Delirium accelerates cognitive decline in
T.G. Fong, MD, PhD
R.N. Jones, ScD
P. Shi, PhD
E.R. Marcantonio, MD,
L. Yap, PhD
J.L. Rudolph, MD
F.M. Yang, PhD
D.K. Kiely, MPH, MA
S.K. Inouye, MD, MPH
Objective: To examine the impact of delirium on the trajectory of cognitive function in a cohort of
patients with Alzheimer disease (AD).
Methods: A secondary analysis of data collected from a large prospective cohort, the Massachu-
setts Alzheimer’s Disease Research Center’s patient registry, examined cognitive performance
over time in patients who developed (n ? 72) or did not develop (n ? 336) delirium during the
course of their illnesses. Cognitive performance was measured by change in score on the
Information-Memory-Concentration (IMC) subtest of the Blessed Dementia Rating Scale. Delirium
was identified using a previously validated chart review method. Using linear mixed regression
models, rates of cognitive change were calculated, controlling for age, sex, education, comorbid
medical diagnoses, family history of dementia, dementia severity score, and duration of symp-
toms before diagnosis.
Results: A significant acceleration in the slope of cognitive decline occurs following an episode of
delirium. Among patients who developed delirium, the average decline at baseline for perfor-
mance on the IMC was 2.5 points per year, but after an episode of delirium there was further
decline to an average of 4.9 points per year (p ? 0.001). Across groups, the rate of change in IMC
score occurred about three times faster in those who had delirium compared to those who did not.
Conclusions: Delirium can accelerate the trajectory of cognitive decline in patients with Alzheimer
disease (AD). The information from this study provides the foundation for future randomized inter-
vention studies to determine whether prevention of delirium might ameliorate or delay cognitive
decline in patients with AD. Neurology®2009;72:1570–1575
AD ? Alzheimer disease; CDR ? Clinical Dementia Rating; IMC ? Information-Memory-Concentration subtest of the Blessed
Dementia Rating Scale; MADRC ? Massachusetts Alzheimer’s Disease Research Center; MGH ? Massachusetts General
Identification of factors that impact cognitive trajectory in Alzheimer disease (AD) may lead to
effective secondary prevention strategies. Studies have shown that older age,1,2male gender,3
genetic predisposition,4rapid onset disease,5higher dementia severity,4and high degree of
medical comorbidity2can influence cognitive decline over time, but these factors are not
modifiable. A potentially preventable condition that may impact cognitive trajectory and
which occurs in up to 66%–89% of patients with AD during hospitalization6-8is delirium.
This syndrome is characterized by acute changes in cognition and attention, and is often the
physiologic consequence of a medical disturbance or complication, such as infection, labora-
Address correspondence and
reprint requests to Dr. Tamara G.
Fong, Institute for Aging
Research, Hebrew SeniorLife,
1200 Centre Street, Boston, MA
From the Aging Brain Center (T.G.F., R.N.J., P.S., J.L.R., F.M.Y., D.K.K., S.K.I.), Institute for Aging Research, Hebrew SeniorLife; Departments of
Neurology (T.G.F.) and Medicine (E.R.M., S.K.I.), Beth Israel Deaconess Medical Center, Harvard Medical School; Department of Neurology
(L.Y.), Massachusetts General Hospital, Harvard Medical School; VA Boston Healthcare System (J.L.R.), Geriatric Research Education and
Clinical Center; and Department of Psychiatry (F.M.Y.) and Division of Aging (J.L.R.), Brigham and Women’s Hospital, Harvard Medical
School, Boston, MA.
Supported in part by a pilot grant from the Massachusetts Alzheimer’s Disease Research Center (P50AG005134) and grants from the National
Institute on Aging, K23 AG 031320 (T.G.F.), R21 AG027549 (E.R.M.), R21 AG026566 (E.R.M.), R01 AG 030618 (E.R.M.), R03 AG 028189
(E.R.M.), R03 AG029861 (J.L.R.), K24AG000949 (S.K.I.), P60 AG008812 (R.N.J.), Alzheimer’s Association Grant #IIRG-08-88737 (S.K.I.), and
VA Rehabilitation Career Development Award (J.L.R.). S.K.I. holds the Milton and Shirley F. Levy Family Chair.
