The brain, as the highest level of the nervous system, serves as the control center for human behavior and cognitive functions. It is also the most energy-consuming organ in the human body. In which neurons exhibit a high metabolic rate but lack energy reserves (Raut et al., 2023). To ensure an adequate energy supply for neurons, the brain has evolved a mechanism to regulate local cerebral blood flow (CBF), known as NVC or functional hyperemia. This mechanism involves dynamic changes in local blood flow supply in response to the electrical activity of neurons to meet metabolic demands. There are three types of neurovascular regulation mechanisms for CBF in the brain (Figure 1): (1) Cortical neuron neurotransmitter regulation mechanism (i.e., the classic NVC pathway); (2) Subcortical nucleus-neurotransmitter regulation mechanism (Kocharyan et al., 2008; Bekar et al., 2012; Cui et al., 2013; Lecrux et al., 2017); (3) Regulation mechanism of peripheral sympathetic/parasympathetic postganglionic neurons vasoactive substances (Hamel, 2006; Seifert and Secher, 2011). The classic NVC pathway relies on the neurovascular unit (NVU), which involves the transmission of information among neurons, astrocytes, endothelial cells, smooth muscle cells (SMCs), and pericytes (Schaeffer and Iadecola, 2021). The generation of neuronal action potentials serves as the initiating factor, with astrocytes sensing neuronal activity and their endfeet directly connecting to blood vessels, facilitating the transmission of neuronal activity signals to the local vascular system (Sweeney et al., 2016; McConnell et al., 2017). The SMCs of arterioles and pericytes of capillaries, serving as effectors in NVC, receive signals from the aforementioned cells to regulate vascular tone (Stackhouse and Mishra, 2021). Any damage to any component of the NVU can lead to functional impairment of NVC, resulting in a mismatch between CBF supply and neuronal activity. This, in turn, leads to chronic damage to brain neurons and a decline in cognitive function (Iadecola, 2017; Turner, 2021).

Diabetes mellitus (DM), characterized by high blood sugar levels, is considered a significant risk factor for cognitive impairment (Roberts et al., 2014; Koekkoek et al., 2015). Previous studies have shown that regional cerebral perfusion in patients with type 2 diabetes mellitus (T2DM) is significantly reduced in multiple locations (including the occipital lobe, regions involved in the default mode network, and cerebellum). Moreover, this reduction is associated with widespread cognitive decline (including impairments in learning, memory, attention, and executive function) (Cui et al., 2017; Bangen et al., 2018; Wang et al., 2021; Liu et al., 2022). However, there were no significant differences in total CBF between the T2DM group and the healthy group (Tiehuis et al., 2008; Brundel et al., 2012). This observation may suggest impaired local regulation of CBF in T2DM, which could contribute to cognitive decline (Mogi and Horiuchi, 2011; Duarte et al., 2015; Lourenço et al., 2017; Shekhar et al., 2017). Given the crucial role of NVC in regulating local CBF, its relationship with T2DM-related cognitive impairment is increasingly being recognized.

In this review, we initiate our exploration from neuroimaging studies of diabetes-associated cognitive decline, focusing on the role of impaired NVC, also known as neurovascular uncoupling, in the context of cognitive deterioration in diabetes. Our emphasis will be on investigating the potential mechanisms through which diabetes induces NVC impairment and on outlining future research directions. By doing so, we aim to provide insights into the diagnosis and treatment strategies for early cognitive decline associated with diabetes.

Diabetes is a risk factor for cognitive decline. Moreover, as the disease progresses, complications emerge, and blood glucose control deteriorates, the risk of developing cognitive impairment increases (Dao et al., 2023; Sakib et al., 2023). Cognitive impairment, in turn, negatively impacts patients’ self-care and blood glucose management, fostering a vicious cycle (Sinclair and Abdelhafiz, 2020). Patients with T2DM experience varying degrees of decline in executive function, memory, and information-processing abilities (Sadanand et al., 2016; Wang H. et al., 2023). These cognitive deficits are closely associated with changes in brain function and structure related to T2DM, such as cerebral perfusion deficits (Cui et al., 2017; Wang et al., 2021), brain white matter damage (Jing et al., 2022; Liu et al., 2024), and hippocampal volume atrophy (Hirabayashi et al., 2016; Ohara et al., 2020; Zhang W. et al., 2021).

