REVIEW

Visualizing Cerebral Small Vessel

Degeneration During Aging and Diseases
Using Magnetic Resonance Imaging
Peiyu Huang, PhD,1* Kang Chen, MD, PhD,2* Chen Liu, MD, PhD,2 Zhiming Zhen, MD,2
and Ruiting Zhang, MD, PhD1*

Cerebral small vessel disease is a major contributor to brain disorders in older adults. It is associated with a much higher
risk of stroke and dementia. Due to a lack of clinical and fluid biomarkers, diagnosing and grading small vessel disease are
highly dependent on magnetic resonance imaging. In the past, researchers mostly used brain parenchymal imaging
markers to represent small vessel damage, but the relationships between these surrogate markers and small vessel pathol-
ogies are complex. Recent progress in high-resolution magnetic resonance imaging methods, including time-of-flight MR
angiography, phase-contrast MR angiography, black blood vessel wall imaging, susceptibility-weighted imaging, and
contrast-enhanced methods, allow for direct visualization of cerebral small vessel structures. They could be powerful tools
for understanding aging-related small vessel degeneration and improving disease diagnosis and treatment. This article will
review progress in these imaging techniques and their application in aging and disease studies. Some challenges and
future directions are also discussed.
Evidence Level: 4.
Technical Efficacy: 3.
J. MAGN. RESON. IMAGING 2023;58:1323–1337.

Cerebral Small Vessel and Related Diseases
The term cerebral small vessel encompasses small arterioles,
capillaries, and small veins.1 The small arteries may originate
either from meningeal arteries or directly from large vessels at
the base of the brain. They pass through the cortical layers or
deep gray matter, transporting blood into capillaries in the whole
brain. Then the blood flows out through superficial venules and
deep medullary veins. Although there is not a clear definition of
the upper limit on the diameters of small vessels, they refer to
those with a diameter ranging from dozens to hundreds of
micrometers, such as the lenticulostriate arteries (LSAs), deep
medullary veins (DMVs), pontine arteries (PA), and so on.
A variety of factors, including aging, gene mutations, and
health conditions (hypertension, diabetes, etc.), can lead to the
degeneration of cerebral small vessels and further causes small
vessel disease (SVD).1 The underlying pathologies can be very
complex, including arteriolosclerosis, cerebral amyloid
angiopathy (CAA), venous collagenosis, neuroinflammation, and
so on,2,3 and are still under investigation. These pathologies can
coexist and cause vessel stenosis\occlusion, thickened and stiffed
vessel walls, increased permeability, and so on. The causal links
from basic pathologies to parenchymal damages and clinical
impairments are very complex and still poorly understood. The
same pathology may act differently on individuals due to both
environmental and genetic factors.1 Nevertheless, it is usually
accepted that these pathologies first lead to altered vascular struc-
tures and functions, resulting in compromised cerebral blood
supply and eventually causing parenchymal damage.4 Mutations

View this article online at wileyonlinelibrary.com. DOI: 10.1002/jmri.28736

Received Jan 8, 2023, Accepted for publication Mar 30, 2023.

*Address reprint requests to: P.H., R.Z., Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, No. 88 Jiefang Road,
Shangcheng District, Hangzhou, China, 310009. E-mail: huangpy@zju.edu.cn, zhangruiting@zju.edu.cn, or K.C., Department of Radiology, Southwest Hospital,
Army Medical University (Third Military Medical University), 30 Gao Tan Yan Street, Shapingba District, Chongqing, China. E-mail: 258410723@qq.com
The authors have been supported by the Natural Science Foundation of Zhejiang Province (Grant No. LQ20H180015 and LSZ19H180001), the National Natural
Science Foundation of China (Grant Nos. 81571654 and 81771820), the China Postdoctoral Science Foundation (Grant No. 2019M662083) and the Zhejiang
province Postdoctoral Science Foundation.

From the 1Department of Radiology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; and 2Department of Radiology,
Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China

© 2023 International Society for Magnetic Resonance in Medicine. 1323

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Journal of Magnetic Resonance Imaging

