ORIGINAL RESEARCH

published: 11 July 2022

doi: 10.3389/fnagi.2022.888470

Sympathoexcitatory Responses to
Isometric Handgrip Exercise Are
Associated With White Matter
Hyperintensities in Middle-Aged and
Older Adults
Andrew G. Pearson 1 , Kathleen B. Miller 1 , Adam T. Corkery 1 , Nicole A. Eisenmann 1 ,
Anna J. Howery 1 , Karly A. Cody 2 , Nathaniel A. Chin 3,4 , Sterling C. Johnson 3,4,5 and
Jill N. Barnes 1*
1
Bruno Balke Biodynamics Laboratory, Department of Kinesiology, University of Wisconsin-Madison, Madison, WI,
Edited by: United States, 2 Waisman Laboratory for Brain Imaging and Behavior, University of Wisconsin-Madison School of Medicine
Robert Matthew Brothers, and Public Health, Madison, WI, United States, 3 Division of Geriatrics and Gerontology, Department of Medicine, University
The University of Texas at Arlington, of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States, 4 Alzheimer’s Disease Research
United States Center, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI, United States, 5 Geriatric
Reviewed by: Research Education and Clinical Center, William S. Middleton Hospital Department of Veterans Affairs, Madison, WI,
Shigehiko Ogoh, United States
Toyo University, Japan
André L. Teixeira,
Vascular dysfunction may occur prior to declines in cognitive function and accumulation
University of Guelph, Canada
Takashi Tarumi, of neuropathology. White matter hyperintensities (WMH) develop due to cerebral
National Institute of Advanced ischemia and elevated blood pressure in midlife. The purpose of this study was
Industrial Science and Technology
(AIST), Japan to evaluate associations between cardiovascular and cerebrovascular responses to
*Correspondence: sympathoexcitatory stimuli and WMH burden in cognitively unimpaired middle-aged and
Jill N. Barnes older adults. Sixty-eight adults (age = 63 ± 4y, men = 20, women = 48) participated
[email protected]
in this study. Participants completed isometric handgrip exercise (IHG) exercise at
Specialty section: 40% of maximal voluntary contraction until fatigue followed by a 90s period of post-
This article was submitted to exercise ischemia. Heart rate (HR), mean arterial pressure (MAP), middle cerebral artery
Alzheimer’s Disease and Related
Dementias,
blood velocity (MCAv), and end-tidal CO2 were continuously measured throughout the
a section of the journal protocol. Cerebrovascular resistance index (CVRi) was calculated as MAP/MCAv. WMH
Frontiers in Aging Neuroscience lesion volume and intracranial volume (ICV) were measured using a FLAIR and T1
Received: 02 March 2022 scan on a 3T MRI scanner, respectively. WMH fraction was calculated as (WMH lesion
Accepted: 05 May 2022
Published: 11 July 2022 volume/ICV)∗ 100 and cubic root transformed. Multiple linear regressions were used to
Citation: determine the association between cardiovascular and cerebrovascular responses to
Pearson AG, Miller KB, IHG exercise and post-exercise ischemia and WMH fraction. Multiple linear regression
Corkery AT, Eisenmann NA,
Howery AJ, Cody KA, Chin NA,
models were adjusted for age, sex, apolipoprotein ε4 status, and total work performed
Johnson SC and Barnes JN (2022) during IHG exercise. During IHG exercise, there were significant increases from baseline
Sympathoexcitatory Responses to in HR (25 ± 12%), MAP (27 ± 11%), MCAv (5 ± 10%), and CVRi (22 ± 17%; P < 0.001
Isometric Handgrip Exercise Are
Associated With White Matter for all). During post-exercise ischemia, HR (8 ± 7%), MAP (22 ± 9%), and CVRi
Hyperintensities in Middle-Aged and (23 ± 16%) remained elevated (P < 0.001) while MCAv (0 ± 10%) was not different
Older Adults.
Front. Aging Neurosci. 14:888470.
compared to baseline. There was an inverse association between the percent change
doi: 10.3389/fnagi.2022.888470 in HR (r = −0.42, P = 0.002), MAP (r = −0.41, P = 0.002), and CVRi (r = −0.31,

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

P = 0.045), but not MCAv (r = 0.19, P = 0.971) in response to IHG exercise and WMH
fraction. There were no associations between responses to post-exercise ischemia and
WMH fraction. Lower sympathoexcitatory responses to IHG exercise are associated
with greater WMH burden in middle-aged to older adults. These findings suggest that
individuals who demonstrate smaller increases in HR, MAP, and CVRi in response to
sympathoexcitatory stress have greater WMH burden.
Keywords: blood pressure, cerebrovascular disease, white matter, cerebral artery blood velocity, cerebrovascular
resistance

INTRODUCTION factors, the physiological response to repeated acute or chronic

physiological and psychological stressors likely contribute to
Identification of novel vascular risk factors is necessary to
future risk of disease (McEwen and Stellar, 1993). The response
understand vascular contributions to the progression of cognitive
to acute physiological stressors may therefore reveal dysfunction
decline and dementia (Gorelick et al., 2011). Specifically,
in the systemic and cerebral circulation that could affect white
investigating mechanisms underlying the reduction in cerebral
matter health. For example, a greater increase in BP in response
blood flow and changes in blood pressure (BP) during the
to mental stress is associated with WMH burden (Waldstein et al.,
presymptomatic phase of dementia could help to elucidate
2004) and impaired hypercapnic cerebrovascular reactivity is
the link between vascular risk and dementia (Snyder et al.,
associated with white matter damage (Sam et al., 2016). Isometric
2015). Impaired peripheral and cerebral vascular regulation as
handgrip (IHG) exercise represents an acute sympathoexcitatory
a consequence of chronic hypertension could contribute to the
stressor indicative of activities of daily living as heart rate
reduction in cerebral blood flow and progression of cognitive
(HR), BP, and sympathetic nerve activity increase in response to
decline (Farkas and Luiten, 2001). Indeed, vascular dysregulation
sustained isometric contractions (Lind and McNicol, 1967; Mark
and impaired hemodynamic responses to stress may occur early
et al., 1985). Post-exercise ischemia occludes blood flow to the
in the progression of cognitive decline, prior to clinically-relevant
previously contracted muscle leading to sustained elevations in
declines in cognitive function (Iadecola, 2004; Iturria-Medina
BP and sympathetic activity, in the absence of muscle contraction
et al., 2016). In fact, vascular risk scores have been used to predict
(Rowell and O’Leary, 1990). Together, IHG exercise and
future risk of dementia 20 years later in middle-aged adults
post-exercise ischemia provide insight into the cardiovascular
(Kivipelto et al., 2006). Further, in individuals with Alzheimer’s
responses to muscle mechanoreflex and metaboreflex activation.
disease (AD), vascular factors including systolic hypertension and
Isometric and rhythmic handgrip exercise responses have been
angina at the time of AD diagnosis are associated with a more
used to evaluate cardiovascular risk in a variety of populations
rapid decline in cognitive function (Mielke et al., 2007).
(Ide et al., 1998; Giller et al., 2000; Ranadive et al., 2017; Miller
White matter hyperintensities (WMH) are areas of increased
et al., 2019; Tarumi et al., 2021). We have previously reported that
brightness and signal density observed on MRI scans indicative
women with a history of preeclampsia (who have an elevated risk
of small vessel cerebrovascular disease which are associated
of cerebrovascular disease and cognitive decline) demonstrated
with cognitive decline and increased severity of dementia
a greater cerebral blood flow velocity response to IHG exercise
in individuals with AD (Heyman et al., 1998). Longitudinal
(Miller et al., 2019), despite similar increases in BP (Ranadive
studies suggest an association between WMH burden and
et al., 2017), compared with women without a history of
cardiovascular risk factors (Breteler et al., 1994; Jeerakathil
preeclampsia. However, the cardiovascular and cerebrovascular
et al., 2004), lower total cerebral perfusion (Vernooij et al.,
response to IHG exercise and post-exercise ischemia have
2008), and lower cerebral blood flow (Promjunyakul et al.,
not been linked to white matter health. The purpose of
2018). Indeed, cerebral blood flow is lower in areas with
this study was to evaluate associations between cardiovascular
WMH compared to areas without WMH (Brickman et al.,
and cerebrovascular responses to sympathoexcitatory stimuli
2009; Stewart et al., 2021). Cerebral blood flow is also lower
and WMH burden in a cohort of cognitively unimpaired
in adults with WMH compared to those without (Fazekas
middle-aged and older adults. We hypothesized that both a
et al., 1988; O’Sullivan et al., 2002). In addition, lower middle
greater cardiovascular and cerebrovascular response to IHG
cerebral artery blood velocity (MCAv) and higher cerebral
exercise and post-exercise ischemia would be associated with
pulsatility index (PI) has been reported in adults with greater
greater WMH burden.
severity of WMH burden (Puglisi et al., 2018). Importantly,
during the presymptomatic phase of dementia, WMH volumes
are associated with increased risk of progression to MCI
(Soldan et al., 2020). MATERIALS AND METHODS
Longitudinal studies have demonstrated that elevated BP and
systolic blood pressure (SBP) variability in midlife increases the Ethics Statement
risk of developing WMH (Dufouil et al., 2001; Havlik et al., All study procedures were approved by the University of
2002; Wartolowska and Webb, 2021). In addition to vascular risk Wisconsin-Madison Institutional Review Board and performed

