Top

BMC Neurology

Published in:

Open Access 01-12-2021 | Amyotrophic Lateral Sclerosis | Research article

Decreased blood CD4+ T lymphocyte helps predict cognitive impairment in patients with amyotrophic lateral sclerosis

Authors: Yuan Yang, Dengji Pan, Zhenxiang Gong, Jiahui Tang, Zehui Li, Fengfei Ding, Mao Liu, Min Zhang

Published in: BMC Neurology | Issue 1/2021

Abstract

Background

ALS patients have changed peripheral immunity. It is unknown whether peripheral immunity is related to cognitive dysfunction in ALS patients.

Objective

To explore the relationship between the peripheral blood lymphocyte subsets and the cognitive status in ALS patients.

Methods

Among 81 ALS patients, we compared the demographic, clinical, and peripheral levels of total T lymphocyte, CD4+ T lymphocyte, CD8+ T lymphocyte, B lymphocyte, and NK cell between those with cognitive impairment (ALS-ci) and those without (ALS-nci). The cognitive status was evaluated via the Chinese version of the Edinburgh cognitive and behavioral screen (ECAS). Significant predictors of cognitive impairment in univariate logistic regression analysis were further examined using multivariate logistic regression analysis.

Results

39.5% of all ALS patients had cognitive impairment. The ALS-ci group had shorter education time, older age at both symptom onset and testing, longer disease duration, and lower levels of peripheral total, CD4+, and CD8+ T lymphocyte and B lymphocyte than the ALS-nci group. Frequency of behavioral impairment did not differ between the two groups. While parameters with significant differences identified by group comparison were also significant predictors of cognitive impairment in univariate logistic regression analysis except the level of B lymphocyte, only older age at testing, education time less than 9 years, and lower level of CD4+ T lymphocyte remained significant in multivariate logistic regression analysis. The predictive model combining these three parameters had an area under the receiver operating characteristic curve value of 0.842 with a sensitivity of 90.6% and a specificity of 67.3%.

Conclusion

In Chinese ALS patients, blood CD4+ T lymphocyte might help evaluate cognitive impairment along with age and education level.

Available only for authorised users

Gordon PH. Amyotrophic lateral sclerosis: an update for 2013 clinical features, pathophysiology, management and therapeutic trials. Aging Dis. 2013;4(5):295–310. https://doi.org/10.14336/ad.2013.0400295.CrossRefPubMedPubMedCentral

Silani V, Ludolph A, Fornai F. The emerging picture of ALS: a multisystem, not only a motor neuron disease. Arch Ital Biol. 2017;155(4):99–109. https://doi.org/10.12871/00039829201741.CrossRefPubMed

Grossman AB, Woolley-Levine S, Bradley WG, Miller RG. Detecting neurobehavioral changes in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2007;8(1):56–61. https://doi.org/10.1080/17482960601044106.CrossRefPubMed

Murphy J, Henry R, Lomen-Hoerth C. Establishing subtypes of the continuum of frontal lobe impairment in amyotrophic lateral sclerosis. Arch Neurol. 2007;64(3):330–4. https://doi.org/10.1001/archneur.64.3.330.CrossRefPubMed

Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol. 2007;6(11):994–1003. https://doi.org/10.1016/s1474-4422(07)70265-x.CrossRefPubMed

Strong MJ, Abrahams S, Goldstein LH, Woolley S, McLaughlin P, Snowden J, et al. Amyotrophic lateral sclerosis - frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(3–4):153–74. https://doi.org/10.1080/21678421.2016.1267768.CrossRefPubMedPubMedCentral

Olney RK, Murphy J, Forshew D, Garwood E, Miller BL, Langmore S, et al. The effects of executive and behavioral dysfunction on the course of ALS. Neurology. 2005;65(11):1774–7. https://doi.org/10.1212/01.wnl.0000188759.87240.8b.

Chiò A, Vignola A, Mastro E, Giudici AD, Iazzolino B, Calvo A, et al. Neurobehavioral symptoms in ALS are negatively related to caregivers' burden and quality of life. Eur J Neurol. 2010;17(10):1298–303. https://doi.org/10.1111/j.1468-1331.2010.03016.x.

Pagnini F, Rossi G, Lunetta C, Banfi P, Castelnuovo G, Corbo M, et al. Burden, depression, and anxiety in caregivers of people with amyotrophic lateral sclerosis. Psychol Health Med. 2010;15(6):685–93. https://doi.org/10.1080/13548506.2010.507773.

10.

Khin Khin E, Minor D, Holloway A, Pelleg A. Decisional capacity in amyotrophic lateral sclerosis. J Am Acad Psychiatry Law. 2015;43(2):210–7.PubMed

11.