in a few genes can cause monogenic SVDs,1 including cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL), cerebral autosomal recessive
arteriopathy with subcortical infarcts and leukoencephalopathy
(CARASIL), and so on.
SVD is highly prevalent in older adults5 and is associ-
ated with a more than 2-fold increased risk of stroke and
nearly 50% of dementia worldwide.6 It is als related to affec-
tive disorders, gait disorders, and Parkinsonism. Because SVD
can either co-occur with large vessel damage or develop inde-
pendently, increasing focus has been given to it clinical man-
agement. Treatment strategies, such as lowering blood
pressure, managing lifestyle and behaviors, and controlling
inflammation, have been proposed to slow down SVD
progression,7 and there are still many ongoing clinical trials.
As most SVD damages develop slowly and the clinical
symptoms are mild, it is difficult to diagnose SVD based on
clinical assessments, either by cognitive assessments or by blood
tests. The current diagnostic criteria of SVD are heavily based
on magnetic resonance imaging (MRI) markers,8 which will be
discussed below.
A General View of MRI Markers
Because of the small diameters, direct detection of vessel alter-
ations is difficult on clinical MR images. Therefore,
parenchymal lesions have been suggested as surrogate markers
to reflect the existence and severity of SVD. In the widely
used STandards for ReportIng Vascular changes on nEuroim-
aging (STRIVE),8 several markers were considered: recent
small subcortical infarct, white matter hyperintensity
(WMH), lacune, perivascular space, cerebral microbleed, and
so on. Visual grading is usually performed to assess the pres-
ence, number, location, and morphometric features of these
markers.8 With machine-learning-based methods, automatic
segmentation has been increasingly used to provide quantita-
tive measures (volume, length, linearity). A demonstration of
these markers can be seen in Fig. 1. As their associations with
aging, vascular risk factors, and severe vascular events have
been repeatedly confirmed,9,10 these structural markers have
been recognized as diagnostic markers of SVD and are widely
used in clinical studies.11
Imaging markers are more sensitive in reflecting disease
progression than clinical assessments.12 It has been estimated
that the sample size could be reduced from 6135 (using exec-
utive function as the outcome measure) to 124 (using WMH
as the outcome measure) in a 3-year clinical trial on managing
SVD progression, assuming a 30% treatment effect.12 How-
ever, the longitudinal changes in traditional parenchymal
markers are still slow (mostly less than 1 mL/year).13,14 To
better monitor disease progression, various diffusion imaging
markers have been adopted.15,16 Metrics such as the peak

FIGURE 1: Clinical markers of SVD. (a–e) Images from one patient with severe SVD. (f) One patient with acute subcortical infarcts. (g, h)
One patient with CADASIL. Yellow: white matter hyperintensities (WMH) can appear near ventricles or in the deep white matter. In
patients with CADASIL, WMH frequently develops into the temporal pole and superficial white matter. Red: lacune appears dark on
T1-weighted images and FLAIR images and bright on T2-weighted images. Blue: perivascular spaces are bright on T2-weighted images
and dark on T1-weighted images. Orange: microbleeds in the basal ganglia and cortical regions; susceptibility-weighted imaging can
detect microbleeds with high sensitivity. Purple: recent small subcortical infarcts appear bright on diffusion-weighted images.

