blood vessel The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...

immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...

pia mater Pia mater ( or ),Entry "pia mater"
in
subarachnoid space. In the brain, ''perivascular cuffs'' are regions of leukocyte aggregation in the perivascular spaces, usually found in patients with

viral encephalitis Viral encephalitis is inflammation of the brain parenchyma, called encephalitis, by a virus. The different forms of viral encephalitis are called viral encephalitides. It is the most common type of encephalitis and often occurs with viral meningiti ...

. Perivascular spaces vary in dimension according to the type of blood vessel. In the brain where most capillaries have an imperceptible perivascular space, select structures of the brain, such as the

circumventricular organs Circumventricular organs (CVOs) ( circum-: around ; ventricular: of ventricle) are structures in the brain characterized by their extensive and highly permeable capillaries, unlike those in the rest of the brain where there exists a blood� ...

, are notable for having large perivascular spaces surrounding highly

permeable Permeability, permeable, and semipermeable may refer to: Chemistry *Semipermeable membrane, a membrane which will allow certain molecules or ions to pass through it by diffusion *Vascular permeability, the movement of fluids and molecules betwe ...

capillaries, as observed by microscopy. The

median eminence The median eminence, part of the inferior boundary of the hypothalamus in the brain, is attached to the infundibulum. The median eminence is a small swelling on the tuber cinereum, posterior to and atop the pituitary stalk; it lies in the area rou ...

, a brain structure at the base of the

hypothalamus The hypothalamus () is a part of the brain that contains a number of small nuclei with a variety of functions. One of the most important functions is to link the nervous system to the endocrine system via the pituitary gland. The hypothalamu ...

, contains capillaries with wide perivascular spaces. In humans, perivascular spaces surround arteries and veins can usually be seen as areas of dilatation on MRI images. While many normal brains will show a few dilated spaces, an increase in these spaces may correlate with the incidence of several

neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

diseases, making the spaces a topic of research.

Structure

Perivascular spaces are gaps containing

interstitial fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

that span between blood vessels and their host organ, such as the brain, which they penetrate and serve as extravascular channels through which solutes can pass. Like the blood vessels around which they form, perivascular spaces are found in both the brain subarachnoid space and the subpial space. Perivascular spaces surrounding

arteries An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...

in the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...

and the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

are separated from the subpial space by one or two layers of leptomeninges, respectively, as well as the

pia mater Pia mater ( or ),Entry "pia mater"
in
veins Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenated b ...

. Use of the scanning electron microscope has determined that the spaces surrounding blood vessels in the subarachnoid space are not continuous with the subarachnoid space because of the presence of pia mater cells joined by

desmosomes A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin for ''adhering spot''), is a cell structure specialized for cell-to- cell adhesion. A type of junctional complex, they are localized spot-like ad ...

. Perivascular spaces, especially around

fenestra A fenestra (fenestration; plural fenestrae or fenestrations) is any small opening or pore, commonly used as a term in the biological sciences. It is the Latin word for "window", and is used in various fields to describe a pore in an anatomical st ...

ted capillaries, are found in many organs, such as the

thymus The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or ''T cells'' mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. ...

,

liver The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...

,

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

s,

spleen The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes .

,

bone A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...

s, and pineal gland. Particularly within the brain circumventricular organs –

subfornical organ The subfornical organ (SFO) is one of the circumventricular organs of the brain. Its name comes from its location on the ventral surface of the fornix near the interventricular foramina (foramina of Monro), which interconnect the lateral ventr ...

,

area postrema The area postrema, a paired structure in the medulla oblongata of the brainstem, is a circumventricular organ having permeable capillaries and sensory neurons that enable its dual role to detect circulating chemical messengers in the blood and t ...

, and median eminence – large perivascular spaces are present around fenestrated capillaries, indicating that the spaces serve a dispersive role for brain- or

bloodborne is a 2015 action role-playing game developed by FromSoftware and published by Sony Computer Entertainment for the PlayStation 4. ''Bloodborne'' follows the player's character, a Hunter, through the decrepit Gothic, Victorian-era–inspired ...

messengers. Perivascular spaces may be enlarged to a diameter of five millimeters in healthy humans and do not imply disease. When enlarged, they can disrupt the function of the brain regions into which they project. Dilation can occur on one or both sides of the brain. Dilated perivascular spaces are categorized into three types: * Type 1 are located on the lenticulostriate arteries projecting into the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

* Type 2 are located in the cortex following the path of the medullary arteries * Type 3 are located in the

midbrain The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', " ...

