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Relationship Between Lymphocyte-Associated Inflammatory Markers and Post-Stroke Cognitive Impairment
Authors Hu QY, Liu J, Cui CH, Guo MF, Shi YT, Zhang XM, Jia BF, Li XY, Sun SJ
Received 10 June 2025
Accepted for publication 6 September 2025
Published 25 September 2025 Volume 2025:18 Pages 13347—13358
DOI https://doi.org/10.2147/JIR.S545953
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Professor Ning Quan
Qian-Ying Hu,1,* Juan Liu,1,* Cai-Hong Cui,1 Mei-Fang Guo,2 Yu-Tong Shi,2 Xiao-Man Zhang,2 Bing-Fei Jia,2 Xin-Yu Li,2 Su-Juan Sun3
1Department of Rehabilitation Medicine, Affiliated Hospital of Hebei University, Baoding, Hebei, 071000, People’s Republic of China; 2Department of Basic Medical Sciences, Hebei University, Baoding, Hebei, 071000, People’s Republic of China; 3Department of Nursing, Hebei General Hospital, Shijiazhuang, Hebei, 050000, People’s Republic of China
*These authors contributed equally to this work
Correspondence: Su-Juan Sun, Department of Nursing, Hebei General Hospital, No. 348 Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050000, People’s Republic of China, Tel +86 13933093071, Email sujuansunssjm@126.com Cai-Hong Cui, Department of Rehabilitation Medicine, Affiliated Hospital of Hebei University, No. 212 of Yuhua East Road, Lianchi District, Baoding, Hebei, 071000, People’s Republic of China, Tel +86 13463236473, Email caihongcuicchk@126.com
Objective: To determine whether differences in lymphocyte-related inflammatory markers in the ultra-early phase of stroke (within 24 hours of onset) are associated with post-stroke cognitive impairment in the early recovery phase (within 30 days of stroke onset), and to further assess the predictive value of these markers.
Methods: The study population consisted of patients who underwent rehabilitation treatment at the Rehabilitation Department of Hebei University Affiliated Hospital between December 2024 and June 2025, within 30 days of stroke onset, ie, during the early recovery phase of stroke. Patients were grouped based on whether they developed cognitive impairment. A retrospective analysis was conducted of patients’ blood markers and neurological deficit scores within 24 hours of stroke onset to examine the relationship between ultra-early blood markers and neurological deficits and post-stroke cognitive impairment.
Results: There were no significant differences in baseline data between the two groups. However, the proportion of hemorrhagic stroke patients was significantly higher in the PSCI group than in the non-PSCI group (39.7% vs 18.8%, P=0.026< 0.05). NLR and NIHSS scores showed significant differences between the two groups. Multivariate analysis indicated that NIHSS (OR=1.297, 95% CI: 1.167– 1.442, p< 0.001) was independently associated with PSCI, while NLR (OR=1.107, 95% CI: 0.995– 1.231, p=0.063) showed a borderline association with PSCI. MLR showed differences between the two groups in univariate analysis (P=0.018) but was excluded in multivariate analysis. ULR did not show significant differences.
Conclusion: NIHSS is a strong predictive factor (P < 0.05), with a cut of value of 12 calculated by the ROC curve. NLR is at the threshold for an independent risk factor. Subsequent ROC curves indicate that NLR has low diagnostic sensitivity but high specificity, making it more suitable for screening rather than diagnostic use. MLR and ULR did not demonstrate high predictive value; further studies should be conducted to expand the sample size, perform subgroup analyses, and increase follow-up.
Keywords: post-stroke cognitive impairment, NIHSS, NLR, MLR, ULR
Background
The 2020 China Stroke Report shows that the prevalence of stroke in China is 1,114.8 per 100,000 people, the annual incidence rate is 246.8 per 100,000 people, and the mortality rate is 149.49 per 100,000 people. China has become the country with the highest lifetime risk of stroke and the heaviest disease burden globally.1 Post-stroke cognitive impairment (PSCI) refers to a clinical syndrome characterized by cognitive impairment that occurs after a stroke event and persists for up to six months. According to literature reports, approximately one-third of stroke patients experience.2 The diagnosis of PSCI is typically based on clinical assessment, neuropsychological assessment, and neuroimaging. The Montreal Cognitive Assessment (MoCA) and the Mini-Mental State Examination (MMSE) are the most widely used cognitive tests in PSCI research.3 However, both are subject to copyright restrictions, which pose challenges for research. Meanwhile, the new cognitive test Mini-Cog, which is simple to administer and time-efficient, can aid in detecting the early stages of cognitive impairment. In a post-hoc analysis of a population-based study of older adults in the United States, the Mini-Cog scores classified as “possibly impaired” or “possibly normal” using the algorithm were comparable to those of the MMSE with a cutoff point of 25 in terms of sensitivity (76% vs 79%) and specificity (89% vs 88%) for dementia.-Cog, which was scored as “possibly impaired” or “possibly normal” by the algorithm, showed similar sensitivity (76% vs 79%) and specificity (89% vs 88%) for dementia compared to the MMSE with a cutoff point of 25. These results were comparable to those obtained using traditional neuropsychological assessments (sensitivity 75%, specificity 90%).4 A meta-analysis indicated that for cognitive impairment (including dementia and mild cognitive impairment) in primary care settings, Mini-Cog showed 73% sensitivity and 84% specificity. In secondary care settings, Mini-Cog showed 73% sensitivity and 76% specificity5 All performed well.