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Huang et al.: Visualizing cerebral small vessel degeneration using MRI
FIGURE 2: A summary of the relationship between SVD pathologies, MRI markers, and clinical dysfunctions. In this article, we mainly
focus on vascular structural imaging.
width of skeletonized mean diffusivity17 and free water18
demonstrated good association with parenchymal SVD
markers and clinical functions.17,19
A potential pitfall of the parenchymal markers is that
they are nonspecific to the underlying small vessel patholo-
gies. For example, WMH can also occur due to other
pathologies,20 such as demyelination and inflammation, and
microbleeds can appear after small infarcts.21 In a recent
study, the authors demonstrated that acute diffusion-weighted
imaging (DWI) lesions could either evolve into WMH,
lacune, or microbleed or just disappear within a year,21 dem-
onstrating the complex associations between disease patholo-
gies and SVD markers. Diffusion imaging markers are also
affected by other pathologies such as demyelination,22
tauopathy,23 and so on. Therefore, while these surrogate
markers could reflect SVD in some respects, one should
always be careful when linking the markers with the pre-
sumed pathologies.
Imaging on the vascular level may provide more direct
evidence of vascular damage (Fig. 2). A variety of MRI
methods enable the noninvasive evaluation of cerebral vascu-
lar functions.24 In addition to the widely used arterial spin
labeling method that assesses cerebral blood flow,25 novel
methods are being continuously developed. Oxygen extrac-
tion fraction26 and cerebral vascular reactivity27 could detect
perfusion deficits at an earlier disease stage. The disruption of
the blood–brain barrier (BBB) could be assessed using
dynamic contrast imaging28 or diffusion-prepared arterial
spin-labeled perfusion MRI.29 These functional markers can
help in understanding the pathologies of SVD from different
aspects. Nonetheless, these markers do not necessarily mean
small vessel damage. For example, cerebral blood flow could
also be related to large artery stenosis.
Visualizing small vessels could provide direct evidence
for understanding brain vasculature and its association with
brain degeneration.30,31 A higher vascular density may pro-
vide resilience against aging and vascular risk factors.32 Some
small arteries, such as the LSAs and anterior choroidal artery,
are crucial for maintaining basic brain functions. Early
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detection of stenosis and abnormal dilation in these arteries
can help make preventive treatment plans.33 In patients with
stroke, visualizing the small vessels may help clinicians to
identify the culprit vessel, assess the degree of damage and
evaluate collateral circulations (will be demonstrated below),
providing information for intervention strategies.
In this review, we will focus on imaging methods that
can visualize small vessel structures and introduce related
studies on aging and cerebral vascular disease. We will cover
techniques including time-of-flight (TOF) MR angiography
(MRA), phase-contrast (PC) MRI, black blood vessel wall
imaging (VWI), susceptibility-weighted imaging (SWI), and
contrast-enhanced imaging. We will also demonstrate the
value of multimodal imaging with clinical cases.
Time-of-Flight MR Angiography
Imaging Principles and Technical Considerations
TOF-MRA is among the most widely used methods for non-
contrast vascular imaging. This technique relies on flow-
related enhancement. By using short repetition time and rela-
tively large flip angles, stationary brain tissue becomes par-
tially saturated, while the inflowing blood remains
unsaturated, thus creating a high contrast between blood ves-
sels and stationary tissues. Therefore, TOF-MRA is more sen-
sitive to large vessels perpendicular to the imaging plane but
relatively insensitive to slow and in-plane flow. In cerebral
vascular imaging, a 3D gradient echo (GRE) sequence is fre-
quently used because of the tortuous blood vessels running at
various orientations. Magnetization transfer pulses are often
adopted to further suppress the stationary tissues, and a pre-
saturation pulse is applied at the upper brain to reduce signal
from traversing veins. Other techniques, such as overlapping
of multiple slabs and variable flip angles, have been used to
reduce the saturation of inflow blood.
Due to the slow blood flow and limited signal-to-noise
ratio (SNR), small cerebral vessels are difficult to be visualized
on 3 T-TOF-MRA images34 (Fig. 3a). A 7 T TOF-MRA
imaging can improve the visualization of cerebral small vessels
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Journal of Magnetic Resonance Imaging
FIGURE 3: Clinical 3 T TOF-MRA image (a, voxel size: 0.75 * 0.6 * 1 mm3) and 7 T high-resolution TOF-MRA image (b, voxel size:
0.18 * 0.18 * 0.4 mm3) showing the lenticulostriate arteries (yellow). (c) An oblique view showing the lenticulostriate arteries
(yellow), anterior choroidal artery (green), and posterior communicating artery (red). (d) The superior cerebellar arteries (blue) and
pontine arteries (grey) can be well displayed.
(Fig. 3b),35 owing to the benefit of a higher SNR and longer
blood T1 relaxation time. Nonetheless, due to a much higher
specific absorption rate (SAR), saturations pulses applied in
clinical images cannot be directly implanted on 7T TOF-
MRA. The problem of field inhomogeneity can also impact
vessel contrast in different brain regions. Several methods,
such as optimized saturating pulses36–38 and parallel
transmission,39 have successfully improved image quality.
For the display of smaller blood vessels, the imaging res-
olution needs to be further increased. Prolonged acquisition
time and head motion could be severe problems. In ultra-fine
resolution imaging, a small head motion can disrupt vessel
display. Clinical patients may find it challenging to keep still
in the scanner due to discomfort. Even in healthy subjects,
head motion due to involuntary movements can still be a
problem during the long scan. Prospective motion correction
(PMC) is an effective solution to the problem. By tracking
body movement through optical cameras or other navigation
methods, feeding back subject position in real-time and
updating the acquisition parameters, adjustments can be
made to compensate for motion-related signal changes.40 Due
to the intrinsic sparsity of TOF-MRA data, compressed sens-
ing (CS)-based image reconstruction can greatly reduce the
amount of data that needs to be acquired. An acceleration
factor larger than seven has been achieved on 7 T TOF-
MRA,36 enabling a 0.3 mm isotropic acquisition covering the
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whole LSAs in less than 8 minutes.36 The image quality may
be further improved by the appropriate choice of under-
sampling parameters.41
TOF-MRA is mainly used to analyze the anatomical
structures of cerebral arteries. The diameters and degree of
stenosis can be measured on TOF-MRA. However, due to its
disadvantage in visualizing slow blood flow, it may over-
estimate stenosis. In high-resolution imaging, the vascular
trees can be tracked and reconstructed, and quantitative met-
rics such as the total length of all sub-branches and shape fea-
tures of the LSAs could be calculated, providing a more
accurate assessment of vascular degeneration.35,42
Research and Clinical Applications
Benefiting from the technical advancements, in vivo imaging
of the exquisite vascular network in the human brain has
been achieved. One study successfully collected data in
2 hours and 14 minutes and reconstructed a 150 μm isotro-
pic TOF-MRA image covering a 46.8 mm thickness of brain
tissue,43 creating an ultra-fine vascular map. The superficial
vessels are crucial for maintaining cortical activities, and col-
lateral circulation in these vessels might prevent brain tissue
from ischemic damage during severe stroke events. One study
optimized TOF-MRA acquisition for imaging pial arteries
through theoretical analyses and experimental acquisitions.44
With the help of PMC, three imaging slabs were acquired in
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Huang et al.: Visualizing cerebral small vessel degeneration using MRI
about an hour, covering 19.6 mm in the head-foot direction.
Combined with postprocessing methods for removing veins,
they successfully demonstrated an exquisite network of small
pial arteries. Although the acquisition time is currently
extremely long, this study showed the possibilities of in vivo
imaging of tiny arterioles in the human brain.
High-resolution TOF-MRA could be a powerful tool
for revealing small vessel changes related to aging and vascular
risk factors. It has long been suspected that the hippocampal
vascular reserve may provide resilience against the occurrence
of Alzheimer’s disease. One study acquired 0.3 mm isotropic
TOF-MRA images covering the whole hippocampus and ana-
lyzed the vascular supply patterns.45 The authors showed that
it is possible to confirm whether there is a redundant supply
of blood from the anterior choroidal artery to the anterior
hippocampus and to analyze the branching patterns of poste-
rior cerebral arteries in the hippocampus. A follow-up study
in 47 older adults showed that the presence of a mixed-
supplied hippocampus could indeed protect against SVD.
