Rationale and Design of a Clinical Trial of Adapted Tango to Improve Negative Health Impacts in Middle Aged African-American Female Caregivers of Persons with Alzheimer’s Disease (ACT Trial)

Abstract

Alzheimer's disease (AD) is a devastating progressive neurodegenerative disease resulting in memory loss and a severe reduction in ability to perform activities of daily living. The role of caring for someone with AD frequently falls to female family members, often daughters. The burden of caregiving can increase stress and anxiety and cause health decline in the caregiver. The combination of ethnicity-related genetic factors promoting the development of dementias among African-Americans (AA) and the increased risk among women for developing AD means that AA women who are caregivers of a parent with AD are at great risk for developing dementias including AD. The proposed study would compare the cognitive, motor, and psychosocial benefits of a well-established 12 week, 20-lesson adapted Argentine Tango intervention (N=30) to a no-contact control group (N=10) in middle-aged (45-65 years) AA women who are caregivers of a parent with AD in the metro Atlanta area.

Full text

Journal of Alzheimer’s Disease 68 (2019) 767–775
DOI 10.3233/JAD-181130
IOS Press
767
Rationale and Design of a Clinical Trial of
Adapted Tango to Improve Negative Health
Impacts in Middle Aged African-American
Female Caregivers of Persons with
Alzheimer’s Disease (ACT Trial)
Madeleine E. Hackneya,b,c,∗, Lauren E. McCulloughd, Allison A. Baya, Hayley A. Silversteina,
Ariel R. Harta, Ryan J. Shineand Whitney Whartonf
aDepartment of Medicine, Division of General Medicine and Geriatrics, Emory School of Medicine,
Atlanta, GA, USA
bAtlanta VA Center for Visual and Neurocognitive Rehabilitation, Decatur, GA, USA
cDepartment of Rehabilitation Medicine, Emory School of Medicine, Atlanta, GA, USA
dEmory University Rollins School of Public Health, Atlanta, GA, USA
eEmory University College of Arts and Sciences, Atlanta, GA, USA
fDepartment of Neurology, Atlanta, Emory University School of Medicine, GA, USA
Accepted 16 January 2019
Abstract. Alzheimer’s disease (AD) is a devastating progressive neurodegenerative disease resulting in memory loss and a
severe reduction in ability to perform activities of daily living. The role of caring for someone with AD frequently falls to
female family members, often daughters. The burden of caregiving can increase stress and anxiety and cause health decline in
the caregiver. The combination of ethnicity-related genetic factors promoting the development of dementias among African-
Americans (AA) and the increased risk among women for developing AD means that AA women who are caregivers of a
parent with AD are at great risk for developing dementias including AD. The proposed study would compare the cognitive,
motor, and psychosocial benefits of a well-established 12 week, 20-lesson adapted Argentine Tango intervention (N= 30) to
a no-contact control group (N =10) in middle-aged (45–65 years) AA women who are caregivers of a parent with AD in the
metro Atlanta area.
Keywords: African American, Alzheimer’s disease, caregiver, clinical trial, dance, inflammation
INTRODUCTION
As of 2018, 16.1 million Americans provide unpaid
care for people with Alzheimer’s disease (AD) and
∗Correspondence to: Dr. Madeleine E. Hackney, PhD, Division
of General Medicine and Geriatrics, Department of Medicine,
Emory School of Medicine, 1841 Clifton Rd NE, #553; Atlanta,
GA 30307, USA. Tel.: +1 404 321 6111/Ext. 5006; E-mails:
mehackn@emory.edu and E-mail: madeleine.hackney@va.gov.
other dementias [1]. Compared to non-caregivers,
caregivers experience more depressive symptoms and
anxiety, lower levels of perceived health, more sleep
problems, and worse physical health. Overall, higher
stress is reported by caregivers compared to non-
caregivers, correlating to increased risk of negative
health outcomes [2]. Furthermore, in an older pop-
ulation, simply being a familial caregiver who is
experiencing physical or psychological strain has
ISSN 1387-2877/19/$35.00 © 2019 – IOS Press and the authors. All rights reserved

