Small vessel disease is a condition causing blood vessel dysfunction that occurs with aging and contributes to the development of cardiovascular disease, dementia, and stroke. As a consequence of the profound effects of small vessel disease on the functioning of the brain and blood-brain barrier, for the purposes of this article, we will focus predominantly on cerebral aspects of small vessel disease, called cerebral small vessel disease.
Small vessel disease in the brain contributes to approximately 50 percent of dementia cases worldwide, including Alzheimer's disease, Parkinson's disease, and other common neurodegenerative diseases.
The functional impact of cerebral small vessel disease on cognition can be predicted through a system of scoring medical images to observe contributing phenomena directly.  The contributing phenomena attributed to cognitive decline as a result of small vessel disease include:
There are a variety of lifestyle behaviors and risk factors that may affect the development of cerebral small vessel disease or pathologies associated with the disease, including:
The blood-brain barrier separates the central nervous system (CNS) and the peripheral circulatory system, tightly controlling what substances pass into or out of the brain; this function (controlling what substances pass into or out of the brain) relies on the integrity small vessels at the blood-brain barrier. The vascular half of the blood-brain barrier is composed of small vessel endothelial cells and pericytes, which are multipurpose cells that control the dilation and constriction of blood vessels. Both types of cells, while present throughout the body, have special characteristics at the blood-brain barrier.
Endothelial cells connect to each other using tight-junction proteins, which can be modified in shape to suit the needs of different tissues in the body. In tissues responsible for the filtering of waste, such as the kidneys and liver, loose tight junctions allow for increased paracellular transport. This mode of nutrient and waste exchange occurs when substances from the blood seep through vessel walls instead of being transported intracellularly using membrane transporters with high selectivity. Tight junctions connecting endothelial cells at the blood-brain barrier form much tighter junctions than those of the liver and take on a structure more similar to epithelial tissue (e.g., skin), which severely limits paracellular transport.
The ratio of endothelial cells to pericytes also varies among the small vessels of the body with the microvasculature of the CNS having the highest proportion of pericytes. Compared to small vessels in the lungs (10:1 ratio of endothelial cells to pericytes), which form a more permeable barrier than the brain, and skeletal muscle (100:1 ratio of endothelial cells to pericytes), which has little barrier capacity, small vessels of the brain form the most restrictive barrier with approximately a 1:1 ratio of endothelial cells to pericytes.
These perciytes strengthen small vessel integrity by controlling vessel dilation, providing trophic support to endothelial cells (e.g., encouraging endothelial cell proliferation and differentiation), and secreting components of the extracellular matrix that connect small vessels to astroglia. These star-shaped cells form the central nervous system half of the blood-brain barrier, bridging the distance between blood vessels and neurons, while selectively choosing which substances come into contact with neurons. The multicellular structures formed by endothelial cells, pericytes, and atroglia contain many sets of connecting membranes and are called a neurovascular unit. These structures serve the purpose of nutrient and waste exchange for neurons while providing many points of regulation to prevent neuronal damage.
Endothelial dysfunction compromises the integrity of neurovascular units, increasing the concentration of toxins and pathogens in the brain and accelerating brain aging.
Endothelial cells line blood vessels throughout the body and require a lot of energy to regulate vascular tone efficiently. Endothelial dysfunction can be caused by hyperglycemia and oxidative stress, which reduces the number of endothelial progenitor cells over time, worsening small vessel disease. Dysfunctional epithelial cells promote blood vessel rigidity, inflammation, and excessive clotting, contributing to cardiovascular and neurodegenerative disease progression.
The mechanisms underlying endothelial dysfunction have yet to be fully elucidated; however, inflammation, a key regulator of blood vessel permeability, is a major contributor. Chronic inflammation caused by lack of micronutrients is common in aging. For example, high levels of serum homocysteine, a byproduct of normal cellular metabolism that is an endothelial toxin at high concentrations, can be caused by vitamin B12 deficiency, a common problem in older adults. Hyperhomocysteinemia is common in individuals with small vessel disease and increases in severity as small vessel disease worsens.
