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

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.

Full text

Vol.:(0123456789)
Journal of Neurology
https://doi.org/10.1007/s00415-024-12337-w
NEUROLOGICAL UPDATE
Healthy blood, healthy brain: awindow intounderstanding
andtreating neurodegenerative diseases
ThyagoR.Cardim‑Pires1· AuréliedeRusJacquet1,2· FrancescaCicchetti1,2
Received: 26 January 2024 / Revised: 17 March 2024 / Accepted: 18 March 2024
© Springer-Verlag GmbH Germany, part of Springer Nature 2024
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.
Keywords Neurodegenerative diseases· Aging· Plasma· Plasma infusion· Plasmapheresis· Rejuvenation
The benets ofblood: ahistorical
perspective
The seventeenth century was marked by a burgeoning of
discoveries in numerous fields including in anatomy and
physiology, which, despite several tribulations, paved the
way to modern medicine. Among them, the English physi-
cian William Harvey provided the first detailed description
of blood circulation and how the heart could pump this fluid
throughout the entire body, including to the brain. A con-
temporary of Harvey, Richard Lower, considered the blood
as a potential treatment for hemorrhage and in 1666, dem-
onstrated the feasibility of blood transfusion in animals. A
few years later, the French physician Jean-Baptiste Denys
performed the first sheep-to-human transfusion (Fig.1).
While the young patient who suffered fever survived the
xenotransfusion, a second subject died and Denys was tri-
aled for homicide, but ultimately acquitted. In the years that
followed, examples of failed attempts outweighed the fore-
seen potential of blood transfusion and led authorities to ban
such practices. It would take more than 150years for this
idea to be revisited and the first human blood transfusion to
be implemented in a patient with postpartum hemorrhage,
thus renewing interest in the use of blood as a therapeutic
means among scientists [1].
The tragedy of World War IIlater prompted increased
investments in science and technologies, in particular in
studies pertaining to blood transfusion. Charles Drew, a
renowned African American surgeon also made a game-
changing discovery by fractionating the blood into red
blood cells and plasma. Drew’s work showed that plasma
is more easily stored than blood, facilitating transportation
[2]. One significant outcome of this new wave of research
led to the development and subsequent use of pooled dried
blood plasma serum, saving the lives of thousands of sol-
diers [3]. Over decades of experimentations, the benefits of
blood became irrefutable, and it propelled the advancement
of approaches using blood from experimental paradigms
to concrete human-based therapies. The concept of blood
banks materialized and heavy campaigning for blood drives
was set in motion (Fig.1).
From an experimental standpoint, the work of the French
physiologist Paul Bert, in the 1800s, was also significant.
Bert developed a model that involved the surgical fusion of
* Francesca Cicchetti
francesca.cicchetti@crchudequebec.ulaval.ca
1 Centre de Recherche du CHU de Québec, Université Laval,
Axe Neurosciences, T2-07, 2705, Boulevard Laurier,
Québec, QCG1V4G2, Canada
2 Département de Psychiatrie & Neurosciences, Université
Laval, Québec, QCG1K0A6, Canada

Journal of Neurology
two living organisms, which he named parabiosis; a term
derived from the English word para (beside) and the Greek
word biosis (model of life) [4]. The ability of parabiosis
to demonstrate the involvement, or lack of involvement, of
circulating factors made it a popular technique to answer a
diverse array of research questions from elements influenc-
ing obesity, to the cause of dental cavities [5]. More recently,
Fig. 1 Chronological timeline of groundbreaking blood-related discoveries

