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Healthy blood, healthy brain: a window into understanding and treating neurodegenerative diseases

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Abstract

Our limited understanding of complex neurodegenerative disorders has held us back on the development of efficient therapies. While several approaches are currently being considered, it is still unclear what will be most successful. Among the latest and more novel ideas, the concept of blood or plasma transfusion from young healthy donors to diseased patients is gaining momentum and attracting attention beyond the scientific arena. While young or healthy blood is enriched with protective and restorative components, blood from older subjects may accumulate neurotoxic agents or be impoverished of beneficial factors. In this commentary, we present an overview of the compelling evidence collected in various animal models of brain diseases (e.g., Alzheimer, Parkinson, Huntington) to the actual clinical trials that have been conducted to test the validity of blood-related treatments in neurodegenerative diseases and argue in favor of such approach.

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Notes

  1. The United Nations defines young subjects, for statistical purposes, as individuals between 15 and 24 years of age. The majority of studies cited in this commentary refer to “young individuals” as being between 18 and 30 years of age, and older individuals as being above 60 years of age. Most of the reports on mouse models consider “young adults” between the ages of 2 and 6 months, while above 18 months or older are considered “aged animals”.

References

  1. Baskett TF (2002) James Blundell: the first transfusion of human blood. Resuscitation 52:229–233. https://doi.org/10.1016/S0300-9572(02)00013-8

    Article  PubMed  Google Scholar 

  2. Tan SY, Merritt C (2017) Charles Richard Drew (1904-1950): father of blood banking. Singap Med J 58:593–594. https://doi.org/10.11622/SMEDJ.2017099

    Article  Google Scholar 

  3. Schmidt PJ (2012) The plasma wars: a history. Transfusion (Paris). https://doi.org/10.1111/J.1537-2995.2012.03689.X

    Article  Google Scholar 

  4. Bert Paul (1864) Expériences et considérations sur la greffe animale, pp 1–23

  5. Kamrin BB (1954) The effects of a high carbohydrate diet on the teeth of parabiosed albino rats. J Dent Res 33:175–180. https://doi.org/10.1177/00220345540330020301/ASSET/00220345540330020301.FP.PNG_V03

    Article  CAS  PubMed  Google Scholar 

  6. Rebo J, Mehdipour M, Gathwala R et al (2016) A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old blood. Nat Commun 7:1–11. https://doi.org/10.1038/ncomms13363

    Article  CAS  Google Scholar 

  7. Huang Q, Ning Y, Liu D et al (2018) A young blood environment decreases aging of senile mice kidneys. J Gerontol Ser A Biol Sci Med Sci 73:421–428. https://doi.org/10.1093/gerona/glx183

    Article  CAS  Google Scholar 

  8. Erdogan K, Ceylani T, Teker HT et al (2023) Young plasma transfer recovers decreased sperm counts and restores epigenetics in aged testis. Exp Gerontol 172:112042. https://doi.org/10.1016/j.exger.2022.112042

    Article  CAS  PubMed  Google Scholar 

  9. Katsimpardi L, Litterman NK, Schein PA et al (1979) (2014) Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science 344:630–634. https://doi.org/10.1126/science.1251141

    Article  CAS  Google Scholar 

  10. Villeda SA, Plambeck KE, Middeldorp J et al (2014) Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 20:659–663. https://doi.org/10.1038/nm.3569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lehallier B, Gate D, Schaum N et al (2019) Undulating changes in human plasma proteome profiles across the lifespan. Nat Med 25:1843–1850. https://doi.org/10.1038/s41591-019-0673-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gan KJ, Südhof TC (2019) Specific factors in blood from young but not old mice directly promote synapse formation and NMDA-receptor recruitment. Proc Natl Acad Sci U S A 116:12524–12533. https://doi.org/10.1073/pnas.1902672116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bieri G, Schroer AB, Villeda SA (2023) Blood-to-brain communication in aging and rejuvenation. Nat Neurosci Rev. https://doi.org/10.1038/s41593-022-01238-8

    Article  Google Scholar 

  14. Villeda SA, Luo J, Mosher KI et al (2011) The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 477:90–96. https://doi.org/10.1038/nature10357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Jeon OH, Mehdipour M, Gil TH et al (2022) Systemic induction of senescence in young mice after single heterochronic blood exchange. Nat Metab 4:995–1006. https://doi.org/10.1038/s42255-022-00609-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Caraceni P, Tufoni M, Bonavita ME (2013) Clinical use of albumin. Blood Transfus. DOI 10(2450/2013):005S

