Neutrophil gelatinase-associated lipocalin as a biomarker for neuropsychiatric complications in acute ischemic stroke

Abstract

This study evaluates the findings of Gu et al, who investigated the role of neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for predicting neuropsychiatric complications in acute ischemic stroke (AIS) patients. The results revealed that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment, anxiety, and depressive symptoms at discharge. The study analyzed 150 AIS patients (mean age 65.4 years, 58% male) using the Mini-Mental State Examination and the Hospital Anxiety and Depression Scale to assess neuropsychiatric outcomes. Multivariate analysis demonstrated that higher NGAL levels were independent predictors of cognitive impairment [odds ratio (OR) = 1.42], anxiety (OR = 1.28), and depression (OR = 1.39). Notably, NGAL exhibited strong predictive power for cognitive impairment, with an area under the curve of 0.78. Despite these promising findings, NGAL’s clinical utility is limited by its non-specificity across various conditions. Nevertheless, NGAL levels could help identify AIS patients at risk for neuropsychiatric complications, enabling timely intervention and comprehensive neuropsychiatric evaluation. The study emphasizes the need for further research to validate NGAL’s predictive accuracy and specificity in diverse AIS populations and advocates for its integration with other diagnostic modalities to enhance clinical decision-making.

Key Words: Acute ischemic stroke; Neutrophil gelatinase-associated lipocalin; Neuropsychiatric complications; Cognitive impairment; Neuroinflammation; Anxiety; Depression; Biomarkers

Core Tip: This study investigates neutrophil gelatinase-associated lipocalin (NGAL) as a potential biomarker for neuropsychiatric complications in patients with acute ischemic stroke. Gu et al demonstrate that elevated NGAL levels at admission are associated with a higher risk of cognitive impairment, anxiety, and depression. These findings are significant because such conditions, often overlooked, substantially impact post-stroke recovery and quality of life. This research broadens the understanding of NGAL’s functions beyond its established role as a biomarker for early kidney injury, emphasizing its relevance in neuroinflammation and neuropsychiatric processes.

TO THE EDITOR

The recent study by Gu et al[1] provides important insights into the role of neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for neuropsychiatric complications in patients with acute ischemic stroke (AIS). The findings indicate that elevated serum NGAL levels at admission are associated with a higher risk of cognitive impairment, anxiety, and depressive symptoms, supporting the potential for early identification and management of these usually under-recognized post-stroke conditions. This research extends the understanding of NGAL beyond its established role as a biomarker of early kidney injury[2], highlighting its involvement in neuroinflammation and neuropsychiatric processes.

Gu et al’s study[1] emphasized the identification and severity of self-reported neuropsychiatric symptoms rather than formal psychiatric diagnoses. The study included a cohort of 150 patients with AIS, with an average age of 65.4 years and 58% of the participants being male. The median National Institutes of Health Stroke Scale (NIHSS) score at the time of admission was 6, reflecting moderate stroke severity. Cognitive impairment was assessed at discharge (approximately 7-10 days post-admission) using the Mini-Mental State Examination, with scores ≤ 24 considered indicative of impairment. Symptoms of anxiety and depression were assessed at discharge using the Hospital Anxiety and Depression Scale. This scale includes two subscales, one for anxiety and another for depression, each consisting of seven items scored on a four-point Likert scale. Clinically significant anxiety or depressive symptoms were defined by subscale scores ≥ 8.

At discharge, 34.7% of patients demonstrated cognitive impairment, 28.0% experienced anxiety, and 32.0% exhibited depressive symptoms. Patients who developed cognitive impairment, anxiety, or depressive symptoms had significantly higher serum NGAL levels at admission, with median values of 5.6 ng/mL compared to 3.2 ng/mL for cognitive impairment, 5.1 ng/mL vs 3.5 ng/mL for anxiety, and 5.4 ng/mL vs 3.3 ng/mL for depressive symptoms. Multivariate analysis revealed that elevated serum NGAL was independently associated with increased risks of cognitive impairment [odds ratio (OR) = 1.42], anxiety (OR = 1.28), and depressive symptoms (OR = 1.39), after adjusting for potential confounders. Receiver operating characteristic curve analysis revealed that NGAL exhibited strong predictive accuracy for cognitive impairment with an area under the curve (AUC) of 0.78 and showed moderate predictive capability for anxiety (AUC = 0.67) and depressive symptoms (AUC = 0.71).