Disclosure: The authors report no disclosures.
Copyright © 2009 by AAN Enterprises, Inc.
tory derangements, adverse medication ef-
fects, or surgery. A diverse nomenclature for
delirium has emerged, including terms such as
acute confusional state, acute brain syndrome,
or toxic-metabolic encephalopathy. For the
purposes of this research these terms are con-
sidered to refer to the same syndrome, and are
generalized under the broad characterization
of acute brain failure. Like heart failure, brain
failure can be conceptualized as a syndrome
resulting from multiple and diverse etiologies,
and contributing to poor outcomes indepen-
dent of specific causes.
This study examines cognitive trajectory in
a cohort of patients with AD before and after
an episode of delirium. We hypothesize that
the occurrence of delirium results in more
rapid cognitive decline, independent of rele-
vant covariates. Ultimately, if delirium irre-
versibly impacts cognitive decline in patients
with AD, this finding would hold substantial
clinical implications for delirium prevention
METHODS Setting and subjects. Potential study partici-
pants were consecutive patients seen at the Memory Disorders
Unit of the Massachusetts Alzheimer’s Disease Research Center
(MADRC) at Massachusetts General Hospital (MGH) from
January 1, 1991, through June 30, 2006. The MGH Memory
Disorders Unit evaluates approximately 200–250 new patients
each year, and is the primary memory clinic serving the
MADRC, a specialized research center that has been funded by
the National Institute of Aging/NIH since 1984. The MGH is a
900-bed Harvard-affiliated acute care teaching hospital with
over 45,000 admissions and 433,000 outpatient visits per year.
Patients included in the study were diagnosed with probable
or possible AD by an attending neurologist in the MGH Mem-
ory Disorders Unit using National Institute of Neurological and
Communicative Disorders and Stroke–Alzheimer’s Disease and
Related Disorders Association guidelines.9All patients had a
minimum of three observations at about 6-month intervals to
determine cognitive trajectory. Written informed consent for use
of their clinic data for research was obtained jointly from the
patients and their family members, next of kin, health care
proxy, or count-appointed guardian, according to procedures
approved by the MGH institutional review board.
Clinical evaluation. Patients were assessed at entry to the
cohort and approximately every 6 to 7 months thereafter, follow-
ing a uniform protocol at the Memory Disorders Unit clinic.
Baseline evaluation included collection of the following vari-
ables: age, sex, race and ethnicity, education, and presence of
comorbid medical conditions including thyroid disorder, heart
disease, hypertension, hypercholesterolemia, diabetes mellitus,
liver disease, kidney disease, cancer, pulmonary disorders, or
stroke. Dementia-related information included family history of
dementia, duration of dementia symptoms before diagnosis, and
dementia severity. Dementia severity was rated across all time-
points using the MGH Dementia Severity Rating scale, an in-
house scale created at the MADRC, which rates general levels of
functional dependence (range 0–5, with 5 indicating profound
impairment). For patients enrolled after 2002, the Clinical De-
mentia Rating (CDR) scale10was also used to assess dementia
severity. Cognitive testing was conducted at baseline and approx-
imately every 6 months using the Information-Memory-
Concentration (IMC) section of the Blessed Dementia Scale,11
further described below.
