Flow State: How Exercise Drives the Brain's Glymphatic System

Abstract

The preservation of cognitive function in the aging human brain represents one of the paramount challenges of modern biomedical science. For decades, the central nervous system (CNS) was regarded as a fortress of "immune privilege," isolated from the systemic clearance mechanisms that maintain homeostasis in peripheral tissues. This paradigmatic view has been dismantled by the recent characterization of the glymphatic system—a glial-dependent perivascular network for waste elimination—and the rediscovery of meningeal lymphatic vessels (mLVs) that drain cerebrospinal fluid (CSF) into the cervical lymph nodes. While animal models have suggested that physical activity can enhance these clearance pathways, direct evidence of functional plasticity in the human brain has remained elusive due to imaging limitations.

This report provides an exhaustive analysis of the landmark 2025 study by Yoo et al., published in Nature Communications, which utilizes novel non-invasive magnetic resonance imaging (MRI) techniques to demonstrate that long-term aerobic exercise structurally and functionally remodels the brain’s waste clearance infrastructure in humans. We explore the biophysical principles of the innovative IR-ALADDIN imaging sequence, the specific enhancement of glymphatic influx in the putamen, and the discovery of a distinct "neuro-protective" plasma proteomic signature characterized by the downregulation of inflammatory biomarkers (S100A8, S100A9, DEFA1A3) and the upregulation of the mucosal immunity marker J chain. By synthesizing these radiological and molecular findings with the broader history of neurophysiology, we propose a unified model of "clearance plasticity," wherein regular physical exertion acts as a dual mechanical and biochemical modulator, preserving the brain's internal environment against the proteopathic accumulation associated with neurodegeneration.

1. Introduction: The Hydraulic Imperative of Brain Health

1.1 The Metabolic Paradox of the CNS

The human brain is a metabolic outlier. Despite constituting only 2% of total body mass, it consumes approximately 20% of the body’s basal energy budget. This intense metabolic activity generates a proportionate burden of biological waste, including oxidized proteins, lactate, and, most critically, prone-to-aggregation peptides such as amyloid-beta (Aβ) and tau. In peripheral organs, the lymphatic system acts as a ubiquitous sewer, collecting interstitial fluid (ISF), filtering it through lymph nodes, and returning it to the venous circulation. For over a century, however, the brain was believed to lack this essential infrastructure.

This absence posed a "metabolic paradox": How does the organ most sensitive to toxic accumulation survive without a dedicated lymphatic drainage system? The classical explanation, dominating neuroscience textbooks throughout the 20th century, posited that the brain recycled its own protein waste or that metabolites slowly diffused into the cerebrospinal fluid (CSF) to be reabsorbed passively into the blood via arachnoid granulations.¹ While diffusion is efficient over microscopic distances (micrometers), it is woefully inadequate for the macroscopic clearance required by the large volume of the human brain. The mathematics of diffusion simply could not account for the speed at which radiolabeled tracers were observed to leave the brain parenchyma in early experiments.

1.2 The Glymphatic Revolution

The resolution to this paradox began in 2012 with the description of the "glymphatic system" by Maiken Nedergaard and colleagues at the University of Rochester.¹ Utilizing two-photon microscopy in living mice, they visualized a highly organized system of fluid transport. They observed that CSF from the subarachnoid space is driven into the brain parenchyma through peri-vascular spaces surrounding penetrating arteries. This influx is facilitated by the polarity of astrocytes—specifically, the high density of Aquaporin-4 (AQP4) water channels located on the astrocytic endfeet that sheath the cerebral vasculature.⁴

Once inside the tissue, the CSF mixes with ISF, exchanging solutes and sweeping metabolic waste products toward the peri-venous spaces, where the fluid exits the brain. This system was termed "glymphatic" to acknowledge the critical role of glial cells (astrocytes) in performing the function of a lymphatic system.³ A crucial early finding was the system's dependence on arousal states; glymphatic flow is dramatically suppressed during wakefulness and upregulated during non-REM sleep, suggesting that the restorative function of sleep is, in part, a literal "brain washing" process.³

1.3 The Meningeal Lymphatic Rediscovery

If the glymphatic system represents the brain's internal plumbing, the question remained: where does the waste go after it leaves the brain? The re-discovery of meningeal lymphatic vessels (mLVs) in 2015 by the labs of Jonathan Kipnis and Kari Alitalo provided the answer.⁸ Buried within the dura mater—the tough outer membrane of the meninges—these vessels run parallel to the major venous sinuses.

