Insulin-like growth factor-1 and insulin-like growth factor binding protein 3 and risk of postoperative cognitive dysfunction

Abstract

Insulin-like growth factor (IGF)-1 is implicated in learning and memory. Experimental studies have suggested that the IGF-1 system is beneficial in cognition, especially in Alzheimer's disease (AD), by opposing Aβ amyloid processing and hyperphosphorylated tau toxicity. Low IGF-I and insulin-like growth factor binding protein (IGFBP)-3 serum levels are significantly associated with AD. To assess the relationship between circulating IGF-I and IGFBP3 levels and change of postoperative cognition. The study was performed in patients scheduled for elective head and neck carcinoma surgery under general anesthesia. On the day before the operation and postoperative days 1, 3 and 7, mini-mental state examination (MMSE) was performed by the same doctor, and blood samples were collected at 08:00 h after overnight fasting. The circulating levels of IGF-1 and IGFBP3 were measured by enzyme-linked immunosorbent assay. One hundred and two patients completed all four MMSE tests and forty-four of them completed all the four blood samples collection. Postoperative circulating IGF-1 level, ratio of IGF-1/IGFBP3 and MMSE score significantly decreased, whereas IGFBP3 level significantly increased compared with preoperative values in total patients. The change trends of circulating IGF-1 level and MMSE score were similar. Preoperative circulating IGF-1 level, ratio and MMSE score were significantly lower in POCD group compared to non-POCD group. There was no significant difference in preoperative level of circulating IGFBP3 between the two groups. Preoperative circulating IGF-1 level was negatively correlated with age and positively with MMSE. Logistic regression analysis revealed that lower preoperative IGF-1 level and elderly patients increased the odds of POCD. Down-regulation of circulating IGF-1 level may be involved in the mechanism of postoperative cognitive dysfunction. Older patients had lower circulating IGF-1 levels and were more susceptible to POCD.

Full text

Jiang et al. SpringerPlus (2015) 4:787
DOI 10.1186/s40064-015-1586-2
RESEARCH
Insulin-like growth factor-1
andinsulin-like growth factor binding protein 3
andrisk ofpostoperative cognitive dysfunction
Jue Jiang, Zhifeng Chen, Bing Liang, Jia Yan, Ying Zhang and Hong Jiang*
Abstract
Insulin-like growth factor (IGF)-1 is implicated in learning and memory. Experimental studies have suggested that the
IGF-1 system is beneficial in cognition, especially in Alzheimer’s disease (AD), by opposing Aβ amyloid processing and
hyperphosphorylated tau toxicity. Low IGF-I and insulin-like growth factor binding protein (IGFBP)-3 serum levels are
significantly associated with AD. To assess the relationship between circulating IGF-I and IGFBP3 levels and change
of postoperative cognition. The study was performed in patients scheduled for elective head and neck carcinoma
surgery under general anesthesia. On the day before the operation and postoperative days 1, 3 and 7, mini-mental
state examination (MMSE) was performed by the same doctor, and blood samples were collected at 08:00 h after
overnight fasting. The circulating levels of IGF-1 and IGFBP3 were measured by enzyme-linked immunosorbent assay.
One hundred and two patients completed all four MMSE tests and forty-four of them completed all the four blood
samples collection. Postoperative circulating IGF-1 level, ratio of IGF-1/IGFBP3 and MMSE score significantly decreased,
whereas IGFBP3 level significantly increased compared with preoperative values in total patients. The change trends
of circulating IGF-1 level and MMSE score were similar. Preoperative circulating IGF-1 level, ratio and MMSE score were
significantly lower in POCD group compared to non-POCD group. There was no significant difference in preopera-
tive level of circulating IGFBP3 between the two groups. Preoperative circulating IGF-1 level was negatively cor-
related with age and positively with MMSE. Logistic regression analysis revealed that lower preoperative IGF-1 level
and elderly patients increased the odds of POCD. Down-regulation of circulating IGF-1 level may be involved in the
mechanism of postoperative cognitive dysfunction. Older patients had lower circulating IGF-1 levels and were more
susceptible to POCD.
