Journal of Molecular Neuroscience

https://doi.org/10.1007/s12031-020-01533-8

Post-Stroke Cognitive Impairment: A Review Focusing

on Molecular Biomarkers
Xinxin Zhang 1 & Xia Bi 2

Received: 8 January 2020 / Accepted: 12 March 2020

# Springer Science+Business Media, LLC, part of Springer Nature 2020

Abstract
Post-stroke cognitive impairment (PSCI), as one of the major complications after stroke, refers to a series of syndromes from mild
cognitive impairment to dementia caused by stroke. Stroke has been reported to increase the risk of cognitive impairment by at
least five to eight times. The assessment of PSCI usually relies on neuropsychological tests, but the results of these tests are
subjective and inaccurate, and can be insufficient for the diagnosis and prognosis of PSCI. In recent years, an increasing number
studies have indicated that changes in the expression of biomarkers such as C-reactive protein (CRP), interleukin 6 (IL-6) and IL-
10 in blood, urine and other body fluids are associated with cognitive decline after stroke. Therefore, the detection of biomarkers
in circulating blood serum, plasma and cerebrospinal fluid (CSF) may improve the accuracy of diagnosis and prognosis in PSCI.
This review aims to summarize the studies on potential molecular biomarkers of PSCI.

Keywords Post-stroke cognitive impairment (PSCI) . Biomarkers . Inflammation . Oxidative damage

Abbreviations CSF Cerebrospinal fluid

MMSE Mini-Mental State Examination PSND Post-stroke none-demented
MoCA Montreal Cognitive Assessment PSD Post-stroke dementia
SD Standard deviation VaD Vascular dementia
T3 Triiodothyronine AD Alzheimer’s Disease
RF Rheumatoid factor SAA Serum amyloid A
OR Odds ratio NCI No cognitive impairment
95% CI 95% Confidence interval CIND Cognitive impairment no dementia
MMP-9 Matrix metalloproteinase-9 T3 Triiodothyronine
tHcy Total homocysteine ICAS Intracranial arterial stenosis
CI Cognitive impairment NT-proBNP N-terminal pro-B-type natriuretic
VCIND Vascular cognitive impairment peptide
with no dementia PSCI Post-stroke cognitive impairment
VD Vascular dementia 8-OhdG 8-Hydroxydeoxyguanosine
Hcy Homocysteine MDA Malondialdehyde
hs-CRP High-sensitivity C-reactive protein CoQ10 Coenzyme Q10
IL Interleukin BDNF Brain-derived neurotrophic factor
IGF-1 Insulin-like growth factor–1;VCI,
vascular cognitive impairment
CST3 cystatin C gene
TMAO Trimethylamine-N-oxide
* Xia Bi
bixiash@126.com RA Retinoic acid
PSNCI Post-stroke non-cognitive impairment
1
School of kinesiology, Shanghai University of sport, No. 200 AUC area under curve
Hengren Road, Yangpu District, Shanghai 200438, China PSCN Post-stroke cognitive normality
2
Department of Rehabilitation Medicine, Shanghai University of miR-132 microRNA-132
Medicine & Health Sciences affiliated Zhoupu Hospital, No. 1500 ROC Receiver operating characteristic
Zhouyuan Road, Pudong New District, Shanghai 201318, China

