Peripheral blood biomarkers and mild behavioral impairment in mild cognitive impairment: Clinical correlations and mechanistic insights

Abstract

In the context of global aging, mild behavioral impairment (MBI) is present in 48.9% of patients with mild cognitive impairment (MCI). MBI, a neurobehavioral syndrome in the elderly, is an independent risk factor for cognitive decline and is closely related to peripheral blood biomarkers associated with Alzheimer's disease, offering new diagnostic and interventional avenues for early MCI. To summarize evidence on peripheral blood biomarkers related to MBI and their underlying mechanisms involving neuroinflammation, tau pathology, and oxidative stress, a systematic review of studies published between 2015 and 2024 was conducted. MBI is closely associated with peripheral blood biomarker changes. Neuroinflammatory markers like glial fibrillary acidic protein and neurofilament light indicate astrocyte activation and neural circuit disruption, with glial fibrillary acidic protein levels correlating with impulse dyscontrol scores. Chitinase-3-like protein 1, a marker of blood-brain barrier integrity, exacerbates neuroinflammation and is linked to depressive symptoms and hippocampal atrophy. Elevated phosphorylated tau proteins in blood correlate with brain tau deposition, increasing the risk of MBI and impairing cognition. Oxidative stress markers damage neurons and disrupt neurotransmission, and concurrent alterations in malondialdehyde and superoxide dismutase levels significantly elevate the risk of MBI. The correlation between MBI and biomarkers offers new diagnostic and interventional directions for early MCI. Future research should standardize MBI assessment, conduct longitudinal studies, explore biomarker-MBI relationships, investigate psychosocial impacts, and develop advanced detection methods.

Key Words: Mild cognitive impairment; Mild behavioral disorders; Peripheral blood biomarkers; Alzheimer’s disease; Relevance

Core Tip: Both mild cognitive impairment and healthy older adults have a higher prevalence of mild behavioral impairment, with changes in impulse control behavior being the most common. Mild behavioral impairment is not only an independent risk factor for cognitive decline but is also associated with peripheral biomarkers associated with Alzheimer’s disease.

INTRODUCTION

Due to the increasing aging of the global population, diseases such as age-related cognitive impairment have become important topics affecting human health and quality of life. Mild cognitive impairment (MCI) is a common condition between normal aging and dementia, characterized by mild cognitive deficits that do not yet meet the diagnostic criteria for dementia[1]. Studies have found that with the rising level of population aging, the incidence of MCI in older adults is higher and on the rise[2]. Mild behavioral impairment (MBI), however, is characterized by behavioral changes in mood, motivation, and impulse control, with impulse control difficulties being the most common[3]. Notably, the prevalence of MBI is high in patients with MCI. The study found that the prevalence of MBI among patients with MCI was 14%, with a standard deviation of 6.41[4]. When the total score of MBI checklist ≥ 9.5 was used as the diagnostic criterion for MBI, after adjusting for age, education level, and sex, the odds ratio of MBI in patients with MCI-Alzheimer’s disease (AD) was 58.39 (95% confidence interval: 12.91-264.06; P < 0.001). This indicates that the risk of MBI in patients with MCI-AD is 58.39 times higher than that in healthy populations[5]. The presence of MBI is closely associated with further cognitive decline; it is not only an independent risk factor for cognitive decline but also linked to AD-related peripheral blood biomarkers.

AD, as one of the most common neurodegenerative diseases worldwide, is clinically manifested by memory and cognitive dysfunction[6]. Currently, it has become a major health problem severely affecting families and societies. The risk of MCI progressing to AD is high, with studies showing that patients with MCI are 10 times more likely to develop AD than healthy older adults[7]. Notably, the association between MBI and AD-related peripheral blood biomarkers suggests that MBI may have been present in the early stages of cognitive decline and has had an impact on disease progression.