768 M.E. Hackney et al. / Rationale and Design of ACT Trial
been identified as an independent risk factor for mor-
tality [3]. As such, caregivers often have considerable
health needs and require interventions for reducing
stress and improving health.
Dementia caregivers have increased risk for
psychological and physiological illness including
depression, hypertension, diabetes mellitus, dimin-
ished quality of life (QOL), disruption of profession,
and increased mortality [4, 5]. AD caregiving has
unique challenges including mood fluctuations, per-
sonality changes, agitation, impaired language and
reasoning, poor safety awareness, and impaired mem-
ory, which interfere with activities of daily living [6].
Stress and depression are independent risk factors for
developing AD [7–9], and caregivers are more prone
to cognitive impairment than healthy controls [10].
As a result, caregivers of those with AD may be at
greater risk for developing AD themselves due to the
increased burden of caring for a person with these
deficits.
Although the current literature on biomarkers
of stress in caregivers is mixed, certain studies
show that AD caregiving is associated with higher
subjective levels of stress and higher quantita-
tive levels of low-grade inflammation, as indicated
by elevated plasma C-reactive protein (CRP) and
inflammatory cytokines [11, 12]. Furthermore, lower
satisfaction with leisure activities was associated
with higher inflammation, pointing to the impor-
tance of interventions which improve quality of life
[13]. Further research is needed to elucidate the
biological consequences of caregiver stress. What
we do know is that inflammation is crucial to the
development of AD pathophysiology, as evidenced
by reactive microglia on autopsy studies and ele-
vated inflammatory-binding on positron emission
tomography (PET) imaging in patients who progress
from mild cognitive impairment (MCI) to AD [14].
Recent literature suggests that an initial inflamma-
tory stimulus triggers activation of microglia and
astrocytes which secrete inflammatory cytokines and
chemokines which lead to further accumulation of
amyloid and further production of pro-inflammatory
cytokines [15]. Inflammation is thought to eventually
lead to increased blood brain barrier permeability,
hypoperfusion, and eventual neuronal damage [16].
Family history of AD increases risk due to both
overrepresentation of the apolipoprotein E type 4
(APOE ␧4) allele and psychosocial variables such
as caregiver-related stress [17]. Ethnicity also plays
a role in the risk for developing AD. African-
Americans (AA) are 1.6 times more likely than
Whites to develop dementia by age 85. Among rel-
atives of White (CC) persons with AD, those with
the APOE ␧4 allele have twice the risk of develop-
ing AD, whereas those of AA ethnicity who have
at least one APOE ␧4 allele have triple the risk of
developing AD. Thus, ethnicity may be very pow-
erful in determining risk of AD [18]. Middle aged
AA female family caregivers who are the children of
AD patients are particularly at risk for developing AD
due to ethnicity, gender, and age. According to a CDC
report on depression in the U.S., minorities including
non-Hispanic blacks, Hispanics, and non-Hispanics
of other races experience higher levels of depression
compared to non-Hispanic whites [19]. Females have
an increased risk of AD due to menopause related
hormonal changes, longer lifespan, and propensity
for caregiving [20]. Adult children are commonly
caught between caring for their children and/or
grandchildren in addition to their parents, while also
maintaining employment. These demands often leave
little time for self-care, including exercise.
This situation is problematic, as exercise may be
preventative to the development of AD secondary to
its effects on inflammation and the pathophysiology
of AD. Exercise has already been shown to improve
cognitive performance and functionality in patients
with AD [21]. Namely, exercise reduces resting heart
rate and blood pressure, increases myocardial oxy-
gen utilization, and in the case of long-term exercise,
prevents endothelial dysfunction and oxidative dam-
age, which contribute to neuronal degeneration in
AD [22]. Reductions in blood pressure, particularly
those that act on the renin-angiotensin system, have
beneficial effects on cognition and can slow con-
version from MCI to AD [23]. Similarly, mid-life
hypertension and cardiovascular disease are linked
to development of dementia in later life [24]. For the
targeted population, lack of exercise may be an addi-
tional contributor to increased risk of developing AD.
Adapted tango is an adapted form of Argentine
tango, and an intervention that has been researched
in individuals with Parkinson’s disease (PD), as
well as in older adults [25–28]. Adapted tango is
a challenging dual-tasking activity promoting social
interaction, cognitive engagement, musical interpre-
tation, and creative thinking along with the physical
demands of coordination, timing of movement, and
balance [28]. While the physical effects of a dance
intervention have yet to be investigated in this popu-
lation, it is known that music alone has some potential
in improving anxiety and depression and in reducing
caregiver burden [29].

