Glucose is the primary form of carbohydrate utilized by the human body after metabolic conversion, and it is primarily metabolized through aerobic oxidation, glycolysis, and the pentose phosphate pathway (15). In the brain, glucose and oxygen levels are crucial for the growth and function of neurons (16, 17). When IS occurs, cerebral blood flow is interrupted, blocking the transportation of oxygen and nutrients (such as glucose and vitamins). As a result, glucose metabolism shifts from aerobic to anaerobic pathways. This shift reduces ATP production, increases lactate production, inhibits the tricarboxylic acid cycle, and disrupts cerebral homeostasis (18, 19). Both glucose and lactate serve as energy substrates for various types of memory neurons (20), with lactate being essential for cognitive tasks that require high attention and corresponding hippocampal enhancement in vivo. Anaerobic glycolysis can benefit cognitive ability by supporting energy production (20). However, during IS, reduced cerebral perfusion and impaired glucose transport (21), lead to the inhibition of both aerobic and anaerobic glycolysis, which in turn impairs the energy supply to memory neurons and contributes to cognitive dysfunction.

The pentose phosphate pathway (PPP) is a branch of glucose metabolism that produces ribose 5-phosphate (R-5-P) and nicotinamide adenine dinucleotide phosphate (NADPH) (22). During the acute phase of cerebral ischemia-reperfusion, glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the PPP pathway, can be activated by ataxia telangiectasia mutated (ATM) kinase. This activation occurs through the phosphorylation of serine 85 (S85) on heat shock protein 27 (HSP27), which in turn initiates the body’s antioxidant protection mechanisms (23). Therefore, the PPP pathway is activated following cerebral ischemia (19). R-5-P and NADPH are essential for the synthesis of nucleic acids in the body and play significant roles in protein synthesis and translation. Memory is closely linked to both protein synthesis and degradation, and cognitive dysfunction can occur when these processes are dysregulated (24) Consequently, patients with PSCI may experience disorders in the PPP pathway, leading to an imbalance between protein synthesis and degradation (25), resulting in cognitive dysfunction.

Glycogen is a branched-chain polymer of glucose that plays a major role in energy storage in eukaryotes. Glycogen synthase (GS) is a key enzyme in glycogen synthesis, while glycogen phosphorylase (GP) is a key enzyme in glycogenolysis (26, 27). GS activity is regulated by the dephosphorylation of glucose 6-phosphate (G6P) and the inhibition of its phosphorylation. In the brain, GS is activated in astrocytes following IS through a cascade involving protein kinase A (PKA), glycogen phosphorylase kinase (PhK), and glycogen phosphorylase (GP). The activation of glycogen synthase kinase-3β (GSK3β) also contributes to the accumulation of glycogen by inactivating PhK and GP (28). This accumulation of glycogen inhibits glycogen breakdown and the supply of energy to the brain during acute cerebral ischemia, which can lead to cognitive impairment.

Glycolysis mainly refers to the metabolic process of synthesizing glucose from non-sugar substances such as amino acids, pyruvate, and glycerol in the body. Glucose-6-phosphatase, fructose diphosphatase-1, pyruvate carboxylase, and phosphoenolpyruvate carboxylase are the key enzymes in the process of gluconeogenesis, and gluconeogenesis may be altered when the activity of any of them is affected (29). Animal studies found that during the acute phase of IS, rats had elevated fasting glucose and insulin levels and up-regulated expression of hepatic gluconeogenesis genes, including phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and fructose-1,6-bisphosphatase, and hepatic gluconeogenesis-associated positive regulators, which suggests that IS may promote gluconeogenesis through activation of the key gluconeogenic enzymes and regulators, and make up in vivo for the organism’s missing energy for anaerobic glycolytic metabolism (30). The body’s physiological concentration of blood glucose fluctuates within a certain range and is regulated by glycogen synthesis and catabolism, and it has been found that patients with IS tend to be hyperglycemic (31), and they may have disorders of glucose metabolism. Hyperglycemia may lead to insulin resistance (32) and atherosclerosis (33), both of which are closely related to cognitive impairment (34, 35). Specific metabolic changes are shown in Figure 1 .