Journal of Neurology
this approachrevealed the benefits of young1 blood in regen-
erating muscle tissue [6], reducing the expression of age-
associated kidney markers, slowing renal tissue damage [7],
and even improving fertility [8]. Exposing an aged animal
to young blood has also proven to promote vascular remod-
eling, neurogenesis, olfactory discrimination, and spatial
memory in older mice [9, 10]. The mechanistic basis for
these striking observations is an active field of investiga-
tion, as the molecular profile of the peripheral circulation
is highly dynamic and reflects general health. For exam-
ple, plasma protein signatures change across the life span
[11]. While aged plasma seemingly contains more “toxic”
elements, young plasma is composed of more protective/
restorative factors [12–15].
While tales of the existence of the fountain of youth have
been recounted for thousands of years, blood, plasma and
their derivatives are now considered in modern medicine
as a way to achieve rejuvenation and have the advantage of
already being approved for use in human in different healthy
or pathological conditions. Several fields related to health,
in particular cosmetics and plastic surgery, are indeed using
plasma for tissue regeneration. If healthy plasma can repair
normal signs of aging, could disease processes, which are
recurrently associated with accelerated aging, also be ame-
liorated…? Would considering such blood-related therapy
to treat neurodegenerative diseases be a stretch of the
imagination?
Manipulation ofblood and/orplasma
totreat brain diseases
Before diving into this topic, it should be understood that
blood and/or plasma can be manipulated using various
methodologies. Plasmapheresis, for example, allows to
remove toxic components from the bloodstream. During
this procedure, the blood is fractionated to discard certain
components and subsequently reinjected into the patient.
Plasma exchange is a type of plasmapheresis which con-
sists of replacing aged or diseased blood with a saline solu-
tion, to which albumin can additionally be incorporated to
help reestablish osmotic pressure and restore volume lost
by blood removal [16]. Finally, healthy plasma can be trans-
fused to a diseased patient by plasma infusion.
To generate a tangible impact on the central nerv-
ous system to treat brain pathologies, favorable elements
of the blood would need to cross the blood–brain barrier
(BBB); an entity that tightly controls the traffic of plasma
components (e.g., proteins) between the periphery and the
brain. However, aging affects BBB permeability and older
mice are characterized by less efficient brain uptake than
younger mice [17]. Crossing of the BBB and internalization
of plasma constituents by various brain cells is a physiologi-
cal process [17] and plasma factors linked with youth have
been shown to prompt several desirable effects within the
central nervous system. Among these, it has now repeat-
edly been demonstrated that young plasma can trigger brain
rejuvenation in aged mice by, among various mechanisms,
reducing microglia and astrocyte reactivity, as well as induc-
ing neuronal remyelination [9, 10] and reversing cognitive
impairments induced by anesthesia and surgery [18].
The infusion of healthy plasma in the triple trans-
genicmouse model of Alzheimer's disease (AD), can
further rescue disease hallmarks such as brain accumula-
tion of Aβ plaque and neuroinflammation [19], and con-
currently improve cognitive impairments [20]. Parabiosis
experiments showed that healthy blood can ameliorate AD
pathology causing similar effects as periodical administra-
tion of healthy plasma [21]. The cognitive deficits classically
observed in AD models can be more significantly attenuated
if the healthy plasma source is from an age-matched con-
trol that is submitted to regular physical exercise (access to
spinning wheels) compared to sedentary controls (no access
to spinning wheels) [20]. While young plasma and young
plasma derived from a donor practicing physical exercise
can induce the same beneficial outcomes on the recipient
organism, the molecular mechanisms underlying the pro-
health benefits differ [22]. At the transcriptomic level, young
plasma transferred by parabiosis triggers a strong rejuvena-
tion effect on aged-neural progenitor cells by decreasing the
expression of aging-related genes (e.g., Bgp3, B2m, Rtp4,
Usp18, and others related to interferon-γ response). In con-
trast, exercised plasma does not extensively rejuvenate the
profile of neural progenitors but does upregulate essential
genes that tend to decrease with age (e.g., Cox17) [22].
Preclinical studies conducted in models of Huntington’s
disease (HD) have also demonstrated that by joining the
circulation of a wildtype (WT) and an HD mouse (i.e., the
knock-in zQ175 model), blood can serve as a vehicle topro-
vide factors that both improve or worsen disease [23]. In
the WT animal paired with an HD model, the presence of
mutant huntingtin (mHtt) was observed within blood cells
and plasma. The circulating mHtt within the WT parabiont
led to abnormal protein accumulation in all organs studied
including the kidneys, liver, muscles, and brain. In contrast,
healthy blood ameliorated several features in the diseased
mouse, while not affecting mHtt plasma levels. For exam-
ple, the HD parabiont receiving WT blood accumulated
fewer mHtt aggregates in the liver and kidney, and levels of
1 The United Nations defines young subjects, for statistical pur-
poses, 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”.

