You do know that prognosticating recovery is FUCKING USELESS TO SURVIVORS! They want EXACT RECOVERY PROTOCOLS! GET THERE!
Do your job, which is to get survivors recovered, prognostication does nothing for survivors.
Circulating Serum VEGF, IGF-1 and MMP-9 and Expression of
Their Genes as Potential Prognostic Markers of Recovery in
Post-Stroke Rehabilitation—A Prospective Observational Study
Lidia Włodarczyk 1,*, Natalia Cicho ́n 2 , Michał Seweryn Karbownik 3 , Luciano Saso 4,* , Joanna Saluk 5
and El ̇zbieta Miller 1
1 Department of Neurological Rehabilitation, Medical University of Lodz, Milionowa 14, 93-113 Lodz, Poland
2 Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz,
Pomorska 141/143, 90-236 Lodz, Poland; natalia.cichon@biol.uni.lodz.pl
3 Department of Pharmacology and Toxicology, Medical University of Lodz, ̇Zeligowskiego 7/9, 90-752 Lodz,
Poland; michal.karbownik@umed.lodz.pl
4 Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, P. le Aldo Moro 5,
00185 Rome, Italy
5 Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz,
Pomorska 141/143, 90-236 Lodz, Poland; joanna.saluk@biol.uni.lodz.pl
* Correspondence: lidia.wlodarczyk@umed.lodz.pl (L.W.); luciano.saso@uniroma1.it (L.S.)
Abstract: The key period in post-stroke recovery is the first three months due to the high activity
of spontaneous and therapeutic-induced processes related to neuroplasticity, angiogenesis and
reperfusion. Therefore, the present study examines the expression of VEGF, IGF-1 and MMP-9
proteins and their genes to identify biomarkers that can prognose brain repair ability and thus
estimate the outcome of stroke. It also identifies possible associations with clinical scales, including
cognitive assessment and depression scales. The study group comprised 32 patients with moderate
ischemic stroke severity, three to four weeks after incident. The results obtained after three-week
hospitalization indicate a statistically significant change in clinical parameter estimations, as well as
in MMP9 and VEGF protein and mRNA expression, over the rehabilitation process. Our findings
indicate that combined MMP9 protein and mRNA expression might be a useful biomarker for
cognitive improvement in post-stroke patients, demonstrating 87% sensitivity and 71% specificity
(p < 0.0001).
Keywords: stroke; recovery; biomarker; rehabilitation
1. Introduction
Stroke still remains a principal cause of adult disability and mortality, and it is regarded
as a priority for both the World Health Organization (WHO) and the United Nations to
decrease the burden of non-communicable diseases [ 1, 2]. The traditional definition of
stroke was mainly clinical, comprising a sudden loss of focal neurological function due
to infarction or hemorrhage lasting longer than 24 h; however, the updated definition
integrates clinical and tissue criteria and is based on neuropathological, neuroimaging
and/or clinical indications of permanent injury of brain, spinal cord or retinal cell [3 ].
Despite the use of increasingly effective early treatment strategies, such as intravenous
tissue plasminogen activator (tPA) or endovascular thrombectomy (EVT) [ 4 ], post-stroke
recovery is often incomplete and recovery rates of neurological function differ.
Stroke rehabilitation depends on both spontaneous and therapeutic-induced processes
of recovery, with important roles played by, inter alia, the extent of a stroke, regeneration,
angiogenesis, neuroplasticity, pharmacotherapy, and neurorehabilitation. The first three
months are the most important period in post-stroke rehabilitation, during which time
spontaneous and therapeutic-induced processes of recovery are most effective. From a clinical point of view, it is important to know which patient may demonstrate the greatest
potential improvement in both cognitive and functional performance several months later.
Therefore, there is a need to identify biomarkers that can be used as prognostic
tools to estimate the brain repair ability in a particular patient and also as predictive
tools for monitoring the response to individually tailored rehabilitation interventions [ 5].