Endothelial dysfunction increases with age and contributes to inflammaging, a process of tissue degeneration characterized by altered cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metabolic inflammation, and gut microbiota dysbiosis. Chronic inflammation and tissue injury at the BBB increases the risk of autoimmunity and neurodegeneration as immune cells encounter damage-associated molecular patterns and risk producing antibodies against self-antigens released from damaged CNS tissues.
Many of the observable cerebral phenomena of small vessel disease, such as white matter hyperintensities and lacunar strokes, are predictive of the amount and degree of blood-brain barrier leakage.
Permeability of the blood-brain barrier, is partially regulated by tight-junction proteins, which form attachments between the cytoskeletons of adjacent cells. High serum phosphate levels, which are common in people with cerebral small vessel disease, downregulate the assembly of tight junction proteins, increasing BBB permeability. Severe vitamin D deficiency increases serum phosphate levels by reducing phosphate excretion by the kidneys and is more common in individuals with severe small vessel disease.
Permeability of the blood-brain barrier is also modulated by the types of lipids used to create neurovascular membranes. For example, unsaturated fats make membranes less compact and more fluid, while saturated fats create rigid membranes that are less efficient at nutrient and waste exchange. Increased permeability of neurovascular units allows endotoxins and inflammatory immune cells to infiltrate the brain, contributing to brain aging.
"Older adults with early cognitive dysfunction display blood-brain barrier leakage in the hippocampus regardless of the deposition of amyloid or tau, demonstrating the importance of vascular markers in the early diagnosis of dementia. 10.1016/j.jalz.2018.07.222" Click To Tweet
Chronic hyperpermeability of the BBB leads to adaptations such as an increased thickness and disorganization of blood vessels, which reduces perfusion, the passage of blood from cardiovascular circulation into tissues, delivering nutrients and diluting waste. Hypoperfusion, a defining characteristic of small vessel disease, deprives tissues of oxygen, causing mitochondrial dysfunction and increasing oxidative stress. Compared to older adults without small vessel disease, patients with overt cerebral small vessel disease had a greater volume of white and grey matter with subtle signs of blood-brain barrier leakage and reduced perfusion and cerebral blood volume.
Hypoperfusion initiates a vicious cycle of nutrient deprivation, metabolic stress, inflammation, and waste accumulation that is central to cognitive impairment. While dementias such as Alzheimer's disease are often diagnosed based on the visual appearance of amyloid-beta plaques and phosphorylated-tau tangles, blood-brain barrier leakage and vascular dysfunction often precede the appearance of amyloid and tau deposits. Older adults with early cognitive dysfunction display blood-brain barrier leakage in the hippocampus regardless of the deposition of amyloid or tau, demonstrating the importance of vascular markers in the early diagnosis of dementia. Intervening in dementia by alleviating the endothelial dysfunction and hypoperfusion associated with small vessel disease may be a more effective strategy than focusing on amyloid-beta removal, as earlier dementia research has done.
Impaired glymphatic function, a feature of small vessel disease, contributes to brain injury and presents as an enlargement of perivascular space.
The glymphatic system circulates interstitial fluid in the brain in an avascular manner, meaning neither blood nor lymph vessels are required for fluid movement. Interstitial fluid is exchanged with fresh plasma, which perfuses from nearby blood vessels. This system of highly controlled fluid movement is responsible for waste disposal during sleep, injury, and illness because, unlike other organs, the brain has no traditional lymphatic structures. Glymphatic dysfunction disturbs normal pressure in the brain and impairs waste disposal, contributing to neurodegeneration.
Using gadolinium-based MRI dye, researchers can measure the rate of fluid exchange in perivascular spaces at the blood-brain barrier. Estimated glymphatic clearance rate is inversely related to cerebral small vessel disease, meaning that as the burden of small vessel disease markers increases, the ability of the glymphatic system to circulate fluid decreases. Impaired exchange of fluids at the blood-brain barrier increases the occurrence of enlarged perivascular spaces, where stagnant interstitial fluid accumulates toxins that injure the brain.