As mentioned earlier, CBF significantly decreases in multiple regions in patients with T2DM (Cui et al., 2017; Bangen et al., 2018; Wang et al., 2021; Liu et al., 2022). Endothelial dysfunction and reduced CBF are considered early changes preceding the occurrence of cognitive deficits (Sadanand et al., 2016; Gorelick et al., 2017; Wang H. et al., 2023). Imbalances in endothelium-derived vasoconstrictors and vasodilators can lead to cerebrovascular dysfunction, which may result in CBF dysregulation, with the endothelium being considered an early target for metabolic diseases, including diabetes (Kiss et al., 2020b). Early studies found decreased levels of Sirtuin1 (SIRT1) in the aorta of diabetic mice compared to normal controls (Zhou et al., 2011). Further research revealed that endothelial-specific overexpression of SIRT1 in diabetic transgenic mice compared to diabetic wild-type mice would decrease levels of aging markers such as p53, p21, PAI-1, and p66Shc in the aorta (Chen et al., 2012). Senthil et al. (2017) study indicated that activation of nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated antioxidant genes could prevent high glucose-induced endothelial aging and apoptosis (Senthil et al., 2017). High glucose conditions induce premature endothelial cell aging, leading to CBF dysregulation (Biessels and Despa, 2018; Prattichizzo et al., 2018; Balasubramanian et al., 2021). A recent review (Hwang et al., 2022) extensively summarized the molecular pathways related to endothelial cell aging. Understanding these diabetes-related changes in pathways is of significant importance for improving endothelial dysfunction and CBF dysregulation. Additionally, Li Y. et al. (2018) recently found that cognitive impairment and CBF reduction in T2DM mice may be associated with the RhoA/ROCK/moesin and Src signaling pathways (Li Y. et al., 2018). Castaneda-Vega et al. (2023) identified the role of brain vascular inhibitory G protein-coupled receptor signaling in maintaining CBF, which may be useful for developing new drug treatment approaches for preventing and treating cerebrovascular dysfunction (Castaneda-Vega et al., 2023).

Numerous clinical studies have found a close relationship between white matter injury and cognitive function (especially executive function) deterioration (Fletcher et al., 2018; Yamanaka et al., 2019; Jeong et al., 2022; Scamarcia et al., 2022; Wang et al., 2022; Dewenter et al., 2023). Simultaneously, researchers have observed abnormal changes in the macrostructure of white matter, including larger volumes of white matter lesions (WMLs), more white matter hyperintensities, and abnormal white matter network connectivity, in prediabetic (Jing et al., 2022) and diabetic patients (Sanahuja et al., 2016; Xiong et al., 2019; Huang et al., 2021). Moreover, these changes are associated with cognitive decline (Jing et al., 2022; Liu et al., 2024). It is widely believed that white matter injury in patients with DM is related to an increased burden of small vessel disease (Novak et al., 2006; Schneider et al., 2017; Georgakis et al., 2021). White matter consists of nerve axons and glial cells supporting the axons, such as oligodendrocytes. Studies have indicated that in the process of WMLs after chronic ischemia in diabetic patients, the proliferation and survival of oligodendrocyte progenitor cells (OPCs) may play an important role (Yatomi et al., 2015; Ma et al., 2018), and inhibiting Na+-K+-Cl- cotransporter 1 can significantly improve white matter injury and cognitive impairment caused by chronic cerebral hypoperfusion by enhancing OPCs proliferation (Yu et al., 2018). Additionally, high glucose concentrations may lead to polarization of microglia/macrophages toward a pro-inflammatory phenotype, severely affecting oligodendrocyte differentiation and white matter repair (Ma et al., 2018). Despite incomplete understanding of the molecular mechanisms, abnormalities in white matter microstructure are still considered an important biomarker and a cause of diabetes-induced neurological disorders (Jing et al., 2022; Liu et al., 2024).

As is well known, the hippocampus is closely associated with learning and long-term memory functions. Imaging studies have suggested that middle-aged and elderly patients with T2DM exhibit more extensive hippocampal atrophy compared to control groups (Hirabayashi et al., 2016; Ohara et al., 2020; Zhang W. et al., 2021). Interestingly, Zhang W. et al.’s (2021) findings indicate that in middle-aged T2DM patients, hippocampal atrophy is more strongly correlated with cognitive impairment than microvascular lesions. Due to differences in microvasculature, the NVC in the hippocampus is weaker than in the neocortex (Shaw et al., 2021). When pathological factors (such as a high glucose environment) impair NVC, the hippocampus is more susceptible to hypoxic damage, leading to hippocampal atrophy (Shaw et al., 2021; Zhang et al., 2022).