    Google Scholar 

  17. Yang AC, Stevens MY, Chen MB et al (2020) Physiological blood–brain transport is impaired with age by a shift in transcytosis. Nature 583:425–430. https://doi.org/10.1038/s41586-020-2453-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Li Y, Zhang Q, Yan W et al (2022) Young plasma reverses anesthesia and surgery-induced cognitive impairment in aged rats by modulating hippocampal synaptic plasticity. Front Aging Neurosci. https://doi.org/10.3389/fnagi.2022.996223

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhao Y, Qian R, Zhang J et al (2020) Young blood plasma reduces Alzheimer’s disease-like brain pathologies and ameliorates cognitive impairment in 3×Tg-AD mice. Alzheimers Res Ther 12:1–13. https://doi.org/10.1186/s13195-020-00639-w

    Article  CAS  Google Scholar 

  20. Kim TW, Park SS, Park JY, Park HS (2020) Infusion of plasma from exercised mice ameliorates cognitive dysfunction by increasing hippocampal neuroplasticity and mitochondrial functions in 3xtg-ad mice. Int J Mol Sci. https://doi.org/10.3390/ijms21093291

    Article  PubMed  PubMed Central  Google Scholar 

  21. Middeldorp J, Lehallier B, Villeda SA et al (2016) Preclinical assessment of young blood plasma for Alzheimer disease. JAMA Neurol 73:1325–1333. https://doi.org/10.1001/jamaneurol.2016.3185

    Article  PubMed  PubMed Central  Google Scholar 

  22. Buckley MT, Sun ED, George BM et al (2023) Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain. Nat Aging 3:121–137. https://doi.org/10.1038/s43587-022-00335-4

    Article  PubMed  Google Scholar 

  23. Rieux M, Alpaugh M, Sciacca G et al (2021) Shedding a new light on Huntington’s disease: how blood can both propagate and ameliorate disease pathology. Mol Psychiatry 26:5441–5463. https://doi.org/10.1038/s41380-020-0787-4

    Article  CAS  PubMed  Google Scholar 

  24. Rieux M, Alpaugh M, Salem S et al (2023) Understanding the role of the hematopoietic niche in Huntington’s disease’s phenotypic expression: in vivo evidence using a parabiosis model. Neurobiol Dis. https://doi.org/10.1016/j.nbd.2023.106091

    Article  PubMed  Google Scholar 

  25. Fung TY, Iyaswamy A, Sreenivasmurthy SG et al (2022) Klotho an autophagy stimulator as a potential therapeutic target for Alzheimer’s disease: a review. Biomedicines. https://doi.org/10.3390/BIOMEDICINES10030705

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sancesario GM, Di Lazzaro G, Grillo P et al (2021) Biofluids profile of α-Klotho in patients with Parkinson’s disease. Parkinsonism Relat Disord 90:62–64. https://doi.org/10.1016/j.parkreldis.2021.08.004

    Article  CAS  PubMed  Google Scholar 

  27. Zhao Y, Zeng CY, Li XH et al (2020) Klotho overexpression improves amyloid-β clearance and cognition in the APP/PS1 mouse model of Alzheimer’s disease. Aging Cell 19:e13239. https://doi.org/10.1111/ACEL.13239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Leon J, Moreno AJ, Garay BI et al (2017) Peripheral elevation of a klotho fragment enhances brain function and resilience in young, aging, and α-synuclein transgenic mice. Cell Rep 20:1360–1371. https://doi.org/10.1016/j.celrep.2017.07.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Islam MR, Valaris S, Young MF et al (2021) Exercise hormone irisin is a critical regulator of cognitive function. Nat Metab 3:1058–1070. https://doi.org/10.1038/s42255-021-00438-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Lourenco MV, Frozza RL, de Freitas GB et al (2019) Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models. Nat Med 25:165–175. https://doi.org/10.1038/s41591-018-0275-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ozek C, Krolewski RC, Buchanan SM, Rubin LL (2018) Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Sci Rep. https://doi.org/10.1038/S41598-018-35716-6

    Article  PubMed  PubMed Central  Google Scholar 

  32. Reger MA, Henderson ST, Hale C et al (2004) Effects of β-hydroxybutyrate on cognition in memory-impaired adults. Neurobiol Aging 25:311–314. https://doi.org/10.1016/S0197-4580(03)00087-3

    Article  CAS  PubMed  Google Scholar 

  33. Xhuti D, Nilsson MI, Manta K et al (2023) Circulating exosome-like vesicle and skeletal muscle microRNAs are altered with age and resistance training. J Physiol. https://doi.org/10.1113/JP282663

