Lipoprotein-associated phospholipase А 2  as a biomarker and potential therapeutic target in post-stroke cognitive impairment

Chandra Wirawan; Вираван Чандра; Desak Ketut Indrasari Utami; Утами Десак Кетут Индрасари; Agung Ayu Meidiary Anak; Анак Агунг Аю Мейдиари; I Wayan Widyantara; Видьянтара И Ваян; I Putu Eka Widyadharma; Видьядхарма И Путу Эка; Ketut Widyastuti; Видьястути Кетут

doi:10.17816/ACEN.1462

Lipoprotein-associated phospholipase А₂ as a biomarker and potential therapeutic target in post-stroke cognitive impairment

Authors: Wirawan C.¹^,2, Utami D.¹^,2, Anak A.¹^,2, Widyantara I.¹^,2, Widyadharma I.¹^,2, Widyastuti K.¹^,3
Affiliations:
1. Universitas Udayana
2. Prof. Dr. I.G.N.G. Ngoerah General Hospital
3. ьProf. Dr. I.G.N.G. Ngoerah General Hospital
Issue: Vol 20, No 2 (2026)
Pages: 70-76
Section: Reviews
Submitted: 15.12.2025
Accepted: 21.01.2026
Published: 30.06.2026
URL: https://annaly-nevrologii.com/pathID/article/view/1462
DOI: https://doi.org/10.17816/ACEN.1462
EDN: https://elibrary.ru/GTHLKV
ID: 1462

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Abstract

Post-stroke cognitive impairment (PSCI) is a major complication of cerebrovascular disease, spanning from mild cognitive impairment to dementia. PSCI pathogenesis involves complex mechanisms, including neuroinflammation, oxidative stress, and neuronal apoptosis. Recent studies have identified lipoprotein-associated phospholipase A₂ (LP-PLA₂) as a key enzyme in vascular inflammation and atherosclerosis, both of which are closely linked to post-stroke cognitive decline. LP-PLA₂ contributes to PSCI pathogenesis via several pathways: (1) promoting vascular injury and neurodegeneration via inflammatory lipid metabolites such as lysophosphatidylcholine; (2) impairing the blood-brain barrier, leading to increased permeability and amyloid-β accumulation; and (3) inducing calcium-dependent neuronal apoptosis through oxidized fatty acids like arachidonic acid. These processes reduce cognitive reserve and neuroplasticity, thereby accelerating cognitive decline in ischemic stroke survivors. In addition, elevated LP-PLA₂ levels have been associated with recurrent vascular events and unfavorable neurological outcomes, suggesting a role in ongoing post-stroke inflammation. Persistent activation of vascular inflammatory pathways may exacerbate cerebral small vessel disease, white matter damage, and synaptic dysfunction, which are critical determinants of long-term cognitive performance. The interaction between vascular injury and neurodegeneration further highlights the importance of inflammatory mediators in PSCI progression. Given its pathophysiological relevance, LP-PLA₂ holds promise as a diagnostic biomarker and a therapeutic target for mitigating cognitive deterioration after stroke.

Keywords

biomarkers, cognitive dysfunction, lysophosphatidylcholines, stroke

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Introduction

Ischemic stroke (IS) is defined as an episode of neurological dysfunction due to focal brain, spinal, or retinal infarction [1]. IS is the second leading cause of mortality worldwide, accounting for about 11.6% of all deaths [2]. Cerebrovascular disease (CVD) is the second leading cause of cognitive impairment [3]. Based on American Heart Association/American Stroke Association (AHA/ASA), PSCI (post-stroke cognitive impairment) is a type of cognitive impairment caused by stroke, ranging from mild cognitive impairment to dementia [4].

The PSCI prevalence varies among countries, with the highest prevalence of 72.7% in the Netherlands, about 58.5% in Australia, 55.3% in Singapore, and 45.3% in India. The lowest PSCI prevalence was found in Italy estimating about 19.1% [5]. The prevalence of PSCI in Indonesia was reported to be about 61.7% in 2013 [6].

Significant heterogeneity exists in the reported one-month PSCI incidence, largely attributable to varying deficit definitions and patient cohorts. Despite the inherent capacity of the brain for compensatory plasticity, which can facilitate initial cognitive gains, the predominant trajectory is stabilization of deficit and subsequent chronic cognitive deterioration [7]. Post-IS cognitive impairment is a critical determinant of patient outcomes. PSCI is associated with impaired daily living, which contributes to increased healthcare burden, including a higher rate of hospital readmissions. Furthermore, these patients experience poorer physical functional recovery, greater dependency, and a significantly reduced quality of life compared to those without cognitive deficits [8].