Those with anterior choroidal artery supply showed higher
anterior hippocampal grey matter volume and better cognitive
functions.46
A recent 7 T TOF-MRA study on 140 healthy volun-
teers with a large age range (21–69 years) showed that the
number of branches and the visible length of LSAs signifi-
cantly decreased during aging.47 In people with diabetes, the
number of stems and branches of LSAs was significantly less
than in nondiabetic subjects.48 These findings might be
related to either narrowed lumen or decreased blood flow
associated with arteriolosclerosis. In stroke patients, a substan-
tially smaller number of LSAs branches was reported.42 In
addition to showing the association between abnormal LSAs
and lesion formation, abnormal dilation and microaneurysm
could be detected in LSAs.33 With the help of CS accelera-
tion, fast acquisition in clinical patients can help detect infarc-
tion in the artery of Percheron and LSAs.49 Future
applications in older adults with high vascular risks may pro-
vide critical information for early diagnosis and intervention,
preventing irreversible parenchymal damage.
Phase-Contrast MR Angiography
Imaging Principles and Technical Considerations
PC-MRA uses a bipolar gradient to create a contrast between
stationary and flowing spins. Because this bipolar gradient has
equal areas in opposite directions, it would not change the
net phase of protons in stationary tissues. However, the blood
that flows through the imaging plane is subjected to higher
gradient variations, thus experiencing a net phase shift. The
phase shift increases linearly with the velocity of blood flow
and can be encoded using flow-encoding gradients. As a
result, the appropriate selection of velocity encoding (VENC)
values is crucial for visualizing blood vessels. Usually, the
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value is set as larger than the maximal blood flow velocity of
the measured vessels. As the blood flow velocity in small ves-
sels can be very slow, a VENC of 15 cm/sec is usually used
in basal ganglia, and a VENC of 4 cm/sec is suitable for deep
white matter regions. For comparison, the VENC for internal
carotid artery and middle cerebral artery (MCA) imaging is
usually set at 100 cm/sec. Because blood velocity is highly
dependent on the cardiac cycle, peripheral pulse or electrocar-
diographic triggering is used for flow quantification.
Detecting cerebral small vessels on 3 T PC-MRA is rela-
tively difficult, because the SNR is low for encoding slow
blood flow. Only a few lenticulostriate arteries with relatively
large diameters could be seen.50 On 7 T PC-MRA, blood
velocities can be assessed with good reproducibility in LSAs
and deep perforating arteries in the semioval center.51,52
Nonetheless, due to the small diameters, deep perforating
arteries appear as only several voxels on the image, and it
could be difficult to identify vessels from artifacts.53 Further-
more, PC-MRA can be performed with 3D imaging, and the
velocity encoding can be simultaneously applied in different
directions, allowing for the assessment of blood flow in com-
plex vessel structures.52,54
Although PC-MRA can simultaneously visualize vessel
lumens and assess hemodynamics within the vessels, its usage
as depicting vessel structures is limited by the prolonged scan
times and the need for appropriate VENC selection for differ-
ent vessels. For assessing hemodynamics, the flow curve
through the cardiac cycle can be plotted to determine the
maximal and minimal velocity and flow volume, as well as
the mean velocity and flow in the whole cardiac cycle. Vascu-
lar pulsatility55 and extensibility,56 which relates to vessel
stiffness and cerebral vascular reactivity, can reflect functional
changes in small vessels.
Research and Clinical Applications
Several studies have used 7 T PC-MRA to assess blood flow
and vessel reactivity in perforating arteries. One study in
10 patients with lacunar infarction, 11 patients with deep
intracerebral hemorrhage, and 18 healthy controls showed
that the patients had fewer detected perforators and higher
pulsatility in both basal ganglia regions and semioval cen-
ters.57 However, a recent study in older adults showed that
the pulsatility of small perforating basal ganglia arteries signif-
icantly increased with age, but no differences were found in
mean velocity and pulsatility in patients with CAA or hyper-
tensive arteriopathy.58 The discrepancy might be due to dif-
ferences in patient status and imaging platforms. A recent
study using 3D-PC-MRA investigated blood flow changes in
patients with cerebral autosomal-dominant arteriopathy with
subcortical infarcts and leukoencephalopathy (CADASIL) and
showed that blood flow velocity was significantly reduced in
LSAs.59 Furthermore, compared to asymptomatic patients,
symptomatic patients had further reduced blood velocity.
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Journal of Magnetic Resonance Imaging
Interestingly, a multisequence study assessed cerebral vascular
reactivity using PC-MRA and blood-oxygen-level-dependent
response to visual stimuli in CADASIL patients.60 They
found consistently decreased vascular reactivity using both
techniques.
Vessel Wall Imaging
Imaging Principles and Technical Considerations
VWI is a technique frequently used in assessing intracranial
vessel wall structures.61 It utilizes 3D fast spin-echo sequences
with variable flip angles and long echo trains, which can
reduce acquisition time and suppress flowing blood signals.
Techniques including the delay alternating with nutation for
tailored excitation62 and motion-sensitized driven equilib-
rium63 can be used to suppress slow blood flows further and
enhance the contrast of vessel wall. While different weightings
can be achieved through this methods, T1-weighted VWI is
most widely used in clinical diagnosis and has demonstrated
excellent contrast for visualizing both large and small arteries.
Previous studies showed that 3 T-T1-VWI could visualize
LSAs at a similar level of 7 T TOF-MRA64 and 7 T VWI,65
although the SNR is significantly higher on 7 T images
(Fig. 4). Careful selection of imaging parameters can substan-
tially improve the contrast of LSAs.65 With the help CS-
based acceleration, 0.5 mm isotropic whole brain imaging
could be achieved in about 5 minutes,66 but whether high
acceleration degrades LSAs visualization still need to be
assessed. Notably, as the vessel wall is very thin for intracra-
nial arteries (MCA, 0.2–0.3 mm), the wall of small vessels is
far below the imaging resolution of VWI. Therefore, visibility
changes in vessels seen on VWI should be interpreted
carefully.
In clinical patients, VWI is primarily used to diagnose
alterations in large arteries, including stenosis, vessel wall
hemorrhage, and dissections, as well as venous thrombosis.
For small vessels, the numbers and length of LSAs have been
used to indicate disease severity.67 The higher SNR of 7 T
FIGURE 4: (a) A 3 T vessel wall imaging clearly displays lenticulostriate arteries originating from the middle cerebral artery. Voxel
size: 0.5 * 0.5 * 0.5 mm3. (b) A 7 T vessel wall imaging shows more lenticulostriate arteries and has a better contras-to-noise rate.
Voxel size: 0.5 * 0.5 * 0.5 mm3.
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VWI may allow for automatic segmentation, vascular model-
ing, and quantitative and morphometric analyses.65
Research and Clinical Applications
3 T-VWI is convenient to use and has been applied in both
community cohorts and stroke patients. Xu et al performed
VWI in 125 middle-to-old age community subjects and
found that smokers had shorter and straighter LSAs compared
to nonsmokers, and the presence of hypertension is associated
with less tortuous LSAs.67 However, due to the limited con-
trast, automatic segmentation has not been performed in this
study. Evaluation of LSA properties has demonstrated prom-
ising clinical values. In patients with different types of stroke,
deep-perforator infarction was associated with a significant
reduction in the length of visualized LSAs.68 The number
and length of LSAs are reduced in patients with lacunar
infarction in the basal ganglia area.69 By combining LSA fea-
tures and other imaging markers, classification of different
types of recent subcortical infarcts is possible.70 Furthermore,
better LSAs visualization was associated with favorable clinical
outcomes in patients with single subcortical infarction.71
Susceptibility-Weighted Imaging
Imaging Principles and Technical Considerations
SWI uses a gradient echo sequence to detect differences in tis-
sue susceptibility.72 A 3D acquisition is typically employed to
achieve high imaging resolutions and flow compensation is
used to reduce flow artifacts. After generating magnitude and
phase images from raw data, the phase images are processed
and multiplied several times with the magnitude image to cre-
ate the final SWI image. Because the venous blood has a
higher concentration of paramagnetic deoxyhemoglobins, sus-
ceptibility difference between venous blood and surrounding
tissues can cause a blooming effect on SWI,72 enabling the
display of small venules with diameters below the imaging
resolution. The visualizing effect could be further improved
by using susceptibility rather than phase images to create
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Huang et al.: Visualizing cerebral small vessel degeneration using MRI

