The blood-brain barrier: geriatric relevance of a critical brain-body interface

Abstract

The blood-brain barrier (BBB) represents the interface between the brain and other body tissues. Its ability to protect the brain from harmful compounds has attracted the attention of clinicians and investigators, but far from being a simple physical barrier, the BBB is a complex, heterogeneous, and dynamic tissue. The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells (BMECs), cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity. Based on the published literature, this study proposes that age- and disease-related BBB alterations play a key role in diminishing the ability of older patients to recover from acute ischemic stroke. Evidence linking deficits in the cerebral microvasculature and BBB integrity to dementia, medication-related cognitive decline, white matter disease (WMD or leukoaraiosis), and related geriatric syndromes including delirium, gait disorders, and urinary incontinence is also reviewed. Priority areas for a future research agenda include strategies to improve clinicians' ability to diagnose, prevent, and manage BBB abnormalities. In future years, in vivo measures such as functional and contrast-enhanced neuroimaging will be used to evaluate BBB integrity in older adults while also assessing the effectiveness of interventions, some targeting inflammatory pathways known to disrupt the BBB, for their ability to prevent or slow the progression of these complex multifactorial geriatric syndromes.

Figure 1. The Neurovascular Unit with normal and disrupted BBB

(I) Functional barrier composed of transport systems and metabolic enzymes. The structural barrier includes tight junctions and basement membrane. (II) Disrupted BBB with (A) Increased paracellular permeability due to tight junction disruption (B) increased transcellular permeability via upregulated transcytosis (C) drug and toxin accumulation due to decreased efflux via P-gp (D) basement membrane disruption (E) decreased nutrient transport TJ = tight junctions, BMEC = brain microvascular endothelial cell, P-gp = permeability glycoprotein, a.a. = amino acids, gluc = glucose, MAO = monoamine oxidase inhibitor, P450 = drug metabolizing enzyme system

Figure 2. Multifactorial Contribution to Blood-Brain Barrier Pathogenesis

Comorbidities and medications compound BBB changes accompanying aging. Compromise of the BBB is also associated with several age-related disorders.

Figure 3

Neuroimaging of an 84 year old woman with a history of gait impairment and urinary incontinence. (A) hypodense lesions on CT and (B) increased signal intensity on FLAIR MRI within cerebral white matter.