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

according to the Declaration of Helsinki by obtaining written separate day, participants visited the Wisconsin Institutes for
informed consent from each participant. Medical Research in Madison, WI for an MRI scan.

Participants Screen Day Measurements

Upon arrival to the laboratory, height and weight were obtained
Participants were recruited from cohorts within the Wisconsin
using a standard scale and stadiometer. The screen day visit
Alzheimer’s Disease Research Center (ADRC). These cohorts
consisted of a brief familiarization with study procedures, a
included the Investigating Memory in Preclinical Alzheimer’s
supine arterial BP measurement using a brachial cuff (Datex
Disease – Causes and Treatments (IMPACT) cohort and the
Ohmeda, GE Healthcare, Fairfield, CT, United States) after
Healthy Older Controls cohort. Within the IMPACT cohort,
resting quietly in a dimly lit room for 10 min, and middle cerebral
participants had either 1) a parent clinically diagnosed with AD
artery (MCA) screening using transcranial Doppler ultrasound
clinical syndrome according to the self-report of the adult child,
(TCD). MCA imaging was conducted to ensure proper angle
2) a biological mother or father that lived to at least 75 years
of the probe, and the anatomical location, depth of the signal,
old or 70 years old, respectively, without symptoms of dementia,
and mean velocity were recorded. Maximal voluntary contraction
or 3) indeterminate parental history of dementia (i.e., parent did
(MVC) was determined from the average of two brief maximal
not live to age limits described above, parent has or had MCI, or
handgrip contractions of the left hand separated by 1 min of rest.
participant is adopted and biological family history is unknown,
etc.). Within the Healthy Older Control cohort, participants
Experimental Study Day Measurements
were at least 65 years old and did not have a family history of
Following 10 min of supine rest, arterial BP was measured in
dementia. Family history of dementia was determined using a
triplicate using a brachial BP cuff and the average value was
self-report dementia questionnaire for each parent or an autopsy
recorded. HR was measured using a 3-lead electrocardiogram
report when available (Johnson et al., 2017). Participants were
(CardioCap, Datex Ohmeda, GE Healthcare, Fairfield, CT,
considered to be cognitively unimpaired based on a consensus
United States). Mean arterial blood pressure (MAP), SBP, and
diagnosis as previously described (Sager et al., 2005; Rivera-
diastolic blood pressure (DBP) were continuously measured
Rivera et al., 2016). Briefly, at least one physician and at least
using a non-invasive finger cuff (NOVA, Finapres Medical
one neuropsychologist met to determine the stage of dementia
Systems, Amsterdam, The Netherlands). End-tidal CO2 (ETCO2 )
severity using the Clinical Dementia Rating scale (Morris, 1997).
was measured using a nasal cannula. MCAv of the left MCA
Additionally, participants underwent a blood draw and MRI
was measured using a 2-MHz TCD (Spencer Technologies,
(Rivera-Rivera et al., 2016).
Seattle, WA, United States). The ipsilateral MCA was used to
Ninety-five cognitively unimpaired adults (32 men, 63
measured MCAv to represent global changes in cerebral blood
women) between 55 and 69 years of age participated in this
flow. Quality MCAv signals were obtained using established
study. The distribution of men and women in this study is
guidelines (DeWitt and Wechsler, 1988) and signal quality was
similar to a previously published study using the Wisconsin
confirmed prior to beginning the IHG exercise protocol.
ADRC IMPACT cohort (Hoscheidt et al., 2016). All participants
had a body mass index (BMI) less than or equal to 34.9 kg/m2 .
Experimental Study Day Protocol
Women were postmenopausal for >1 year and were not currently
Participants were fitted with a BP cuff on the upper left arm (D.
taking oral menopausal hormone therapy. Exclusion criteria
E. Hokanson, Inc., Bellevue, WA) and a handgrip dynamometer
consisted of a confirmed diagnosis of MCI or dementia of
(AD Instruments, Colorado Springs, United States) was placed
any kind, uncontrolled hypertension, significant surgical history,
in their left hand. Due to the experimental setup, all participants
history of clinically significant stroke, cerebrovascular disease, or
performed the IHG exercise protocol using their left hand
other major neurological disorders. Participants with controlled
apart from two participants due to medical history. Prior
hypertension were included in the study.
to exercise, participants rested quietly in the supine position
for 3 min while baseline measurements were collected. Then,
Experimental Procedures participants completed an IHG exercise protocol at 40% of
Participants visited the Bruno Balke Biodynamics Laboratory at their previously determined MVC until fatigue as previously
the University of Wisconsin-Madison on two separate occasions described (Ranadive et al., 2017; Miller et al., 2019). Fatigue
for a screen day and experimental study day. On the experimental was defined as the time at which participants were no longer
study day, participants arrived at the laboratory after a 4-h fast able to maintain 40 ± 5% of their MVC despite verbal
and having refrained from performing strenuous exercise in the encouragement by the researchers. Upon reaching fatigue,
previous 24 h. Participants were instructed to avoid consumption a BP cuff was rapidly inflated to a pressure 100 mmHg
of caffeine or chocolate in the previous 12 h, alcohol in the above resting SBP to elicit a period of post-exercise ischemia.
previous 24 h, and avoid the use of aspirin or non-steroidal anti- Following 90 s of cuff inflation, participants rested quietly for
inflammatory drugs for 48 h prior to the study visit. Participants 2 min. All cardiovascular and cerebrovascular variables were
were asked to withhold over-the-counter medications on the closely monitored throughout the experimental protocol. The
experimental study day. All experimental study day procedures percentage of MVC was continuously monitored throughout
were performed while participants lied supine in a dimly lit, the protocol and participants were verbally instructed and
temperature-controlled room kept between 22 and 24◦ C. On a encouraged to maintain the target intensity. Grip force (kg) was