weighted images.73 As T2* signal can change with the
deoxyhemoglobin/hemoglobin ratio, administering vasocon-
striction substances such as caffeine can further increase the
contrast. It has been estimated that vein signals decreased by
about 20% post-caffeine administration, and the visualization
became significantly better.74 Nonetheless, this effect may be
subject to differences in individual habits of caffeine
consumption.
SWI is mainly used for the detection of microbleeds
and assessing DMVs in small vessel imaging. On 3 T images,
the contrast of DMVs is relatively low. Visual assessment
methods, such as comparing the prominence of DMVs from
bilateral hemispheres75 and grading based on the number and
continuity of venules,76 have been used in clinical studies.
On 7 T images, higher SNR and smoother venous structures
allow for manual tracing and automatic segmentation.77,78
Quantitative measures could be calculated, such as the num-
ber, length, and shape of DMVs,79 and vascular density.77
Research and Clinical Applications
DMVs can be easily visualized on 3 T SWI and thus have
been well-studied in clinical patients. Visual assessments of
the thickening or asymmetry of DMVs can provide informa-
tion regarding tissue oxygenation,75,80 which is related to
clinical outcomes in stroke patients. One study showed that
the number of detected venules significantly decreased after
carotid artery stenting.81 Quantitative measures, including
numbers, length, and signal continuity, have been used to
reflect venous pathologies.78,82 A few studies conducted visual
evaluations of DMVs on 3 T SWI images from community
subjects and patients with SVD. In a series of studies on
1056 community subjects, the number of DMVs decreased
with age,82 and fewer DMVs were independently associated
with brain atrophy.83 Interestingly, the number of DMVs
was not associated with vascular risk factors and parenchymal
markers but related to serum inflammatory biomarkers as
demonstrated in a follow-up study.84 In patients with spo-
radic SVD, increased DMVs score (indicating more damage)
was independently associated with higher WMHs volume,
which might be related to increased water content in peri-
ventricular regions.76
The number of DMVs is significantly higher on 7 T
SWI, and the vessel lines are sharper and smoother (Fig. 5a).
Interestingly, many of the findings on 3 T studies were not
replicated in 7 T studies.31,79 While a study in CADASIL
patients found reduced venule density,77 several studies in
community cohorts31,79 and patients with Dutch-type heredi-
tary cerebral amyloid angiopathy78 had not found associations

