International Psychogeriatrics: page 1 of 12 © International Psychogeriatric Association 2017

doi:10.1017/S104161021700151X

Prevalence of mild behavioral impairment in mild cognitive

impairment and subjective cognitive decline, and its
association with caregiver burden
...........................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................................

Faisal Sheikh,1 Zahinoor Ismail,1,2,3,4,5 Moyra E. Mortby,6,7 Philip Barber,3

Alicja Cieslak,3,4 Karyn Fischer,4 Robert Granger,1 David B. Hogan,3,5,8
Aaron Mackie,1 Colleen J Maxwell,5,9 Bijoy Menon,3 Patricia Mueller,4 David Patry,3
Dawn Pearson,3 Jeremy Quickfall,3 Tolulope Sajobi,3,5 Eric Tse,3 Meng Wang1,2
and Eric E. Smith2,3,4 , for the PROMPT registry investigators
1
Department of Psychiatry, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
2
Mathison Centre for Mental Health Research & Education, University of Calgary, Calgary, Alberta, Canada
3
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
4
Ron and Rene Ward Centre for Healthy Brain Aging Research, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
5
Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
6
Australian National University, Canberra, Australia
7
NHMRC National Institute for Dementia Research, Canberra, Australia
8
Division of Geriatric Medicine, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
9
University of Waterloo, Waterloo, Ontario, Canada

ABSTRACT

Background: Mild behavioral impairment (MBI) describes later life acquired, sustained neuropsychiatric
symptoms (NPS) in cognitively normal individuals or those with mild cognitive impairment (MCI), as an
at-risk state for incident cognitive decline and dementia. We developed an operational definition of MBI and
tested whether the presence of MBI was related to caregiver burden in patients with subjective cognitive
decline (SCD) or MCI assessed at a memory clinic.
Methods: MBI was assessed in 282 consecutive memory clinic patients with SCD (n = 119) or MCI (n = 163)
in accordance with the International Society to Advance Alzheimer’s Research and Treatment – Alzheimer’s
Association (ISTAART–AA) research diagnostic criteria. We operationalized a definition of MBI using the
Neuropsychiatric Inventory Questionnaire (NPI-Q). Caregiver burden was assessed using the Zarit caregiver
burden scale. Generalized linear regression was used to model the effect of MBI domains on caregiver burden.
Results: While MBI was more prevalent in MCI (85.3%) than in SCD (76.5%), this difference was not
statistically significant (p = 0.06). Prevalence estimates across MBI domains were affective dysregulation
(77.8%); impulse control (64.4%); decreased motivation (51.7%); social inappropriateness (27.8%); and abnormal
perception or thought content (8.7%). Affective dysregulation (p = 0.03) and decreased motivation (p=0.01) were
more prevalent in MCI than SCD patients. Caregiver burden was 3.35 times higher when MBI was present
after controlling for age, education, sex, and MCI (p < 0.0001).
Conclusions: MBI was common in memory clinic patients without dementia and was associated with greater
caregiver burden. These data show that MBI is a common and clinically relevant syndrome.

Key words: mild behavioral impairment (MBI), mild cognitive impairment (MCI), caregiver burden, subjective cognitive decline, memory clinic,
prodromal dementia

Introduction importance as an intrinsic aspect of prodromal

stages of dementia that can precede the onset
Neuropsychiatric symptoms (NPS) are common of cognitive symptoms is increasingly being
in Alzheimer’s disease (Zhao et al., 2016). Their recognized both in clinical practice and research
(Mortby and Anstey, 2015). Mild behavioral
Correspondence should be addressed to: Zahinoor Ismail, 3280 Hospital Dr NW, impairment (MBI) has been proposed as a later-
TRW Building 1st Floor, Calgary T2N 4Z6, Alberta, Canada. Phone: +1
life at-risk state for incident cognitive decline and
(403) 210-6900. Email: zahinoor@gmail.com Received 22 Feb 2017; revision
requested 2 Apr 2017; revised version received 9 Jul 2017; accepted 12 Jul dementia in those who have at most mild cognitive
2017. impairment (MCI) (Ismail et al., 2016).

