Annals of Neurology: CADASIL affects multiple aspects of cerebral small blood vessel function on 7T-MRI

Diseases of small blood vessels of the brain (cSVDs) are the leading cause of
stroke and dementia.
In brain MRIs, lesions associated with cSVD are found in about 70 percent of 65-year-olds and almost all
90-year-olds.
Despite the far-reaching health effects of cSVDs, there are no specific treatments, possibly due to our limited
understanding of the underlying disease mechanisms.
Because the affected vessels in cSVDs have small diameters and traditional in vivo imaging techniques have limited resolution, cSVDs are primarily studied
by markers of parenchymal injury (e.
g.
, fissure, white matter hyperplasia (WMH), microbleed, enlargement of perivascular space, white matter microstructural changes, blood-based markers of nerve axis damage.
While these markers are important because they are associated with major clinical outcomes including stroke, cognitive decline, and dementia, they represent downstream consequences
of cSVDs.
To understand the underlying mechanisms of cSVDs, the core of the disease, the blood vessels themselves
, must be studied.

Figure 1: Cover image of the paper

Autosomal dominant arterial disease of the brain with subcortical infarction and white matter encephalopathy (CADASIL) is a single-gene form of cSVD
caused by mutations in the NOTCH3 gene.
Previous studies of cerebrovascular studies of CADASIL have mostly been limited to the examination
of autopsy material.
Lesions of the myeloid artery and cerebellar perforated artery are an important feature, including degeneration of vascular smooth muscle cells and thickening
of the arterial wall.
This is likely to have an effect on the function of small blood vessels, which is indeed observed in the cortex and perforated arteries of experimental animal models, as well as in small blood vessels outside the brain in humans, for example in the heart
.
Now, ultra-high-field imaging by 7T-MRI provides in vivo measurements of several aspects of small vessel function in the human brain, including flow rate and volatility of perforated arteries, and endothelial-dependent and independent vascular responsiveness
in different brain regions.
These measures could provide clues
to the disease mechanisms of CADASIL and other forms of cSVDs.

Thus, Hilde van den Brink et al.
of Utrecht University in the Netherlands used 7T-MRI to assess cerebral small blood vessel function
in patients with CADASIL.
Specifically, they assessed which small vessel function on 7T-MRI was affected in patients with CADASIL compared to the control group, and whether small vessel dysfunction on 7T-MRI was associated
with CADASIL's WMH.

They recruited 23 CADASIL patients (ages 51.
1±10.
1 years, 52% female) and 13 age- and sex-matched controls (46.
1±12.
6, 46% female).

Small-vessel function measurements include: basal ganglia and centriocture arterial velocity and pulsation, vascular responsiveness of the occipital cortex to visual stimuli and cortical responsiveness to hypercapnia, and high concentration
of subcortical gray, white, and white matter.

They found that patients with CADASIL had lower blood flow velocities and greater
pulsation indices in the puncture artery (mean difference -0.
09 cm/s, p=0.
03 and 0.
20, p=0.
009) and basal ganglia (mean difference -0.
98 cm/s, p=0.
003 and 0.
17, p=0.
06) compared with the control group.

Figure 2: Graph of paper results

The patient's small vessel responsiveness to short visual stimuli decreased (mean BOLD difference -0.
21%, p=0.
04), while responsiveness to hypercapnia was preserved
in cortical, subcortical gray matter, and normally occurring white matter.

In patients, the responsiveness to hypercapnia in areas with high white matter density decreased compared with the normally occurring white matter (mean difference in BOLD - 0.
29%, P = 0.
02).

The significance of the study lies in the discovery that: Multiple aspects of cerebral small blood vessel function on 7T-MRI in patients with CADASIL indicate increased arterial fluctuation hardness and abnormal regional reactivity, which are also locally associated
with white matter damage.
These observations provide new cSVD markers for mechanistic and intervention studies
.

Van den Brink H, Kopczak A, Arts T, et al.
CADASIL affects multiple aspects of cerebral small vessel function on 7T‐MRI ; _Annals of Neurology_.
Published online October 12, 2022:ana.
26527.
doi:[10.
1002/ana.
26527](https://doi.
org/10.
1002/ana.
26527)