Goldstein LH, Abrahams S. Changes in cognition and behaviour in amyotrophic lateral sclerosis: nature of impairment and implications for assessment. Lancet Neurol. 2013;12(4):368–80. https://doi.org/10.1016/s1474-4422(13)70026-7.CrossRefPubMed

12.

Ye S, Ji Y, Li C, He J, Liu X, Fan D. The Edinburgh cognitive and behavioural ALS screen in a Chinese amyotrophic lateral sclerosis population. PLoS One. 2016;11 5:e0155496; doi: https://doi.org/10.1371/journal.pone.0155496.

13.

Abrahams S, Newton J, Niven E, Foley J, Bak TH. Screening for cognition and behaviour changes in ALS. Amyotrophic Lateral Scler Frontotemporal Degener. 2014;15(1–2):9–14. https://doi.org/10.3109/21678421.2013.805784.CrossRef

14.

Niven E, Newton J, Foley J, Colville S, Swingler R, Chandran S, et al. Validation of the Edinburgh cognitive and Behavioural amyotrophic lateral sclerosis screen (ECAS): a cognitive tool for motor disorders. Amyotrophic Lateral Scler Frontotemporal Degener. 2015;16(3–4):172–9. https://doi.org/10.3109/21678421.2015.1030430.

15.

Lulé D, Burkhardt C, Abdulla S, Böhm S, Kollewe K, Uttner I, et al. The Edinburgh cognitive and Behavioural amyotrophic lateral sclerosis screen: a cross-sectional comparison of established screening tools in a German-Swiss population. Amyotrophic Lateral Scler Frontotemporal Degener. 2015;16(1–2):16–23. https://doi.org/10.3109/21678421.2014.959451.

16.

Poletti B, Solca F, Carelli L, Madotto F, Lafronza A, Faini A, et al. The validation of the Italian Edinburgh cognitive and Behavioural ALS screen (ECAS). Amyotrophic Lateral Scler Frontotemporal Degener. 2016;17(7–8):489–98. https://doi.org/10.1080/21678421.2016.1183679.

17.

Siciliano M, Trojano L, Trojsi F, Greco R, Santoro M, Basile G, et al. Edinburgh cognitive and behavioural ALS screen (ECAS)-Italian version: regression based norms and equivalent scores. Neurol Sci. 2017;38(6):1059–68. https://doi.org/10.1007/s10072-017-2919-4.

18.

Mora JS, Salas T, Fernández MC, Rodríguez-Castillo V, Marín S, Chaverri D, et al. Spanish adaptation of the Edinburgh cognitive and behavioral amyotrophic lateral sclerosis screen (ECAS). Amyotrophic Lateral Scler Frontotemporal Degener. 2018;19(1–2):74–9. https://doi.org/10.1080/21678421.2017.1406952.

19.

Gustafson MP, Staff NP, Bornschlegl S, Butler GW, Maas ML, Kazamel M, et al. Comprehensive immune profiling reveals substantial immune system alterations in a subset of patients with amyotrophic lateral sclerosis. PLoS One. 2017;12(7):e0182002. https://doi.org/10.1371/journal.pone.0182002.CrossRefPubMedPubMedCentral

20.

Mantovani S, Garbelli S, Pasini A, Alimonti D, Perotti C, Melazzini M, et al. Immune system alterations in sporadic amyotrophic lateral sclerosis patients suggest an ongoing neuroinflammatory process. J Neuroimmunol. 2009;210(1–2):73–9. https://doi.org/10.1016/j.jneuroim.2009.02.012.

21.

Murdock BJ, Zhou T, Kashlan SR, Little RJ, Goutman SA, Feldman EL. Correlation of peripheral immunity with rapid amyotrophic lateral sclerosis progression. JAMA Neurol. 2017;74(12):1446–54. https://doi.org/10.1001/jamaneurol.2017.2255.CrossRefPubMedPubMedCentral

22.

Rentzos M, Evangelopoulos E, Sereti E, Zouvelou V, Marmara S, Alexakis T, et al. Alterations of T cell subsets in ALS: a systemic immune activation? Acta Neurol Scand. 2012;125(4):260–4. https://doi.org/10.1111/j.1600-0404.2011.01528.x.

23.

Zhang R, Gascon R, Miller RG, Gelinas DF, Mass J, Hadlock K, et al. Evidence for systemic immune system alterations in sporadic amyotrophic lateral sclerosis (sALS). J Neuroimmunol. 2005;159(1–2):215–24. https://doi.org/10.1016/j.jneuroim.2004.10.009.

24.

Chen X, Feng W, Huang R, Guo X, Chen Y, Zheng Z, et al. Evidence for peripheral immune activation in amyotrophic lateral sclerosis. J Neurol Sci. 2014;347(1–2):90–5. https://doi.org/10.1016/j.jns.2014.09.025.