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 2 F. Sheikh et al.
MBI is characterized by later life acquired,
sustained, and impactful NPS of any severity
that cannot be better accounted for by other
formal medical and psychiatric nosology. MBI is
an “at-risk” state for incident cognitive decline
and dementia, and for some, MBI is the index
manifestation of neurodegeneration, observed in
advance of cognitive impairment (Ismail et al.,
2016). The genesis of the MBI concept originated
with work by Taragano which recognized NPS
as the early manifestations of Frontotemporal
Dementia (Taragano et al., 2009). Following on
from this original work, the NPS Professional
Interest Area (PIA) of the International Society
to Advance Alzheimer’s Research and Treatment
(ISTAART), a subgroup of the Alzheimer’s
Association (AA) formalized the assessment of later
life onset NPS within a newer construct of MBI
as predictive of all cause dementia, and clarified
the relationship between MBI and MCI (Ismail
et al., 2016). The operationalized criteria for
MBI require the emergence in later-life behavioral
changes in at least one of the following domains:
decreased motivation (e.g. apathy, aspontaneity,
indifference); affective dysregulation (e.g. anxiety,
dysphoria, changeability, euphoria, irritability);
impulse dyscontrol (e.g. agitation, disinhibition,
gambling, obsessiveness, behavioral perseveration,
stimulus bind); social inappropriateness (e.g. lack of
empathy, loss of insight, loss of social graces or
tact, rigidity, exaggeration of previous personality
traits); and abnormal perception or thought con-
tent (e.g. delusions, hallucinations). Importantly,
the construct of MBI describes a population
which does not have dementia and is precluded
by formal psychiatric diagnosis (Ismail et al.,
2016).
To meet criteria for MBI, the preceding
behaviors must be of sufficient severity to produce
at least minimal impairment in interpersonal
relationships, other aspects of social functioning,
or ability to perform in the workplace. Individuals
with MBI generally maintain independence in
activities of daily living, requiring at most minimal
assistance. According to MBI criteria, individuals
can have comorbid conditions, but the behavioral
or personality changes may not be attributable to
another co-existing formal psychiatric disorder (e.g.
generalized anxiety disorder, major depression,
manic, or psychotic disorders), traumatic or general
medical causes, or the physiological effects of a
substance or medication, nor may they meet clinical
criteria for a dementia syndrome (e.g. Alzheimer’s
disease, frontotemporal dementia, dementia with
Lewy bodies, vascular dementia, other dementia).
However, MCI can be concurrently diagnosed with
MBI (Ismail et al., 2016).
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To date, little is known about the prevalence or
impact of MBI among individuals with subjective
concerns of cognitive decline (SCD). SCD as
reported by the affected person or informant
is associated with an increased risk for future
progression to MCI and dementia (Donovan et al.,
2014; Gifford et al., 2014). Given NPS are
linked to cognitive decline and disease progression
(Donovan et al., 2014), an important research
question is clarifying the role of NPS in SCD.
This is particularly the case as the concept of MBI
recognizes another population that may be at risk of
developing dementia, which so far has received little
attention. Early detection may lead to treatment of
distressing symptoms or possibly even approaches
to the prevention and treatment of dementia by
providing a better understanding of the very early
consequences of neurodegenerative disease (Ismail
and Mortby, 2017).
It is well established that NPS are associated
with higher levels of caregiver burden in dementia
(Allegri et al., 2006; Fischer et al., 2012; Dauphinot
et al., 2016). There are comparatively little data on
the specific prevalence of NPS in MCI or SCD,
and their impact on caregiver burden in these
populations. Improving our understanding of the
interplay between MBI, states without dementia
such as SCD and MCI, and caregiver burden
could have significant implications for improving
quality of life, functional outcomes, and resource
utilization (Ismail et al., 2015).
This study aims to address the above mentioned
gaps in the literature by using operationalized
MBI criteria to (1) investigate the prevalence
rates of MBI in a memory clinic population;
(2) determine whether there are differences in
prevalence estimates of MBI between patients
presenting with SCD or MCI; and (3) determine
the association of MBI with caregiver burden.
Methods
Participants
Participants were enrolled in the Prospective Study
for Persons With Memory Symptoms (PROMPT)
registry. The PROMPT Registry was established
in July 2010 and gathers information on patients
seen in the University of Calgary’s Cognitive
Neurosciences Clinic offered at two urban tertiary
care centers. Participants included in this study
attended the Cognitive Neurosciences Clinics
between January 2010 and September 2015.
Patients were referred for assessment of suspected
impairment in cognitive or behavioral function.
Their evaluation included a detailed medical