Keywords: Postoperative cognition dysfunction, Insulin-like growth factor-1, Insulin-like growth factor binding
protein3, General anesthesia
© 2015 Jiang et al. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,
provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license,
and indicate if changes were made.
Background
Since Savageau first described an association between
postoperative cognitive dysfunction (POCD), surgery
and anesthesia exposure in 1982 (Hartmann etal. 2007),
many studies have documented the onset of POCD,
which manifests as a decline in brain function, typically
resolving within 12months. Although POCD may only
last for a short period (days or weeks) in most patients
after cardiac and non-cardiac surgery, POCD in some
patients can last for several months or longer, and even
increase mortality (Nelson et al. 2012). It is conceiv-
able that general anesthesia may contribute to POCD.
Rats exposed to volatile anesthetics develop cognitive
impairment (Duyckaerts etal. 2009), and β-amyloid pep-
tide (Aβ) production is increased in mouse brains after
volatile anesthetic exposure (Carro and Torres-Ale-
man 2006). Aβ oligomerization invitro can be induced
by volatile anesthetics (Saenger etal. 2011). It has been
proposed that Aβ overproduction, oligomerization and
accumulation in the brain contribute to the development
Open Access
*Correspondence: dr_jianghong@163.com
Department of Anesthesiology, Shanghai Ninth People’s Hospital,
Shanghai Jiao Tong University School of Medicine, Zhizaoju Road 639,
Shanghai 200011, China

Page 2 of 7
Jiang et al. SpringerPlus (2015) 4:787
of Alzheimer’s disease (AD) (Cohen etal. 2009), the most
common form of dementia in elderly patients.
It was reported that insulin-like peptide signaling (ILPs)
(includes IGF-1 and IGF-2) correlated with sporadic AD
(Piriz etal. 2011). Evidence gathered from human studies
shows a positive correlation between insulin-like growth
factor (IGF)-I levels and mental ability (Lan etal. 2012),
while cognitive impairment has been found in human
patients affected by growth hormone/IGF-I deficiency
(Hanning 2005). Administration of sevoflurane might
temporally affect the ability of cognitive function in rats,
through suppressing IGF-1 mRNA expression in the hip-
pocampus (Kuningas etal. 2008). Although IGF-1 and its
receptor and binding proteins are locally produced in the
brain (Alvarez etal. 2007), IGF-1 is actively transported
across the blood–brain barrier, and therefore changes in
circulating IGF-1 can lead to changes in IGF-1 input to
the brain (Creyghton etal. 2004). e bioavailability and
bioactivity of IGF-1 is regulated by six IGFBPs (IGFBP1-
6) and several IGFBP proteases (Carro and Torres-Ale-
man 2004). Quantitatively the most important binding
protein in the circulation is IGFBP3 which binds>80% of
the circulating IGF-1 (Culley etal. 2003). us, measure-
ment of circulating IGFBP3 levels, in addition to IGF-1
levels, allows the amount of bioavailable IGF-1 to be
determined (Alvarez etal. 2006). In contrast to IGFBP1
to IGFBP6, which bind to the IGFs (Firth and Baxter
2002), IGFBP7 is a critical regulator of memory consoli-
dation that can attenuate the function of ILPs (Agbemen-
yah etal. 2013) and can directly bind to the IGF-1R and
thereby inhibit its activity (Evdokimova etal. 2012). e
relationship between circulating IGFBP7 level and POCD
had been discussed in previous work (Jiang etal. 2015).
Hence, the present study was designed to investigate
the perioperative changes of circulating IGF-1 (total
IGF-1), ratio of IGF-1/IGFBP3 (bioavailable IGF-1) and
IGFBP3 levels and the risk of POCD.