Blood glucose is the amount of glucose in the blood, and it is an important indicator for assessing the normalcy of glucose metabolism (36). Hyperglycemia has been found to occur after IS in most patients in the absence of diabetes (37, 38), which is an independent risk factor for cognitive dysfunction 6 months after IS and can be used as a predictor of PSCI at 3 months (39, 40). The body experiences stress-responsive elevation of glucose after IS, and in the state of ischemia and hypoxia, the anaerobic fermentation of glucose is accelerated, and the level of lactic acid rises markedly, causing acidosis. Acidosis further promotes biochemical changes in the ischemic area, exacerbates cerebral tissue hypoxia and edema, and leads to enlargement of the infarct foci (41). In addition, hyperglycemia attenuates the therapeutic effect of early tissue plasminogen activator (IV-tPA) in patients with IS and contributes to the alteration of blood-brain screen permeability in the context of tPA (42, 43), both of which cause cognitive dysfunction.

Glycosylated hemoglobin (HbA1c) is formed when hemoglobin in red blood cells combines with sugars, primarily glucose, in serum through a non-enzymatic reaction (44). A nonlinear relationship between HbA1c and PSCI was found to exist 3-6 months after IS, with a positive correlation between HbA1c and PSCI when HbA1c was greater than 8.2% and a 0.96-fold increase in the risk of PSCI for every 1% increase in HbA1c (45). A cohort study found that HbA1c was an independent risk factor for cognitive impairment 6-12 months after acute mild IS (46). Xu et al. suggested that cognitive impairment was associated with insulin dysregulation and increased expression of insulin-degrading enzymes (45). Gong et al. found that serum HbA1c had a sensitivity and specificity of 67.9% and 82.8%, respectively, with an AUC of 0.829 for predicting the development of PSCI 6-12 months after stroke (46), and the relationship between glycated hemoglobin and PSCI should be further explored in the future.

Lipid diets are an essential source of energy and nutrition in human life, and they play an important role in the prevention or treatment of chronic diseases (47). Some studies have reported that saturated fatty acids help improve memory and exogenous fatty acids slow cognitive decline (48, 49). Currently, omega-3 and omega-6 fatty acids are used in the clinical treatment of patients with cognitive impairment (50). The metabolism of lipids in the human body is mainly a process of fatty acid synthesis and fatty acid β-oxidation (51). In organisms, acetyl coenzyme A, ATP, and NADPH are involved in fatty acid synthesis as raw materials, in which acetyl coenzyme A needs to be transferred from mitochondria to the periplasm to generate fatty acids through the citric pyruvate cycle, and acetyl coenzyme A carboxylase is the key enzyme in this synthesis pathway, and the enzyme loses its activity after phosphorylation and glucagon and epinephrine can make the enzyme phosphorylated to be ineffective, while insulin can Insulin enhances the enzyme activity to promote fatty acid synthesis. After IS, due to hypoxia, the glucose metabolic pathway is shifted to anaerobic glycolysis, ATP and acetyl coenzyme A production is reduced, and the tricarboxylic acid cycle is inhibited (30), which may hinder fatty acid synthesis by reducing the raw materials for fatty acid synthesis. In addition, it has been found that acute events of stroke cause activation of the hypothalamic-pituitary-adrenal (HPA) axis (52), the elevation of cortisol and glucagon, which in turn may prevent fatty acid synthesis by phosphorylating acetyl coenzyme A carboxylase. In summary, fatty acid synthesis may be inhibited after the onset of IS.