history, neurological examination, caregiver
interview, and cognitive testing.
This study only included participants with MCI
(n = 163) or objectively normal cognition who were
categorized with SCD (n = 119). A diagnosis of
dementia was an exclusion criterion, as was pres-
ence of psychiatric conditions (e.g. schizophrenia,
bipolar disorder, major depression). MCI was
diagnosed using the International Working Group
Criteria (Winblad et al., 2004). According to these
criteria, a person is considered to have MCI if
cognitive performance was more than 1.5 SD below
the normative expectations. Patients not meeting
criteria for MCI who reported cognitive problems
were classified as SCD. Informed consent was
obtained from all participants, and the Research
Ethics Board of the University of Calgary approved
the study.
Measures
Patients completed a cognitive assessment bat-
tery which included the Montreal Cognitive
Assessment (MoCA) (Nasreddine et al., 2005)
and Folstein Mini-Mental State Exam (MMSE)
(Folstein et al., 1975). NPS were assessed using
the informant-rated Neuropsychiatric Inventory
Questionnaire (NPI-Q) (Kaufer et al., 2000), which
was completed by a family member or close
informant. The NPI-Q assesses the presence and
severity of ten NPS (delusions, hallucinations,
agitation/aggression, dysphoria/depression, anxiety,
irritability, disinhibition, euphoria, apathy, aber-
rant motor behavior) and two neurovegetative
domains (sleep and night-time behavior change,
and appetite/eating change). Symptom severity is
scored on a scale from 1 (mild) to 3 (severe).
Caregiver burden was assessed using the 22-item
Zarit Caregiver Burden Interview (Zarit et al.,
1985), which has demonstrated utility in SCD
and MCI as well as in dementia (Stagg and
Larner, 2015). A Zarit Caregiver Burden Score
(ZCBS) was calculated for all patients with a
range of 0–88.
Socio-demographic measures
Patients’ age, sex, and education were obtained as
part of the general medical history. Information
on medical co-morbidities (based on physician-
made diagnoses) were obtained from the patient,
caregiver, and review of medical records.
Mild behavioral impairment
MBI was assessed in accordance with the
ISTAART-AA research diagnostic criteria (Ismail
et al., 2016). Ten NPS domains from the
NPI-Q were used to operationalize the five
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PROMPT MBI caregiver burden 3
ISTAART-AA MBI domains of decreased motivation
(NPI-Q apathy/indifference); emotional/ affective
dysregulation (NPI-Q depression/dysphoria, anxi-
ety, elation/euphoria); impulse dyscontrol (NPI-Q
agitation/aggression, irritability liability, aberrant
motor behavior); social inappropriateness (NPI-Q
disinhibition); and abnormal perception or through
content (NPI-Q delusions, hallucinations). Presence
of at least one behavior comprising a specific
domain meant the domain criteria was met. The
neurovegetative domains of sleep and appetite
changes, as described in the NPI-Q, are not
reflected in the ISTAART-AA MBI criteria. MBI
was stated to be present if at least one of the
five domains were present. Of note, a modified
reference range was used to ascertain MBI as
the NPI-Q has a reference range of one month,
while MBI requires six months of new-onset
symptoms.
Statistical analyses
Sample characteristics were described using de-
scriptive statistics and frequency distributions and
appropriate non-parametric tests (Bootstrapping,
χ 2 , Mann–Whitney U, and Kendall Tau) were
conducted as necessary. ZCBS was investigated for
its association with socio-demographic variables,
MCI or SCD classification, NPS, MBI, and each
individual MBI domain using Mann–Whitney U
and Kendall Tau tests. Additional analysis of
caregiver burden and its associations to MBI and
MCI was done by grouping the population into
four distinct categories: (1) SCD without MBI;
(2) MCI without MBI; (3) SCD with MBI, and
(4) both MCI and MBI. The ZCBS scores of
categories 2–4 were first individually compared
with the ZCBS score of category 1, and then
compared with each other. Mann–Whitney U tests
and bootstrap means were used to estimate non-
parametric mean difference and the associated 95%
confidence intervals (95%CI). Since the observed
distribution of ZCBS was positively skewed and
distinctly non-normal, bootstrapping was used to
estimate the population mean and its confidence
interval from our sample. Bootstrapping is a
non-parametric approach in which the original
data is randomly sampled with replacement and
the parameter of interest estimated in each
sample. Statistical inferences (e.g. standard errors,
confidence intervals) are derived based on the
distribution of the parameter estimates obtained
from the bootstrap samples. This approach is
known to be more robust to the impact of non-
normal distributions on parameter estimation and
statistical inference. Cliff delta (d) was used as a
measure of effect size for the group comparisons
 4 F. Sheikh et al.

Table 1. Sample characteristics

t ota l s a m p l e
(n = 282) MCI (n = 163) SCD (n = 119) M W U /χ 2
............................................................................................................................................................................................................................................................................................................................

Age, median (IQR) 62 (55–66) 64 (58–70) 59 (50–63) U (279) = 12678.5,

Z = 4.66, p < 0.0001
Range (years) 23–94 24–94 35–84
Gender, n (%)
Female 142 (50.4%) 69 (42.3%) 67 (56.3%) χ 2 (1) = 5.07, p = 0.024
Male 136 (48.2%) 91 (55.8%) 51 (42.9%)
Education, median (IQR) 14 (12–16) 13 (12–16) 14 (12–16) U (273) = 7810.5,
Z = −2.08, p = 0.038
Range 0–27 12–16 16–23
MoCA, median (IQR) 24 (21–26) 22 (20–24) 27 (24–28) U (271) = 3,162,
Z = −9.18, p < 0.0001
Range 6–30 6–29 12–30
MMSE, median (IQR) 29 (27–30) 28 (26–29) 29 (29–30) U (260) = 3960.55,
Z = −7.40, p < 0.0001
Range 16–30 16–30 19–30
Neuropsychiatric
symptoms, n (%)
Reported 241 (85.5%) 147 (90.2%) 94 (79.0%) χ 2 (1) = 6.94, p = 0.008
NPI domains, n (%)
Delusions 12 (4.3%) 10 (6.1%) 2 (1.7%) χ2 (1) = 3.35, p = 0.067
Hallucinations 9 (3.2%) 6 (3.7%) 3 (2.5%) χ2 (1) = 0.30, p = 0.584
Agitation 111 (39.4%) 71 (43.6%) 40 (33.6%) χ2 (1) = 2.85, p = 0.091
Depression 151 (53.5%) 94 (57.7%) 57 (47.9%) χ2 (1) = 2.64, p = 0.104
Anxiety 116 (41.1%) 75 (46.0%) 41 (34.5%) χ2 (1) = 3.80, p = 0.051
Euphoria 24 (8.5%) 15 (9.2%) 9 (7.6%) χ2 (1) = 0.24, p = 0.626
Apathy 119 (42.2%) 80 (49.1%) 39 (32.8%) χ2 (1) = 7.50, p = 0.006
Disinhibition 64 (22.7%) 38 (23.3%) 26 (21.8%) χ2 (1) = 0.084, p = 0.772
Irritability 135 (47.9%) 80 (49.1%) 55 (46.2%) χ2 (1) = 0.23, p = 0.635
Aberrant motor behavior 38 (13.5%) 28 (17.2%) 10 (8.4%) χ2 (1) = 4.54, p = 0.033
MBI, n (%)
Reported 230 (81.5%) 139 (85.3%) 91 (76.5%) χ 2 (1) = 3.55, p = 0.060
MBI domains, n (%)
Affective dysregulation 179 (63.5%) 112 (68.7%) 67 (56.3%) χ2 (1) = 4.57, p = 0.033
Impulse dyscontrol 148 (52.5%) 91 (55.8%) 57 (47.9%) χ2 (1) = 1.73, p = 0.188
Decreased motivation 119 (42.2%) 80 (49.1%) 39 (32.8%) χ2 (1) = 7.50, p = 0.006
Social inappropriateness 64 (22.7%) 38 (23.3%) 26 (21.8%) χ2 (1) = 0.084, p = 0.772
Abnormal 20 (7.1%) 15 (9.2%) 5 (4.2%) χ2 (1) = 2.61, p = 0.106
perception/thought
content

