Keywords
Alzheimer's disease - glymphatic system - meningeal lymphatic system - intramural
periarterial drainage - lymphatic reconstruction - lymphovenous anastomosis - supermicrosurgery
Introduction
The progression of Alzheimer's disease (AD) is a complex pathological process characterized
by heterogeneous clinical presentation, level of cognitive impairment, and neuropathologic
characteristics.[1]
[2] Memory loss and confusion are perhaps the most familiar manifestations of the disease,
but people with AD can also exhibit a spectrum of deficits in language, visuospatial
perception, behavior, and praxis that correlate with the specific region of the brain
affected by atrophy.[1]
[2]
[3]
While AD is well known for its hallmark neuropathology—the abnormal accumulation,
aggregation, and deposition of the neurotoxic AD protein biomarkers amyloid beta (Aβ)
and tau[4]—the primary events that precipitate disease onset and lead to its progression have
not been established definitively. AD is a complex puzzle; genetic factors as well
as disruptions in cholesterol metabolism, inflammation, and even intracellular functions
have increasingly been implicated in AD pathogenesis and progression, but the causal
relationships between these many processes, and their potential utility as therapeutic
targets, are not completely understood.[1]
[2]
[3]
An emerging concept that has particular relevance to the practice of lymphatic surgery
is the potential connections between AD neuropathology, the physiologic and anatomical
mechanisms of central nervous system (CNS) waste clearance, and lymphatic drainage.[5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15] Several lines of evidence have together suggested that AD could, at least in part,
be a disorder of lymphatic obstruction that hinders clearance of Aβ and other neurotoxic
products from the brain, thus making surgical improvement of lymphatic drainage an
intriguing and novel therapeutic target.[5]
[6]
Previously, AD and related pathologies have been approached as problems to be solved
medically; should research confirm a role for lymphatic obstruction in the pathogenesis
of AD, then it suggests the potential for a surgical solution requiring microsurgical
techniques and expertise. Therefore, this study is written to introduce reconstructive
microsurgeons to the key concepts and to inspire scientific curiosity.
We provide a brief overview of brain anatomy and new insights into the presence of
a brain-specific lymphatic system and study the evidence supporting the idea that
the mechanisms for clearing toxins from the CNS connect to, and drain through, this
lymphatic system into the deep cervical lymph nodes (dcLN). We then summarize current
efforts to demonstrate that lymphovenous reconstruction can improve waste clearance
from the brain as well as clinical outcomes in AD. Finally, we present our own hypothesis
that supermicrosurgical, side-to-end anastomosis is the surgical technique of choice
to improve drainage and the clearance of potentially toxic waste products, including
Aβ and tau, from the brain.
Overview of Cerebral Clearance and Drainage: An Evolving Understanding
Overview of Cerebral Clearance and Drainage: An Evolving Understanding
The brain is the most metabolically active organ of the human body,[16] producing numerous waste products that collect within the interstitial fluid (ISF)
that bathes the neurons and glial cells of the brain parenchyma.[17] These include byproducts of metabolism, cellular debris, degraded or misfolded proteins,
and other macromolecules. Throughout the rest of the body, interstitial debris and
toxins would be directed through the lymphatic system into the venous circulation
for processing and clearance, but it has long been understood that a conventional,
histologically identifiable lymphatic vasculature does not exist within the brain
parenchyma.[18]
[19]
[20]
Nevertheless, the mammalian brain does have mechanisms for waste clearance and drainage.
Waste products in the ISF within the brain parenchyma are exchanged with cerebrospinal
fluid (CSF), which fills the compartmentally distinct cerebral ventricles and subarachnoid
space of the brain meninges (membranes that enclose the CNS).[20]
[21]
[22] Until recently, the prevailing hypothesis was that the solute exchange between ISF
and CSF occurred through the convective bulk flow of the ISF,[23]
[24]
[25] and that the CSF carrying waste products eventually passed through the cervical
lymph nodes (cLN) to be reabsorbed into the bloodstream.[20] Some of the proposed routes for reabsorption included the arachnoid villi within
the dural sinuses, along cranial nerve sheaths, through the olfactory lymphatics,
or the dcLNs.[24]
[26]
[27]
[28]
Discoveries made within the last decade have changed our understanding of the waste-clearance
process significantly. Novel, brain-specific anatomical and functional systems have
been discovered that suggest that the cerebral drainage pathway includes a paravascular
glial-lymphatic (glymphatic) system, paired with a novel lymphatic network that permeates
the meninges and ultimately drains CSF and waste products to the dcLN. These findings
have important implications in developing treatment strategies for age-related and
neurodegenerative diseases.
