Six proteins can be used to assess a risk of developing cerebral small vessel disease (CSVD)

Comparison of gray matter volume between CSVD patients with and without VCIND. Blue to green represents regions of the brain that have significantly larger GM volume in CSVD patients without than with VCIND at a threshold of p=0.001, uncorrected. Red to yellow represents regions of the brain that have significantly larger GM volume in CSVD patients with than without VCIND at a threshold of p=0.001, uncorrected.

A UCLA-led study has found that levels of six proteins in the blood can be used to gauge a person’s risk for cerebral small vessel disease, or CSVD, a brain disease that affects an estimated 11 million older adults in the U.S. CSVD can lead to dementia and stroke, but currently it can only be diagnosed with an MRI scan of the brain.

“The hope is that this will spawn a novel diagnostic test that clinicians can start to use as a quantitative measure of brain health in people who are at risk of developing cerebral small vessel disease,” said Dr. Jason Hinman, a UCLA assistant professor of neurology and lead author of the paper, which is published in the journal PLOS ONE.

CSVD is characterized by changes to the brain’s white matter — the areas of the brain that have a high concentration of myelin, a fatty tissue that insulates and protects the long extensions of brain cells.

In CSVD, small blood vessels that snake through the white matter become damaged over time and the myelin begins to break down.

This slows the communication between cells in the brain and can lead to problems with cognition and difficulty walking.

And if the blood vessels become completely blocked, it can cause stroke.

The disease is also associated with a heightened risk for multiple forms of dementia, including Alzheimer’s disease.

Typically, doctors diagnose CSVD with an MRI scan after a person has experienced dementia or suffered a stroke.

About a quarter of all strokes in the U.S. are associated with CSVD. But many cases of the disease go undiagnosed because of mild symptoms, such as trouble with walking or memory, that can often be attributed to normal aging.

In the new study, Hinman and colleagues focused on six proteins related to the immune system’s inflammatory response and centered on a molecule called interleukin-18, or IL-18.

They hypothesized that inflammatory proteins that damage the brain in CSVD may be detectable in the bloodstream.

The researchers measured the levels of the proteins in the blood of 167 people whose average age was 76.4, and who had either normal cognition or mild cognitive impairment.

As part of their voluntary participation in the study, 110 participants also underwent an MRI brain scan and 49 received a more advanced scan called diffusion tensor imaging.

This shows brain scans from the study

MRI scans shows showing the average measurable difference in white matter brain damage in people with low inflammatory blood test scores (below median) and those with high scores (above median). Image is credited to UCLA Health.

People whose MRI or diffusion tensor imaging tests showed signs of CSVD had significantly higher levels of the six blood proteins, the researchers discovered.

If a person had higher-than-average levels of the six inflammatory proteins, they were twice as likely to have signs of CSVD on an MRI scan and 10% more likely to very early signs of white matter damage.

Moreover, for every CSVD risk factor that a person had — such as high blood pressure, diabetes, or a previous stroke — the inflammatory protein levels in their blood were twice as high, on average.

To confirm the results, the team performed the blood test in a group with a much higher risk for CSVD: 131 people who visited a UCLA Health emergency department with signs of stroke. Once again, the blood test results were correlated with white matter changes in the brain that were detected by an MRI.

“I was pleasantly surprised that we were able to associate blood stream inflammation with CSVD in two fairly different populations,” Hinman said.

In MRI reports, the changes in the brain’s white matter caused by CSVD are usually only categorized in general terms — as mild, moderate or severe.

The blood test is a step forward, Hinman said, because it provides a more quantitative scale for evaluating the disease.

That means the blood test can be used to follow the progression of the disease or to identify people who are candidates for prevention efforts or treatments for CSVD.

“We’re hopeful that this will set the field on more quantitative efforts for CSVD so we can better guide therapies and new interventions,” Hinman said.

The blood test is not commercially available at this time.

The study’s first author is Marie Altendahl, a UCLA medical student who was at UC San Francisco at the time of the study. Other UCLA-affiliated authors are former undergraduate researcher Visesha Kakarla and former postdoctoral research fellow Guanxi Xiao. Other authors are from UC San Francisco and UC Davis.

Funding: The study was funded by the National Institutes of Health, the American Heart Association, the MarkVCID consortium and the Lillian R. Gleitsman Foundation.