Perivascular spaces are most commonly located in the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

and

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

of the

cerebrum The cerebrum, telencephalon or endbrain is the largest part of the brain containing the cerebral cortex (of the two cerebral hemispheres), as well as several subcortical structures, including the hippocampus, basal ganglia, and olfactory bulb ...

, and along the

optic tract In neuroanatomy, the optic tract () is a part of the visual system in the brain. It is a continuation of the optic nerve that relays information from the optic chiasm to the ipsilateral lateral geniculate nucleus (LGN), pretectal nuclei, and su ...

. The ideal method used to visualize perivascular spaces is

T2-weighted MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

. The MR images of other

neurological Neurology (from el, νεῦρον (neûron), "string, nerve" and the suffix -logia, "study of") is the branch of medicine dealing with the diagnosis and treatment of all categories of conditions and disease involving the brain, the spinal c ...

disorder Disorder may refer to randomness, non-order, or no intelligible pattern. Disorder may also refer to: Healthcare * Disorder (medicine), a functional abnormality or disturbance * Mental disorder or psychological disorder, a psychological pattern ...

s can be similar to those of the dilated spaces. These disorders are: * cystic neoplasms * lacunar infarctions * cystic periventricular leukomalacia *

cryptococcosis Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the ...

* multiple sclerosis * mucopolysaccharidoses * neurocysticercosis * arachnoid cysts * neuroepithelial cysts Perivascular spaces are distinguished on an MRI by several key features. The spaces appear as distinct round or oval entities with a signal intensity visually equivalent to that of

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

in the subarachnoid space. In addition, a perivascular space has no mass effect and is located along the blood vessel around which it forms.

Function

One of the most basic roles of the perivascular space is the regulation of fluid movement in the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...

and its drainage. The spaces ultimately drain fluid from neuronal cell bodies to the

cervical lymph nodes Cervical lymph nodes are lymph nodes found in the neck. Of the 800 lymph nodes in the human body, 300 are in the neck. Cervical lymph nodes are subject to a number of different pathological conditions including tumours, infection and inflammati ...

. In particular, the “tide hypothesis” suggests that the cardiac contraction creates and maintains pressure waves to modulate the flow to and from the subarachnoid space and the perivascular space. By acting as a sort of sponge, they are essential for signal transmission and the maintenance of

extracellular fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a low ...

. Another function is as an integral part of the blood–brain barrier (BBB). While the BBB is often described as the tight junctions between the endothelial cells, this is an oversimplification that neglects the intricate role that perivascular spaces take in separating the venous blood from the parenchyma of the brain. Often, cell debris and foreign particles, which are impermeable to the BBB will get through the endothelial cells, only to be

phagocytosed Phagocytosis () is the process by which a cell uses its plasma membrane to engulf a large particle (≥ 0.5 μm), giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is c ...

in the perivascular spaces. This holds true for many T and B cells, as well as

monocyte Monocytes are a type of leukocyte or white blood cell. They are the largest type of leukocyte in blood and can differentiate into macrophages and conventional dendritic cells. As a part of the vertebrate innate immune system monocytes also ...

s, giving this small fluid filled space an important

immunological Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...

role. Perivascular spaces also play an important role in immunoregulation; they not only contain

interstitial An interstitial space or interstice is a space between structures or objects. In particular, interstitial may refer to: Biology * Interstitial cell tumor * Interstitial cell, any cell that lies between other cells * Interstitial collagenase ...

and cerebrospinal fluid, but they also have a constant flux of macrophages, which is regulated by blood-borne mononuclear cells, but do not pass the basement membrane of the glia limitans. Similarly, as part of its role in signal transmission, perivascular spaces contain vasoactive

neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...

s (VNs), which, aside from regulating blood pressure and heart rate, have an integral role in controlling microglia. VNs serve to prevent inflammation by activating the enzyme

adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

which then produces

cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...

. The production of cAMP aids in the modulation of auto-reactive

T cells A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...

by regulatory T cells. . The perivascular space is susceptible space for VN compromise and when their function is reduced in the space, immune response is adversely affected and the potential for degradation increases. When inflammation by T cells begins,

astrocyte Astrocytes (from Ancient Greek , , "star" + , , "cavity", "cell"), also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord. They perform many functions, including biochemical control of e ...

s begin to undergo apoptosis, due to their CD95 receptor, to open up the glia limitans and let T cells into the parenchyma of the brain. Because this process is aided by the perivascular macrophages, these tend to accumulate during neuroinflammation and cause dilation of the spaces.

