Abstract
Abnormal synaptic plasticity leads to cognitive impairment in schizophrenia. Markers of synaptic plasticity are known to be altered in schizophrenia, but there are limited data available about neural cell adhesion molecule-1 (NCAM-1) levels and its association with cognitive functions in schizophrenia. The objective of the study was to analyze NCAM-1 levels and its association with various cognitive domains in schizophrenia. One hundred and seventy-six schizophrenia cases and 176 controls were recruited for the study. Serum NCAM-1 levels were analysed in both the groups. Cognitive examination was performed using Addenbrooke cognitive examination-III (ACE-III) and disease severity was assessed using Positive and negative symptoms scale (PANSS). Serum NCAM-1 levels were elevated in schizophrenia cases (p = 0.006) compared to controls. NCAM-1 was positively associated with attention (r = 0.196, p = 0.009), language (r = 0.192, p = 0.011), visuospatial abilities (r = 0.207, p = 0.006) and total ACE-III score (r = 0.189, p = 0.012). We conclude that elevated levels of NCAM-1 are associated with better cognitive functioning in schizophrenia.
Keywords: Neural Cell Adhesion Molecule, Cognition, Synaptic plasticity, Schizophrenia
Introduction
Schizophrenia is one of the leading causes of disability globally associated with poor quality of life [1]. Decline in cognitive function is known to be associated with progression of schizophrenia. Earlier studies have demonstrated that cognitive impairment precedes the onset of psychotic symptoms in schizophrenia [2]. Previous investigators have attributed cognitive impairment to neurodevelopmental defects in schizophrenia [3]. Matsuda et al. have suggested cognitive remediation therapy (CRT) in schizophrenia patients and concluded that associated neural changes with CRT improve cognitive functions in these patients [4].
Neural cell adhesion molecule-1 (NCAM-1), is a cell adhesion molecule which belongs to Ig G superfamily. It is expressed in glia cells and neurons and plays a role in growth of neurons and interaction of cells with cytokines and ion channels [5]. Gascon et al. have hypothesized that NCAM is involved in synaptic plasticity and regulation of cognitive functions [6]. Earlier investigators have reported altered NCAM levels in bipolar disorders, anxiety disorders and Alzheimer disease [7, 8]. Experimental studies have documented increased mRNA expression NCAM in early stages of schizophrenia [9]. Single nucleotide polymorphism of NCAM 1 was shown to increase the risk of schizophrenia in Chinese Han population [10]. Recent studies have demonstrated an association between low NCAM 1 levels in serum and cerebrospinal fluid (CSF) and cognitive impairment in schizophrenia [11, 12].
Since synaptic plasticity and cognitive impairment are related to each other, our hypothesis was alteration in the markers of synaptic plasticity can lead to cognitive dysfunction. To test this hypothesis, we designed this study to investigate whether cognitive function varies with alteration in the levels of NCAM 1 in schizophrenia.
Materials and Methods
It is a cross sectional study carried out in Jawaharlal Institute of Post Graduate Medical Education and Research, Puducherry, India. The institute ethics committee approved the study and written informed consent was taken from the participants and their legally accepted representatives prior to the study. One hundred and seventy-six schizophrenia patients and 176 age and gender matched controls were enrolled in the study. Schizophrenia spectrum disorder was diagnosed based on DSM-5 criteria [13], in the age group of 18–45 years included in the study. Subjects with medical and neurological co-morbidities and those with the history of substance abuse in the past 12 weeks were excluded from the study. The controls were recruited from healthy volunteers who came for routine health check-up and patient bystanders other than relatives. Their physical health status was ascertained as recorded in the available health records and directly querying them. Modified MINI screen was used to screen the controls for the presence of psychiatric morbidity. The MINI-International Neuropsychiatric Interview (MINI) is a structured diagnostic interview, used to assess the diagnoses of psychiatric disorders in subjects according to DSM-IV and ICD-10 criteria [14].