Introduction
Stroke, a common cerebrovascular disease, is a major cause of
death and long-term disability. Each year, about 16 million
people worldwide have their first stroke, among whom about
5.7 million die and about five million are disabled (Kulesh
et al. 2018; Zhu et al. 2019b). Post-stroke cognitive impair-
ment (PSCI) is one of the major complications after a stroke
and is a subtype of vascular cognitive impairment (VCI). It
has been reported that stroke increases the risk of cognitive
impairment by at least five to eight times (Kulesh et al. 2018).
Cognition is the category of higher brain functions including
orientation, memory, delayed memory, visuospatial dysfunction,
executive function, attention, calculation and other aspects.
Patients with PSCI may have damage to one or more cognitive
domains, in which executive dysfunction is the first and the core
symptom (Carlson et al. 2009). PSCI appears to have negative
effects on the recovery of motor function, activities of daily living
and other functions in patients with stroke. It increases the difficul-
ty of overall rehabilitation, preventing patients from returning to
family and society, and finally brings heavy financial burden. An
increasing number of studies have shown that cognitive function
can be used as a predictor of functional outcome in patients with
stroke (Almalki et al. 2018). Therefore, it is particularly important
for the assessment, treatment and prognosis of PSCI, and has
drawn much attention from many researchers around the world.
The assessment of PSCI is usually based on neuropsycholog-
ical evaluations, which are limited in terms of accuracy and ob-
jectivity and are prone to the influence of age and education.
Thus, neuropsychological tests are not sufficient for the reliable
prognosis and diagnosis of PSCI. However, in recent years, a
number of studies have indicated that biomarkers in circulating
blood serum, plasma and cerebrospinal fluid (CSF) of PSCI pa-
tients can be key determinants for the diagnosis and prediction of
cognitive impairment. It has been found that the levels of serum
inflammatory factors, such as interleukin 6 (IL-6), IL-10 and IL-
1β, are increased in patients with dementia (Rothenburg et al.
2010). In patients with ischemic stroke, elevated plasma C-
reactive protein (CRP) levels have been shown to be associated
with decreased cognitive function. Biomarkers may therefore
improve the accuracy of prognosis and diagnosis, and are of great
importance for understanding the development of disease condi-
tion and targeted therapy. Hence, this review aims to summarize
the studies exploring potential biomarkers for PSCI diagnosis
and prognosis.
Biomarkers of Inflammation
Il-6, Il-8, Il-10, Il-1β
IL is a class of multifunctional cytokines including IL-1β, IL-
6, IL-7, IL-8, IL-10, IL-16 and IL-1α. It is involved in
J Mol Neurosci
information transmission and immune regulation and plays
an important role in inflammatory response (Scheller et al.
2011). Levels of cytokines are usually low in the central ner-
vous system but will increase significantly when the central
nervous system is damaged and infected (Schultzberg et al.
2007). The expression of several cytokines in patients with
post-stroke dementia is different from that in patients with
no dementia (Chen et al. 2016). Kulesh et al. (2018) found
that serum IL-6 levels and levels of IL-1β and IL-10 in the
CSF of patients with executive dysfunction were significantly
higher than those in patients without cognitive impairment.
They found a significant correlation between IL-1β expres-
sion in CSF and Frontal Assessment Battery (FAB) score (P =
0.033), and between IL-1β and IL-6 expression in serum and
the Mini-Mental State Examination (MMSE) score (P =
0.048, P = 0.039, respectively). The expression of serum IL-
10 correlated with MMSE score (P < 0.001), the Montreal