Clinical significance

The clinical significance of perivascular spaces comes primarily from their tendency to dilate. The importance of dilation is hypothesized to be based on changes in shape rather than size. Enlarged spaces have been observed most commonly in the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

, specifically on the lenticulostriate arteries. They have also been observed along the paramedial mesencephalothalamic artery and the substantia nigra in the

mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...

, the brain region below the insula, the dentate nucleus in the cerebellum, and the

corpus callosum The corpus callosum (Latin for "tough body"), also callosal commissure, is a wide, thick nerve tract, consisting of a flat bundle of commissural fibers, beneath the cerebral cortex in the brain. The corpus callosum is only found in placental m ...

, as well as the brain region directly above it, the

cingulate gyrus The cingulate cortex is a part of the brain situated in the medial aspect of the cerebral cortex. The cingulate cortex includes the entire cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the ...

. Upon the clinical application of MRI, it was shown in several studies that perivascular space dilation and

lacunar stroke Lacunar stroke or lacunar cerebral infarct (LACI) is the most common type of ischemic stroke, resulting from the occlusion of small penetrating arteries that provide blood to the brain's deep structures. Patients who present with symptoms of a lac ...

s are the most commonly observed histological correlates of signaling abnormalities.

Senescence

Dilation is most commonly and closely associated with aging. Dilation of perivascular spaces has been shown to correlate best with age, even when accompanying factors including hypertension,

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

, and

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

lesions are considered. In the elderly, such dilation has been correlated with many symptoms and conditions that often affect the arterial walls, including vascular hypertension,

arteriosclerosis Arteriosclerosis is the thickening, hardening, and loss of elasticity of the walls of arteries. This process gradually restricts the blood flow to one's organs and tissues and can lead to severe health risks brought on by atherosclerosis, which ...

, reduced cognitive capacity, dementia, and low post-mortem brain weight. In addition to dilation among the elderly, dilation in young, healthy individuals can also be observed. This occurrence is rare and there has been no observed association in such cases with reduced cognitive function or white matter abnormalities. When dilated VRS are observed in the corpus callosum, there is generally no neurological deficit associated. They are often observed in this region as cystic lesions with cerebrospinal-like fluid.

Symptoms of dilation

Extreme dilation has been associated with several specific clinical symptoms. In cases of severe dilation in only one hemisphere, symptoms reported include a non-specific fainting attack, hypertension, positional

vertigo Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...

, headache, early recall disturbances, and hemifacial tics. Symptoms associated with severe bilateral dilation include ear pain (which was reported to have resolved on its own), dementia, and seizures. This data was compiled from case studies of individuals with severe VRS dilation. Considering the anatomical abnormality presented in such cases, these findings were considered surprising in that the symptoms were relatively mild. In most cases, there is in fact no mass effect associated with some VRS dilation. An exception to the mildness of clinical symptoms associated with VRS dilation is when there is extreme dilation in the lower

mesencephalon The midbrain or mesencephalon is the forward-most portion of the brainstem and is associated with vision, hearing, motor control, sleep and wakefulness, arousal (alertness), and temperature regulation. The name comes from the Greek ''mesos'', "m ...

at the junction between the substantia nigra and

cerebral peduncle The cerebral peduncles are the two stalks that attach the cerebrum to the brainstem. They are structures at the front of the midbrain which arise from the ventral pons and contain the large ascending (sensory) and descending (motor) nerve tract ...

. In such cases, mild to moderate obstructive

hydrocephalus Hydrocephalus is a condition in which an accumulation of cerebrospinal fluid (CSF) occurs within the brain. This typically causes increased pressure inside the skull. Older people may have headaches, double vision, poor balance, urinary inc ...

was reported in most patients. Associated symptoms ranged from headaches to symptoms more severe than those just discussed in the cases of dilation in the cerebral hemispheres. Other general symptoms associated with VRS dilation include headaches, dizziness, memory impairment, poor concentration, dementia, visual changes, oculomotor abnormality, tremors, seizures, limb weakness, and

ataxia Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements. Ataxia is a clinical manifestation indicating dysfunction of ...

.

Associated disorders

Dilation is a typical characteristic of several diseases and disorders. These include diseases from metabolic and genetic disorders such as mannosidosis,

myotonic dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intel ...

, Lowe syndrome, and

Coffin–Lowry syndrome Coffin–Lowry syndrome is a genetic disorder that is X-linked dominant and which causes severe mental problems sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis, as well as auditory and visual abnormalities. ...

. Dilation is also a common characteristic of diseases or disorders of vascular pathologies, including

CADASIL CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the '' Notch 3'' g ...