Though Italian anatomist Paolo Mascagni had depicted lymphatic vessels on the surface of the human brain in wax models as early as 1787, his findings were dismissed as artifacts for over two centuries. Modern immunohistochemistry confirmed their existence, showing that they express classical lymphatic markers (Lyve-1, Prox1, Podoplanin) and drain directly into the deep cervical lymph nodes (dCLNs).¹⁰ This finding physically connected the CNS to the peripheral immune system, shattering the dogma of immune isolation and establishing a complete circuit for fluid egress: Arterial Influx -> Glymphatic/Parenchymal Exchange -> Venous Efflux -> Meningeal Lymphatic Drainage -> Cervical Lymph Nodes.¹¹

1.4 The Exercise Hypothesis and the Human Gap

With the anatomy defined, the focus shifted to modulation. If this system clears neurotoxins like amyloid-beta, can we voluntarily enhance its function? Animal studies provided a promising lead: voluntary wheel running in mice was shown to increase glymphatic influx and reduce amyloid plaque burden.¹³ The proposed mechanisms included increased arterial pulsatility (the "pump" of the system), modulation of astrocyte AQP4 expression, and enhanced respiratory drivers of lymph flow.¹⁴

However, translating these findings to humans has been stalled by a technological barrier. We cannot perform two-photon microscopy on living human brains, and the standard clinical resolution of MRI is often insufficient to visualize the microscopic, slow-flowing meningeal lymphatics against the bright signal of the adjacent venous sinuses. Consequently, whether human mLVs possess the plasticity to adapt to exercise—and whether this correlates with deep brain clearance—has remained a matter of speculation.

The study by Yoo et al. (2025) bridges this gap. By deploying a sophisticated MRI protocol known as IR-ALADDIN and combining it with plasma proteomics, the researchers have provided the first in vivo evidence of exercise-induced glymphatic and meningeal lymphatic plasticity in healthy humans.¹⁶ This report dissects their findings, the physics of their imaging tools, and the molecular biology of the biomarkers they identified, offering a comprehensive view of how movement cleans the mind.

2. Technical Frontiers: Imaging the Invisible

To understand the magnitude of the findings by Yoo et al., one must first appreciate the formidable challenge of imaging neurofluids. The meningeal lymphatics are delicate, transparent vessels, roughly 50-100 micrometers in diameter, carrying a fluid (lymph) that is isointense to CSF on standard MRI sequences. Furthermore, they are located immediately adjacent to the Superior Sagittal Sinus (SSS), a massive vein whose turbulent, rapid blood flow creates significant magnetic artifacts that can obscure nearby structures.

2.1 The Limits of Conventional MRI

Standard structural MRI (T1 or T2-weighted imaging) provides excellent contrast between gray matter, white matter, and CSF. However, it is static. It shows anatomy, not flow or function.

• Contrast-Enhanced T1: Administering a gadolinium-based contrast agent (GBCA) can highlight vessels. However, distinguishing a lymphatic vessel from a small venule is difficult, as both enhance.

• Phase Contrast MRI: This technique is used to measure blood flow velocity. It relies on the phase shift of moving protons. However, it is typically tuned to the high velocities of arterial (>50 cm/s) or venous flow (>10 cm/s). The flow in meningeal lymphatics is estimated to be mere millimeters per second—too slow for standard velocity encoding (VENC) settings to detect without overwhelming noise.¹⁸

2.2 The Innovation: IR-ALADDIN

The Yoo et al. study employed a specialized sequence called IR-ALADDIN (Inversion Recovery Alternate Ascending/Descending Directional Navigation).¹⁸ This technique is a brilliant application of nuclear magnetic resonance physics designed to isolate slow flow.