Cognitive Assessment (MoCA) score (P = 0.01) and FAB
score (P = 0.03). In addition, the study reported that IL-1β
and IL-10 expression were associated with global cognitive
function and executive function, whereas IL-6 expression was
only associated with global cognitive status during the acute
period of stroke. In another prospective study investigating the
association between a broader group of inflammatory bio-
markers and post-stroke cognitive function, the researchers
measured the expression of CRP, IL-1β, IL-6, IL-8, IL-12,
IL-10 and TNF-α in serum. The results showed that higher
serum IL-8 in patients with ischemic stroke was independently
associated with baseline cognitive impairment, while higher
serum IL-12 expression was associated with subsequent cog-
nitive decline (Narasimhalu et al. 2015). Together these find-
ings indicate that IL-1β, IL-6, IL-8 and IL-10 may become
molecular biomarkers of PSCI, although the level of bio-
markers for PSCI diagnosis was not reported and requires
further clinical study.
CRP
CRP is a plasma protein synthesized by the liver and is often
used as a nonspecific biomarker of inflammation. Elevated
CRP levels are associated with increased risk of cerebrovas-
cular disease and dementia. Increased CRP may cause cogni-
tive impairment through two different mechanisms. First, en-
dothelial function is impaired, and abnormal migration and
proliferation of vascular smooth muscle cells occurs, mediated
by the macrophage uptake of low-density lipoprotein and the
promotion of the formation of foam cells, which cause brain
lesions. Brain lesions disrupt the integrity of the prefrontal-
subcortical circuits, leading to cognitive impairment. Second,
the complement system may be activated, which in turn may
lead to the damage of brain tissue and decline in cognitive
function (Guo et al. 2018). Irimie et al. (2018) indicated that
poor cognitive outcome in patients with ischemic stroke is
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associated with CRP levels (β = 0.441, P = 0.000), and the use
of CRP together with triiodothyronine (T3) levels in determin-
ing poor cognition at discharge demonstrated predictive prob-
ability as high as 80.42%. According to receiver operating
characteristic (ROC) curve analysis, the area under the curve
(AUC) of CRP was 0.748, with a cut-off level of serum CRP
on admission of 3.035 mg/dL, in predicting poor cognitive
outcome, with sensitivity of 75.6% and specificity of 83.3%.
The AUC of T3 was 0.633, and a cut-off value for T3 on
admission of 1.115 nmol/L was found to predict poor cogni-
tive outcome, with sensitivity of 66.7% and specificity of
58.9%. This means that when the serum CRP level is higher
than 3.035 mg/dL and the T3 level is lower than 1.115 nmol/L
in patients with stroke, there may be cognitive impairment. A
10-year follow-up study involving 5267 participants reported
that the level of hs-CRP was associated with long-term cog-
nitive decline (Zheng and Xie 2018). Alexandrova and
Danovska reported that age and hs-CRP were the only inde-
pendent predictors of PSCI, with an increase of 1 year in age
associated with an increase of 1 mg/L in hs-CRP. In addition,
age increased the probability of cognitive decline by 30.9% in
the first year after stroke, and high hs-CRP expression in-
creased the probability of cognitive decline by 18.9%
(Alexandrova and Danovska 2016). Patients with deteriorat-
ing cognitive function had a stronger immune state than pa-
tients with normal cognitive function, which was manifested
in increased white blood cell and granulocyte counts
(Alexandrova and Danovska 2016). Bunevicius et al. (2015)
reported that elevated hs-CRP levels were associated with
poorer cognitive function at discharge (β = −0.269, P =
0.014), consistent with previous results.
Rheumatoid Factor (RF)