POTENTIAL OF NGAL AND CHALLENGES IN IMPLEMENTATION

Biomarkers play a crucial role in the diagnosis, prognosis, and therapeutic monitoring of numerous conditions. In AIS, biomarkers such as C-reactive protein, P-selectin, fibrinogen, glutamate, and D-dimers have been associated with diagnostic accuracy, prognostic assessments, and inflammatory processes[3]. However, the association between biomarkers and neuropsychiatric complications following stroke remains poorly understood. The study by Gu et al[1] provides valuable insights by evaluating NGAL, a protein involved in inflammation, oxidative stress, and tissue injury, as a potential biomarker for AIS-related neuropsychiatric outcomes. The authors performed a thorough evaluation of cognitive function and mood symptoms using validated assessment tools, while adjusting for various potential confounding factors. These included demographic variables (age, sex), lifestyle and anthropometric factors (body mass index, smoking status), clinical comorbidities (such as hypertension, diabetes, dyslipidemia, and prior stroke), and stroke severity (NIHSS score at admission) in their multivariate analyses. Additionally, receiver operating characteristic curve analysis was used to assess the discriminative power of serum NGAL levels.

The findings indicate that NGAL demonstrates good discriminative ability in predicting neuropsychiatric outcomes following AIS. If validated in larger, multicenter studies, NGAL testing could be incorporated into routine clinical protocols for stroke prognosis. The use of NGAL levels for risk stratification aligns with the principles of personalized medicine, enabling healthcare providers to tailor interventions according to an individual’s risk profile. Despite its potential, several challenges hinder the immediate clinical application of NGAL. First, the study evaluated neuropsychiatric outcomes only at discharge (7-10 days post-stroke), limiting its utility in predicting long-term complications. Neuropsychiatric symptoms frequently manifest over weeks to months, leaving NGAL’s role as a long-term prognostic biomarker unproven[4,5]. Second, the study did not compare NGAL’s predictive performance with other established stroke biomarkers or clinical predictors, such as C-reactive protein, NIHSS scores, or neuroimaging findings[1]. Without demonstrating a clear advantage over existing tools, NGAL’s unique clinical utility remains uncertain. Additionally, the single-center design and relatively small sample size (150 patients) raise concerns regarding the generalizability of the findings.

CLINICAL IMPLICATIONS

NGAL demonstrates multifaceted utility as a biomarker, extending beyond stroke to include well-established roles in heart failure and acute kidney injury (AKI). Its versatility spans various age groups and clinical scenarios, including contrast-induced AKI, kidney transplant rejection, and chronic heart failure[6]. In cardiovascular diseases, elevated NGAL levels are associated with adverse outcomes in heart failure patients and correlate with the severity of both cardiac dysfunction and renal impairment[7]. This association is particularly relevant given that heart failure and acute myocardial infarction “conditions characterized by elevated NGAL” are major risk factors for stroke[8,9]. Furthermore, NGAL’s upregulation in ischemic brain tissue suggests its involvement in the biological mechanisms underlying post-stroke cognitive and emotional impairments. Notably, in late-life depression, elevated NGAL levels have been linked to depressive disorders, particularly recurrent episodes[10]. Mechanistically, these associations are thought to involve inflammation, microglial activation, and reactive astrocytosis in the brain[11]. Interestingly, the association between NGAL levels and cognitive domains seems to differ by sex: In women, elevated NGAL levels are linked to poorer verbal memory and slower processing speed, whereas in men, they correlate with poorer interference control and executive functioning. These findings indicate that NGAL may serve as a biomarker for cognitive impairment in AIS and late-life depression, with implications for sex-specific cognitive outcomes. Early identification of patients at risk for cognitive impairment, anxiety, or depression through NGAL measurement could facilitate targeted interventions, including neuroprotective therapies and cognitive rehabilitation programs.