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

recorded throughout the protocol. An experimental study day continuously recorded during the IHG exercise and post-
timeline is shown in Figure 1. exercise ischemia protocols. Time to fatigue was recorded for
each participant in seconds. Due to individual differences in
handgrip MVC and time to fatigue, work performed was
MRI Measurements
derived by calculating the integral of grip force throughout the
On a separate visit, MRI brain scans were done on a 3T
IHG exercise protocol. To account for individual differences
clinical MRI scanner (MR750, GE Healthcare, Waukesha, WI,
in the time to fatigue during IHG exercise and consistent
United States) at the Wisconsin Institutes for Medical Research.
with our previous work, data was divided into tertiles for
In the supine position, participants were fitted and imaged
analysis (Ranadive et al., 2017; Miller et al., 2019). Briefly,
with a 32-channel or 48-channel head coil (Nova Medical Head
the time to fatigue for each participant was recorded during
Coil, Nova Medical, Wilmington, MA, United States) with a
the IHG exercise protocol using an electronic handgrip device
gradient strength of 50 mT/m and a gradient slew rate of
interfaced with LabChart. Then, the response to IHG exercise
200 mT/m/ms. Intracranial volume (ICV) was measured using
was divided into tertiles for analysis. Cardiovascular and
a T1-weighted structural brain volume (BRAVO) scan with
cerebrovascular variables were averaged during each tertile of
the following parameters: fast spoiled gradient echo sequence,
IHG exercise. The response to post-exercise ischemia during
inversion time = 450 ms, repetition time = 8.1 ms, echo
the final 60 s was used for analysis. The percent change from
time = 3.2 ms, flip angle = 12◦ , acquisition matrix = 256 × 256,
baseline during the IHG exercise and post-exercise ischemia
field of view = 256 mm, slice thickness = 1.0 mm, and
protocol was calculated for all cardiovascular and cerebrovascular
scan time ∼8 min. Total WMH lesion volume was measured
variables and the average of each variable of interest was
using a FLAIR scan.
used for analysis.
WMH were assessed using a lesion prediction algorithm
Apolipoprotein E Genotyping from the Lesion Segmentation Tool (LST) in SPM (Schmidt,
Apolipoprotein E (APOE) is a genetic risk factor for Alzheimer’s 2017). The LST lesion prediction algorithm uses a FLAIR
disease and presence of one or more copies of the ε4 allele is scan (with the optional co-registration and resampling to the
associated with increased risk of cognitive decline (Liu et al., resolution of a T1-weighted reference image) to estimate the
2013). APOE status was determined using competitive allele- lesion probability at each voxel, outputting a lesion probability
specific polymerase chain reaction-based genotyping assays (LGC map. In the quantification step, the lesion probability was
Genomics, Beverly, MA) as previously described (Johnson et al., thresholded to 0.5 and constrained to voxels at least 4mm from
2017). Participants were considered APOE ε4 positive if they had the estimated edge of brain tissue. The resulting lesion probability
one or more copies of the ε4 allele. map for each scan underwent visual quality assessment by
trained reviewers, where the probability map was overlayed
Data Analysis onto the FLAIR scan and compared side by side for accuracy
Cardiovascular and cerebrovascular variables were recorded to the unsegmented FLAIR scan. As needed, segmentations
using LabChart 8 at 250 Hz (AD Instruments, Dunedin, were secondarily reviewed by an experienced neuroradiologist
New Zealand) and stored offline for analysis. Cardiovascular and excluded when warranted. WMH fraction was calculated
variables included: HR, cardiac output (CO), MAP, SBP, DBP, by dividing WMH lesion volume (mm3 ) by ICV (mm3 ) and
and pulse pressure (PP). Cerebrovascular variables included: multiplying by 100. As WMH lesion volume and fraction are
MCAv, cerebral PI, and cerebrovascular resistance index (CVRi). highly skewed measures, data were cubic root transformed for
CO was calculated as HR x stroke volume. Stroke volume analysis to produce a normal distribution and reduce skewness
was derived from finger BP using Modelflow analysis (NOVA, (Habes et al., 2016).
Finapres Medical Systems). Cerebral PI was calculated as (systolic
MCAv – diastolic MCAv)/mean MCAv. CVRi was calculated as Statistical Analysis
MAP/MCAv. ETCO2 was measured throughout the protocol. Normality of all variables was assessed using Shapiro-Wilk tests
Baseline measurements were recorded during the middle 60 s and visually inspected using histograms and QQ plots. Equal
of the 3 min baseline period prior to exercise. Variables were variance across time points (baseline, each tertile of IHG exercise,

FIGURE 1 | Experimental study day timeline. ETCO2 , end-tidal CO2 ; HR, heart rate; MAP, mean arterial pressure; MCAv, middle cerebral artery blood velocity.