Lipoprotein-associated phospholipase A2 (LP-PLA₂) is an enzyme secreted by inflammatory cells, characterized by high sensitivity and specificity for detecting vascular inflammation. Studies have demonstrated that elevated levels of LP-PLA₂ are associated with increased vascular inflammation and atherosclerosis progression [9]. LP-PLA₂ (also known as platelet-activating factor acetylhydrolase (PAF-AH)) belongs to the calcium-independent group of phospholipase A₂ enzymes and is produced by various cell types, including both inflammatory cells (such as monocytes/macrophages and mast cells) and non-inflammatory cells (such as Kupffer cells, platelets, and erythrocytes) [10].

The pro-inflammatory products generated by LP-PLA₂ can cause death and dysfunction of endothelial cells. LP-PLA₂ plays a role in triggering cardio- and cerebrovascular diseases. Research has shown that LP-PLA₂ is a marker of oxidative stress and inflammatory responses, and an increased level of LP-PLA₂ raises the risk of cardio- and cerebrovascular diseases [11]. Epidemiological and experimental studies have shown that atherosclerosis and vascular disease are associated with a cognitive function decline [12]. Therefore, this literature review aims at highlighting the role of LP-PLA₂ in PSCI.

Post-Stroke Cognitive Impairment

PSCI is a concept that encompasses the entire spectrum from mild cognitive impairment to dementia caused by vascular abnormalities. PSCI is defined as a decline in cognitive function following a cerebrovascular event and is generally diagnosed within a period of 3 to 6 months after the event [13]. PSCI is characterized by persistent impairment in one or more cognitive domains, such as memory, attention, executive function, language, and visuospatial ability [3].

Non-modifiable risk factors for PSCI include genetic variations, age, and a previous history of stroke. Modifiable risk factors for PSCI include hypertension, smoking, atrial fibrillation (AF), type 2 diabetes mellitus (DM), and a sedentary lifestyle. Older age is associated with a more rapid decline in cognitive function after stroke. AF can increase the risk of brain ischemia or cerebral small vessel disease (SVD), as a result of microthrombi or hemodynamic challenges to cerebral autoregulation, which contribute to cognitive decline. Type 2 DM can worsen SVD and increase the incidence of brain ischemia, typically seen as lacunar infarcts. Temporal lobe atrophy is a strong risk factor for PSCI [14].

Several factors potentially triggering a decline in cognitive function in a damaged brain include the lesion severity, location, and the relationship between pre-existing brain pathology and the acute ischemic stroke event. The concepts of brain reserve and brain resilience, as well as the contributing factors, determine the degree of cognitive impairment in cases of stroke-related brain injury [4].

Brain reserve refers to the innate, quantitative capacity of the brain to tolerate abnormal damage before reaching a threshold for the clinical manifestation of the symptoms. It is a premorbid, passive model based on the anatomical and physiological features of the individual. This reserve is constituted by morphological metrics such as total brain volume, neuronal count, synaptic density, and the integrity of white matter tracts. An individual with high brain reserve, by virtue of greater neuronal and synaptic redundancy, may tolerate a larger volume of ischemic infarction with a lower likelihood of overt cognitive impairment. Conversely, an individual with diminished reserve, perhaps due to age-related atrophy or pre-existing microvascular disease, tends to demonstrate clinical deficits from a comparatively smaller lesion [15, 16].

Brain resilience, in contrast, denotes its active, adaptive capacity to maintain or restore cognitive and behavioral function in the face of adversity or following an acute stroke. It is a dynamic process that engages during post-stroke period. Resilience reflects functional and plastic capabilities of the neural system to compensate for damage. It is not merely the absence of pathology, but the positive adaptation of neurological systems to challenge. The principal mechanism underlying resilience is neuroplasticity, encompassing synaptic plasticity, functional reorganization, and axonal sprouting. Following a stroke, a highly resilient brain will effectively initiate these plastic mechanisms, leading to a more substantial and rapid functional recovery. A lack of resilience, even in the presence of substantial brain reserve, may result in a failure to improve and in chronic cognitive deterioration [17, 18].

