Brain Functional Changes In Type 2 Diabetes And Its Relation To Cognitive Impairment:A Study Using Resting-State Functional Magnetic Resonance Imaging

Part 1: Altered Amplitude of Low-frequency Fluctuation (ALFF) and Regional Hmogeneity (ReHo) Values in Type 2 Diabetes PatientsObjective: Previous research has shown that type 2 diabetes mellitus (T2DM) is associated with an increased risk of cognitive impairment. Patients with impaired cognition often show decreased spontaneous brain activity on resting-state functional magnetic resonance imaging (rs-fMRI). This study used rs-fMRI to investigate changes in spontaneous brain activity among patients with T2DM and to determine the relationship of these changes with cognitive impairment.Methods: T2DM patients (n = 29) and age-, sex-, and education-matched healthy control subjects(n = 27) were included in this study. Amplitude of low- frequency fluctuation (ALFF) and regional homogeneity (ReHo) values were calculated to represent spontaneous brain activity. Brain volume and cognition were also evaluated among these participants.Results: Compared with healthy control subjects, patients with T2DM had significantly decreased ALFF and ReHo values in the occipital lobe and postcentral gyrus. Patients performed worse on several cognitive tests; this impaired cognitive performance was correlated with decreased activity in the cuneus and lingual gyrus in the occipital lobe. Brain volume did not differ between the two groups.Conclusion: The abnormalities of spontaneous brain activity reflected by ALFF and ReHo measurements in the absence of structural changes in T2DM patients may provide insights into the neurological pathophysiology underlying diabetes-associated cognitive decline.Part 2: Aberrant Functional Connectivity of Default-mode Network in Type 2 Diabetes PatientsObjective: Type 2 diabetes mellitus is associated with increased risk for dementia. Patients with impaired cognition often show default-mode network disruption. We aimed to investigate the integrity of a default-mode network in diabetic patients by using independent component analysis,and to explore the relationship between network abnormalities, neurocognitive performance and diabetic variables.Methods: Forty-two patients with type 2 diabetes and 42 well- matched healthy controls were included and underwent resting-state functional MRI in a 3 Tesla unit. Independent component analysis was adopted to extract the default-mode network, including its anterior and posterior components. Z- maps of both sub-networks were compared between the two groups and correlated with each clinical variable.Results: Patients showed increased connectivity around the medial prefrontal cortex in the anterior sub-network, but de- creased connectivity around the posterior cingulate cortex in the posterior sub-network. The decreased connectivity in the posterior part was significantly correlated with the score on Complex Figure Test-delay recall test (r=0.359, p=0.020), the time spent on Trail-Making Test-part B (r=-0.346, p= 0.025) and the insulin resistance level (r=-0.404, p=0.024).Conclusion: Dissociation pattern in the default-mode network was found in diabetic patients, which might provide powerful new insights into the neural mechanisms that underlie the diabetes-related cognitive decline.Part 3: Disrupted Brain Connectivity Patterns in Patients with Type 2 DiabetesObjective: Type 2 diabetes is associated with increased risk for dementia. This study aims to investigate the global connectivity pattern in patients with type 2 diabetes using resting-state functional MRI technique.Methods: Forty patients and 43 age-, sex- and education-matched healthy controls were included and underwent MRI scanning. Global functional connectivity strength (FCS) was computed and compared between the two groups in a voxel-wise manner. Brain regions with aberrant connectivity strength were then set as seed (reference) regions to identify specific brain circuits that contribute to the aberrant connectivity strength in the patient group. Finally, voxel-wise correlation analyses were performed to examine the relationships between each brain circuit connectivity, cognitive performance and clinical variables.Results: Patients exhibited decreased connectivity strength in the left lingual gyrus, and increased strength in the right insula and dorsal anterior cingulate cortex. Seed-based analyses revealed that the occipital network anchored in the lingual gyrus showed extensively reduced connectivity, while the network connectivity anchored in insula and cingulate cortex (mostly included in the salience network) was significantly elevated. The occipital hypoconnectivity was correlated with impaired performance in both visual memory and executive functioning, while the anterior cingulate cortex hyperconnectivity was related to higher fasting plasma glucose level and better executive functioning.Conclusion: The current results represent the effects of type 2 diabetes on global functional organization, which may provide critical insights into the neural substrate of cognitive decline under the context of hyperglycemia.Part 4: Cerebral Perfusion Alterations in Type 2 Diabetes and Its Relation to Insulin Resistance and Cognitive DysfunctionObjective: To compare the cerebral perfusion between T2DM and healthy controls, and to explore the relationship between perfusion changes and cognitive impairment as well as diabetic variables in T2DM patients, by using a whole-brain arterial spin-labeling (ASL) MRI technique.Methods: This prospective study was approved by the local institutional review board and was performed between November 2012 and October 2013. All subjects provided informed consent.Forty T2DM patients and 41 age-, sex- and education-matched healthy controls were included.Cerebral blood flow (CBF) map was obtained by pulsed ASL perfusion imaging at 3T MRI. Voxel-wise comparisons on CBF maps with and without partial volume effects (PVEs) correction were performed between groups. Associations between CBF and cognitive functioning, and between CBF and diabetic variables were investigated by using voxel-wise, whole-brain correlation analyses.Results: In T2DM patients, PVEs uncorrected CBF was decreased in the posterior cingulate cortex(PCC), precuneus and bilateral occipital lobe, and increased in the anterior cingulate cortex(corrected P < .05). These findings were largely unchanged after PVEs correction. Correlation analyses revealed that in patients, hypoperfusion in PCC and precuneus regions were related to higher insulin resistance level and deficits in clock-drawing performance, while the occipital hypoperfusion was associated with worse visual-memory performance, regardless of PVEs correction.Conclusion: The cerebral hypoperfusion pattern in T2DM resembles the pattern observed in the early stage of dementia, and increased insulin resistance might be an important risk factor as well as treatment target for such CBF dysregulation.