13 Sep 2023

Could aggregated Aβ seeds be passed from one person to another via blood transfusions? In the September 12 JAMA, researchers led by Jingcheng Zhao at Karolinska University Hospital in Solna, Stockholm, raised this alarming specter. In a retrospective study of more than one million medical records from Sweden and Denmark, they found that people who received blood from a person who went on to suffer multiple intracerebral hemorrhages were themselves at a threefold higher risk of having a brain bleed within the next few years. Because cerebral amyloid angiopathy is a main cause of such bleeds, the findings imply that aggregated amyloid in the donor's blood could potentially seed vascular deposits in the recipient, the authors argued. However, they acknowledged the evidence is indirect, since the medical records contained no information on CAA itself.

Receiving blood from someone who had multiple brain bleeds upped a person’s risk of such a bleed.
The results hint at a transmissible agent in blood that damages vasculature.
β-amyloid is one possibility, but the relatively fast onset makes this less likely.

In an accompanying editorial, Steven Greenberg at Massachusetts General Hospital, Boston, noted additional reasons for skepticism. CAA usually takes decades to develop, not years, and would likely require a larger amount of seeding material than is found in blood. The existence of other transmissible agents that might damage vasculature should be explored, Greenberg wrote. Alzheimer’s researchers agreed. “This impressive and provocative study raises important questions that will stimulate necessary research on the mechanisms underlying vascular aging,” Lary Walker at Emory University, Atlanta, wrote to Alzforum (comment below).

Concern about the transmissibility of Aβ has grown in recent years, with reports of Aβ deposits forming in the brain and blood vessels of relatively young people who received pituitary growth hormone or dural grafts from older donors (Sep 2015 news; Jan 2016 news; Jan 2019 news). Some data even hint that Aβ seeds could be transferred on neurosurgical instruments, with a few people who had brain surgery as children developing CAA at an unusually young age (Feb 2018 news). A 2020 white paper recommended further studies to test the risk of transmission through surgery or donated blood (Sep 2020 news).

The current study is one fruit of that effort. Zhao and colleagues examined medical records from 759,858 people in Sweden who received a blood transfusion. After excluding patients who had an intracerebral hemorrhage (ICH) or other brain injury before transfusion, and those who received blood from someone who had already had an ICH, 558,032 participants remained. Of these, 503 received blood from someone who went on to have multiple ICHs within the next 20 years. During an average post-transfusion follow-up period of eight years, 18 of those 503 had a brain bleed. This represented a 3.2-fold higher incidence than seen in those who received blood from someone who later had one or no ICHs.

The findings replicated in a set of 329,512 medical records from Denmark. Among 210,663 participants who met the criteria, 249 received blood from someone who later had multiple ICHs, and six of those had a brain bleed themselves, a 2.8-fold higher risk. Overall, receiving blood from someone who later had multiple ICHs nudged up the cumulative risk of ICH by about 2 percent over 30 years, the researchers calculated.

The authors believe the findings point toward Aβ as the transmissible agent. They noted that recurrent ICH is highly associated with CAA. So is dementia, and notably, people who received blood from someone who had only a single ICH, but later developed dementia, also had a threefold higher risk of a brain bleed.

Alzheimer’s experts had doubts. David Werring at University College London noted that CAA accounts for only about a quarter of recurrent ICH cases. “This makes it difficult to know the type of underlying small-vessel disease the blood donor cohort had,” he wrote to Alzforum (comment below). Many thought the short time course made CAA less likely. “The relatively rapid appearance of ICH in recipients is inconsistent with seeded cerebral β-amyloidosis, which generally takes many years or decades to reveal itself in humans,” Walker wrote.