M.E. Hackney et al. / Rationale and Design of ACT Trial 769
Here we describe the design and rationale of a
pilot clinical trial to evaluate whether AD risk factors
can be mitigated using an adapted tango interven-
tion versus control. The trial will determine whether
adapted tango is efficacious in improving quality of
life (QOL), mood, cognitive and physical function,
plasma inflammatory cytokines, and blood pressure
within AA caregivers. We hypothesize that adapted
tango will be a safe, enjoyable, and effective inter-
vention that will reduce stress, and improve quality
of life, balance, walking, and mobility, with a positive
effect on inflammation and blood pressure.
STUDY DESIGN
This is a 12-week, randomized, placebo-controlled
Phase I clinical trial. Thirty participants will be ran-
domized in a 2:1 ratio to treatment (N = 20) and
control (N = 10) conditions with controls frequency
matched to cases based on two age stratifications
(45–55 years and 56–65 years of age). Participants
undergo blood biomarker, cognitive, physical/motor,
and mood testing pre and post intervention or con-
trol conditions. Participants will attend two clinical
visits (pre and post intervention/control). Clinic vis-
its will last approximately 2 h and will entail: 1) a 1 h
cognitive testing battery; 2) blood draw for inflamma-
tory cytokines, rapid blood glucose level, homeostatic
model assessment for insulin resistance (HOMA-IR),
and ApoE4 genotyping; 3) height, weight, and blood
pressure measurement. Cognitive testing includes
a comprehensive pre/post battery in domains of
memory [30, 31], spatial ability [32, 33], executive
function [34–36], language [37], quantitative mea-
sures that assess mood, and positive and negative
aspects of caregiving [38–42]; and 4) physical func-
tion testing includes a pre/post battery in the domains
of balance [43, 44], walking [45, 46], and motor
function [44, 47]. Details of the physiological and
cognitive measures are described below.
Participants
Informed consent will be obtained prior to ran-
domization at the first clinic visit. Thirty AA women
family caregivers (aged 45–65 years) from the Emory
Alzheimer’s Disease Research Center (ADRC) and
Dr. Wharton’s studies of AD caregivers will be
asked to participate in the proposed trial. The par-
ticipants’ parents will have a diagnosis of probable
AD as defined by National Institute of Neurological
Disorders and Stroke-Alzheimer’s Disease and
Related Disorders Association (NINDS-ADRDA)
criteria and will be verified using the validated
Dementia Questionnaire [48] and medical records,
when available. Participants with a parental diagno-
sis have increased risk for AD and overrepresentation
of the ApoE4 allele, a genetic risk factor for AD. In
Dr. Wharton’s previous studies, we have reported that
50–67% of the AD adult child sample is ApoE4 pos-
itive [49, 50]. Participants will be compensated $50
for their participation in the form of gift cards.
Intervention
Adapted tango dance intervention (N = 20)
Participants randomized to the experimental group
will take part in 20, 1.5 h long adapted tango dance
sessions over 12 weeks. Participants will be encour-
aged to participate in classes two times per week.
Dance interventions will take place at the Atlanta VA
Medical Center in the Movement Studies Laboratory
(MSL) of the Center for Visual and Neurocognitive
Rehabilitation (CVNR), which Dr. Hackney (Co-PI,
CVNR) has used in previous studies. We will use a
program previously tested in people with PD, visual
impairment and older adults with cognitive impair-
ment: an adapted Argentine tango (adapted tango)
program. Adapted tango has benefitted spatial cog-
nition, gait, balance, and disease severity in PD [51].
Classes taught by trained and experienced instructors
will be offered four times per week for a total of
12 weeks in a movement studies laboratory at the
VA. Our prior studies showed offering 4 class times
per week allowed schedule flexibility for the partici-
pants, which increased the likelihood of participants
completing 20 classes. Therefore, classes in the cur-
rent study will be offered at four times per week. The
classes will follow methods outlined in an adapted
tango manual, which has been developed empirically
through several studies [27]. The manual delineates
older adult motor impairments and challenges,
fall risk and prevention, partnering enhancement
exercises, rhythmic entrainment, and a structured
syllabus and format. Classes will begin with a 20 min
standing warm-up followed by partnering and
rhythmic exercises. Next, novel step elements will
be introduced and participants will be taught how to
combine the new steps with previously learned steps
via improvisational. Caregivers will dance with each
other or student volunteers. Music will be played
throughout classes. Artistic expression, i.e., attention
to aesthetics, and improvisation, will be encouraged.
Adapted tango classes improve spatial cognition in