Abbreviations: SCD = subjective cognitive decline; MCI = mild cognitive impairment; MoCA = montreal cognitive assessment; MMSE =
Mini-Mental State Exam; NPI = neuropsychiatric inventory; MBI = mild behavioral impairment; MWU = Mann–Whitney U;
χ 2 = chi-square test. Underlined p-values are significant.

(Cliff, 2014). Generalized linear model (with a Results

log link function) was adopted to examine the
associations between ZCBS and MBI/MCI, while Sample characteristics are presented in Table 1.
controlling for age, sex, and education. Rate ratios MCI was diagnosed in 57.8%, and SCD was
and confidence intervals were reported and model diagnosed in 42.2% of patients included in this
fit was assessed based on Pearson χ 2 and Akaike study. The diagnostic groups differed significantly
information criterion. Results were considered by age (U (279) = 12678.5, Z = 4.66, p < 0.0001),
statistically significant with a two-sided p-value of sex (χ 2 (1) = 5.07, p = 0.024), and education
less than 0.05. All analyses were conducted in SAS (U (273) = 7810.5, Z = −2.08, p = 0.038). They
v9.4 (SAS-Institute-Inc., 2014). also differed in terms of cognitive test performance

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on the MoCA (U (271) = 3,162, Z = −9.18, p
< 0.0001) and MMSE (U (260) = 3960.55, Z =
−7.40, p < 0.0001), where MCI patients had lower
median scores compared to SCD patients for both
the MoCA (22 vs. 27) and MMSE (28 vs. 29). NPS
were reported in 85.5% of the total population and
were significantly more prevalent in patients with
MCI (90.2%) than in SCD patients (79.0%; χ 2 (1,
n = 241) = 6.94, p = 0.008).
Prevalence of MBI in a memory clinic
population
Among the 282 patients included in this study,
81.5% met the operationalized MBI criteria
(Table 1). In descending order, the prevalence of
the various MBI domains were as follows: affect
dysregulation (63.5%), impulse dyscontrol (52.5%,
decreased motivation (42.2%), social inappropriateness
(22.7%), and abnormal perception or thought content
(7.1%).
Overall, no statistically significant differences
were found between the MCI and SCD groups
for MBI though there was a trend for a higher
prevalence in MCI (85.3%) compared to SCD
(76.5%; (χ 2 (1) = 3.55, p = 0.06). There were
significant differences between the two groups for
two MBI domains, specifically affective dysregulation
(68.7% vs. 56.3%; χ 2 (1, n = 179) = 4.57, p =
0.03) and decreased motivation (49.1% vs. 32.8%;
χ 2 (1, n = 119) = 7.50, p = 0.006) that were both
more prevalent in the MCI group.
Association of cognitive status and MBI with
caregiver burden
Caregiver burden scores were significantly higher
in patients with MBI versus those without (U
(244) = 1,453, Z = 7.10, p < 0.0001) (Table 2).
Across the entire sample, the presence of each MBI
domain individually was directly associated with
greater caregiver burden: affective dysregulation (U
(244) = 4,071, Z = 5.28, p < 0.0001), impulse
dyscontrol (U (244) = 4,178, Z = 5.92, p < 0.0001),
decreased motivation (U (244) = 4,091, Z = 5.99,
p < 0.0001), social inappropriateness (U (244) =
2,619, Z = 5.74, p < 0.0001), and abnormal
perception or thought content (U (244) = 1,106, Z =
3.24, p = 0.0012). The bootstrapped mean ZCBS
for the MBI domains were affective dysregulation
– 19.6 (95%CI = 17.5–21.4), impulse dyscontrol –
21.2 (95%CI = 19.3–21.3), decreased motivation –
22.2 (95%CI = 19.1–24.6), social inappropriateness
– 25.1 (95%CI = 22.6–28.9), and abnormal
perception or thought content − 25.5 (95%CI =
22.2–32.0) (Figure 1). Additional analysis of the
association of caregiver burden with MCI and MBI
are also presented in Figure 1. The bootstrapped
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PROMPT MBI caregiver burden 5
mean ZCBS of the four sub-groups stratified based
on diagnostic classifications were – SCD only (no
MBI) – 4.5 (SD = 0.69; 95%CI,3.0–6.4), MCI
only (no MBI) – 6.4 (SD = 1.48; 95%CI = 4.1–
9.7), SCD+MBI – 15.0 (SD = 1.23; 95%CI =
12.9–17.8), and MCI+MBI – 21.7 (SD = 1.06;
95%CI,19.1–23.9). Relative to the SCD only group,
the caregiver burden was significantly higher for
the MBI+MCI group (U (144) = 251.5, Z =
6.24, p < 0.0001), d = 0.82, followed by the
