SpringerLink
Log in

Relationship between [123I]FP-CIT SPECT data and peripheral CD4 + T cell profile in newly-diagnosed drug-naïve Parkinson’s disease patients

  • Short Commentary
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

Dysregulation of the CD4 + T cell compartment occurs in Parkinson’s Disease (PD). Nonetheless, the exact relationship with dopamine transporter (DAT) SPECT denervation patterns is currently unknown.

Methods

Expression of transcription factors and levels of circulating CD4 + T cell subsets were assessed in peripheral blood mononuclear cells (PBMC) from 23 newly diagnosed drug-naïve PD patients. Semi-quantitative [123I]-FP-CIT SPECT data, i.e. uptake in the most and least affected putamen (maP, laP) and caudate (maC, laC), total striatal binding ratio (tSBR), and total putamen-to-caudate ratio (tP/C) were obtained.

Results

FOXP3 mRNA levels correlated with the uptake in maC (r = − 0.542, P = 0.011), laP (r = − 0.467, P = 0.033), and tSBR (r = − 0.483, P = 0.027). Concerning flow cytometry analysis of circulating CD4 + T cell subsets, a significant relationship between tP/C, caudate uptake, and the levels of both T helper (Th)1 and 2, was detected. Furthermore, we found significant correlations between the uptake in maP and the total count of naïve and activated T regulatory cells (Treg) (r = − 0.717, P = 0.001; r = − 0.691, P = 0.002), which were confirmed after the Benjamini–Hochberg correction for multiple comparisons using a false discovery rate at level q = 0.10. Levels of circulating naïve Treg were higher (P = 0.014) in patients with more extensive dopaminergic denervation, suggesting a compensatory phenomenon.

Conclusions

Peripheral CD4 + T cell immunity is involved in early-stage PD and novel correlations with striatal DAT loss were observed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Availability of data and material

Anonymized data presented in this article will be shared by request from any qualified investigator.

References

  1. Gerhard A, Pavese N, Hotton G et al (2006) In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis 21:404–412. https://doi.org/10.1016/j.nbd.2005.08.002

    Article  CAS  PubMed  Google Scholar 

  2. Stokholm MG, Iranzo A, Østergaard K et al (2017) Assessment of neuroinflammation in patients with idiopathic rapid-eye-movement sleep behaviour disorder: a case–control study. Lancet Neurol 16:789–796. https://doi.org/10.1016/S1474-4422(17)30173-4

    Article  PubMed  Google Scholar 

  3. GerselStokholm M, Garrido A, Tolosa E et al (2020) Imaging dopamine function and microglia in asymptomatic LRRK2 mutation carriers. J Neurol 267:2296–2300. https://doi.org/10.1007/s00415-020-09830-3

    Article  CAS  Google Scholar 

  4. McGeer PL, Itagaki S, Akiyama H, McGeer EG (1988) Rate of cell death in parkinsonism indicates active neuropathological process. Ann Neurol 24:574–576. https://doi.org/10.1002/ana.410240415

    Article  CAS  PubMed  Google Scholar 

  5. Brochard V, Combadière B, Prigent A et al (2009) Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest 119:182–192. https://doi.org/10.1172/JCI36470

    Article  CAS  PubMed  Google Scholar 

  6. Kustrimovic N, Comi C, Magistrelli L et al (2018) Parkinson’s disease patients have a complex phenotypic and functional Th1 bias: cross-sectional studies of CD4+ Th1/Th2/T17 and Treg in drug-naïve and drug-treated patients. J Neuroinflammation 15:205. https://doi.org/10.1186/s12974-018-1248-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. De Francesco E, Terzaghi M, Storelli E et al (2020) CD4+ T-cell transcription factors in idiopathic REM sleep behavior disorder and Parkinson’s disease. Mov Disord. https://doi.org/10.1002/mds.28137

    Article  PubMed  Google Scholar 

  8. Contaldi E, Magistrelli L, Milner AV et al (2020) Expression of transcription factors in CD4 + T cells as potential biomarkers of motor complications in Parkinson’s disease. J Parkinsons Dis. https://doi.org/10.3233/JPD-202417