MBI refers to a neurobehavioral impairment that persists in late life without a diagnosis of dementia or significant psychiatric illness. MBI has been shown to be a robust syndrome, predicting faster cognitive decline and a poorer clinical trajectory[8]. As an important tool for assessing MBI, the MBI Checklist scale has certain sensitivity and specificity in identifying this syndrome - the sensitivity is usually about 70%-85%, which can well capture early behavioral changes related to neurodegenerative diseases and correctly identify individuals with true MBI; the specificity is generally between 65% and 80%, which can effectively distinguish normal aging or other non-pathological behavioral changes from pathological MBI symptoms and accurately rule out individuals without MBI.

The symptoms of MBI are not occasional or transient mood swings but rather pattern changes involving multidimensional dysfunction (e.g., emotion regulation, motivational drive, impulse control) that last for more than 6 months[9]. As a potential early marker of cognitive decline and disease progression, MBI is clinically significant not only for directly impairing patients’ social function and quality of life but also as an important biobehavioral marker during neurodegeneration.

The core characteristic of patients with MBI is persistent depressed mood. Neurobiological studies have shown that these disorders are closely associated with dysfunction of the monoamine neurotransmitter system, with impulsive behavior in patients with MBI manifesting as pathological excitement, compulsive consumption, or aggressive speech involving widespread impairment of the executive control network[10]. Diffusion tensor imaging revealed a 15%-20% reduction in fractional anisotropy of the fibrous bundles between the dorsolateral prefrontal cortex and striatum in these patients, leading to disruption of behavioral inhibition[11]. Lack of motivation, characterized by persistent decreases in goal-oriented behavior and apathy, is the most disabling symptom of MBI. Neuromechanistic studies suggest that functional deterioration of dopamine in the mesolimbic pathway is the core trigger factor[12].

RELATIONSHIP BETWEEN MBI AND COGNITIVE DECLINE

In recent years, several studies have shown that the presence of MBI is strongly associated with a significantly increased risk of cognitive decline[13]. MBI is an independent risk factor for cognitive decline, accelerating the deterioration of cognitive function through neurobiological mechanisms. For example, patients with MBI often exhibit heightened anxiety, depression, and impulsive behaviors, which may exacerbate neuroinflammation and oxidative stress and promote cognitive decline.

The interaction between MBI and cognitive decline is complex, involving bidirectional influences and feedback loops. MBI may accelerate the deterioration of cognitive function by influencing neurobiological mechanisms. MBI is associated with different domains of cognitive function, such as memory, executive function, and attention, and this correlation is particularly pronounced in memory and executive function[14]. Cognitive decline is likely to further aggravate MBI. This interaction creates a vicious circle that accelerates the progression of the disease to a deeper extent.

MBI can serve as a predictive marker to identify individuals at higher risk of dementia during the cognitively normal stage. The prevalence of MBI has been reported as 27.6% in cognitively normal individuals and as high as 48.9% in patients with MCI[15]. Other studies have shown that both MBI and subjective cognitive decline are associated with an increased risk of dementia[16], highlighting the importance of MBI in the early identification of at-risk individuals and the provision of timely clinical interventions.

RELATIONSHIP BETWEEN MBI AND PERIPHERAL BLOOD BIOMARKERS

Neuroinflammation is one of the important pathological features of AD. In patients with MCI, peripheral blood markers such as glial fibrillary acidic protein (GFAP) and neurofilament light (NFL) chain show significant increases. These markers reflect the inflammatory state of the central nervous system associated with MBI: Elevated levels of GFAP and NFL indicate astrocyte activation and neuronal damage through the following mechanisms: Astrocyte activation releases pro-inflammatory factors (e.g., interleukin 6, tumor necrosis factor alpha), which disrupt the inhibitory function of the prefrontal cortex-striatum circuit[17]. For example, a 1-standard deviation increase in GFAP is associated with a 0.52-point increase in the impulse control behavior score (Neuropsychiatric Inventory impulse subscale) (P < 0.01), possibly linked to dopamine neuronal dysfunction mediated by inflammation (Table 1).

Table 1 Core mild behavioral impairment domain and associated biomarkers.

