Correlation between neuroimaging, neurological deficits, and neurotrophic proteins in predicting rehabilitation potential in ischemic stroke patients

Introduction

Ischemic stroke (IS) is a leading cause of disability, resulting from the interruption of blood supply to specific regions of the brain. This vascular disruption causes a cascade of hemodynamic, metabolic, and neurotrophic disturbances, impairing brain function and leading to a wide range of neurological symptoms (1). The acute phase of cerebrovascular disorders (CVD) results in the onset of functional impairment and neurodegeneration, often manifesting as motor deficits, cognitive disturbances, and changes in speech and sensory functions (2).

While neuroimaging and clinical scales, such as NIHSS and the modified Rankin scale (mRS), are used to assess the severity of stroke and guide prognosis, they do not fully capture the underlying biological processes influencing stroke recovery (3). The role of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) (2), has gained increasing attention due to their involvement in neuronal survival, repair, and plasticity after ischemic injury. Astrocytes and pericytes produce NGF in response to inflammatory mediators, which reduces neuronal apoptosis and plays a significant role in the neuroprotective response post-stroke (4-6). Despite their potential, the functional implications of these biomarkers remain underexplored in clinical scenarios. Although previous studies have indicated altered levels of BDNF and NGF in patients’ post-stroke, few have directly linked these biomarkers with clinical outcomes or recovery (5,7). Neuroplasticity, the brain’s ability to reorganize itself by forming new synaptic connections, is a key factor in post-stroke recovery. However, the degree of recovery is influenced by factors such as the ischemic focus, the patient’s age, and rehabilitation efforts (8,9). This study aims to explore the relationship between BDNF, NGF, and functional recovery in patients with IS. By correlating these biomarkers with clinical outcomes, we propose a model that may serve as a more effective tool for prognosis and personalized rehabilitation strategies.

In conclusion, this study focusses on understanding the role of BDNF and NGF in stroke recovery, providing valuable insights for improving the accuracy of prognostic models and optimizing rehabilitation strategies for stroke patients (10,11). We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2231/rc).

Methods

We examined 120 patients aged 36–86 (average age 66.3±0.88 years) (standard deviation =9.64 years) who suffered from an acute period of IS between 2021–2023. Of these, 67 were men, and 53 were women. The average age of the observed men was 64.6±1.3 years, and for women, it was 68.3±1.2 years. The gender distribution of the examined patients is shown in Figure 1.

Figure 1 Gender distribution of patients.

As shown in the Figure 1, among the patients examined for IS, men outnumber women (with a ratio of 1.9:1). The predominance of men in the study is explained by their characteristics related to the prevention of serious pathologies (concern for their health, discipline, higher social activity, and communication with the doctor).

The study includes the following criteria: patients aged 36–80 years diagnosed with IS; hospitalization within the first 36 hours of IS onset; IS severity ranging from 3 to 26 points on the National Institutes of Health Stroke Scale (NIHSS). Arterial hypertension (AH), arrhythmia, and ischemic heart disease (IHD) are considered the main risk factors for IS.

In our study, it was found that the majority of patients (49.2%) had the atherothrombotic subtype of IS. This aligns with the global trends in the development of pathogenetic subtypes of IS.

The severity of IS was compared between the two groups. The location of IS was shown to correspond with focal neurological symptoms (Table 1). The duration of treatment ranged from 10 to 21 days (13.5±0.3 days). Prolonged hospital stays of more than 10 days were required for 59.2% of patients (71 out of 120).

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted in accordance with ethical principles and approved by the Expert Council of the Tashkent State Medical University (Conclusion No. 04-з/48, February 15, 2024). Informed consent was obtained from all participants prior to their inclusion in the study.

All patients underwent standard clinical and neurological examinations, including an analysis of patient complaints, medical history, physical examination, and a comprehensive neurological assessment. Somatic evaluations were also conducted. The pathogenetic subtypes of IS were classified according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria, which is widely used globally. Patients with IS of unknown etiology were excluded from the study. Upon hospital admission and on the 20th day, we assessed the general clinical-somatic and neurological condition of the patients. The degree of neurological deficit was evaluated using the NIHSS. On the final day of hospitalization, we examined the patient’s level of dependency on external assistance in daily life using the Barthel Index and the mRS. The NIHSS and the RS are widely used and scientifically validated tools to evaluate neurological deficits and functional recovery in stroke patients. NIHSS: 0–6: mild stroke 7–12: moderate stroke >12: severe stroke. mRS: 0–2: good recovery (independent) 3–5: poor recovery (dependent) 6: death.