In addition to clinical examinations, neuropsychological assessments, and imaging studies, various blood biomarkers have become a focal point of research. By measuring indicators associated with brain injury in the early stages of stroke, it is possible to predict the occurrence of PSCI, which aids in the early identification of PSCI and facilitates further rehabilitation interventions. Inflammatory factors are closely associated with cognitive impairment. Clinically, lymphocyte-related inflammatory markers, such as the neutrophil-lymphocyte ratio (NLR), have been shown to have predictive value in a prospective cohort study of cognitive impairment following ischemic stroke. Peripheral NLR levels are significantly elevated in PSCI patients.3
Another inflammatory marker closely related to lymphocytes—the monocyte-to-lymphocyte ratio (MLR)—is more commonly used in the prediction of cardiovascular disease.6 The serum uric acid to lymphocyte ratio (ULR) has been validated as a new lymphocyte-related inflammatory marker with superior predictive value for hemorrhagic stroke compared to uric acid or lymphocyte levels alone in a large prospective cohort study conducted in China.7 This study was conducted to further clarify whether differences in inflammatory markers, especially lymphocyte-related inflammatory markers, in the ultra-early stage of stroke (within 24 hours of onset), including hemorrhagic stroke, are associated with post-stroke cognitive impairment in the early recovery stage (within 30 days of stroke onset).8
Research Methods
This study is a retrospective study targeting patients who underwent rehabilitation therapy at the Rehabilitation Department of Hebei University Affiliated Hospital between December 2024 and June 2025, specifically those within 30 days post-stroke, ie, in the early recovery phase of stroke. The study population was divided into an observation group (PSCI group) and a control group (non-PSCI group) based on the occurrence of cognitive impairment. A retrospective analysis was conducted of blood markers and neurological deficit scores within 24 hours of stroke onset, to investigate the relationship between ultra-early blood markers and neurological deficits and the occurrence of cognitive impairment after stroke.
Refer to previous literature,3 the inclusion criteria are as follows: (1) age ≥ 18 years; (2) confirmed by cranial computed tomography (CT) or magnetic resonance imaging (MRI);2 (3) Patients who have experienced a stroke within the past 30 days, are in the early stages of recovery, have stable conditions, are conscious, can speak fluently, and are able to cooperate with rehabilitation assessments and treatments; (4) Patients who visited the Department of Neurology, Department of Neurosurgery, Department of Critical Care Medicine, or other relevant departments at Hebei University Affiliated Hospital within 24 hours of experiencing a stroke, with complete clinical data and traceable medical records from within 24 hours of the onset of symptoms.
Refer to previous literature,3 the exclusion criteria are as follows: (1) Patients who had been diagnosed with cognitive impairment disorders prior to the stroke, including Alzheimer’s disease, frontotemporal dementia, Parkinson’s disease dementia, Lewy body dementia, mixed dementia, and other types of cognitive impairment or dementia caused by various reasons; (2) Patients unable to cooperate with cognitive function assessments, including those with severe aphasia, hearing impairments, dysarthria, impaired consciousness, visual impairments, or those unable to write normally due to limb dysfunction caused by stroke; (3) Patients with unstable conditions who are unable to cooperate with assessments and rehabilitation therapy, including but not limited to those with severe illnesses such as cardiovascular diseases (eg, severe heart failure, severe arrhythmias), renal diseases (eg, renal failure), pulmonary diseases (eg, severe pneumonia, respiratory failure), etc.; (4) Patients who had conditions prior to the stroke that could trigger inflammatory and immune responses (eg, acute infections, tumors, blood disorders, autoimmune diseases, recent major surgeries, or trauma); (5) Patients who had been taking medications that could interfere with the inflammatory and immune systems prior to the stroke (eg, antibiotics, corticosteroids, immunosuppressants, targeted therapies, etc).; (6) Patients with a history of recurrent strokes.
Based on the Mini-Cog score, patients were divided into a post-stroke cognitive impairment (PSCI) group and a group without post-stroke cognitive impairment. This study complies with the World Medical Association’s Declaration of Helsinki and has been approved by the Ethics Committee of Hebei University Affiliated Hospital (the Ethics Committee of Affiliated Hospital of Hebei University:HDFYLL - KY - 2024 - 120).
Data Collection
Baseline Characteristics
Age, sex, body mass index (BMI), educational attainment (elementary, middle school, university),smoking and alcohol use,were collected.
Clinical Variables
This included past medical history (including coronary heart disease, diabetes, and hypertension, the definition criteria are a previous clear diagnosis of a related disease and/or long-term use of therapeutic drugs prior to onset, stroke type (hemorrhagic or ischemic).
Observation Indicators
Extract and analyze medical records from the acute phase within 24 hours of onset, extracting data on neutrophils, lymphocytes, monocytes, and uric acid, and calculate NLR, MLR, and ULR. Uric acid levels were analyzed using the Fusion biochemical analyzer from Johnson & Johnson, and blood cell counts were measured using the XN-L™ Series blood analyzer from Sysmex Corporation. Stroke severity was assessed using the National Institute of Health Stroke Scale (NIHSS) to evaluate neurological deficit scores.9
Cognitive Function Assessment and Grouping
The official Chinese version of the Mini-Cog official website was used to assess the cognitive function of the patients, which was truncated into a control group (no cognitive impairment group) and an observation group (cognitive impairment group) with 4 points.
The sample size calculation formula is: 
where the expected prevalence rate (P) is 1/3 (33%) as described in the background section above, the confidence interval is 95%, and the allowable error is 0.1. The minimum sample size calculated is 85 cases, which will be assessed by therapists who are trained and proficient in using the Mini-Cog. A total of 127 cases were ultimately included in this study, 69 in the control group and 58 in the observation group.
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