The Glial-Lymphatic (Glymphatic) and IPAD Systems: Competing Hypotheses with a Common
Endpoint
The concept of a paravascular space within the brain parenchyma has long been theorized,[20] but in 2012, Iliff and colleagues used modern tracer and imaging techniques in mice
to fully characterize a paravascular pathway that begins with an influx of subarachnoid
CSF along para-arterial spaces infiltrating the brain parenchyma.[19] After solute exchange from ISF to CSF takes place within the capillaries of the
neurovascular unit,[29] CSF efflux occurs along the paravenous space surrounding the large deep veins.[18] This pathway was termed the “glymphatic” pathway because, while it has functional
similarity to the peripheral lymphatic system, it is anatomically distinct and mediated
principally by glial cells.
Competing models of parenchymal waste clearance exist, with significant controversy
over the specific anatomical space and direction in which waste fluid flows. The most
prominent of these alternative hypotheses is the intramural periarterial drainage
(IPAD) model, in which waste fluid travels along a periarterial space that is anatomically
distinct from the paravascular compartment, with the direction of efflux opposite
of that of the paravascular model.[18]
[30]
[31]
[32]
Despite these major and unresolved differences in the two leading models for brain-waste
clearance, there is evidence that interstitial metabolic waste products and solutes,
including Aβ, may be cleared from the brain by one or both of these pathways,[30]
[32]
[33]
[34]
[35]
[36] and that the postparenchymal drainage pathway exits the brain through a novel lymphatic
system within the meninges.[37]
[38]
Meningeal Lymphatic System Connects the Brain's Clearance Pathways to the Peripheral
Lymphatic System
The meninges are three membranes, separated by fluid-filled spaces that serve to cushion
and protect the brain and spinal cord and maintain fluid homeostasis.[22] The innermost pia mater and the middle arachnoid mater layers enclose the subarachnoid
space, which is filled with CSF produced within the cerebral ventricles. Covering
these two membranes is the outermost dura mater, which is in direct contact with the
skull, and surrounds and supports the dural venous sinuses. The subdural space is
a compartment distinct from the subarachnoid space and is filled with serous fluid,
not CSF.
In 2015, research groups at the University of Virginia and the University of Helsinki
independently published reports identifying and characterizing a novel lymphatic network
within the meninges in separate mouse models.[37]
[38] Aspelund and colleagues showed that meningeal (dural) lymphatic vessels absorb CSF
and waste products from the subarachnoid space, and then drain to the dcLN via foramina
at the base of the skull.[38] Louveau and colleagues also demonstrated that the meningeal lymphatic vessels (mLVs)
communicate directly with the dcLNs and that they, rather than the superficial cLN
or the lymphatics of the nasal mucosa, were the primary drainage route into the dcLNs
for waste products derived from subarachnoid CSF.[37] In a later study, Ahn and colleagues showed that the basal mLVs exhibited specific
morphologic features associated with fluid uptake and drainage, including blunt-ended
lymphatic capillaries with button-like junctional patterns, and lymphatic valves that
resemble precollectors.[10] They went on to demonstrate that the basal mLVs are the main pathway for clearance
of waste-laden CSF into the peripheral lymphatic system.
While these groups were not the first to suggest the presence of a brain-specific
lymphatic system, their discoveries confirmed prior hypotheses that had not been accepted
previously by the scientific community.[20] Critically, the revelation of these hidden, atypical lymphatic vessels answered
the lingering question of how the immunologically privileged compartments holding
the CSF and ISF connect to the peripheral lymphatic system.