Cerebral small vessel disease (CSVD) refers to a diverse range of clinical and neuroimaging findings resulting from pathological changes of various etiologies affecting the cerebral small vessels, particularly small veins, venules, capillaries, arterioles, and small arteries (Pantoni and Gorelick, 2014).

More prevalent in the elderly, CSVD doubled the risk of stroke (Bernick et al., 2001Vermeer et al., 2007) and has been shown to be responsible for about 30% of ischemic strokes (Warlow et al., 2003Pantoni, 2010Bath and Wardlaw, 2015).

Importantly, CSVD is recognized as an important cause of cognitive dysfunction, dementia, and functional disability among the sufferers (Pantoni and Gorelick, 2014Zwanenburg and van Osch, 2017).

In fact, a recent systematic review had concluded that some neuroimaging features of CSVD are associated with an increased risk of Alzheimer’s disease (AD), a disease clinically characterized by cognitive dysfunction and dementia.

However, the causal link between the two diseases remains inconclusive (Liu et al., 2018).

Notably, the inconsistency in terms of the definition, unstandardized neuroimaging reporting, and silent nature of the disease at the early stage hampers a deeper understanding of its pathogenesis and subsequent effective therapeutic measures (Wardlaw et al., 2013a).

These challenges had instigated efforts among researchers to establish a standard framework in the CSVD research field.

In a recent development, a standard approach in reporting neuroimaging findings had been proposed in CSVD based on the Standards for Reporting Vascular changes in neuroimaging (STRIVE) (Wardlaw et al., 2013b).

In particular, the STRIVE collaborative group had advised the minimum standard requirement for image acquisition and analysis, a scientific reporting standard technique for neuroimaging features of CSVD, and suggested common terms and definitions for neuroimaging changes found in CSVD, namely

(i) white matter hyperintensity of presumed vascular origin;

(ii) lacunae of presumed vascular origin;

(iii) recent small subcortical infarct;

(iv) perivascular space;

(v) cerebral microbleed; and

(vi) brain atrophy (Wardlaw et al., 2013b).

Nonetheless, notably, due to the current limitation of standard neuroimaging techniques, the term CSVD reflects only the neuroradiological changes of the brain parenchyma rather than the small vessels of interest (Pantoni and Gorelick, 2014).

Meanwhile, postmortem examinations of the diseased small vessels revealed distinct histopathological changes, such as fibrinoid necrosis, arteriosclerosis, and atherosclerosis (Lammie, 2002Pantoni and Gorelick, 2014).

In view of the social and healthcare burden it may incur, contemporary and collaborative efforts are necessary to generate and expand our current understanding of CSVD from the aspects of its pathomechanism, systems biology, opportunities for early disease biomarkers, and potential therapeutic approaches. This chapter summarizes these core topics from the perspectives of numerous experimental animal models of CSVD.

Cerebral Small Vessel Disease (CSVD) – Classification and Pathogenesis

One of the predominant types of strokes resulting from the occlusion (ischemia) of small blood vessels deep within the brain is an ischemic stroke (Rouhl et al., 2009Smith, 2017). About 30% of ischemic or lacunar strokes are thought to be due to CSVD (Rouhl et al., 2009Patel and Markus, 2011Heye et al., 2015).


The definition of CSVD remains contentious due to its complex and overlapping pathophysiological mechanism. However, it is generally accepted that CSVD is mainly due to the pathological consequences of small vessel disease on the brain parenchyma rather than the underlying diseases of the vessels (Wardlaw et al., 2013c).

Therefore, the term CSVD is preferred to describe a brain parenchyma injury that is associated with distal leptomeningeal and intracerebral vessel pathology that resides in poorly collateralized subcortical gray and deep white matter.

Moreover, it is mainly due to several vasculo-pathological processes that affect and cause occlusion to the small perforating cerebral capillaries (of sizes 50–400 μm), small arteries (mostly branches of middle cerebral arteries [MCAs]), arterioles, and venules that penetrate and supply the brain subcortical region (Pantoni, 2010Novakovic, 2010Hinman et al., 2015Benjamin et al., 2016) (Figure 1).

Several manifestations of CSVD can be seen through clinical, radiological, or pathological phenomena with various etiologies (Ogata et al., 2014Sorond et al., 2015Yakushiji et al., 2018).