RF, an autoantibody specific to the IgG antibody, is ubiquitous
in the human body and can reflect the process of autoimmu-
nity, with physiological functions such as regulation of the
immune response and elimination of infection (Aletaha et al.
2010). It was found that the risk of stroke in patients with
rheumatoid arthritis is higher than that in the general popula-
tion, and rheumatoid arthritis is associated with increased
mortality and poor functional outcome in patients with stroke
(Nguyen-Oghalai et al. 2008; Sodergren et al. 2009).
However, the relationship between RF and PSCI is unclear.
A prospective multicenter study reported that RF levels were
independently related to PSCI, and the risk of PSCI increased
with the increase in RF levels (Zhu et al. 2019c). Zhu et al.
studied the relationship between serum RF level in the acute
phase 3 months after ischemic stroke and cognitive impair-
ment, and the results showed that higher RF levels in the acute
phase were independently correlated with cognitive impair-
ment in the acute phase 3 months after ischemic stroke (Zhu
et al. 2019b) (Tables 1, 2, 3, 4, 5 and 6).
Biomarkers of Oxidative Damage
8-Hydroxydeoxyguanosine (8-OHdG)
8-OHdG is an oxidized adduct produced by reactive oxygen
species such as hydroxyl radicals and singlet oxygen that at-
tacks guanine base 8 carbon atoms in DNA molecules. It can
be used to evaluate the degree of oxidative damage and repair
and is an internationally recognized sensitive indicator and
biomarker for evaluating oxidative stress status (Fukuda
et al. 2008; Honda et al. 2000; Wu et al. 2004). It has been
known for many years that oxidative stress is associated with
cognitive impairment (Bulzacka et al. 2016; Chang et al.
2014). Serum levels of 8-OhdG are elevated in patients with
mild cognitive impairment. Liu et al. (2017) showed that high
levels of serum 8-OHdG were independently correlated with
PSCI during 1-month follow-up after stroke. According to the
receiver operating characteristic (ROC) curve analysis, the
AUC of 8-OHdG was 0.700 (95% CI 0.626–0.773;
P < 0.001) and the optimal cut-off value for 8-OHdG as a
diagnostic biomarker for PSCI was 185.63 ng/L, with sensi-
tivity of 68.3% and specificity of 67.4%.
Malondialdehyde (MDA)
MDA, an important oxidative stress indicator in the human body,
is the end product of peroxidation of lipids by oxygen free rad-
icals. The concentration of MDA can reflect the degree of cell
damage. A study found that MDA levels in patients with acute
ischemic stroke were significantly higher than those in healthy
individuals, and were negatively correlated with MMSE score
(r = −0.4, P = 0.001) (Simani et al. 2018). Liu et al. (2017)
showed that serum levels of MDA in a PSCI group was signif-
icantly higher than those of the non-PSCI group [3.6 (2.8–5.6)
vs. 2.3 (1.7–3.0); P < 0.001], and the levels of MDA were inde-
pendently correlated with PSCI. According to ROC curve anal-
ysis, the AUC value for MDA was 0.793 (95% CI 0.731–0.856;
P < 0.001) and the optimal cut-off for MDA was 2.59 nmol/ml,
with sensitivity of 83.2% and specificity of 62.0%.
Coenzyme Q10 (CoQ10)
Many studies have shown that the nervous system has a low
tolerance to oxidative stress, and CoQ10, as an endogenous
liposophile antioxidant, has been proven effective in the preven-
tion of oxidative stress (Kaufmann et al. 2009; Sohmiya et al.
2004). Simani et al. (2018) reported that serum CoQ10 levels
were significantly lower in stroke patients than in a control
group (P = 0.001), and the investigation of correlations between
biomarkers revealed a negative correlation between levels of
CoQ10 and MDA (r = −0.5, P = 0.001). Jorat et al. (2019) also
confirmed that CoQ10 could effectively reduce the level of
MDA and improve the activity of superoxide dismutase.
Table 1 Summary of inflammatory biomarkers for PSCI