Therefore, it is less sensitive in cases of mild IS. The socioeconomic challenges faced by post-stroke patients were analyzed, and the degree of dependency on external assistance at the end of the acute phase of IS was determined using the mRS. A score of 0 indicates no neurological impairments, while a score of 5 indicates severe neurological dysfunction, with the patient requiring daily assistance. The Frenchay Arm Test was used to assess the functionality of the affected upper limbs in daily activities. The patient’s initial position is seated at a table with hands on their knees. The patient is given 1 point for each successfully completed task, while failure to complete a task results in 0 points. The total score is calculated at the end of the test. Cerebral hemodynamics were assessed using transcranial duplex scanning (TCDS) in 2D mode, and Doppler ultrasonography was performed through the transtemporal window to measure the middle cerebral artery (MCA). TCDS was used to evaluate artery patency, size, and deformations. At the first day of the stroke, Doppler ultrasonography provided information on pulse waveform, spectral distribution of flow, linear blood flow velocity (maximum, mean, and minimum), index of resistance (IR), pulsatility index (PI), and blood flow volume. Magnetic resonance imaging (MRI) (3) was conducted using a Siemens Magnetom Symphony apparatus with a 1.5 Tesla superconducting magnet. Tomograms were obtained in axial, sagittal, and coronal projections using T2, T1, FLAIR, and DWI sequences. The MRI scans were analyzed for focal, diffuse (leukoaraiosis), and atrophic changes in the white matter. Hemorrhagic stroke was excluded.

CT scans of the head were performed using a Siemens Somatom Perspective (Siemens, Germany) machine with slice thicknesses of 5–10 mm and 64-slice acquisition. Scans were obtained parallel to the orbitomeatal line, and the slice thickness and scanner step were 5 and 10 mm, respectively.

Peripheral blood was collected from the cubital vein in the morning (between 8:00 and 9:00 AM) on an empty stomach using a “Vacuette” tube (with a clot activator) for the determination of neuropeptide concentrations. This was done during hospitalization, at the peak of free radical and inflammatory changes. The concentration of NGF and BDNF was studied during the acute phase of IS immediately upon patient admission to the hospital. The study was conducted at the central clinical laboratory of the Tashkent State Medical University and included the measurement of the following biomarkers in serum: NGF and BDNF. Peripheral blood samples were centrifuged to separate serum without hemolysis using a standard method. The serum was then aliquoted into “Eppendorf” tubes, labeled, and stored in freezers at −80 ℃ until the analysis of neuropeptide levels. For comparison, a control group of 20 healthy individuals of the same age and gender as the patients was formed.

Statistical analysis of the study results was conducted using Microsoft Excel 2019 and STATISTICA 6.0 software. The results were presented as the mean and standard deviation for normally distributed data and the median (Me) and quartiles for data with non-normal distribution. The normality of distribution was assessed using the Shapiro-Wilk test. Comparisons between independent groups were made using the Student’s t-test for normally distributed data and the Mann-Whitney U test or Wilcoxon test for non-normally distributed data. Differences with a significance level of 95% (P≤0.05) were considered statistically significant. Correlation relationships were evaluated using Spearman’s non-parametric method.

Results

Rehabilitation potential (RP) and its determinants in patients during the acute phase of IS. In recent years, stroke has begun to be viewed as a systemic pathological process within the human body, leading to the development of acute IS (AIS) due to the distinct heterogeneity and variability of risk factors contributing to focal brain damage (4-8). This suggests that all components involved in the pathogenesis of homeostasis participate in the process.

In forming the RP, we identified the following areas in the study (Table 2).

Identify and differentiate the most important assessment scores and indicators used to determine the negative consequences of IS, specifically those affecting neurogenesis and neurotrophic factors.

Upon admission, most patients with IS reported cerebral symptoms, as shown in Figure 2, which illustrates their complaints, including headache, dizziness, weakness, numbness, and speech disturbances. Analysis of disease severity in Figure 3 showed that the majority of patients were in the moderate condition group (75.8%), while 24.2% of patients presented with a severe condition.