Identification of delirium. Delirium and its date of onset
was identified among cohort members hospitalized at MGH
during the course of the study by using a previously validated
chart review method12based on recognition of key terms or pres-
ence of mental status or behavioral changes by trained clinical
chart abstractors. In a previous study, the chart-based method
demonstrated a sensitivity of 74%, specificity of 83%, likelihood
ratio of 4.4, and overall agreement of 82% (kappa ? 0.41) for
delirium diagnoses.12To verify reliability of ratings, interrater
reliability assessments were conducted among the three actual
chart reviewers for the present study, and demonstrated an agree-
ment of 100% (kappa ? 1.0) for delirium ratings across 21
Outcome. The primary outcome for this study was rate of cog-
nitive decline, as measured by changes in the IMC score over
time. The IMC is a well-validated, widely used summary mea-
sure that measures domains of orientation, memory, knowledge
of personal information/current events, and performance on
three concentration tests. IMC scores range from 0 to 37, with
higher scores indicating impairment.11
Statistical analyses. For all patients, three sequential study
timepoints were identified (labeled A, B, and C in the figure). In
the delirium group, all timepoints were defined relative to the
date of onset of the delirium. For example, point B represents the
MADRC assessment most proximal but prior to the delirium. In
the nondelirium group, point B was randomly chosen from
among multiple assessments except for the first or last visit. In
both groups, point A represents the MADRC visit prior to point
B and point C represents the next visit after point B. For these
analyses, the date of delirium onset was required to fall in the
interval between points B and C. To assure that the selection of
timepoints in the nondelirium group did not bias our results, a
random selection of timepoints was performed for this group five
times and the analysis was replicated in each of the derived data-
sets. For this analysis, time period AB was considered as the
baseline interval (prior to delirium), and BC was the outcome
interval (including delirium occurrence).
Crude changes in IMC score across baseline (AB) and out-
come (BC) intervals in delirium and the nondelirium groups
were calculated. Because there was some variability in assessment
intervals, an annualized change in the slope of IMC scores for
both intervals was used in all analyses. Using a paired t test,
baseline slope and the outcome slope for both groups was com-
pared. The crude change and slope among those with and with-
out delirium was also assessed.
To calculate adjusted slopes, a linear mixed regression model
was used and controlled for age, sex, education, dementia sever-
ity score, duration of symptoms prior to diagnosis, family history
of dementia, and number of comorbid medical conditions. Time
was included as a random effect. The hypothesis that cognitive
change is greater after delirium was tested. Change was antici-
pated to be constant between the two study intervals for the
Neurology 72 May 5, 2009
A small number of missing values were present for duration
of symptoms before diagnosis (3%) and number of comorbid
medical diagnoses (4%) for the delirium group and for education
(2%), family history of dementia (0.3%), dementia severity score
(1%), duration of symptoms before diagnosis (1%), and number
of comorbid medical diagnoses (2%) for the nondelirium group.
All analyses were conducted using the SAS version 9.1 statis-
tical analysis program (SAS Institute, Cary, NC). All statistical
tests were two-tailed, and an alpha level of less than 0.05 was
used to indicate statistical significance.
RESULTS A total of 990 patients were potentially eli-
gible to participate. Over the course of the study, 195
patients were hospitalized at MGH and underwent
chart review. A total of 112 of these patients were con-
firmed to have developed delirium. For some of these
patients, the date of delirium onset did not fall in the
from primary analysis. The remaining patients who de-
median time to delirium from point B of 0.3 years
(75% interquartile range, 0.13–0.45 years). Thus, a to-
tal of 72 patients were used to determine cognitive tra-
jectory for the delirium group.
Of the remaining 878 patients, 540 were ex-
cluded due to a caregiver report of acute illness or
possible delirium or hospitalization outside the
MGH that could not be confirmed by medical
record review, and 2 were excluded due to lack of
follow-up visits during the target (6-month) time in-
terval. Thus, 336 patients were included in the non-
delirium comparison group.
The characteristics of the patients in the overall
cohort (n ? 408) and the delirium (n ? 72) and
nondelirium (n ? 336) subgroups are shown in table
1. Compared with the nondelirium group, the delir-
ium group was significantly older, more likely to be
male, had less years of formal education, and had
more comorbid illnesses. The patients with delirium
were significantly more likely to have a positive fam-
Figure Cognitive trajectories of patients
with Alzheimer disease with and
This figure depicts the slopes of the cognitive trajectories
in patients with Alzheimer disease over time in our cohort.