770 M.E. Hackney et al. / Rationale and Design of ACT Trial
PD patients [51] and motor-cognitive integration in
older adults [28], which we reported can last up to
3 months post treatment. Adapted tango has been
introduced in AA communities successfully: in 2012,
18 retired AA participants began a 20-lesson adapted
tango program and 14 of these participants com-
pleted 20 lessons within 12 weeks and were satisfied.
Our prior data show also that a 12-week intervention
is an acceptable period to show cognitive benefits
of adapted tango in an AA population. Moreover,
12-week dance interventions have successfully
improved inflammatory, vascular, and subjective
mood measures in younger populations [52].
Non-intervention control group (N = 10)
Ten participants will take part in the pre-
assessment and blood draw followed by the post
assessment and blood draw 12 weeks later. Partici-
pants in this group will be instructed not to change
anything from their daily routine during the time
between appointments.
Trial description summary
Figure 1 shows the timeline and detailed visit
procedures.
STUDY VISIT SPECIFICS
Screening –performed as a phone screen.
PRETEST AND POSTTEST PROCEDURE
DESCRIPTIONS
Inflammatory, cognitive, motor, and mood indices
collected pre and post intervention:
Biological and clinical data
Participants will undergo blood draw for E4 sta-
tus and inflammatory cytokines before and after
the trial using well-established research procedures.
All blood samples will be collected after an 8 h
overnight fast by a member of the research team.
Participants will complete medical and medica-
tion questionnaires, anthropometric measures, and 2
resting blood pressure reads. Biomarkers include tar-
geted, inflammatory, and depression indices that have
been linked to AD family caregiver stress [12] and
have been shown to change over a 3-month period,
the same duration of this trial [53]. Moreover, these
inflammatory and stress markers are easily obtained,
affordable, and likely measurable at a large number
of clinics and research institutions.
Inflammatory and depression blood biomarkers
will be batched and assayed at Emory University.
Four panels of biomarkers will be measured in plasma
using commercially available singleplex or multiplex
assays in a Luminex 200 platform: Cytokines and
chemokines (including interleukin-7, interleukin-8,
interleukin-9, interleukin-10, interferon induced pro-
tein 10, macrophage derived chemokine, monocyte
chemoattractant protein 1, transforming growth fac-
tor alpha, and tumor necrosis factor alpha); C-reactive
protein and serum amyloid protein; stress-related
cortisol; endothelial markers ICAM-1 and VCAM-
1; metabolic variables including homeostasis model
assessment for insulin resistance index (HOMA-IR)
and rapid blood glucose homeostasis.
Cognitive data
Cognitive testing will last 1.5 h and will take place
at the Memory Disorders Clinic at Emory University.
To determine the extent to which the dance interven-
tion affects cognition, we will use a comprehensive
battery in cognitive domains of memory, spatial abil-
ity, executive function and language, with a focus on
executive function. Testing will be conducted by a
trained Research Coordinator during the same clin-
ical visit that blood and vitals are collected. Tests
include but are not limited to: the Montreal Cogni-
tive Assessment [54], the Tower of London [55], the
Stroop Color Word Interference test [56], Trails B
[57], Digit Span [58], the Buschke Selective Remind-
ing Test [59], the Reverse Corsi Blocks [33], the
Brooks spatial memory test [60], and the body posi-
tion spatial task [61].
Motor and physical function data
To determine the extent to which the dance inter-
vention affects physical function, we will use a
comprehensive battery in motor domains of balance,
walking, and lower body strength. Motor and phys-
ical function testing will be conducted by a trained
Research Coordinator during the same clinical visit
that blood and vitals are collected. Tests include but
are not limited to the 30 s chair stand [47], four-square
step test [43], 6 min walk [46], Miniature Balance
Evaluation Systems Test (mini-BEST) [44], and gait
speed tests (preferred, fast, backward) [45].

M.E. Hackney et al. / Rationale and Design of ACT Trial 771
Fig. 1. Study tasks and timeline.