Study Country Type of Post-stroke patients Normal cognition Biomarkers Results

study
Subjects Number Subjects Number

Kulesh et al. 2018 Russian Prospective Dysexecutive CI 21 Stroke patients 15 CSF IL-1β Significant correlations were found between IL-1β expression
Mixed CI 21 with normal Serum IL-6 in CSF and FAB score (P = 0.033), IL-1β (P = 0.048) and IL-6
cognition Serum IL-1β (P = 0.039) expression in serum and MMSE score, and IL-10
Serum IL-10 expression in serum and MMSE score (P < 0.001), MoCA score
(P = 0.01), and FAB score (P = 0.03)
Narasimhalu et al. Singapore Prospective CIND-mild 65 Stroke patients 102 Serum IL-8 IL-8 (OR 1.23 CI 1.05–1.44) level was independently associated
2015 CIND-moderate 67 with normal Serum IL-12 with baseline cognitive status. IL-12 (OR 25.02 CI 3.73–168.03)
Dementia 9 cognition was an independent predictor of subsequent cognitive decline
Guo et al. 2018 China Prospective PSCI 92 ICAS patients 219 Serum CRP A significant association was observed between CRP levels at
with normal admission and cognitive performance at 6 months among the
cognition subgroup of 311 patients with ICAS, and it persisted even after
adjusting for potential confounders (OR 1.038, 95% CI
1.015–1.061)
Irimie et al. 2018 Romania Prospective Mild NIHSS 32 Not mentioned Serum CRP Poor cognitive prognosis was associated with CRP levels
Moderate NIHSS 65 (β = 0.441, P = 0.000). Using CRP and T3 as prognostic
Severe NIHSS 23 factors resulted in a
probability of 80.42% in predicting a poor cognitive outcome in
stroke patients at discharge
Alexandrova and Bulgaria Prospective Risk of CI 16 Stroke patients 11 Serum Hs-CRP (P = 0.013) and age (P = 0.010) were independent
Danovska 2016 Mild to moderate 20 with normal hs-CRP predictors of patients’ cognitive status 1 year after stroke
CI cognition
Bunevicius et al. 2015 Lithuanian Prospective PSCI 63 Not mentioned Serum Hs-CRP remained associated with worse cognitive (β = −0.269,
hs-CRP P = 0.014) outcomes at discharge
Zhu et al. 2019c China Prospective PSCI 340 Stroke patients 298 Serum RF Among all 12 biomarkers tested, only RF, MMP-9 and tHcy were
with normal Serum found to be associated with subsequent cognitive impairment
cognition MMP-9
Plasma tHcy
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Table 2 Summary of biomarkers of oxidative damage for PSCI

