In this study, we found significant differences in the regional susceptibility values in the putamen, dentate nucleus and thalamus between patients with T2DM and healthy elderly individuals. In iron-rich gray matter nuclei, the brain iron deposits in patients with T2DM have obviously increased in some gray nuclei in vivo. The increased iron content in these gray matter nuclei may be related to the iron ions influencing the synthesis of neurotransmitters and the various metabolic activities across regions and types of neurons. There were significant correlations between the changes in iron deposition across hemispheres in the dentate nucleus and the putamen. These brain regions contain important structures closely involved in cognitive, emotional, and motor functions, which suggests that the synergy of these changes may affect the neural pathways in the brain and impact the neural function of the brain. These findings suggest that increased iron deposition in the brain may be used for measuring the risk of the severity of brain injury in patients with T2DM. QSM can be used as a noninvasive quantitative analysis to assess brain iron deposition in patients with T2DM.
Iron is a fundamental requirement for most known life forms and is the richness trace element in the human body (25). Iron acts as a significant component of hemoglobin that participates in oxygen transport. Iron in the nervous system can also affect catecholamine neurotransmitter metabolism and myelin formation. Hence, it is necessary to strictly regulate the metabolism of iron. Even so, excessive deposition of iron in the brain of the aged will easily lead to different kinds of neurodegenerative diseases (26). Therefore, studying and understanding the iron metabolism mechanism in the brain together with its regulation are of vital significance. (27). In normal healthy people, the deep gray matter nuclei have higher iron content and contain important structures closely involved in cognitive, emotional, and motor functions. This study consequently selected these areas as the research object.
We know that iron is an essential regulatory factor for glucose and lipid metabolism (28). As revealed by many studies, ferritin as the standard marker specific to iron stores can assist in increasing diabetes risk, such as insulin resistance (29) (30). Clinical studies have reported the direct association between iron overload in the human body and glucose intolerance, which can accordingly result in diabetes. Insulin resistance causes high permeability of the blood-brain barrier and induces a cognitive decrease in a mouse model induced by diabetic insulin resistance and in an AD model (31). Additionally, an overload of brain iron results in insulin resistance together with cognitive decrease in animal obesity models and human obesity models (32). In general, iron overload and iron deficiency can greatly affect the action of insulin as well as its relation to insulin resistance. As insulin resistance could trigger iron overload, we intended to identify the relationship between iron accumulation and central nervous system injury in patients with T2DM.
The dentate nucleus is the most lateral deep cerebellar nucleus and is rich in iron. The cerebellar vermis and roof of the fourth ventricle are adjacent to the dentate nucleus. A sagittal section through the dentate nucleus shows its serrated appearance (33). The dentate nucleus is capable of regulating fine control regarding voluntary movements, language, cognition, and sensory functions. Utilizing the dentatothalamic tract, the dentate nucleus sends output signals through the ipsilateral superior cerebral peduncle and then decussates to synapse in the contralateral ventrolateral (VL) thalamic nucleus. VL neurons send fibers to the precentral gyrus, premotor cortex, prefrontal gyri, posterior parietal areas, and basal ganglia, specifically the striatum (34) (35). Different parts of the striatum receive afferent input from various cortical regions, followed by projecting efferent output to the cortex through the thalamus (36). The anterior putamen links to the associative regions in the cortex, and the posterior portion links to the primary motor cortex as well as the supplementary motor area (37). We found significant changes in the susceptibility values in the putamen, dentate nucleus and left thalamus in the patients with T2DM. This may indicate that the increased iron deposition will cause damage to the gray matter nuclei, which may affect voluntary movements, cognition, language, and sensory functions.
The striatum plays a significant role in various brain functions, including language, motor learning and control, reward, cognitive functioning, and addiction through the functional cortico-striato-thalamocortical neural pathways (38) (39). Therefore, a pathologic state in the striatum can lead to a broad range of clinical manifestations from motor dysfunction, such as Parkinson’s disease, to various psychiatric disorders (40). Studies have shown that the dentate nucleus in the cerebellum leads to a tight disynaptic projection to the striatum. The basal ganglia, the cerebral cortex and the cerebellum together constitute an integrated network, which undergoes topographical organization to ensure the interconnection among the motor, affective and cognitive domains of every node (35) (41). The iron deposition changes were significantly correlated across hemispheres in the dentate nucleus and the putamen, and the iron deposition in the left thalamus also increased. It was hinted that the synergy of these changes may potentially affect the cortico-striato-thalamocortical neural pathways and impact the neural function of the brain in patients with T2DM.