The median time to delirium from point B was 0.3 years
(75% interquartile range, 0.13–0.45 years). The slopes are
based on the changes in the Blessed Information-Memory-
Concentration (IMC) subscore over time, and the scores
for relevant covariables (age, sex, educational level, Massa-
chusetts General Hospital dementia severity rating score,
duration of dementia symptoms before diagnosis, family
history of dementia, and number of comorbid medical diag-
noses). The solid line indicates the trajectory for patients
with delirium (n ? 72) and the dashed line indicates the tra-
jectory for patients without delirium (n ? 336).
Table 1 Characteristics of the Massachusetts Alzheimer’s Disease Research Center study sample
Characteristic* Overall (n ? 408) Delirium (n ? 72)Nondelirium (n ? 336)p Value†
Age at initial visit in analysis, y
73.9 ? 8.1 76.9 ? 6.6 73.2 ? 8.30.001
176 (43.1)39 (54.2) 137 (40.8) 0.04
24 (5.9)4 (5.6) 20 (6.0)0.92
13.9 ? 3.5 13.0 ? 3.414.1 ? 3.40.02
Number of medical diagnoses
1.3 ? 1.21.7 ? 1.31.3 ? 1.1 0.01
Family history of dementia
22 (5.4)8 (11.1)14 (4.2)0.02
Baseline Blessed IMC score
11.1 ? 6.7 9.7 ? 5.411.4 ? 6.90.04
Baseline MGH dementia severity score
2.1 ? 0.9 2.1 ? 0.82.1 ? 0.8 0.54
Duration of symptoms before diagnosis, y
3.1 ? 2.1 2.6 ? 1.5 3.2 ? 2.20.01
Values are mean ? SD or n (%).
*Missing values were present for the following: race (n ? 3 in nondelirium group); education (n ? 8 in nondelirium group);
family history of dementia (n ? 1 in nondelirium group); baseline dementia severity score (n ? 4 in nondelirium group);
in delirium group and n ? 5 in nondelirium group).
†For comparisons of all characteristics in delirium vs nondelirium groups.
IMC ? Information-Memory-Concentration test; MGH ? Massachusetts General Hospital.
Neurology 72May 5, 2009
ily history of dementia and shorter duration of
dementia-related symptoms prior to diagnosis. These
baseline differences were controlled for in subsequent
analyses. Of note, the delirium group showed less
cognitive impairment by IMC scores at baseline
compared to the nondelirium patients. Finally, there
were no significant differences between the two
groups in baseline MGH dementia severity score or
duration of follow-up in the analyses.
In order to correlate the MGH Severity Scale with
the more widely used CDR scale,10a Spearman cor-
relation coefficient was calculated. In 4,296 paired
ratings, the Spearman correlation coefficient for the
CDR and MGH Severity Scale was 0.87 (p ?
0.0001), confirming a high degree of correlation.
Comparisons of changes in cognitive scores or
slopes at baseline and outcome interval for delirium
and nondelirium patients are presented in table 2.
For the delirium group, results are shown for the 72
patients who had complete data available. The crude
change in Blessed IMC scores was significantly
greater in the outcome interval compared with the
baseline interval (3.9 vs 2.1, p ? 0.02). The rates of
change for baseline and outcome intervals were 3.1
and 5.4 points per year (p ? 0.05). There was a sig-
nificant acceleration in the adjusted mean slope after
delirium, 4.9 points per year, compared to the base-
line interval prior to delirium, 2.5 points per year
(p ? 0.001). To verify the results in the entire delir-
ium group (n ? 112), the analyses were repeated
using multiple imputation to model adjusted slopes
for the interval prior to and with delirium, and found
an adjusted mean slope of 3.8 points per year after
delirium, in comparison to 2.2 points per year at
baseline (p ? 0.02, data not shown).