Figure 2 Complaints of IS patients upon admission (n=120). IS, ischemic stroke.

Figure 3 Distribution of patients with IS by severity upon admission. IS, ischemic stroke.

The clinical signs of IS in the examined patients corresponded to classical IS in the MCA basin: “motor impairments (hemiparesis and monoparesis of varying severity), facial muscle paralysis, sensory disturbances, aphasia, and neglect of varying severity” (9,10). IS in the vertebrobasilar basin (VBB) was characterized by ataxia, dysarthria, oculomotor disturbances, and hemianopia (11,12). Upon hospital admission, 55.5% of patients had contralateral central hemiparesis (13), 52.5% had contralateral hemihypesthesia (13), and 55.0% had aphasia based on NIHSS assessments (14). In 2.5% of patients with IS and normal consciousness, the “triple hemiparesis” syndrome (hemiparesis, hemianesthesia, and hemianopia) was identified due to proximal occlusion of the MCA. A deep sopor or coma was observed in 5.0% of patients upon admission (Table 3).

Among the 120 examined patients, neurological impairment was predominantly of moderate severity, observed in 70 patients (58.3%) with an average score of 14.9±0.61 points. Mild impairment was identified in 20 patients (16.7%) with an average score of 4.4±0.52, while severe impairment was noted in 30 patients (25.0%) with an average score of 22.5±0.54 (Table 4).

Ischemic damage to the MCA’s lenticulostriate branches affects speech centers and the internal capsule, as shown by NIHSS scores. Sensory aphasia and upper quadrantanopia were observed in 2.5% of patients, while lower quadrant hemianopia occurred in 1.7%. Paresis of the lower facial muscles was seen in 63.3%. NIHSS scores ranged from 3 to 26, with an average of 14.4±0.63 (Table 5).

The Barthel Index showed an average score of 85.4±1.3, indicating a need for moderate to mild assistance in daily activities. Specifically, 40.8% required mild assistance, 49.2% needed moderate assistance, and 10.0% required significant assistance. These results are shown in Figure 4.

Figure 4 Barthel Index, Frenchay Test.

The average Frenchay test score was 4.2±0.24 points. Of the patients, 32.5% required no assistance, 55.0% needed partial assistance, and 12.5% needed full assistance. On the Rankin Scale, the average score was 2.4±0.16 points, indicating mild to moderate impairment in most patients. In 2.5% of patients, severe impairment was recorded, while 43.3% had moderate impairment, requiring partial assistance. 37.5% of patients could perform tasks independently. At discharge, NIHSS scores improved, showing a 3.4-fold decrease, reflecting mild neurological deficits. The Frenchay test score increased to 4.9 points, a 1.2-fold improvement from day 3 (Table 5).

On the 3rd day of the illness, the Barthel Index showed that the level of dependence on external assistance for daily activities corresponded to moderate or mild levels. By the time of hospital discharge, the average score had increased by 1.2 times (P<0.05), and the scores indicated that most patients required only minimal assistance (scores ranging from 90 to 100). The majority of patients (96.7%) did not require external assistance. On the 3rd day of illness, the average score on the Rankin Scale for patients with IS was 2.4±0.16. By hospital discharge, this score had decreased 1.4 times.

These results suggest that even in the presence of clinical symptoms after IS, there was little or no impairment of independent daily activities, indicating that most patients could perform routine tasks without external assistance or difficulty.

Thus, the scales used in the study can be relevant areas for establishing RP in patients with IS. The data obtained support the recommendation of amantadine sulfate and tricortin in patients during the acute phase of IS, as these therapies can improve RP.

Neuroimaging findings revealed perifocal edema with displacement of intermediate brain structures after IS, periventricular leukoaraiosis, cerebral atrophy (15). Stroke lesion localization; number of brain lobes involved in the stroke; the volume of scar-atrophic changes (16). Additionally, there was the expansion of the third ventricle (17).

In the Doppler examination of brachiocephalic arteries, stenosis of the brain’s main arteries was studied in ipsilateral and contralateral centers of IS on the side of hemiparesis (18). Periventricular leukoaraiosis significantly affects the functional reserve of the cerebral hemisphere depending on the stroke’s localization (19). During MRI/CT studies, we examined pathological changes in the brain of patients with IS according to their degree of neurological deficit (based on the NIHSS scale). We identified the forms presented in Table 6.