2.2.1 The ALADDIN Principle

ALADDIN is a form of perfusion imaging related to Arterial Spin Labeling (ASL). It does not require the injection of a contrast agent to detect flow (though the study used contrast for validation). Instead, it uses the water molecules in the body as an endogenous tracer.

• Inter-slice Flow Saturation: The sequence acquires images in an alternating fashion—slice by slice, moving structurally up (ascending) and then down (descending).

• The Labeling Effect: When imaging a specific slice, the radiofrequency (RF) pulses applied to adjacent slices act as a "label." If fluid is flowing from a labeled slice into the imaging slice, its magnetic state is different from the static tissue in that slice.

• Directional Sensitivity: Because the acquisition alternates direction, the signal intensity varies depending on whether the flow is concurrent or counter-current to the acquisition order. By subtracting the ascending and descending images, static tissue signal cancels out, leaving only the signal from moving fluid.¹⁸

2.2.2 The Inversion Recovery (IR) Filter

The "IR" component is the critical modification for lymphatic imaging.

• Nulling the Background: An Inversion Recovery pulse is a preparatory radiofrequency wave that flips the net magnetization of protons 180 degrees. The protons then relax back toward equilibrium at a rate defined by their T1 relaxation time.

• Timing (TI): By selecting a specific Inversion Time (TI)—in this study, 2300 ms ¹⁸—the researchers timed the image acquisition to the exact moment when the signal from CSF passes through zero (the "null point").

• Suppression of Venous Blood: This long TI also helps suppress the signal from the rapid venous blood in the sagittal sinus.

• Result: The background CSF is dark (nulled), the venous blood is suppressed, and static tissue is subtracted out by the ALADDIN processing. What remains is the signal from the slow-moving lymph in the meningeal vessels, which has a distinct T1/flow profile.¹⁸

2.3 Dynamic T1 Mapping for Glymphatic Influx

To measure the upstream glymphatic flow (from CSF into brain tissue), the researchers used Dynamic T1 Mapping with an intravenous contrast agent.¹⁷

• Method: A Gadolinium-based contrast agent (GBCA) was injected intravenously. While the blood-brain barrier (BBB) prevents the contrast from entering the brain directly from capillaries, a small fraction filters into the CSF or enters via the choroid plexus over time.

• Infiltration: Once in the CSF, the contrast enters the brain parenchyma along the perivascular spaces (the glymphatic route).

• Quantification: Gadolinium shortens the T1 relaxation time of water. By acquiring T1 maps (quantitative images of T1 values) repeatedly over time, the researchers could calculate the rate at which T1 values dropped in specific brain regions. A faster drop indicates faster accumulation of contrast, serving as a proxy for glymphatic influx efficiency.²²

3. Study Design: Dissecting the Exercise Effect

The experimental design of the Yoo et al. study was meticulously crafted to distinguish between acute physiological responses (hemodynamics) and chronic adaptations (plasticity).

3.1 Participant Cohorts and Protocol

The study recruited healthy human volunteers, ensuring that the baseline physiology was not confounded by pre-existing neurodegenerative pathology. This is crucial for establishing normative data on how a healthy system responds to intervention.

• Long-Term Exercise Group: This cohort underwent a 12-week supervised exercise program utilizing a cycle ergometer.¹⁷

• Protocol Rationale: Cycling is a controllable, measurable aerobic activity. The 12-week duration is a standard timeframe in exercise physiology to observe structural cardiovascular adaptations (e.g., ventricular hypertrophy, increased capillary density). The hypothesis was that similar structural changes would occur in the lymphatic system.

• Intensity: While specific heart rate zones were individualized, the protocol was designed to maintain an aerobic training zone sufficient to elicit systemic cardiovascular adaptation.²⁵

• Single-Bout Exercise Group: A separate condition involved participants performing a single session of exercise.

