Blood-Brain Barrier (BBB) - Case Study 3 PDF

**Learning goals: ** 1. **What is the BBB and what is its function? ** Anatomical structure of the blood--brain barrier (BBB). The wall of all\... \| Download Scientific Diagram **What can get through the BBB?** Some things can get through your BBB if they're small enough. Others can get throug...

**Learning goals: ** 1. **What is the BBB and what is its function? ** Anatomical structure of the blood--brain barrier (BBB). The wall of all\... \| Download Scientific Diagram **What can get through the BBB?** Some things can get through your BBB if they're small enough. Others can get through because they're lipid-soluble. That means they can pass through your blood-brain barrier without it repelling them. Larger or water-soluble molecules can't get through the BBB on their own. Large molecules can't slip between the interlocking endothelial cells because of their size. Water-soluble molecules can't easily pass through your BBB because its cell membranes are lipid-based, which repels water-soluble molecules. If large or water-soluble molecules --- including nutrients --- need to get through, they need transportation to help them across. Some examples of drugs and substances that can get through the BBB (either on their own or with transport help) include: - Alcohol. - [Anesthetics](https://my.clevelandclinic.org/health/treatments/15286-anesthesia). - [Antidepressant medications](https://my.clevelandclinic.org/health/treatments/9301-antidepressants-depression-medication). - [Anxiolytics (antianxiety medications)](https://my.clevelandclinic.org/health/treatments/24776-anxiolytics). - [Antipsychotic medications](https://my.clevelandclinic.org/health/treatments/24692-antipsychotic-medications). - Medications that treat [seizures](https://my.clevelandclinic.org/health/diseases/22789-seizure) or [epilepsy](https://my.clevelandclinic.org/health/diseases/17636-epilepsy). - [Caffeine](https://my.clevelandclinic.org/health/drugs/20956-caffeine-tablets). - Acetaminophen and most [nonsteroidal anti-inflammatory drugs (NSAIDs)](https://my.clevelandclinic.org/health/drugs/11086-non-steroidal-anti-inflammatory-medicines-nsaids). - Sedative hypnotics (such as [barbiturates](https://my.clevelandclinic.org/health/treatments/23271-barbiturates), [benzodiazepines](https://my.clevelandclinic.org/health/treatments/24570-benzodiazepines-benzos) and similar drugs). CBF and its regulation The brain is endowed with vasoregulatory mechanisms that assure that it receives enough blood to support the energy needs of its cellular constituents. Thus, neural activity is the major determinant of the dynamic regulation of CBF. The increases in blood flow induced by activation depend on the concerted action of neurons, astrocytes, and vascular cells through a wide variety of molecular signals including ions, arachidonic acid metabolites, nitric oxide (NO), adenosine, neurotransmitters, and neuropeptides. - The hemodynamic changes underlying the increase in blood flow are mediated by vasoactive agents with opposing vascular actions (vasodilation or vasoconstriction), generated by synaptic activity, astrocytes, interneurons, and afferent projections from the basal forebrain and brainstem. - Endothelial cells are a major regulator of vasomotor tone by releasing vasoactive factors in response to chemical signals, such as transmitters, or mechanical forces, such as shear stress. Cerebral endothelial cells in most brain regions are adjoined by intricate junctional complexes formed by occludins and claudins (tight junctions). These prevent the bidirectional exchange of hydrophilic substances between blood the brain. Specialized transport proteins on the endothelial cell membrane control the traffic of solutes in and out of the brain. - CBF autoregulation →the ability of arteries and arterioles to dilate or constrict when intravascular pressure decreases or increases to maintain CBF relatively constant over a range of systemic blood pressures (from 60 to 150 mmHg). - Vascular smooth muscle cellshave the ability to constrict when intravascular pressure increases (myogenic tone), adjust vascular tone in response to changes on arterial pressure to maintain CBF relatively constant within a range of pressure (cerebrovascular autoregulation). - Autoregulation protects cerebral blood vessels from the wide swings in arterial pressure associated with the activities of daily living and provides a stabile CBF baseline on which the dynamic changes induced by neurovascular coupling and endothelium are superimposed. o These neurovascular control mechanisms work in concert to assure that the brain receives sufficient blood