Overall, researchers emphasized the need for further study. “The results suggest there may be something transmissible in the blood … Aβ could well be the agent, but this has not been proven yet,” wrote Henrik Zetterberg at Gothenburg University, Sweden (comment below). For his part, Greenberg concluded, “The current study is not yet a reason for alarm, certainly not a reason to avoid otherwise indicated blood transfusion, but it is a strong call for more scientific digging.”—Madolyn Bowman Rogers

Comments

- Lary Walker
  Emory University
- Posted: 13 Sep 2023
In this intriguing retrospective analysis of two large, independent databases, Zhao and colleagues report that the risk of spontaneous intracerebral hemorrhage (ICH) was significantly increased in recipients of red-blood-cell transfusions from donors who manifested multiple intracerebral hemorrhages in the years following donation. Because multiple spontaneous hemorrhages are often associated with cerebral amyloid angiopathy (CAA), the authors make the reasonable assumption that many of these donors are likely to have had CAA, and that this may have incited CAA in transfusion recipients. They hypothesize that a specific agent, possibly Aβ seeds in the transfusate, transmitted CAA via the prion-like process of seeded Aβ aggregation. The researchers also found that the risk of ICH was increased in recipients of blood from donors who later developed both a single spontaneous ICH and dementia. Since most dementia is due to Alzheimer's disease (and nearly half of all Alzheimer patients have moderate to severe CAA) this finding further supports Aβ seeding as a potential causative mechanism.

However, neither Alzheimer's disease nor CAA per se could be meaningfully assessed in the donors or recipients, so the factor(s) driving the heightened risk of ICH remain unknown. Proteopathic seeding certainly is a contender; the prion-like properties of Aβ are well-established, and CAA has been shown to be inducible in animal models by blood-borne Aβ seeds. The relatively rapid appearance of ICH in recipients, however, is inconsistent with seeded cerebral β-amyloidosis, which generally takes many years or decades to reveal itself in humans. Clearly, more definitive research is needed to rule seeded CAA (and other possible mechanisms) in or out.

In this regard, more detailed information on both the donors and recipients would be helpful, but humans are complex and heterogeneous research subjects for which potentially relevant data may never be accessible. Here, controlled, systematic research in animal models can be informative. For instance, what role might the age of donors alone (or the senescence profile of their vasculature) influence the risk of intracerebral hemorrhage in recipients? Research on mice has found that substances in blood can rejuvenate the aging brain (Park et al., 2023; Schroer et al., 2023; Villeda et al., 2014), including the cerebral vasculature (Katsimpardi et al., 2014). Vice versa, a single exchange of blood from aged mice induces signs of premature senescence in young mice (Jeon et al., 2022). Thus, perhaps rather than Aβ seeds, the blood of subjects with multiple ICHs includes other agents that compromise the vasculature of recipients, e.g., by accelerating the aging of vascular cells.

In any case, the results of this impressive and provocative study raise important questions that will stimulate necessary research on the mechanisms underlying vascular aging, including the development of cerebral amyloid angiopathy. They also underscore the importance of understanding as fully as possible factors in blood that might undermine the considerable benefits of transfusion.

References:

Jeon OH, Mehdipour M, Gil TH, Kang M, Aguirre NW, Robinson ZR, Kato C, Etienne J, Lee HG, Alimirah F, Walavalkar V, Desprez PY, Conboy MJ, Campisi J, Conboy IM. Systemic induction of senescence in young mice after single heterochronic blood exchange. Nat Metab. 2022 Aug;4(8):995-1006. Epub 2022 Jul 28 PubMed.

Katsimpardi L, Litterman NK, Schein PA, Miller CM, Loffredo FS, Wojtkiewicz GR, Chen JW, Lee RT, Wagers AJ, Rubin LL. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science. 2014 May 9;344(6184):630-4. Epub 2014 May 5 PubMed.

Park C, Hahn O, Gupta S, Moreno AJ, Marino F, Kedir B, Wang D, Villeda SA, Wyss-Coray T, Dubal DB. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice. Nat Aging. 2023 Aug 16; PubMed.

Schroer AB, Ventura PB, Sucharov J, Misra R, Chui MK, Bieri G, Horowitz AM, Smith LK, Encabo K, Tenggara I, Couthouis J, Gross JD, Chan JM, Luke A, Villeda SA. Platelet factors attenuate inflammation and rescue cognition in ageing. Nature. 2023 Aug;620(7976):1071-1079. Epub 2023 Aug 16 PubMed.

Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, Wabl R, Udeochu J, Wheatley EG, Zou B, Simmons DA, Xie XS, Longo FM, Wyss-Coray T. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014 Jun;20(6):659-63. Epub 2014 May 4 PubMed.