Enlarged perivascular spaces are a feature of neurodegeneration and are associated with other markers of small vessel disease, such as white matter hyperintensities, and other signs of brain disease such as chronic inflammation and blood-brain barrier dysfunction.
Perivascular spaces are fluid-filled spaces that form around blood vessels in several organs including the brain that participate in normal nutrient and waste exchange. These spaces are filled with interstitial fluid that seeps into the space due to increased blood vessel permeability. Perivascular spaces are common in the body and may have an immunological function, as increased blood vessel permeability facilitates diapedesis, the movement of white blood cells from the bloodstream into tissues. Enlarged perivascular spaces are commonly found in healthy adults in small number; however, an increased occurrence of enlarged perivascular spaces in the brain is associated with aging, depression, cognitive decline, and diabetes.
As a result of perivascular enlargement, the efficiency of fluid exchange at the BBB is reduced, resulting in the accumulation of misfolded proteins such as amyloid-beta, which contributes to Alzheimer's pathology, and alpha-synuclein, which contributes to Parkinson's pathology. The accumulation of toxins is greatest when fluid exchange is disrupted during sleep, a time when the brain cleans out toxins that build up during the day from normal metabolism and harmful environmental exposures. During sleep, fluid volume in the brain increases to dilute waste and exchange cerebrospinal fluid with plasma from the bloodstream. Enlarged perivascular spaces and poor sleep are both common in people with Alzheimer's disease and other neurodegenerative diseases. Interventions that increase sleep duration, such as short daily naps, and sleep quality, such as light exercise, have demonstrated efficacy in alleviating symptoms of Alzheimer's disease.
Over time, hypoxia, reduced delivery of nutrients and growth factors, accumulation of toxins and dysfunctional proteins, and chronic inflammation leads to long-term structural changes in the brain that are visible using medical imaging and include white matter hyperintensities, occluded vessels, cerebral microbleeds, lacunes, enlarged perivascular spaces, and brain atrophy — the defining cerebral traits of small vessel disease.
Tissues in the CNS are characterized as gray matter, which are areas in the brain, brainstem, and cerebellum where neuron bodies are concentrated, or white matter, which are bundles of axon fibers that form connections among neurons. White matter appears white in tissue samples compared to gray matter due to an increased concentration of lipids, which form the insulating myelin sheaths around axon fibers. Gray matter is concentrated in the cerebral cortex, the outermost layer of brain tissue, with white matter positioned under this layer, deeper in the brain. White matter is highly vascularized and vulnerable to ischemia (i.e., reduced blood flow) due to its deep location.
White matter hyperintensities are lesions found in white matter that appear bright white on a magnetic resonance imaging (MRI) scan because the area has a decreased density of axons and blood vessels. Often, this reduced cell density is the result of hypoxia and cell death. White matter hyperintensities of vascular origin are also referred to as leukoaraiosis.
Studies utilizing diffusion tensor imaging, a sophisticated type of MRI that measures the movement of water in white matter, have detected white matter dysfunction that precedes the visual appearance of white matter hyperintensities, suggesting that white matter hyperintensities are the final stage of a pathological process that involves long-term small vessel disease. White matter hyperintensities increase with age, hypertension, and obesity and are associated with depression, cognitive impairment, and physical disability. The association between white matter hyperintensities and disease follows a stepwise pattern, meaning the more lesions that are visible, the greater the risk of impairment. This relationship is especially strong when lesions are confluent, so that larger continuous areas of white matter die, disrupting communication between different hubs of gray matter neurons.
Neurodegenerative diseases include hundreds of distinct illnesses that present with specific sets of symptoms based on the location of brain lesions such as the cerebral cortex, basal ganglia, brainstem and cerebellum, and spinal cord. Degeneration in the cerebral cortex causes dementia and Alzheimer's disease. Lesions located in the basal ganglia result in movement disorders such as Parkinson's disease. Small vessel disease leads to hypoperfusion and hypoxia in the brain, causing protein misfolding and downstream endothelial dysfunction, BBB break-down, and inflammation.
