Due to differences in factors such as etiology, injury location, type, and severity of TBI, there are significant variations in the occurrence rate and baseline characteristics of cognitive dysfunction among TBI patients. Additionally, it is scientifically unsound to compare epidemiological data across different regions and populations because current studies employ diverse methods and assessment criteria. There is still a lack of standardized tools and criteria for assessing and diagnosing cognitive dysfunction in TBI patients. We are aware that TBI can result in acute neurological deficits during the initial phase and can lead to various complications in the chronic phase, with cognitive dysfunction being the most common and severe. However, the non-specific manifestations of cognitive dysfunction are diverse and challenging to diagnose. These may include declines or losses in cognitive domains such as memory, attention, executive function, language, and visual-spatial abilities, which may impact the daily life, work, study, and social interactions of patients. The relative scarcity of epidemiological studies on cognitive dysfunction in Chinese TBI patients may be attributed to the difficulty in diagnosing these diverse and non-specific manifestations. Furthermore, most studies are single-center, small-sample studies, lacking nationwide large-scale multicenter cohort studies.

To date, the largest-scale clinical characteristics and outcomes study of TBI patients in China, known as CENTER-TBI, was conducted by Gao et al. (2020). This prospective, longitudinal observational study took place across multiple centers in China and included 13,627 cases of TBI from 56 hospitals in 22 provinces. The aim was to depict the epidemiological pattern of contemporary TBI in China. The study revealed that TBI in China predominantly occurs in young and middle-aged males between the ages of 18 and 65, with the primary cause being traffic accidents. The overall mortality rate was 5%, which was lower than the expected value predicted by the CRASH prognostic model (Perel et al., 2008; Lingsma et al., 2011). Furthermore, substantial differences were identified in the treatment methods for TBI across various hospitals and regions. The study suggests that these findings provide an opportunity for comparative effectiveness research to identify optimal practices for TBI treatment and underscore the necessity of improving TBI systems in different regions. Despite the substantial TBI burden, no FDA-approved therapeutics currently exist due to an incomplete understanding of the mechanisms underlying persistent cognitive dysfunction and post-injury degeneration.

Traumatic Brain Injury resulting from external head impact triggers a series of neuroinflammatory and pathophysiological events leading to neuropsychiatric disorders, affecting cognitive function in 15–30% of TBI patients (Jackson et al., 2004; Himanen et al., 2006; Fleminger, 2008; Till et al., 2008; Silver et al., 2009; Wang et al., 2012). Cognitive impairment in TBI patients is a complex, multifactorial process involving several potential mechanisms. Structural damage to brain tissue, especially in functional areas like the frontal lobe and hippocampus, emerges as a primary cause of cognitive dysfunction after brain trauma (Peters et al., 2009). Research showed that damage to the right hemisphere causes more severe cognitive impairment, with damage to the frontal lobe being particularly prominent (Fletcher and Henson, 2001). The neurotransmitter 5-HT, crucial for memory regulation and brain function maintenance, has shown significance in TBI research. Kline et al. discovered that selective 5-HT1A receptor agonists can reduce neuronal damage in the cerebral cortex and hippocampus, suggesting a potential avenue for therapeutic intervention in a rat TBI model (Meneses, 2003). Additionally, Sen et al. (2017) found that endoplasmic reticulum stress-activated PKR-like ER kinase (PERK) phosphorylates CREB and PSD95 proteins, reducing BDNF levels and impairing synaptic structure and function, ultimately affecting memory. This study suggests that inhibiting PERK phosphorylation may protect dendritic spines and synapses, presenting a potential therapeutic strategy. Recently, another team found that aberrant production of TDP-43 is a key factor in promoting AD neuropathology and synaptic and cognitive deterioration in mouse models of mild closed head injury (CHI). They show that excessive production of TDP-43 either resulting from a single mild CHI or from repeated mild CHI in WT mice is an important mechanism common to both AD and TBI-induced AD-like neurodegenerative disease (Gao et al., 2022). This drives our strategy to limit TDP-43 overproduction to potentially provide therapeutic approaches to prevent the development of TBI-induced AD neuropathology. Recent research also has increasingly focused on the significant role of microglia in cognitive impairment post-TBI (Willis et al., 2020; Krukowski et al., 2021; Bray et al., 2022; Packer et al., 2024). Common findings across these studies suggest that regulating microglia can reduce cognitive impairment after TBI, hinting at microglia as a potential breakthrough in future treatments for cognitive dysfunction post-TBI.