• Scientific Control: This group served to test the "pump vs. pipe" hypothesis. Does exercise simply flush the system momentarily due to high blood pressure (the pump), or does it physically enlarge the vessels (the pipes)? If changes were seen only after 12 weeks and not after one session, it would point to structural remodeling.¹⁵

3.2 The Target: The Putamen

The researchers focused their glymphatic analysis on specific Regions of Interest (ROIs), with particular attention to the putamen.¹⁵

• Anatomical Significance: The putamen is a central component of the basal ganglia, located deep within the brain. It is perfused by the lenticulostriate arteries—thin, end-arteries that branch directly off the high-pressure middle cerebral artery.

• Vulnerability: The putamen is a site of early pathology in Parkinson’s disease (alpha-synuclein aggregation) and Huntington’s disease. Its vascular supply is highly sensitive to pulsatility. Demonstrating glymphatic access to this deep structure is clinically vital, as it confirms that the clearance system reaches the deep gray matter, not just the superficial cortex.²²

4. Radiological Results: Evidence of Structural Plasticity

The findings from the imaging analysis were robust and statistically significant, painting a picture of a system that grows and accelerates in response to demand.

4.1 Enhanced Glymphatic Influx

After 12 weeks of training, the putative glymphatic influx (measured by the rate of T1 shortening) significantly increased in the putamen (P =.01).¹⁵

• Interpretation: This indicates that chronic exercise improves the efficiency of CSF transport into deep brain structures. The specificity of the putamen suggests that the lenticulostriate arteries, which are subjected to high pulsatile stress, may adapt their perivascular spaces or astrocytic endfeet to facilitate greater fluid movement.

• Mechanistic Link: This finding aligns with the "pulsatility hypothesis." Exercise increases arterial compliance (elasticity). More compliant arteries transmit the cardiac pulse wave more effectively along the vessel wall, driving the peristaltic pumping of CSF in the perivascular space.¹⁵

4.2 Meningeal Lymphatic Remodeling

The most groundbreaking data came from the IR-ALADDIN analysis of the parasagittal meningeal lymphatics.

1. Increased Vessel Size: The cross-sectional area (size) of the mLV signal increased significantly (P =.008) in the long-term group.¹⁷

2. Implication: This suggests lymphangiogenesis (growth of new vessels) or lymphangiodilation (widening of existing vessels). Just as muscles grow capillaries (angiogenesis) to support increased oxygen demand, the meninges appear to grow lymphatic vessels to support increased clearance demand.

3. Increased Flow Velocity: The flow speed within these vessels also increased significantly (P =.002).¹⁷

4. Implication: The system is not just bigger; it is faster. This could be due to improved valve function within the lymphatics or a greater pressure gradient driving fluid from the subarachnoid space into the vessels.

4.3 The Critical Distinction: Chronic vs. Acute

Crucially, these changes were absent in the single-bout exercise group.¹⁵

• The "Pipe" Hypothesis Confirmed: A single session of exercise raises heart rate and blood pressure, which might transiently increase influx (the pump), but it does not change the capacity of the efflux vessels (the pipes). The lack of mLV changes after one session confirms that the findings in the 12-week group represent a slow, structural adaptation—true plasticity.²⁷ This underscores the clinical message: consistency is key. You cannot "binge clean" the brain; the infrastructure must be built over months.

Table 1: Summary of Radiological Findings (Yoo et al., 2025)

Metric	Region / Technique	Long-Term Exercise (12 Weeks)	Single-Bout Exercise	Statistical Significance (Long-Term)
Glymphatic Influx	Putamen (Dynamic T1 Mapping)	Significantly Increased	No significant change	P =.01
mLV Size	Parasagittal Dura (IR-ALADDIN)	Significantly Increased	No significant change	P =.008
mLV Flow Velocity	Parasagittal Dura (IR-ALADDIN)	Significantly Increased	No significant change	P =.002
Mechanism	-	Structural Plasticity / Remodeling	Transient Hemodynamics	-

5. Proteomic Insights: The Molecular Signature of Clearance

The study did not stop at anatomy. By analyzing plasma samples, Yoo et al. identified a specific "proteomic signature" that correlated with the imaging improvements. This signature reveals that exercise modulates the immune environment to favor clearance.