For the nondelirium group of 336 patients (table
2), there was no significant difference in the change
in Blessed IMC scores between baseline and outcome
interval (1.8 vs 2.1, p ? 0.54). In addition, no signif-
icant differences were found between unadjusted
slopes (2.9 vs 3.3, p ? 0.55) or adjusted slopes (2.4
vs 3.2, p ? 0.07). These results indicate no signifi-
cant acceleration of change in cognitive decline in the
outcome interval in the nondelirium group.
The figure depicts the adjusted model implied
slope (annualized change in Blessed IMC) of the cog-
nitive performance over time in the cohorts with and
without delirium. These slopes, derived from linear
mixed regression models adjusting for relevant co-
variables as described in Methods, again demonstrate
the significant acceleration in the slope of cognitive
decline after delirium.
DISCUSSION This study demonstrates that incident
that patients with dementia who develop delirium have
increased rates of hospitalization, institutionalization,
and mortality.6,13-15In this sample, after adjusting for
baseline differences, the change in score on the Blessed
IMC prior to an episode of delirium was 2.5 points per
year, consistent with prior reported increases in patients
with AD of about 3 points per year.16-18In the delirium
group, the relative change in IMC score doubled from
2.5 points per year at baseline to a postdelirium rate of
4.9 points per year. In comparisons across groups, the
rate of change in IMC score occurred about three times
faster in those who had delirium compared to those
who did not. In other words, these data estimate a 53%
absolute increase in the rate of change. From a clinical
tients with AD who become delirious experience the
equivalent of an 18-month decline compared to those
who do not experience delirium.
Delirium used to be viewed as a transient cogni-
tive disorder, but research has shown that delirium is
not always temporary and can often result in persis-
tent functional19,20and cognitive losses among gen-
eral medical hospitalized elderly. For example,
delirium has been linked to long-term cognitive im-
pairment, as demonstrated by lower Mini-Mental
State Examination scores and lowered performance
on tasks of executive functioning, attention, and pro-
cessing speed.14,21-23Furthermore, subjective memory
complaints, newly diagnosed dementia, and need for
long-term care have been associated with delirium in
elderly patients after hospitalization24or hip sur-
gery.25,26While these studies demonstrate adverse
long-term outcomes, this study is noteworthy in that
it demonstrates the adverse impact of an episode of
delirium on cognitive trajectory in patients with AD.
There are a number of strengths of this study.
First is the relatively large sample size from the well-
Table 2 Comparisonofcognitivescorechangeatbaselinevsoutcomeinterval
Delirium patients (n ? 72)
IMC score change ? SE
2.1 ? 0.43.9 ? 0.6 0.02
Slope (points/year) ? SE
3.1 ? 0.75.4 ? 0.8 0.05
Adjusted slope (points/year)* ? SE
2.5 ? 0.44.9 ? 0.70.001
Nondelirium patients (n ? 336)
IMC score change ? SE
1.8 ? 0.2 2.1 ? 0.30.54
Slope (points/year) ? SE
2.9 ? 0.4 3.3 ? 0.50.55
Adjusted slope (points/year)* ? SE
2.4 ? 0.33.2 ? 0.30.07
*Adjusted for age, sex, educational level, number of comorbid medical diagnoses at baseline
visit, family history of dementia, Massachusetts General Hospital dementia severity rating
score, and duration of dementia symptoms before diagnosis.
IMC ? Information-Memory-Concentration test.
Neurology 72May 5, 2009
characterized MADRC cohort. Second, although
baseline differences emerged between the patients
with AD with and without delirium, these factors
were controlled in all subsequent analysis. Of note,
these differences, including age, male gender, lower
baseline education, and higher number of comorbid
illnesses, are well described risk factors for delirium27
and such group differences were not unexpected.
The delirium group demonstrated lower baseline
IMC scores on average than the nondelirium group.