Consequently, the findings may support the development of new algorithms to estimate
the outcome of stroke patients and subsequent treatment. For example, upon admission
to hospital, patients could be tested against a panel of biochemical and genetic laboratory
tests, which are aimed at genes and proteins involved in recovery processes such as
neuroplasticity [6].
Post-stroke recovery mechanisms remain poorly understood; however, circulating
molecules related to neuroplasticity, such as MMP-9, VEGF and IGF-1, can influence the
outcome when accompanied by extensive rehabilitation [6 ]. Molecular pathways involved
in brain repair after stroke are supposed to vary over time and those related to neuroplas-
ticity become relevant later in the subacute phase [7]. Furthermore, we hypothesize that
serum molecular differences between patients might provide a possible neurophysiologi-
cal and biochemical basis for differences in treatment responsiveness. Studies on animal
models indicate that changes in circulating proteins and expression of their genes correlate
with post-stroke recovery, and this has been supported to some degree by clinical research
studies [8–12].
It is generally believed that stroke recovery may be associated with the genes and
proteins known to play significant roles in neuroplasticity. For example, matrix metallopro-
teinase 9 (MMP-9), a zinc-dependent endopeptidase, is associated with both physiological
and pathological tissue reorganization or remodeling, including neovascularization. Its lev-
els are upregulated in post-stroke patients, which correlates with a poorer outcome [ 13 –15 ].
It has been shown that in post-stroke patients the concentration of MMP9 is significantly
higher compared to healthy volunteers [ 16 , 17]. Furthermore, MMP-9 levels appear to have
predictive value for hemorrhagic transformation, with the highest level of MMP-9 recorded
six hours after stroke onset, and an increased level of MMP-9 being associated with infarct
exacerbation and hemorrhage conversion [18 ]. Furthermore, in cases of acute stroke, the
serum MMP-9 level was found to predict post-stroke cognitive impairment three months
later [19].
Vascular endothelial growth factor (VEGF) is a well-known strong angiogenic factor
that was first described as specific for endothelial cell mitogen [20 ]. VEGF has a well-
documented role in the nervous system, where it promotes neuroplasticity, including
nerve repair, neurogenesis, and glial growth [21]. During ischemic stroke, VEGF gene
expression is upregulated as a result of hypoxia; the protein usually binds to the VEGF
second receptor, which is a crucial mediator of angiogenesis and increased permeability.
The second receptor may stimulate the production of matrix metalloproteinases (MMPs)
and induce the release of endothelial growth factors [ 22 ]. Increases in circulating VEGF
have been shown to aid neurological recovery in animal models of acute stroke [9 ,10]. An
animal model study showed that treadmill exercise may promote post-stroke recovery by
regulating the caveolin-1/VEGF pathway in the ischemic zone [23 ]. In addition, higher
exercise intensity has been found to be related to increased VEGF levels in post-stroke
rehabilitation [24]. VEGF expression was found to be significantly elevated for the 90-
day period after stroke onset, and this may have a significant influence on the functional
outcome for cardioembolic infarction origin stroke with higher VEGF values predicting
poorer outcomes [25].
The insulin-like growth factor 1 (IGF-1) protein is structurally and functionally similar
to insulin and as a neurotrophic hormone, it plays a crucial role in the development and
maturation of the central nervous system. IGF-1 serum level has been found to be influenced
by stroke, with a decrease in IGF-1 in acute stroke being related to a positive outcome [26].
However, IGF-1 only has a modest influence on long-term post-stroke recovery persisting
after seven years, as reflected in the mRS score distributions at all time points and is not irmed that IGF-1 serum level plays a key role in short-term outcomes (three months),
whereas in the longer term, e.g., two years, the associations are weakened and attenuated
by other factors, such as diabetes, smoking, hypertension and hyperlipidemia [28].