MBI behavioral domain	Typical symptoms	Peripheral blood biomarkers	Pathological mechanism	Ref.
Impulse control disorder	Compulsive spending, aggressive speech	GFAP, NFL	Astrocyte activation → neuroinflammation → disruption of prefrontal inhibitory function	[9,16]
Apathy	Reduced goal-directed behavior	YKL-40	Blood-brain barrier disruption → central inflammation → dopaminergic pathway degeneration	[17,18]
Emotional dysregulation	Depression, anxiety	P-tau181, P-tau217	Tau protein pathology → neurotransmitter imbalance in limbic system	[19-21]
Oxidative stress-related	Cognitive-behavioral vicious cycle	MDA, SOD	Free radical damage → neuronal dysfunction → exacerbation of neuroinflammation	[22]

GFAP: Glial fibrillary acidic protein; MBI: Mild behavioral impairment; MDA: Malondialdehyde; NFL: Neurofilament light; P-tau: Phosphorylated tau; SOD: Superoxide dismutase; YKL-40: Chitinase-3-like 1.

The integrity of the blood-brain barrier (BBB) is critical for maintaining central nervous system stability. Patients with MBI exhibit significantly elevated peripheral blood markers of BBB integrity, such as chitinase-3-like protein 1 (also known as YKL-40). YKL-40, a protein secreted by reactive astrocytes, reflects BBB disruption and neuroinflammation via its elevated peripheral levels. Secreted by reactive astrocytes, elevated YKL-40 indicates increased BBB permeability. Studies have shown that YKL-40 promotes β-amyloid deposition by activating microglia and exacerbates neuroinflammation through the Toll-like receptor 4 pathway, thereby affecting limbic emotion regulation[18]. In patients with MBI, YKL-40 Levels positively correlate with depressive symptom scores (r = 0.38, P < 0.05)[19]. Additionally, cognitive decline and brain atrophy are closely associated with elevated YKL-40 Levels.

Aberrant phosphorylation of tau protein leads to the formation of neurofibrillary tangles, destabilizing neural networks. Peripheral blood phosphorylated tau (p-tau) levels correlate significantly with brain tau deposition, exacerbating cognitive impairment and behavioral abnormalities by disrupting neurotransmitter synthesis and release. Notably, in patients with MCI, peripheral p-tau181 and p-tau217 concentrations are significantly elevated and associated with MBI[20]. P-tau181-induced neurofibrillary tangles interfere with axonal trafficking, impairing prefrontal cortex-limbic neurotransmission (e.g., serotonin, dopamine, norepinephrine). Specifically, the accumulation of tau pathology impairs the synaptic vesicle transport mechanism in the presynaptic membrane, leading to significant downregulation in the expression levels of 5-hydroxytryptamine 1A receptors and β2-adrenergic receptors in the dorsolateral prefrontal cortex and hippocampus. These receptors mediate signal transmission for emotional regulation and attention maintenance, respectively, and their impaired function directly exacerbates the coordination disorder of the executive control network. In MCI, each 10 pg/mL increase in p-tau181 raises MBI odds by 40% (odds ratio = 1.40, 95% confidence interval: 1.12-1.75), likely via disruption of the executive function network[21]. Studies have shown that the total MBI score is negatively correlated with plasma p-tau217 Levels (r = -0.330, P = 0.041), suggesting that MBI may be associated with the abnormal phosphorylation process of tau protein[22]. These biomarkers not only reflect brain Tau pathology but may also drive a bidirectional feedback loop accelerating cognitive-behavioral decline and neural network dysfunction.

Oxidative stress plays a pivotal role in the progression of cognitive decline and MBI. Studies show that peripheral blood markers of oxidative stress, such as malondialdehyde (MDA), are significantly elevated in patients with MBI, while antioxidant enzymes like superoxide dismutase (SOD) exhibit reduced activity[23]. Oxidative stress exacerbates cognitive and behavioral impairment by damaging neurons and disrupting neurotransmitter synthesis and release.

It is worth noting that although MBI has overlapping symptoms (such as mood swings and impulsive behaviors) in MCI and early AD, there are differences in the expression patterns of peripheral blood biomarkers. These differences provide a potential basis for distinguishing MBI between the two groups of people. For example, the level of p-tau217 is higher in patients with early AD than in patients with MCI, and its correlation with MBI is more significant.