While this difference was significant, the impact of
lesser degrees of cognitive impairment at baseline
would be a conservative bias. An analysis using base-
line IMC scores in the logistic regression model was
conducted (data not shown) and the results did not
substantively alter the findings of our study. Further,
substantially worsened cognitive functioning in the
delirium group despite this baseline difference lends
support for the robustness of the finding. Third, du-
ration of follow-up time was consistent in the analy-
ses. Fourth, the time of delirium onset was identified
from medical chart review. Finally, this work is proof
of concept for what is commonly observed in clinical
practice, that is, older patients—particularly those
with dementia—may decline at a faster rate or never
fully recover their cognitive function following an
episode of delirium.
Bias may have been introduced into the analysis
by missing data, or by excluding those patients who
experienced delirium before a baseline cognitive tra-
jectory could be established (n ? 27), or who lacked
a final measure to establish their trajectory following
delirium (n ? 13). To evaluate for the possibility of
survivor bias in the 72 patients with data at all three
timepoints, the analyses were repeated using multiple
imputation for missing observations to model ad-
justed slopes in all 112 patients with delirium, and
still demonstrated significant acceleration in cogni-
tive trajectory following delirium.
There are limitations in the current study that
should be noted. First, this was a single site study
with a low representation of minorities and findings
may not be generalizable to all patient populations.
Second, the diagnosis of delirium was made by chart
diagnosis, and although a validated method was uti-
lized,12some cases of delirium may have been missed
due to lack of documentation. Moreover, duration
and severity of delirium could not be determined by
chart review, which represents an important area for
future investigation. Third, while inclusion of an ad-
ditional timepoint post-delirium (point D) would
have been ideal, we were unable to conduct such
analyses due to substantial attrition from this frail,
elderly, cognitively impaired cohort over time (55%
did not have point D). An important limitation of
the current analysis is that the concurrent effects of
delirium, which may not have resolved during the
delirium interval (BC), may confound the cognitive
trajectory. Future studies with longer-term follow-up
post-delirium will be required to validate our find-
ings. Fourth, 43% of the hospitalized patients (83 of
195) did not develop delirium, and the effects of hos-
pitalization on cognitive trajectory could not entirely
be disentangled from the current study. Finally, not
all patients in the MADRC cohort had complete
chart reviews or hospitalization data.
Replication of this study is needed to confirm that
delirium alters the trajectory of cognitive decline in
AD. Other important features that might affect cog-
nitive trajectory will need to be studied, including
more diverse populations, longer time periods, and
specific causes, duration, and severity of delirium. If
delirium does indeed precipitate a more rapid decline
in dementia severity, such a finding would necessi-
tate changes in the standard of care for patients with
dementia. For example, patients with AD would
need to be monitored closely for delirium, and when
in high-risk settings, delirium prevention strategies
should be utilized. It has been previously shown that
multicomponent risk factor strategies,28proactive ge-
riatric consultation,7educational interventions tar-
geted toward staff,29and avoidance of medications
with high risk for delirium can be beneficial. Treat-
ing patients as outpatients where the risk of delirium
may be lower could be another potential strategy for
minimizing delirium. The area of delirium among
hospitalized patients with AD has been largely unad-
dressed.30Given their high risk of accelerated long-
term decline, new approaches to care for these
patients to improve early identification and preven-
tion of delirium are greatly needed.
Ultimately, the information derived from this
study provides the foundation for future randomized
intervention studies to determine whether preven-
tion of delirium might ameliorate and/or delay cog-
nitive decline in patients with AD. Understanding
the pathophysiologic mechanisms for how delirium
impacts cognitive trajectory in dementia is another
area of important future work.
Statistical analysis was conducted by Dr. Peilin Shi, Aging Brain Center,
Institute for Aging Research, Hebrew SeniorLife, Boston, MA.
The authors thank Dr. Bradley Hyman and Dr. John Growdon at the
Massachusetts Alzheimer’s Disease Research Center for their collabora-
tion, support, and access to the MADRC patient registry and data.
Neurology 72May 5, 2009
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