Methods
Patient population
e study was performed in patients scheduled for elec-
tive head and neck carcinoma surgery under general
anesthesia. e data can be seen in our previous work
(Jiang etal. 2015). All patients underwent a standardized
clinical evaluation that included medical history and cog-
nitive function assessment (mini-mental state examina-
tion; MMSE) (Rosario 2010).
MMSE test
MMSE is a 30-point scale that measures global cognitive
function, with higher scores indicating better function,
with scores<24 suggestive of cognitive impairment (Fol-
stein etal. 1975). Patients with MMSE≤23 or diagnosed
with depression or delirium before operation, operation
time<8h were excluded. For statistical analysis, accord-
ing to previous report (Linstedt etal. 2002), a decline of
more than 10% or 2 points in MMSE test was regarded
as POCD. Patients were classified as having or not POCD
according to this definition and were compared in terms
of age, gender, MMSE scores, circulating IGF-1 and
IGFBP3 levels, and etal.
Anesthesia andsurgery
e details of procedure of anesthesia and surgery can be
seen in our previous work (Jiang etal. 2015).
Assays
Reference to previous work (Jiang et al. 2015), On the
day before the operation and postoperative days1, 3 and
7, MMSE was performed, circulating IGF-1 and IGFBP3
levels were measured and the ratio of IGF-1/IGFBP3
was calculated (recorded as MMSE1, MMSE2, MMSE3
and MMSE4, IGF-11, IGF-12, IGF-13, IGF-14, IGFBP31,
IGFBP32, IGFBP33 andIGFBP34, and ratio1, ratio2, ratio3,
ratio4 respectively). According to the manufacturer’s
data sheets, assay range for the IGF-1 was 10–200 and
5–100μg/L for the IGFBP3 assay.
Statistical analysis
All statistical analyses were performed using Stata12.0
and P≤0.05 was considered to be statistically significant.
Normal data are presented as mean ± SD. e paired
or unpaired t test was used to compare mean values of
normally distributed data. Differences in categorical data
(expressed as percentages) were assessed using the χ2
test. Logistic regression analysis was used to investigate
factors contributing to the risk of POCD. e model of
logistic regression includes age, gender, height, weight,
body mass index (BMI), education level, MMSE, IGF-1,
IGFBP3 and ratio. Correlation analysis was used to illus-
trate the relationship of different parameters.
Results
One hundred and forty-five patients were
screened:≥60years old, scheduled for elective head and
neck carcinoma surgery under general anesthesia. Forty-
three patients were exclude for the operation time<8h or
preoperative MMSE score≤23. A total 102 patients com-
pleted all four MMSE tests, Forty-four of 102 patients
completed collection of all four blood samples, and were
divided into two groups: POCD and non-POCD (Fig.1).
There were no significant differences between the
patients completing collection of all four blood sam-
ples and total patients in terms of age, sex, height,
weight, BMI, education level, history of diabetes
mellitus (DM), hypertension, smoking, drinking,

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Jiang et al. SpringerPlus (2015) 4:787
cardiovascular disease, albumin, creatinine, blood
sugar and operation time (P > 0.05). The incidence
of POCD in patients undergoing elective head and
neck carcinoma surgery under general anesthesia was
40.9% (18/44) (Table1).
Comparison of circulating IGF-1 level pre- and post-
operatively showed that IGF-12, IGF-13 and IGF-14
were significantly lower than IGF-11 (117.13 ± 14.78,
120.78±15.99, 124.15±16.43 versus 127.20±14.77μg/L,
P < 0.0001, P < 0.0001, P= 0.0006 respectively). e
changes of MMSE scores and ratio of IGF-1/IGFBP3 were
similar (24.32 ± 3.13, 25.82 ± 2.17, 27.50 ±1.91 versus
28.14±1.89, P<0.0001, P<0.0001, P=0.0022 respectively;
0.0711±0.0188, 0.0767±0.0215, 0.08155±0.02420 versus
0.0846±0.0247, P<0.0001, P<0.0001, P=0.0002 respec-
tively). IGFBP32, IGFBP33 and IGFBP34 were significantly
higher than IGFBP31 (4307.03±904.16, 4139.42±897.56,
4022.69±913.42 versus 3968.82±880.17μg/L, P<0.0001,
P<0.0001, P=0.0325 respectively) (Fig.2).