    Article  Google Scholar 

  9. Sanjari Moghaddam H, Ghazi Sherbaf F, Mojtahed Zadeh M et al (2018) Association between peripheral inflammation and DATSCAN data of the striatal nuclei in different motor subtypes of Parkinson disease. Front Neurol 9:234. https://doi.org/10.3389/fneur.2018.00234

    Article  PubMed  PubMed Central  Google Scholar 

  10. Liu S-Y, Qiao H-W, Song T-B et al (2022) Brain microglia activation and peripheral adaptive immunity in Parkinson’s disease: a multimodal PET study. J Neuroinflam 19:209. https://doi.org/10.1186/s12974-022-02574-z

    Article  CAS  Google Scholar 

  11. Kustrimovic N, Rasini E, Legnaro M et al (2016) Dopaminergic receptors on CD4+ T naive and memory lymphocytes correlate with motor impairment in patients with Parkinson’s disease. Sci Rep 6:33738. https://doi.org/10.1038/srep33738

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184. https://doi.org/10.1136/jnnp.55.3.181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease (2003) The unified Parkinson’s disease rating scale (UPDRS): status and recommendations. Mov Disord 18:738–750. https://doi.org/10.1002/mds.10473

    Article  Google Scholar 

  14. Goetz CG, Poewe W, Rascol O et al (2004) Movement disorder society task force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19:1020–1028. https://doi.org/10.1002/mds.20213

    Article  PubMed  Google Scholar 

  15. Skanjeti A, Angusti T, Iudicello M et al (2014) Assessing the accuracy and reproducibility of computer-assisted analysis of (123) I-FP-CIT SPECT using BasGan (V2). J Neuroimaging 24:257–265. https://doi.org/10.1111/jon.12008

    Article  CAS  PubMed  Google Scholar 

  16. Nobili F, Naseri M, De Carli F et al (2013) Automatic semi-quantification of [123I]FP-CIT SPECT scans in healthy volunteers using BasGan version 2: results from the ENC-DAT database. Eur J Nucl Med Mol Imaging 40:565–573. https://doi.org/10.1007/s00259-012-2304-8

    Article  PubMed  Google Scholar 

  17. Christensen JAE, Jennum P, Koch H et al (2016) Sleep stability and transitions in patients with idiopathic REM sleep behavior disorder and patients with Parkinson’s disease. Clin Neurophysiol 127:537–543. https://doi.org/10.1016/j.clinph.2015.03.006

    Article  PubMed  Google Scholar 

  18. Holcar M, Goropevšek A, Ihan A, Avčin T (2015) Age-related differences in percentages of regulatory and effector T lymphocytes and their subsets in healthy individuals and characteristic STAT1/STAT5 signalling response in helper T lymphocytes. J Immunol Res 2015:1–13. https://doi.org/10.1155/2015/352934

    Article  CAS  Google Scholar 

  19. Piasecka B, Duffy D, Urrutia A et al (2018) Distinctive roles of age, sex, and genetics in sha** transcriptional variation of human immune responses to microbial challenges. Proc Natl Acad Sci USA 115:E488–E497. https://doi.org/10.1073/pnas.1714765115

    Article  CAS  PubMed  Google Scholar 

  20. Chen Y, Yu M, Liu X et al (2015) Clinical characteristics and peripheral T cell subsets in Parkinson’s disease patients with constipation. Int J Clin Exp Pathol 8:2495–2504

    PubMed  PubMed Central  Google Scholar 

  21. Baba Y, Kuroiwa A, Uitti RJ et al (2005) Alterations of T-lymphocyte populations in Parkinson disease. Parkinsonism Relat Disord 11:493–498. https://doi.org/10.1016/j.parkreldis.2005.07.005

    Article  PubMed  Google Scholar 

  22. Saunders JAH, Estes KA, Kosloski LM et al (2012) CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson’s disease. J Neuroimmune Pharmacol 7:927–938. https://doi.org/10.1007/s11481-012-9402-z