Despite its promise as a biomarker and potential therapeutic target, challenges remain in improving the clinical utility of NGAL. One major limitation is its lack of specificity, as NGAL levels increase in a range of conditions beyond neuropsychiatric complications associated with AIS, including AKI, cardiovascular diseases, cancers, and chronic kidney disease. NGAL’s expression across diverse cell types and pathological states-such as infection, inflammation, and ischemia-complicates its interpretation when used as a standalone biomarker[11]. For instance, in AKI, NGAL is rapidly released following tubular necrosis and can be detected in both blood and urine, serving as an early indicator of kidney injury. However, its diagnostic utility is constrained by the existence of multiple molecular forms and the lack of standardized testing methods. Ronco et al[12] in 2012 propose that employing a more comprehensive NGAL monitoring approach, such as extended-range assays to track temporal changes rather than relying on single measurements, may enhance its diagnostic value.

The observation by Gu et al[1] of elevated NGAL levels in AIS patients with cognitive decline suggests a systemic inflammatory response potentially driven by the release of pro-inflammatory cytokines and chemokines. This underscores the need for further research to delineate NGAL’s role across various conditions. Moreover, post-stroke neuropsychiatric complications are influenced by multiple biological pathways, including neuroinflammation, oxidative stress, and neurotransmitter dysregulation. Thus, relying on NGAL as a sole biomarker may not adequately capture the complexity of these conditions. A more effective strategy may involve combining NGAL with other biomarkers and clinical factors, such as stroke severity and neuroimaging findings. For example, integrating NGAL measurements with advanced imaging modalities, including diffusion tensor imaging and functional magnetic resonance imaging, could enhance the predictive accuracy for identifying patients at risk of neuropsychiatric complications. Such a multimodal approach underscores the importance of employing diverse diagnostic tools to improve risk stratification and patient prognosis.

FUTURE DIRECTIONS AND RESEARCH OPPORTUNITIES

To facilitate the clinical translation of findings from Gu et al[1], further research is required to validate NGAL as a biomarker across diverse AIS patient populations. Key factors such as age, comorbidities, and stroke severity may influence NGAL levels and their association with neuropsychiatric outcomes. Additionally, investigating the temporal dynamics of NGAL levels, particularly through extended follow-up periods, is critical. The present study was limited to the acute phase of AIS, with cognitive and mood assessments conducted at discharge (7-10 days post-admission). Future studies should include longitudinal follow-up, with evaluations at multiple intervals, such as 3 months, 6 months, and 12 months after a stroke, to elucidate the relationship between NGAL levels and the progression of neuropsychiatric complications over time.

An important avenue for further investigation is the specificity of NGAL as a biomarker. Although serum NGAL has been shown to be elevated in ischemic stroke patients, its clinical utility may be limited by its lack of specificity, given its involvement in other pathological conditions such as cardiovascular disease[6]. Measuring cerebrospinal fluid (CSF) NGAL levels, particularly in animal models of stroke, could provide a more direct assessment of neuroinflammatory processes within the central nervous system and enhance the biomarker’s specificity for post-stroke neuropsychiatric complications. Prior studies, including those in canine models, have reported elevated CSF NGAL levels in neuroinflammatory diseases, suggesting that CSF NGAL may better reflect neuroinflammatory activity within the brain[13].

Large-scale, multicenter trials with extended follow-up periods are needed to confirm the prognostic value of NGAL for neuropsychiatric outcomes in AIS. Experimental studies exploring the mechanistic links between NGAL, neuroinflammation, and neuropsychiatric symptoms could also provide valuable insights into potential therapeutic strategies. Furthermore, determining whether interventions to lower NGAL levels might mitigate the incidence or severity of post-stroke cognitive and emotional impairments represents a critical step toward clinical application. Finally, the single-time-point measurement of NGAL in this study, performed at admission, may not fully capture its temporal variations. Serial measurements throughout the post-stroke recovery period could provide a more comprehensive understanding of NGAL’s role in predicting neuropsychiatric outcomes and enhance its utility as a clinical biomarker.

CONCLUSION

The study by Gu et al[1] highlights the potential of NGAL as a biomarker for AIS management, presenting a novel approach to identifying post-stroke neuropsychiatric symptoms. While the findings are promising, NGAL’s clinical application is limited by its lack of specificity, as elevated levels may also be observed in conditions such as AKI, heart failure, and systemic inflammation. To enhance its clinical relevance, further research is necessary to validate NGAL in diverse AIS patient populations and to assess its integration with other diagnostic modalities, including neuroimaging and complementary biomarkers, to improve diagnostic accuracy.