Regarding the deposition of brain iron in T2DM patients, previous study results regarding the content of iron in the pulvinar nuclei of patients who have neurodegenerative diseases are not consistent. A previous study investigated the deposition of iron in T2DM patients’ brains and related cognitive impairments using QSM. The susceptibility of T2DM patients who did not undergo MCI and T2DM patients who underwent MCI remarkably increased in the left putamen. The susceptibility values in the left putamen can significantly affect the neuropsychological cognitive score (42). Our study showed similar results, which also suggested that there were obviously higher susceptibility values in the putamen in T2DM patients than in healthy elderly individuals. However, no correlations between susceptibility values and cognitive function scores were found, which may be due to the different research populations. T2DM patients were not divided into subgroups according to the degree of impairment in cognitive function. Some researchers have evaluated the effects of DM in patients with cognitive impairment using QSM. DM could lead to lower susceptibility changes in the pulvinar thalamus as well as hippocampus. The study showed region-specific changes in calcium deposition in DM subjects with cognitive impairment (43). Therefore, the reason for the difference between studies was the selection of patients with cognitive impairments with different independent risk factors in the previous study, and they did not make comparisons with healthy elderly individuals.
The comparison of the MoCA and SCWT scores between the patients with T2DM and healthy elderly individuals demonstrated that the patients with T2DM showed potential cognitive impairment compared to the healthy elderly individuals. MCI is generally considered to be the precursor of AD. The susceptibility values increased in the gray matter nuclei. However, a significant relationship between iron deposition and cognitive assessment scores was not found. It is suggested that the dentate nucleus-thalamus-putamen is the pivotal part of the cortico-striato-thalamocortical neural pathways that predict the conversion of MCI to AD in patients with T2DM. The increase in susceptibility values can be used as an important quantitative imaging marker. Previous studies have also shown that isolated putamen hemorrhage can lead to impaired frontal lobe function in patients, leading to attention-executive dysfunction (44); there are also task-related attentional and executive function disruptions involving the putamen of patients with multiple sclerosis clinically isolated syndrome (42, 45).
QSM acts as a new MRI approach that can quantify materials with changing susceptibility and has been shown to provide a noninvasive quantitative analysis of brain iron deposition (12) (13). It exhibits a stronger selectivity for iron compared with T2* relaxometry and can serve for data obtained via standard sequence acquisition that is available for a majority of commercial scanners. It acts as a useful computer algorithm for deriving values with sensitivity to the iron level from proper MRI data (14) (46). The iron stored in ferritin, neuromelanin and hemosiderin in the brain tissue leads to high local magnetic and paramagnetic distortion (47). As a way to measure the level of brain iron, QSM boosts many advantages (14), which have been validated by MRI techniques sensitive to brain iron. It has been reported that brain iron burden under the measurement of the above techniques increases in AD subjects, with a positive relation to the amyloid-β burden and an inverse relation to cross-sectional cognitive performance in older and AD subjects (48) (49). In addition, the process of iron deposition in the brain during normal aging and neurodegenerative changes may cause neuronal damage through oxidative stress (42, 50). According to a review of the current literature, there are several potential reasons for cerebral iron deposition in patients with T2DM. Iron binds to amyloid-β to catalyze pro-oxidant radicals to be produced, thereby increasing the toxicity of peptide, which binds to tangles as well, leading to the formation of toxic radicals in neurons in a similar way (51). Synthetic amyloid-β intoxication in the mouse brain causes tau-dependent iron accumulation as well as cognitive impairment (52), which demonstrates that tau can mediate the effects of iron.
The study was a preliminary cross-sectional design study of brain iron changes in T2DM patients in a relatively small sample size. The iron deposition dynamics shall be observed, together with the examination of longitudinal levels of brain iron in T2DM patients in larger samples at different stages. It is necessary to perform a prospective study covering a large scale for determining the changes of magnetic susceptibility in certain regions as well as further exploring the potential mechanisms and the effect posed by iron deposition in gray matter nuclei pathology. Although automatic segmentation is the most appropriate method specific for imaging analysis based on previous studies, in this study, we use manual segmentation as the reference standard for complicated structures and try to use methods of whole-brain voxel analysis to make comparisons in further research.