Study Country Type of Post-stroke patients Normal cognition Biomarkers Results

study
Subjects Number Subjects Number

Liu et al. 2017 China Prospective PSCI 101 Stroke patients 92 Serum 8-OhdG Serum Serum 8-OHdG and MDA levels remained as independent markers
with normal MDA of PSCI. High serum levels of MDA and 8-OHdG were
cognition associated with the presence of PSCI at 1 month after stroke.
Simani et al. Iran Prospective Ischemic stroke 76 Healthy individuals 34 Serum MDA Stroke patients had significantly lower serum level of CoQ10 than
2018 patients controls (P = 0.001). Regarding the association between MMSE score
and biochemical
markers, only the MDA level was found to be inversely correlated
(r = 0.4, P = 0.001)

Table 3 Summary of growth factor biomarkers for PSCI

Study Country Type of Post-stroke patients Normal cognition Biomarkers Results

study
Subjects Number Subjects Number

Chen et al. 2018 China Prospective Ischemic stroke 30 Healthy 30 Serum Correlation analysis showed that the MMSE score was positively
patients individuals BDNF related to the level of BDNF (r2 = 0.827, P < 0.01).
Hassan and Yarube Nigeria Prospective PSCI 47 Healthy 35 Serum A very high prevalence of cognitive impairment observed during the
2018 individuals BDNF period 10 months post-stroke was associated with reduced levels of
BDNF in the peripheral blood of stroke survivors
Ploughman et al. Canada Prospective Stroke patients 52 Not mentioned Serum Levels of serum IGF-1 in response to acute exercise at baseline
2019 IGF-1 significantly predicted improvements in fluid intelligence among the
groups receiving cognitive training, supporting its usefulness as a recovery bio-
marker in stroke
Table 4 Summary of genetic biomarkers for PSCI

Study Country Type of Post-stroke patients Normal cognition Biomarkers Results

study
Subjects Number Subjects Number

Kim et al. Korea Prospective Ischemic stroke 423 Not mentioned BDNF Val66Met gene BDNF Val66Met polymorphism was independently associated with
2012 patients poor outcome at 2 weeks and at 1 year, and with worsening physical
disability and cognitive function over that period
Zeng et al. China Case–control VCI 71 Not mentioned CST3 B allele The frequency of the CST3 B allele was found to be higher in the VCI
2019 CIND 81 group as compared with that of the CIND group (18.5% vs. 7.7%,
P = 0.006). In logistic regression analysis, a significant association
was found between VCI and CST3 B allele (OR 2.038
(1.048–3.963), P = 0.036)
Wu and Cai China Case–control NCI 103 Healthy 187 CAPN10 SNP43 (G / A) Patients with cerebral small vessel disease and with the GG genotype
2018 VCI 121 individuals gene were more likely to suffer from cognitive impairment than those with
the GA+AA genotype. SNP43 (G/A), total cholesterol, triglyceride,
low-density lipoprotein and high-density lipoprotein were
independent risk factors for cognitive impairment in small vessel
disease

