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Corresponding author: Teodora Yaneva-Sirakova ( teodora.yaneva@gmail.com ) © 2023 Teodora Yaneva-Sirakova, Dobrin Vassilev, Kiril Karamfiloff, Julieta Hristova, Monika Shumkova, Latchezar Traykov.
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation:
Yaneva-Sirakova T, Vassilev D, Karamfiloff K, Hristova J, Shumkova M, Traykov L (2023) Clinical effect of carotid stenting on cognitive abilities - possible evaluation using candidates for biomarkers. Folia Medica 65(2): 193-198. https://doi.org/10.3897/folmed.65.e79996
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Micro- and macrovascular consequences of atherosclerosis, arterial hypertension, dyslipidemia, and smoking can affect neurotransmission and markers for neuronal activity. The potential direction and specifics are under study. It is also known that optimal control of hypertension, diabetes, and dyslipidemia in midlife may positively affect cognitive functioning later in life. However, the role of hemodynamically significant carotid stenoses in neuronal activity markers and cognitive functioning is still being debated. With the increased use of interventional treatment for extracranial carotid disease, the question of whether it might affect neuronal activity indicators and whether we can stop or even reverse the path of cognitive deterioration in patients with hemodynamically severe carotid stenoses naturally emerges. The existing state of knowledge provides us with ambiguous answers. We sought the literature for possible markers of neuronal activity that can explain any potential difference in cognitive outcomes and guide us in the assessment of patients throughout carotid stenting. The combination of biochemical markers for neuronal activity with neuropsychological assessment and neuroimaging may be important from practical point of view and may provide the answer to the question for the consequences of carotid stenting for long-term cognitive prognosis.
BDNF, carotid stenting, cognitive impairment, dementia, FABP7, NGF, VEGF, neurotrophins, neurofilament light, S100 protein
There are three major types of candidate biomarkers that may potentially be responsive to cerebral hemodynamics, can be followed, and assessed at the time of carotid stenting: 1. biomarkers of neuronal activity and repair (neurotrophins); 2. structural neuronal molecules, and 3. endothelium derived molecules with the function of neurotransmitters.
The development and the survival of the neurons are at least partly dependent on extracellular regulation from the neurotrophins. These molecules have a major role in the proliferation, migration, and the phenotypic differentiation of the neural cells. They ensure neural structural and functional integrity. Several proteins are included in this group, among them the neuronal growth factor (NGF), the brain-derived neurotrophic factor (BDNF), the neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), all of which have 50% coincidence in their amino acid sequence, and neurofilament light chain.[
The regulation, serum concentration, and functional modulation of biomarkers for neuronal activity in patients with extra- and intracranial atherosclerotic disease are an evolving field, especially in terms of invasive interventional treatment. It would be of significant value if we could define a set of biomarkers that would have a prognostic implication for mid- and long-term interventional outcomes.
The aim of this review is to discuss several promising biochemical markers for neuronal activity, which may prove of prognostic value in clinical practice. Another aspect of the problem is how to properly and easily assess clinical effectiveness and neuronal functioning in real practice. One possible way is directly with neuroimaging – computer tomography, functional magnetic resonance, near infrared optical tomography. This will be discussed elsewhere. Another possible way is indirectly with the assessment of cognition via neuropsychological tests as a surrogate marker. In the current review, we tried to correlate biochemical biomarkers with neuropsychological outcome in patients with extracranial carotid stenosis-revascularization.
BDNF has a very important role for the function of many neuronal groups in the dorsal ganglia[
To conclude, with reference to BDNF as a potential marker for functional outcome in stenting of the extracranial carotid segment, it can be associated both with endothelia functioning and hemodynamic stress, as well as with neuronal functioning. These processes, however, are also physiologically associated and their artificial separation for scientific purposes may be impossible.
NGF participates in the growth and differentiation of the sympathetic and some sensory neurons.[
In a rat study[
The above mentioned studies make it clear that NGF may be a good candidate surrogate marker for cognitive functioning; however, its significance in terms of symptomatic extracranial carotid disease is unknown.[
Genetic studies have demonstrated that NT-3 polymorphism rs6332 had a significant association with executive functioning and for the progression of Alzheimer’s disease.[
Neurotrophin-4/5 is another member of the neurotrophin family. Its role in ischemic brain injury is not known. There are several reports for a potential correlation in rodents, but such is lacking for humans. In a study, the intraventricular application of NT-4/5 in acute stroke reduced the infarct size.[
VEGF is a cytokine, a member of a large group of proteins that stimulate angiogenesis.[
Another point to be considered in the role of the neuro and angiotrophic factors at the time of central nervous system ischemia is the time of their maximal concentration. [
S100 is a Ca2+-binding protein which, depending on its concentration, can have local trophic or toxic effect.[
NFL is a marker for neurodegenerative diseases. It is a component of the large, myelinated axons and its cerebrospinal or plasma levels are elevated in neurodegenerative diseases as amyotrophic lateral sclerosis and Alzheimer’s disease.[
FABP7 is important in early astrocyte and neuronal development. Its concentration also shoes diurnal variation, and it was shown that FABP7 was elevated in dementia-related diseases.[
Mathiesen et al.[
The usefulness of carotid stenting, especially in the acute setting of stroke, is a relatively new and quickly evolving subject. The search for a way to improve the functional capacity after ischemic brain injury (acute and chronic) is gaining speed and the scientific community is on the search of biomarkers that may help to better define the prognosis for patients, as well as to stratify the expected functional (motor and cognitive) benefit after revascularization. Carotid stenting stimulates blood flow and regeneration, reduces ischemic and ischemic brain injury. However, in some cases it may lead to significant edema and reperfusion injury. Carotid interventions, in particular stenting, lead to local stimulation of inflammatory markers such as IL6. They influence blood flow distally and may be the reason for local changes and even hypoperfusion.[
The triple correlation between laboratory neural biomarkers, brain perfusion, and cognition before and after stenting may be important for the midterm clinical prognosis in patients with significant carotid stenoses. Laboratory markers may provide the missing link between restoration of cerebral blood flow and the differential impact[
The reperfusion after carotid revascularization can lead to elevated levels of neurotrophin and better functional outcome. It can potentially increase the risk for edema, local inflammation, which in turn can reduce the neurotrophins. These seemingly conflicting effects may be intimately correlated and the precise outcome in each patient may rely on factors still unknown for the general practice. A difference should be made between neurotrophic factors, inflammatory proteins and growth cytokines, and structural neuronal proteins. These different groups of markers may change independently in chronic ischemia-reperfusion and may have different significance. However, the need for better prognostication, both functional and cognitive, stimulates the search of the precise mechanisms and effects of neurotrophic and vasotrophic factors in chronic brain ischemia and their correlation with the results of carotid interventions.
The current review is part of a scientific project conducted with the financial support of Medical University Sofia: Contract D-133/24.06.2020 from the competition GRANT 2020 of Medical University Sofia. Project title: The role of biochemical biomarkers for neuronal activity and clinical neuropsychological tests in patients with carotid stenting.
The authors have no conflicts of interest to declare.