SCD+MBI group (U (100) = 365, Z = 4.31, p <
0.0001, d = 0.59). In contrast, the MCI only group
did not demonstrate significantly higher caregiver
burden than the SCD only group (U (44) = 240,
Z = 0.29, p = 0.78, d = 0.05). Furthermore,
the caregiver burden for the SCD+MBI group was
significantly higher than the MCI only group (U
(99) = 448, Z = 3.42, p = 0.0006, d = 0.48, but
significantly lower than the MCI+MBI group (U
(199) = 6,260, Z = 3.76, p = 0.0002, d = 0.32).
Importantly, caregiver burden was also significantly
higher (Kendall rτ = 0.40, 95%CI = 0.33–0.47,
p < 0.0001) with increasing cumulative severity of
MBI-specific NPS (Figure 2).
Negative binomial regression models were used
to assess the association of MBI and the five MBI
domains with ZCBS while controlling for age,
gender, education, and MCI diagnosis (Figure 3).
ZCBS was 3.35 times (95% CI, 2.51–4.47) higher
(p < 0.0001) in patients with MBI (compared
to no MBI) and 1.47 times (95%CI = 1.18–
1.83; p < 0.001) higher in patients with MCI
(compared to no MCI), with all other factors
held constant. Age (1.0, 95%CI = 0.99–1.01,
p = 0.44), sex (1.0, 95%CI = 0.81–1.23, p =
0.98), or education years (1.01, 95%CI = 0.98–
1.04, p = 0.64) were not significantly associated
with ZCBS.
Discussion
This study is one of the first to determine
the prevalence of MBI in a clinical sample (as
operationalized in the ISTAART-AA criteria, using
the NPI-Q) and investigate its association with
caregiver burden. Our four primary findings were
(1) there was a high prevalence of MBI in this
memory clinic population of patients with MCI
or SCD; (2) MBI prevalence was numerically
higher in MCI versus SCD but did not meet
the threshold for statistical significance though
both decreased motivation and affective dysregulation
domains were significantly more prevalent in MCI;
(3) MBI with or without MCI was associated
with higher scores on a caregiver burden scale;
and (4) cumulative severity of MBI symptoms
 6 F. Sheikh et al.

Table 2. Prevalence of variables and their associations with caregiver burden

median
caregiver
d e m o g r a ph i c median bu r d e n – zc b s a s s o c i at i o n w i t h c a r e g i v e r
characteristics p r eva l e n c e (IQR) s co r e ( I Q R ) bu r d e n k e n da l l tau / M W U
............................................................................................................................................................................................................................................................................................................................

All patients 282 (100%) – 13 (6–26) –

Age (years) – 62 (55–66) – Kendall rτ = 0.047, p = 0.284
Female 136 (48.2%) – 12 (6–24) U (241) = 6662.5, Z = 1.20, p = 0.230
Male 142 (50.4%) – 16 (7–26)
Education years – 14 (12–16) – Kendall rτ = −0.055, p = 0.234
completed
MoCA score – 24 (21–26) – Kendall rτ = −0.123, p = 0.007
MMSE score – 29 (27–30) – Kendall rτ = −0.137, p = 0.005
Binary variables
Mild cognitive 163 (57.8%) – 18 (8–28) U (244) = 9,528, Z = 4.13, p < 0.0001
impairment
Subjective cognitive 119 (42.2%) – 9 (4–20.5)
decline
Any neuropsychiatric 241 (85.5%) – 17(8–27) U (244) = 1,220, Z = 6.48, p < 0.0001
symptom
No neuropsychiatric 41 (14.5%) – 4 (0–7)
symptom
Mild behavioral 230 (81.5%) – 18 (8–27) U (244) = 1,453, Z = 7.10, p < 0.0001
impairment
No MBI diagnosis 52 (18.5%) – 4.5 (0–8)
MBI affect dysregulation 179 (63.5%) – 18 (8.5–27.5) U (244) = 4,071, Z = 5.28, p < 0.0001
domain
No affect dysregulation 103 (36.5%) – 7.5 (3.75–15.5)
symptom
MBI impulse dyscontrol 148 (52.5%) – 21.5 (9.5–29.75) U (244) = 4,178, Z = 5.92, p < 0.0001
domain
No impulse dyscontrol 134 (47.5%) – 8 (4–17)
symptom
MBI decreased 119 (42.2%) – 22 (10–30.25) U (244) = 4,091, Z = 5.99, p < 0.0001
motivation domain
No decreased motivation 163 (57.8%) – 8 (4–18)
symptom
MBI social 64 (22.7%) – 25 (17–31) U (244) = 2,619, Z = 5.74, p < 0.0001
inappropriateness
domain
No social inappropriate 218 (77.3%) – 10 (5–21)
symptom
MBI thought/perceptual 20 (7.1%) – 26 (16–34.5) U (244) = 1,106, Z = 3.24, p = 0.0012
disturbance domain
No thought/perceptual 262 (92.9%) – 12 (5.75–24.25)
disturbance symptom