Table 5 Summary of metabolic biomarkers for PSCI

Study Country Type of Post-stroke patients Normal cognition Biomarkers Results

study
Subjects Number Subjects Number

Yan et al. 2017 China Prospective VCIND 62 Stroke patients with 13 Serum Hcy Serum Hcy and hs-CRP were significantly lower after treatment, and
VD 29 normal cognition serum Hcy level was a risk factor for = dementia 1 month after
acute ischemic stroke
Zhu et al. 2019a China Prospective PSCI 86 Stroke patients with 170 Plasma TMAO After controlling for potential confounders, multivariable logistic
normal cognition analysis showed that higher levels of plasma TMAO were an
independent predictor of cognitive
impairment in post-stroke patients (quartile 1 was used as
reference; quartile 4 OR 3.304; 95% CI 1.335–8.178; P = 0.010)
Hou et al. 2019 China Prospective Ischemic stroke 261 Not mentioned Serum RA Univariate analysis showed that reduced RA levels were correlated
patients with PSCI at 3 months post-stroke (P = 0.003) but not at admission
(P = 0.416) or 1 month
post-stroke (P = 0.117).
Liu et al. 2015 China Prospective PSCI 30 Healthy individuals 20 Serum glutamine, In total, three serum metabolites (glutamine, kynurenine and LysoPC
PSNCI 30 kynurenine and LysoPC (18:2) (18:2)) were identified as candidate diagnostic biomarkers for PSCI,
and their combined use yielded good diagnostic ability for PSCI by
receiver operating characteristic curves analysis
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Table 6 RNA-based PSCI biomarkers

Study Country Type of study Post-stroke Normal cognition Biomarkers Results

patients

Subjects Number Subjects Number

Huang et al. 2016 China Cross-sectional PSCI 39 Healthy 38 miR-132 The level of miR-132 in PSCI patient serum
PSCN 37 individuals was significantly elevated compared
with that of PSCN and AMC subjects.
The ROC curve showed that
miR-132 achieved an AUC of 0.961
(P < 0.0001). Importantly, the miR-132
level was correlated with the MoCA score
in PSCI patients

NIHSS NIH Stroke Scale/Score

Growth Factors et al. (2019) reported that the level of serum IGF-1 at baseline
could significantly predict the improvement of cognition in
Brain-Derived Neurotrophic Factor (BDNF) stroke patients undergoing cognitive training, suggesting that
it was effective as a biomarker for the restoration of cognitive
BDNF is the main neurotrophic protein involved in impairment. The decrease in serum IGF-1 level is indepen-
neuroplasticity after stroke; it exists in the blood and is mainly dently related to cognitive impairment after ischemic stroke,
concentrated in the central nervous system (Rodier et al. 2015; and it is speculated that IGF-1 can be used as a new therapeu-
Siuda et al. 2017). The level of BDNF in brain tissues is tic target for cognitive impairment after ischemic stroke.
decreased in animal models of ischemic stroke, suggesting
that BDNF may be involved in the pathological mechanism
of stroke. Studies have found that serum BDNF levels are
Genetic Biomarkers
significantly decreased in dementia patients, and severe cog-
nitive impairment is associated with decreased BDNF levels
Cystatin C (CST3) B Allele
(He et al. 2017). O’Bryant et al. (2011) found that BDNF
levels were negatively correlated with immediate memory,
CST3, a protein encoded by the CST3 gene, has been proven
delayed verbal memory and immediate visual memory
to play a role in neuron repair and nerve regeneration, and has
scores. Chen et al. (2018) reported that the expression of
a protective effect on cognitive impairment (Ghidoni et al.
BDNF in serum of stroke patients was significantly decreased
2010). The CST3 BB genotype was found to be associated
(P < 0.01) and was positively correlated with MMSE score
with decreased CST3 secretion and considered to be an allele
(r = 0.827, P < 0.01). This is consistent with the results of a
susceptible to Alzheimer’s disease (Bertram et al. 2007). Zeng
study by Hassan and Yarube (2018), who also found that a
et al. (2019) examined the correlation between serum CST3
high incidence of cognitive impairment observed during a 10-
and CST3 gene polymorphism and cognitive impairment in
month follow-up period after stroke was related to decreased
patients with acute cerebral infarction, and the results showed
BDNF levels in peripheral blood. These results suggest that
that, compared with patients with cognitive impairment non-
BDNF may be an effective biomarker for assessing the risk of
dementia (CIND), patients with VCI had lower MoCA scores
PSCI.
(P < 0.001) and significantly higher serum CST3 levels (P =
0.024), and a negative correlation with MoCA score was
found (r = −0.174, P = 0.032); in addition, patients with the
Insulin-Like Growth Factor 1 (IGF-1)
CST3 B allele had a threefold higher risk of cognitive impair-
ment than patients without the CST3 B allele. Thus, the CST3
Insulin-like growth factor-1 (IGF-1) is primarily produced by
B allele is a risk gene of PSCI and might be indicative for early
the liver and is also produced by neurons and glial cells in the
diagnosis of the disease.
central nervous system. IGF-1 is known to protect nerves and
promote nerve growth (Zhang et al. 2004; Zhao et al. 2005).
De Smedt et al. (2011) found that IGF-1 levels in acute stroke BDNF Val66Met Gene
were related to the recovery of neurological function and
prognosis: a higher level of IGF-1 was associated with recov- To date, various studies have focused on the correlation be-
ery of neurological function and better outcome. Ploughman tween the BDNF Val66Met gene polymorphism and cognitive