    Article  PubMed  PubMed Central  Google Scholar 

  23. Grossman WJ, Verbsky JW, Barchet W et al (2004) Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 21:589–601. https://doi.org/10.1016/j.immuni.2004.09.002

    Article  CAS  PubMed  Google Scholar 

  24. Silva SL, Albuquerque AS, Serra-Caetano A et al (2016) Human naïve regulatory T-cells feature high steady-state turnover and are maintained by IL-7. Oncotarget 7:12163–12175. https://doi.org/10.18632/oncotarget.7512

    Article  PubMed  PubMed Central  Google Scholar 

  25. Espinosa-Cárdenas R, Arce-Sillas A, Álvarez-Luquin D et al (2020) Immunomodulatory effect and clinical outcome in Parkinson’s disease patients on levodopa-pramipexole combo therapy: a two-year prospective study. J Neuroimmunol 347:577328. https://doi.org/10.1016/j.jneuroim.2020.577328

    Article  CAS  PubMed  Google Scholar 

  26. Magistrelli L, Storelli E, Rasini E et al (2020) Relationship between circulating CD4+ T lymphocytes and cognitive impairment in patients with Parkinson’s disease. Brain Behav Immun 89:668–674. https://doi.org/10.1016/j.bbi.2020.07.005

    Article  CAS  PubMed  Google Scholar 

  27. Williams-Gray CH, Wijeyekoon R, Yarnall AJ et al (2016) Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord 31:995–1003. https://doi.org/10.1002/mds.26563

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Feng Y, Lu Y (2021) Immunomodulatory effects of dopamine in inflammatory diseases. Front Immunol 12:663102. https://doi.org/10.3389/fimmu.2021.663102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Matt SM, Gaskill PJ (2020) Where is dopamine and how do immune cells see it?: Dopamine-mediated immune cell function in health and disease. J Neuroimmune Pharmacol 15:114–164. https://doi.org/10.1007/s11481-019-09851-4

    Article  CAS  PubMed  Google Scholar 

  30. Levite M (2016) Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases. Acta Physiol 216:42–89. https://doi.org/10.1111/apha.12476

    Article  CAS  Google Scholar 

  31. Ilani T, Strous RD, Fuchs S (2004) Dopaminergic regulation of immune cells via D3 dopamine receptor: a pathway mediated by activated T cells. FASEB J 18:1600–1602. https://doi.org/10.1096/fj.04-1652fje

    Article  CAS  PubMed  Google Scholar 

  32. Engler H, Doenlen R, Riether C et al (2009) Time-dependent alterations of peripheral immune parameters after nigrostriatal dopamine depletion in a rat model of Parkinson’s disease. Brain Behav Immun 23:518–526. https://doi.org/10.1016/j.bbi.2009.01.018

    Article  CAS  PubMed  Google Scholar 

  33. Nurmi E, Ruottinen HM, Bergman J et al (2001) Rate of progression in Parkinson’s disease: a 6-[18F]fluoro-L-dopa PET study. Mov Disord 16:608–615. https://doi.org/10.1002/mds.1139

    Article  CAS  PubMed  Google Scholar 

  34. Farmen K, Nissen SK, Stokholm MG et al (2021) Monocyte markers correlate with immune and neuronal brain changes in REM sleep behavior disorder. Proc Natl Acad Sci U S A 118:e2020. https://doi.org/10.1073/pnas.2020858118

    Article  CAS  Google Scholar 

  35. Zhang H, Wang T, Li Y et al (2020) Plasma immune markers in an idiopathic REM sleep behavior disorder cohort. Parkinsonism Relat Disord 78:145–150. https://doi.org/10.1016/j.parkreldis.2020.07.017

    Article  PubMed  Google Scholar 

  36. LindestamArlehamn CS, Dhanwani R, Pham J et al (2020) α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease. Nat Commun 11:1875. https://doi.org/10.1038/s41467-020-15626-w