Abbreviations: MoCA = montreal cognitive assessment; MMSE = Mini-Mental State Exam; MBI = mild behavioral impairment; MWU =
Mann–Whitney U; Kendall rτ = Kendall Tau correlation test. Underlined p-values are significant.

had a dose–response relationship with caregiver common in clinical versus community samples
burden. (Monastero et al., 2009; Ismail et al., 2017b).
MBI was common in our memory clinic pre- In fact, in our non-dementia sample, an MBI
dementia population with SCD or MCI with a diagnosis was made more often than that of MCI.
prevalence of 81.5%. Using a similar methodology This suggests that neuropsychiatric comorbidity
and the NPI to estimate MBI, prevalence of MBI along with cognitive symptoms increase the
was determined to be 34.1% in a population-based likelihood of seeking clinical care, and that MBI is
sample of older adults (Mortby et al., in press). a relevant and important aspect of how and why
Prior literature has shown that NPS are more patients present to memory clinics.

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 PROMPT MBI caregiver burden 7

35
p =0.001
Zarit Caregiver Burden scale score (Bootstrapped mean with 95% confidence

p <0.0001
30

p <0.0001

p <0.0001 p <0.0001
25
p <0.0001

20
intervals)

p <0.0001

15

p = 0.78
10

0
SCD only(n=23) MCI only(n=22) SCD + MBI MCI + MBI Affect domain Impulse Movaon Social domain Psychosis
(n=78) (n=122) (n=158) domain domain (n=56) domain (n=18)
(n=133) (n=107)
MBI - MCI comparison groups Mild Behavioral Impairment Domains

Figure 1. Zarit caregiver burden scale scores for MCI, SCD, MBI, and the five individual MBI domains.

While there was no statistically significant (Richard et al., 2013). Evidence also suggests
difference in the prevalence of MBI between SCD a relationship between executive dysfunction in
and MCI, it was more common in MCI. Previous MCI and the presence of NPS. A study of 1,779
studies have consistently demonstrated increasing participants with MCI in the National Alzheimer’s
NPS burden with declining cognition and function Coordinating Center demonstrated that executive
(Fernandez-Martinez et al., 2010; Zhang et al., dysfunction was linked to NPS, specifically anxiety
2012). It is unclear whether there is in fact and depression (Rosenberg et al., 2011). One
no difference or if our study was underpowered can speculate that anxiety and depression may
to show a 10%–15% difference in prevalence. be neuropsychiatric manifestations of executive
Assessment of MBI domains, however, did reveal dysfunction in a pre-dementia population. This is
significant differences between the groups. The certainly in keeping with the overall conceptualiza-
affective dysregulation and decreased motivation tion of NPS as early markers of neurodegenerative
domains were statistically more likely to be present disease (Ismail et al., 2017a) and may explain
in patients with MCI. These findings might the later emergence of affective dysregulation in
indicate a difference in the timing of the onset of our population with a higher prevalence in MCI
MBI domains in early neurodegenerative disease versus SCD. To our knowledge, there is little
with a later emergence of changes in motivation, evidence on the relative emergence of NPS and
drive, and emotional regulation. Evidence suggests MBI domains. Longitudinal studies are required
that apathy (Lanctôt et al., 2017) and anxiety to clarify the timelines and role of individual MBI
(Gulpers et al., 2016) predict cognitive decline domains on cognitive and functional outcomes over
and dementia. Depression is a more heterogeneous time, and the predictive nature of MBI domains
concept (Ismail et al., 2017b), and while there is on different dementia subtypes. A longitudinal
extensive evidence that depression precedes cog- study in a dementia population demonstrated that
nitive impairment (Saczynski et al., 2010; Luppa anosognosia as well as apathy and agitation are
et al., 2013), some data indicate that depressive factors that should be considered in assessing
symptoms may accompany cognitive impairment quality of life ratings by patients and caregivers

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 8 F. Sheikh et al.