"Newer research finds that small vessel disease burden has a greater effect on cognition in those with dementia than amyloid-beta and tau burden, demonstrating a shift in how scientists and clinicians should research and diagnose Alzheimer's disease. 10.1038/s44161-021-00014-4'" Click To Tweet
Alzheimer's disease is a type of dementia that presents with plaques of misfolded amyloid-beta and phosphorylated tau proteins in the brain. While early research of Alzheimer's disease implicated these proteins as a cause of the disease, recent research suggests misfolded proteins accumulate secondary to metabolic disease, small vessel disease, and chronic inflammation. Therapies that target the removal of misfolded proteins have been largely unsuccessful in reducing Alzheimer's disease severity, revealing the need for therapies upstream of protein misfolding. Newer research finds that small vessel disease burden has a greater effect on cognition in those with dementia than amyloid-beta and tau burden, demonstrating a shift in how scientists and clinicians should research and diagnose Alzheimer's disease.
Maintaining the lipid membranes that comprise the blood-brain barrier may be an important area for intervention, as older adults with greater serum concentration of small high-density lipoprotein (HDL) particles and cerebrospinal fluid concentrations of the lipids phosphatidylcholine, sphingomyelin, and lysophosphatidylcholine had less amyloid-beta. Small HDL particles remove oxidized lipids from endothelial cells at the BBB, reducing inflammation, small vessel dysfunction, and amyloid-beta deposition. Strategies for increasing small HDL particle number include pharmaceutical drugs and exercise. In one study, four weeks of daily supplementation with four grams of the omega-3's eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) combined with exercise had a uniquely powerful effect on raising small HDL levels. A growing body of evidence suggests that omega-3 intake during the early stages of Alzheimer's disease may reduce disease severity.
Parkinson's disease is characterized by motor neuron dysfunction, resulting in tremors, muscle rigidity, and movement difficulties. However, some people with the disease may also experience depression and cognitive impairment. The brains of people with Parkinson's disease display multiple markers of cerebral small vessel disease. One study with more than 100 Parkinson's disease patients found lacunes in 9 percent of the patients, deep white matter hyperintensities in 81 percent, enlarged perivascular spaces in 85 percent, and cerebral microbleeds in 3 percent. A greater burden of small vessel disease markers was related to greater disease severity.
Neuroinflammation is a driver of cerebral small vessel disease and early neuron dysfunction in Parkinson's disease. The transcription factor NFkB activates the expression of pro-inflammatory genes, and its activity is increased in Parkinson's disease. Polyphenols from foods such as berries, greens, and tea inhibit the NFkB inflammatory pathway and, therefore, may reduce Parkinson's disease risk. In studies with mice, polyphenol treatments reduce inflammation and oxidative stress and protect dopaminergic neurons. Human trials demonstrate that a diet rich in polyphenols improves small vessel function and robustly improves executive function, language, attention, concentration, and active memory in people with Parkinson's disease.
Q: What is the overall prevalence of cerebral small vessel disease?
A: The prevalence of cerebral small vessel diseases increases with age, affecting about 5 percent of people aged 50 years and older and nearly 100 percent of people older than 90 years and causing an estimated 25 percent of strokes.
Q: How can clinicians track or diagnose small vessel disease and/or the permeability of the blood-brain barrier?
A: Currently, there are no clinically-approved methods for measuring blood-brain barrier permeability. However, research methods exist that use a standard 15-minute MRI with an injection of a gadolinium tracer that helps to visualize the severity of blood-brain barrier leakiness. With aging, the hippocampus, medial temporal lobe, and the caudate nucleus are specific brain areas where barrier dysfunction is concentrated and this is represented by a leaking of the gadolinium tracer into deeper brain tissue.
Researchers at the University of Southern California are currently investigating other potential ways to track cerebral small vessel disease with varying degrees of invasiveness. For example, soluble platelet-derived growth factor-beta receptor is a protein released from damaged pericytes that can be measured in plasma from a standard blood draw. Other techniques rely on analysis of cerebrospinal fluid. Hopefully, these and other research methods could be approved for clinical practice in diagnosing dementia early in the disease process.