Journal of Neurology
mitochondrial stress markers were lowered in these organs
when compared with a non-parabiont HD mouse. These
findings were not restricted to the periphery, as an improve-
ment in BBB leakage was observed in the HD mouse after
healthy plasma exposure. In a subsequent study, it was dem-
onstrated that the beneficial effects of parabiosis originated
from soluble molecules and not cellular components of
the blood since bone marrow irradiation of a parabiont did
not abrogate the beneficial and/or deleterious effects in the
paired animal [24].
What factors inyoung orhealthy blood are
benecial tothebrain?
By definition, factors in young blood refer to elements that
differ from an aged subject while healthy blood refers to
factors that differ from a diseased subject. In theory, both
young and healthy blood are enriched with protective fac-
tors when compared to older or ill individuals. To this day,
a number of both young and healthy plasma-derived fac-
tors have been identified as being potentially beneficial for
the brain. For example, low plasmatic levels of α-klotho are
observed during aging as well as in early onset AD [25]
and Parkinson’s disease (PD) patients [26]. Overexpress-
ing this factor in APP/PS1 AD mice enhanced Aβ clearance
and short-term memory [27], while peripheral administra-
tion improved spatial and working memory in both aged
and transgenic mice overexpressing human α-synuclein,
respectively [28]. The myokine FNDC5/Irisin mediates
the advantages of physical exercise on cognitive function
[29] and the overexpression of the recombinant protein
using an adenoviral vector can rescue synaptic plasticity in
an AD mouse model that expresses both human amyloid
precursor protein (APP) and presenilin 1 (PS1) [30]. The
administration of growth differentiation factor 11 to aged
WT mice restored the vascularization of the subventricular
zone and enhanced neurogenesis [31]. This factor does not
cross the BBB and may act on the brain indirectly through
mechanisms involving the regulation of brain endothelial
cells [31]. While these proteins have indeed been tested
in clinical trials for various illnesses (ClinicalTrials.gov
Identifier: NCT03532568, NCT05144672, NCT04133896,
NCT02856074), they have not been evaluated in the realm
of neurodegenerative diseases.
While most studies have looked into proteins to identify
beneficial blood factors, other components such as small
molecules associated with metabolism, exosomes and/or
miRNAs have all been considered [32–34]. For example,
ketone bodies — small chain fatty acids mainly produced
by the liver — showed increased plasma levels in young
humans submitted to mixed aerobic and strength exercise
[35]. The metabolic impairments such as decreased glucose
uptake, defective mitochondrial metabolism, reduction of
oxygen consumption and ATP levels or imbalance in reac-
tive oxygen speciesobserved in aged or diseased brains (e.g.,
AD, HD, and Amyotrophic lateral sclerosis) can be attenu-
ated by a ketogenic diet in humans [36–40]. In fact, some
clinical trials have already reported the beneficial effect of
ketone bodies in AD patients with significant improvements
in memory-related tests [32, 36].
Can old blood be shaped togenerate
benets tothebrain?
Plasma-derived from both older humans and mice is char-
acterized by the presence of more toxic factors [41, 42].
Accordingly, it can be speculated that the benefits gener-
ated by young orhealthy plasma infusion originate from
the “dilution or elimination” of deleterious components. A
number of studies have shown that in heterochronic parabio-
sis, where animals of different ages are paired together, the
young mouse suffers more damaging effects (i.e., decreased
neurogenesis and hepatogenesis, muscular atrophy, reduced
life expectancy, etc.) than the aged parabiont [6, 15, 43].
Similarly, substituting low amounts of aged plasma with
a saline-albumin solution by plasma exchange can trigger
beneficial effects (i.e., hippocampal neurogenesis) [44–46].
Patients with Guillain–Barre syndrome, a demyelinat-
ing disease, are often treated with plasma exchange on the
grounds that this condition has an immune basis triggered
by an infection such as the Zika virus, the cytomegalovirus
or others [47–49]. In elderly healthy humans, the removal
of plasma by plasma exchange is associated with decreased
expression of age-related markers (such as oxidized DNA)
within blood cells and the newly generated protein signature
resembles more closely the profile of that found in younger
subjects [45]. Hence, filtration/cleansing of plasma could be
considered a therapeutic approach to treat neurodegenerative
diseases that present with an accumulation of toxic media-
tors such as AD and the amyloid peptide [50].
The use ofblood‑derived products totreat
brain diseases: frombench tobedside
Considering the promising preclinical results obtained in
models of AD, AD-related studies are largely ahead of this
field of investigation and two distinct clinical trials have
already been conducted: the AMBAR and the PLASMA
study. The AMBAR (Alzheimer’s management by albumin
replacement) initiative was a multicentric (US and Spain),
randomized, blinded, and placebo-controlled trial that evalu-
ated the effects of therapeutic plasma exchange (using a 5%
albumin solution) in more than 300 mild-to-moderate AD

