🧠 Neurovascular Unit Dysfunction: A Key Mechanism Behind Seizures and Epilepsy in Aging

As global populations age, the incidence of seizures and epilepsy rises sharply—particularly after age 65. Yet the mechanisms that make the aging brain more vulnerable to abnormal electrical activity remain poorly understood. A growing body of evidence points toward dysfunction in one crucial system: the neurovascular unit (NVU).

In their 2022 review, Van Vliet and Marchi propose a compelling framework:

NVU dysfunction is a unifying mechanism linking aging, neurological disease, and the development of late-onset seizures and epilepsy.

They argue that vascular deterioration, inflammation, and blood–brain barrier breakdown converge to create a “seizure-prone” environment in the elderly brain. Moreover, seizures themselves may worsen NVU pathology - driving a vicious cycle of neurodegeneration.

This article summarizes their comprehensive review and highlights why the NVU may be one of the most important - and overlooked - targets in epilepsy research.

🔬 What Is the Neurovascular Unit (NVU)?

The NVU is the structural and functional interface between:

• Brain microvascular endothelial cells

• Pericytes and vascular smooth muscle cells

• Astrocytes

• Microglia

• Perivascular macrophages

• Neurons

  
  

Together, these components maintain:

• The blood–brain barrier (BBB)

• Regulation of blood flow (neurovascular coupling)

• Immune surveillance

• Metabolic exchange

• Ion and neurotransmitter homeostasis

  
  

In a healthy brain, the NVU ensures that neurons receive steady, precisely regulated support. When NVU integrity declines, this balance collapses—making neuronal networks more prone to hyperexcitability and seizures.

🧓 Why the Aging Brain Is Vulnerable

Aging causes predictable NVU deterioration:

1️⃣ Loss of endothelial cells and pericytes → BBB leakage

Density and coverage decline with age, especially in the hippocampus.

2️⃣ Reduced transporter function

This impairs nutrient delivery and waste removal.

3️⃣ Thickening of the basement membrane

Blood vessels stiffen, impairing vascular responsiveness.

4️⃣ Astrocyte and microglia changes

Aging leads to astrocytic hypertrophy, microglial heterogeneity, and inflammation.

5️⃣ Glymphatic impairment

Reduced clearance of toxic proteins (e.g., amyloid-β).

These changes collectively reduce neurovascular coupling efficiency and destabilize neural circuits, making the brain more susceptible to abnormal electrical activity and seizures.

⚡ How NVU Dysfunction Leads to Seizures

A dysfunctional NVU increases seizure likelihood through several mechanisms:

• Blood–brain barrier breakdown

BBB leakiness allows serum proteins to enter the brain. For example, albumin entry activates astrocytic TGFβ signaling, which induces hyperexcitability and seizure vulnerability.

• Inflammation

Activated microglia and perivascular macrophages produce inflammatory molecules that disrupt neural stability.

• Ion homeostasis disruption

NVU damage alters extracellular ion concentrations, enabling uncontrolled neuronal firing.

• Reduced metabolic support

Impaired blood flow regulation means neurons cannot meet energy demands during high-activity states.

These processes often accelerate one another, particularly under disease conditions.

🧨 Clinical Evidence: NVU Dysfunction as a Driver of Late-Onset Epilepsy

The paper reviews extensive clinical evidence showing that NVU breakdown is a major risk factor for seizures in older adults.

1. Cerebrovascular disease

Stroke is the leading cause of late-onset epilepsy, accounting for up to 50% of cases. BBB permeability increases immediately after stroke, generating ionic imbalance and inflammation that promote seizures.

2. Traumatic brain injury (TBI)

Older adults have a high risk of falls, and TBI frequently leads to BBB disruption. This early vascular injury is strongly linked to post-traumatic epilepsy.

3. Neurodegenerative diseases (Alzheimer’s, vascular dementia, CAA)

Alzheimer’s disease, cerebral amyloid angiopathy, and vascular dementia all involve NVU deterioration—particularly BBB leakage, amyloid accumulation, and inflammation. These conditions can cause seizures even in early disease.

4. “Silent” vascular dysfunction

NVU dysfunction often occurs before symptoms of cognitive decline appear. Imaging studies show BBB leakage in individuals with mild cognitive impairment- even in the absence of amyloid or tau elevations.

Together, these findings support the authors’ central thesis: NVU dysfunction is a converging pathway linking aging, disease, and seizures.

🧪 Experimental Evidence: What Animal Studies Reveal

Animal models reinforce clinical observations:

• Aging causes pericyte loss, BBB permeability, and reduced transporter expression.

• Infusing albumin into young rodent brains replicates “aged” electrical patterns, including seizure susceptibility and cognitive deficits.

• Status epilepticus induces rapid NVU remodeling, including pericyte redistribution and endothelial dysfunction.

  
  

This confirms that BBB dysfunction and NVU failure directly contribute to epileptogenesis.

🔍 Diagnosing NVU Dysfunction: Emerging Tools

The authors highlight several promising diagnostic techniques:

• MRI-based BBB permeability imaging

Useful in aging, dementia, and post-seizure assessment.

• PET and SPECT

Identify inflammation, blood flow changes, and amyloid/tau deposition.

• Advanced imaging methods

Two-photon microscopy and functional ultrasound imaging (fUSi) enable high-resolution NVU analysis in research settings.

• Blood biomarkers

• S100B (BBB permeability)

• GFAP and neurofilament light chain (neuronal damage)

• NVU-related microRNAs

  
  

These tools could eventually predict seizure risk in older adults before epilepsy develops.

💊 Therapeutic Opportunities: Restoring the NVU

While no approved NVU-targeted epilepsy therapy exists, several strategies show promise:

1. Anti-inflammatory agents

Corticosteroids, anakinra, and VX-765 reduce BBB permeability and seizure frequency in models.

2. PDGF/TGF pathway modulators

Losartan, imatinib, PDGF-BB, and IPW improve BBB stability and reduce epileptogenesis.

3. mTOR inhibitors (rapamycin)

Shown to reduce BBB leakage after seizures and modify disease progression.

4. Antioxidants and MMP inhibitors

Reduce inflammation and protect NVU integrity.

Although preclinical evidence is strong, more studies in aging populations are needed.

🔁 A Vicious Cycle: Seizures Accelerate NVU Damage

One of the paper’s most significant insights is the bidirectional relationship:

• NVU dysfunction increases seizure risk.

• Seizures worsen NVU inflammation, BBB leakage, and neurodegeneration.

  
  

This cycle may help explain why seizures in Alzheimer’s disease or vascular dementia are often associated with faster cognitive decline.

🔮 Future Directions

The authors emphasize several urgent needs:

• Better biomarkers to identify NVU dysfunction early

• Targeted therapeutic trials focused on vascular and inflammatory pathways

• Personalized medicine approaches based on imaging and blood markers

• Studies exploring how lifestyle, diet, exercise, and cognitive activity influence NVU

  
  

Understanding NVU deterioration could transform epilepsy prevention and treatment for the aging population.

This review makes a compelling case that the neurovascular unit is a central player in the development of seizures and epilepsy during aging. Instead of seeing seizures in older adults as isolated events, we should view them within the broader context of vascular dysfunction, inflammation, and neurodegeneration.

By focusing research and clinical attention on the NVU, we may unlock new ways to:

• Predict who will develop epilepsy

• Prevent seizures before they occur

• Slow cognitive decline in vulnerable populations

In short: protecting the NVU may be one of the most promising strategies for maintaining brain health in an aging world.