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Baseline Cognitive Function, Recurrent Stroke, and Risk

of Dementia in Patients With Stroke


Pamela M. Rist, ScD; John Chalmers, MD; Hisatomi Arima, MD; Craig Anderson, MD;
Stephen MacMahon, PhD; Mark Woodward, PhD; Tobias Kurth, MD, ScD; Christophe Tzourio, MD, PhD

Background and PurposeTo determine the interrelationships between baseline Mini-Mental State Examination (MMSE)
score and risk of overall dementia, post-recurrent stroke dementia, and dementia without recurrent stroke among patients
with a history of stroke.
MethodsProspective cohort study among participants enrolled in the Perindopril Protection Against Recurrent Stroke
Study (PROGRESS) for whom baseline MMSE score was available. Baseline MMSE score was divided into 4 categories:
30, 2927, 2624, and <24. Participants were followed for incident dementia and recurrent stroke. Logistic regression
models were used to examine the association between MMSE score and dementia.
ResultsOf the 6080 participants included in this analysis, 2493 had an MMSE score of 30, 1768 had a score of 2928,
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1369 had a score of 2624, and 450 had a score of <24. Average follow-up time was 3.8 years. There were 407 cases
of dementia, 106 of which were preceded by a recurrent stroke. The risk of overall dementia increased with decreasing
MMSE score. However, the impact of MMSE score on the risk of dementia without recurrent stroke was much stronger
than the impact of MMSE score on the risk of post-recurrent stroke dementia. For those with MMSE score <24, the risk of
dementia without recurrent stroke was 47.89 (95% confidence interval, 28.5780.26), whereas the risk of post-recurrent
stroke dementia was only 7.17 (95% confidence interval, 3.7013.89). Higher MMSE scores were even less strongly
associated with the risk of post-recurrent stroke dementia.
ConclusionsPatients with stroke with low MMSE scores are at high risk of dementia over time, even in the absence of a
recurrent stroke, and should therefore be followed closely for further cognitive decline.(Stroke. 2013;44:1790-1795.)
Key Words: cerebrovascular disease cognitive functioning dementia epidemiology

S troke and dementia are 2 of the largest morbidity burdens


worldwide.1 Previous research has shown that cognitive
status and stroke occurrence are strongly related to the risk
between incident stroke and prestroke cognition on the risk of
dementia.5 However, very few studies have specifically tested
this interaction or assessed the impact of baseline cognitive
of future dementia. Individuals who experience a stroke have status on the risk of dementia preceded by or not preceded by
double the risk of dementia, including delayed dementia com- stroke. Learning more about the associations among baseline
pared to those who do not experience stroke.2 Other studies cognitive functioning, stroke, and risk of dementia would help
have also shown that lower scores on tests of cognitive func- determine whether the risk of dementia is driven primarily by
tion like the Mini-Mental State Examination (MMSE) are also the stroke event, which would suggest a vascular pathology, or
highly predictive of future risk of dementia.3,4 by the level of cognitive functioning before the stroke event,
However, little research has examined whether prestroke which would suggest pathologies independent of the stroke
cognitive function is still a strong predictor of the risk of event.
dementia after a stroke event because most previous stud- The Perindopril Protection Against Recurrent Stroke
ies have not assessed cognitive function before the stroke Study (PROGRESS) was a randomized trial among people
event. A review article on the impact of stroke on the risk of with a history of cerebrovascular disease in which a blood
dementia concluded that prestroke cognitive decline did not pressure regimen was tested against placebo for the secondary
seem to account for the association between stroke and cogni- prevention of stroke. The study assessed participants cognitive
tive impairment and did not find evidence for an interaction function at baseline and followed them for recurrent stroke

Received October 18, 2012; accepted April 11, 2013.


From the Division of Preventive Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard Medical School, Boston, MA (P.M.R.,
T.K.); Departments of Epidemiology (P.M.R., T.K.) and Social and Behavioral Sciences (P.M.R.), Harvard School of Public Health, Boston, MA; The George
Institute for Global Health, University of Sydney, New South Wales, Australia (J.C., H.A., C.A., S.M., M.W.); and INSERM Unit 708Neuroepidemiology,
Bordeaux, France (T.K., C.T.); and University of Bordeaux, U708, Bordeaux, France (T.K., C.T.).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.
111.680728/-/DC1.
Correspondence to Pamela M. Rist, ScD, Division of Preventive Medicine, Brigham and Womens Hospital, 900 Commonwealth Ave, 3rd Floor, Boston,
MA 02215. E-mail prist@mail.harvard.edu
2013 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.111.680728