The neurovascular unit (NVU) is a group of cells consisting of neurons, glia, vascular cells, pericytes, and the extracellular matrix (ECM). The NVU plays a crucial role in maintaining brain homeostasis. The cascade of ischemic damage — including energy failure due to disrupted blood flow, calcium accumulation, oxidative stress, and blood-brain barrier (BBB) dysfunction — leads to NVU impairment and results in neurological deficits. Structural damage to the NVU caused by ischemic stroke can lead to PSCI [4, 13]. Disruption of the BBB leads to hypoperfusion and contributes to the accumulation of amyloid-β in the brain parenchyma, triggering a neuroinflammatory response. The mechanism of recruitment of local and systemic immune cells to the lesion area causes irreversible astrocyte damage and gliovascular disruption in the frontal white matter, initiating PSCI. Additionally, the complement system activated by IS functions in tissue repair but also plays a role in triggering an inflammatory response. This reduces neuroplasticity and results in a poorer cognitive prognosis [13].

The signaling pathways between neurons, astrocytes, and blood vessels are disrupted. Therefore, the brain loses its ability to dynamically increase blood flow to regions engaged in cognitive tasks. This vascular steal phenomenon means that active neurons, particularly in peri-infarct areas and connected networks, are functionally silenced due to inadequate energy supply. This directly manifests as cognitive decline in domains like attention, processing speed, and executive function. Moreover, chronic global or regional hypoperfusion creates an energy crisis, depriving the brain of the fuel necessary for both baseline function and the high-energy demands of repair and plasticity. This ongoing ischemia further damages white matter tracts, leading to network disconnection and eroding brain reserve [19, 20].

The glymphatic pathway is a brain waste clearance system that facilitates the circulation of cerebrospinal fluid (CSF) through the brain parenchyma. In mice, microinfarcts can rapidly reduce CSF flow throughout the brain and lead to debris accumulation in the tissue. Research findings indicate that small, scattered ischemic lesions can disrupt the glymphatic pathway and trap interstitial solutes within the brain parenchyma, thereby increasing the risk of amyloid plaque formation [13]. In addition, the IS and subsequent neuroinflammation cause astrocyte reactivity and dysfunction. A critical consequence is the mis-localization or downregulation of aquaporin-4 channels. Instead of being densely concentrated on the end-feet facing the vessels, they become dispersed over the entire astrocyte membrane. Thus, this loss of polarity severely impairs the convective influx of CSF into the brain parenchyma. Without this driving force, the glymphatic flow stagnates, and waste clearance is dramatically reduced [21]. Furthermore, the acute IS phase involves cytotoxic edema, which physically compresses the narrow perivascular spaces (Virchow–Robin spaces) through which CSF must flow. This obstruction prevents the entry of clean CSF and the exit of waste-laden fluid, leading to a logjam of toxic metabolites [22].

Lipoprotein-Associated Phospholipase A2

LP-PLA₂ is an enzyme involved in the development of atherosclerosis [23]. Approximately 80% of this enzyme is bound to LDL, and LDL is converted into oxidized LDL through various mechanisms after accumulating in the arterial wall of the subintimal layer. LP-PLA₂ specifically hydrolyses phosphatidylcholine into oxidized fatty acids and lysophosphatidylcholine (LPC) [24]. These pro-inflammatory products play an important role in endothelial dysfunction and plaque formation. The involvement of this lipoprotein as a proactive trigger in the inflammatory and atherosclerotic process is a major factor contributing to dementia [25]. Several hypotheses have been proposed to explain how LP-PLA₂ contributes to PSCI. Firstly, as an indicator of inflammation, LP-PLA₂ may lead to cognitive decline by promoting vascular injury and neurodegeneration, ultimately diminishing the brain’s cognitive reserve. Secondly, the inflammatory response triggered by LP-PLA₂ can compromise the BBB integrity, resulting in an increased vascular permeability. Lastly, LP-PLA₂ is thought to play a role in cognitive impairment by affecting key dementia-related molecules, such as amyloid-β and tau [9].

LP-PLA₂ impacts both brain reserve by contributing to the silent, pre-stroke accumulation of pathology, and brain resilience by influencing the inflammatory milieu critical for post-stroke recovery. LP-PLA₂ actively undermines this reserve by promoting two key pathological processes: chronic cerebral SVD and covert vascular brain injury. These bioactive products perpetuate a localized cycle of vascular inflammation, attracting monocytes, impairing endothelial function, and promoting smooth muscle cell apoptosis. This leads to the BBB destruction, increased vessel wall permeability, and chronic hypoperfusion. Over time, this low-grade, LP-PLA₂-driven vasculopathy manifests as white matter hyperintensities, cerebral microbleeds, and lacunar infarcts — the hallmarks of SVD. These lesions represent a direct, silent erosion of the brain structure (neurons, axons, and synapses), thereby diminishing brain reserve [26, 27].