Biochemical Assays
Five milliliter of fasting blood sample was collected using aseptic precautions. The sample was centrifuged at 3500 rpm for 10 min, serum was separated and stored at −40 °C for the analysis of NCAM-1. NCAM-1 was analysed by ELISA using reagent kits from RayBiotech, USA. The sensitivity for NCAM-1 estimation was 0.5 ng/ml. The inter-assay and intra assay coefficient was <12% and <10% respectively.
Psychiatric Scales
The assessment of cognition was done using Addenbrooke’s cognitive examination-III [15]. It asses five elements of cognition like memory, attention, language, visuospatial abilities and fluency.
Positive and negative symptom scale (PANSS) was used to evaluate the disease severity [16]. It is a 30-item clinician rated measure widely used to rate symptom severity in schizophrenia. Individual items are scored on a 7-point Likert scale ranging from 1 (absent) to 7 (extreme). It measures three domains which include positive symptoms (7 items), negative symptoms (7 items) and general psychopathological symptoms (16 items). The scores for each domain are computed by summing the rating across component items. The scale has demonstrated good construct validity and high internal consistency.
Statistical Analysis
Continuous variables such as age, body mass index (BMI), PANSS, cognitive function scores and NCAM-1 levels were expressed as mean ± SD or median with interquartile range based on the distribution of normality. The normality of the data was checked using one sample Kolmogorov–Smirnov test. Mann Whitney-U test was performed to find differences in NCAM-1 levels between schizophrenia and controls. Spearman rank correlation was used to test the association of NCAM-1 with PANSS score and ACE-III score. A p value <0.05 was considered as statistically significant.
Result
Table 1 shows the demographical details, cognitive scores and PANSS in schizophrenia cases and controls. Forty-seven percent of schizophrenia cases and 52% of the controls were educated and 21% of cases and 73% of controls were employed. NCAM-1 was significantly elevated in schizophrenia cases compared to controls (p = 0.006). There was no significant difference in age and BMI between the two groups.
Table 1.
Demographic details, clinical characteristics, biochemical parameters and cognitive impairment scores in controls and schizophrenia cases
| Parameter | Controls (n = 176) |
Schizophrenia (n = 176) |
P |
|---|---|---|---|
| Age (years) | 37.21 ± 8.57 | 35.40 ± 9.3 | 0.062 |
| Gender (M/F) | 77/99 | 98/78 | – |
| Body mass index (kg/m2) | 25.56 ± 4.02 | 25.44 ± 4.26 | 0.778 |
| Educated/uneducated | 92/84 | 83/93 | – |
| Employed/unemployed | 129/47 | 38/138 | – |
| Duration of illness (years) | – | 4 (1–7) | – |
| Drug naive/drug free | – | 50/126 | – |
| Positive symptom score | – | 15.33 ± 6.75 | – |
| Negative symptom score | – | 16.23 ± 7.01 | – |
| General psychopathology score | – | 30.30 ± 11.08 | – |
| Total symptom score | – | 29.02 ± 13.44 | – |
| Memory | – |
11.00 (4–18.75) |
– |
| Attention | – | 13.00 ± 4.18 | – |
| Fluency | – | 6.27 ± 2.9 | – |
| Language | – | 22.15 ± 4.29 | – |
| Visiospatial abilities | – | 11.46 ± 3.20 | – |
| Total ACE III score | – | 64.01 ± 17.99 | – |
| Neural cell adhesion molecule-1 (μg/L) |
615.82 (526.77–761.42) |
704.926 (538.50–895.33) |
0.006 |
The bold value indicate p value less then 0.05 which is significant
When drug free and drug naïve schizophrenia cases were compared, we did not observe any significant difference in NCAM-1 levels between two groups (p = 0.45). NCAM-1 levels were significantly increased in drug free cases compared to controls (P = 0.005) (Data not shown).
The association of NCAM-1 with disease severity and cognitive scores of schizophrenia cases were shown in Table 2. NCAM-1 was positively associated with attention (r = 0.196, p = 0.009), language (r = 0.192, p = 0.011), visuospatial abilities (r = 0.207, p = 0.006) and total ACE-III score (r = 0.189, p = 0.012). There was no significant association between NCAM-1 levels and disease severity.