CSF and Cerebral Waste Drain through the dcLN
In summary, whether the exact anatomical pathway by which waste-laden CSF enters the
lymphatic system is from the glymphatic or IPAD pathway, for the purposes of the plastic
and reconstructive surgeon, the end is the same ([Fig. 1]). Extracellular Aβ and other macromolecules and inflammatory mediators are carried
away from the cerebral ISF by the subarachnoid CSF, exit the brain through the basal
mLVs, drain directly into the dcLNs, and then enter the peripheral venous circulation
through the jugular lymphatic trunk.[10]
[37]
[38]
[39]
Fig. 1 A simplified schematic of the waste clearance and drainage pathway. Waste products
such as metabolic products, cellular debris, and degraded or misfolded proteins are
collected in the interstitial fluid (ISF) within the brain parenchyma. Through an
as-yet debated pathway, the waste is exchanged between the ISF and cerebrospinal fluid
(CSF) in the subarachnoid space. The CSF and waste then travel into the meningeal
lymphatics, which drain to the deep cervical lymph nodes and then out to the peripheral
circulation. (The images of the skull and brain were designed by Freepik and are available
for free.)
This summary is an oversimplification of a vastly complicated system that depends
on the proper functional interaction of numerous cell types, membrane proteins, anatomical
structures, and fluid dynamics, many of which are not completely established. For
the reader who is interested in a more detailed and nuanced background on these topics,
we suggest several recent studies.[17]
[20]
[33]
[35]
[36]
[37]
[38]
[40]
[41]
[42]
[43]
[44]
[45]
[46]
Ultimately, numerous hypotheses based on diverse lines of investigation converge on
the concept that the accumulation of the Aβ and tau aggregates that characterize AD,
aging, cognitive impairment, and other neurodegenerative conditions result from impairment
in the clearance of these macromolecules from the brain and that dysfunctions in clearance
may, in part, be attributable to lymphatic dysfunction.
Evidence Connecting Lymphatic Obstruction and Pathogenesis of Alzheimer's Disease
Evidence Connecting Lymphatic Obstruction and Pathogenesis of Alzheimer's Disease
Evidence from Preclinical Models
A great deal of the evidence for the brain-waste clearance pathways is derived from
studies in normal mice and transgenic or knockout mouse models of AD and other neuropathologies
with specific features of Aβ or tau pathology. For example, in 2018, Da Mesquita and
colleagues used multiple techniques (photodynamic drugs, surgical ligation, and a
transgenic mouse deficient in lymphatic vessel function) to ablate mLV in mice.[13] The results of this perturbation were impaired perfusion of the brain by CSF, as
well as an increase of Aβ deposition and inflammatory response within the meninges
and hippocampus of a mouse model of AD and in aged mice. The authors concluded that
meningeal lymphatic dysfunction may exacerbate AD and age-associated cognitive decline
and that improvement in the function of mLV is a potential therapeutic target for
these pathologies.
Subsequently, Patel and colleagues used imaging and blood plasma quantification to
trace the pathway and clearance rate of dye-labeled tau from the brain parenchyma
of wild-type and transgenic mice engineered to lack a functional cerebral lymphatic
system. They showed that the brain parenchyma of mice lacking a CNS lymphatic system
retained greater amounts of tau, and exhibited significantly delayed clearance of
a reference tracer, compared to wild-type controls.[11]
Consistent with these studies, Wang and colleagues investigated the effect of blocking
the dcLNs, in wild-type mice and a mouse model of AD, using surgical ligation.[12] They found that dcLN ligation in AD mice exhibited increased accumulation of Aβ
within the brain, neuroinflammation, synaptic protein loss, impaired polarization
of the key glial-cell water channel AQP4, and cognitive and behavioral deficits. The
authors concluded that impairment of lymphatic clearance from the brain is an important
factor in AD progression and a potential therapeutic target.