Following an acute stroke, a well-orchestrated inflammatory response is necessary for clearing debris and initiating repair. However, a pre-existing or persistent state of LP-PLA₂-mediated inflammation can dysregulate this response. The pro-inflammatory mediators produced by LP-PLA₂ activity can directly inhibit mechanisms of synaptic plasticity, such as long-term potentiation, which is the cellular basis for learning, memory, and functional reorganization. In addition, this chronic inflammatory milieu is detrimental to neurogenesis and oligodendrocyte progenitor cell maturation. It creates an environment that hampers the innate ability of the brain cellular components to rewire circuits around the lesion. Furthermore, in the chronic stroke, continued LP-PLA₂ activity can contribute to ongoing white matter damage and network disruption, further impeding the functional connectivity required for cognitive recovery. Therefore, high LP-PLA₂ activity after an ischemic stroke can compromise brain resilience by stifling the plastic and reparative processes [27, 28].

The LPC and oxidized fatty acids produced by LP-PLA₂ act as damage-associated molecular patterns that activate the NVU resident immune sentinels [20]. Increased LPC levels enhance the expression of adhesion molecules, stimulate pro-inflammatory cytokines (TNF-α and IL-6), and attract macrophages to the arterial intima. This leads to endothelial dysfunction, accelerates plaque formation, and results in the development of necrotic areas [25]. The atherosclerotic process contributes to the formation of amyloid-β in the brain, which is a key factor in the development of dementia [9]. Pericytes, crucial for capillary stability and BBB integrity, are highly susceptible to LPC-induced apoptosis and contraction, leading to capillary destabilization. This sustained assault on the BBB cellular components results in a leaky BBB, allowing neurotoxins, inflammatory cells, and other blood-derived factors to enter the brain parenchyma post-stroke. This perpetuates a cycle of inflammation and neuronal damage, directly undermining brain resilience [19].

Endothelial dysfunction, vascular inflammation, and atherosclerosis lead to stiffened, less compliant arteries. Reduced arterial pulsatility weakens the essential hydraulic force that drives CSF into and through the perivascular spaces [29]. The pro-inflammatory state induced by LP-PLA₂ products triggers astrocyte reactivity. Reactive astrocytes often undergo a loss of aquaporin-4 polarity, dispersing the channels from the end-feet to the rest of the cell membrane. This mislocalization severely impairs the convective influx of CSF from the perivascular space into the brain interstitium [21, 30].

LP-PLA₂ metabolites also disrupt the vasoactive signaling pathways. LPC inhibits endothelial nitric oxide synthase, reducing the production of the potent vasodilator nitric oxide. This leads to endothelial dysfunction and impaired vasodilation. In astrocytes, the ability to relay vasodilatory signals from neurons to vascular smooth muscle cells is compromised. Therefore, active brain regions involved in cognitive tasks fail to receive an adequate blood supply. This vascular uncoupling results in a functional hypoperfusion, effectively silencing neural networks and manifesting as cognitive deficits in attention, processing speed, and executive function [20, 31]. In neuronal cells, an excess of oxidized fatty acids (primarily arachidonic acid) triggers neuronal cell depolarization through calcium-dependent apoptosis. Arachidonic acid can also be converted into prostaglandins, which are inflammatory mediators involved in the etiopathogenesis of neurodegenerative diseases. Additionally, the hydrolysis by LP-PLA₂ increases the expression of TNF-α, a key cytokine that affects hippocampal neuroplasticity [12].

Conclusion

LP-PLA₂ is a central mechanistic player in the development and progression of PSCI. Its role can be understood through a dual impact on both brain reserve and brain resilience. Prior to IS, LP-PLA₂ actively erodes brain reserve by driving a chronic, subclinical inflammation that promotes cerebral SVD, covert vascular brain injury, and atherosclerosis. This silent accumulation of pathology diminishes the brain integrity, making it more vulnerable to the impact of acute IS. Following IS, LP-PLA₂ undermines brain resilience by perpetuating a harmful inflammatory milieu that disrupts critical recovery processes. It contributes to BBB dysfunction, impairs neurovascular coupling, and stifles the neuroplasticity essential for functional reorganization and cognitive recovery. Furthermore, by promoting astrocyte dysfunction and aquaporin-4 mislocalization, LP-PLA₂ impedes the glymphatic system’s waste-clearance function, potentially leading to the accumulation of toxic metabolites like amyloid-β. Therefore, elevated LP-PLA₂ represents a significant biological link between vascular injury and cognitive decline. It creates a pre-stroke brain that is more susceptible to damage and a post-stroke environment that is less conducive to repair. Targeting the LP-PLA₂ pathway may hold promise not only for primary IS prevention but also as a therapeutic strategy to preserve cognitive function and enhance recovery in stroke survivors.

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