Comparison of MMSE score, circulating IGF-1 and
IGFBP3 levels and ratio of IGF-1/IGFBP3 between
POCD group and non-POCD group showed that MMSE,
Fig. 1 The trial flowchart
Table 1 Characteristics ofthe total patients included inthis study andpatients completing collection ofall four blood
samples
Data are shown as mean±SD or number (%)
MMSEa : the score of MMSE on the day before operation
Total patients
(n=102) Patients withblood
collection (n=44) p
POCD 35 18 0.447
Gender (men %) 72 (70.6) 30 (68.2) 0.864
Age (y) 67.3 ± 5.9 67.4 ± 6.4 0.9636
Height (cm) 166.3 ± 6.8 166.7 ± 6.8 0.7523
Weight (kg) 64.6 ± 10.1 64.1 ± 11.0 0.7619
BMI (kg/m2) 23.4 ± 3.6 23.0 ± 3.5 0.5427
Education level 0.681
Primary school (%) 30 (29.4) 14 (31.8)
Middle school (%) 56 (54.9) 21 (47.7)
College or university (%) 16 (15.7) 9 (20.5)
History of DM (%) 14 (13.7) 8 (18.2) 0.490
History of hypertension (%) 54 (52.9) 24 (54.5) 0.858
History of smoking (%) 19 (18.6) 10 (22.7) 0.569
History of drinking (%) 11 (10.8) 4 (9.1) 0.757
History of cardiovascular diseases (%) 29 (28.4) 12 (27.3) 0.886
Albumin (g/L) 41.0 ± 3.6 40.9 ± 4.4 0.8863
Creatinine (μmol/L) 88.0 ± 16.8 89.9 ± 13.7 0.5179
Blood sugar (mg/L) 5.1 ± 0.7 5.3 ± 0.7 0.1292
Operation time (h) 9.5 ± 1.4 9.9 ± 1.8 0.0851
MMSEa27.9 ± 1.7 28.1 ± 1.9 0.472

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Jiang et al. SpringerPlus (2015) 4:787
IGF-1 and ratio were significant lower in the POCD
group than non-POCD group, whereas there was no sig-
nificant difference in IGFBP31 (Fig.3).
Among age, IGF-11, IGFBP31, ratio1 and MMSE1, there
was a negative relationship between age and IGF-11
(R=−0.3823, P=0.0084), positive correlation between
MMSE1 and IGF-11 (R = 0.3743, P= 0.0123), positive
correlation between MMSE1 and ratio1 (R = 0.3573,
P= 0.0173), but IGFBP31 was not significantly cor-
related with age (R=–0.2348, P=0.1250) or MMSE1
(R=−0.1362, P=0.3780), and MMSE1 and ratio1 was
not significantly correlated with age (R=−0.08945,
P=0.3713, R=–0.07465, P=0.6301 respectively).
Logistic regression analysis was performed to deter-
mine independent associations between particular
parameters and the risk of POCD. Of the factors in the
model, elderly patients, lower MMSE score, and preop-
erative circulating level of IGF-1 significantly increased
the odds of POCD (OR = 1.39, P < 0.001; OR = 0.47,
P=0.004; OR=0.87, P=0.008 respectively).
Discussion
Anesthetics can lead to cognitive impairment (Dwyer
et al. 1992; Ghoneim and Block 1997). However, the
mechanism of the influence of anesthetics on neurologi-
cal function is not completely understood. In this study,
the incidence of POCD was 40.9% (18/44) on the 1st day
after the operation, which is similar to the incidence in
elderly patients undergoing orthopedic surgery (Gustaf-
son etal. 1991).