25.

Provinciali L, Laurenzi MA, Vesprini L, Giovagnoli AR, Bartocci C, Montroni M, et al. Immunity assessment in the early stages of amyotrophic lateral sclerosis: a study of virus antibodies and lymphocyte subsets. Acta Neurol Scand. 1988;78(6):449–54. https://doi.org/10.1111/j.1600-0404.1988.tb03686.x.

26.

Busse M, Michler E, von Hoff F, Dobrowolny H, Hartig R, Frodl T, et al. Alterations in the peripheral immune system in dementia. J Alzheimers Dis. 2017;58(4):1303–13. https://doi.org/10.3233/jad-161304.

27.

Bonotis K, Krikki E, Holeva V, Aggouridaki C, Costa V, Baloyannis S. Systemic immune aberrations in Alzheimer's disease patients. J Neuroimmunol. 2008;193(1–2):183–7. https://doi.org/10.1016/j.jneuroim.2007.10.020.CrossRefPubMed

28.

Hu ZX, Song WN, Lu XD, Zhou ML, Shao JH. Peripheral T lymphocyte immunity and l-dopamine in patients with Parkinson's disease. J Biol Regul Homeost Agents. 2018;32(3):687–91.PubMed

29.

Magistrelli L, Storelli E, Rasini E, Contaldi E, Comi C, Cosentino M, et al. Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson's disease. Brain Behav Immun. 2020;89:668–74. https://doi.org/10.1016/j.bbi.2020.07.005.

30.

Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293–9. https://doi.org/10.1080/146608200300079536.CrossRefPubMed

31.

Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;169(1–2):13–21. https://doi.org/10.1016/s0022-510x(99)00210-5.CrossRefPubMed

32.

Brugger F, Erro R, Balint B, Kägi G, Barone P, Bhatia KP. Why is there motor deterioration in Parkinson's disease during systemic infections-a hypothetical view. NPJ Parkinsons Dis. 2015;1(1):15014. https://doi.org/10.1038/npjparkd.2015.14.CrossRefPubMedPubMedCentral

33.

Sonar SA, Lal G. Blood-brain barrier and its function during inflammation and autoimmunity. J Leukoc Biol. 2018;103(5):839–53. https://doi.org/10.1002/jlb.1ru1117-428r.CrossRefPubMed

34.

Neumann H, Wekerle H. Neuronal control of the immune response in the central nervous system: linking brain immunity to neurodegeneration. J Neuropathol Exp Neurol. 1998;57(1):1–9. https://doi.org/10.1097/00005072-199801000-00001.CrossRefPubMed

35.

Brynskikh A, Warren T, Zhu J, Kipnis J. Adaptive immunity affects learning behavior in mice. Brain Behav Immun. 2008;22(6):861–9. https://doi.org/10.1016/j.bbi.2007.12.008.CrossRefPubMed

36.

Kipnis J, Cohen H, Cardon M, Ziv Y, Schwartz M. T cell deficiency leads to cognitive dysfunction: implications for therapeutic vaccination for schizophrenia and other psychiatric conditions. Proc Natl Acad Sci U S A. 2004;101(21):8180–5. https://doi.org/10.1073/pnas.0402268101.CrossRefPubMedPubMedCentral

37.

Radjavi A, Smirnov I, Kipnis J. Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire. Brain Behav Immun. 2014;35:58–63. https://doi.org/10.1016/j.bbi.2013.08.013.CrossRefPubMed

38.

Filiano AJ, Gadani SP, Kipnis J. How and why do T cells and their derived cytokines affect the injured and healthy brain? Nat Rev Neurosci. 2017;18(6):375–84. https://doi.org/10.1038/nrn.2017.39.CrossRefPubMedPubMedCentral

39.

Garbuzova-Davis S, Sanberg PR. Blood-CNS barrier impairment in ALS patients versus an animal model. Front Cell Neurosci. 2014;8:21. https://doi.org/10.3389/fncel.2014.00021.CrossRefPubMedPubMedCentral

40.

Nicaise C, Mitrecic D, Demetter P, De Decker R, Authelet M, Boom A, et al. Impaired blood-brain and blood-spinal cord barriers in mutant SOD1-linked ALS rat. Brain Res. 2009;1301:152–62. https://doi.org/10.1016/j.brainres.2009.09.018.CrossRefPubMed

41.

Garbuzova-Davis S, Haller E, Saporta S, Kolomey I, Nicosia SV, Sanberg PR. Ultrastructure of blood-brain barrier and blood-spinal cord barrier in SOD1 mice modeling ALS. Brain Res. 2007;1157:126–37. https://doi.org/10.1016/j.brainres.2007.04.044.CrossRefPubMed

42.