FIGURE 5: (a) A comparison of 3 T (voxel size: 0.47 * 0.47 * 2 mm3) and 7 T SWI images (voxel size: 0.25 * 0.25 * 1.2 mm3). The 7 T
images showed significantly more deep medullary veins (right lower corner) and could display superficial medullary veins not seen on
the 3 T image. (b) Venous trees in the subcortical nuclei. (c) Small venules near substantia nigra in the middle brain.

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Journal of Magnetic Resonance Imaging

between venules properties and parenchymal SVD markers.
The discrepancy might be due to variations in SVD sub-
types and disease burdens and also the increased clarity of
DMVs seen on 7 T images. Benefiting from increased
image quality, tracing DMVs and quantitative shape ana-
lyses are possible. By manually tracing the vessels in the
axial slice right above the lateral ventricle, one study found
that subjects with the APOE4 allele had a higher tortuosity
ratio in the DMVs.79 In a related study, the authors
observed increased tortuosity in patients with mild cogni-
tive impairments and early Alzheimer’s disease.85 It seems
that DMVs tortuosity might be associated with Alzheimer’s
disease pathology.
Other small venules, such as those penetrating the corti-
cal gray matter86 and those in the deep gray matter nuclei
and mid-brain,87 can also be seen on 7 T SWI images
(Fig. 5b,c). Currently, degeneration of small venules in other
brain regions has remained relatively unexplored. In cortical
gray matter and juxta-cortical regions, pathologies in superfi-
cial medullary veins may play more important roles in
vascular-related damage, because there is an abundant blood
supply so that the ischemia-related damage might be less. In
the midbrain, degeneration of the substantia nigra is the cen-
tral pathology of Parkinson’s disease.88 Disruption in adjacent
small venules may contribute to the process due to their sus-
ceptibility to inflammation.
Contrast-Enhanced MR Vessel Imaging
Administering gadolinium-based contrast agents can enhance
the visualization of small vessels on TOF MRA. The
improvement is relatively small on 3 T but observable on
7 T.89 Although the total number of LSAs remained
unchanged, the display of distal LSAs segments was signifi-
cantly better on contrast-enhanced images.89 A pitfall of this
method is the increased venous contamination.
It is also possible to enhance the display of small vessels
through the usage of ultrasmall superparamagnetic iron oxide
(USPIO) agent.90,91 By changing blood susceptibility, the
SWI blooming effect could be magnified so that vessel signals
surpass the partial volume effect, enabling the visualization of
sub-voxel blood vessels. A recent analysis showed that the
USPIO agent could significantly increase the blooming effect
in small vessels, allowing for detecting small vessels with a
diameter less than 100 μm.90 With a sufficient concentration
of USPIO (about one-third of the dose used for treating ane-
mia), both small venules and arterioles could be well-dis-
played.91 However, when blood susceptibility increases,

FIGURE 6: A 49-year-old female patient presented with episodic headaches for 1 year. Diagnostic cerebral angiography (DSA) was
performed, revealing a 50% stenosis in the left MCA; (a, b) were 7 T-TOF-MRA images obtained before and after DSA, which
indicated good agreement between the images. The images show severe stenoses of the left middle cerebral artery (MCA) (red
arrow) surrounded by multiple collateral vessels (yellow arrow), which supply the distal lenticulostriate arteries (green arrow). The
VWI images demonstrated less severe stenosis but similar collaterals (c, d).

1330 Volume 58, No. 5

 15222586, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.28736 by Manager Information Resources Bond University Library, Wiley Online Library on [14/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Huang et al.: Visualizing cerebral small vessel degeneration using MRI

FIGURE 7: A male patient aged 58 years presented to the emergency department with acute-onset left-sided weakness. An acute
infarct was subsequently detected in the supply area of the right lenticulostriate artery (LSA) (a, blue arrow). The patient was found
to have severe stenosis of the left middle cerebral artery (MCA) as shown in 7 T-TOF-MRA (yellow arrow in b) with disrupted distal
lenticulostriate arteries demonstrated by both TOF-MRA and vessel wall imaging (yellow arrowhead in b and c); 7 T-SWI showed that
the patient had reduced venous signal on the right side compared to the left side (d). Very small microbleeds were also detected
near the lesion region (e, red arrowhead).