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- David Werring
  UCL Queen Square Institute of Neurology
- Posted: 13 Sep 2023
These findings are intriguing, although there are some methodological limitations which mean that interpretation is challenging. First, the authors did not directly assess cerebral amyloid angiopathy (CAA) as an exposure, but instead used recurrent ICH as a proxy for CAA in the donor cohort. CAA only accounts for a proportion of ICH (likely around one in four overall, but a higher proportion of lobar ICH), and recurrent ICH is not limited to people with CAA. This makes it difficult to know the type(s) of underlying small vessel disease the blood donor cohort had. The same limitation (lack of knowledge of the underlying cause of ICH) applies to recipients of transfusions who subsequently had ICH.

Second, the follow-up period to detect the risk of ICH in blood recipients was much lower than the typical latency described for iatrogenic CAA associated with previous potential Aβ exposure, typically several decades. Whether and how transmission of Aβ might occur within a shorter time from exposure remains unclear, with no obvious alternative plausible transmissible agent to explain the findings.

Third, the number of outcome events was small, limiting statistical power and precision. Fourth, blood transfusion recipients may not be representative of the general spontaneous ICH population, as they will likely have had blood transfusion for an underlying condition or procedure (e.g., diseases associated with anemia, trauma, or surgery). Nevertheless, these hypothesis-generating data should stimulate further research into possible transmissible factors associated with cerebral CAA.

View all comments by David Werring

- Henrik Zetterberg
  University of Gothenburg
- Posted: 13 Sep 2023
This is such an interesting article! It is known that neurodegeneration-related proteins, including Aβ, tau, α-synuclein, and TDP-43, have some prion-like characteristics in vitro and in some in vivo models, although they appear less infective and less aggressive. Their transmissible capacity in humans has been debated a lot, with little solid evidence except for prion disease.

I find this paper highly intriguing, and the results suggest that there may be something transmissible in the blood increasing the risk of cerebrovascular disease if a person receives blood from a donor with angiopathy. As cerebral amyloid angiopathy appears to be a common cause of multiple ICH, Aβ could well be the agent, but this has not been proven yet. If it is, its "infectivity" is probably weak, if it is mainly seen in a disease where there is a direct contact between the carrier (blood) and the tissue that gets affected (the cerebrovasculature).

Nevertheless, we should now carefully look into the potential transmissibility of other neurodegenerative proteinopathies as well. This paper discusses the topic in detail: Lauwers et al., 2020.

References:

Lauwers E, Lalli G, Brandner S, Collinge J, Compernolle V, Duyckaerts C, Edgren G, Haïk S, Hardy J, Helmy A, Ivinson AJ, Jaunmuktane Z, Jucker M, Knight R, Lemmens R, Lin IC, Love S, Mead S, Perry VH, Pickett J, Poppy G, Radford SE, Rousseau F, Routledge C, Schiavo G, Schymkowitz J, Selkoe DJ, Smith C, Thal DR, Theys T, Tiberghien P, van den Burg P, Vandekerckhove P, Walton C, Zaaijer HL, Zetterberg H, De Strooper B. Potential human transmission of amyloid β pathology: surveillance and risks. Lancet Neurol. 2020 Oct;19(10):872-878. Epub 2020 Sep 16 PubMed.

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- Colin Masters
  University of Melbourne
- Posted: 14 Sep 2023
This study of more than a million transfusion recipients sends us a warning signal of what might be in store. Several years ago we (Alnakhli et al., 2020) published a similar finding on 184 persons with death certificates from the 2,940-person cohort of Australian cadaveric pituitary hormone recipients. Clearly, further studies on blood transfusion recipients are warranted.

A first step would be a look back on the prevalence of preclinical AD in the routine blood donor/recipient populations in relation to subsequent ICH, something easily achieved with the development of high-performance plasma Aβ/p-tau assays.

References:

Alnakhli SH, Wand H, Law M, Sarros S, Stehmann C, Senesi M, Klug GM, Simpson M, Lewis V, Masters CL, Collins SJ. Intra-cerebral haemorrhage but not neurodegenerative disease appears over-represented in deaths of Australian cadaveric pituitary hormone recipients. J Clin Neurosci. 2020 Nov;81:78-82. Epub 2020 Sep 29 PubMed. Correction.

View all comments by Colin Masters