1790
Rist et al Cognitive Function, Recurrent Stroke, and Dementia 1791

and incident dementia. Using data from this study, we aimed (possible) dementia, or no dementia. No attempt was made to further
to determine the interrelationships between baseline MMSE classify cases into subtypes of dementia because all participants had
a history of cerebrovascular disease and often had other vascular risk
score and the risk of overall dementia, post-recurrent stroke factors. The main outcome for this analysis was the occurrence of
dementia, and dementia without the presence of a recurrent dementia, either certain dementia or fairly certain dementia.
stroke. We hypothesized that recurrent stroke is a strong risk
factor for the development of dementia and cognitive status Stroke Assessment
before recurrent stroke may modify the impact of recurrent Recurrent fatal or nonfatal stroke was defined as an acute disturbance
stroke on the development of dementia. of focal neurological function with symptoms lasting >24 hours (or
resulting in earlier death) thought to be because of either cerebral in-
farction or cerebral hemorrhage.7,10 All suspected strokes and deaths
Methods were first reported by local study investigators and then reviewed by
Previous studies have described the design of PROGRESS.6,7 In experts on the central End Point Adjudication Committee. This com-
brief, PROGRESS was a randomized, double-blind, placebo-con- mittee was provided with a clinical summary of the event and copies
trolled trial to determine the effectiveness of a blood pressure of any available investigation reports (eg, biochemistry, hematology,
lowering regimen to prevent recurrent stroke and dementia among radiology, and autopsy findings).11 Strokes were classified as cerebral
6105 participants with previous stroke or transient ischemic attack. hemorrhage, ischemic stroke, or stroke of unknown pathological type.
Participants were recruited from 172 collaborating centers in 10 If dementia occurred before the recurrent stroke event, the person
countries from May 1995 to November 1997. To be eligible, partici- was classified as dementia without recurrent stroke. If stroke event
pants needed to have had either a stroke or transient ischemic attack occurred before dementia, the person was classified as post-recurrent
(but not subarachnoid hemorrhage) within the past 5 years and have stroke dementia.
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no clear indication for, nor a contraindication to, treatment with an