Animal studies suggest that diabetes leads to a decrease in the number of active neurons in the hippocampal region, possibly due to reduced neural stem cell proliferation and differentiation (Hwang et al., 2008, 2010; Ho et al., 2015), hippocampal cell aging (Wu et al., 2019) and increased apoptosis (Yan et al., 2019). In the hippocampus of diabetic rats, early mechanistic studies have reported impaired protein transport from the soma to dendrites (Gaspar et al., 2010), synaptic vesicle depletion (Magariños and McEwen, 2000), and altered neurotransmitter release (Misumi et al., 2008; Satoh and Takahashi, 2008). These diabetes-related effects may also contribute to the development of cognitive decline (Gaspar et al., 2010). Recently, Xiang et al. (2024) conducted single-cell RNA sequencing of the hippocampus in db-/- diabetic mice and found upregulation of genes involved in neuroactive ligand-receptor interaction, nervous system development, and inflammatory processes in the cognitive impairment group compared to the normal control group. Among them, the cross-gene Sstr2 may play an important role in regulating synaptic plasticity (Xiang et al., 2024). Research by Burillo et al. (2021) suggests that the harmful accumulation of amylin protein (a pancreatic secretory amyloid-like protein hormone) in pancreatic β cells may cause damage through the release of exosomes, which may be captured by hippocampal cells via endocytosis mechanisms, resulting in damage. Meanwhile, accumulation of amylin in the blood and brain microvasculature can lead to cerebral microbleeds, decreased CBF, white matter ischemia, and neurofunctional deficits. This is believed to cause oxidative damage to cell membrane lipids and activation of pro-inflammatory signaling pathways, leading to macrophage activation and vascular infiltration (Ly et al., 2017; Despa and Goldstein, 2021). Although cognitive decline in T2DM patients is associated with the aforementioned changes in brain function and structure, specific molecular mechanisms and effective preventive and therapeutic measures require further research and exploration.

Technic used for NVC measurement: The NVC mechanism also forms the physiological basis for blood oxygenation level-dependent (BOLD) functional imaging techniques of the brain, including functional magnetic resonance imaging (fMRI) and functional near-infrared spectroscopy (fNIRS) (Howarth et al., 2021). These imaging techniques monitor changes in the concentrations of oxygenated and deoxygenated hemoglobin in response to increased local CBF caused by neuronal electrical activity. By observing the relative changes in hemoglobin concentration, these imaging techniques allow for the examination of alterations in neuronal activity. The combination of functional imaging techniques with arterial spin labeling (ASL) MRI, which reflects cerebral tissue perfusion, enables the non-invasive measurement of the NVC status in the human brain under disease conditions (Howarth et al., 2021).

Hu et al. (2019) used fMRI and ASL to measure NVC in the brains of age-matched T2DM patients and healthy controls. They found that T2DM patients exhibited significantly lower NVC in nearly all brain regions. Specifically, lower NVC in the left hippocampus and amygdala was significantly correlated with poorer performance on the Stroop Color-Word Test, which reflects inhibitory functions in executive function (Okayasu et al., 2023). Yu et al. (2019) further confirmed the presence of NVC impairment in early-stage T2DM patients and established a correlation between NVC impairment and decline in executive function, with improved executive function performance as NVC improves (Yu et al., 2019). They suggest that NVC dysfunction is one of the potential mechanisms underlying mild cognitive impairment (MCI) associated with T2DM. Yu et al. (2019) also found that certain NVC parameters could serve as biomarkers for early assessment of cognitive decline in T2DM patients, which also contribute to a better understanding of NVC mechanisms (Ni et al., 2023). Additionally, three other clinical studies have identified changes in NVC during the early stages of diabetes (Duarte et al., 2015, 2023; Monteiro et al., 2021). These findings collectively validate previous conclusions that neurovascular uncoupling occurs in the early stages of T2DM and promotes the transition from diabetes-related mild cognitive impairment to dementia (Mogi and Horiuchi, 2011; Duarte et al., 2015; Venkat et al., 2016; Shekhar et al., 2017). T2DM patients without mild cognitive impairment are considered the best target population for preventive interventions (Yu et al., 2019; Kovacs-Oller et al., 2020; Ni et al., 2023). Furthermore, a longitudinal study by Zhang Y. et al. (2021) over 5 years indicated that T2DM may accelerate NVC damage in specific brain regions (left insula), leading to memory decline (Zhang Y. et al., 2021). Canna et al. (2022) identified spatial patterns of decreased NVC in the default mode network of T2DM patients, accompanied by isolated increases in NVC in the dorsal attention network (DAN) and ventral attention network (VAN), with DAN and VAN NVC abnormalities associated with declines in visual-spatial cognitive abilities (Canna et al., 2022). This may reflect the emergence of compensatory processes in response to changes in neurovascular status in T2DM patients. While these clinical studies have revealed the association between diabetes and NVC impairment, the mechanisms underlying diabetes-induced NVC disruption remain unclear, and targeted diagnostic and preventive interventions lack theoretical foundations and direction.