5.1 The Downregulation Cluster: Quelling the Fire

The researchers observed a significant downregulation of four proteins: S100A8, S100A9, PSMA3, and DEFA1A3.¹⁵ These proteins share a common theme: they are markers of inflammation and neutrophil activation.

5.1.1 S100A8 and S100A9 (Calprotectin)

• Biochemistry: S100A8 and S100A9 form a heterodimer known as calprotectin. They are calcium-binding proteins abundant in the cytoplasm of neutrophils and monocytes. They function as Damage-Associated Molecular Patterns (DAMPs) or "alarmins." When released, they bind to Toll-Like Receptor 4 (TLR4) and RAGE (Receptor for Advanced Glycation End-products), triggering potent pro-inflammatory cascades.³⁰

• Neurodegenerative Role: These proteins are villains in the story of Alzheimer's. S100A9 is inherently amyloidogenic; it can self-assemble into amyloid-like fibrils and has been found co-aggregated within amyloid plaques in the brains of AD patients.³² Elevated levels in the CSF correlate with cognitive decline.³³

• The Exercise Connection: Exercise reduced the circulating levels of these proteins. By lowering the systemic load of S100A8/A9, exercise likely reduces neuroinflammation. Less inflammation means less astrogliosis. Since reactive astrocytes lose their AQP4 polarity (the critical channel for glymphatic flow), reducing inflammation preserves the structural integrity of the glymphatic "pump".⁴

5.1.2 DEFA1A3 (Alpha-Defensins)

• Biochemistry: Defensins are antimicrobial peptides stored in neutrophil granules. While they kill bacteria, they are also cytotoxic to host tissue and can increase the permeability of the blood-brain barrier (BBB).³⁵

• Implication: Their downregulation indicates a reduction in neutrophil activation. In models of Alzheimer's, neutrophils have been observed to adhere to CNS capillaries, stalling blood flow ("capillary stalling") and reducing clearance. A reduction in defensins suggests better capillary perfusion and a tighter, healthier BBB.³⁰

5.1.3 PSMA3 (Proteasome Subunit Alpha Type-3)

• Biochemistry: PSMA3 is a core component of the 20S proteasome, the cellular trash compactor. Interestingly, it is also a component of the immunoproteasome, a specialized variant induced by interferon-gamma during stress and infection to process antigens.³⁶

• Interpretation: The downregulation of PSMA3, alongside the inflammatory markers, suggests a shift away from a stressed, immunologically reactive state toward a basal, homeostatic state. The system is under less "proteotoxic stress," requiring less immunoproteasome activity.¹⁷

5.2 The Upregulation Target: The J Chain and Barrier Immunity

Conversely, the study found a significant upregulation of the Joining (J) chain protein.¹⁵ This finding connects the brain to the cutting edge of mucosal immunology.

• Function: The J chain is a small polypeptide required for the polymerization of IgM and IgA antibodies. It allows these antibodies to bind to the Polymeric Immunoglobulin Receptor (pIgR) and be transported across epithelial cells onto mucosal surfaces.³⁹

• The Meningeal Link: Until recently, the meninges were not thought to harbor significant immune populations. However, studies in 2020-2021 revealed the presence of IgA-secreting plasma cells residing along the dural venous sinuses—exactly where the lymphatic vessels are located.⁴⁰

• The Protective Mechanism: These IgA cells act as a firewall. They secrete antibodies that entrap pathogens and toxins, preventing them from entering the brain or damaging the lymphatic vessels. Crucially, IgA neutralizes threats without triggering the violent inflammation associated with IgG (complement activation).

• Exercise Effect: The upregulation of J chain suggests that exercise boosts this specific "barrier immunity." By strengthening the IgA shield around the meningeal lymphatics, exercise protects the drainage vessels from infectious or inflammatory damage, keeping the clearance routes open.⁴¹

Table 2: The Proteomic Balance Sheet

Protein Marker	Change with Exercise	Biological Role	Implications for Brain Clearance
S100A8/A9	Decrease	Pro-inflammatory DAMP; Amyloidogenic	Reduced amyloid seeding; Preservation of AQP4 polarity on astrocytes.
DEFA1A3	Decrease	Neutrophil Antimicrobial Peptide	Reduced BBB permeability; Reduced capillary stalling.
PSMA3	Decrease	Immunoproteasome Subunit	Indicator of reduced systemic/CNS inflammatory stress.
J Chain	Increase	IgA/IgM Polymerization	Enhanced meningeal mucosal immunity; Protection of lymphatic vessels.