blooming artifacts from relatively larger vessels could be
extensive and cover neighboring tissues and vessels. A recent
method called “MICRO” was invented to enable simulta-
neous imaging of large, medium, and small vessels.92 To alle-
viate blooming artifacts from large vessels, three postcontrast
SWI images were acquired during a gradual increase in dose
so that the dynamic blooming effect could be assessed. A
postprocessing method was then used to combine all the
images to produce a final vasculature map. Simulation analy-
sis and comparison with previous histological studies suggest
that small vessels with a diameter ranging from 50 to 100 μm
could be visualized on 3 T scanners. A follow-up study used
MICRO to investigate the degenerating processing of hippo-
campal vasculature during aging.32 The authors showed that
CA1, subiculum, and hippocampal tail exhibited lower vascu-
lar density than the other subfields. Furthermore, vascular
density in the CA1 region showed a significant association
with both age and CA1 volume changes.32
The MICRO protocol has great potential for both neu-
roscience research and clinical applications. Many imaging
studies have already used Ferumoxytol, a USPIO drug
initially approved for the treatment of iron deficiency anemia,
for diagnostic imaging of vascular disease, tumors, etc. A
recent multicenter study in 3215 patients and 4240 injections
showed that the Ferumoxytol dose for diagnostic imaging
could be well tolerated, with a very low rate of adverse
events.93 With good safety and no need for expensive ultra-
high-field MR scanners, this method may serve as a conve-
nient tool for small vessel imaging research.
Multimodal Imaging
The full spectrum of SVD-related brain alterations can be
better evaluated through multimodal imaging. Due to the rel-
atively low SNR of small vessels, abnormal findings on a sin-
gle modality may need to be confirmed by other modalities.
Figure 6 shows images from a 49-year-old female patient who
presented with episodic headaches for 1 year. The patient
underwent a diagnostic cerebral angiography, revealing a 50%
stenosis in the left MCA. Compared to VWI images, TOF-
MRA overestimated the degree of stenosis. Furthermore, the
sites of stenosis were surrounded by multiple collateral vessels

November 2023 1331

 1332
TABLE 1. Comparison of In vivo MRI Methods for Visualizing Cerebral Small Vessels (eg Lenticulostriate Arteries and Medullary Veins)

TOF-MRA PC-MRA VWI SWI USPIO-SWI

Imaging principles Inflow enhancement Phase shift of Dephasing of Blooming effect of Changing blood susceptibility
Journal of Magnetic Resonance Imaging

moving protons moving protons blood susceptibility

Arterioles/venulesa Arterioles Arterioles Arterioles Venules Venules, arterioles (with high
USPIO concentration)
Required field 7 T required 7 T required 3T=7T 7 T is significantly better 3T=7T
strength than 3 T
Typical imaging 0.3–0.5 mm isotropic 2D: 0.3 * 0.3 * 2 mm3 0.5–0.6 mm isotropic 3 T: 0.5 * 0.5 * 2 mm3 3 T: 0.2 * 0.4 * 1 mm3
resolution
3D: 0.3–0.4 mm isotropic 7 T: 0.3 * 0.3 * 1.2 mm3 7 T: 0.1 * 0.1 * 1.2 mm3
Comments High vessel contrast Blood flow data available, Large brain coverage Depends on the Need contrast agent, can
need proper VENC oxygenation status display vessels <100 μm
Recommendation for \ \ √ √ Optional
3 T clinical study
Recommendation for √ Optional √ √ Optional
7 T study
a
This does not mean that the method can only display arteries or veins. It indicates that the method has been proven suitable for imaging small arterioles and venules.
USPIO = ultrasmall superparamagnetic iron oxide; VENC = velocity encoding.

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 15222586, 2023, 5, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/jmri.28736 by Manager Information Resources Bond University Library, Wiley Online Library on [14/12/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Huang et al.: Visualizing cerebral small vessel degeneration using MRI

(yellow arrow), which further connected to distal LSAs. Both
imaging modalities showed the stenoses, collaterals, and distal
LSAs (c and d), providing confident diagnostic information.
By combining small vessel structural imaging with
parenchymal SVD markers and vascular functional markers,
one can build associations between upstream pathologies and
downstream damages, which can help understand the full
spectrum of disease-related alterations. Figure 7 demonstrates
a male patient aged 58 years presented to the emergency
department with acute-onset left-sided weakness. An acute
infarct was subsequently detected in the supply area of the
right LSAs. The patient was found to have severe stenosis of
the left MCA as shown on 7 T-TOF-MRA. Unlike the previ-
ous patient, this patient showed disrupted and significantly
shorter LSAs compared to the unaffected side. Therefore, the
stenosis is likely to be the reason for acute infarction. SWI
also showed that the patient had reduced venous signal on
the right side compared to the left side. These cases demon-
strated variations in the association between large and small
vessel alterations, highlighting the need for small vessel
imaging.
Challenges and Future Directions
We summarized some key information about the methods
mentioned above in Table 1 to provide a general view. One
may choose suitable imaging sequences from the table
according to the possessed imaging resources and research
goals. While plenty of progress has been made in visualizing
cerebral small vessels, a few pitfalls still limit the application
of high-resolution vessel imaging. Here, we would like to dis-
cuss some challenges and directions.
First, ultra-high-resolution vessel imaging is susceptible
to patient compliance and physiological status. Head motion
in clinical patients would cause severe degradation of image
qualities and loss of visualization of small vessels. If tech-
niques for reducing the scan time and controlling head
motion were readily available, clinical imaging would be more