(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), hereditary infantile hemiparesis, retinal arteriolar tortuosity and leukoencephalopathy, migraines, and vascular dementia. A third group of disorders typically associated with VRS dilation is neuroectodermal syndromes. This includes polycystic brains associated with ectodermal

dysplasia Dysplasia is any of various types of abnormal growth or development of cells (microscopic scale) or organs ( macroscopic scale), and the abnormal histology or anatomical structure(s) resulting from such growth. Dysplasias on a mainly microscopi ...

, frontonasal dysplasia, and

Joubert syndrome Joubert syndrome is a rare autosomal recessive genetic disorder that affects the cerebellum, an area of the brain that controls balance and coordination. Joubert syndrome is one of the many genetic syndromes associated with syndromic retinitis pi ...

. There is a fourth miscellaneous group of disorders typically associated with dilation that includes autism in children, megalencephalopathy, secondary

Parkinson’s disease Parkinson's disease (PD), or simply Parkinson's, is a chronic condition, long-term neurodegeneration, degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disea ...

, recent-onset multiple sclerosis, and chronic

alcoholism Alcoholism is, broadly, any drinking of alcohol that results in significant mental or physical health problems. Because there is disagreement on the definition of the word ''alcoholism'', it is not a recognized diagnostic entity. Predomi ...

. Because dilation can be associated with several diseases but also observed in healthy patients, it is always important in the evaluation of VRS to study the tissue around the dilation via MRI and to consider the entire clinical context.

Current research

Causes of dilated VRS

Much of the current research concerning Virchow–Robin spaces relates to their known tendency to dilate. Research is presently being performed in order to determine the exact cause of dilation in these perivascular spaces. Current theories include mechanical trauma resulting from

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

pulsation, elongation of ectactic penetrating blood vessels, and abnormal vascular permeability leading to increased fluid exudation. Further research has implicated shrinkage or atrophy of surrounding brain tissue, perivascular

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

, coiling of the arteries as they age, altered permeability of the arterial wall and obstruction of lymphatic drainage pathways. In addition, insufficient fluid draining and injury to

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems w ...

perivascular tissue resulting in an ex vacuo effect have been suggested as possible causes for dilated VRS.Dilated VRS might also be linked to vascular damage, blood leakage and microaeurysm formation.

Association of dilated VRS and other diseases

Recent and ongoing research has found associations between enlarged VRS and several disorders.

Dementia

At one point in time, dilated Virchow–Robin spaces were so commonly noted in autopsies of persons with

dementia Dementia is a disorder which manifests as a set of related symptoms, which usually surfaces when the brain is damaged by injury or disease. The symptoms involve progressive impairments in memory, thinking, and behavior, which negatively affe ...

, they were believed to cause the disease. However, additional research is currently being performed in order to confirm or refute a direct connection between dilation of VRS and dementia. Analysis of VRS may distinguish dementia caused by

arteriosclerotic Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no sy ...

microvascular disease Microangiopathy (also known as microvascular disease, small vessel disease (SVD) or microvascular dysfunction) is a disease of the microvessels, small blood vessels in the microcirculation. It can be contrasted to coronary heart disease, an angio ...

from dementia caused by

neurodegenerative A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic ...

disease. A 2005 study has evidenced that a substantial amount of VRS in the substantia innominata,

lentiform nucleus The lentiform nucleus, or lenticular nucleus, comprises the putamen and the globus pallidus within the basal ganglia. With the caudate nucleus, it forms the dorsal striatum. It is a large, lens-shaped mass of gray matter just lateral to the inter ...

, and the

caudate nucleus The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's d ...

of the basal ganglia may implicate dementia due to arteriosclerotic microvascular disease, in particular Ischemic Vascular Dementia, as opposed dementia due to neurodegenerative disease, specifically Alzheimer’s disease and frontotemporal dementia. Thus, perhaps VRS dilation can be used to distinguish between diagnoses of vascular dementias and degenerative dementias.

Alzheimer's disease

Some studies have assessed the spatial distribution and prevalence of VRS in people with Alzheimer's disease versus those without the disease. Researchers have found that while VRS appear to be correlated with natural aging, MR imaging reveals a greater prevalence of VRS in those with Alzheimer's. Cerebral amyloid angiopathy (CAA), a blood vessel failure often associated with Alzheimer's disease, utilizes dilated VRS to spread inflammation to the parenchyma. Because the VRS often have an extra membrane in gray matter, the ischemic CAA response is often observed in white matter. It has been hypothesized that the structure of VRS in the

cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consistin ...

may contribute to the development of Alzheimer’s disease. In contrast to VRS of the

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an exter ...

