Effects of Neurocognitive Rehabilitation on the Levels of Neurotransmitters and Memory Proteins in Patients with Multiple Sclerosis

Abstract

Objective: This study aimed to investigate the role of neurotrophic factors and neurotransmitters in the neurocognitive impairments observed in Multiple Sclerosis (MS) patients, explore potential biomarkers, and evaluate the impact of computer-assisted cognitive rehabilitation (CCR) on these biomarkers. Materials and Methods: The study included 20 healthy volunteers and 23 relapsing-remitting MS patients with a beck depression inventory score below 17, who could use computers and had no attack in the last 6 months. Serum levels of brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), melatonin, and orexin-A were measured using enzyme-linked immunosorbent assay (ELISA) and compared between patients and controls. MS patients underwent assessment using the brief repeatable battery of neuropsychological tests (BRB-N) before (baseline) and after (sixth month) CCR their biomarker levels were measured again, along with administering neuropsychological tests. Results: Results showed lower levels of BDNF, CREB, melatonin, and orexin-A in MS patients compared to healthy controls before neurorehabilitation. Among the measured cognition-related proteins in the MS group, only BDNF was insignificantly decreased after neurorehabilitation. No significant differences were found in orexin-A, melatonin, and CREB levels before and after neurorehabilitation. Although, correlation analysis revealed no significant correlation between biomarkers and clinical parameters, paced auditory serial addition test and stroop tests which pointed to sustaining attention, information processing speed, verbal fluency, and categorical reasoning were found meaningful after CCR. Conclusions: CCR may have beneficial effects on cognitive functions, particularly executive functions. However, the four examined molecules did not reflect cognitive changes in MS and cannot be used as biomarkers. Further investigation of other molecules related to CREB and BDNF pathways may shed light on cognitive impairment in MS.

Keywords

• Multiple Sclerosis
• CCR
• BDNF
• CREB
• melatonin
• orexin-A

References

1. 1. Bar-Or A, Oliveira EM, Anderson DE, Hafler DA. Molecular pathogenesis of multiple sclerosis. J Neuroimmunol 1999; 100(1-2): 252-9. google scholar
2. 2. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol 2008; 7(12): 1139-51. google scholar
3. 3. Deloire MS, Salort E, Bonnet M, Arimone Y, Boudineau M, Amieva H, et al. Cognitive impairment as marker of diffuse brain abnormalities in early relapsing remitting multiple sclerosis. J Neurol Neurosurg Psychiatry 2005; 76(4): 519-26. google scholar
4. 4. Benedict RH, Weinstock-Guttman B, Fishman I, Sharma J, Tjoa CW, Bakshi R. Prediction of neuropsychological impairment in multiple sclerosis: comparison of conventional magnetic resonance imaging measures of atrophy and lesion burden. Arch Neurol 2004; 61(2): 226-30. google scholar
5. 5. Castellucci VF, Kandel ER, Schwartz JH, Wilson FD, Nairn AC, Greengard P. Intracellular injection of the catalytic subunit of cyclic AMP-dependent protein kinase simulates facilitation of transmitter release underlying behavioral sensitization in aplysia. Proc Natl Acad Sci USA 1980; 77(12): 7492-6. google scholar
6. 6. Sharma SK, Bagnall MW, Sutton MA, Carew TJ. Inhibition of calcineurin facilitates the induction of memory for sensitization in aplysia: requirement of mitogen-activated protein kinase. Proc Natl Acad Sci USA 2003; 100(8): 4861-6. google scholar
7. 7. Zhang G, Zhang T, Li N, Wu L, Gu J, Li C, et al. Tetramethylpyrazine nitrone activates the BDNF/Akt/CREB pathway to promote post-ischaemicneuroregeneration and recovery of neurological functions in rats. Br J Pharmacol 2018; 175(3): 517-31. google scholar
8. 8. Alvarez XA, Alvarez I, Iglesias O, Crespo I, Figueroa J, Aleixandre M, et al. Synergistic increase of serum BDNF in Alzheimer patients treated with cerebrolysin and donepezil: Association with cognitive improvement in ApoE4 cases. Int J Neuropsychopharmacol 2016; 19(6): pyw024. google scholar