Fatty acid β-oxidation (FAO) consists of three major steps: activation of fatty acids, transfer of lipoyl CoA, and β-oxidation of lipoyl CoA. The activation phase is catalyzed by lipoyl CoA synthetase located in the endoplasmic reticulum and the outer mitochondrial membrane in the presence of ATP, CoA-SH, and Mg²⁺ to generate lipoyl CoA, and the activated lipoyl CoA has to be transferred to the mitochondria with the help of carnitine-lipoyltransferase 1 (the key enzyme). After entering the mitochondrial matrix, lipoyl CoA undergoes a biochemical reaction catalyzed by the fatty acid β-oxidation enzyme system while releasing a large amount of energy, and carnitine lipoyltransferase 1 is the key enzyme in the process of β-oxidation (53). In the vigorous glucose metabolism, acetyl CoA, citrate increase can allosterically activate acetyl CoA carboxylase, promote malonate monoacyl CoA synthesis, and competitively inhibit carnitine lipoyltransferase 1. Post-stroke inhibition of aerobic oxidation, weakening of glucose metabolism, inhibition of the tricarboxylic acid cycle, and reduction of the production of acetyl CoA, citrate, etc. (30) may lead to a reduction in malonic acid monoacyl CoA synthesis, and a decrease of competitive inhibition, and therefore may enhance fatty acid beta-oxidation. Thus it may lead to enhanced fatty acid β-oxidation.

Animal studies have shown that reduced peroxisomal β-oxidation enhances amyloid-β production and leads to spatial memory deficits in diabetic rats through oxidative stress (54). Peroxisome proliferator-activated receptor α (PPARα) is a key transcription factor involved in fatty acid oxidation. It facilitates the transfer of fatty acids into mitochondria for oxidation. In postoperative cognitive dysfunction (POCD) mice, pretreatment with the PPARα agonist FF prevents long-term isoflurane anesthesia-induced POCD by enhancing fatty acid oxidation (55). Similarly, it was found that SUL-138 increased the levels of proteins involved in fatty acid degradation and oxidation, improving cognitive function in both wild-type and APP/PS1 mice (56). Furthermore, fatty acid β-oxidation generates a significant amount of energy for the organism, suggesting that it may contribute to the protection of cognitive function after IS. However, due to the inhibition of fatty acid synthesis following stroke, the corresponding β-oxidation may also be suppressed, thereby losing its protective effect and potentially leading to cognitive dysfunction. Specific metabolic changes are depicted in Figure 2 .

Triglycerides (TGs) are an efficient source of energy in the body (57). Both fasting triglycerides (FTGs) and non-fasting triglycerides (NFTGs) levels were found to be elevated after IS (58). Triglycerides may promote amyloid-β (Aβ) protein deposition by affecting membrane fluidity and by acting as a carrier for Aβ-protein aggregation, thereby influencing Aβ aggregation kinetics (59). Aβ-protein deposition has also been observed in the brains of IS patients during autopsy (60). Aβ-protein can disrupt cerebrovascular homeostasis by directly interacting with blood-brain barrier (BBB) cellular components or by promoting neuroinflammation, which increases BBB permeability (61, 62). Studies have shown that increased BBB permeability can lead to cognitive dysfunction (63).

Triglycerides (TGs) circulate in the blood as triglyceride-rich lipoproteins (TRL). When circulating TG levels are elevated, TRL and their residual particles can accumulate in the plasma, penetrate the intimal layer of the artery, and, once embedded in the subendothelium, TRL can be scavenged by resident macrophages. This contributes to the formation of foam cells and the progression of atherosclerotic disease (64, 65). Additionally, TRL remnants, although larger than low-density lipoproteins (LDL), are smaller than their natural counterparts—very low-density lipoproteins (VLDL) and chylomicrons. These remnants are relatively cholesterol-rich and can enter the arterial wall, where they are ingested by macrophages, leading to cholesterol accumulation in atherosclerotic lesions (57, 66). Atherosclerosis may cause cognitive impairment through chronic cerebral underperfusion and cerebral embolism (35). Cheng et al. found that a high triglyceride-to-glucose ratio on admission was associated with cognitive impairment and was able to predict the occurrence of PSCI after 3 months (67, 68). In a Meta-analysis study by Kim et al., triglycerides were also recommended as a potential metabolic marker for PSCI (69). Feng et al. used recombinant human growth hormone to treat patients with PSCI, which significantly reduced triglyceride levels and improved Moca scores in patients (70). Future studies should be conducted on triglycerides to explore their up-to-value as a biomarker for PSCI.