    Article  PubMed  Google Scholar 

  34. Yang P, Dong X, Zhang Y (2020) MicroRNA profiles in plasma samples from young metabolically healthy obese patients and miRNA-21 are associated with diastolic dysfunction via TGF-β1/Smad pathway. J Clin Lab Anal. https://doi.org/10.1002/JCLA.23246

    Article  PubMed  PubMed Central  Google Scholar 

  35. Koay YC, Stanton K, Kienzle V et al (2021) Effect of chronic exercise in healthy young male adults: A metabolomic analysis. Cardiovasc Res 117:613–622. https://doi.org/10.1093/cvr/cvaa051

    Article  CAS  PubMed  Google Scholar 

  36. Taylor MK, Sullivan DK, Mahnken JD et al (2018) Feasibility and efficacy data from a ketogenic diet intervention in Alzheimer’s disease. Alzheimer’s Dement Transl Res Clin Interv 4:28–36. https://doi.org/10.1016/j.trci.2017.11.002

    Article  Google Scholar 

  37. Gómora-García JC, Montiel T, Hüttenrauch M et al (2023) Effect of the ketone body, D-β-hydroxybutyrate, on sirtuin2-mediated regulation of mitochondrial quality control and the autophagy-lysosomal pathway. Cells. https://doi.org/10.3390/CELLS12030486

    Article  PubMed  PubMed Central  Google Scholar 

  38. Vandoorne T, De Bock K, Van Den Bosch L (2018) Energy metabolism in ALS: an underappreciated opportunity? Acta Neuropathol 135:489. https://doi.org/10.1007/S00401-018-1835-X

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Pagano G, Niccolini F, Politis M (2016) Current status of PET imaging in Huntington’s disease. Eur J Nucl Med Mol Imaging 43:1171–1182. https://doi.org/10.1007/S00259-016-3324-6/TABLES/2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cunnane S, Nugent S, Roy M et al (2011) Brain fuel metabolism, aging, and Alzheimer’s disease. Nutrition 27:3–20. https://doi.org/10.1016/J.NUT.2010.07.021

    Article  CAS  PubMed  Google Scholar 

  41. Sathyan S, Ayers E, Gao T et al (2020) Plasma proteomic profile of age, health span, and all-cause mortality in older adults. Aging Cell. https://doi.org/10.1111/ACEL.13250

    Article  PubMed  PubMed Central  Google Scholar 

  42. Smith LK, He Y, Park JS et al (2015) β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis. Nat Med 21:932–937. https://doi.org/10.1038/NM.3898

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yankova T, Dubiley T, Shytikov D, Pishel I (2022) Three month heterochronic parabiosis has a deleterious effect on the lifespan of young animals, without a positive effect for old animals. Rejuvenation Res 25:191–199. https://doi.org/10.1089/rej.2022.0029

    Article  PubMed  Google Scholar 

  44. Mehdipour M, Mehdipour T, Skinner CM et al (2021) Plasma dilution improves cognition and attenuates neuroinflammation in old mice. Geroscience 43:1–18. https://doi.org/10.1007/s11357-020-00297-8

    Article  CAS  PubMed  Google Scholar 

  45. Kim D, Kiprov DD, Luellen C et al (2022) Old plasma dilution reduces human biological age: a clinical study. Geroscience 44:2701–2720. https://doi.org/10.1007/s11357-022-00645-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Mehdipour M, Etienne J, Liu C et al (2021) Attenuation of age-elevated blood factors by repositioning plasmapheresis: a novel perspective and approach. Transfus Apheres Sci 60:103162. https://doi.org/10.1016/j.transci.2021.103162

    Article  Google Scholar 

  47. Chevret S, Hughes RAC, Annane D (2017) Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD001798.PUB3

    Article  PubMed  PubMed Central  Google Scholar 

  48. Tiwari A, Setya D, Tanna D et al (2023) Patient outcome in antibody-positive systemic vasculitis treated with therapeutic plasma exchange. Asian J Transfus Sci 17:79–84. https://doi.org/10.4103/AJTS.AJTS_50_21

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Madden J, Spadaro A, Koyfman A, Long B (2024) High risk and low prevalence diseases: Guillain-Barré syndrome. Am J Emerg Med 75:90–97

    Article  PubMed  Google Scholar 

  50. Bu XL, Xiang Y, Jin WS et al (2018) Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Mol Psychiatry 23:1948–1956. https://doi.org/10.1038/mp.2017.204