6. Discussion: A Unified Model of Exercise-Induced Neuroprotection

The integration of the radiological and proteomic data from Yoo et al. allows us to construct a unified model of how exercise protects the brain. It is not a single pathway, but a synergy of biomechanics and biochemistry.

6.1 The "Pump and Pipe" Biomechanical Model

Fluid dynamics relies on pressure gradients (the pump) and resistance (the pipe).

1. The Pump (Arterial Pulsatility): Aerobic exercise increases cardiac output and stroke volume. This amplifies the pulsatile wave traveling up the carotid and vertebral arteries. As these arteries enter the brain and become penetrating arterioles, their expansion drives the convective influx of CSF into the parenchyma via the Virchow-Robin spaces. The study’s finding of increased influx in the putamen validates this "pump" enhancement.¹⁵

2. The Pipe (Lymphatic Remodeling): Increased fluid input requires increased output capacity. The sustained increase in CSF flux across the cribriform plate and into the dural lymphatics creates fluid shear stress on the lymphatic endothelial cells. In vascular biology, shear stress is the primary trigger for angiogenesis (via VEGF and eNOS pathways). It is highly probable that a similar mechanotransduction pathway drives the lymphangiogenesis (increased size) observed in the study. The system remodels to handle the load.²⁴

6.2 The "Anti-Inflammatory Shield" Biochemical Model

A mechanical system will fail if it becomes clogged or corroded. Inflammation is the corrosion of the glymphatic system.

1. Corrosion Control: S100A8/A9 and defensins promote inflammation that leads to fibrosis and astrogliosis. Reactive astrocytes lose their AQP4 organization, effectively sealing the perivascular space and blocking flow. By suppressing these proteins, exercise acts as a "rust inhibitor," maintaining the delicate molecular architecture required for fluid exchange.⁴

2. Barrier Defense: The upregulation of J chain indicates a fortification of the meningeal barrier. A robust IgA response prevents low-grade infections or gut-derived toxins (leaking via the gut-brain axis) from establishing a foothold in the meninges, where they could damage the lymphatic vessels and impair drainage.³⁸

6.3 Clinical Implications for Neurodegeneration

The implications for Alzheimer’s (AD) and Parkinson’s (PD) disease are profound.

• Prevention vs. Cure: Most AD trials have failed because they target amyloid plaques after they have accumulated and caused irreversible damage. This study suggests that exercise is a preventative mechanism that keeps the clearance system functional, washing away soluble amyloid and tau before they aggregate.

• The "Prescription" of Movement: The requirement for long-term (12 weeks) adherence to see structural changes provides a clear clinical directive. Patients must be counseled that the neuroprotective benefits of exercise are cumulative. The brain’s plumbing takes time to widen.

• Biomarkers: The identification of S100A8/A9 and J chain as correlates of clearance opens the door to blood tests that could monitor brain health. A rising S100/J-chain ratio could serve as an early warning of "lymphatic failure" in the brain, years before cognitive symptoms arise.

7. Conclusion

The study by Yoo et al. (2025) represents a seminal moment in the field of neurofluids. By rendering the invisible visible through IR-ALADDIN MRI, they have provided the first concrete proof that the human brain's waste clearance system is plastic and responsive to physical activity. The findings dismantle the old view of the brain as a static, isolated organ, revealing it instead as a dynamic hydraulic system deeply integrated with the body’s cardiovascular and immune physiology.

The message is clear: The act of moving the body does more than strengthen the heart or muscles; it physically reconstructs the drainage systems of the brain, widening the vessels that carry away the toxic byproducts of thinking. In doing so, exercise creates a biochemical environment—low in inflammation, high in barrier immunity—that ensures these vessels remain open and efficient. As the global burden of neurodegenerative disease rises, understanding and harnessing this intrinsic "self-cleaning" capacity may prove to be our most powerful therapeutic tool.