function after stroke. It has been shown that the BDNF
Val66Met polymorphism is associated with cognitive function
decline and is independently related to poor long-term out-
come, and higher methylation status of the BDNF promoter
is significantly correlated with cognitive function decline after
1 year (Kim et al. 2012). Experiments using a mouse stroke
model showed that mice with the BDNFMet/Met gene had more
significant motor defects and decreased angiogenesis (Qin
et al. 2011). A study from Iran showed that post-stroke de-
mentia (PSD) patients had a higher frequency of the Val allele
than the Met allele compared with patients without PSD, a
lower probability of Met/Met homozygote and a higher inci-
dence of Val /Met heterozygote associated with PSD (39.6 vs.
19.6%). The results showed that BDNF Val is a dangerous
allele in PSD patients, which may accelerate the development
of PSD and make patients more prone to PSD (Rezaei et al.
2016).
CAPN10 SNP43 (G/A) Gene
Calpain plays an important role in the pathogenesis of
Parkinson’s disease and Alzheimer’s disease. An increased
level of CAPN10 enhances the accumulation of β-amyloid
peptide and induces hyperphosphorylation of the central ner-
vous system, which lead to neurodegeneration (Wu and Cai
2018). The CAPN10 GG genotype has been shown to be
significantly correlated with atherosclerosis (Feng et al.
2014). Wu and Cai (2018) studied the role of CAPN10
SNP43(G/A) and SNP63(C/T) polymorphisms in cognitive
impairment, and found that the SNP43(G/A) gene was an
independent factor influencing the cognitive function of pa-
tients with cerebral vascular disease, and patients with the G
allele might have worse cognitive function performance (.
Metabolic Biomarkers
Homocysteine (Hcy)
Hcy, an intermediate product of methionine metabolism cycle,
is a sulfur-containing amino acid in the human body. As in-
creased Hcy can cause endothelial dysfunction which is relat-
ed to stroke, and stroke may lead to cognitive impairment, it is
speculated that there may be a causal relationship between
plasma Hcy and PSCI. It has been reported that a high level
of expression of Hcy is a risk factor for mild cognitive impair-
ment and dementia (Ma et al. 2017). Yan et al. (2017) treated
patients with acute ischemic stroke with dl-3-n-butylphthalide
and found that global cognitive function was improved, while
serum Hcy (P = 0.013) and hs-CRP (P = 0.026) levels were
significantly decreased after treatment compared with the con-
trol group. Therefore, the authors concluded that serum Hcy
levels might be used as a predictor of cognitive impairment at
J Mol Neurosci
3–6 months after acute ischemic stroke, with higher levels of
serum Hcy indicating a proportionally greater risk of
dementia.
Trimethylamine-N-Oxide (TMAO)
TMAO is a metabolic product produced by intestinal flora and
plays a role in promoting thrombosis and atherosclerosis.
Previous studies found that the level of TMAO in urine is
elevated, suggesting that TMAO may be involved in the pa-
thology of stroke. The elevated TMAO level is associated
with PSCI (Li et al. 2017; Senthong et al. 2016). Zhu et al.
found that elevated plasma TMAO level was an independent
predictor of PSCI (OR 3.304; 95% CI 1.335–8.178; P =
0.010) (Zhu et al. 2019a), which is consistent with the results
of previous studies.
Retinoic Acid (RA)
RA is a metabolite of vitamin A, which can protect blood
vessels. Hou et al. (2019) studied the correlation between the
RA levels in serum and PSCI, and cognitive function at ad-
mission and after 1 and 3 months. The results showed that
serum RA levels were not related to PSCI at admission (P =
0.416), and RA level in serum decreased at 1 month (P =
0.117) and 3 months (P = 0.003). After adjusting for all the
confounding factors, it was confirmed that decreased levels of
RA level in serum at 3 months may be related to PSCI.
RNA-Based PSCI Biomarkers
microRNA (miRNA) is a type of non-coding single-stranded
small RNA that plays a role in biological functions by regu-
lating post-transcriptional gene expression. miRNA is in-
volved in the regulation of synaptic plasticity and is related
to learning and memory. Abnormal expression of miRNA is
involved in the pathogenesis of cognitive dysfunction in pa-
tients with Alzheimer’s disease or Parkinson’s disease, and
can be detected not only in the affected brain region but also
in peripheral body fluids such as plasma and cerebrospinal
fluid (Packer et al. 2008; Sarkar et al. 2019). It has been found
that serum levels of miR-93, miR-146a and miR-31 are sig-
nificantly increased in patients with vascular dementia
(Mijajlovic et al. 2017). Huang et al. (2016) showed that the
expression of miR-132 in serum of PSCI patients was signif-
icantly increased and correlated negatively with MoCA score
(r = −0.859, P < 0.001). The ROC curve analysis results
showed an AUC of 0.961 (95% CI 0.931–0.991; P < 0.001),
with sensitivity of 94.9%, specificity of 86.7% and accuracy
of 89.5%. This suggests that miR-132 in circulating blood has
a great ability to predict PSCI and can be used as a risk bio-
marker for PSCI. To date, miRNA has rarely been studied in
J Mol Neurosci
PSCI; however, its effect in diseases related to cognitive im-
pairment of the nervous system, learning and memory has
been confirmed. Thus, miRNA has great potential as a risk
predictor of PSCI.
Conclusions
In general, the diagnosis and prediction of PSCI functional
recovery by biomarkers has become a hot research topic.
Based on the existing research, it can be roughly divided into
inflammatory biomarkers, growth factors, oxidative damage
biomarkers, genetic biomarkers and metabolic biomarkers.
Changes in the levels of these molecular biomarkers in the
blood and urine are related to a decline in cognitive function.
Thus, the determination of biomarkers can improve the accu-
racy of diagnosis and prognosis, and is helpful for targeted
therapy of diseases. However, there is still a lack of large-scale
clinical trials to further examine and support the existing re-
search results. Single biomarkers may not be sufficient, and
multiple biomarkers should be combined for diagnosis and
prognosis of PSCI.
Author Contributions Xinxin Zhang designed the article contents and
wrote the original manuscript. Xia Bi made revisions to the manuscript
and provided financial support.
Funding Information This work was supported by funding from scien-
tific research of Shanghai Municipal Health Bureau (201940031) and the
Leading Personnel Training Project of Shanghai Pudong New District
Municipal Health Bureau (No. PWR12018-04).
Compliance with Ethical Standards
Competing Interests The authors have declared that no competing in-
terest exists.
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