The comparison of fMRI vs. fNIRS on NVC functional evaluation: Current fMRI studies have certain limitations. Most studies focus on detecting the state of neuronal activity and CBF in the resting state of the brain. In reality, the energy demands of the brain are higher during cognitive tasks than during rest. Therefore, observations made in the resting state may only reflect a partial understanding of impaired NVC in diabetes patients. In comparison to fMRI, functional near-infrared spectroscopy (fNIRS) can be conducted in a more real-life environment, making it easier to observe and record cortical activity during cognitive tasks (Mazaika et al., 2020). Tamas’s review discusses the potential applications of fNIRS-based methods in studying NVC responses (Mazaika et al., 2020). However, research on diabetes-related NVC changes using fNIRS is relatively sparse at the moment, making it a fertile area for future investigation.

The characteristics of diabetes include impaired glucose metabolism and a hyperglycemic environment resulting from insulin resistance and/or deficiency. High blood sugar is the initial pathological factor in diabetes complications, leading to cellular damage in the brain by elevating glucose levels. Dorner et al. (2003) utilized a retinal vessel analyzer to measure the retinal vessel diameter, observing a significant reduction in the responsiveness of retinal vessels to flickering light stimuli in healthy young males during acute hyperglycemia (Dorner et al., 2003). Vetri et al. (2017) employed a closed cranial window technique and found that the reactivity of the pial arterioles in the somatosensory cortex decreased in response to sciatic nerve stimulation in type 1 diabetic mice (Vetri et al., 2017). Chhabria et al. (2020) established a zebrafish NVC model, combined with light sheet microscopy, revealing that prolonged exposure to high glucose levels damages NVC in zebrafish (Chhabria et al., 2020). In summary, both acute and chronic hyperglycemia can impair NVC.

The implementation of NVC relies on the NVU. Currently, studies have confirmed that certain components of the NVU exhibit abnormal morphology and function under diabetic conditions (Hayden, 2019; Yan et al., 2020; Little et al., 2022). Oxidative stress is considered one of the pathological mechanisms by which diabetes damages the NVU (Li et al., 2021), including increased levels of reactive oxygen species (ROS) (Jha et al., 2018; Li et al., 2023), the generation of advanced glycation end-products (AGEs) (Yamagishi et al., 2017; Li Y. et al., 2018), abnormal transcriptional activation of nuclear factor kappa B (NF-κB) (Homme et al., 2021), and excessive activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Rezende et al., 2018; Moon, 2023), among others. Additionally, chronic inflammation is recognized as an important feature of the pathophysiology of central nervous system diseases related to diabetes and is well demonstrated in diabetes experimental models (Robb et al., 2020). Among these, microglia play a role in the invasive destruction within the NVU and are associated with dysfunction of astrocytes (Hayden, 2019). In diabetic animal models, a shift from the M1/M2 polarization phenotype of microglia toward the M1 phenotype is detected in the cortex and hypothalamus, leading to excessive secretion of inflammatory cytokines, which is associated with downregulation of miR-146a expression under high glucose and glucose fluctuations (Huang et al., 2019). Indeed, the mechanisms underlying NVU damage are multifactorial and complex, and some review articles have summarized changes in the NVU under diabetic conditions and their mechanisms (Yan et al., 2020). Based on the current known mechanisms, from the perspective of understanding the implementation process of NVC, diabetes may damage NVC through two main aspects: disrupting key normal structures of neurovascular units and interfering with the transmission of cell signals related to NVC.

Early fMRI studies on healthy humans (Anderson et al., 2006; Driesen et al., 2007) and rats (Kennan et al., 2000) found a reduced blood flow response to stimulation during low blood sugar, attributing this phenomenon to impaired NVC. However, during hypoglycemia, the basal CBF increases to ensure glucose supply to brain neurons (McManus et al., 2020; Nippert et al., 2022), thought to be related to adenosine-induced increases in astrocyte Ca2+ signaling (Nippert et al., 2022). The mentioned studies did not record neuronal activity, and the observed changes in blood flow responses by fMRI might also be influenced by the increased basal CBF during hypoglycemia (McManus et al., 2020; Nippert et al., 2023). In a recent study, Nippert et al. (2023) simultaneously monitored the responses of neurons and blood vessels in the somatosensory cortex of awake healthy mice to whisker stimulation. They concluded that neuronal activity and NVC remain unchanged during hypoglycemia (Nippert et al., 2023). Although more experiments are needed to confirm this, Nippert et al.’s conclusion may be one of the more convincing for now.