Although IGF-1 is a multifunctional polypeptide essen-
tial for normal growth and development, IGF-I also plays
an important role in neuroprotection. IGF-1 decreases
the Aβ level in the brain (Carro etal. 2002) and induces
inhibition of glycogen synthase kinase 3, which results
in tau dephosphorylation and increased microtubule
binding of tau (Hong and Lee 1997). In elderly humans,
serum IGF-I levels positively correlate with cognitive
status (Aleman etal. 1999), and a similar correlation in
mice unveiled a trophic action of circulating IGF-I on
glutamate neurotransmission affecting synaptic plasticity
Fig. 2 Perioperative changes of circulating IGF-1, IGFBP3, their ratio and MMSE scores. MMSE score on the day before operation (MMSE1), post-
operative day 1(MMSE2), 3 (MMSE3) and 7(MMSE4); the circulating level of IGF-1 on the day before operation (IGF-11), postoperative day 1 (IGF-12),
3 (IGF-13) and 7 (IGF-14); the circulating level of IGFBP-3 on the day before operation (IGFBP31), opostoperative day 1 (IGFBP32), 3 (IGFBP33) and 7
(IGFBP34); and the ratio of IGF-11 and IGFBP31 (ratio1), the ratio of IGF-12 and IGFBP32 (ratio2), the ratio of IGF-13 and IGFBP33 (ratio3), the ratio of IGF-
14 and IGFBP34 (ratio4). **P < 0.01, *P < 0.05 (compared with the value on the day before operation). Bars represent mean ± SD

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Jiang et al. SpringerPlus (2015) 4:787
and cognition (Trejo etal. 2007). Namely, IGF-I improves
learning and memory (Markowska et al. 1998). It has
been demonstrated that exogenous IGF-1 both protects
neurons from diverse forms of injuryin vivo and in vitro
(Cheng and Mattson 1992; Gluckman etal. 1998). IGF-1
can be produced in the brain (Alvarez etal. 2007), but it is
mainly produced in the liver, and can enter the brain via
the blood–brain barrier (Creyghton etal. 2004). Accord-
ing with previous report (Piriz etal. 2011), the present
study revealed that circulating IGF-1 level negatively
correlated with age, which gave evidence that circulat-
ing IGF-1 level decreased with increasing age. According
with report of Aleman etal. (Aleman etal. 1999), change
trends in circulating IGF-1 level were similar to those of
MMSE score, and the circulating IGF-1 level positively
correlated with MMSE score. At the same time, circulat-
ing IGF-1 level was significantly lower in POCD group
than the level in non-POCD group. Hence, the down-reg-
ulation of circulating IGF-1 level may be involved in the
mechanism of POCD. Furthermore, it was proved that
cognitive function in Sprague–Dawley rats was reduced
by sevoflurane accompanied by decreased expression of
IGF-1 (Peng etal. 2011).