Hence, the aim of the present study was to evaluate the prognostic value of proteins
VEGF, IGF-1 and MMP-9 and the expression of their genes as markers of recovery in
stroke patients. The expression data was compared with patient demographics and vari-
ous clinical scales, including cognitive assessment and depression scales, with the goal of
identifying a recovery biomarker associated with individual functional domains. The
study was performed in the early subacute phase of stroke, i.e., from seven days to three
months, according to the Consensus Statements from the Stroke Recovery and Rehabili-
tation Roundtable [7].
and El ̇zbieta Miller 1
1 Department of Neurological Rehabilitation, Medical University of Lodz, Milionowa 14, 93-113 Lodz, Poland
2 Biohazard Prevention Centre, Faculty of Biology and Environmental Protection, University of Lodz,
Pomorska 141/143, 90-236 Lodz, Poland; natalia.cichon@biol.uni.lodz.pl
3 Department of Pharmacology and Toxicology, Medical University of Lodz, ̇Zeligowskiego 7/9, 90-752 Lodz,
Poland; michal.karbownik@umed.lodz.pl
4 Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University, P. le Aldo Moro 5,
00185 Rome, Italy
5 Department of General Biochemistry, Faculty of Biology and Environmental Protection, University of Lodz,
Pomorska 141/143, 90-236 Lodz, Poland; joanna.saluk@biol.uni.lodz.pl
* Correspondence: lidia.wlodarczyk@umed.lodz.pl (L.W.); luciano.saso@uniroma1.it (L.S.)
Abstract: The key period in post-stroke recovery is the first three months due to the high activity
of spontaneous and therapeutic-induced processes related to neuroplasticity, angiogenesis and
reperfusion. Therefore, the present study examines the expression of VEGF, IGF-1 and MMP-9
proteins and their genes to identify biomarkers that can prognose brain repair ability and thus
estimate the outcome of stroke. It also identifies possible associations with clinical scales, including
cognitive assessment and depression scales. The study group comprised 32 patients with moderate
ischemic stroke severity, three to four weeks after incident. The results obtained after three-week
hospitalization indicate a statistically significant change in clinical parameter estimations, as well as
in MMP9 and VEGF protein and mRNA expression, over the rehabilitation process. Our findings
indicate that combined MMP9 protein and mRNA expression might be a useful biomarker for
cognitive improvement in post-stroke patients, demonstrating 87% sensitivity and 71% specificity
(p < 0.0001).
Keywords: stroke; recovery; biomarker; rehabilitation
1. Introduction
Stroke still remains a principal cause of adult disability and mortality, and it is regarded
as a priority for both the World Health Organization (WHO) and the United Nations to
decrease the burden of non-communicable diseases [ 1, 2]. The traditional definition of
stroke was mainly clinical, comprising a sudden loss of focal neurological function due
to infarction or hemorrhage lasting longer than 24 h; however, the updated definition
integrates clinical and tissue criteria and is based on neuropathological, neuroimaging
and/or clinical indications of permanent injury of brain, spinal cord or retinal cell [3 ].
Despite the use of increasingly effective early treatment strategies, such as intravenous
tissue plasminogen activator (tPA) or endovascular thrombectomy (EVT) [ 4 ], post-stroke
recovery is often incomplete and recovery rates of neurological function differ.
Stroke rehabilitation depends on both spontaneous and therapeutic-induced processes
of recovery, with important roles played by, inter alia, the extent of a stroke, regeneration,
angiogenesis, neuroplasticity, pharmacotherapy, and neurorehabilitation. The first three
months are the most important period in post-stroke rehabilitation, during which time
spontaneous and therapeutic-induced processes of recovery are most effective. From a clinical point of view, it is important to know which patient may demonstrate the greatest
potential improvement in both cognitive and functional performance several months later.
Therefore, there is a need to identify biomarkers that can be used as prognostic
tools to estimate the brain repair ability in a particular patient and also as predictive
tools for monitoring the response to individually tailored rehabilitation interventions [ 5].
Consequently, the findings may support the development of new algorithms to estimate
the outcome of stroke patients and subsequent treatment. For example, upon admission
to hospital, patients could be tested against a panel of biochemical and genetic laboratory
tests, which are aimed at genes and proteins involved in recovery processes such as
neuroplasticity [6].