Donnenfeld H, Kascsak RJ, Bartfeld H. Deposits of IgG and C3 in the spinal cord and motor cortex of ALS patients. J Neuroimmunol. 1984;6(1):51–7. https://doi.org/10.1016/0165-5728(84)90042-0.CrossRefPubMed

43.

Garbuzova-Davis S, Hernandez-Ontiveros DG, Rodrigues MC, Haller E, Frisina-Deyo A, Mirtyl S, et al. Impaired blood-brain/spinal cord barrier in ALS patients. Brain Res. 2012;1469:114–28. https://doi.org/10.1016/j.brainres.2012.05.056.CrossRefPubMed

44.

Kawamata T, Akiyama H, Yamada T, McGeer PL. Immunologic reactions in amyotrophic lateral sclerosis brain and spinal cord tissue. Am J Pathol. 1992;140(3):691–707.PubMedPubMedCentral

45.

McGeer PL, McGeer EG. Inflammatory processes in amyotrophic lateral sclerosis. Muscle Nerve. 2002;26(4):459–70. https://doi.org/10.1002/mus.10191.CrossRefPubMed

46.

Byrne S, Elamin M, Bede P, Shatunov A, Walsh C, Corr B, et al. Cognitive and clinical characteristics of patients with amyotrophic lateral sclerosis carrying a C9orf72 repeat expansion: a population-based cohort study. Lancet Neurol. 2012;11(3):232–40. https://doi.org/10.1016/S1474-4422(12)70014-5.

47.

Jiao B, Tang B, Liu X, Yan X, Zhou L, Yang Y, et al. Identification of C9orf72 repeat expansions in patients with amyotrophic lateral sclerosis and frontotemporal dementia in mainland China. Neurobiol Aging. 2014;35(4):936 e19–22. https://doi.org/10.1016/j.neurobiolaging.2013.10.001.CrossRef

48.

Carelli L, Solca F, Faini A, Madotto F, Lafronza A, Monti A, et al. The complex interplay between depression/anxiety and executive functioning: insights from the ECAS in a large ALS population. Front Psychol. 2018;9:450. https://doi.org/10.3389/fpsyg.2018.00450.

49.

Kim SM, Lee KM, Hong YH, Park KS, Yang JH, Nam HW, et al. Relation between cognitive dysfunction and reduced vital capacity in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2007;78(12):1387–9. https://doi.org/10.1136/jnnp.2006.111195.

50.

Llewellyn D, Langa K, Friedland R, Lang I. Serum albumin concentration and cognitive impairment. Curr Alzheimer Res. 2010;7(1):91–6. https://doi.org/10.2174/156720510790274392.CrossRefPubMedPubMedCentral

51.

Ng TP, Feng L, Niti M, Yap KB. Albumin, haemoglobin, BMI and cognitive performance in older adults. Age Ageing. 2008;37(4):423–9. https://doi.org/10.1093/ageing/afn102.CrossRefPubMed

52.

Ahmed RM, Highton-Williamson E, Caga J, Thornton N, Ramsey E, Zoing M, et al. Lipid metabolism and survival across the Frontotemporal dementia-amyotrophic lateral sclerosis Spectrum: relationships to eating behavior and cognition. J Alzheimers Dis. 2018;61(2):773–83. https://doi.org/10.3233/jad-170660.

Title: Decreased blood CD4+ T lymphocyte helps predict cognitive impairment in patients with amyotrophic lateral sclerosis
Authors: Yuan Yang
Dengji Pan
Zhenxiang Gong
Jiahui Tang
Zehui Li
Fengfei Ding
Mao Liu
Min Zhang
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Amyotrophic Lateral Sclerosis
Published in: BMC Neurology / Issue 1/2021
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/s12883-021-02185-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Decreased blood CD4+ T lymphocyte helps predict cognitive impairment in patients with amyotrophic lateral sclerosis

Abstract

Background

Objective

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

Blood flow response to orthostatic challenge identifies signatures of the failure of static cerebral autoregulation in patients with cerebrovascular disease

Perfusion CT detects alterations in local cerebral flow of glioma related to IDH, MGMT and TERT status

Combination of structural MRI, functional MRI and brain PET-CT provide more diagnostic and prognostic value in patients of cerebellar ataxia associated with anti-Tr/DNER: a case report

Effectiveness of paranasal air suction on acute migraine using portable air sucker – a randomized, double blind study

Correlation of active contact location with weight gain after subthalamic nucleus deep brain stimulation: a case series

The parameters of gait analysis related to ambulatory and balance functions in hemiplegic stroke patients: a gait analysis study