Table 2.
Correlation of Neural cell adhesion molecule-1 with disease severity score and cognitive impairment scores in schizophrenia (n = 176)
| Parameters | Neural cell adhesion molecule-1 | |
|---|---|---|
| rho | p | |
| Positive symptom score | 0.053 | 0.485 |
| Negative symptom score | −0.050 | 0.511 |
| General psychopathology score | 0.025 | 0.749 |
| Total symptom score | 0.054 | 0.483 |
| Memory | 0.140 | 0.063 |
| Attention | 0.196 | 0.009 |
| Fluency | 0.070 | 0.356 |
| Language | 0.192 | 0.011 |
| Visio-spatial abilities | 0.207 | 0.006 |
| Total ACE III score | 0.189 | 0.012 |
The bold values indicate p value less then 0.05 which is significant
Discussion
In the current study, serum NCAM-1 level was significantly increased and positively associated with attention, language, visuospatial abilities and total cognitive scores. There was no significant difference in age, gender and body mass index between schizophrenia cases and controls.
NCAM is involved in neurodevelopmental process and its levels are known to be altered in neuropsychiatric disorders [7, 8]. Earlier investigators have estimated NCAM-1 levels in schizophrenia, but the results are not consistent. An et al. and Hidese et al. have documented reduced levels of NCAM-1 and Tanaka et al. have reported elevated NCAM-1 levels in drug free schizophrenia compared to controls [11, 12, 17]. The main limitation of these studies is small sample size and inadequate power to conclude their findings. In the present study, we found elevated NCAM 1 levels in schizophrenia cases compared to controls. When drug free and drug naïve schizophrenia cases were compared, we did not observe any significant difference in NCAM-1 levels between two groups (p = 0.45). NCAM-1 levels were significantly increased in drug free cases compared to controls (P = 0.005) indicating antipsychotic drugs may not reduce NCAM-1 levels. In contrast to earlier studies, we did not found any significant correlation between NCAM-1 levels and PANSS scores in schizophrenia cases.
NCAM is known to influence the cognitive functions and suggested to play a role in learning and memory [18, 19]. Experimental studies have demonstrated impairment in the process of spatial learning and long term potentiation in NCAM knocked out animals [20, 21]. Anne Albrecht et al. have demonstrated severely impaired social behaviour in NCAM deficient mice when compared to wild mice [22]. Bisaz et al. have shown in mice model that NCAM mediates stress induced cognitive dysfunction [23]. Experimental studies have shown that NCAM-mimetic peptides like FGL and Enreptin restored disrupted neuronal plasticity in mice [24]. NCAM is considered to increase the risk of cognitive dysfunction in schizophrenia and a previous study has found positive correlation between serum NCAM levels and fluency scores in patients with schizophrenia [11, 12]. In the present study, we observed positive association of NCAM-1 with attention, language, visuospatial abilities and total ACE-III scores. These findings suggest that elevated NCAM-1 levels can improve cognitive function in schizophrenia patients. Even though the mechanism for improved cognitive function is unclear, we speculate that elevated NCAM-1 levels may improve synaptic plasticity which in turn may increase the cognitive functions in schizophrenia.
The strength of our study is higher sample size compared to earlier studies. One of the limitation was NCAM-1 was not estimated in CSF due to ethical issues. The number of drug naive cases was less and the influence of drugs used in the treatment of schizophrenia on NCAM-1 levels was not investigated. Based on our findings we could not establish the causal relationship of NCAM with cognitive dysfunction in schizophrenia.
Conclusion
We conclude that NCAM-1 levels are elevated and associated with better cognitive functions in schizophrenia. Further genetic studies are needed to investigate the NCAM-1 gene expression and its association with cognitive performances in schizophrenia.
Acknowledgements
This work was supported by a grant from JIPMER intramural fund sanctioned to the Corresponding author.