Post-stroke recovery mechanisms remain poorly understood; however, circulating
molecules related to neuroplasticity, such as MMP-9, VEGF and IGF-1, can influence the
outcome when accompanied by extensive rehabilitation [6 ]. Molecular pathways involved
in brain repair after stroke are supposed to vary over time and those related to neuroplas-
ticity become relevant later in the subacute phase [7]. Furthermore, we hypothesize that
serum molecular differences between patients might provide a possible neurophysiologi-
cal and biochemical basis for differences in treatment responsiveness. Studies on animal
models indicate that changes in circulating proteins and expression of their genes correlate
with post-stroke recovery, and this has been supported to some degree by clinical research
studies [8–12].
It is generally believed that stroke recovery may be associated with the genes and
proteins known to play significant roles in neuroplasticity. For example, matrix metallopro-
teinase 9 (MMP-9), a zinc-dependent endopeptidase, is associated with both physiological
and pathological tissue reorganization or remodeling, including neovascularization. Its lev-
els are upregulated in post-stroke patients, which correlates with a poorer outcome [ 13 –15 ].
It has been shown that in post-stroke patients the concentration of MMP9 is significantly
higher compared to healthy volunteers [ 16 , 17]. Furthermore, MMP-9 levels appear to have
predictive value for hemorrhagic transformation, with the highest level of MMP-9 recorded
six hours after stroke onset, and an increased level of MMP-9 being associated with infarct
exacerbation and hemorrhage conversion [18 ]. Furthermore, in cases of acute stroke, the
serum MMP-9 level was found to predict post-stroke cognitive impairment three months
later [19].
Vascular endothelial growth factor (VEGF) is a well-known strong angiogenic factor
that was first described as specific for endothelial cell mitogen [20 ]. VEGF has a well-
documented role in the nervous system, where it promotes neuroplasticity, including
nerve repair, neurogenesis, and glial growth [21]. During ischemic stroke, VEGF gene
expression is upregulated as a result of hypoxia; the protein usually binds to the VEGF
second receptor, which is a crucial mediator of angiogenesis and increased permeability.
The second receptor may stimulate the production of matrix metalloproteinases (MMPs)
and induce the release of endothelial growth factors [ 22 ]. Increases in circulating VEGF
have been shown to aid neurological recovery in animal models of acute stroke [9 ,10]. An
animal model study showed that treadmill exercise may promote post-stroke recovery by
regulating the caveolin-1/VEGF pathway in the ischemic zone [23 ]. In addition, higher
exercise intensity has been found to be related to increased VEGF levels in post-stroke
rehabilitation [24]. VEGF expression was found to be significantly elevated for the 90-
day period after stroke onset, and this may have a significant influence on the functional
outcome for cardioembolic infarction origin stroke with higher VEGF values predicting
poorer outcomes [25].
The insulin-like growth factor 1 (IGF-1) protein is structurally and functionally similar
to insulin and as a neurotrophic hormone, it plays a crucial role in the development and
maturation of the central nervous system. IGF-1 serum level has been found to be influenced
by stroke, with a decrease in IGF-1 in acute stroke being related to a positive outcome [26].
However, IGF-1 only has a modest influence on long-term post-stroke recovery persisting
after seven years, as reflected in the mRS score distributions at all time points and is not irmed that IGF-1 serum level plays a key role in short-term outcomes (three months),
whereas in the longer term, e.g., two years, the associations are weakened and attenuated
by other factors, such as diabetes, smoking, hypertension and hyperlipidemia [28].
Hence, the aim of the present study was to evaluate the prognostic value of proteins
VEGF, IGF-1 and MMP-9 and the expression of their genes as markers of recovery in
stroke patients. The expression data was compared with patient demographics and vari-
ous clinical scales, including cognitive assessment and depression scales, with the goal of
identifying a recovery biomarker associated with individual functional domains. The
study was performed in the early subacute phase of stroke, i.e., from seven days to three
months, according to the Consensus Statements from the Stroke Recovery and Rehabili-
tation Roundtable [7].
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