The energy synthesis of astrocytes themselves is crucial for supporting NVC and neurons. On one hand, ATP and its metabolites serve as important signaling molecules for intercellular communication among astrocytes and NVC (Robinson and Jackson, 2016). On the other hand, during periods of high neuronal activity, astrocytes can replenish the neurotransmitter pool in neurons (Bélanger et al., 2011) and supply energy substrates to axons (González-Gutiérrez et al., 2020; Guo et al., 2021). Recurrent low glucose (RLG) reduces the expression of Sirtuin-3 (SIRT3) (a key deacetylase for mitochondrial proteins) in astrocytes cultured in a hyperglycemic environment, impairing mitochondrial homeostasis (Zhou et al., 2018; Gao et al., 2022), leading to disturbances in neuronal nutrition and neuronal cell death (Gao et al., 2021). Overexpression of SIRT3 can improve the function of astrocytic mitochondria by increasing mitochondrial bioenergetic status and reducing mitochondrial oxidative stress levels (Gao et al., 2022). Recently, some 1,4-dihydropyridine-based compounds have been suggested as specific activators of SIRT3 (Suenkel et al., 2022; Zwergel et al., 2023), providing a framework for drug research to treat RLG-induced neuronal injury and NVC impairment.

Antidiabetic medications, such as metformin (Secnik et al., 2021), sodium-dependent glucose co-transporter 2 inhibitors (SGLT2i) (Rizzo et al., 2022), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) (Ma et al., 2015), and glucagon-like peptide-1 receptor agonists (GLP-1RAs) (Cukierman-Yaffe et al., 2020), are believed to have potential benefits in improving cognitive function. However, it remains unclear whether the improvement in NVC is one of the mechanisms. Some drugs have been found to enhance NVC, such as the SGLT2 inhibitor tofogliflozin (Hanaguri et al., 2022c), peroxisome proliferator-activated receptor alpha (PPARα) agonist Fenofibrate (Hanaguri et al., 2022a), and Lutein (Hanaguri et al., 2022b), which improve retinal NVC in Type 2 Diabetic Mice. Resveratrol, a polyphenolic compound primarily found in fruits, can enhance NVC and cognitive function in T2DM (Wong et al., 2016; Tu et al., 2023). This is not only related to the improvement of endothelial BH4/eNOS mentioned above, but also to the inhibition of the activation of NF-κB signaling to play an anti-inflammatory role (Parsamanesh et al., 2021). Nicotinamide mononucleotide (Kiss et al., 2020a) and dipeptide (Rom et al., 2018) are considered to improve NVC by enhancing endothelial function. Modulating the NO pathway in the human body may be an effective approach for treating NVC disruptions associated with T2DM (Lourenço and Laranjinha, 2021). Nitroprusside can ameliorate the adverse effects of persistent hyperglycemia on NVC in zebrafish (Chhabria et al., 2020). In addition to providing NO directly, nitroprusside has also been found to reduce astrocyte reactivity (Chhabria et al., 2020). Most of these drugs are still in the experimental stage. primarily in animal studies, and further research, including clinical trials, is needed for validation. Additionally, the development of mitochondria-targeted antioxidants can enhance mitochondrial antioxidant defenses, potentially increasing the bioavailability of NO and rescuing NVC responses in aged mice (Csiszar et al., 2019). Developing antioxidants targeted at mitochondria could be a promising direction for future drug development.

In summary, the diabetic environment may impair NVU structure and NVC signal transduction, leading to cognitive decline (Figure 3). Research on therapeutic drugs targeting known mechanisms is still in the experimental stage. The intricate network of interacting factors contributing to NVC damage induced by diabetes requires further in-depth investigation. In addition to NVC, we also need to consider a relatively new model known as vascular-neuronal coupling (VNC), where changes in vascular tension can influence neuronal electrical activity (Kim et al., 2016). Diabetes is widely recognized as a risk factor for brain arteriolosclerosis (B-ASC) (Borshchev et al., 2019). B-ASC is characterized by pathological thickening of the small arterial walls and decreased compliance, and it is associated with cognitive impairment (Blevins et al., 2021). Could the reduction in vascular compliance caused by B-ASC lead to cognitive decline through VNC? This is a relatively unexplored area that may offer new insights into the mechanisms of diabetes-related cognitive impairment.

LF: Writing – original draft, Writing – review & editing. LG: Resources, Supervision, Writing – original draft, Writing – review & editing.