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

and post-exercise ischemia) for each variable was assessed using RESULTS
Brown-Forsythe tests. One-way repeated measures ANOVA were
performed to evaluate if raw cardiovascular and cerebrovascular Participants
variables differed from baseline during the IHG exercise and Of the 95 participants recruited for this study, 27 participants
post-exercise ischemia protocol. One-way repeated measures were not included in the final analysis due to not completing
ANOVA were performed to evaluate if the percent change the IHG exercise protocol (n = 2), inadequate data quality
from baseline in cardiovascular and cerebrovascular variables (i.e., MAP or MCAv signal loss; n = 8), incomplete APOE
differed between time points (each tertile of IHG exercise and genotype data (n = 7), or incomplete WMH data (n = 9).
post-exercise ischemia). Pairwise comparisons for each variable In addition, one participant was excluded from analysis due
were assessed using Bonferroni post hoc testing and effect sizes to having a WMH lesion volume > 7 standard deviations
were calculated as eta squared. All statistical analyses were above the mean (mean WMH lesion volume = 776.0 mm3 ).
completed using R software. Means ± standard deviation for all Participant characteristics and cardiovascular variables at rest
variables are presented. Statistical significance was set a priori at in the 68 participants (20 men, 48 women) with complete data
P < 0.05. are located in Table 1. The average age of participants during
To determine the association between the cardiovascular their most recent MRI was 62 ± 4 years. The average difference
and cerebrovascular response to IHG exercise and post-exercise between the ages of participants at their most recent MRI to
ischemia and WMH fraction, multiple linear regression was the experimental study day visit in the laboratory was 0.2 years.
performed. The final tertile of IHG exercise was used for The average WMH lesion volume was 776.0 ± 1118.4 mm3 ,
statistical analysis as the final tertile represents the greatest average ICV was 1.4 × 106 ± 1.4 × 105 mm3 , and average
sympathoexcitatory stress experienced by participants prior to WMH fraction was 0.05 ± 0.07. Sixty-two participants (91%)
onset of fatigue as indicated by a progressive increase in were right hand dominant.
HR and MAP in all participants (Figures 2, 3 and Ranadive
et al., 2017). In each multiple linear regression analysis,
independent variables of age at MRI, sex, APOE ε4 status,
Cardiovascular and Cerebrovascular
and work performed during the IHG exercise protocol were Responses to Sympathoexcitatory
added to the model as independent variables. Age at MRI Stimuli
was included as an independent variable in the model due The average handgrip MVC for participants was 25.3 ± 10.0 kg.
to increases in WMH burden with age (de Leeuw et al., The average time to fatigue during IHG exercise was
2001). For sex, women were assigned a value of 1 and 153.6 ± 49.1 s and average work performed during IHG
men assigned a value of 0 as WMH burden is greater exercise was 1,371.4 ± 539.8 kg/s. During IHG exercise, HR,
in women compared to men (Fatemi et al., 2018). WMH CO, MAP, PP, MCAv, and CVRi increased compared with
burden is associated with APOE status such that homozygous baseline (P < 0.001; Figure 2 and Table 2), as expected. Cerebral
APOE ε4 individuals have greater rates of WMH accumulation PI decreased during IHG exercise compared with baseline
compared to individuals without a copy of the APOE ε4 allele (P < 0.001; Table 2). During post-exercise ischemia, HR, CO,
(Sudre et al., 2017). Accordingly, participants with one or
more copies of the APOE ε4 allele were considered APOE
ε4 positive and assigned a value of 1 while participants TABLE 1 | Participant characteristics and selected cardiovascular variables at
without a copy were considered APOE ε4 negative and rest.
assigned a value of 0 (Kaufman et al., 2021). Finally, the
Variable Value
pressor response to handgrip exercise may be dependent upon
absolute contraction loads during exercise (Lee et al., 2021). Sex (M/W) 20/48
Therefore, work performed during the IHG exercise protocol Age (y) 63 ± 4
was added as an independent variable to account for inter- Education (y) 17 ± 3
individual differences in MVC and absolute contraction load Weight (kg) 76 ± 15
during exercise. Height (cm) 168 ± 8
Participants with controlled hypertension were included in Body mass index (kg/m2 ) 27 ± 4
the study. As such, we also evaluated the effect of controlled Heart rate (bpm) 60 ± 7
hypertension on our results. To determine the influence Mean arterial blood pressure (mmHg) 93 ± 10
of controlled hypertension on our results, participants with Systolic blood pressure (mmHg) 126 ± 15
controlled hypertension (n = 13) were assigned a value of 1 Diastolic blood pressure (mmHg) 76 ± 8
while normotensive participants (n = 55) were assigned a value MoCA 28 ± 2
of 0 (Dufouil et al., 2001) when added to the multiple linear Family history positive (n,%) 48, 71
regression models. APOE ε4 positive (n,%) 27, 40
Due to the uneven distribution of men and women, we Hypertension (n,%) 13, 19
did not evaluate sex differences in the cardiovascular and Diabetes (n,%) 2, 3
cerebrovascular response to IHG exercise and post-exercise Values expressed as mean ± SD. MoCA, Montreal Cognitive Assessment; APOE,
ischemia or associations with WMH fraction a priori. apolipoprotein E.

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

FIGURE 2 | Raw values of cardiovascular and cerebrovascular variables at baseline and during each tertile of isometric handgrip exercise (EX T1, EX T2, EX T3,
respectively) followed by a period of post-exercise ischemia (PEI). Means and individual data presented. The solid black line represents mean values. (A) Heart rate,
HR; (B) Mean arterial pressure, MAP; (C) Middle cerebral artery blood velocity, MCAv; (D) Cerebrovascular resistance index, CVRi. Significance is indicated by the
following: a P < 0.05 vs. baseline, b P < 0.05 vs. exercise T1, c P < 0.05 vs. exercise T2, d P < 0.05 vs. exercise T3 (n = 68; One-way repeated measures ANOVA
with Bonferroni post hoc testing).

MAP, PP, and CVRi remained elevated compared with baseline and PP (P < 0.001) at rest were positively associated with
(P < 0.001) whereas MCAv did not differ compared with WMH fraction. There were no significant associations between
baseline values (P > 0.05; Figure 2 and Table 2). Cerebral PI the cerebrovascular variables at rest (MCAv, cerebral PI, or
increased during post-exercise ischemia compared with baseline CVRi) and WMH fraction (P > 0.05 for all). All multiple
(P < 0.001, Table 2). ETCO2 was similar between baseline and linear regressions between cardiovascular and cerebrovascular
IHG exercise until the final tertile of IHG exercise when ETCO2 responses to sympathoexcitatory stimuli and WMH fraction
decreased and remained lower during post-exercise ischemia were adjusted for age at MRI, sex, APOE ε4 status, and
(P < 0.001, Table 2). The percent change from baseline in HR, work performed during the IHG exercise protocol. Results of
MAP, MCAv, and CVRi during IHG exercise and post-exercise multiple linear regression analyses during the final tertile of
ischemia are presented in Figure 3. The percent change from IHG exercise and WMH fraction are presented in Table 4.
baseline in all cardiovascular and cerebrovascular variables There was a negative association between the percent change
during IHG exercise and post-exercise ischemia are located in in HR (P = 0.002), MAP (P = 0.002), SBP (P = 0.005), DBP
Table 3. (P = 0.002), and CVRi (P = 0.045) during the final tertile of IHG
exercise and WMH fraction (Table 4). Unadjusted individual
Associations Between Cardiovascular data between the percent change in HR, MAP, MCAv, and CVRi
during the final tertile of IHG exercise and WMH fraction are
and Cerebrovascular Responses to presented in Figure 4. There were no significant associations
Sympathoexcitatory Stimuli and White between cardiovascular and cerebrovascular variables during
Matter Hyperintensities post-exercise ischemia and WMH fraction (Table 5).
All multiple linear regressions between cardiovascular and Additionally, we evaluated the effect of controlled
cerebrovascular variables at rest and WMH fraction were hypertension on our findings. After correction for age at
adjusted for age at MRI, sex, and APOE ε4 status. HR (P = 0.006), MRI, sex, APOE ε4 status, and controlled hypertension, HR
MAP (P < 0.001), SBP (P = 0.002), DBP (P < 0.001), (P = 0.023), MAP (P = 0.006), SBP (P = 0.012), and DBP

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

FIGURE 3 | Percent change (% change) from baseline values in cardiovascular and cerebrovascular variables during each tertile of isometric handgrip exercise (EX
T1, EX T2, EX T3, respectively) followed by a period of post-exercise ischemia (PEI). Means and individual data presented. The solid black line represents mean
values. (A) % change in heart rate, HR; (B) % change in mean arterial pressure, MAP; (C) % change in middle cerebral artery blood velocity, MCAv; (D) % change in
cerebrovascular resistance index, CVRi. Significance is indicated by the following: b P < 0.05 vs. exercise T1, c P < 0.05 vs. exercise T2, d P < 0.05 vs. exercise T3 (n
= 68; One-way repeated measures ANOVA with Bonferroni post hoc testing).