With regard to the association of IGF-I and IGFBP3
with cognition, Kalmijn etal. (Kalmijn etal. 2000) have
disclosed that total IGF-I and total IGF-I/IGFBP3 molar
ratio are negatively associated with cognitive decline. A
further transverse study has also reported an associa-
tion between free IGF-I, IGFBP3, and cognitive impair-
ment among community-living elderly subjects, after
adjusting for numerous potential confounders (age, sex,
education, cerebrovascular disease, ischemic heart dis-
ease, congestive heart failure, hypertension, diabetes,
depression, Parkinson’s disease, thyroid disease, smoking
Fig. 3 Circulating IGF-1, IGFBP3, their ratio and MMSE score in POCD and non-POCD group. MMSE score on the day before operation (MMSE1),
postoperative day 1 (MMSE2), 3 (MMSE3) and 7 (MMSE4) in POCD and non-POCD groups; the circulating level of IGF-1 on the day before operation
(IGF-11), postoperative day 1 (IGF-12), 3 (IGF-13) and 7 (IGF-14)day after operation in POCD and non-POCD groups; the circulating level of IGFBP3 on
the day before operation (IGFBP31), postoperative day 1 (IGFBP32), 3 (IGFBP33) and 7 (IGFBP34) in POCD and non-POCD groups; and the ratio of IGF-
11 and IGFBP31 (ratio1), the ratio of IGF-12 and IGFBP32 (ratio2), the ratio of IGF-13 and IGFBP33 (ratio3), the ratio of IGF-14 and IGFBP34 (ratio4) in POCD
and non-POCD groups. **P < 0.01, *P < 0.05. Bars represent mean ± SD

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Jiang et al. SpringerPlus (2015) 4:787
status, alcohol abuse, BMI, and number of medications)
(Landi et al. 2007). In the present study, the circulat-
ing levels of IGF-1 (total IGF-1) and the ratio of IGF-1/
IGBP3, indicative of bioavailability of IGF-1 significantly
decreased and circulating IGFBP3 level significantly
increased after surgery under general anesthesia, on the
orther hand, IGF-1 levels and ratios were all significantly
lower in POCD group than in non-POCD group at dif-
ferent times, whereas there was no significant difference
in level of IGFBP3 between the patients with or without
POCD. Further analysis showed that preoperative level of
IGF-1 (total IGF-1) was independently, significantly asso-
ciated with POCD, and lower preoperational circulating
IGF-1 level (total IGF-1) increased the risk of POCD, but
IGFBP3 and molar ratio were not significant determi-
nants of POCD. us, it was the preoperative circulating
level of IGF-1, and not IGFBP3 or their molar ratio, that
negatively correlated with POCD in the present study,
which suggested that preoperative circulating level inde-
pendently affected the incidence of POCD. We showed
that the relationship of IGF-1, IGFBP3, molar ratio of
IGF-1/IGFBP3and POCD was not the same as their rela-
tionship with AD. e probable reason was that POCD
was caused by the operation, anesthesia, and other rele-
vant factors, whereas AD is a primary neurodegenerative
disorder in the elderly population. ere are some differ-
ences in their pathophysiological mechanism. Operation,
anesthesia or other relevant factors down-regulated the
circulating IGF-1 level [maybe inhibited the synthesis
of IGF-1 in liver based on the previous report that it is
mainly produced in the liver, and can enter the brain via
the blood–brain barrier (Creyghton et al. 2004)], then
decreased the amount of IGF-1 entering to brain through
the blood–brain barrier. Decrease of IGF-1 in brain
leaded to attenuate ILPs function, increase of Aβ level in
the brain and tau hyperphosphorylation and decrease of
microtubule binding of tau, ultimately impaired cogni-
tive function. However, this hypothesis is needed to be
proved in the future researches.
In conclusion, the present study provides evidence that
postoperative circulating IGF-1 level (total IGF-1) and
the ratio of IGF-1/IGFBP3 (bioavalable IGF-1) were sig-
nificantly lower than preoperative level, whereas post-
operative circulating IGFBP3 level was higher. Elderly
patients have lower circulating IGF-1 levels and are more
susceptible to POCD. Lower preoperative MMSE score
and the circulating level of IGF-1, not the ratio or IGFBP3
level, significantly increase the risk of POCD. Down-
regulation of circulating IGF-1 level may be involved in
the mechanism of POCD. Preoperative measurement of
MMSE and circulating level of IGF-1 are likely to be use-
ful in screening for onset of POCD.
Authors’ contributions
Conceived and designed the experiments: JJ, HJ. Performed the experiments:
JJ, ZC, BL, JY, YZ. Analyzed the data: JJ, ZC. Contributed reagents/materials/
analysis tools: JJ, BL. Contributed to the writing of the manuscript: JJ. All
authors read and approved the final manuscript.