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Object name is fphys-10-01317-g001.jpg
Illustration of cerebral vasculature and vasculo-pathological process of CSVD. (A) Different branches of cerebral arteries and their territories that supply cerebral white matter. (1) represent cortical arteries, (2) pial arterioles that supply deep white matter, (2.1) short branches, (3) anterior choroidal arteries that branch into sub-ependymal arteries, (4) arterioles of sub-ependymal, (5) MCA branches into thalamic and lenticulostriate perforating arteries that supply basal ganglia (Image source: Martorell et al., 2012). (B) Illustration of general aetiophatogenic features of CSVD. The picture shows branches of MCA that penetrate the subcortical region of white matter and gray matter. Embolus or thrombus may accumulate and cause occlusion (atheroma) upon the parent MCA and penetrating arteriolar. The occlusion of perforating arteriolar can cause ischemia and eventually a lacunar infarct may be formed. The core infarcts might affect surrounding tissue (penumbra). Diffused disruption of the BBB following intrinsic CSVD also occurred at the arteriolar level (Image source: Shi and Wardlaw, 2016).


There are several etiopathogenic classifications of CSVD. However, the most prevalent forms of CSVD are amyloidal CSVD (sporadic and hereditary cerebral amyloid angiopathy [CAA]) and non-amyloidal CSVD (age-related and vascular risk-factor-related small vessel, i.e., arteriolosclerosis) (Pantoni, 2010).

Other less common forms of CSVD include inherited or genetic CSVD that is recognizably different from CAA (i.e., Fabry’s disease and cerebral autosomal dominant arteriopathy with subcortical ischemic strokes and leukoencephalopathy [CADASIL]), inflammatory and immunologically mediated CSVD, venous collagenosis, and other CSVD (i.e., non-amyloid microvessel degeneration in AD and post-radiation angiopathy). 

Table 1 describes the two major etiopathogenic classes of CSVD based on clinical and neuroimaging characteristic differences.


Etiopathogenic classification based on clinical and neuroimaging characteristic differences in two major classes of CSVD (Vinters, 1987McCarron and Nicoll, 2004Love et al., 2009Pantoni, 2010Biffi and Greenberg, 2011Charidimou et al., 2012Charidimou and Jäger, 2014Cuadrado-Godia et al., 2018Li et al., 2018).

ClassificationCharacteristicsPathologyNeuroimaging featuresClinical syndromes
Form 1• Non-amyloidal CSVD• Arteriolosclerosis (age-related and vascular risk-factor-related small vessel diseases)• Advances with age• Degenerative microangiopathy• Loss of smooth muscle cells from the tunica media (i.e., arteriolosclerosis)• Deposit of fibro-hyaline material (i.e., lipohyalinosis)• Narrowing of lumen (i.e., microatheroma)• Thickening of vessel wall (i.e., microaneurysms)• Segmental arterial disorganization• Deep cerebral microbleeds• Rare cortical superficial siderosis• Basal ganglia perivascular space• Non-specific cerebral region of WMHs• Lacunar strokes• Often deep (basal ganglia, thalamus, pons, cerebellum ICH)• Cognitive impairment and dementia
Form 2• Amyloidal CSVD• Sporadic and hereditary CAA• Advances with age• Accumulation of amyloid-β (Aβ) in the cortical walls (type 1) and leptomeningeal small arteries, but not capillaries (type 2) due to vascular occlusion and rupture• Vasculopathy (i.e., fibrinoid necrosis, loss of smooth muscle cells, wall thickening, perivascular blood breakdown, and microaneurysm)• APOE gene polymorphism (i.e., APOE ε2 and APOE ε4 allele related to types 2 and 1, respectively)• Lobar cerebral microbleeds• Most significant feature (marker of CAA): cortical superficial siderosis• Centrum semiovale perivascular space• Posterior dominance WMHs• Lobar ICH• Non-lacunar strokes• Transient focal neurological episodes, cognitive impairment, and dementia• Hallmarks of AD

AD, Alzheimer’s disease; APOE, apolipoprotein E; CAA, cerebral amyloid angiopathy; CSVD, cerebral small vessel disease; ICH, intracerebral hemorrhage; WMHs, white matter hyperintensities.



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