angiotensin-converting enzyme inhibitor. In addition, dementia was
an exclusion criterion. After a run-in period, participants who toler- Statistical Analysis
ated and adhered to perindopril therapy were randomly assigned to First, we used logistic regression models to calculate the odds ratio
continued active treatment or placebo. Randomization was stratified as a measure for the relative risk (RR) of developing dementia for the
by study center, age, sex, systolic blood pressure at entry, inclusion 4 categories of the baseline MMSE score using the highest category
diagnosis, and the intention to begin combination therapy or single of MMSE as the reference category. Next, to examine the impact of
drug therapy. MMSE score on the joint outcome of recurrent stroke and dementia,
we divided incident dementia into post-recurrent stroke dementia and
dementia without recurrent stroke. We then used logistic regression
Cognitive Decline and Dementia Assessment models to assess the RR of both dementia types compared to no de-
At baseline, the 6- and 12-month visits, and annually thereafter, par- mentia for each of our MMSE categories.
ticipants completed the MMSE.3 One point was awarded for each All models were adjusted for variables that we believed could be
successfully completed item (maximum score of 30); no points were potential confounders based on biological mechanisms. These vari-
awarded for any missing item. Baseline MMSE score was divided a ables were age (continuous), sex, height (continuous), smoking status
priori into 4 categories: 30 (high MMSE score), 2928 (medium-high (never smoked regularly, past, current), current alcohol consumption
MMSE score), 2724 (medium-low MMSE score), and <24 (low (currently do not drink more than once/wk, currently drink <8 drinks/
MMSE score). In the event that baseline MMSE score was missing wk, currently drink 8 drinks/wk), educational status (stopped edu-
(n=32), baseline MMSE score was imputed using the MMSE score cation by 14, 16, 19, and >19 years of age), diabetes mellitus status
from the 6-month visit (n=7). Participants for whom baseline MMSE (yes/no), and systolic blood pressure (continuous). We also adjusted
score could not be imputed were excluded from the analysis (n=25). for randomized treatment assignment.
Throughout the follow-up, a 2-phase screening and assessment In secondary analyses, we explored the relationship between base-
process was used to diagnose dementia.8 Participants meeting any line MMSE score and recurrent stroke and risk of dementia strati-
of the following criteria were considered to be screened positive for fied by the recurrent stroke subtype (ischemic versus hemorrhagic
dementia: an MMSE score 25 at any follow-up visit, a decline in stroke). We additionally performed all analyses using only those
the MMSE score of 3 points between any 2 follow-up visits, an randomized to placebo. Finally, we performed separate sensitivity
MMSE score missing for 2 scheduled follow-up visits, or a positive analyses in which we adjusted for baseline Barthel index in addi-
response by the investigator to the question: In your opinion, does this tion to our potential confounders, excluded patients who screened
patient have dementia? All participants who screened positive were positive for dementia at baseline, and excluded patients with MMSE
referred to a local specialist experienced in diagnosing dementia. The scores <18 at baseline.
specialists were blinded to treatment assignment and to all clinical No participant had missing information on age, sex, current alco-
data. Participants who screened negative were classified as not hav- hol consumption, diabetes mellitus status, or baseline systolic blood
ing dementia. pressure. Fewer than 100 people were missing information on height
The local specialist used a checklist based on the criteria for the and smoking and were assigned to the median and past smoker, re-
diagnosis of dementia as defined in the Diagnostic and Statistical spectively. More than 100 people had missing information on educa-
Manual of Mental Disorder, Fourth Edition.9 The questionnaire in- tion status so we used the missing indicator method.
cluded systematic questions on the presence of poststroke focal defi- All statistical analyses were performed using SAS 9.1.3. All P val-
cits, such as aphasia or motor deficit, and on the presence of more ues are 2-tailed, and P<0.05 was considered statistically significant.
global problems, such as depressed mood, that could have altered
the diagnosis of dementia. Local specialists were also systematically
asked whether the diagnosis of dementia was reliable. Whenever Results
possible, the specialist examined the patient. If an interview could Of the 6080 participants included in this analysis, 2493 (41.0%)
not be conducted, data were sought from all other available sources, had an MMSE score of 30, 1768 (29.1%) had an MMSE score
including medical records, interviews with family members, and con- of 2927, 1369 (22.5%) had an MMSE score of 2624, and 450
sultations with other medical professionals. After receiving the infor- (7.4%) had an MMSE score of <24. Average follow-up time was
mation from and diagnosis of the local specialist, a 2-person central
Dementia Adjudication Committee confirmed or refuted the diagnosis 3.8 years. There were 407 cases of dementia, 106 of which were
and assigned each screen-positive case to 1 of the following 4 catego- preceded by a recurrent stroke. A total of 709 strokes occurred
ries: certain dementia, fairly certain (probable) dementia, uncertain either before dementia onset or the end of the follow-up.
1792StrokeJuly 2013

Table1 shows covariates by baseline MMSE categories for The effect estimates for the association between baseline
our study population. Those with the lowest MMSE scores MMSE score and post-recurrent stroke dementia and between
were older, shorter in stature, had stopped schooling at a MMSE score and dementia without recurrent stroke can be
younger age, more likely to be female, consumed alcohol less seen in Table2. For both outcomes, we observed an increase in
frequently, had higher systolic blood pressure, were more the risk of dementia with decreasing MMSE scores. However,
likely to have diabetes mellitus, and were less likely to be cur- the impact of MMSE score on risk of dementia without recur-
rent smokers than participants with higher MMSE scores. rent stroke was much stronger than the impact of MMSE score
The impact of baseline MMSE score on the risk of overall on the risk of post-recurrent stroke dementia. For those with
dementia is presented in Table2. The risk of dementia increased an MMSE score <24, the risk of dementia without stroke was
with decreasing MMSE scores. Those with an MMSE score of 47.89 (95% CI, 28.5780.26), whereas the risk of post-recur-
2829 had an RR of dementia of 2.15 (95% confidence interval rent stroke dementia was only 7.17 (95% CI, 3.7013.89).
[CI], 1.433.24), whereas those with an MMSE score of <24 Higher MMSE scores were even less strongly associated with
had an RR of dementia of 26.81 (95% CI, 18.0839.76) com- the risk of post-recurrent stroke dementia. The risk of post-
pared to those with an MMSE score of 30. recurrent stroke dementia was only 1.32 (95% CI, 0.702.49)
The Figure shows the proportion of post-recurrent stroke among those with an MMSE score 2928, whereas the risk of
dementia and dementia without recurrent stroke by MMSE cate- dementia without stroke was 2.99 (95% CI, 1.735.18).
gory. Among those with an MMSE score of 30, 50% of those who Results stratified by stroke subtype (ischemic versus
develop dementia had dementia without recurrent stroke. In con- hemorrhagic; results not shown) were similar to those shown
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trast, among those with a low MMSE score (<24), nearly all those above. Results among those assigned to placebo were similar
who develop dementia had dementia without recurrent stroke. to those seen for the full cohort (results not shown). Results of