Acknowledgements
We thank Professor Zhong for providing access to equipment.
Competing interests
All authors certify that they have no affiliations with or involvement in any
organization or entity with any financial interests.
Funding
The authors received funding for this work from Shanghai Municipal Commis-
sion of Health and Family Planning, grant number: 201540104.
Received: 16 September 2015 Accepted: 4 December 2015
References
Agbemenyah HY, Agis-Balboa RC, Burkhardt S, Delalle I, Fischer A (2013) Insulin
growth factor binding protein 7 is a novel target to treat dementia.
Neurobiol Dis 62:135–143
Aleman A, Verhaar HJ, de Haan EH et al (1999) Insulin-like growth factor-I and
cognitive function in healthy older men. J Clin Endocrinol Metab 84:471–475
Alvarez A, Cacabelos R, Sanpedro C, García-Fantini M, Aleixandre M (2006)
Endocrine, liver-derived IGF-I is of importance for spatial learning and
memory in old mice. J Endocrinol 189:617–627
Alvarez A, Cacabelos R, Sanpedro C, García-Fantini M, Aleixandre M (2007)
Serum TNF-alpha levels are increased and correlate negatively with free
IGF-I in Alzheimer disease. Neurobiol Aging 28:533–536
Carro E, Torres-Aleman I (2004) The role of insulin and insulin-like growth factor
I in the molecular and cellular mechanisms underlying the pathology of
Alzheimer’s disease. Eur J Pharmacol 490:127–133
Carro E, Torres-Aleman I (2006) Serum insulin-like growth factor I in brain func-
tion. Keio J Med 55:59–63
Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I (2002) Serum
insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med
8:1390–1397
Cheng B, Mattson MP (1992) IGF-I and IGF-II protect cultured hippocampal
and septal neurons against calcium-mediated hypoglycemic damage. J
Neurosci 12:1558–1566
Cohen E, Paulsson JF, Blinder P, Burstyn-Cohen T, Du D, Estepa G, Adame A,
Pham HM, Holzenberger M, Kelly JW, Masliah E, Dillin A (2009) Reduced
IGF-1 signaling delays age-associated proteotoxicity in mice. Cell
139:1157–1169
Creyghton WM, van Dam PS, Koppeschaar HP (2004) The role of the somato-
tropic system in cognition and other cerebral functions. Semin Vasc Med.
4(2):167–172
Culley DJ, Baxter M, Yukhananov R, Crosby G (2003) The memory effects of
general anesthesia persist for weeks in young and aged rats. Anesth
Analg 96:1004–1009
Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology
of Alzheimer disease. Acta Neuropathol 118:5–36
Dwyer R, Bennett HL, Eger EI II, Heilbron D (1992) Effects of isoflurane and
nitrous oxide in subanesthetic concentrations on memory and respon-
siveness in volunteers. Anesthesiology 77:888–898
Evdokimova V, Tognon CE, Benatar T, Yang W, Krutikov K, Pollak M et al (2012)
IGFBP7 binds to the IGF-1 receptor and blocks its activation by Insulin-like
growth factors. Sci Signal 5:1–11
Firth SM, Baxter RC (2002) Cellular actions of the insulin-like growth factor-
binding proteins. Endocr Rev 23:824–854
Folstein MF, Folstein SE, McHugh PR (1975) Mini mental state: a practical
method for grading the cognitive state of patients for the clinician. J
Psychiatr Res 12:189–198

Page 7 of 7
Jiang et al. SpringerPlus (2015) 4:787
Ghoneim MM, Block RI (1997) Learning and memory during general anesthe-
sia: an update. Anesthesiology 87:387–410