TABLE 2 | Cardiovascular and cerebrovascular variables during isometric handgrip exercise and post-exercise ischemia.

Variable Baseline Exercise T1 Exercise T2 Exercise T3 PEI P-value (effect size)

HR (bpm) 60 ± 7 65 ± 8a 70 ± 8a,b 74 ± 9a,b,c 65 ± 8a,c,d <0.001 (0.266)

CO (L/min) 5.3 ± 1.2 5.3 ± 1.2 5.6 ± 1.3a,b 6.0 ± 1.4a,b,c 5.5 ± 1.2a,b,d <0.001 (0.045)
MAP (mmHg) 103 ± 12 110 ± 12a 122 ± 14a,b 131 ± 16a,b,c 125 ± 15a,b,d <0.001 (0.359)
SBP (mmHg) 143 ± 18 150 ± 19a 166 ± 21a,b 178 ± 23a,b,c 175 ± 23a,b,c <0.001 (0.310)
DBP (mmHg) 76 ± 9 81 ± 9a 89 ± 11a,b 95 ± 13a,b,c 89 ± 10a,b,d <0.001 (0.312)
PP (mmHg) 67 ± 13 69 ± 14a 77 ± 15a,b 82 ± 15a,b,c 86 ± 16a,b,c,d <0.001 (0.199)
MCAv (cm/s) 55 ± 11 59 ± 13a 60 ± 13a 58 ± 14a 56 ± 13b,c,d <0.001 (0.021)
Cerebral PI (A.U.) 0.80 ± 0.09a 0.76 ± 0.09a 0.75 ± 0.09a 0.75 ± 0.09a 0.83 ± 0.10a,b,c,d <0.001 (0.096)
CVRi (mmHg/cm/s) 1.9 ± 0.48 1.9 ± 0.49 2.1 ± 0.51a,b 2.4 ± 0.60a,b,c 2.4 ± 0.60a,b,c <0.001 (0.112)
ETCO2 (mmHg) 39 ± 3 39 ± 4 38 ± 4 37 ± 4b,c 38 ± 3a,b,c <0.001 (0.021)

Values are expressed as means ± SD. Data for isometric handgrip exercise are divided into tertiles (Exercise T1, T2, and T3). Data for post-exercise ischemia (PEI)
presented during the final 60s of PEI. Cerebral PI, cerebral pulsatility index; CO, cardiac output; CVRi, cerebrovascular resistance index; DBP, diastolic blood pressure;
ETCO2, end-tidal CO2; HR, heart rate; MAP, mean arterial blood pressure; MCAv, middle cerebral artery blood velocity; PP, pulse pressure; SBP, systolic blood pressure.
Bolded P-values indicate a significant effect of condition. a P < 0.05 vs. baseline, b P < 0.05 vs. exercise T1, c P < 0.05 vs. exercise T2, d P < 0.05 vs. exercise T3;
(n = 68; repeated measures ANOVA with Bonferroni post hoc testing. Effect sizes calculated as eta squared).

(P = 0.008) at rest remained positively associated with WMH the IHG exercise protocol, and controlled hypertension
fraction. There were no significant associations between PP, during IHG exercise and post-exercise ischemia are located in
MCAv, cerebral PI, or CVRi at rest and WMH fraction after Supplementary Tables 1, 2. Following correction for controlled
correction for confounding variables (P > 0.05 for all). The hypertension, the inverse associations between the percent
results of multiple linear regression analyses corrected for change in HR (P = 0.014), MAP (P = 0.013), SBP (P = 0.032),
age at MRI, sex, APOE ε4 status, work performed during and DBP (P = 0.008) during the final tertile of IHG exercise and

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

TABLE 3 | Percent change from baseline in cardiovascular and cerebrovascular variables during isometric handgrip exercise and post-exercise ischemia.

Variable Exercise T1 Exercise T2 Exercise T3 PEI P-value (effect size)

HR (%) 10 ± 6 17 ± 9b 25 ± 12b,c 8 ± 7c,d <0.001 (0.348)

MAP (%) 7±5 19 ± 9b 27 ± 11b,c 22 ± 9b,d <0.001 (0.432)
SBP (%) 5±5 17 ± 8b 25 ± 10b,c 23 ± 9b,c <0.001 (0.465)
DBP (%) 7±6 19 ± 10b 26 ± 12b,c 18 ± 9b,d <0.001 (0.356)
PP (%) 3±6 12 ± 8b 7 ± 5b,c 29 ± 14b,c,d <0.001 (0.555)
MCAv (%) 7±6 8±7 5± 10c 0 ± 10b,c,d <0.001 (0.115)
Cerebral PI (%) −5 ± 4 −6 ± 6 −5 ± 7 4 ± 7b,c,d <0.001 (0.312)
CVRi (%) 0±6 11 ± 9b 22 ± 17b,c 23 ± 16b,c <0.001 (0.354)

Values are expressed as means ± SD. Data for isometric handgrip exercise are divided into tertiles (Exercise T1, T2, and T3). Data for post-exercise ischemia (PEI)
presented during the final 60s of PEI. Cerebral PI, cerebral pulsatility index; CVRi, cerebrovascular resistance index; DBP, diastolic blood pressure; HR, heart rate; MAP,
mean arterial blood pressure; MCAv, middle cerebral artery blood velocity; PP, pulse pressure; SBP, systolic blood pressure. Bolded P-values indicate a significant effect
of condition. b P < 0.05 vs. exercise T1, c P < 0.05 vs. exercise T2, d P < 0.05 vs. exercise T3; (n = 68; repeated measures ANOVA with Bonferroni post hoc testing. Effect
sizes calculated as eta squared).

FIGURE 4 | Associations between the percent change (% change) from baseline values in cardiovascular and cerebrovascular variables during the final tertile of
isometric handgrip exercise (EX T3) and white matter hyperintensity (WMH) fraction (n = 68). WMH fraction was calculated by dividing WMH lesion volume by
intracranial volume, converting to a percentage, and applying a cubic root transformation to reduce skewness. Men are shown in black squares and women are
shown in open circles. (A) % change in heart rate, HR vs. WMH; (B) % change in mean arterial pressure, MAP vs. WMH; (C) % change in middle cerebral artery
blood velocity, MCAv vs. WMH; (D) % change incerebrovascular resistance index, CVRi vs. WMH. Note: data and statistics shown in figure have not been adjusted
for age at MRI, sex, APOE 4 status, or work performed during isometric handgrip exercise. After adjustment for confounding variables, there was a negative
association between the % change in HR (P = 0.002), MAP (P = 0.002), and CVRi (P = 0.045) during the final tertile of isometric handgrip exercise and WMH
fraction. Corresponding results from multiple linear regression analyses are presented in Tables 4, 5.