flow to meet the metabolic needs of its active cellular constituents. Major vascular risk factors lead to endothelial dysfunction and damage, which causes neurovascular dysfunction, increased BBB permeability and microvascular thrombosis. - Endothelial dysfunction leads to reduced NO bioavailability. ROS scavenge or suppress NO synthesis by inactivating critical cofactors. ROS produced bya NOX2-containing NADPH oxidase via angiotensin II receptor type 1 cause endothelial dysfunction and cognitive impairment in a model of chronic hypertension. Dysfunctional endothelial cells can also secrete toxic factors that block oligodendroglial differentiation, hence impairing myelination, essential for WM integrity. They can undergo deleterious proteomic changes with aging. 2. **What is the neurovascular unit and neurovascular coupling? ** Neurovascular coupling - Neurovascular coupling is the relationship between local neural activity and subsequent changes in CBF. - The neurovascular unit is made up of - Vascular smooth muscle - Neuron - Astrocyte glial cell - Primary glutaminergic pathways involved in cerebral blood flow regulation. - Glutamate release by the synapse activates NMDAR on neurons and metabotropic glutamate receptors (mGluR) on astrocytes. Both of these receptors act by increasing cytosolic Ca2+concentration. - In the neuron, Ca2+ activated neuronal nitric oxide synthase (nNOS) produces nitric oxide (NO). - Increases in Ca2+ within the astrocytes activate phospholipase A2 (PLA2),which generates arachodonic acid (AA), and therefore both epoxyeicosatrienoic acid (EET) and prostaglandin E2 (PGE2) →cerebral arteries dilation. - NOexerts diverse effects including: 1) activating cyclic guanosine monophosphate (cGMP) in smooth muscle leading to dilation,2) inhibiting 20-hydroxyeicosatetraenoic acid (20-HETE) in smooth muscle to inhibit constriction, and 3) inhibiting production of EET in astrocytes which inhibits the vasodilatory action of EET on smooth muscle. 3. **What is vascular dementia?** Vascular dementiais a heterogenous group of brain disorders in which cognitive impairment is attributable to cerebrovascular pathologies.It is caused by problems in the supply of blood to the brain, typically a series of minor strokes. - VaD can be classified into 4 major subtypes - Post-stroke dementia (PSD)→ defined as dementia manifesting within 6 months after a stroke. Strategic single stroke dementia - Subcortical ischemic vascular dementia (SIVaD): most common type, thickening of blood vessel in the brain. - Multi-infarct (cortical) dementia: series of smaller strokes - Mixed dementia: caused by more than one disease. - Cerebrovascular disease plays a role as a primary cause of cognitive impairment and as an adjuvant to the expression of dementia caused by other factors. - Vascular cognitive impairment refers to all forms of cognitive disorder associated with cerebrovascular disease, regardless of the specific mechanisms involved. It encompasses the full range of cognitive deficits from mild cognitive impairment to dementia. - CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. 4. **What are the subtypes of vascular dementia?** 5. **What is cerebral small vessel disease? ** Arteriosclerosis or cerebral small vessel disease (SVD) →comprises small vessel arteriosclerosis, lipohyalinosis, and arteriolosclerosis. These vessel wall changes are similar to that of larger blood vessels except for calcifications not seen in small arteries. SVD can result in lacunar infarcts, microinfarcts, hemorrhages,and microbleeds. It affects first arteries of the basal ganglia, then expands into the peripheral white matter, leptomeningeal arteries, and into thalamic and cerebellar white matter vessels, and, finally, involves brain stemarteries 1. **Epidemiology** CNS small vessel disease (CSVD) causes 25% of strokes and contributes to 45% of dementia cases. Prevalence increases with age, affecting about 5% of people aged 50 years to almost 100% of people older than 90 years. 