Zarit Caregiver Burden scores (Bootstrapped mean and 95% confidence intervals) 60

50

40

30

20

10 Kendall tau rτ=0.40 (95% CI, 0.33−0.47);

0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
Cumulave severity scores of MBI-specific Neuropsychiatric symptoms using NPI-Q

Figure 2. Dose–response relationship between cumulative severity of MBI-specific neuropsychiatric symptoms and caregiver burden
(bootstrapped mean Zarit caregiver burden scores with 95% confidence intervals).

4.5

4
Adjusted rate raos (and 95%CI) for predicted caregiver burden

3.5
***

2.5

2 ***
***
*** *** ***
1.5 ** * **
** * *

0.5

0
Model #1 MBI Model #2 Affect Domain Model #3 Impulse domain Model #4 Movaon Model #5 Social domain Model #6 Psychosis domain
domain
MBI / MBI domain CB MCI CB Age CB Gender CB Educaon years

Figure 3. Six separate negative binomial regression models predict that MBI and its five domains have higher adjusted ratios of caregiver
burden (CB) when compared with MCI, age, gender, and educational years. ***p-value < 0.0001, **p-value < 0.001, *p-value < 0.05.

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(Conde-Sala et al., 2016). The assessment of
anosognosia may help in clarifying the association
between MBI and caregiver burden.
We found important associations between MBI
and a measure of caregiver burden. First, the
presence of MBI was associated with greater
burden scores with co-morbid MCI+MBI patients
showing higher scores than SCD+MBI patients.
Second, SCD patients who were also diagnosed
with MBI had a significantly higher caregiver
burden score than patients who had MCI without
MBI. Third, in our total population, MCI was
associated with a significantly higher caregiver
burden score than SCD, but this association
was driven primarily by the presence of MBI
as suggested by the non-significant difference in
caregiver burden score between MCI and SCD in
the group of patients without MBI.
The association of NPS and caregiver burden is
well documented in dementia (Fischer et al., 2012).
In MCI, evidence suggests less caregiver burden
than in AD dementia (but more than in normal
controls) with the presence of NPS related to
greater burden (Ryan et al., 2012). There appears
to be a dose–response relationship between the
cumulative severity of MBI symptoms and reported
caregiver burden. Similarly, there is evidence for
a dose–response curve between symptom severity
in AD dementia and caregiver distress (Tun et al.,
2008). The aging, demographics, and memory
study (ADAMS) demonstrated a dose–response
effect of NPS on caregiving time in both pre-
dementia (Cognitive Impairment No Dementia)
and AD dementia participants (Okura and Langa,
2011). Those with no NPS received an average
of 10.2 hours of active help and 10.9 hours of
supervision per week from informal caregivers.
Those with one or two NPS received an additional
10.0 hours of active help and 12.4 hours of
supervision per week, while those with three or
more NPS received an additional 18.2 hours of
active help and 28.7 hours of supervision per week
(p < 0.001).
Each of the five MBI domains individually had a
significant association with the measure of caregiver
burden. Even though affective dysregulation was
the most frequent MBI domain present in the
population, it had the lowest median caregiver
burden score of the five domains, while the
inverse was true for the abnormal perception or
thought content domain. Comparable findings are
present in the dementia literature. An Argentinian
study of memory clinic patients with Alzheimer’s
disease dementia showed that psychotic symptoms
were most predictive of caregiver burden (also
measured with the Zarit), while there was little
predictive value of apathy or depression (Allegri
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PROMPT MBI caregiver burden 9
et al., 2006). Similarly, a predominantly apathetic
subgroup of AD dementia patients had the least
caregiver distress compared to more symptomatic
groups (Tun et al., 2008). Systematic reviews have
demonstrated a differential association between
specific NPS and caregiver burden (Fischer et al.,
2012), while others state that the evidence is yet
inconclusive (Feast et al., 2016). The ADAMS
study described a symptom hierarchy. The presence
of irritation (14.7 additional hours) was associated
with the greatest number of additional hours of
active help, while aberrant motor behaviors (17.7
additional hours) and disinhibition (17.5 additional
hours) were associated with the greatest number of
additional hours of supervision (Okura and Langa,
2011).
There are a number of strengths and limitations
of this study. The PROMPT registry enrolls
patients who have been referred to a tertiary care
academic memory clinic for cognitive concerns.
Approximately, 97% of referrals are enrolled in the
registry. Thus, our study reports on a representative
sample of patients who present for specialist care
in our clinic. Additionally, clinic data gathering
is systematic with respect to cognitive screening
instruments and informant-rated scales, improving
data quality. However, patients managed in primary
care or in facilities may not be represented by
those patients referred to our academic memory
clinic and our results may not be applicable
to them. Similarly, our results should not be
generalized to population-based samples, as the
relatively high prevalence of MBI we found
could be related to the setting of our study –
tertiary care academic memory clinic. SCD was a
diagnosis of exclusion, made in those with cognitive
complaints, but not meeting criteria for MCI,
as opposed to more rigorous criteria. Further, it
is possible that functional impairment is present
in the SCD population, driving the caregiver
burden, but it has not been assessed in this
study. However, by definition, MBI is precluded
by functional impairment, as this would result in a
dementia diagnosis. Further exploration is needed
for this important question. We have also not well