The correlation between MBI and peripheral blood biomarkers suggests that MBI is not only an independent risk factor for cognitive decline but may also accelerate disease progression by influencing neurobiological mechanisms. Future research should further explore the relationship between MBI and AD-related biomarkers to develop more precise assays for MBI, as well as study the impact of psychosocial factors on MBI. These efforts are expected to provide a new direction for early diagnosis and intervention in MCI, potentially delaying or preventing the progression of cognitive decline.

Against the backdrop of aging populations, this study explored potential associations between patients with MCI and peripheral blood biomarkers. A systematic review of existing literature revealed that MBI is not only an independent risk factor for cognitive decline but is also closely linked to diverse peripheral blood biomarkers. These include inflammatory markers (e.g., GFAP, NFL), BBB integrity markers (e.g., YKL-40), p-tau proteins (e.g., p-tau181, p-tau217), and oxidative stress markers (e.g., MDA, SOD). Changes in these biomarkers not only reflect central nervous system pathology but also correlate with the onset and progression of MBI.

The interplay between MBI and cognitive decline is complex, involving bidirectional influences. MBI may accelerate cognitive decline through neurobiological mechanisms, while MBI symptoms may be further aggravated by cognitive function decline, thus leading to a vicious cycle. Studies show a high prevalence of MBI in both cognitively normal individuals and patients with MCI, with impulse control behavior changes as the most common manifestation. Most of the included studies are cross-sectional, so exact causal relationships cannot be established. However, these findings further emphasize the importance of MBI in the early risk identification of cognitive decline and provide a new direction for future clinical interventions. Currently studies on the relationship between MBI and peripheral blood biomarkers have limitations.

First, the causal link between MBI and peripheral blood biomarkers remains unclear, as most existing studies are cross-sectional, making it difficult to determine their temporal sequence. Moreover, the lack of uniform standards for MBI assessment scales across studies has led to insufficient data comparability. Additionally, the influence of psychosocial factors on MBI is not fully understood. Future research should focus on the mechanisms of these factors to gain a more comprehensive understanding of MBI's pathophysiological processes.

Peripheral biomarkers offer significant practical application value in clinical settings, enabling early diagnosis and risk screening for AD and MCI. For example, peripheral blood p-tau proteins (p-tau181, p-tau217) combined with NFL can enhance AD diagnostic accuracy, while elevated GFAP levels indicate active neuroinflammation and are associated with impulse control disorders in patients with MBI. The BBB marker YKL-40 warns of brain atrophy in patients with MCI. In terms of disease monitoring and prognosis, levels of oxidative stress markers MDA and SOD reflect brain oxidative damage, and dynamic changes in p-tau181 correlate with hippocampal atrophy rates. Biomarkers can also evaluate the efficacy of anti-inflammatory therapies. In clinical translation applications, peripheral blood testing offers non-invasiveness and cost-effectiveness. The Point-of-Care Testing platform enables rapid result generation, and multi-marker panels combined with MBI behavior assessment improve early AD identification accuracy, making them suitable for community and primary care settings. However, it should be noted that there are still challenges in the implementation of primary healthcare: The stability of blood biomarkers (such as p-tau181) is relatively poor, which is easily affected by the post-collection processing time, temperature and type of anticoagulant of the samples. Therefore, the standardization of pre-analytical blood sample processing is crucial. Future optimization of biomarker applications in clinical practice will rely on advancements in liquid biopsy technology and the construction of artificial intelligence-assisted diagnostic models, providing more precise support for early intervention in cognitive impairment disorders.

CONCLUSION

In conclusion, the association between MBI and peripheral blood biomarkers offers a new perspective for the early diagnosis and intervention of MCI. Future research should focus on developing more accurate biomarker detection methods, clarifying the causal relationship between MBI and biomarkers, and exploring the influence of psychosocial factors on MBI. Through these efforts, this approach is expected to provide a new direction for early intervention in MCI, aiming to delay or prevent the progression of cognitive decline and improve patient outcomes and quality of life.