Works cited

1. Glymphatic System - Lab Focuses - University of Rochester Medical Center, accessed December 3, 2025, https://www.urmc.rochester.edu/labs/nedergaard/projects/glymphatic-system

2. The Glymphatic System – A Beginner's Guide - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4636982/

3. accessed December 3, 2025, https://www.jneurosci.org/content/41/37/7698#:~:text=The%20glymphatic%20hypothesis%20postulates%20that,counteracting%20protein%20accumulation%20and%20the

4. The newly discovered glymphatic system: the missing link between physical exercise and brain health? - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11058641/

5. Maiken Nedergaard's power of disruption | The Transmitter, accessed December 3, 2025, https://www.thetransmitter.org/glymphatic-system/maiken-nedergaards-power-of-disruption/

6. The glymphatic system // Maiken Nedergaard - YouTube, accessed December 3, 2025, https://www.youtube.com/watch?v=He6HMnMbxAc

7. Glymphatic-meningeal lymphatic system, a new therapeutic target for sleep disorders | Request PDF - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/395336359_Glymphatic-meningeal_lymphatic_system_a_new_therapeutic_target_for_sleep_disorders

8. The meningeal lymphatic system: a new player in neurophysiology - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC6268162/

9. Understanding the functions and relationships of the glymphatic system and meningeal lymphatics - JCI, accessed December 3, 2025, https://www.jci.org/articles/view/90603

10. Structural and functional features of central nervous system lymphatic vessels - PubMed, accessed December 3, 2025, https://pubmed.ncbi.nlm.nih.gov/26030524/

11. Meningeal Lymphatics in Central Nervous System Diseases - Annual Reviews, accessed December 3, 2025, https://www.annualreviews.org/content/journals/10.1146/annurev-neuro-113023-103045

12. The Therapeutic Potential of Glymphatic System Activity to Reduce the Pathogenic Accumulation of Cytotoxic Proteins in Alzheimer's Disease - MDPI, accessed December 3, 2025, https://www.mdpi.com/1422-0067/26/15/7552

13. Voluntary Exercise Promotes Glymphatic Clearance of Amyloid Beta and Reduces the Activation of Astrocytes and Microglia in Aged Mice - Frontiers, accessed December 3, 2025, https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00144/full

14. Voluntary running enhances glymphatic influx in awake behaving, young mice - PMC, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5696653/

15. Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/390639646_Long-term_physical_exercise_facilitates_putative_glymphatic_and_meningeal_lymphatic_vessel_flow_in_humans

16. Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans - Research Highlights - Seoul National University, accessed December 3, 2025, https://en.snu.ac.kr/research/highlights?md=v&bbsidx=154119

17. ProteomeXchange Dataset PXD058255, accessed December 3, 2025, https://proteomecentral.proteomexchange.org/cgi/GetDataset?ID=PXD058255

18. Non-invasive flow mapping of parasagittal meningeal lymphatics using 2D interslice flow saturation MRI - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10224581/

19. Follow Keyword - Read by QxMD, accessed December 3, 2025, https://www.readbyqxmd.com/keyword/143130

20. IR-ALADDIN signal intensity simulation. Simulation results with varying... - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/figure/IR-ALADDIN-signal-intensity-simulation-Simulation-results-with-varying-inversion-time_fig3_371079607

21. IR-ALADDIN images of flow phantom. a, d Baseline images of flow... - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/figure/IR-ALADDIN-images-of-flow-phantoma-dBaseline-images-of-flow-phantom-b-csubtracted_fig4_371079607

22. Contrast-enhanced MRI T1 Mapping for Quantitative Evaluation of Putative Dynamic Glymphatic Activity in the Human Brain in Sleep, accessed December 3, 2025, https://pubs.rsna.org/doi/pdf/10.1148/radiol.2021203784