Abbreviations
- ACE
Addenbrooke’s cognitive examination
- DSM-5
Diagnostic and Statistical Manual of Mental disorders edition 5
- NCAM-1
Neural cell adhesion molecule 1
- PANSS
Positive and Negative Syndrome Scale
Author Contributions
NK: Acquisition and analysis of data, drafting the article. HN: the conception and design of the study, Analysis and interpretation of data, final approval of the article, funding. MR: Design of the study, revision of the article critically. VM: Design of the study, Interpretation of the data, revision of the article critically.
Compliance with Ethical Standards
Conflict of interest
The authors declare that they have no conflict of interest.
Ethics Approval
Institute ethics committee for human studies approved the study (JIP/IEC/2018/076).
Footnotes
Publisher's Note
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Contributor Information
Neha Keshri, Email: nehakeshri@gmail.com.
Hanumanthappa Nandeesha, Email: nandijipmer@gmail.com.
Medha Rajappa, Email: linkmedha@gmail.com.
Vikas Menon, Email: drvmenon@gmail.com.
References
- 1.Bhugra D. The global prevalence of schizophrenia. PLoS Med. 2005;2(5):e151. doi: 10.1371/journal.pmed.0020151. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Díaz-Soto CM, Castaño-Pérez GA, Pineda-Salazar DA. Cannabis, schizophrenia and cognition: the contribution of brain connectivity. Adicciones. 2020;0:1307. doi: 10.20882/adicciones.1307. [DOI] [PubMed] [Google Scholar]
- 3.Bora E. Neurodevelopmental origin of cognitive impairment in schizophrenia. Psychol Med. 2015;45:1–9. doi: 10.1017/S0033291714001263. [DOI] [PubMed] [Google Scholar]
- 4.Matsuda Y, Makinodan M, Morimoto T, Kishimoto T. Neural changes following cognitive remediation therapy for schizophrenia. Psychiatry Clin Neurosci. 2019;73(11):676–684. doi: 10.1111/pcn.12912. [DOI] [PubMed] [Google Scholar]
- 5.Sytnyk V, Leshchyns’ka I, Schachner M. Neural cell adhesion molecules of the immunoglobulin superfamily regulate synapse formation, maintenance, and function. Trends Neurosci. 2017;40(5):295–308. doi: 10.1016/j.tins.2017.03.003. [DOI] [PubMed] [Google Scholar]
- 6.Gascon E, Vutskits L, Kiss JZ. Polysialic acid-neural cell adhesion molecule in brain plasticity: from synapses to integration of new neurons. Brain Res Rev. 2007;56(1):101–118. doi: 10.1016/j.brainresrev.2007.05.014. [DOI] [PubMed] [Google Scholar]
- 7.Brennaman LH, Maness PF. NCAM in neuropsychiatric and neurodegenerative disorders. Adv Exp Med Biol. 2010;663:299–317. doi: 10.1007/978-1-4419-1170-4_19. [DOI] [PubMed] [Google Scholar]
- 8.Jesudas BR, Nandeesha H, Menon V, Allimuthu P. Relationship of elevated neural cell adhesion molecule 1 with interleukin-10 and disease severity in bipolar disorder. Asian J Psychiatr. 2020;47:101849. doi: 10.1016/j.ajp.2019.101849. [DOI] [PubMed] [Google Scholar]
- 9.Gibbons AS, Thomas EA, Dean B. Regional and duration of illness differences in the alteration of NCAM-180 mRNA expression within the cortex of subjects with schizophrenia. Schizophr Res. 2009;112(1–3):65–71. doi: 10.1016/j.schres.2009.04.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Zhang W, Xiao MS, Ji S, Tang J, Xu L, Li X, et al. Promoter variant rs2301228 on the neural cell adhesion molecule 1 gene confers risk of schizophrenia in Han Chinese. Schizophr Res. 2014;160(1–3):88–96. doi: 10.1016/j.schres.2014.09.036. [DOI] [PubMed] [Google Scholar]