Q: What exercise activities may be best suited to reducing the risk of cerebral small vessel disease?
A: Improving cardiovascular fitness, especially with the aim of better management of blood pressure and reducing the pathological processes contributing to the production of white-matter hyperintensities, may be a particularly high-leverage prevention activity. In one study with middle-aged and older adults without cognitive impairment, hypertension was associated with accelerated brain aging in a dose-dependent manner. For every 10 mmHG increase in blood pressure (systolic or diastolic), estimated brain age increased by about 65 days. Hypertension may be even riskier for people with an apolipoprotein E4 allele, a genetic variant that increases Alzheimer's disease risk, because it increases the amount of amyloid-beta deposition in the brain.
In another study supporting the role of hypertension in small vessel disease and dementia, elevated blood pressure in midlife increased the burden of white matter hyperintensities in the brain. Maintaining a systolic blood pressure of less than 120 mmHG may be optimal for reducing the risk of cerebral small vessel disease and dementia. Aerobic exercise, in particular, helps maintain healthy blood pressure. For example, one study showed that men who completed a 12-week exercise program that included 40 to 60 minutes of walking or jogging one to three days per week reduced their systolic blood pressure by 15 mmHg and diastolic pressure by 10 mmHg.
Q: What foods or nutrients may be helpful in reducing the risk of cerebral small vessel disease?
A: The marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) profoundly affect brain health. The brain accumulates DHA in its cellular membranes more than any other organ in the body. To do this, it uses a transporter called Mfsd2a. Because DHA has a long and irregular shape, it increases membrane fluidity while also restricting transport across membranes.
These qualities make DHA well suited for the needs of the blood-brain barrier. Illustrative of the functional importance of omega-3 DHA in the healthy maintenance of the blood-brain barrier, blocking the transport of DHA has been investigated in the lab as a drug action that temporarily permeabilizing the brain-brain barrier for specialized purpose (e.g., enhancing brain drug delivery of chemotherapeutics).
Common dietary sources of EPA and DHA include seafood and fish (salmon, mackerel, anchovies, sardines, and herring are particularly dense sources), but can also be found in microalgae. Fish and seafood provide omega-3s in long-chain form, which are used by the body differently from plant sources of omega-3s. Learn about this specialized role of omega-3 DHA in our overview of the blood-brain barrier here.
Polyphenols, a large class of bioactive plant compounds found in foods such as berries and green tea, have also notably been shown to improve endothelial function. In one study involving participants with white matter hyperintensities, a supplement containing apple and apple polyphenols, lemon balm, ginger, choline, and vitamin B6 reduced markers of oxidative stress and reduced dizziness and disability.
Diets that minimize salt and sugar intake have a demonstrated relationship with lower small vessel disease risk. Among individuals who had experienced a stroke, a dietary history that minimized salt intake was protective against signs of small vessel disease. In another study with individuals who had experienced a stroke, a lower current intake of high glycemic foods was associated with reduced small vessel disease burden.
Q: How does the gut microbiota contribute to small vessel disease?
Among participants without a history of dementia or stroke, an enterotype (i.e., broad categorization of the types of bacteria that predominate in the microbiota) predominated by the genera Bacteroides was associated with more signs of cerebral small vessel disease, cognitive decline, and behavioral and psychological symptoms. In another study, depletion of beneficial microbes that strengthen the gut barrier, such as Akkermansia muciniphila, increases blood pressure and small vessel disease burden.
Previous research demonstrates that a Western diet pattern, heavy in animal fat and protein, shifts the gut microbiota toward the Bacteroides enterotype, while a diet high in fiber-rich plant foods shifts the microbiota toward an enterotype predominated by the genus Prevotella. Among patients with Parkinson's disease, an enterotype predominated by Bacteroides was associated with a reduced concentration of barrier-strengthening fecal short-chain fatty acids (e.g., butyrate) and increased concentration of fecal calprotectin, a marker of intestinal inflammation, and zonulin, a tight-junction protein and marker of intestinal barrier dysfunction.