WMH fraction remained significant (Supplementary Table 1). DISCUSSION

However, there was no longer a negative association between the
percent change in CVRi during the final tertile of IHG exercise The primary aim of this study was to evaluate associations
and WMH fraction (P = 0.136, Supplementary Table 1). There between cardiovascular and cerebrovascular responses to
were no significant associations between cardiovascular and sympathoexcitatory stimuli and WMH burden. The novel
cerebrovascular variables during post-exercise ischemia and finding of this study was that a lower percent change in HR,
WMH fraction (Supplementary Table 2). BP, and CVRi in response to IHG exercise was associated with

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

TABLE 4 | Results of multiple linear regression analysis between cardiovascular TABLE 5 | Results of multiple linear regression analysis between cardiovascular
and cerebrovascular variables during isometric handgrip exercise and white matter and cerebrovascular variables during post-exercise ischemia and white matter
hyperintensity fraction. hyperintensity fraction.

Variable Standardized β P-value Variable Standardized β P-value

HR HR
HR (bpm) 0.067 0.586 HR (bpm) 0.232 0.059
% Change HR −0.432 0.002 % Change HR −0.135 0.265
MAP MAP
MAP (mmHg) −0.018 0.886 MAP (mmHg) 0.180 0.153
% Change MAP −0.380 0.002 % Change MAP −0.143 0.256
SBP SBP
SBP (mmHg) 0.031 0.806 SBP (mmHg) 0.181 0.149
% Change SBP −0.361 0.005 % Change SBP −0.146 0.251
DBP DBP
DBP (mmHg) −0.094 0.479 DBP (mmHg) 0.141 0.270
% Change DBP −0.383 0.002 % Change DBP −0.149 0.231
PP PP
PP (mmHg) 0.119 0.348 PP (mmHg) 0.171 0.170
% Change PP −0.110 0.406 % Change PP −0.105 0.408
MCAv MCAv
MCAv (cm/s) −0.022 0.868 MCAv (cm/s) 0.034 0.799
% Change MCAv −0.005 0.971 % Change MCAv 0.116 0.356
Cerebral PI Cerebral PI
PI (A.U.) 0.127 0.350 PI (A.U.) −0.037 0.775
% Change PI 0.181 0.145 % Change PI −0.037 0.759
CVRi CVRi
CVRi (mmHg/cm/s) 0.005 0.973 CVRi (mmHg/cm/s) 0.061 0.647
% Change CVRi −0.271 0.045 % Change CVRi −0.183 0.162

Data presented as standardized β estimates for raw values and the percent Data presented as standardized β estimates for raw values and the percent change
change (% change) from baseline during the final tertile of isometric handgrip (% change) from baseline during the finals 60s of post-exercise ischemia. Cerebral
exercise. Cerebral PI, cerebral pulsatility index; CVRi, cerebrovascular resistance PI, cerebral pulsatility index; CVRi, cerebrovascular resistance index; DBP, diastolic
index; DBP, diastolic blood pressure; HR, heart rate; MAP, mean arterial blood blood pressure; HR, heart rate; MAP, mean arterial blood pressure; MCAv, middle
pressure; MCAv, middle cerebral artery blood velocity; PP, pulse pressure; SBP, cerebral artery blood velocity; PP, pulse pressure; SBP, systolic blood pressure.
systolic blood pressure. White matter hyperintensity (WMH) fraction was calculated White matter hyperintensity (WMH) fraction was calculated by dividing WMH lesion
by dividing WMH lesion volume by intracranial volume, converting to a percentage, volume by intracranial volume, converting to a percentage, and applying a cubic
and applying a cubic root transformation to reduce skewness. Linear regression root transformation to reduce skewness. Linear regression estimates adjusted for
estimates adjusted for age at MRI (y), sex (Women = 1; Men = 0), APOE ε4 status age at MRI (y), sex (Women = 1; Men = 0), APOE ε4 status (APOE ε4 positive = 1;
(APOE ε4 positive = 1; APOE ε4 negative = 0), and work performed during the APOE ε4 negative = 0), and work performed during the isometric handgrip exercise
isometric handgrip exercise protocol (kg/s). (n = 68. Bolded p-values indicate a protocol (kg/s). (n = 68).
significant association between the cardiovascular or cerebrovascular variable and
WMH fraction).
our previous work and others, we observed similar sustained
increases in cardiovascular (Lewis et al., 1983; Sander et al.,
greater WMH burden in middle-aged and older adults, which 2010; Ranadive et al., 2017; Lee et al., 2021) and cerebrovascular
was opposite of our original hypothesis. These results persisted variables (Miller et al., 2019) during IHG exercise and post-
when accounting for potentially confounding variables including exercise ischemia. A unique aspect of this study is the inclusion
age at MRI, sex, APOEε4 status, and work performed during of cerebral hemodynamics (MCAv and CVRi) to assist in
the IHG exercise protocol. Our results indicate that individuals interpretation of hemodynamic changes in the cerebral vessels
with greater WMH burden may have impaired cardiovascular in response to two sympathoexcitatory stressors. In response
and cerebrovascular responses to sympathoexcitatory stress. to IHG exercise at 40% MVC, we observed a 25% increase
Together, our findings suggest that blunted HR, BP and CVRi in in HR, a 27% increase in MAP, a 5% increase in MCAv,
response to acute sympathoexcitatory stress are associated with and a 22% increase in CVRi during the final tertile of IHG
greater WMH burden in cognitively unimpaired middle-aged exercise. Compared to our previous work, the larger increases
and older adults. in HR, MAP, SBP, and DBP observed in this study are likely
We have previously reported a 10-14% increase in HR, 7-20% due to the inclusion of both men and women as well as a
increase in MAP, and 9-13% increase in MCAv in response to greater relative workload (40 vs. 30% MVC). Our findings
IHG exercise at 30% of MVC until fatigue in postmenopausal build upon our previous work in this area by including a
women with or without a history of hypertensive pregnancy larger sample size of both sexes and evaluating associations
(Ranadive et al., 2017; Miller et al., 2019). Consistent with between cardiovascular and cerebrovascular responses to acute

