic and environmental etiology to diagnosis and treatment insights. Psychiatr Genet, 30(1), 1-9. doi:10.1097/YPG.0000000000000245
Zeger, S. L., Liang, K. Y., & Albert, P. S. (1988). Models for longitudinal data: a generalized estimating equation approach. Biometrics, 44(4), 1049-1060. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/3233245
Zhang, X. Y., Xiu, M. H., Song, C., Chen da, C., Wu, G. Y., Haile, C. N., . . . Kosten, T. R. (2010). Increased serum S100B in never-medicated and medicated schizophrenic patients. J Psychiatr Res, 44(16), 1236-1240. doi:10.1016/j.jpsychires.2010.04.023
Zhang, X. Y., Xiu, M. H., Song, C., Chen, D. C., Wu, G. Y., Haile, C. N., . . . Kosten, T. R. (2010). Increased serum S100B in never-medicated and medicated schizophrenic patients. J Psychiatr Res, 44(16), 1236-1240. doi:10.1016/j.jpsychires.2010.04.023