The presented data shows that in most cases, the lesion in patients with IS is located on the right side, with varying degrees of neurological deficit. The displacement of intermediate brain structures due to perifocal edema is significantly more frequent in severe neurological deficits (P<0.05). A correlation was also established between the worsening of neurological deficits and the increasing frequency of intermediate structure displacement (χ²=0.678; P<0.05; r=0.689). Leukoaraiosis was significantly more frequently observed in patients with severe neurological deficits (100%), whereas in mild cases, its frequency was 2.2 times lower (45.0%). Leukoaraiosis is a significant risk factor for developing severe neurological deficits, as confirmed by correlation analysis (χ²=0.852; P<0.01; r=0.801). The localization of the ischemic lesion in the brainstem and subcortical areas significantly increases the severity of neurological deficits. Correlation analysis identified a strong direct relationship between severe neurological deficits and ischemic lesions in the brainstem and subcortical regions (χ²=0.754; P<0.05; r=0.659). A correlation was also established between mild neurological deficits and the localization of ischemic lesions in subcortical areas (χ²=0.824; P<0.05; r=0.719).

Moreover, the development of severe neurological deficits is associated with the number of affected brain lobes. In mild neurological deficits, the ischemic lesion was limited to one brain lobe in 55.0% of cases, while in severe cases, 50.0% of the lesions were in the brainstem, and 30.0% involved three or more lobes. Cerebral atrophy tends to increase with the severity of neurological deficits. However, no significant deviations or correlations were found.

The volume of the ischemic lesion significantly increased with the severity of neurological deficits, being 1.8 times larger in severe cases than in mild cases (P<0.01). A correlation was found between the ischemic lesion volume and the development of severe neurological deficits (χ²=0.912; P<0.01; r=0.806). Thus, neuroimaging risk factors associated with the development of severe neurological deficits and poor RP include displacement of intermediate structures due to perifocal edema, leukoaraiosis, the localization of the ischemic lesion in the brainstem and subcortical areas, and the extent and volume of the ischemic lesion.

Here are several MRI and multislice computed tomography (MSCT) images of brain imaging for examples, illustrated in Figure 5.

Figure 5 The MRI imaging is included to illustrate the localization and volume of ischemic lesions, which correlate with clinical severity and rehabilitation potential. (A) MRI brain scan of a patient with ischemic stroke. The green arrow indicates a subacute ischemic infarction of the right pontine region (bridge) in the vascular territory of the basilar artery. MRI, magnetic resonance imaging.

During the duplex scanning analysis of brachiocephalic vessels, we identified characteristic indicators of cerebral hemodynamics, leading to severe neurological deficits. The data obtained is presented in Table 7.

The presented data shows that patients with severe neurological deficits due to IS have a significantly higher frequency of arterial deformations (UUA, IUA, and UA) compared to patients with moderate neurological deficits. In certain arteries, hemodynamic stenosis significantly increases with the rising degree of neurological deficit. For instance, in mild neurological deficits, stenosis was observed in only 5% of cases, while in moderate instances, its detection increased by 3.7 times, and in severe cases, by 8.7 times.

Intima-media thickness (IMT) values also significantly increased with the level of neurological deficit. To determine the strength of the factors affecting the negative outcomes of the RP in patients with IS, we conducted a correlation analysis. The obtained data are presented in Table 8.

The presented data show a moderate to high correlation between the indicators of RP, MRI/CT parameters, and cerebral hemodynamics, indicating the prognostic significance of the identified pathological disorders.

Identifying these factors allows for a differential approach to assess the RP prognosis for patients with IS in Figure 6.

Figure 6 The level of rehabilitation potential in patients with ischemic stroke during the acute phase.

The individual RP can be categorized into three types:

• High RP: achieving complete or significant recovery of certain life activities during rehabilitation.
• Moderate RP: ensuring partial recovery of specific life activities during rehabilitation.
• Low RP: indicating the complete non-recovery or minimal recovery of certain life activities during rehabilitation efforts.

Based on the results of our research, we established the RP for patients suffering from IS during the acute phase, relying on the scales, instrumental methods, neurogenesis indicators, and significant points related to the development of adverse outcomes in IS.