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

sympathoexcitatory stimuli and WMH. To our knowledge, this with greater WMH burden in middle-aged and older adults. One
is the first study to examine associations between cardiovascular explanation for these findings is that failure to increase resistance
and cerebrovascular responses to sympathoexcitatory stimuli in the cerebral circulation (i.e., CVRi) may lead to propagation
and WMH burden. All participants in this study were enrolled of highly pulsatile blood flow into the delicate microcirculation
in Wisconsin ADRC cohorts. Participants enrolled in these suggesting that individuals with greater WMH burden may
cohorts are part of a larger longitudinal study of over 1,200 have impaired regulation of cerebral blood flow. Along these
individuals focused on early detection of AD, identification of lines, following an acute hypertensive stimulus (a single bout of
both protective and risk factors, and developing strategies to resistance training), older adults demonstrated a greater increase
delay onset and progression of AD (Johnson et al., 2017). The in cerebral PI despite no change in mean MCAv compared with
participants recruited for this study were relatively young and young adults (Rosenberg et al., 2020). These results suggest that
were healthy, free of cardiovascular disease (other than controlled cerebral blood flow regulation may be impaired following an
hypertension n = 13), dementia of any kind, and history of acute hypertensive stimulus in older adults, which may lead to
clinically significant stroke, cerebrovascular disease, or other greater transmission of pulsatile flow into the microcirculation
major neurological disorders. Therefore, collecting physiological and increased risk of end-organ damage.
data in this cohort provides insight beyond aging alone. As a Consistent with this idea, carotid artery PP, carotid PI, cerebral
result, the stressors used in this study in cognitively unimpaired PI, and aortic stiffness are associated with increased risk for
middle-aged and older adults have the potential to serve as silent subcortical infarcts (Mitchell et al., 2011). Additionally,
useful tools for early detection and identification of risk factors aortic stiffness is associated with higher WMH volume and
associated with cognitive decline and dementia. carotid PI is associated with lower gray and white matter volumes
The relationship between elevated BP at rest and WMH (Mitchell et al., 2011). In the cerebral circulation, cerebral PI
burden has been previously reported (van Dijk et al., 2004) is positively associated with greater WMH volume in middle-
and elevated BP and BP variability during the middle-aged aged and older adults (Tarumi et al., 2014). These findings
years are associated with increased WMH burden (Dufouil suggest that aortic stiffness and transmission of pulsatile flow into
et al., 2001; Havlik et al., 2002; Wartolowska and Webb, 2021). the microcirculation may lead to quantifiable changes in brain
Elevated BP at midlife is also associated with increased risk volume and increased WMH burden. A recent study conducted
of cognitive decline (Swan et al., 1998; DeCarli et al., 2001), by Tarumi et al. in young adults investigated cardiovascular
dementia (McGrath et al., 2017; Walker et al., 2019), and AD variables and cerebral blood flow in response to repeated bouts
(Lennon et al., 2019; Ou et al., 2020). However, epidemiological of rhythmic handgrip exercise using phase-contrast MRI (Tarumi
and longitudinal studies only provide insight into associations et al., 2021). Using a similar relative intensity of handgrip
between BP values at rest and WMH burden or retrospective exercise (30-40% MVC), HR, BP, CVRi, cerebral blood flow,
analysis based on historical BP measurements. Cardiovascular and respiratory rate increased during rhythmic handgrip exercise
and cerebrovascular responses to acute or chronic physiological despite no change in vessel cross-sectional area (Tarumi et al.,
stimuli in healthy adults may reveal dysfunction in the systemic 2021). Thus, higher resistance in the cerebral vessels may
and cerebral circulation prior to significant damage to or changes attenuate an increase in cerebral blood flow and prevent cerebral
in brain volumes. Indeed, greater BP responses to mental stress hyperperfusion during rhythmic handgrip exercise, which may
are associated with poor performance on cognitive challenges represent a compensatory myogenic response to a hypertensive
(Waldstein and Katzel, 2005) and WMH burden (Waldstein et al., stimulus in order to dampen pulsatile flow. Failure to increase
2004). Acceleration of WMH burden occurs prior to presentation resistance in the cerebral vessels (indicated by a smaller increase
of MCI (Silbert et al., 2012) and midlife represents a unique in CVRi) during an acute sympathoexcitatory stimulus suggests a
period during the presymptomatic phase of dementia in which potential lack of active vasoconstriction occurring in the cerebral
intervention may be beneficial to delay the onset of cognitive circulation that may allow for propagation of pulsatile flow into
decline. As such, identifying potential mechanisms contributing the microcirculation. Broadly, acute instances of physiological
to the increase in WMH burden during midlife may be important stressors that affect BP and cerebral blood flow, experienced
for understanding the progression from normal cognition to across the lifespan, may affect white matter health. We report
presentation of symptoms of cognitive decline. that individuals who demonstrated greater increases in HR,
Isometric handgrip exercise followed by a period of post- BP, and CVRi in response to IHG exercise had lower WMH
exercise ischemia represent acute physiological stimuli that elicit burden, which was opposite of our hypothesis. It is possible that
a marked increase in HR, BP, and sympathetic nervous system increases in CVRi during a sympathoexcitatory stress, indicating
activity. In agreement with our original hypothesis, the expected active vasoconstriction, may protect the cerebral circulation
response to a sympathoexcitatory stimulus is a substantial from increases in pulsatile flow. For example, in spontaneously
increase in HR, BP, and CVRi. Indeed, we observed a 25% hypertensive rats, smooth muscle hypertrophy in the cerebral
increase in HR, 27% increase in MAP, 25% increase in SBP, arteries occurs, leading to increased cerebrovascular resistance
26% increase in DBP, and a 22% increase in CVRi during the (Tayebati et al., 2012). Changes in structure and function
final tertile of IHG exercise. Moreover, each of these variables in the cerebral circulation may protect the brain from high
remained elevated during post-exercise ischemia. Contrary to perfusion pressures during periods of elevated BP and augmented
our hypothesis, however, a lower percent change in HR, MAP, cerebral blood flow (Faraci and Heistad, 1990; Tayebati et al.,
SBP, DBP, and CVRi in response to IHG exercise was associated 2012). Alternatively, individuals with greater WMH burden or