Also of interest is a 2019 report from Ahn and colleagues,[10] in which they performed anatomical, morphologic, and functional characterization
of basal mLVs in mice. In addition to demonstrating that basal mLVs represent the
primary drainage pathway for CSF containing cerebral waste products, they also found
that, as mice age, the basal mLVs acquire lymphedematous characteristics with associated
impairment in CSF drainage. Together with prior findings that CSF production and turnover
have also been shown to slow with aging,[14] the authors speculated that the result is dysfunction and delayed clearance of cerebral
waste products leading to increased risk for AD and other age-related disorders of
cognitive impairment.[10]
Finally, in a 2024 report, Wang and colleagues used noninvasive, near-infrared light
to modulate mLV drainage in mouse models of aging an AD. Remarkably, treated mice
showed a significant reduction in deposition of Aβ, neuroinflammation, and neuronal
damage with associated improvement in cognition. The results of this study support
prior work suggesting that the exit route for the brain clearance system should be
a target of interest for treatment of AD.[7]
Evidence in Humans
Although the majority of studies regarding the existence, structure, function, and
connectivity of the proposed para- and perivascular pathways and mLVs have been performed
in mice, the presence of these systems in the human brain has been confirmed through
imaging and other functional studies.[8]
[9]
[15]
[47]
[48]
[49] In 2018, Eide and colleagues demonstrated CSF tracer drainage to dcLNs in humans.[48] This group presented the mechanism of CSF transport to the dural lymphatics, suggesting
that the parasagittal dural space serves as a bridging link between the human brain
and the dural lymphatic vessels.[50] They also showed that CSF drainage via the cribriform plate is negligible in humans,
which is different from the CSF efflux to the nasal mucosa in animals.[51] The identification of dcLNs responsible for CNS waste clearance was made possible
through the capture of CSF-draining dcLNs in contrast-enhanced magnetic resonance
imaging.[48] This localization of the dcLNs that drain CSF has since been independently verified.[52]
Furthermore, in 2022 Nauen and Tronosco confirmed that Aβ is present in human lymph
nodes, suggesting that glymphatic clearance of Aβ through the mLV pathway described
in rodent models is conserved in the human brain.[9]
Recently, Chao and colleagues investigated the incidence of new-onset dementia in
patients, aged 60 years or older, who had undergone cLN dissection for treatment of
head and neck cancer.[53] Out of a total of 251 patients, 9 of 234 male patients developed dementia, on average
within 4.2 ± 2.9 years after surgery. This corresponded with a dementia incidence
rate of 0.7 per 100 patient-years and a cumulative incidence of 10.34% over 8.6 years—higher
than published incidence rates of dementia in the general population. They also found
a significant association between dementia onset and bilateral cLN dissection compared
to patients who underwent a unilateral procedure. As a retrospective analysis, the
study has a number of limitations including those related to cause and effect; however,
the results are another piece of evidence supporting a role for cLN in preserving
healthy brain function.
New data from a forthcoming research report from Hong and colleagues has used ultrasound
to compare cLN characteristics between 25 healthy patients (258 lymph nodes) and 25
patients (207 lymph nodes) with a positive diagnosis of dementia (manuscript in preparation).
A preliminary analysis has found that in zones I–IV, there is no statistically significant
difference in the number and shape of cLN between groups. However, the numbers and
symmetry of cLNs are significantly different between groups in zone V and, in fact,
are asymmetrical between the left and the right sides in dementia patients. The findings
provide further indirect evidence that lymphatic obstruction is associated with dementia
and suggest that cLNs in zone V that collect drainage from the anterior and posterior
pathways should be studied as potential sites for lymphovenous anastomosis (LVA).
Lymphatic Reconstruction as a Potential Therapeutic Target for Alzheimer's Disease
Lymphatic Reconstruction as a Potential Therapeutic Target for Alzheimer's Disease
Given the body of evidence supporting the hypothesis that lymphatic obstruction is
a likely contributor to the pathogenesis and/or progression of AD, we and others have
proposed that lymphovenous bypass within the dcLNs could potentially improve drainage,
clearance, and clinical outcomes.[5]
[6] Indeed, investigation of the potential efficacy of this kind of bypass for the treatment
of cognitive dysfunction is already underway, in both animal models and in human subjects.
This year, Xie and colleagues at Qiushi Hospital in the People's Republic of China
reported that their group has completed extracranial lymphatic reconstruction in at
least 50 patients with AD, with a mean of nine months follow-up.[5] To date they have presented video from one case, in an 84-year-old man with AD,
to show his improvement from a bedridden preoperative baseline to marked functional
improvement at three days, six months, and eight months postprocedure. We await a
full analysis of their findings and details of their procedural approach with great
interest.