In studies evaluating the composition of neurotrophic factor biomarkers in the blood serum of 70 patients with IS during the acute phase. Thus, considering the RP indicators in this group of patients, there is a basis to believe that implementing comprehensive rehabilitation measures can lead to a further reduction in the degree of disability and a favorable clinical and rehabilitation prognosis (Table 9).

Thus, considering the RP indicators in this group of patients, there is a basis to believe that implementing comprehensive rehabilitation measures can lead to a further reduction in the degree of disability and a favorable clinical and rehabilitation prognosis.

The study of neurotrophic factors (NGF and BDNF) levels in peripheral blood serum during the acute phase of IS showed that, compared to patients with hypertension (AG), the levels of BDNF and NGF were, respectively, 6.9 and 2.9 times lower (Table 10).

The Control Group shows significantly higher levels of BDNF and NGF than the Main Group. The reliability between the groups for BDNF and NGF levels is highly significant (P<0.001). The ratios indicate that the BDNF level in the Control Group is approximately 6.9 times higher, and the NGF level is about 2.9 times higher compared to the main group.

Neurotrophic factor decline indicates the degree of hypoxic-ischemic injury. To determine the role of neurotrophic factors in the development of neurological deficiency, we analyzed their levels according to the degree of deficiency, and the obtained data are presented in Table 11.

BDNF levels decrease significantly as neurological deficiency worsens. Mild deficiency is associated with a BDNF level of 812.6±11.3 pg/mL, while in severe deficiency, the level drops by 1.6 times to 547.1±10.4 pg/mL (P<0.05). NGF levels follow a similar trend, decreasing as the severity of the neurological deficit increases. The composition of NGF in peripheral blood also depends on the degree of neurological deficiency, with the lowest values observed in severe deficiency (172.8±5.9 pg/mL). In severe neurological deficiency, there is a decrease of 2 times and a reduction of 1.4 times compared to moderate deficiency.

Analysis of neurotrophic factors (NGF and BDNF) in peripheral blood serum during the acute phase of IS shows that patients with complete disability have higher levels of BDNF and NGF compared to those with mild disability, depending on the impairment of daily life activities (P<0.01). The data obtained are presented in Table 12.

The level of BDNF in the serum of patients with complete disability is 1.4 times lower than that of patients with mild disability (P<0.05), while the NGF composition is reduced by 1.8 times (P<0.05). The table displaying the levels of neurotrophic factors (NGF and BDNF) based on disability level according to the Barthel index has been created. The levels of BDNF and NGF decrease with increasing severity of disability. Patients with mild disability had significantly higher concentrations of BDNF compared to those with moderate and complete disabilities (P<0.05), indicating a clear association between neurotrophin levels and functional status. Similarly, NGF levels showed a consistent downward trend across disability categories, with the lowest levels observed in patients with complete disability. In the next phase of analysis, we examined the distribution of BDNF and NGF in peripheral blood in relation to life activity impairment, as assessed by the mRS in patients with IS. These findings confirm the inverse relationship between neurotrophic factor levels and the degree of functional impairment. The strengthening of correlation relationships increased with the severity of neurological deficiency and impairments in daily functional activities and life. The obtained data are presented in Figure 7.

Figure 7 Correlation between the levels of NGF, BDNF, and the development of neurological deficits. BDNF, brain derived nerve factor; NGF, nerve growth factor; NIHSS, National Institutes of Health Stroke Scale.

The data show negative correlations between NIHSS scores and neurotrophic factors, with lower NGF (r=−0.689, P<0.01) and BDNF (r=−0.457, P<0.05) linked to higher deficits. Positive correlations were found with the Frenchay scale (NGF r=0.526, P<0.05; BDNF r=0.423, P<0.05), indicating their role in predicting limb dysfunction. Low NGF (r=0.698, P<0.01) and BDNF (r=0.457, P<0.05) levels also correlate with lower Barthel index scores, reflecting increased daily activity impairments. Inverse correlations with Rankin scale (NGF r=−0.781, P<0.01; BDNF r=−0.541, P<0.05) suggest worse functional outcomes. These findings underscore the link between neuropeptide levels and stroke severity. Data reliability for IS patients without disability is indicated (*, P<0.05; **, P<0.01; ***, P<0.001).

A hospitalization period of more than two weeks is also associated with low levels of NGF and BDNF (see Table 13).