Low-density lipoprotein (LDL) is the end product of lipoprotein degradation and is closely associated with cardiovascular disease (71). Numerous studies have found that high LDL levels cause cognitive dysfunction (72, 73), and LDL levels tend to be elevated in patients with IS (74). Jurcau et al. reported that LDL is associated with PSCI (75), but other studies have found no correlation between LDL and cognitive decline in stroke (76, 77). The relationship between LDL and cognitive impairment remains inconclusive and requires further investigation. Atherosclerosis (AS), a high-risk factor for IS, involves LDL in its atherogenic processes. While natural LDL does not exert atherogenic mechanisms in vitro, it is modified to oxidized LDL (Ox-LDL) under oxidative stress. Ox-LDL can promote atherosclerosis by reducing nitric oxide (NO) production and antioxidant enzymes, which impair endothelial integrity (78). Furthermore, atherosclerosis itself can contribute to cognitive dysfunction (35). Feng et al. treated PSCI patients with recombinant human growth hormone, which significantly reduced LDL levels and improved MOCA scores (70).

Non-HDL cholesterol (non-HDL-C) refers to the sum of cholesterol contained in lipoproteins other than HDL, primarily including low-density lipoprotein cholesterol (LDL-C) and very low-density (79). lipoprotein cholesterol (VLDL-C) levels of non-HDL-C lipoproteins in IS are associated with more severe cognitive dysfunction, showing a positive correlation between the two (80). Similarly. reported that elevated serum non-HDL-C levels significantly increase the risk of cognitive dysfunction following acute ischemic stroke (AIS). They suggested that serum non-HDL-C includes all known or potentially atherosclerotic fatty particles, which may promote atherosclerosis (81). In a study by Jiaolving 583 AIS patients diagnosed with post-stroke cognitive impairment (PSCI), it was found that using 3.52 mmol/L as the cutoff for serum non-HDL-C levels, the sensitivity and specificity for diagnosing PSCI were 90.3% and 63.7%, respectively, with an area under the curve (AUC) of 0.773 (81).

Proteins are integral components of the organism, providing essential nutrients and maintaining protein homeostasis primarily through degradation and synthesis pathways, which help keep the body healthy (82, 83). The endoplasmic reticulum is a eukaryotic organelle within the cytoplasm that produces and modifies proteins. When IS occurs, the delivery of oxygen and glucose to neural tissues can be stopped to trigger the endoplasmic reticulum stress cascade, which rapidly induces protein misfolding and endoplasmic reticulum stress, and when blood flow is restored, reperfusion of the affected tissues leads to oxidative stress as well as alterations in the redox state of the endoplasmic reticulum, which disrupts protein disulfide bonding, leading to misfolding of endoplasmic reticulum proteins (84, 85). To mitigate this damage, eukaryotic cells activate the unfolded protein response (UPR). The UPR helps alleviate ER stress by upregulating cofactors, chaperones, and enzymes in the ER, while simultaneously downregulating protein translation. This response provides neuroprotection during IS by addressing the protein folding defects induced by the stressor. However, prolonged or excessive ER stress can overwhelm the UPR, rendering it ineffective (30, 86).

Furthermore, the activation of the pentose phosphate pathway (PPP) due to impaired oxygen transport after IS (19) leads to the production of ribose 5-phosphate (R-5-P) and nicotinamide adenine dinucleotide phosphate (NADPH). Consequently, both ER stress and PPP activation after IS may result in disturbances in protein synthesis and degradation, which can contribute to cognitive dysfunction (87).