9. 9. Peng C, Hong X, Chen W, Zhang H, Tan L, Wang X, et al. Melatonin ameliorates amygdala-dependent emotional memory deficits in Tg2576 mice by up-regulating the CREB/c-Fos pathway. Neurosci Lett 2017; 638: 76-82. google scholar
10. 10. Bonzano L, Pedulla L, Pardini M, Tacchino A, Zaratin P, Battaglia MA, et al. Brain activity pattern changes after adaptive working memory training in multiple sclerosis. Brain Imaging Behav 2020; 14(1): 142-54. google scholar
11. 11. Covey TJ, Shucard JL, Benedict RH, Weinstock-Guttman B, Shucard DW. Improved cognitive performance and event-related potential changes following working memory training in patients with multiple sclerosis. MultScler J Exp Transl Clin 2018; 4(1): 2055217317747626. google scholar
12. 12. BoringaJB,LazeronRH,ReulingIE,AderHJ,PfenningsL,Lindeboom J, et al. The brief repeatable battery of neuropsychological tests: normative values allow application in multiple sclerosis clinical practice. Mult Scler 2001; 7: 263-7. google scholar
13. 13. Mesaros S, Rovaris M, Pagani E, Pulizzi A, Caputo D, Ghezzi A, et al. A magnetic resonance imaging voxel-based morphometry study of regional gray matter atrophy in patients with benign multiple sclerosis. Arch Neurol 2008; 65(9): 1223-30. google scholar
14. 14. Gajofatto A, Turatti M, Bianchi MR, Forlivesi S, Gobbin F, Azzara A, et al. Benign multiple sclerosis: physical and cognitive impairment follow distinct evolutions. Acta Neurol Scand 2016; 133(3): 183-91. google scholar
15. 15. Rocca MA, Valsasina P, Ceccarelli A, Absinta M, Ghezzi A, Riccitelli G, et al. Structural and functional MRI correlates of stroop control in benign MS. Hum Brain Mapp 2009; 30(1): 276-90. google scholar
16. 16. Cerasa A,Gioia MC,Valentino P, Nistico R,ChiriacoC,Pirritano D,et al. Computer-assisted cognitive rehabilitation of attentiondeficits for multiple sclerosis: a randomized trial with fMRIcorrelates. Neurorehabil Neural Repair 2013; 27(4): 284-95. google scholar
17. 17. Hansen S, Muenssinger J, Kronhofmann S, Lautenbacher S, Oschmann P, Keune PM. Cognitive screening in Multiple Sclerosis: the Five-Point Test as a substitute for the PASAT in measuring executive function. Clin Neuropsychol 2017; 31(1): 179-92. google scholar
18. 18. Hansen PE, Videbech P, Clemmensen K, Sturlason R, Jensen HM, Vestergaard P. Repetitive transcranial magnetic stimulation as add-on antidepressant treatment. The applicability ofthe method in a clinical setting. Nord J Psychiatry 2004; 58(6): 455-7. google scholar
19. 19. Lin R, Lin Y, Tao J, Chen B, Yu K, Chen J, et al. Electroacupuncture ameliorates learning and memory in rats with cerebral ischemia-reperfusion injury by inhibiting oxidative stress and promoting p-CREB expression in the hippocampus. Mol Med Rep 2015; 12(5): 6807-14. google scholar
20. 20. Wang X, Chen A, Wu H, Ye M, Cheng H, Jiang X, et al. Enriched environment improves post-stroke cognitive impairment in mice by potential regulation of acetylation homeostasis in cholinergic circuits. Brain Res 2016;1650: 232-42. google scholar
21. 21. Chen BH, Park JH, Lee TK, Song M, Kim H, Lee JC, et al. Melatonin attenuates scopolamine-induced cognitive impairment via protecting against demyelination through BDNF-TrkB signaling in the mouse dentate gyrus. Chem Biol Interact 2018; 285: 8-13. google scholar
22. 22. Alzoubi KH, Mayyas FA, Mahafzah R, Khabour OF. Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress. Behav Brain Res 2018; 336: 93-8. google scholar 23. Zhang S, Wang P, Ren L, Hu C, Bi J. Protective effect of melatonin on soluble A01-42-induced memory impairment, astrogliosis, and synaptic dysfunction via the Musashi1/Notch1/Hes1 signaling pathway in the rat hippocampus. Alzheimers Res Ther 2016; 8(1): 40. google scholar
23. 24. Mavanji V, Butterick TA, Duffy CM, Nixon JP, Billington CJ, Kotz CM. Orexin-A/hypocretin treatment restores hippocampal-dependent memory in orexin-A-deficient mice. Neurobiol Learn Mem 2017; 146: 21-30. google scholar
24. 25. Ardeshiri MR, Hosseinmardi N, Akbari E. The effect of orexin-A 1 and orexin-A 2 receptors antagonisms in the basolateral amygdala on memory processing in a passive avoidance task. Physiol Behav 2017; 174: 42-8. google scholar
25. 26. Prokopova B, Hlavacova N, Vlcek M, Penesova A, Grunnerova L, Garafova A, et al. Early cognitive impairment along with decreased stress-induced BDNF in male and female patients with newly diagnosed multiple sclerosis. J Neuroimmunol 2017; 302: 34-40. google scholar
26. 27. Oka Y, Kanbayashi T, Mezaki T, Iseki K, Matsubayashi J, Murakami G, et al. Low CSF hypocretin-1/orexin-A-A associated with hypersomnia secondary to hypothalamic lesion in a case of multiple sclerosis. J Neurol 2004; 251(7): 885-6. google scholar
27. 28. Dokoohaki S, Ghareghani M, Ghanbari A, Farhadi N, Zibara K, Sadeghi H. Corticosteroid therapy exacerbates the reduction of melatonin in multiple sclerosis. Steroids 2017; 128: 32-6. google scholar
28. 29. Fatemi I, Shamsizadeh A, Ayoobi F, Taghipour Z, Sanati MH, Roohbakhsh A, et al. Role of orexin-A-A in experimental autoimmune encephalomyelitis. J Neuroimmunol 2016; 291: 101-9. google scholar
29. 30. Jana M, Ghosh S, Pahan K. Upregulation of myelin gene expression by a physically-modified saline via phosphatidylinositol 3-kinase-mediated activation of CREB: Implications for multiple sclerosis. Neurochem Res 2018; 43(2): 407-19. google scholar