Chen and colleagues at Cleveland Clinic recently provided a basis for how lymphatic
reconstruction may help with AD and how extracranial lymphatic reconstruction may
improve intracranial lymphatic dysfunction. Using indocyanine-green imaging in 152
patients with primary lymphedema, they demonstrated that primary lymphedema, despite
often presenting with localized symptoms, is a systemic condition affecting the entire
body.[54]
In a subsequent study of 124 primary lymphedema patients, 32% exhibited cognitive
deficits—a rate nearly three times higher than the general population. Notably, patients
who underwent lymphatic reconstruction, such as LVA, experienced systemic improvements,
including better cognitive function (manuscript in preparation). These patients reported
enhanced memory and mental clarity and scored significantly higher on validated cognitive
tests compared to those without surgery.
Based on these findings, the team hypothesized that brain lymphatic dysfunction contributes
to the elevated incidence of cognitive impairment in primary lymphedema and that lymphatic
reconstruction indirectly improves brain lymphatic function. Extending this concept,
they proposed that AD, characterized by cognitive decline linked to lymphatic dysfunction,
could be treated through extracranial lymphatic reconstruction, which has consistently
demonstrated systemic therapeutic effects.
Building on this foundation, Li and colleagues at Shanghai Jiao Tong University School
of Medicine recently announced the initiation of an investigator-initiated trial of
a novel, extracranial procedure they call “cervical shunting to unclog cerebral lymphatic
systems (CSULS).”[6] This approach involves LVA to connect the bilateral deep cervical lymphatic vessels
to the low-pressure venous system. While it has not been demonstrated that the brain
lymphatic system has a pressure gradient, the venous pressure in the neck is naturally
low (between 0 and 6 mmHg)[55] and the effect of gravity is likely to exert pressure on the draining lymphatic
system. Therefore, the authors' assumption is that their CSULS procedure will bring
about lymphatic trunk decompression and improved drainage,[6] in a manner analogous to that of LVA treatment for peripheral lymphedema.
This group has recently published observations from the first case from this trial
in a 76-year-old female patient who met guideline diagnostic criteria for AD.[6] Within 5 weeks after the procedure, favorable changes in Mini-Mental Status Examination
score, Clinical Dementia Rating-sum of boxes test, Geriatric Depression Scale score,
and objective positron-emission tomography (PET) scan measures were observed, as well
as subjective measures from the patient's family. This group has reported that they
have performed procedures on six patients and plan to publish their findings once
all patients have completed prespecified follow-up milestones.
Nguyen and colleagues at Stanford University are currently investigating the feasibility
of a treatment to induce directional lymphatic regeneration and establish new lymphatic
pathways using a novel, biodegradable, implantable nanofibrillar scaffold.[56]
[57] This material has not yet been evaluated for addressing neurological disorders,
but has been successfully and safely applied in upper- and lower-limb secondary lymphedema
as well as head and neck lymphedema.[58]
[59]
[60]
[61] The potential benefits of using bioengineered scaffolds to promote lymphatic regeneration
in the treatment of AD is an intriguing area for further study.
Meanwhile, a collaboration between groups at the Cleveland Clinic and the University
of Wisconsin is conducting investigations in an established murine model of AD to
evaluate AD biomarkers before and after extra-anatomic, supermicrosurgical lymphatic
reconstruction.[5] This quantitative evaluation within a highly controlled preclinical setting will
provide much-needed basic evidence with which to interpret findings in human studies.
Proposed Role for Supermicrosurgery in Brain Lymphatic Reconstruction
Proposed Role for Supermicrosurgery in Brain Lymphatic Reconstruction
We applaud the pioneering work of Xie and colleagues in conducting and extending these
studies, which hold promise to provide valuable proof of concept to understand the
feasibility of a lymphatic reconstructive approach to AD treatment. As with any surgical
innovation, it is the job of those who follow to refine the technique to optimize
it for safety and enhance its outcomes. Thus, given our extensive experience with
lymphatic microsurgery and the growing field of supermicrosurgery,[56]
[59]
[60]
[61]
[62]
[63]
[64]
[65] as a group we urge our colleagues to exercise caution with full consideration to
the gaps in knowledge that could negatively affect patient safety and the acceptance
of novel findings.
