Discussion
To our knowledge, this is the first study to investigate longitudinal changes of regional NVC in patients with T2DM by combining BOLD and ASL techniques. Patients with T2DM showed decreased mReHo:mCBF ratio in the left insula, the left postcentral gyrus, the right Rolandic operculum, and the right precentral gyrus. The mReHo:mCBF ratio was associated with memory performance in patients with T2DM. These findings may improve our understanding of the neural mechanisms of T2DM-related memory changes from the perspective of regional NVC.
ReHo based on BOLD signals is a voxel-based measure of neuronal activity.35 Although ReHo is an indirect measure of neural activity, it is one of the most commonly used rs-fMRI analytical methods36 37 and has high test–retest reliability.38 Majority of studies on T2DM displayed reduced ReHo values in occipital regions, with mixed findings in other regions such as the temporal lobe, postcentral gyrus, olfactory cortex, putamen, and so on.12 Increased ReHo in the precuneus and insula in patients with T2DM was also reported.11 39 40 As to the superior frontal gyrus, both increased and decreased ReHo values have been observed.39 40 ASL-CBF provides a quantitative measure of cerebral blood supply. The results of ASL study in T2DM are controversial,2 which may be due to the different patients included, including differences in age and differences in disease severity and duration. Although the exact pathophysiological mechanism underlying brain dysfunction and cognitive impairments in patients with T2DM remains uncertain, it is more likely to be a combination of neurodegenerative and vascular factors than any single one. This point was based on several experiments3 5 6 41 that confirmed NVC changes in patients with T2DM. NVC refers to the association of neural activity and CBF. Therefore, a combination of ReHo and CBF images (ReHo:CBF) reflecting the NVC may serve as a valuable in vivo method to elucidate the neural mechanisms of T2DM-related cognitive decline. Actually, the MRI method combining quantified neural activities and CBF has been successfully used for evaluating NVC changes in neuromyelitis optica19 and schizophrenia.18
In the current study, patients with T2DM exhibited decreased mReHo:mCBF ratio in the left insula, the right Rolandic operculum, the left postcentral gyrus, and the right precentral gyrus at 5-year follow-up. This decreased neuronal activity per unit CBF reflects the deviation from the previous balance (abnormal NVC). This can be interpreted as: under the same cerebral blood supply condition, the neural activity of patients with T2DM is reduced compared with that in 5 years ago. In other words, the brain needs to obtain more blood supply to maintain the same neural activity as it was 5 years ago.
The precentral/postcentral gyrus is not only associated with sensorimotor function, but also critical for cognitive activities42 and function of execution and attention.43 The posterior insula connects to the sensorimotor cortex, the dorsal-posterior cingulate, and occipital areas, functionally involved in processing and integrating external tactile, auditory, and intrinsic sensory information. It was also implicated in advanced cognitive functions such as language-related topics.44 The left insula was shown to be closely related to phonological working memory,45 and left insula damage was associated with poorer verbal memory performance.46 Given these roles, a healthy NVC state in the insula and precentral/postcentral gyrus should be essential for memorizing vocabulary (language-related). Therefore, disturbed regional NVC in these regions may interfere with the process of verbal memory. This was supported by the positive correlation between the mReHo:mCBF ratio in the left postcentral gyrus and the left insula and several memory metrics from the AVLT, which means that patients with higher mReHo:mCBF ratio demonstrated better memory performance. These results suggested that the NVC in the left postcentral gyrus and the left insula was critical for verbal memory, and patients with T2DM could maintain memory function at a relatively normal level through a brain compensation mechanism. Once the balance of the coupling deviates to a severe extent, the decompensation might occur and lead to decreased cognitive performances. However, this speculation should be verified in a longer-time follow-up study.
The right Rolandic operculum was expected to be involved in the compensation mechanism in the aging process,47 and therefore the right Rolandic operculum might be a reserved compensation-related brain region and could work with the left brain areas to maintain memory function during the neurodegenerative process in T2DM. Disturbed NVC in the right Rolandic operculum may lead to a diminished compensatory capacity.