    Article  CAS  Google Scholar 

  37. Kosloski LM, Kosmacek EA, Olson KE et al (2013) GM-CSF induces neuroprotective and anti-inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine intoxicated mice. J Neuroimmunol 265:1–10. https://doi.org/10.1016/j.jneuroim.2013.10.009

    Article  CAS  PubMed  Google Scholar 

  38. Gendelman HE, Zhang Y, Santamaria P et al (2017) Evaluation of the safety and immunomodulatory effects of sargramostim in a randomized, double-blind phase 1 clinical Parkinson’s disease trial. NPJ Parkinsons Dis 3:10. https://doi.org/10.1038/s41531-017-0013-5

    Article  PubMed  PubMed Central  Google Scholar 

  39. Chen X, Feng W, Ou R et al (2021) Evidence for peripheral immune activation in Parkinson’s disease. Front Aging Neurosci 13:617370. https://doi.org/10.3389/fnagi.2021.617370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Álvarez-Luquín DD, Arce-Sillas A, Leyva-Hernández J et al (2019) Regulatory impairment in untreated Parkinson’s disease is not restricted to Tregs: other regulatory populations are also involved. J Neuroinflammation 16:212. https://doi.org/10.1186/s12974-019-1606-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors wish to express their gratitude to Massimiliano Legnaro and Natasa Kustrimovic for the execution of experiments and to Professors Marco Cosentino and Franca Marino for the constructive feedback. EC participated in the study as part of her work for the PhD Course in Medical Sciences and Biotechnology, University of Piemonte Orientale (XXXV Cycle), and is supported by a PhD fellowship grant from Fondazione Cariplo—Medical Scientist Training Program 2017 (Progetto 2017-1086—Recruiting and training physician-scientists to empower translational research: a multilevel transdisciplinary approach focused on methodology, ethics, and integrity in biomedical research). The research leading to these results has also received support from Fondazione UBI per Varese Onlus (grant 18/7/2017) and the AGING Project, Department of Excellence, Università degli Studi del Piemonte Orientale.

Funding

No specific funding was received for conducting this study.

Author information

Authors and Affiliations

  1. Department of Translational Medicine, Neurology Unit, Movement Disorders Centre, University of Piemonte Orientale, Corso Mazzini 18, 28100, Novara, Italy

    Elena Contaldi, Luca Magistrelli & Silvia Gallo

  2. PhD Program in Medical Sciences and Biotechnology, University of Piemonte Orientale, 28100, Novara, Italy

    Elena Contaldi

  3. Center of Research in Medical Pharmacology, University of Insubria, 21100, Varese, Italy

    Alessia Furgiuele & Cristoforo Comi

  4. Department of Translational Medicine, Neurology Unit, S. Andrea Hospital, University of Piemonte Orientale, 13100, Vercelli, Italy

    Cristoforo Comi

Authors
  1. Elena Contaldi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luca Magistrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alessia Furgiuele
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Silvia Gallo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cristoforo Comi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EC: study concept, data analysis and interpretation, writing of the first draft of the manuscript; EC, LM, AF, SG: data collection and analysis; EC, LM, CC: study design, data interpretation, and manuscript editing. All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved and declare confidence in the integrity of the contributions of their co-authors.

Corresponding author

Correspondence to Elena Contaldi.

Ethics declarations

Conflicts of interest

The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The study was performed following the ethical standards as laid down in the 1964 Declaration of Helsinki and following the international research ethical principles involving human subjects. The institutional Ethics Committee of Novara University Hospital “Maggiore della Carità” approved the study protocol (CE 65/16) and all subjects gave their informed consent.

Consent to participate

Written informed consent was obtained from all participants.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 204 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Contaldi, E., Magistrelli, L., Furgiuele, A. et al. Relationship between [123I]FP-CIT SPECT data and peripheral CD4 + T cell profile in newly-diagnosed drug-naïve Parkinson’s disease patients. J Neurol 270, 2776–2783 (2023). https://doi.org/10.1007/s00415-023-11635-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-023-11635-z

Keywords

Search

Navigation