- 11.Hidese S, Hattori K, Sasayama D, Miyakawa T, Matsumura R, Yokota Y, et al. Cerebrospinal fluid neural cell adhesion molecule levels and their correlation with clinical variables in patients with schizophrenia, bipolar disorder, and major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2017;76:12–18. doi: 10.1016/j.pnpbp.2017.02.016. [DOI] [PubMed] [Google Scholar]
- 12.An H, Zhou L, Yu Y, Fan H, Fan F, Tan S, et al. Serum NCAM levels and cognitive deficits in first episode schizophrenia patients versus health controls. Schizophr Res. 2018;192:457–458. doi: 10.1016/j.schres.2017.06.011. [DOI] [PubMed] [Google Scholar]
- 13.American Psychiatric Association . Diagnostic and statistical manual of mental disorders. 5. Arlington, VA: American Psychiatric Association; 2013. [Google Scholar]
- 14.van Vliet IM, de Beurs E. The MINI-International Neuropsychiatric Interview. A brief structured diagnostic psychiatric interview for DSM-IV en ICD-10 psychiatric disorders. Tijdschr Psychiatr. 2007;49(6):393–397. [PubMed] [Google Scholar]
- 15.Bruno D, Vignaga SS. Addenbrooke’s cognitive examination III in the diagnosis of dementia: a critical review. Neuropsychiatr Dis Treat. 2019;15:441–447. doi: 10.2147/NDT.S151253. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Kay SR, Opler LA, Lindenmayer JP. Reliability and validity of the positive and negative syndrome scale for schizophrenics. Psychiatry Res. 1988;23:99–110. doi: 10.1016/0165-1781(88)90038-8. [DOI] [PubMed] [Google Scholar]
- 17.Tanaka Y, Yoshida S, Shimada Y, Ueda H, Asai K. Alteration in serum neural cell adhesion molecules in patients with schizophrenia. Hum Psychopharmacol. 2007;22:97–102. doi: 10.1002/hup.828. [DOI] [PubMed] [Google Scholar]
- 18.Kiryushko D, Berezin V, Bock E. Regulators of neurite outgrowth: role of cell adhesion molecules. Ann N Y Acad Sci. 2004;1014:140–154. doi: 10.1196/annals.1294.015. [DOI] [PubMed] [Google Scholar]
- 19.Kiss JZ, Muller D. Contribution of the neural cell adhesion molecule to neuronal and synaptic plasticity. Rev Neurosci. 2001;12(4):297–310. doi: 10.1515/REVNEURO.2001.12.4.297. [DOI] [PubMed] [Google Scholar]
- 20.Wood GK, Tomasiewicz H, Rutishauser U, Magnuson T, Quirion R, Rochford J, et al. NCAM-180 knockout mice display increased lateral ventricle size and reduced prepulse inhibition of startle. Neuroreport. 1998;9(3):461–466. doi: 10.1097/00001756-199802160-00019. [DOI] [PubMed] [Google Scholar]
- 21.Senkov O, Sun M, Weinhold B, Gerardy-Schahn R, Schachner M, Dityatev A, et al. Polysialylated neural cell adhesion molecule is involved in induction of long-term potentiation and memory acquisition and consolidation in a fear-conditioning paradigm. J Neurosci. 2006;26(42):10888–109898. doi: 10.1523/JNEUROSCI.0878-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Albrecht A, Stork O. Are NCAM deficient mice an animal model for schizophrenia? Front Behav Neurosci. 2012;6:43. doi: 10.3389/fnbeh.2012.00043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Bisaz R, Conboy L, Sandi C. Learning under stress: a role for the neural cell adhesion molecule NCAM. Neurobiol Learn Mem. 2009;91(4):333–342. doi: 10.1016/j.nlm.2008.11.003. [DOI] [PubMed] [Google Scholar]
- 24.Aonurm-Helm A, Jaako K, Jürgenson M, Zharkovsky A, et al. Pharmacol Res. 2016;113(Pt B):731–738. doi: 10.1016/j.phrs.2016.04.011. [DOI] [PubMed] [Google Scholar]