Since the first description of the meningeal lymphatic vessels (MLVs), their unique anatomical and physiological features have been gradually revealed (Louveau et al., 2015; Antila et al., 2017). Exciting recent work revealed MLVs play an important drainage pathway in the elimination of neurotoxic substances, including Aβ aggregates, extracellular tau, and alpha-synuclein aggregates in mice. Moreover, Recent studies have also revealed that MLVs play an important role in various neurological diseases, including AD, Parkinson’s disease (PD), and glioblastoma (Da Mesquita et al., 2018; Song et al., 2020; Ding et al., 2021). Great progress has also been made in the critical role of the meningeal lymphatic system in the pathogenesis of TBI (Bolte et al., 2020; Liu et al., 2023). Bolte etc. revealed even mild head trauma can lead to prominent defects in the drainage of fluorescent beads via the meningeal lymphatic system (Bolte et al., 2020). Mouse studies from our group indicate that exogenous IL-33 exert a protective effect on cognitive functions and improve the drainage of MLVs to deep cervical after TBI (Liu et al., 2023). These studies suggest that cognitive impairment after TBI may be closely related to disruption of meningeal lymphatic drainage. This provides new avenues for future intervention in cognitive impairment after brain trauma.

It includes factors such as the type, severity, location, and frequency of the injury, determining the extent and severity of brain damage as well as secondary damages like bleeding, hypoxia, inflammatory responses, edema, and ischemia following brain injury (Mendez, 2017; Ma et al., 2019).

Types of injuries can be classified into open and closed injuries. Open TBIs are associated with a higher incidence of coagulopathies, which may exacerbate bleeding and further increase the morbidity and mortality rates of TBI (Chen et al., 2021). Compared to open TBIs, closed injuries often result in mild TBI (Nokkari et al., 2015).

The severity of the injury can be assessed based on indicators such as duration of loss of consciousness, increased intracranial pressure, and abnormalities in neuroimaging. Generally, the higher the severity of the injury, the greater the extent and range of brain damage, and the higher the risk and degree of cognitive impairment (Lennon et al., 2023). Cognitive deficits resulting from mild TBI mostly recover completely within 3–6 months (Rabinowitz and Levin, 2014), whereas up to 65% of patients with moderate to severe TBI suffer from long-term cognitive impairments (Whiteneck et al., 2004).

The location of the injury can affect different cognitive domains. Generally, the frontal and temporal lobes are critical structures for cognitive functions, and damage to these areas can lead to cognitive and social dysfunction (Cristofori and Levin, 2015). Lesions in the left temporal lobe can cause a decline in conversational speech and auditory comprehension, lesions in the left frontal lobe can result in reduced verbal fluency, and lesions in the right parietal lobe can lead to decreased auditory comprehension and reasoning abilities (Gauthier et al., 2018).

The frequency of injuries reflects the cumulative effects of brain damage, where multiple TBIs lead to more severe brain damage and cognitive impairment, with slower and more difficult recovery in patients with multiple TBIs (Lennon et al., 2023). An animal study showed that repeated mild TBIs led to cognitive dysfunction in mice during both acute and chronic phases, along with changes in the expression of genes related to inflammation and excitotoxicity. Especially in mice subjected to 15 impacts, compared to the control group, their hippocampal spatial learning and memory abilities were impaired in the acute phase, with this damage persisting into the chronic phase (Hiskens et al., 2021).

Individual-related factors refer to those associated with the patient themselves, such as age, gender, baseline cognitive level, genetic factors, and comorbidities. These factors affect the sensitivity and plasticity of brain injury, as well as the capacity for repair and reorganization post-injury. Different individual-related factors may impact various cognitive domains differently, and there may be interactions between these factors, making the risk and degree of cognitive impairment more difficult to predict and assess (Himanen et al., 2011; Skaansar et al., 2020; Gomez et al., 2021; Mollayeva et al., 2021; Izzy et al., 2022; Kennedy et al., 2022; Mair et al., 2022; Hume et al., 2023).