Table 1. Baseline Characteristics of Participants in the PROGRESS Trial by Baseline MMSE Score (n=6080)
MMSE Score
Characteristic 30 2928 2624 <24
Age, mean (SE) 61.4 (9.5) 64.8 (9.5) 66.0 (8.8) 67.6 (8.9)
Female, % 27.8 30.7 32.1 37.6
Height, mean (SE) 167.3 (8.9) 167.2 (8.9) 165.4 (9.4) 164.1 (9.0)
Smoking status, %
Never smoked regularly 44.7 40.0 40.0 42.7
Past smoker 33.8 41.7 39.7 39.8
Current smoker 21.6 18.3 20.4 17.6
Current alcohol consumption, %
<1/wk 60.5 56.6 59.9 66.7
1 to 8 drinks/wk 18.0 20.8 20.0 17.1
8 drinks/wk 21.5 22.6 20.1 16.2
Age at which schooling stopped, y
14 22.3 36.3 42.5 61.5
1516 20.1 25.4 25.1 19.2
1719 26.4 18.4 17.2 13.1
>19 31.3 19.9 15.2 6.3
Diabetes mellitus, % 12.0 11.8 12.5 17.8
Systolic blood pressure, mean (SE) 145.4 (18.8) 147.2 (19.0) 148.5 (18.7) 150.4 (20.4)
Type of qualifying event, %
TIA 22.9 24.4 18.5 18.2
Ischemic stroke 64.6 61.4 64.5 64.7
Hemorrhagic stroke 9.8 8.9 11.8 10.9
Unknown 2.7 5.3 5.2 6.2
Medication, %
Antihypertensive therapy 57.6 57.1 61.5 61.1
Antiplatelet therapy 71.9 73.9 71.6 71.3
Oral anticoagulants 7.1 11.9 8.7 11.8
Lipid-lowering therapy 15.8 13.9 12.4 10.7
PROGRESS indicates Perindopril Protection Against Recurrent Stroke Study; and TIA, transient ischemic attack.
Rist et al Cognitive Function, Recurrent Stroke, and Dementia 1793

Table 2. Multivariate-Adjusted* Relative Risks of Overall Dementia, Post-recurrent stroke Dementia, and Dementia Without
Recurrent Stroke by Baseline MMSE Score
No
Dementia
(n=5673) All Dementia (n=407) Post-recurrent stroke Dementia (n=106) Dementia Without Recurrent Stroke (n=301)
Crude Incidence Crude Incidence Crude Incidence
Rate (Per 1000 Rate (Per 1000 Rate (Per 1000
Baseline MMSE n No. Cases Person-Years) RR (95% CI) No. Cases Person-Years) RR (95% CI) No. Cases Person-Years) RR (95% CI)
30 2455 38 3.86 1.00 19 1.93 1.00 19 1.93 1.00
2829 1703 65 9.54 2.15 21 3.08 1.32 44 6.46 2.99
(1.433.24) (0.702.49) (1.735.18)
2427 1218 151 28.87 6.59 44 8.41 3.67 107 20.45 9.56
(4.549.55) (2.106.43) (5.7915.80)
<24 297 153 105.08 26.81 22 15.11 7.17 131 89.97 47.89
(18.0839.76) (3.7013.89) (28.5780.26)
CI indicates confidence interval; MMSE, Mini-Mental State Examination; and RR, relative risk.
*Results have been adjusted for age, sex, height, smoking status, current alcohol consumption, educational status, diabetes mellitus, baseline systolic blood pressure,
and randomized treatment assignment.
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our other sensitivity analyses were also similar to those seen the interrelationships among prestroke cognitive functioning,
for the full cohort (online-only Data Supplement). stroke, and cognitive impairment. Data from the Framingham
To further explore why baseline MMSE score was not as Heart Study showed that participants who experienced a
strongly associated with the risk of post-recurrent stroke demen- stroke had significantly lower mean MMSE scores prestroke
tia, we examined the associations between baseline MMSE and poststroke compared to the stroke-free participants.12 The
and the risk of recurrent stroke as well as between recurrent Baltimore Longitudinal Study of Aging found that those with
stroke and the risk of dementia. Baseline MMSE score was not mild cognitive impairment who experience a stroke are at
associated with the risk of recurrent stroke (results not shown). increased risk of developing dementia (odds ratio, 12.4; 95%
However, recurrent stroke was significantly associated with the CI, 1.599) compared to those with mild cognitive impair-
risk of dementia (RR, 2.93; 95% CI, 2.243.82). ment who do not experience a stroke. In addition, those who
were cognitively normal at the time of their stroke did not
Discussion have an increased risk of dementia compared to those with-
In this prospective cohort of patients with stroke, baseline out stroke.13 Another study using data from the Health and
MMSE score was strongly associated with the risk of devel- Retirement Study found that the rate of cognitive decline was
oping dementia. Analyses examining post-recurrent stroke faster among those who later survived a stroke compared to
dementia versus dementia without recurrent stroke suggested those who remained stroke-free throughout follow-up. Those
stronger associations between baseline MMSE score and risk who died after stroke had even faster rates of decline. After the
of dementia without recurrent stroke than with post-recurrent stroke event, the rate of decline among stroke survivors was
stroke dementia. similar to their rate of decline before the stroke event.14
Previous studies have shown that both lower MMSE scores Although these studies were able to examine the relationships
and stroke predict the risk of subsequent dementia.24 However, between cognitive functioning and first stroke, research on the
data on the interrelationships among prestroke MMSE, stroke, interrelationships among cognitive function, recurrent stroke,
and the risk of dementia in one study are sparse, mainly and risk of subsequent dementia is sparse. A few studies that
because small numbers of stroke or dementia events prohibits assessed cognitive functioning in patients with stroke have
the evaluation of joint effects. Three studies have examined shown links between cognitive decline and dementia,15,16 but

100.0%
90.0%
80.0%
70.0%
Percentage

60.0%
Post-recurrent stroke dementia
50.0%
Dementia without stroke Figure. Proportion of types of dementia
40.0%
according to baseline Mini-Mental State
30.0% Examination (MMSE).
20.0%
10.0%
0.0%
MMSE 30 MMSE 28-29 MSME 24-27 MMSE <24
MMSE category
1794StrokeJuly 2013

many could not specifically examine the effect of recurrent wide. In addition, we did not have information on MMSE
stroke on the association between cognitive functioning and score before first stroke, which prevented us from determining
dementia. One study directly tested the interaction between whether first stroke may be the triggering factor for cogni-
baseline cognitive status and incident stroke using participants tive decline or whether the patients had already experienced
in the Rotterdam Study who were free of dementia or a history decline before stroke. We took several steps to obtain a consis-
of stroke at baseline and found no interactive effect of incident tent diagnosis of dementia across the various centers, includ-
stroke and measures of prestroke cognitive function on the ing using standardized forms and having a central Dementia
risk of dementia.17 Adjudication Committee to minimize heterogeneity. Although
The present study showed that among those who have it is possible that people with undiagnosed or mild cognitive
already experienced a stroke or transient ischemic attack, base- impairment at baseline may have been included in our study,
line MMSE score is a strong predictor of the risk of dementia dementia was an exclusion criterion for entry into the trial, and
without recurrent stroke. Results from our study suggest that we used the original trial cohort for these analyses. Although
patients with stroke with low MMSE score are already on a 4 different tools were used to screen for dementia, they were
trajectory of cognitive decline related to preexisting neuro- mainly based on MMSE score, which is not sensitive to vas-
degenerative lesions or other undetermined factors triggered cular cognitive impairment. Therefore, it is possible that some
by the initial stroke event. The stroke event may increase the cases of dementia may have been missed.
risk of dementia either because of the direct impact of vas- To summarize, these results carry important messages for
cular disease on other neuropathological changes associated patients with stroke and their physicians that vary accord-
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with Alzheimer disease or by synergistic effects of Alzheimer ing to the baseline MMSE score of the patient with stroke.
neuropathology and vascular neuropathology.18 This has Patients with stroke with low MMSE scores are at high risk of
important clinical implications because it demonstrates that dementia over time, even in the absence of a recurrent stroke,
for those with low MMSE score, a recurrent stroke is not nec- and should therefore be followed closely for further cognitive
essary to develop dementia. This result could seem counter- decline.
intuitive because in patients with stroke, one would expect a
second stroke to result in a greater risk of cognitive decline
and vascular dementia. A review article found that the rate of
Sources of Funding
The Perindopril Protection Against Recurrent Stroke Study was
dementia was at least twice as high after recurrent stroke as it funded by grants from Servier (Paris, France), the Health Research
was after first stroke and the rate of dementia after recurrent Council of New Zealand (Auckland, New Zealand), and the National
stroke may depend on the number of recurrent strokes.19 Health and Medical Research Council of Australia (Canberra,
An important finding from the main analyses of PROGRESS Australia). The study was designed, conducted, analyzed, and inter-
is that a blood pressurelowering regimen decreased the risk preted by the investigators independent of all sponsors. Dr Rist was
funded by a training grant from the National Institute of Aging (AG-
of recurrent stroke and the risk of post-recurrent stroke demen- 00158) and by the Rose Traveling Fellowship Program in Chronic
tia.20 In the present study, the associations between baseline Disease Epidemiology and Biostatistics at the Harvard School of
MMSE score and post-recurrent stroke dementia were weaker Public Health.
than those seen for the associations between baseline MMSE
score and dementia without recurrent stroke. Although base- Disclosures
line MMSE score is highly predictive of dementia in the Drs Chalmers and MacMahon have received lecture fees and research
absence of stroke, the impact of recurrent stroke on the risk grants from Servier. Dr Arima holds a Future Fellowship from the
of dementia outweighs the impact of baseline MMSE score. Australian Research Council. Dr Anderson holds a Senior Principal
Therefore, patients, especially those with high MMSE score Research Fellowship from the National Health and Medical Research
Council. Dr Woodward has received lecture fees from Servier. Dr
who have the lowest risk of dementia without recurrent stroke, Kurth has received funds from Allergan and the American Academy
should be delivered strong stroke prevention messages. Given of Neurology for educational lectures. Dr Tzourio has received fees
the associations seen between blood pressurelowering drugs from the ABBOTT Company for participating in scientific commit-
and a reduced risk of recurrent stroke, patients with high tees. The other author has no conflict to report.
MMSE score may want to consider a blood pressurelower-
ing regimen to avoid another stroke and the associated risk of References
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Baseline Cognitive Function, Recurrent Stroke, and Risk of Dementia in Patients With
Stroke
Pamela M. Rist, John Chalmers, Hisatomi Arima, Craig Anderson, Stephen MacMahon, Mark
Woodward, Tobias Kurth and Christophe Tzourio
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Stroke. 2013;44:1790-1795; originally published online May 16, 2013;


doi: 10.1161/STROKEAHA.111.680728
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2013 American Heart Association, Inc. All rights reserved.
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Supplemental Methods

Antibodies
Rabbit polyclonal anti-Akt, anti-p-Akt (Ser473), anti-MKK7, anti-p-MKK7 (Ser171, Thr275),
anti-p-MLK3 (Thr277, Ser281), monoclonal anti-JNK3 (55A8) and monoclonal anti--actin
(13E5) antibodies were purchased from Cell Signaling Biotechnology (Boston, MA). Rabbit
polyclonal anti-GluK2, anti-MLK3, and mouse monoclonal anti-p-JNKs (Thr 183, Tyr 185, G-7)
antibodies were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). A mouse
monoclonal anti-PSD-95 (clone 7E3-1B8) antibody was obtained from Sigma (Saint Louis,
MO).

Drug Administration
A selective PI3K inhibitor LY294002 (BioMol, Plymouth Meeting, PA), a specific Akt inhibitor
Akt inhibitor IV (Calbiochem) and a potent MEK1 inhibitor PD98059 (Cell Signaling
Biotechnology) were used to detect the role of PI3K-Akt and MEK1 signaling in the
postconditioning-mediated neuroprotection respectively. LY294002 (100 nmol) or PD98059 (20
nmol) in 10l DMSO was infused into the rat cerebral ventricle (from the bregma: posterior, 0.8
mm; lateral, 1.5 mm; depth, 3.5 mm) through a stepper-motorized microsyringe (Stoelting,
Wood Dale, IL) 20 minutes before ischemia. Akt inhibitor IV (100 nmol) in 10l DMSO was
infused into the rat cerebral ventricle 2 hours after ischemia.