Protein synthesis and degradation are both ATP-consuming processes and are therefore closely regulated by energy metabolism. Following IS, ATP production is reduced due to changes in glucose metabolic pathways (18), which in turn can regulate both protein synthesis and degradation. Additionally, the endoplasmic reticulum (ER) undergoes stress after IS (88), and the eukaryotic translation initiation factor 2α (eIF2α) plays a role in the morphology and function of vascular smooth muscle cells in atherosclerotic plaques under the influence of ER stress. Elevated expression of eIF2α has been shown to alleviate the progression of atherosclerosis (89). However, patients with IS often exhibit severe atherosclerosis, which may result in decreased levels of eIF2α. Furthermore, stress-induced phosphorylation of eIF2α further inhibits protein translation and reduces protein synthesis.

TORC1 is a key regulator of cell growth, controlling processes such as protein biosynthesis, transcription, nutrient uptake, energy expenditure, and autophagy activity. Two central downstream effector proteins of TORC1, the eukaryotic translation initiation factor 4E-binding protein (4E-BP) and ribosomal protein S6 kinase 1 (S6K1) regulate protein biosynthesis and promote its synthesis when activated (90). In contrast, mTORC1 activity has been found to be reduced after IS (91), which leads to the inhibition of protein synthesis.

The ubiquitin-proteasome system (UPS) and autophagy are two major protein degradation pathways in eukaryotic cells (92). The emergence of endoplasmic reticulum stress (ERS) after stroke further activates the unfolded protein response (UPR), which is associated with reduced translational activity, increased protein folding capacity, and the activation of protein degradation pathways (88). Additionally, autophagy is activated after stroke, further promoting proteolysis (93). The process of memory consolidation is closely related to both protein synthesis and degradation (24). In summary, protein synthesis is inhibited and degradation is enhanced after IS, disrupting the balance of protein metabolism and leading to cognitive dysfunction (87). Specific metabolic changes are shown in Figure 3 .

Elevated levels of homocysteine, a non-proteinogenic sulfhydryl-containing amino acid derived from methionine, are known as hyperhomocysteinemia and are closely associated with neurovascular diseases, dementia, and other disorders (94). Increased homocysteine (HCY) levels have been observed in the blood of IS patients (95), and higher HCY levels correlate with more severe cognitive dysfunction, with a positive association between the two (80). HCY has also been recommended as a potential metabolic marker for PSCI in a meta-analysis by Kim et al (69). However, one study found that the relationship between HCY levels and cognitive impairment was age-dependent, being more pronounced in individuals under 65 years of age. This relationship disappeared after adjusting for confounders in the population over 65 years of age (96).

In addition, Li et al. found that homocysteine (Hcy) was associated with PSCI in males, but not in females. This difference may be due to the weakened protective effect of estrogen in females after menopause (97). The presence of Hcy has been shown to exacerbate amyloid-beta (Aβ)-induced apoptosis of brain endothelial cells and promote blood-brain barrier (BBB) disruption in animal studies (98). Furthermore, excessive Tau protein and phosphorylated Tau protein aggregation have been linked to blood-brain barrier disruption (99). Elevated Hcy levels also lead to abnormally reduced vasodilatory responses and compromised cyclooxygenase (CO) synthase activity. This exacerbates endothelial damage, further impairing endothelial function, which facilitates the shedding of large numbers of endothelial cells and promotes the development of atherosclerosis (AS) (80). Therefore, homocysteine may induce cognitive dysfunction by disrupting the blood-brain barrier and promoting the progression of atherosclerosis.