, VRS in the cerebral cortex are surrounded by only one layer of leptomeninges. As such, VRS in the cerebral cortex may drain

β-amyloid Amyloid beta (Aβ or Abeta) denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid precursor protein (APP), which ...

in

interstitial fluid In cell biology, extracellular fluid (ECF) denotes all body fluid outside the cells of any multicellular organism. Total body water in healthy adults is about 60% (range 45 to 75%) of total body weight; women and the obese typically have a lower ...

less effectively than VRS in the basal ganglia. The less-effective drainage may lead to the development of the β-amyloid plaques that characterize Alzheimer’s disease. In support of this hypothesis, studies have noted the greater frequency of β-amyloid plaques in the cerebral cortex than in the basal ganglia of Alzheimer’s disease patients.

Stroke

Because dilated perivascular spaces are so closely correlated with

cerebrovascular disease Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. Th ...

, there is much current research on their use as a diagnostic tool. In a recent study of 31 subjects, abnormal dilation, along with irregular CSF pulsation, were correlated with those subjects having three or more

risk factors In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...

for strokes. Therefore, perivascular spaces are a possible novel

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

for hemorrhagic strokes.

CADASIL syndrome CADASIL or CADASIL syndrome, involving cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, is the most common form of hereditary stroke disorder, and is thought to be caused by mutations of the '' Notch 3'' ...

(cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy syndrome) is a hereditary stroke condition due to a Notch 3 gene mutation on Chromosome 19. Studies have noted that in comparison to family members lacking the affected haplotype that leads to the condition, an increased number of dilated spaces is observed in individuals with CADASIL. These perivascular spaces are localized primarily in the

putamen The putamen (; from Latin, meaning "nutshell") is a round structure located at the base of the forebrain (telencephalon). The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that compose the basal ...

and temporal subcortical

white matter White matter refers to areas of the central nervous system (CNS) that are mainly made up of myelinated axons, also called tracts. Long thought to be passive tissue, white matter affects learning and brain functions, modulating the distributi ...

and they appear to correlate with age of the individual with the condition rather than severity of the disease itself. There has been a high risk of stroke associated with dilated perivascular spaces in the elderly according to the Framingham Stroke Risk Score. In contrast, other studies have concluded that the dilation of these spaces is a normal phenomenon in aging with no association with arterosclerosis. This remains, therefore, an important point of research in the field.

Multiple sclerosis

Similar to the research concerning a potential connection between perivascular spaces and Alzheimer's, MRI scans of people recently diagnosed with multiple sclerosis (MS) have been studied. Larger, more prevalent spaces have been observed in those with MS. Additional studies with similar findings have suggested that the inflammatory cells which contribute to the

demyelination A demyelinating disease is any disease of the nervous system in which the myelin sheath of neurons is damaged. This damage impairs the conduction of signals in the affected nerves. In turn, the reduction in conduction ability causes deficiency i ...

that characterizes MS also attack the perivascular spaces. Studies using advanced MRI techniques will be necessary to determine if the perivascular spaces can be implicated as a potential marker of the disease.

Autism

Dilated perivascular spaces are common among the elderly and uncommon in children. Studies have noted the association between both

developmental delay Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...

and non-syndromic autism and enlarged or dilated perivascular spaces. Non-syndromic autism categorizes autistic patients for which there is no known cause.

History

The appearance of perivascular spaces was first noted in 1843 by Durant-Fardel. In 1851,

Rudolph Virchow Rudolf Ludwig Carl Virchow (; or ; 13 October 18215 September 1902) was a German physician, anthropologist, pathologist, prehistorian, biologist, writer, editor, and politician. He is known as "the father of modern pathology" and as the founde ...

was the first to provide a detailed description of these microscopic spaces between the outer and inner/middle lamina of the brain vessels. Charles-Philippe Robin confirmed these findings in 1859 and was the first to describe the perivascular spaces as channels that existed in normal anatomy. The spaces were called ''Virchow-Robin spaces'' and are still also known as such. The immunological significance was discovered by Wilhelm His, Sr. in 1865 based on his observations of the flow of interstitial fluid over the spaces to the lymphatic system. For many years after Virchow-Robin spaces were first described, it was thought that they were in free communication with the

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

in the subarachnoid space. It was later shown with the use of electron microscopy that the

pia mater Pia mater ( or ),Entry "pia mater"
in
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...

, measurements of the differences of signal intensity between the perivascular spaces and cerebrospinal fluid supported these findings. As research technologies continued to expand, so too did information regarding their function, anatomy and clinical significance.

References

{{Meninges Rudolf Virchow Meninges Neurohistology