Journal of Neurology
patients [51]. In addition to being safe and well-tolerated,
replacing AD plasma with an albumin solution improved
clinical outcomes including memory and language functions
[52]. While patients with milder AD improved in language
fluency, moderate disease patients demonstrated ameliorated
short-term verbal memory [53]. Plasma exchange further
decreased the levels of specific AD markers such as Aβ1-42 in
both blood and cerebrospinal fluid [52]. It was suggested that
the capacity of albumin to bind to Aβ fragments could be
responsible for some of these benefits [51]. The PLASMA
(Plasma for Alzheimer symptom amelioration) study was
conducted by Stanford University and evaluated the effects
of plasma injection in mild-to-moderate AD patients. This
small-scale (n = 18) trial confirmed tolerability and fea-
sibility [54]. One specific plasma fraction, referred to as
GRF6019, was used in a phase II, double-blind, placebo-
controlled in AD patients with mild-to-moderate (n = 47)
[55] or severe dementia (n = 26) [56]. The plasma fraction
infusion proved to be safe and well-tolerated but with no
difference in the preliminary analysis of cognitive func-
tion in either case. A new trial (ExPlas) is set to evaluate
the beneficial effects in early-stage AD patients but using
plasma from exercised donors (ClinicalTrials.gov Identifier:
NCT05068830). The hypothesis is that, as shown in pre-
clinical studies, physical exercise will enrich the blood with
additional beneficial factors.
A second plasma fraction, GRF6021, was tested in PD
patients (n = 79) in a phase II, double-blind, placebo-con-
trolled study to assess safety and tolerability (Clinical-
Trials.gov Identifier: NCT03713957) but the results are
pending. This same fraction is currently being tested to
evaluate its effect on postoperative recovery for primary
hip or knee arthroplasty (ClinicalTrials.gov Identifier:
NCT03981419). In another PD trial (n = 15), the safety
of weekly plasma infusions during a 1-month period was
also evaluated [57] and highlighted, once more, the safety
of this approach. Improvements in phonemic fluency and
in the stigma subscore were measured immediately after
plasma infusion and lasted up to 4weeks. Another clini-
cal trial evaluating the role of young plasma (from 18 to
25years old donors) infused intravenously to PD patients
(n = 22) has been conducted (ClinicalTrials.gov Identifier:
NCT04202757) but results are pending. The infusion of
young plasma in patients with Progressive Supranuclear
Palsy, a primary tauopathy, was also performed (Clini-
calTrials.gov Identifier: NCT02460731). Although there
Fig. 2 Past and current clinical trials involving plasma treatment for neurodegenerative diseases and various conditions

Journal of Neurology
was no difference on disease progression between con-
trol and treated patients, the study revealed that plasma
infusions were safe and well-tolerated [58]. Another trial
was conducted in ALS (ClinicalTrials.gov Identifier:
NCT04454840) but the literature search failed to identify
any reported observations (see Fig.2).
Plasmapheresis, plasma exchange, and plasma infusion
all present with advantages and disadvantages. Plasma-
pheresis and plasma exchange do not require donors and
therefore are less likely to generate an allergic reaction
that would be associated with the procedure per se [59].
While plasma exchange may also lower blood pressure, the
main risk associated with this approach relates to the fact
that the methodology is not restricted to eliminating toxic
factors but also essential components such as electrolytes
and immunoglobulin. By removing such proteins, there is
an increased risk of opportunistic infections [60]. While
plasma infusion requires sample collection from another
individual that increases the risk of allergies and infec-
tions, it allows the transfusion of nutrients and protective
factors found in the young and/or healthy blood. A com-
bination of these approaches, by clearing toxic elements
and replenishing the blood with beneficial factors, may
ultimately be the best angle to tackle neurodegenerative
diseases.
Final consideration
Based on the compelling preclinical evidence reported in
the literature, which has rapidly translated into a number
of clinical trials, blood-related approaches to treat neu-
rodegenerative diseases are not a stretch of the imagina-
tion. The brain is the most vascularized organ of the entire
human body and a continuous source of healthy blood is
needed for its optimal function. While we still need to
interrogate the blood to zoom in on the key components
that can have beneficial or detrimental effects, perhaps
the twenty-first century will be mirrored by the pioneer-
ing work of Harvey, Lower, Denys, Drew and others, and
lead to the treatment of neurodegenerative diseases using
blood.
Acknowledgements FC is a recipient of a Researcher Chair from the
Fonds de Recherche du Québec en Santé (FRQS, 35059) providing sal-
ary support and operating funds, and receives funding from the Cana-
dian 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.
Author contributions 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.
Declarations
Conflicts of interest The authors declare that they have no conflict of
interest.
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