Among the four clusters, only the mReHo:mCBF ratio in the left insula decreased more severely in patients with T2DM than in the HCs, while the changes in the other three clusters were similar in the two groups. These results were within our expectations and consistent with previous research. Cerebral matter volume changes in the sensorimotor cortex and Rolandic operculum area have been found in the normal aging processes.48 In addition, a previous review reported most patients with T2DM exhibit changes in cognition and brain that are comparable with their peers without diabetes who are 3–5 years older.49 Based on these, we speculated that patients with T2DM and HCs could share a common brain aging pattern; as shown in our results, the NVC changes in the left postcentral gyrus, the right Rolandic operculum, and the right precentral gyrus were similar within the two groups. However, the long-term persistent hyperglycemia, inflammatory, and oxidative stress processes could lead to neurovascular damage and blood–brain barrier dysfunction,50 which may accelerate the aging-related neurodegeneration in patients with T2DM. Therefore, it is explicable to find a more obvious mReHo:mCBF ratio decline in the left insula in patients with T2DM than that in the HCs. More significantly decreased mReHo:mCBF ratio in the left insula indicated more severe NVC damage of this area in patients with T2DM. The correlation between the mReHo:mCBF ratio in the left insula and verbal memory was found in patients with T2DM but not in the HCs, which suggested that neurovascular compensation may occur earlier in patients with T2DM than in HCs. With the disease progressing, the neurovascular damage may exceed the range of compensating ability; patients with T2DM will have to face decompensation and show a more severe memory dysfunction. The Δr of the mReHo:mCBF ratio in the right Rolandic operculum of the patient group was higher than that of the HCs (p=0.045) in the between-group comparisons without multiple comparisons (see online supplemental material 1 for specific methods and results). As mentioned, the right Rolandic operculum may be related to the compensatory reserve capacity of the brain. In patients with T2DM, compensation of the brain was likely to be activated earlier than in the HCs due to their accelerated brain degeneration and was manifested by increased NVC at an early stage. As the disease progresses, decompensation gradually appears and the NVC would decrease at an accelerated rate. However, this dynamic changing pattern of the NVC with the development of the disease is only a speculation. Unfortunately, this study only collected data at two time points spanning 5 years, which could not confirm this speculation. Therefore, a longer-term and multipoint longitudinal study is needed. No correlation was found between any memory performance and the mReHo:mCBF ratio value of any area of the brain in HCs. This may be due to the fact that the cognition level of HCs at this stage was still above the ceiling of the cognitive assessment in this study.
Baseline HbA1c of patients with T2DM was found to be positively correlated with follow-up mReHo:mCBF ratio in the left insula, which is exactly the region with severely decreased mReHo:mCBF ratio in patients with T2DM compared with HCs. The positive correlation between HbA1c and the mReHo:mCBF ratio suggested that hyperglycemia seems to help maintain a relatively higher brain activity per unit blood flow supply in patients with T2DM. However, the 5-year decrease in mReHo:mCBF ratio was more severe in patients with T2DM than HCs. Therefore, this positive effect of hyperglycemia could be limited and might only exist in specific conditions, such as patients with T2DM who have not developed complications and whose brain function is still compensable. Additionally, the correlation was not found between follow-up HbA1c and follow-up mReHo:mCBF ratio. It suggested that the effect of hyperglycemia on NVC was not immediate; that is, early sustained hyperglycemia would have an impact on NVC at a later stage. Nevertheless, this explanation should be taken with caution.
In conclusion, this study conducted a 5-year follow-up study on patients with T2DM. It was found that the mReHo:mCBF ratio decreased in four brain regions, among which three brain regions showed a similar pattern of decline between the two groups while the left insula exhibited a more severe decline in patients with T2DM than in HCs. Positive correlations were detected between the mReHo:mCBF ratio and memory performance in patients with T2DM. These results suggested that T2DM may accelerate NVC disorder in specific brain regions, and the left insula may be one vulnerable target. This study implies that the mReHo:mCBF ratio is a potential imaging marker for detecting neurovascular impairment in patients with T2DM.
There are three limitations to our study. First, our 5-year follow-up study found decreased mReHo:mCBF ratio in the precentral and postcentral gyri, which are closely related to sensorimotor function. Diabetic peripheral neuropathy is a common complication in patients with T2DM, manifested as numbness, pain, and other paresthesias. Patients with T2DM in this study did not have peripheral neuropathy; therefore, our result suggested that disturbed NVC may occur before the appearance of clinically measurable symptoms. However, sensorimotor functions were not quantitatively tested in our study, and the relationship between the mReHo:mCBF ratio and the sensorimotor function was not assessed. Therefore, this assumption needs to be verified in future studies. Second, due to the long follow-up interval and the need for long-term medication to control blood glucose in patients with T2DM, the interference of treatment on the follow-up results could not be ruled out. Third, this study was the first to explore mReho:mCBF ratio longitudinal changes in patients with T2DM, and whether the results of this study can be generalized to the general diabetic population still needs to be verified by further research.