Considering the principle of “first, do no harm,” we assert that further pursuit of
this hypothetical approach must be conducted through rigorous, systematic science,
with preclinical studies and clinical trials designed after a thorough study of the
potential merits and drawbacks of lymphovenous reconstruction techniques in the setting
of the CNS. Above all, any clinical investigation should prioritize patient safety
over a drive to evaluate clinical effectiveness.
A number of critical questions must be considered before initiating new clinical efforts;
these include the relative safety and effectiveness of the types of lymphatic dissection,
and the number and types of anastomoses that will maximize drainage while preserving
flow and distal function in the treated vessels. For example, it is not known whether
it is sufficient to dissect the entire posterior bundle en masse and connect it to the surrounding superficial veins. The potential complications
and downstream consequences of this relatively rudimentary approach are unknown and
should be compared to a more refined, supermicrosurgical technique that creates a
1:1 vessel coaptation, intima to intima. The risk of scarring and thrombosis are concerns
in this context, and unlike in lymphatic reconstruction of the extremities, the head
and neck may lack collateral drainage pathways that could compensate for unsuccessful
reconstruction. Indeed, the recent publication from Chao and colleagues demonstrating
higher levels of dementia in patients with head and neck cancer who underwent dissection
of the cLNs reinforces the wisdom of protecting lymphatic function.[53]
There are also numerous mechanical and physiological mechanisms that are not yet understood,
including whether the brain lymphatic system has a pressure gradient as has been observed
in peripheral lymphatics, or instead relies on gravity for drainage. The presence
and function of valves within this system remain unexplored.
Another emerging area to be studied is a comparison of the safety and efficacy of
end-to-end versus side-to-end lymphaticovenous anastomoses.[62] End-to-end approaches may be of concern for obstruction, scarring, and loss of distal
function, while the concept behind side-to-end anastomosis is that this connection
may produce a more favorable pressure gradient, enable both anterograde and retrograde
flow, and preserve the downstream distal function of the involved lymphatic vessels.
In a recent, retrospective comparison of outcomes, after 123 patients with peripheral
lymphedema were treated with either end-to-end (n = 63) or side-to-end (n = 60) lymphaticovenous
anastomoses, the side-to-end group experienced a significantly better volume reduction
in all time intervals (p < 0.03) and longitudinal outcome (p = 0.004).[62] While early-phase patients showed no difference between the two groups, advanced
lymphedema patients in the side-to-end group experienced a significantly better volume
reduction ratio at all time intervals (p < 0.025) and on the overall longitudinal outcome (p = 0.004) compared to end-to-end patients.
Therefore, it is our opinion that true supermicrosurgical techniques, performed with
precision and efficiency, should be the gold standard for these reconstructions in
AD patients. These entail side(lymphatic)-to-end(venous) anastomosis of individual
vessels or lymph-node-to-vein anastomosis.[66] These approaches have been proven in the treatment of peripheral lymphedema and
we speculate that, in the even more delicate setting of lymphatic surgery aimed at
relieving obstruction of drainage from the brain, supermicrosurgery may help to avoid
unanticipated complications of a macro-scale dissection and anastomosis.[62]
[63]
[64] Again, the aim of using these advanced supermicrosurgical approaches is to preserve
remnant lymphatic function and normal, physiologic flow to minimize the possibility
of unintended long-term consequences and potential obstruction over time.
Conclusion and Future Directions
Conclusion and Future Directions
At present, the hypothesis that extracranial lymphovenous reconstruction of any kind
could be used to treat AD and related disorders of cognitive impairment remains a
hypothesis. While an intriguing base of evidence supports the concept, continued investigation
in animal models and rigorously designed clinical studies with appropriate controls
and quantitative outcome measures will be required to validate—or refute—the efficacy
and safety of this approach. Objective quantitative evidence is needed, including
biomarker measurements, imaging studies, and validated neuropsychological evaluations.
Extensive work must be undertaken to refine surgical techniques to identify the best
possible method for maximal outcomes and minimal complications. Should the research
prove fruitful, it could represent a new way of thinking about solutions to the problem
of dementia. We encourage our surgical colleagues to monitor and participate in this
exciting new direction of study.