FIGURE 8: (a) Comparison of TOF-MRA images acquired from 3 T, 5 T, and 7 T scanners for visualizing small cerebral arteries. Voxel
size: 0.5 mm isotropic reconstructed to 0.25 mm isotropic. (b) Comparison of SWI images acquired from 3 T and 5 T scanners for
visualizing deep medullary veins. Voxel size: 0.3 * 0.3 * 1.2 mm3. Source: The reproduction of these images has been permitted by
Dr. Zhang Shi from the Zhongshan Hospital, Fudan University, and Dr. Weijun Zhang from United Imaging. Red arrow: LSA,
lenticulostriate arteries; blue arrow: SCA, superior cerebellar arteries; yellow arrow: PA, pontine arteries.

November 2023 1333


Journal of Magnetic Resonance Imaging
practical. While PMC has been used in several 7 T studies, it
requires specific sequence design and other auxiliary equip-
ment. It may also need the cooperation of the subject to
attach location markers to the head. Therefore, its application
in clinical patients is still limited. Some physiological factors,
such as diurnal rhythm,94 caffeine consumption,74 and body
exercise95 may influence cerebral blood flow and oxygenation.
Some of the above techniques rely on flow-related inflow
enhancement, phase shift, or dephasing. Therefore, altered
blood flow velocity may have a significant impact on the
detecting ability.96 If fewer or short vessel structures are
detected, it might be unclear whether this is associated with
decreased blood flow velocity, better oxygenation, or altered
vasculature.47 Other factors, such as the optimization of
acquisition parameters and slice orientation with respect to
the vessel, may also impact vessel visibility. Further studies
are needed to understand better the influence of these factors
on the reproducibility of small vessel imaging.
Second, many of the advanced sequences, coils, and
reconstruction methods are only available in a few high-end
machines. Many 7 T scanners were installed in research cen-
ters rather than clinical centers. Due to the high experimental
costs, most of the clinical studies to date only enrolled dozens
of subjects. The numbers are very small, considering the large
variations and communications in different levels of vascular
trees.97 Therefore, normative data such as the number,
length, and thickness of LSAs/DMVs under certain imaging
conditions are still unknown. The association between small
vessel structural properties (eg length, tortuosity) and vascular
risk factors, functional changes, and parenchymal damages
also need to be better understood. Because a major purpose
of imaging the small vessels is to aid early detection and inter-
vention, understanding their relationships is necessary for
relating small vessel structural alterations to meaningful clini-
cal outcomes. The prevalence of dangerous microaneurysm in
people with high vascular risks needs to be assessed to make
screening and early intervention plans.33 With more available
facilities and methods, studies in large sample-sized cohorts
may provide crucial evidence for understanding these
questions.
A recently developed 5 T MR system may achieve a bal-
ance between the benefits and costs for clinical applications.
Compared to 7 T, this system has significantly less weight
and occupies smaller spaces and thus is much easier to be
installed in hospitals. The advantages of less peripheral nerve
stimulation and lower SAR may also increase patient compli-
ance.98 The disadvantages of lower SNR may be compensated
by advanced sequence design, image reconstruction, and ana-
lytical methods. Compared to the TOF-MRA images
acquired from 7 T (Fig. 8), those acquired with the 5 T scan-
ner showed a similar number and length of the LSAs.35
While some distal segments were not as good as 7 T images,
they were significantly better than 3 T images. Nonetheless,
1334
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due to the rareness of 5 T systems, these results of small ves-
sel imaging have not been validated in large-scale studies yet.
Third, with more blood vessels displayed, an important
issue is how to derive quantitative parameters from these
maps for measuring the reduction of vessel density and the
disruption of vessel structures during aging and early disease
stages. While traditional imaging processing tools work well
on large vessels, it could be difficult to segment small vessels,
which are less evident and continuous due to the small voxel
size and low SNR. Other demands, such as tracing the vascu-
lar trees, separating arterioles and venules, and removing
unwanted blood vessels, must also be automatized. Some
deep-learning-based methods have shown good accuracy and
robustness in tracking small vessels,99 but the tasks could still
be challenging when considering malformed vessels in disease
conditions.100
Conclusion
Brain small vessel structural imaging techniques have seen
rapid developments, and studies of brain aging and related
diseases have demonstrated the extraordinary potential of
these methods for neuroscience research and clinical applica-
tions. With further technical advancement and readily avail-
able tools, alleviating the harmfulness of SVD through early
and high-resolution vascular imaging is possible.
Acknowledgments
The authors want to thank Dr. Zhang Shi from the
Zhongshan Hospital, Fudan University, and Dr. Weijun
Zhang from United Imaging for providing exemplary figures.
Conflict of Interest
The authors declare no conflict of interest.
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