Galactoglucan lectins are a family of carbohydrate-binding proteins found in vertebrates, characterized by significant abundance and diversity in their structure, ligand-binding properties, and physiological functions. Galectin-3, a member of this family, is notably elevated after IS (100). It tends to cause neurotoxic effects during the acute inflammatory phase while exerting neuroprotective effects in the subacute phase by promoting the polarization of classical pro-inflammatory M1 microglia to the anti-inflammatory M2 phenotype, which has healing activity (101). Qian Wang et al. found that the incidence of PSCI increased progressively with the elevation of serum Gal-3 levels (102). Elevated Gal-3 levels are also present in atherosclerotic (AS) vessels, where they affect endothelial cells, macrophages, and vascular smooth muscle cells (VSMCs), all of which are involved in the development of atherosclerosis (103, 104). Atherosclerosis can lead to cognitive dysfunction by restricting blood flow and nutrient supply to the brain. Moreover, Qian Wang et al. found that serum Gal-3 levels could be used to diagnose PSCI, with a cutoff value of 6.3 ng/mL. At this level, the sensitivity and specificity were 66% and 94%, respectively, with an area under the curve (AUC) of 0.803 (102).

Cystatin C (CysC) is a potent lysosomal cysteine protease inhibitor that plays a critical role in human vascular pathology by controlling tissue proteases and serving as a marker of renal function (105). A meta-analysis has shown that patients with IS exhibit significantly higher serum cystatin C concentrations compared to control groups (106). Zuo et al. found a U-shaped correlation between CysC levels and PSCI (107). A clinical study has also found that elevated serum CysC levels in IS patients were associated with a reduced risk of cognitive impairment at 3 months. This suggests that CysC may act as a protective factor against PSCI. However, it is important to note that this protective effect was only observed in patients with normal renal function and was not established in those with abnormal renal function. CysC may protect cognitive function by inhibiting oxidative stress in the post-IS period (108). Additionally, some studies have suggested that elevated serum CysC levels in the acute phase of IS could be an independent risk factor for PSCI. It is believed that CysC may contribute to cognitive dysfunction by promoting stenosis of the major arteries and increasing the risk of cerebral hemorrhage (109–111).

Fibrinogen, also known as coagulation factor I, plays a significant role in the development and progression of cardiovascular diseases (112). Elevated fibrinogen levels have been observed in patients with IS (113). In a study by Liu et al., blood fibrinogen levels were found to be higher in patients with PSCI compared to the non-PSCI group, and plasma fibrinogen levels were negatively correlated with Mini-Mental State Examination (MMSE) scores at 3 months (114). Additionally, a study by Roseborough et al. suggested that fibrinogen might be transmitted through NLRP3 signaling via an inflammatory response, which damages the blood-brain barrier (BBB) and contributes to cognitive dysfunction (115). Fibrinogen has also been shown to activate microglia, induce dendritic loss, and promote neuroinflammation, leading to synaptic deficits and cognitive decline (116).

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, with MMP-9 being a prominent member of the gelatinase subclass (117). Some researchers have found that elevated serum MMP-9 levels are associated with impaired cognition after IS at three months (118). Serum MMP-9 levels have been shown to be negatively correlated with MoCA scores and cognitive functioning in patients with PSCI (119, 120). Furthermore, researchers have found that adding rheumatoid factor, MMP-9, and total homocysteine to conventional prediction models enhances the ability to predict PSCI (121). In contrast, the use of MMP inhibitors has been shown to improve the integrity of the blood-brain barrier (122). In an animal study by Lee et al., treadmill exercise before ischemia inhibited the activation of MMP-9, which improved short-term memory in rats (123). The precise mechanism by which MMP-9 contributes to PSCI remains unclear, and further research is needed to explore its potential as a therapeutic target for post-PSCI cognitive decline.

Studies have shown that metabolites and metabolic pathways are influenced by various factors, including diet, medications, underlying diseases, and the time of onset (159). However, current research often does not account for these confounding factors, which may impact the findings. Future studies should focus on exploring the specific mechanisms of metabolic pathways and biomarkers while controlling for these variables.