characterized the caregivers. For both the SCD
and MCI group, the caregiver that completed the
informant questionnaires was the family member
or friend who accompanied the referred patient
to the clinic appointment. For the majority of
participants, this was a spouse or child. The median
ZCBS scores seen observed were generally low
indicating no or little caregiver burden, though the
presence of certain MBI domains did show median
scores suggesting mild to moderate burden (Hébert
et al., 2000). The clinical importance of the median
scores observed will require additional research, in
 10 F. Sheikh et al.
particular longitudinal studies. Another limitation
is that the NPI-Q may not capture MBI and
its symptoms accurately. For example, the NPI-Q
has a one-month reference range of symptoms since
the onset of cognitive impairment, but is silent
on the overall duration of symptoms, while MBI
criteria stipulate later life acquired NPS of six
months duration. Thus, the use of the NPI-Q may
overestimate the prevalence of MBI, as evidence
by our very high prevalence estimates. Further, the
NPI was designed for use in a dementia patient
population. Given the variability in performance
of NPS rating scales (Ismail et al., 2013), it may
not be entirely representative of and appropriate
for prodromal populations. The recently published
MBI checklist (www.MBItest.org) was developed
specifically to reflect the ISTAART-AA MBI
criteria. The MBI-C is a 34-item instrument which
can be completed by a patient, close informant,
or clinician. It is explicit on the natural history
of NPS (later life emergence, sustained for at
least six months), and was designed for MBI case
detection and monitoring the emergence of MBI
symptoms over time (Ismail et al., 2017a). Further
studies using the MBI-C, as well as comparison
studies between the MBI-C and the NPI-Q are
required to help frame the results of this study and
address the question of cognitive outcomes over
time. For example, NPS trajectories from baseline
in MCI participants of the Alzheimer’s Disease
Neuroimaging Initiative were assessed on their
ability to predict the development of dementia. The
group with moderate level of NPS at baseline, as
measured by the NPI-Q, and had an increasing
burden of NPS over time were the most likely
to develop dementia. In contrast, those with low-
grade sustained symptoms or those with symptoms
that resolved were less likely to develop dementia
(David et al., 2016). Longitudinal data are needed
to evaluate the predictive utility of MBI for
cognitive decline and dementia.
Conclusion
In a non-dementia memory clinic population
with SCD and MCI, we assessed the prevalence
of MBI in accordance with the ISTAART-MBI
criteria, operationalized using the NPI-Q. The
prevalence of MBI was high. Though more
common among MCI patients, this difference
was not statistically significant. MBI domains of
decreased motivation and affective dysregulation were
statistically more likely in MCI. There was a strong
and direct relationship between the presence of
MBI and greater caregiver burden. Further, a dose–
response relationship exists between cumulative
MBI symptom severity and caregiver burden. In
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the absence of MBI, caregiver burden was not
significantly different between MCI and SCD, but
in the presence of MBI patients with MCI had
a significantly higher caregiver burden than SCD.
Patients with SCD and MBI had a significantly
higher caregiver burden than MCI without MBI.
These findings have potential implications for
ambulatory practice. MBI is more common than
MCI, which highlights the importance of assessing
NPS in prodromal populations. The presence of
MBI is associated with a higher risk of burden
in family members of memory clinic patients.
Further studies are required to determine if MBI
symptoms are modifiable, and if so, whether
their management affects caregiver burden over
time. Longitudinal research is needed to assess
for changes in MBI and specific MBI domains,
and their association with other factors linked
with cognitive and functional outcomes. This may
inform targeted strategies for treating affected
patients and potentially preventing cognitive and
functional decline.
Conflict of interest
None.
Description of authors’ roles
F. Sheikh wrote the paper, analyzed the data,
carried out statistical analyses, prepared the figures,
and was involved in designing the study and
its statistical components. Z. Ismail designed the
study, wrote the paper, did clinical assessments for
data collection, consented patients, and supervised
all aspects of the study. F.Sheikh supervised
throughout the study. E. Smith was involved in
designing the study, writing the paper, did clinical
assessments for data collection, consented patients,
and supervised aspects of the study, along with
supervising the PROMPT registry database. M.
Mortby assisted in writing the paper. P. Barber,
A Cieslak, K.Fischer, R. Granger, A. Mackie,
B.Menon, P.Mueller, D.Patry, D.Pearson, J. Quick-
fall, and E.Tse were involved in data collection
and patient consent to build the PROMPT registry
database. D. Hogan and C.Maxwell assisted in
writing the paper, data collection, and patient
consent. Tolulope Sajobi and Meng Wang were
involved in designing the statistical components,
supervising statistical analysis, and performing the
multivariate analysis for this study.
Acknowledgments
We would like to acknowledge the support of the
Ron and Irene Ward foundation, the Taylor family

foundation, the Clinician Engagement Grant from
the Addiction and Mental Health Strategic Clinical
Network of Alberta Health Services, and the
Alzheimer’s Society of Calgary, via the Hotchkiss
Brain Institute. M. E. Mortby is supported by the
Australian National Health and Medical Research
Council (NHMRC) and Australian Research
Council (ARC) Dementia Research Development
Fellowship #1102028.
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