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

reduced white matter integrity (which was not measured in the in the change in raw MAP and CVRi values between adults
present study) may have impaired cardiovascular responses to with controlled hypertension and those who were normotensive
sympathoexcitatory stress. However, this is unlikely as WMH (P > 0.05 for both), although the aims of the present study
volumes in the present study are low, likely due to the average did not include evaluating the effects of controlled hypertension.
age of participants in this study being only ∼63 years. One possible explanation for the discrepancy between previous
In agreement with the findings from Tarumi et al., we report studies (Delaney et al., 2010; Greaney et al., 2015) and our
significant increases in HR, BP, MCAv, and CVRi during IHG findings is that individuals with uncontrolled hypertension
exercise in middle-aged and older adults. Yet, the cardiovascular were excluded from our study. Additionally, participants in the
and cerebrovascular responses were highly variable. While IHG present study were instructed to take prescription medication
exercise was performed at the same relative intensity for all on the day of the study, which could have influenced the
participants, we observed a wide range of responses in HR (3- response to IHG and post-exercise ischemia. Nevertheless, when
63% increase), MAP (8-57% increase), MCAv (−20 to + 23% controlled hypertension was added to the linear model, the
change), and CVRi (−4 to + 80% change) during the final inverse association between the percent change in HR, MAP,
tertile of IHG exercise. In agreement with our findings, the SBP, and DBP during IHG exercise and WMH fraction remained
percent change in MAP and MCAv in response to rhythmic significant (P < 0.05 for all; Supplementary Table 1). These
handgrip exercise appears to be heterogeneous (Giller et al., 2000) results suggest that regardless of controlled hypertension status,
whereby MCAv may decrease in some individuals. Our findings an attenuated increase in HR and BP in response to IHG
indicate that middle-aged and older adults demonstrate varying exercise is associated with greater WMH burden in middle-aged
responses to an acute sympathoexcitatory stimulus performed and older adults.
at the same relative intensity. IHG exercise represents an acute
sympathoexcitatory stimulus that may be comparable to carrying
an object for an extended period of time. As these types LIMITATIONS
of activities are performed frequently throughout activities of
daily living, evaluating the cardiovascular and cerebrovascular In order to determine CVRi, we measured the cerebral
response to repeated bouts of acute sympathoexcitatory stress hemodynamic response to IHG exercise in the MCA using
may be important for understanding changes in the brain prior to TCD. A major assumption of TCD is that the MCA diameter
presentation of symptoms of cognitive decline. Altered expected remains constant at rest and during a stimulus. Previous work
responses to acute physiological stressors such as IHG exercise, evaluating MCAv and MCA diameter in response to rhythmic
which induce brief, large increases in BP, may be associated with handgrip exercise has demonstrated that MCA diameter may
measurable changes in brain volume and WMH. decrease by ∼ 2% in adults aged 20-59 years old suggesting active
Hypertension is associated with increased risk of developing vasoconstriction in the cerebral circulation during rhythmic
WMH (Dufouil et al., 2001). Although we may be underpowered handgrip exercise (Verbree et al., 2017). However, the cross
to adequately control for controlled hypertension (n = 13, 19% sectional area of the internal carotid and vertebral arteries do not
of participants) in our population of middle-aged and older change in response to rhythmic handgrip exercise performed at
adults, associations with WMH fraction were evaluated with 30-40% MVC in young adults (Tarumi et al., 2021). It is possible
controlled hypertension included in the linear model (in addition that IHG exercise causes vasoconstriction of the MCA which
to age at MRI, sex, APOE ε4 status, and work performed may cause an increase in MCAv despite little or no change in
during the IHG exercise protocol). After adjusting for controlled cerebral blood flow (Giller et al., 2000), though the effect of
hypertension, negative associations between the percent change isometric versus rhythmic handgrip exercise on MCA diameter
in HR, MAP, SBP, and DBP during IHG exercise and WMH is currently unknown. While the present study evaluated MCAv
fraction remained significant. Yet, there was no longer an in response to IHG exercise in a robust sample size of middle-
association between the percent change in CVRi during IHG aged and older adults, the cerebrovascular response to IHG
exercise and WMH fraction. Although the individuals with exercise and potential associations with WMH burden should be
controlled hypertension were evenly distributed throughout the interpreted with caution. Additionally, all participants performed
entire group for the variables of interest, previous work has the IHG exercise protocol using their left hand, regardless of
suggested that older hypertensive adults demonstrate greater handedness. Due to the experimental setup, we evaluated MCAv
increases in raw MAP values and sympathetic nerve activity in the left (ipsilateral) MCA. When MCAv was evaluated in both
in response to IHG exercise performed at 30 and 40% MVC the right and left MCA during rhythmic handgrip exercise in
compared with normotensive older adults (Delaney et al., 2010). adults aged 21-43 years old, previous studies have shown that
Additionally, older hypertensive adults exhibit a more rapid MCAv increased in the contralateral side only (Jørgensen et al.,
increase in MAP and sympathetic nerve activity (within the 1993; Linkis et al., 1995). In the present study, we report a
first 10s of muscular contraction) compared with normotensive significant, albeit variable, increase in MCAv in the ipsilateral
older adults (Greaney et al., 2015). In the aforementioned MCA during IHG exercise in adults aged 55-69 years old, which
studies, older adults in the hypertensive group currently we interpret as a global response. It is possible that we could
taking antihypertensive medication (80% of participants) were have observed a greater increase in MCAv in the contralateral
instructed to refrain from taking medication for two days (right) MCA during IHG exercise, and follow-up studies should
prior to the experimental study (Delaney et al., 2010; Greaney perform bilateral MCA assessments. Lastly, arterial CO2 is a
et al., 2015). In the present study, there were no differences powerful regulator of cerebral vascular tone (Brian, 1998) and

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Pearson et al. Sympathoexcitation and White Matter Hyperintensities

we utilized ETCO2 as a surrogate measure of arterial CO2 . AUTHOR CONTRIBUTIONS

A reduction in ETCO2 may cause cerebral vasoconstriction and
potentially a decrease in cerebral blood flow. We observed a JB conceived and designed the research. AP, KM, AC, NE, AH,
small (1-2 mmHg), but significant, reduction in ETCO2 during and JB performed the experiments. AP analyzed the data. AP,
the final tertile of IHG exercise which persisted during post- KC, and JB interpreted the results of experiments. AP prepared
exercise ischemia. Similarly, reductions in ETCO2 have also the figures. AP and JB drafted the manuscript. All authors edited
been observed during isometric (Muza et al., 1983; Fontana and revised the manuscript, and approved the final version of the
et al., 1993), and rhythmic handgrip exercise (Jørgensen et al., manuscript.
1993; Tarumi et al., 2021). It is possible that a 1-2 mmHg
decrease in ETCO2 could have resulted in a decrease in
MCAv in this study. FUNDING
This research was supported by the Wisconsin Alzheimer’s
CONCLUSION Disease Research Center (P30-AG062715). This research was also
supported by the National Institutes of Health, under a Ruth
In summary, IHG exercise performed at 40% MVC until fatigue L. Kirschstein National Research Service Award T32 from the
elicited significant increases in HR, BP, MCAv, and CVRi in National Heart Lung and Blood Institute to the University of
cognitively unimpaired middle-aged and older adults. Individuals Wisconsin–Madison Cardiovascular Research Center (HL007936
with greater WMH burden demonstrated a lower percent change to KM), a University of Wisconsin Institute for Clinical and
in HR, BP, and CVRi in response to IHG exercise. Together, Translational Research Grant (#UL1TR002373 to KC), and an
these results indicate an inverse association between WMH Alzheimer’s Association Research Grant (#17-499398 to JB).
burden and cardiovascular and cerebrovascular responses to a
sympathoexcitatory stimulus.
ACKNOWLEDGMENTS
DATA AVAILABILITY STATEMENT The authors would like to thank the research participants who
volunteered to participate in this study and the Wisconsin
The raw data supporting the conclusions of this article will be Alzheimer’s Disease Research Center. The authors would also
made available by the authors, without undue reservation. like to thank Rehan Iftikhar for his technical assistance with data
collection and analysis.

ETHICS STATEMENT
SUPPLEMENTARY MATERIAL
The studies involving human participants were reviewed and
approved by University of Wisconsin-Madison Institutional The Supplementary Material for this article can be found
Review Board. The patients/participants provided their written online at: https://www.frontiersin.org/articles/10.3389/fnagi.
informed consent to participate in this study. 2022.888470/full#supplementary-material

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and transit time in small vessel disease: an updated meta-analysis. Front. Neurol. Conflict of Interest: The authors declare that the research was conducted in the
12:647848. doi: 10.3389/fneur.2021.647848 absence of any commercial or financial relationships that could be construed as a
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(2017). APOE ε4 status is associated with white matter hyperintensities volume
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