1. **Symptoms** Symptoms vary, and unfortunately are not usually present until a later stage of the disease. They can include: - Forgetfulness - Fatigue - Difficulty thinking clearly and communicating - Difficulty walking - Difficulty with balance - Depression - Strokes - Slurred speech - Difficulty swallowing Small vessel disease symptoms often mimic those of a heart attack. Some of the symptoms include the following: - [**Chest pain**](https://www.rwjbh.org/treatment-care/heart-and-vascular-care/diseases-conditions/angina-chest-pain-/), fullness, discomfort or pressure. - Discomfort or pain in one or both arms, the back, neck, jaw, or stomach. - Lightheadedness/Fainting - Fatigue - Rapid heart rate (tachycardia) of over 100 beats per minute. - [**Heart palpitations**](https://www.rwjbh.org/treatment-care/heart-and-vascular-care/diseases-conditions/heart-palpitations/) - Shortness of breath - Nausea and/or vomiting - Sweating Genetic form: cadasil 1. **Risk factors (diabetes and cardiovascular health)** Small vessel disease is caused by several factors. However, certain traits, conditions or habits may raise your risk for the disease. These are known as risk factors and include: **Non-Modifiable Risk Factors:** These factors are irreversible and cannot be changed. The more of these risk factors you have, the greater your chance of developing small vessel disease: - Family history/Genetics - Female gender **Modifiable Risk Factors: **These factors can be modified, treated or controlled through medications or lifestyle changes. - [**High blood pressure**](https://www.rwjbh.org/treatment-care/heart-and-vascular-care/diseases-conditions/high-blood-pressure/) - [**High cholesterol**](https://www.rwjbh.org/treatment-care/heart-and-vascular-care/diseases-conditions/high-cholesterol/) - Little to no physical activity. - Obesity or having a body mass index "BMI" of 30 or greater. - Extreme emotional stress. - [**Diabetes**](https://www.rwjbh.org/treatment-care/diabetes-care/): When your blood glucose, also called blood sugar, is too high. Known causes and risk factors include age, hypertension, branch atheromatous disease, cerebral amyloid angiopathy, radiation exposure, immune-mediated vasculitides, certain infections, and several genetic diseases. Hypertension is considered the main risk factor, but other cardiovascular risk factors may be related to these lesions as well. We found in a population-based sample of nondemented people between 60 and 90 years that older age, female sex, higher blood pressure, current cigarette smoking, and the presence of severe WMLs and lacunar brain infarcts at baseline were associated with progression of WMLs. Baseline carotid atherosclerosis was related to incident lacunar infarcts. These associations were independent of other cardiovascular risk factors. In people with already severe small vessel disease at baseline and in those in the oldest age category, higher blood pressure seemed no longer related to WML progression.  1. **Hallmarks (pathophysiology)** cSVDs are primarily defined by their hallmark features on brain MRI, including white matter (WM) hyperintensities (WMHs)(damages to the white matter), small subcortical infarcts or lacunes (small infarcts make a small hole, these small holes are filled with fluid, become black spots), visible perivascular spaces (PVSs) (with MRI, , microbleeds , intracerebral hemorrhage (ICH), and brain atrophy ([Figure 1](https://www.jci.org/articles/view/172841#F1)) ((https://www.jci.org/articles/view/172841#B2)).  2 major hallmarks Cerebral amyloid...: deposition of amyloid b in wall of cerebral bloods vessel - leads to microbleeds and microbleeds are a hallmark 1. **Biomarkers (diagnosis)** CSVD is diagnosed on the basis of brain imaging biomarkers, including recent small subcortical infarcts, white matter hyperintensities, lacunes, cerebral microbleeds, enlarged perivascular spaces, and cerebral atrophy. Advanced imaging modalities can detect signs of disease even earlier than current standard imaging techniques. Diffusion tensor imaging can identify altered white matter connectivity, and blood oxygenation level-dependent imaging can identify decreased vascular reactivity.  Ct extensive white matter lesions and infarcts Csf amyloid beta and tau protein levels to differentiate between ad and csvd. First clinical biomarkers 1. **Treatment (prevention)** Current treatment options for CSVD are limited. They generally focus on reducing risk factors and avoiding or delaying complications like stroke and dementia. Individuals each have different risk factors, so personalized treatment regimens are the most effective. Treatment may include medications to reduce cholesterol, regulate glucose levels, and lower high blood pressure. Healthy lifestyle habits such as regular exercise, eating nutrient-rich foods, and quitting smoking are often recommended as well. Some symptoms, such as nervous system issues and depression, may be addressed with specialized therapies. **Medications** - Aspirin will treat pain, inflammation, and reduce risk of a heart attack. - Vasodilators will help the muscle in the walls of the blood vessels to relax, allowing the vessel to dilate. - ACE inhibitors will help blood vessels relax and open up, leading to a lower blood pressure. - Beta blockers will help reduce your blood pressure.