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Henley et al.
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Figure 3. Twelve-month mean CVR changes in candesartan (green) versus placebo (blue) for whole brain (A), frontal (B),
parietal (C), temporal (D) lobes, and hippocampus (E)-results from CEDAR trial only. p-values correspond to between-group
differences (visit × group), calculated from mixed-model repeated measures of CVR over the study period. Error bars are
standard errors. Change in ETCO2 during CO2 exposure and sitting systolic blood pressure were included as covariates in all
repeated measure models.
Figure 4. Voxel-wise mapping of significant 12-month CVR
changes in candesartan compared to placebo in CEDAR trial
only. This voxel-wise color map corresponds to the value of
the F statistic with a false discovery rate <0.2.
Discussion
This report shows that candesartan was associated with
improved CVR compared to lisinopril and placebo. These
effects were consistent in the whole brain, as well as across
key brain region of interest (ROI) related to cognition-the
frontal, parietal, temporal, and hippocampal regions.
Further exploratory analyses suggest that improved CVR
with candesartan in the hippocampal region may be associated
with improved cognition. A few drugs have been
shown to affect cerebral vasoreactivity.25,26 Prior work has
shown that ARB treatment preserves cerebral hemodynamics
in humans with stroke or small vessel disease.27,28 To
our knowledge, this is the first study to show evidence of
candesartan improving CVR in two independent populations
of MCI.
ARBs block AT1 leading to the likely activation of AT2
receptors in the brain.29 AT1 activation increases oxidative
stress, neuroinflammation, endothelial dysfunction, and
reduced cerebral perfusion.30 AT2 activation produces antiinflammatory
effects that can be neuroprotective,31 including
inhibition of cerebral ischemia.32 Previous studies
report that ARBs can reduce cerebrovascular inflammation
resulting in neuroprotective effects. A randomized study of
losartan versus atenolol showed improvements in episodic
memory in losartan compared to no change with atenolol
(β-blocker) in just 6 months.33 Similar benefits to episodic
memory have also been reported in studies comparing valsartan
with enalapril (ACEI) with valsartan showing more
specific vasodilation and endothelial modulation.34
MRI-derived CVR maps allow for the examination of
regional effects beyond what is seen using transcranial
Doppler measurements, previously the most common
method for assessing CO2 responses. Our data suggest that
the effects of candesartan are evident in brain regions that
are critical for cognition in both VCI and prodromal AD.
These results in the context of brain RAS suggest that ARBs
preserve cerebral microvascular function by selective AT1
blockade and AT2 activation.35 Decreased CVR has been
linked with age-related cognitive decline, AD, and vascular
dementia.36-38 The observed effect of candesartan on CVR
in this study and on cognitive performance in previous studies
by our group led us to explore the association of changes
in CVR with changes in cognitive performance.11,14 Our
data suggest that candesartan, compared to other antihypertensives,
has a specific effect on CVR and hence may offer
a therapeutic modality for cognitive impairment due to the
International Journal of Stroke, 18(6)
WSO - July 2023

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