Age is a significant factor affecting cognitive impairment, generally, the older the age, the higher the risk and degree of cognitive impairment (Hukkelhoven et al., 2006). Elderly patients with TBI, despite higher initial GCS scores, still have higher overall mortality and disability rates. This adverse prognosis may not only stem from the biological aging process and pre-existing comorbidities but also be influenced by medical decision-making biases, such as more conservative or limited diagnostic and therapeutic measures for elderly patients due to anticipated poor treatment outcomes (Skaansar et al., 2020).

Gender is also a factor affecting cognitive impairment. This may be related to differences in brain structure and function between males and females, as well as the role of sex hormones (Daneshvar et al., 2011). Compared to males, female patients have poorer cognitive recovery at 6 months, and more severe symptoms of depression and anxiety (Moretti et al., 2012).

Baseline cognitive level refers to the cognitive abilities of a patient before the occurrence of TBI. Increasing or maintaining cognitive reserve may help prevent the exacerbation of cognitive decline in the elderly following TBI (Moretti et al., 2012). TBI patients without education have worse cognitive performance compared to those with education, and a higher level of education may help to delay or mitigate the decline in cognitive functions post-TBI (Sharbafshaaer, 2018).

Genetic factors refer to those associated with the genes of TBI patients, which can influence the sensitivity and plasticity of brain injury, as well as the capacity for post-injury repair and reorganization, thereby affecting the risk and severity of cognitive impairments. Studies have shown that certain genetic variations, such as APOE ε4, result in TBI patients carrying the ε4 allele being more prone to adverse outcomes (Zhou et al., 2008; McFadyen et al., 2021). Studies on other genetic variations, like BDNF, indicate that individuals under 45 years old carrying the rs6265 Val (Val66Met) homozygote and rs712444 T allele have the highest survival probabilities in the subacute phase, suggesting that these genes may reduce the risk and severity of cognitive impairments in TBI patients (Failla et al., 2015). The GRIN genotype may affect the plasticity and cognitive function recovery post-TBI, leading to cognitive impairments (Raymont et al., 2008).

Comorbidities refer to other diseases or symptoms that occur concurrently with or subsequent to TBI, such as depression, anxiety, insomnia, pain, diabetes, hypertension, etc. These comorbidities can affect the daily living activities of TBI patients, as well as their abilities in communication, perception, thinking, reasoning, and memory, thereby impacting their overall rehabilitation progress and quality of life (Mollayeva et al., 2017; Hanafy et al., 2021). Additionally, post-concussion syndrome (PCS) that develops after TBI may have lasting effects on cognitive, memory, learning, and executive functions (McInnes et al., 2017).

As the foundation of cognitive dysfunction management, the purpose of cognitive function assessment is to determine the patient’s level of cognitive function, the extent of impairment, and the scope of impact, providing a basis for the formulation of intervention plans and the evaluation of outcomes (Woodford and George, 2007).

Neuropsychological assessment, traditionally used to evaluate the degree of impairment in specific skills and identify potentially affected brain regions, focuses on assessing cognition and behavior, with a crucial emphasis on evaluating the patient’s mental state (Sun et al., 2017). The currently validated cognitive function assessment tools include the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Neurobehavioral Cognitive Status Examination (NCSE), Cognitive Abilities Screening Instrument (CASI), Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) (Mitrushina et al., 1994; Teng et al., 1994; Nasreddine et al., 2005; Mitchell, 2009; Almomani et al., 2018). The main advantages and disadvantages are summarized in Table 1.

Electrophysiological markers, including electroencephalogram (EEG), sensory-evoked potentials (EPs), and event-related potentials (ERPs), can be used for electrophysiological diagnosis and monitoring of brain function (Amantini et al., 2005; Carrai et al., 2010; Dockree and Robertson, 2011). Valuable indicators such as P300 and mismatch negativity (MMN) are included (Zarza-Luciáñez et al., 2007; Kodama et al., 2010).

Brain imaging methods, such as computerized tomography (CT) and magnetic resonance imaging (MRI), provide essential information, especially for moderate to severe TBI. Diffusion tensor imaging (DTI) can measure changes in brain microstructure and white matter connectivity related to TBI (Hashim et al., 2017; Sun et al., 2017; Königs et al., 2018).

Genetic polymorphisms, such as Brain-derived neurotrophic factor (BDNF), 5-HTTLPR, and the functional catechol-O-methyltransferase genotype (rs4680), are associated with cognitive and social function recovery after TBI (Krueger et al., 2011; Kurowski et al., 2016).

Currently, interventions for cognitive impairment in patients after TBI mainly include the following aspects: