a) Supplementary methods:
All T1 axial sequences were analyzed systematically. First, we rated small voids (i.e.
parenchymal hypodensities) of < 5 mm in axial diameter without associated FLAIR
hyperintensities as small PVS. Due to the high number of small PVS observed and the inability
to accurately count each of them, a semi-quantitative score was created. The extent of small PVS
by anatomical brain region was rated as 0=No small PVS voids, 1=1-3 voids, 2=4 or more voids
in each of 12 anatomical brain regions. The total small PVS score was created by adding the
subscores for each of the 12 anatomical regions. This method has good-to-excellent reliability. 1
Parenchymal voids observed in 3D T1 and FLAIR sequences with a diameter of > 5 mm were
individually characterized for the purpose of classifying them as large PVS or lacunar LPI in the
following brain regions: inferior third of putamen and anterior perforating substance, upper two
thirds of putamen, anterior limb of internal capsule, thalamus, head of the caudate, globus
pallidus, subinsular cortex, the frontal, parietal, temporal (including the hippocampus) and
occipital white matter. Brainstem areas included the midbrain, pons, medulla, middle cerebellar
peduncle and the cerebellum. Each hypodensity was measured in its longest axial diameter and
perpendicularly to it. The number of axial images in which the same void was observed was used
to calculate the vertical diameter (# slices x slice thickness). The void volume was calculated
with the abc/2 formula used to obtain the volume of ellipsoid bodies.2 Using a cutoff of 5 mm in
axial images yielded a minimum effective diameter of 3 mm typically used to differentiate small
from large perivascular spaces or infarcts.3-5 We also noted the appearance of large hypodensities
on the FLAIR sequence, such as cavitation (defined by a corresponding FLAIR hypointensity as
compared to the brain parenchyma intensity), lack of cavitation (defined by isointensity), and
white matter hyperintensity (WMH, defined by a hyperintense lesion) as well as the presence and
extent of a hyperintense rim around each cavitated void (thick, equivocal or absent). Finally, we
rated the intensity of each void on proton density images as hypointense, isointense, or
hyperintense in respect to the lateral ventricle CSF. The collection of these data was performed
blindly to demographic or clinical information, and the rater did not attribute a label to each void.
The characteristics of large PVS and lacunar LPI vary by anatomical areas (Table e1). To
enhance the ability of brain imaging to differentiate large PVS from what we define as lacunar
lesions presumably ischemic (LPI), we created post-hoc criteria to classify each lesion seen on
MRI using characteristics determined by imaging-pathological correlational studies in other
cohorts. We rated each lesion as presumed large PVS, uncertain, or lacunar LPI to reflect the
uncertainty of accurate discrimination when pathological data is not available. Voids located
where perivascular spaces are known to occur, such as voids in the subcortical white matter
(representing the course of radially-oriented periventricular medullary arteries), in the inferior
third of the putamen (representing the lenticulostriate arteries piercing the anterior perforating
substance), or voids in the subinsular region, were presumed to be large PVS if they were slitlike, ovoid or even round but lacked a thick hyperintense rim on FLAIR.6-8 Conversely, any void
in the brainstem or cerebellum larger than 5 mm was rated as an infarct because large PVS are
rarely found in this region.9 Thus, a slit-like void in white matter tracts outside the periventricular region would be more compatible with a perivascular space, while an ovoid or round
lesion in this same area would be more likely to represent a LI, particularly in the subcortical
areas.10 A thick FLAIR hyperintensity surrounding a lesion would be overall more consistent
with lacunar LPI than large PVS.11, 12 MRI voids that were classified as uncertain (4 %) based on
table 1 were excluded from this analysis.
Some authors have used proton density sequences to distinguish between lacunar LPI and large
PVS, but less pathological data exist to validate this approach.3, 7, 13 As internal validation and to
facilitate comparisons, we analyzed the intensity of the large PVS on proton density in respect to
the ventricular CSF. The large PVS were more likely to be hypointense (OR 23.0, 95% CI 5.1103.6) or isointense (OR 7.2, 95% CI 1.6-31.8) in comparison to the ventricular CSF intensity,
while lacunar LPI were more likely to be hyperintense in respect to ventricular CSF (OR 27.9,
95% 6.2-126.5). Only 0.8% of the lesions thought to be large PVS according to table 1 were
hyperintense compared to the ventricular CSF.
table e1: Pathology-driven MRI classification of brain parenchymal hypodensities > 5 mm
in axial diameter.
Uncertain
characteristics
Probable large
perivascular
space
Probable
lacunar lesions
presumably
ischemic
Shape
slit or ovoid
slit or ovoid
round or
FLAIR rim
absent
equivocal
thick (any shape)
Shape
any shape
*
any shape and
cortex
FLAIR rim
absent or
equivocal
*
thick
Anterior
perforating
substance,
putamen (lower
third)
Shape
any shape
Slit and
Not a slit AND
absent or
equivocal
thick
FLAIR rim
Upper putamen, Shape
slit or
ovoid and
round or
thalamus,
globus pallidus,
absent or
absent or
thick (any shape)
Anatomical
region
Hypodensities
Subcortical
Subinsular
FLAIR rim
thick
(any shape)
caudate head,
equivocal
equivocal
internal capsule
Midbrain, pons
Shape
*
Slit AND
ovoid or round
middle
cerebellar
peduncle
FLAIR rim
*
absent
Any
*The evaluated void must have all characteristics in each box in order to be ascertained.
b)Supplemental statistical analysis:
To verify non-liner associations exist between mean arterial pressure and pulse pressure, we
plotted the residual against the predicted scores. We interpreted a homogenous distribution of the
residual in the X axis as evidence of linear associations. We did not find evidence of a non-linear
association between blood pressure parameters and the studied outcomes (Figure e1).
c) Supplementary results:
Table e3: Statistical interactions by ethnicity
Small
Number of large
Number of
perivascular
perivascular
lacunar LPI
spaces score
spaces
B (P value)
B (P value)
B (P value)
Log of WMHV
B (P value)
Ethnicity * MAP
-0.027 (0.17)
0.035 (0.52)
-0.033 (0.70)
-0.030 (0.41)
Ethnicity * PP
0.028 (0.16)
-0.053 (0.33)
-0.029 (0.72)
0.071 (0.05)
Abbreviations: MAP. Mean arterial pressure; PP, pulse pressure; B, beta coefficient for the interaction,
LPI, lesions presumably ischemic; WMHV, white matter hyperintensity volumes.
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