Blood Brain Barrier and Cerebral Blood Flow

Blood Brain Barrier (BBB)

• The BBB is a protective layer of tightly packed cells that surrounds the brain and prevents harmful substances from entering.
• Small and lipid-soluble molecules can pass through the BBB easily.
• Large and water-soluble molecules are unable to pass through the BBB on their own, requiring transport proteins to help.
• Examples of substances that can pass through the BBB: alcohol, anesthetics, antidepressants, anxiolytics, antipsychotics, medications for seizures/epilepsy, caffeine, acetaminophen, NSAIDs, and sedative hypnotics.
• The BBB is essential for maintaining a stable environment for brain function.

Cerebral Blood Flow (CBF) and Regulation

• The brain's vasculature is highly regulated to ensure adequate blood flow, enabling the energy needs of the brain's cellular components.
• Neural activity is the primary driver of CBF regulation.
• Increased CBF is a result of coordinated action by neurons, astrocytes, and vascular cells through various signalling molecules like ions, arachidonic acid metabolites, nitric oxide (NO), adenosine, neurotransmitters, and neuropeptides.
• This coordination results in the release of vasoactive agents that control the diameter of blood vessels, influencing blood flow.
• Endothelial cells play a crucial role in regulating vasomotor tone by releasing vasoactive factors in response to chemical signals and mechanical forces.
• Tight junctions between endothelial cells in most brain regions prevent the exchange of hydrophilic substances between the blood and brain.
• Specialized transport proteins in the endothelial cell membrane regulate the flow of solutes into and out of the brain.
• The brain has autoregulation mechanisms that maintain a consistent CBF despite changes in arterial pressure, ranging from 60 to 150 mmHg.
• Vascular smooth muscle cells can constrict in response to increased intravascular pressure, contributing to autoregulation.
• Autoregulation provides a stable CBF baseline, allowing dynamic changes induced by neurovascular coupling and endothelium to be superimposed.
• Major vascular risk factors can lead to endothelial dysfunction and damage, resulting in neurovascular dysfunction, increased BBB permeability, and microvascular thrombosis.
• Reduced NO bioavailability is a consequence of endothelial dysfunction, as ROS scavenge or suppress NO synthesis.
• ROS produced by NADPH oxidase, activated by angiotensin II, can cause endothelial dysfunction and cognitive impairment.
• Dysfunctional endothelial cells can also secrete toxic factors that impair myelination, impacting white matter integrity.

Neurovascular Unit and Coupling

• The neurovascular unit is a functional unit composed of vascular smooth muscle, neurons, astrocyte glial cells, and primary glutaminergic pathways involved in CBF regulation.
• Neurovascular coupling refers to the relationship between local neural activity and resulting alterations in CBF.
• Glutamate release from synapses activates NMDAR on neurons and mGluR on astrocytes, leading to an increase in cytosolic Ca2+ concentration.
• This increase in Ca2+ activates nNOS in neurons, which produces nitric oxide (NO).
• NO has diverse effects, including activating cGMP in smooth muscle for dilation, inhibiting 20-HETE in smooth muscle to inhibit vasoconstriction, and inhibiting EET production in astrocytes.
• Increased Ca2+ within astrocytes activates PLA2, which generates AA, leading to the production of both EET and PGE2, resulting in cerebral artery dilation.

Vascular Dementia

• Vascular dementia (VaD) is a brain disorder caused by cerebrovascular pathologies, usually a series of minor strokes, leading to cognitive impairment.
• VaD is classified into four subtypes: post-stroke dementia (PSD), subcortical ischemic vascular dementia (SIVaD), multi-infarct (cortical) dementia, and mixed dementia.
• Cerebrovascular disease can be a primary cause of cognitive impairment or contribute to dementia caused by other factors.
• Vascular cognitive impairment refers to any cognitive disorder associated with cerebrovascular disease, encompassing various levels of cognitive deficits, from mild impairment to dementia.
• CNS small vessel disease (CSVD) causes a significant portion of strokes and contributes to dementia cases.

Cerebral Small Vessel Disease (CSVD)

• Arteriosclerosis or CSVD encompasses small vessel arteriosclerosis, lipohyalinosis, and arteriolosclerosis, characterized by changes in vessel walls similar to those seen in larger blood vessels, but without calcifications.
• CSVD can cause lacunar infarcts, microinfarcts, hemorrhages, and microbleeds.
• Initially affecting arteries in the basal ganglia, CSVD progresses to involve peripheral white matter, leptomeningeal arteries, thalamic and cerebellar white matter vessels, and ultimately, brain stem arteries.

Epidemiology of CSVD

• CSVD causes 25% of strokes and contributes to 45% of dementia cases.
• Prevalence increases with age, affecting about 5% of individuals between 50 and 90 years old, and close to 100% of people over 90 years old.

CSVD Symptoms

• Symptoms are often absent until the later stages of the disease and are variable.
• Common symptoms include forgetfulness, fatigue, difficulty thinking clearly and communicating, impaired walking and balance, depression, strokes, slurred speech, and difficulty swallowing.
• Some symptoms can mimic those of a heart attack, including chest pain, discomfort or pressure, pain in arms/back/neck/jaw/stomach, lightheadedness/fainting, fatigue, rapid heart rate, palpitations, shortness of breath, nausea/vomiting, and sweating.

CSVD Genetics

• Cadasil is a genetic form of CSVD.

CSVD Hallmarks

• cSVD is characterized by specific features on brain MRI, including WMHs, small subcortical infarcts or lacunes, visible PVSs, microbleeds, intracerebral hemorrhage (ICH), and brain atrophy.
• Two major hallmarks of CSVD are cerebral amyloid deposition in the walls of cerebral vessels, leading to microbleeds and microbleeds themselves serving as a hallmark.

CSVD Biomarkers

• CSVD diagnosis relies on brain imaging biomarkers, including small subcortical infarcts, WMHs, lacunes, cerebral microbleeds, enlarged PVSs, and cerebral atrophy.
• Advanced imaging techniques like diffusion tensor imaging and blood oxygenation level-dependent imaging can detect early signs of disease.
• Clinical markers like cerebrospinal fluid amyloid beta and tau protein levels help differentiate between AD and CSVD.

CSVD Treatment and Prevention

• Current CSVD treatment is limited and focuses on reducing risk factors and preventing complications like stroke and dementia.
• Treatment includes personalized regimens to address individual risk factors, involving medications to regulate cholesterol, glucose, and blood pressure, coupled with healthy lifestyle habits that include exercise, nutrient-rich diet, and smoking cessation.
• Medications for CSVD include aspirin, vasodilators, ACE inhibitors, and beta-blockers.