Histological Assessment
Rats were perfusion-fixed with 4% paraformaldehyde under anesthesia after 5 days of
reperfusion. Brains were removed and further fixed with the same fixation solution at 4C
overnight. Post-fixed brains were embedded by paraffin and then coronal sections (6m thick)
were prepared using a microtome. The paraffin embedded brain sections were deparaffinized
with xylene and rehydrated in a gradient of ethanol, followed by washing with distilled water.
The sections were stained with cresyl violet for the assessment of neuronal survival in the
hippocampus. The number of surviving hippocampal CA1 neurons per 1 mm length was
counted as the neuronal density.

Immunoprecipitation
The hippocampal CA1 regions were isolated after the indicated times of reperfusion and rapidly
frozen in liquid nitrogen. Samples were homogenized in ice-old homogenization buffer. 1 The
homogenates were centrifuged at 800g'/4C for 10 minutes and the supernatants were collected.
Sample proteins were incubated overnight at 4C with appropriate antibodies diluted in
immunoprecipitation buffer. 1 After the addition of protein A/G, the mixture was incubated at
4C for an additional 2 hours. The bound proteins were collected from Protein A/G by boiling
for 5 minutes in Laemmli sample buffer.

1
Immunoblot
Protein samples were separated by SDS-PAGE and then electrotransferred onto a nitrocellulose
membrane. After blocking, the membranes were probed with primary antibodies overnight at
4C. Detection was carried out by appropriate alkaline phosphatase-conjugated IgG (Sigma) and
developed with NBT/BCIP assay kit (Promega).

Statistical Analysis
The results are expressed as meansstandard deviation (SD). For each type of experiment, data
were obtained from at least three independent measurements. Statistical analysis of the results
was carried out using one-way analysis of variance (ANOVA) followed by the least significant
difference test or Newman-Keuls test. Differences were considered significant at P<0.05.

Supplemental Figure

Figure S1. LY294002 (LY) or Akt inhibitor IV (AI) has no effect on the neuronal survival
in the rat hippocampal CA1 subregion. Nissl staining on neuronal survival after 5 days
following drug administration. (a-c) Low-power views of hippocampus sectors. Scale bars =
500 m. (d-f) High-power views of hippocampal CA1 pyramidal cell layer of (a-c). Scale bars =
50 m. Neuronal density was counted as numbers of surviving pyramidal neurons per 1mm
length. Data are mean SD (n=5).

Supplemental Discussion

The role of MEK1-ERK1/2 pathway remains controversial, since both activation and inhibition
of ERK1/2 are reported to mediate neuronal survival in conditions associated with cerebral
ischemia. 2,3 Although different changes in ERK1/2 phosphorylation after postconditioning have
been reported, 4,5 Pignataro and colleagues found that ERK1/2 may be unrelated to the
protective effect of postconditioning after focal ischemia. 4 In this work, our result showed that
inhibiting MEK1-ERK1/2 signal by PD98059 didnt affect protective effect of postconditioning
after global ischemia, which is consistent with the study by Pignataro and colleagues.

2
Considering dual effects of ERK1/2 in ischemic brain damage and controversial data for
ERK1/2 phosphorylation in postconditioning, more studies are needed to clarify the role of
MEK1-ERK1/2 in the postconditioning neuroprotection.

Supplemental References

1. Du CP, Gao J, Tai JM, Liu Y, Qi J, Wang W, et al. Increased tyrosine phosphorylation of
PSD-95 by Src family kinases after brain ischemia. Biochem J. 2009;417:277-285.
2. Zhuang S, Schnellmann RG. A death-promoting role for extracellular signal-regulated
kinase. J Pharmacol Exp Ther. 2006;319:991-997.
3. Franceschini D, Giusti P, Skaper SD. MEK inhibition exacerbates ischemic calcium
imbalance and neuronal cell death in rat cortical cultures. Eur J Pharmacol.
2006;553:18-27.
4. Pignataro G, Meller R, Inoue K, Ordonez AN, Ashley MD, Xiong Z, et al. In vivo and in
vitro characterization of a novel neuroprotective strategy for stroke: ischemic
postconditioning. J Cereb Blood Flow Metab. 2008;28:232-241.
5. Gao X, Zhang H, Takahashi T, Hsieh J, Liao J, Steinberg GK, et al. The Akt signaling
pathway contributes to postconditioning's protection against stroke; the protection is
associated with the MAPK and PKC pathways. J Neurochem. 2008;105:943-955.