23. Radiology | Vol 300, No 3 - RSNA Journals, accessed December 3, 2025, https://pubs.rsna.org/toc/radiology/300/3

24. (PDF) Long-term exercise enhances meningeal lymphatic vessel plasticity and drainage in a mouse model of Alzheimer's disease - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/394381489_Long-term_exercise_enhances_meningeal_lymphatic_vessel_plasticity_and_drainage_in_a_mouse_model_of_Alzheimer's_disease

25. Physical Exercise as a Preventive or Disease-Modifying Treatment of Dementia and Brain Aging | Request PDF - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/51606398_Physical_Exercise_as_a_Preventive_or_Disease-Modifying_Treatment_of_Dementia_and_Brain_Aging

26. (PDF) Study design: The effect of aerobic exercise on cerebral perfusion in patients with vascular cognitive impairment - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/314301439_Study_design_The_effect_of_aerobic_exercise_on_cerebral_perfusion_in_patients_with_vascular_cognitive_impairment

27. Roh-Eul Yoo's research works | Seoul National University and other places - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/scientific-contributions/Roh-Eul-Yoo-56769836

28. Changes in ΔT1 values (ΔT1influx and ΔT1efflux) at the putamen after... - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/figure/Changes-in-DT1-values-DT1influx-and-DT1efflux-at-the-putamen-after-exercise-in-each_fig1_390639646

29. Move to Remember: The Role of Physical Activity and Exercise in Preserving and Enhancing Cognitive Function in Aging—A Narrative Review - MDPI, accessed December 3, 2025, https://www.mdpi.com/2308-3417/10/6/143

30. Inflammatory role of S100A8/A9 in the central nervous system non-neoplastic diseases, accessed December 3, 2025, https://pubmed.ncbi.nlm.nih.gov/39396712/

31. Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes - MDPI, accessed December 3, 2025, https://www.mdpi.com/1422-0067/13/3/2893

32. The role of pro-inflammatory S100A9 in Alzheimer's disease amyloid-neuroinflammatory cascade - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4148179/

33. Mechanism of action and therapeutic potential of S100A8/A9 in neuroinflammation and cognitive impairment: From molecular target to clinical application (Review), accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12289131/

34. Pathogenic mechanisms and therapeutic targets of inflammation in acquired hydrocephalus - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7375440/

35. Long-term physical exercise facilitates putative glymphatic and meningeal lymphatic vessel flow in humans - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11982307/

36. PSMA3 - Proteasome subunit alpha type-3 - Homo sapiens (Human) | UniProtKB | UniProt, accessed December 3, 2025, https://www.uniprot.org/uniprotkb/P25788/entry

37. Expanding the role of proteasome homeostasis in Parkinson's disease: beyond protein breakdown - PMC - NIH, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7862491/

38. Role of meningeal lymphatic vessels in brain homeostasis - PMC - PubMed Central, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC12221947/

39. Exercise, Immunity, and Illness - PMC - PubMed Central - NIH, accessed December 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7149380/

40. The meningeal transcriptional response to traumatic brain injury and aging - eLife, accessed December 3, 2025, https://elifesciences.org/articles/81154

41. The gut–meningeal immune axis: Priming brain defense against the most likely invaders, accessed December 3, 2025, https://rupress.org/jem/article/219/3/e20211520/213031/The-gut-meningeal-immune-axis-Priming-brain

42. (PDF) Role of meningeal lymphatic vessels in brain homeostasis - ResearchGate, accessed December 3, 2025, https://www.researchgate.net/publication/393335008_Role_of_meningeal_lymphatic_vessels_in_brain_homeostasis

43. The functions and regulatory pathways of S100A8/A9 and its receptors in cancers - Frontiers, accessed December 3, 2025, https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2023.1187741/full

44. Effects of Exercise on Glymphatic Functioning and Neurobehavioral Correlates in Parkinson's Disease - Congressionally Directed Medical Research Programs, accessed December 3, 2025, https://cdmrp.health.mil/prp/research_highlights/23Claassen_highlight

45. PSMA3 - Wikipedia, accessed December 3, 2025, https://en.wikipedia.org/wiki/PSMA3