Based on the provided data, it can be concluded that in patients with IS during the acute phase, the lower the levels of NGF and BDNF in peripheral blood, the longer their hospital stay will be. This indicates that the lower the concentration of NGF, the more prolonged the hospital treatment. the levels of BDNF and NGF in patients with different disease durations, indicating significant differences in both markers with data reliability at P<0.01. Thus, NGF levels may serve as an important biomarker for detecting and treating IS, as they are related to both the severity of the disease and treatment outcomes.

In patients with AIS, an analysis of the influence of each factor on dynamics during hospital-stage therapy, based on a three-factor linear regression, enabled the development of a mathematical model for the early detection of NIHSS scores at the end of the early recovery phase.

The method is based on assessing the recovery of functional neurological disorders according to the NIHSS scale and the Barthel Index and evaluating NGF levels in plasma during IS therapy. The following formula calculates the regression rate for the recovery of functional neurological disorders: “Y=1.58+0.82×X1−0.04×X2+0.00025×X3 (P<0.0001, RI =0.87), where Y: the level of neurological deficit according to the NIHSS stroke scale 3 months after treatment, X1: the level of neurological deficit before treatment based on the NIHSS stroke scale, X2: the level of daily motor activity before treatment according to the Barthel Index, X3: the quantitative concentration of NGF before treatment (pg/mL)”.

If Y is less than 10, the probability of positive recovery of functional neurological disorders is 60–70%, while if Y is more than 20, the probability is between 4–16%.

To illustrate this more clearly, we provide clinical examples.

To illustrate the application of the prognostic formula, two clinical cases were evaluated.

In Patient 1, the initial NIHSS score was 6, Barthel Index was 70, NGF and BDNF plasma levels were 234 and 740 pg/mL, respectively. Using the predictive formula: Y=1.58+0.82×NIHSS−0.04×Age+0.00025×NGF, the calculated post-treatment NIHSS score was 4.8, indicating a 60–70% probability of favorable recovery.

In Patient 2, with an NIHSS score of 5, Barthel Index of 90, NGF and BDNF levels of 112 and 605 pg/mL, respectively, the calculated post-treatment NIHSS score was 4.1, also corresponding to a 60–70% RP.

These examples confirm that the proposed model reliably reflects the relationship between clinical status, neurotrophin levels, and recovery potential in IS patients. The method recommended for early detection of functional neurological recovery and independent performance in daily life in patients with IS is easy to use, requires minimal time, and does not need extensive diagnostic equipment.

Discussion

The present study elucidates the critical role of neurotrophic factors, specifically NGF (2) and BDNF, in the prognosis and recovery of patients with AIS. The majority of patients demonstrated moderate neurological impairment (58.3%), while severe deficits were observed in one-quarter of cases and only 16.7% had mild impairment. The higher average NIHSS scores in the moderate and severe groups highlight the predominance of substantial neurological dysfunction in this cohort, underscoring the need for intensive rehabilitation strategies (Table 4). Our findings reveal that both NGF and BDNF levels in peripheral blood serum are significantly reduced in patients with IS compared to healthy controls, with NGF showing a decrease of 6.9 times and BDNF 2.9 times (20,21). This reduction in neurotrophic factors is not merely a marker of stroke severity; it also correlates strongly with the functional deficits and recovery trajectories of these patients. Neurotrophic Factors and Neurological Deficits correlation analysis performed in this study indicated strong negative associations between NGF and BDNF levels and the NIHSS scores. Specifically, lower levels of NGF (r=−0.689; P<0.01) and BDNF (r=−0.457; P<0.05) correspond to higher NIHSS scores, suggesting that diminished neurotrophic support exacerbates neurological deficits (15,22). This finding aligns with existing literature that highlights the importance of NGF and BDNF in neuroprotection and neuronal survival during ischemic events (2,14).

The relationship between neurotrophic factors and neurological impairment extends to other functional scales, such as the Barthel Index and the Rankin scale, reinforcing the notion that lower neurotrophic factor levels can serve as predictors of functional disability in daily living activities (16,23). The direct correlation between decreased NGF levels and increased disability (Barthel Index: r=0.698; P<0.01) further solidifies the argument that monitoring neurotrophic factors can offer valuable insights into patient recovery (14).