Gluckman PD, Guan J, Williams CE, Scheepens A, Zhang R, Bennet L, Gunn
AJ (1998) Asphyxial brain injury—the role of the IGF system. Mol Cell
Endocrinol 140:95–99
Gustafson Y, Brannstrom B, Berggren D et al (1991) A geriatricanesthesiologic
program to reduce acute confusional states in elderly patients treated for
femoral neck fractures. J Am Geriatr Soc 39:655–662
Hanning CD (2005) Postoperative cognitive dysfunction. Br J Anaesth 95:82–87
Hartmann T, Kuchenbecker J, Grimm MO (2007) Alzheimer’s disease: the lipid
connection. J Neurochem 103(Suppl 1):159–170
Hong M, Lee VM (1997) Insulin and insulin-like growth factor-1 regu-
late tau phosphorylation in cultured human neurons. J Biol Chem
272:19547–19553
Jiang J, Chen Z, Liang B, Yan J, Zhang Y, Xu H, Huang Y, Jiang H (2015) The
change of circulating insulin like growth factor binding protein 7 levels
may correlate with postoperative cognitive dysfunction. Neurosci Lett
588:125–130
Kalmijn S, Janssen JA, Pols HA, Lamberts SW, Breteler MM (2000) A prospec-
tive study on circulating insulin-like growth factor I (IGF-I), IGF-binding
proteins, and cognitive function in the elderly. J Clin Endocrinol Metab
85:4551–4555
Kuningas M, Mooijaart SP, van Heemst D, Zwaan BJ, Slagboom PE, Westendorp
RG (2008) Genes encoding longevity: from model organisms to humans.
Aging Cell 7:270–280
Lan Z, Liu JP, Chen L, Fu Q, Luo J, Qu R, Kong LY, Ma SP (2012) Danggui-
Shaoyao-San ameliorates cognition deficits and attenuates oxidative
stress-related neuronal apoptosisin d-galactose-induced senescent mice.
J Ethnopharmacol 141:386–395
Landi F, Capoluongo E, Russo A, Onder G, Cesari M, Lulli P, Minucci A, Pahor M,
Zuppi C, Bernabei R (2007) Free insulin-like growth factor-I and cognitive
function in older persons living in community. Growth Hormon IGF Res
17:58–66
Linstedt U, Meyer O, Kropp P, Berkau A, Tapp E, Zenz M (2002) Serum con-
centration of S-100 protein in assessment of cognitive dysfunction after
general anaesthesia in different types of surgery. Acta Anaesthesiol Scand
46:384–389
Markowska A, Mooney M, Sonntag W (1998) Insulin-like growth factor-1 ame-
liorates age-related behavioral deficits. Neuroscience 87:559–569
Nelson PT, Alafuzoff I, Bigio EH et al (2012) Correlation of Alzheimer disease
neuropathologic changes with cognitive status: a review of the literature.
J Neuropathol Exp Neurol 71:362–381
Peng S, Zhang Y, Sun D, Zhang D, Fang Q, Li G (2011) The effect of sevoflu-
rane anesthesia on cognitive function and the expression of insulin-like
growth factor-1 in CA1 region of hippocampus in old rats. Mol Biol Rep
38:1195–1199
Piriz J, Muller A, Trejo JL, Torres-Aleman I (2011) IGF-I and the aging mamma-
lian brain. Exp Gerontol 46:96–99
Rosario PW (2010) Normal values of serum IGF-1 in adults: results from a Brazil-
ian population. Arq Bras Endocrinol Metabol 54:477–481
Saenger S, Goeldner C, Frey JR, Ozmen L, Ostrowitzki S, Spooren W et al (2011)
PEGylation enhances the therapeutic potential for insulin-like growth
factor I in central nervous system disorders. Growth Hormon IGF Res
21:292–303
Trejo J, Piriz J, Llorens-Martin M, Fernandez A, Bolos M, LeRoith D, Nunez A,
Torres-Aleman I (2007) Central actions of liver-derived insulin-like growth
factor I underlying its pro-cognitive effects. Mol. Psychiatry 12:1118–1128