    Article  CAS  PubMed  Google Scholar 

  51. Boada M, López O, Núñez L et al (2019) Plasma exchange for Alzheimer’s disease Management by Albumin Replacement (AMBAR) trial: Study design and progress. Alzheimer’s Dement Transl Res Clin Interv 5:61–69. https://doi.org/10.1016/j.trci.2019.01.001

    Article  Google Scholar 

  52. Boada M, Anaya F, Ortiz P et al (2017) Efficacy and safety of plasma exchange with 5% albumin to modify cerebrospinal fluid and plasma amyloid-β concentrations and cognition outcomes in Alzheimer’s disease patients: A multicenter, randomized, controlled clinical trial. J Alzheimer’s Dis 56:129–143. https://doi.org/10.3233/JAD-160565

    Article  CAS  Google Scholar 

  53. Boada M, López OL, Olazarán J et al (2022) Neuropsychological, neuropsychiatric, and quality-of-life assessments in Alzheimer’s disease patients treated with plasma exchange with albumin replacement from the randomized AMBAR study. Alzheimer’s Dement 18:1314–1324. https://doi.org/10.1002/alz.12477

    Article  CAS  Google Scholar 

  54. Sha SJ, Deutsch GK, Tian L et al (2019) Safety, tolerability, and feasibility of young plasma infusion in the plasma for Alzheimer symptom amelioration study: a randomized clinical trial. JAMA Neurol 76:35–40. https://doi.org/10.1001/jamaneurol.2018.3288

    Article  PubMed  Google Scholar 

  55. Hannestad J, Koborsi K, Klutzaritz V et al (2020) Safety and tolerability of GRF6019 in mild-to-moderate Alzheimer’s disease dementia. Alzheimer’s Dementia Transl Res Clin Interv 6:1–10. https://doi.org/10.1002/trc2.12115

    Article  Google Scholar 

  56. Hannestad J, Duclos T, Chao W et al (2021) Safety and tolerability of GRF6019 infusions in severe Alzheimer’s disease: a phase II double-blind placebo-controlled trial. J Alzheimer’s Dis 81:1649–1662. https://doi.org/10.3233/JAD-210011

    Article  CAS  Google Scholar 

  57. Parker JE, Martinez A, Deutsch GK et al (2020) Safety of plasma infusions in Parkinson’s disease. Mov Disord 35:1905–1913. https://doi.org/10.1002/mds.28198

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. VandeVrede L, Dale ML, Fields S et al (2020) Open-label phase 1 futility studies of salsalate and young plasma in progressive supranuclear palsy. Mov Disord Clin Pract 7:440–447. https://doi.org/10.1002/mdc3.12940

    Article  PubMed  PubMed Central  Google Scholar 

  59. Altobelli C, Anastasio P, Cerrone A et al (2023) Therapeutic plasmapheresis: a revision of literature. Kidney Blood Press Res 48:66–78. https://doi.org/10.1159/000528556

    Article  CAS  PubMed  Google Scholar 

  60. Weinstein R (2023) Basic principles of therapeutic plasma exchange. Transfus Apher Sci. https://doi.org/10.1016/J.TRANSCI.2023.103675

    Article  PubMed  Google Scholar 

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Acknowledgements

FC is a recipient of a Researcher Chair from the Fonds de Recherche du Québec en Santé (FRQS, 35059) providing salary support and operating funds, and receives funding from the Canadian Institutes of Health Research (CIHR, PJT162164 and PJT168865) to conduct her HD-related research. ADRJ is supported by a Launch Award from the Parkinson’s Foundation and funds from the Fondation CHU de Québec.

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Authors and Affiliations

  1. Centre de Recherche du CHU de Québec, Université Laval, Axe Neurosciences, T2-07, 2705, Boulevard Laurier, Québec, QC, G1V 4G2, Canada

    Thyago R. Cardim-Pires, Aurélie de Rus Jacquet & Francesca Cicchetti

  2. Département de Psychiatrie & Neurosciences, Université Laval, Québec, QC, G1K 0A6, Canada

    Aurélie de Rus Jacquet & Francesca Cicchetti

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  1. Thyago R. Cardim-Pires
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TRCP reviewed the literature, conceptualized figures and wrote the manuscript. ADRJ contributed to the literature review and edited the manuscript. FC contributed to the literature review, conceptualized figures and wrote the manuscript.

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Correspondence to Francesca Cicchetti.

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Cardim-Pires, T.R., de Rus Jacquet, A. & Cicchetti, F. Healthy blood, healthy brain: a window into understanding and treating neurodegenerative diseases. J Neurol (2024). https://doi.org/10.1007/s00415-024-12337-w

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