The mechanisms underlying the effects of NGF and BDNF in the context of stroke involve their neuroprotective properties. NGF is crucial for the survival and maintenance of certain neurons, particularly cholinergic neurons, and it promotes neurogenesis and synaptic plasticity (24,25). BDNF is similarly involved in promoting neuronal survival, differentiation, and growth (26,27). In acute ischemic conditions, the reduced levels of these factors may lead to increased neuronal apoptosis, exacerbating ischemic damage and functional deficits. Moreover, the established correlation between the neurotrophic factors and clinical scales indicates that these factors may reflect the restoration of the structural and functional relationships between neurons and glial cells in the ischemic region. This restoration is vital for enhancing neuroplasticity and recovery post-stroke (2,28).

The study also highlights implications for recovery and rehabilitation and the potential for developing a mathematical model using a three-factor linear regression approach to predict recovery outcomes based on neurotrophic factor levels and clinical scores. The model suggests that if the predicted score (Y) is less than 10, there is a 60–70% probability of positive functional recovery, whereas a score greater than 20 suggests only a 4–16% probability (29). This model may serve as a useful tool for clinicians in evaluating RP and tailoring individualized treatment plans for patients post-stroke (Figure 6). The correlation analysis (Table 8) revealed moderate to high associations between instrumental examination parameters (MRI/CT and cerebral hemodynamics) and RP indicators. These findings underscore the prognostic value of structural and functional brain changes in the acute phase of IS. MRI and CT imaging parameters reliably reflect the extent of cerebral damage, which correlates closely with patient outcomes and recovery potential. The observed relationships suggest these imaging modalities could serve as valuable tools in clinical decision-making and personalized rehabilitation planning.

Our investigation into neurotrophic factors (NGF and BDNF) revealed significantly decreased serum levels in stroke patients compared to hypertensive control subjects (Table 10). Specifically, BDNF and NGF concentrations were 6.9 and 2.9 times lower, respectively, highlighting their potential roles as biomarkers for ischemic neuronal damage severity. Such pronounced reductions in neurotrophic factor levels suggest considerable neuronal distress and decreased neuroplastic capacity, essential in recovery processes.

Furthermore, a clear inverse relationship between neurotrophic factor concentrations and the severity of neurological deficits was documented (Table 11). Patients with mild neurological impairment exhibited significantly higher BDNF and NGF levels compared to those with moderate to severe deficits. These results align with the biological functions of BDNF and NGF, which support neuronal survival, growth, and plasticity. Therefore, measuring neurotrophic factor levels during the acute phase can provide critical insights into the potential for neurological improvement and guide therapeutic interventions.

Analysis using the Barthel Index further emphasized the clinical relevance of neurotrophic factors concerning functional disability (Table 12). Patients with mild disability demonstrated significantly elevated serum BDNF and NGF levels compared to those experiencing moderate or complete disability. This indicates a direct relationship between the neurobiological status (neurotrophic support) and functional recovery capability, reinforcing the value of these biomarkers in prognostic assessments and rehabilitation strategy formulation.

The association between neurotrophic factors and functional impairment was further confirmed through assessment with the mRS. Consistent with the Barthel Index findings, a marked reduction in BDNF and NGF was observed with increasing disability levels, confirming their critical involvement in functional restoration post-stroke. This consistency across assessment scales underscores the reliability of neurotrophic factors as indicators of RP.

Finally, our study identified a significant association between neurotrophic factor concentrations and the duration of hospital stays (Table 13). Lower levels of NGF and BDNF correlated with prolonged hospitalization, emphasizing the predictive value of these biomarkers in clinical practice.

The findings suggest that monitoring NGF and BDNF levels could be instrumental in identifying patients at risk for poor recovery outcomes. This approach may guide therapeutic interventions aimed at enhancing neurotrophic support, thereby improving functional recovery (14,16). Future research should focus on exploring the therapeutic applications of neurotrophic factors and their role in rehabilitation strategies, particularly the efficacy of neuroprotective agents in enhancing NGF and BDNF levels.

Conclusions

Taken together, this study emphasizes the importance of neurotrophic factors in predicting functional recovery in patients with AIS. The significant correlations between NGF and BDNF levels and clinical outcomes underline their potential utility as biomarkers in stroke management.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2231/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-24-2231/dss

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-2231/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was conducted in accordance with ethical principles and approved by the Expert Council of the Tashkent State Medical University (Conclusion No. 04-з/48, February 15, 2024). Informed consent was obtained from all participants prior to their inclusion in the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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