772 M.E. Hackney et al. / Rationale and Design of ACT Trial
Mood and stress data
In light of recent literature linking caregiver stress
to increased inflammation and cognitive decline, we
have compiled a battery of stress measures that assess
both positive and negative aspects of caregiving. We
also include measures to assess the physical and
cognitive status of the care recipient, which likely
contributes to caregiver stress. Measures include:
Positive Aspects of Caregiving Scale (11 item) [38,
39], Pearlin Caregiver Stress Scale [62], The Zarit
Burden Interview [40], Center for Epidemiologic
Studies Depression Scale (CES-D) [41], Dementia
Quality of Life measure (DEMQOL) (Carer v4) [42].
Evaluations and data collection timelines
Figure 1 shows the timeline and detailed visit pro-
cedures.
ANALYSES
We will assess the biological, cognitive, and mood
outcomes pre and post intervention for both experi-
mental and control groups. All tests will be two-tailed
and use a 0.05 significance level. Models will be
adjusted for age, education, and other covariates,
as appropriate, based on a priori knowledge, and
directed acyclic graph analyses. While we will use
inferential statistics to compare function before treat-
ment with after treatment, this pilot trial has been
primarily designed to provide information about the
feasibility of a dance intervention among AA female
caregivers, appropriate clinical and patient reported
outcomes, as well as clinically meaningful effect
sizes. Feasibility will be determined by a conserva-
tive estimate of attrition rate less than 30% in both
groups based on Dr. Wharton’s and Hackney’s previ-
ous studies and documented adherence tendencies in
caregiver interventions which literature suggests may
be as high as 70% in a similar population after 15
months [63]. Appropriateness of clinical and patient-
reported outcomes will be determined by number
of refusals to perform the tests, all of which will
be documented. This population, which consists of
AA female caregivers, has an overrepresentation of
diabetes and high blood pressure, symptoms which
are exacerbated by caregiver physiological and psy-
chological stress, all of which will be measured and
assessed in this trial. We will also observe all tests
for ceiling effects in determining appropriateness.
Literature has shown that interventions and pharma-
ceutical therapies have made clinically meaningful
reductions on inflammation and blood pressure in less
than 12 weeks; therefore, the data we gather related to
the effect of the dance intervention will be compared
to these studies’ findings and effect sizes.
DISCUSSION
Several studies have examined the relationship
between caregiving and cognitive, motor, and psy-
chosocial measures. A comprehensive literature
review by Vitaliano et al. found that people who
are caregivers of a spouse with dementia are at an
increased risk for cognitive impairment than non-
caregivers [64]. Similarly, Caswell et al. (2003) found
evidence that caregivers of spouses with demen-
tia may also have negative impacts on cognitive
and psycho-social health as a result of caregiv-
ing [65]. Another study by Canonici et al. (2012)
found evidence that motor interventions for peo-
ple with probable AD improved motor function for
AD patients and decreased caregiver burden among
the caregivers of the patients involved in the motor
intervention [66]. The body of previous literature
suggests that caregiving increases risk for negative
cognitive, mood, and psycho-social indicators among
caregivers, while motor interventions improve cog-
nition among individuals with cognitive impairment
including dementias. However, no study has exam-
ined the impact of a neuro-cognitive intervention on
a population consisting of AA women who are also
caregivers for a parent with probable AD, and there-
fore at greater risk for developing AD themselves.
Given the multi-faceted nature of the increased risk
for cognitive impairment in this population, our pro-
posed study would fill a gap in existing knowledge
about the relationship between caregiving and AD.
With the increasing incidence and prevalence of
AD, research efforts should target high-risk groups to
prevent or slow disease progression in tandem with
cure-driven research directives in established disease.
Interventions that may impart physiological, cogni-
tive, physical and mood related benefits, including
adapted tango intervention, is a cost-effective way
of slowing AD, particularly in high-risk individuals,
and allow for more rapid research trajectories over
conventional drug discovery approaches [67]. While
longer interventions are optimal, early intervention
is critical and assessing the impact on biomarkers
in addition to cognitive changes is also of great

M.E. Hackney et al. / Rationale and Design of ACT Trial 773
importance. Because we know that inflammation and
vascular health are implicated in AD neuropathol-
ogy, and exercise is beneficial in preventing AD,
research should clinically investigate the extent to
which adapted tango interventions could confer AD-
related benefits in African Americans at high risk for
AD, during middle age. This pilot clinical trial will
provide data to address these issues.
ACKNOWLEDGMENTS
A Department of Veterans Affairs Career Devel-
opment award supported ME Hackney (N0780W).
W Wharton is supported by NIH-NIA grants:
K01AG042498. This trial is supported by the Emory
Goizueta Alzheimer’s Disease Research Center and
the Atlanta VA Center for Visual and Neurocognitive
Rehabilitation.
Authors’ disclosures available online (https://
www.j-alz.com/manuscript-disclosures/18-1130r1).
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