Pre-diabetes is associated with altered functional connectivity density in cortical regions of the default-mode network

Abstract

Insulin resistance and glucose dysregulation are associated with patterns of regional brain hypometabolism characteristic of Alzheimer’s disease (AD). As predicted by evidence linking brain glucose metabolism to brain functional connectivity, type 2 diabetes is accompanied by altered functional connectivity density (FCD) in regions highly vulnerable to AD, but whether these alterations start at earlier stages such as pre-diabetes remain to be elucidated. Here, in addition to assessing whether pre-diabetes leads to a functional reorganization of densely connected cortical areas (hubs), we will assess whether such reorganization is conditioned by sex and/or insulin resistance, and contributes to improved cognition. One hundred and forty-four cognitively unimpaired middle-aged and older adults (55–78 years, 79 females), 73 with normoglycemia and 71 with pre-diabetes, underwent resting-state fMRI scanning. We first computed FCD mapping on cortical surfaces to determine the number of short- and long-range functional connections of every vertex in the cortex, and next used hubs showing aberrant FCD as seeds for the resting-state functional connectivity (rs-FC) calculation. ANCOVAs and linear multiple regression analyses adjusted by demographic and cardiometabolic confounders using frequentist and Bayesian approaches were applied. Analyses revealed higher long-range FCD in the right precuneus of pre-diabetic females and lower short-range FCD in the left medial orbitofrontal cortex (mOFC) of pre-diabetic individuals with higher insulin resistance. Although the mOFC also showed altered rs-FC patterns with other regions of the default mode network in pre-diabetic individuals, it was FCD of the precuneus and mOFC, and not the magnitude of their rs-FC, that was associated with better planning abilities and Mini-Mental State Examination (MMSE) scores. Results suggest that being female and/or having high insulin resistance exacerbate pre-diabetes-induced alterations in the FCD of hubs of the default-mode network that are particularly vulnerable to AD pathology. These changes in brain network organization appear to be compensatory for pre-diabetic females, likely assisting them to maintain cognitive functioning at early stages of glucose dysregulation.

Insulin effects on core neurotransmitter pathways involved in schizophrenia neurobiology: a meta-analysis of preclinical studies. Implications for the treatment

“…Consistently, in first-episode psychosis and antipsychotic naïve patients, a potential association of insulin resistance with diminished response to antipsychotic treatment can be identified [ 8 ]. Further, abnormal neuroimaging findings have been detected in diabetic and pre-diabetic patients without psychiatric illness [ 177 – 179 ]. Thus, greater attention should be paid to different patterns of brain functional and structural connectivity in psychotic patients detected in the absence or presence of metabolic abnormalities, with further implications for treatment responsiveness and resistance.…”

The Interaction Effects of Age, Sex, APOE and Common Health Risk Factors on Human Brain Functions

“…Except for the L_PBelt-L_V3, the positive directions of 88.8% of these associations in the British cohort were validated by the non-British population. These results suggest that females with diabetes experience a greater reduction in visual-auditory connectivity than males, highlighting the greater impact of diabetes on connectivity in females 41 .…”

“…This positive association was particularly evident between multiple ROIs within these networks, such as L_PBelt and L_V3. These results suggest that diabetes may impact brain connectivity differently based on sex, with females showing a greater change in visual-auditory connectivity 41 .…”

“…The aim of this study is to perform a comprehensive association analysis between brain FCs and various risk factors, including APOE genotype, age, sex, ten MHRFs, as well as their interactions. The ten primary MHRFs include six adverse factors-hypertension [36][37][38][39][40] , diabetes [41][42][43] , smoking [44][45][46] , obesity [47][48][49] , excessive alcohol consumption 50,51 , and social deprivation 52 , that have been extensively studied for their association with disrupted brain functional network connectivity, leading to cognitive impairments. Additionally, four beneficial MHRFs-higher education [53][54][55] , physical activity 56,57 , healthy diet 58,59 and adequate sleep 60 are included as they have been shown to enhance functional connectivity, promote more segregated and resilient functional networks 61,62 and improve the neuroplasticity 63 .…”

Structural and functional connectivity alteration patterns of the cingulate gyrus in Type 2 diabetes

“…This study implies that this “seesaw” relationship may also exists in T2DM patients without MCI, and that the LPFC may compensate for poor hippocampal function in T2DM patients. Although several previous neuroimaging studies 62–64 have suggested a compensatory mechanism in the brain function of T2DM patients without MCI, none of them can provide strong evidence. Our results may provide some imaging basis for the compensatory mechanisms in the brain network in T2DM, which have been difficult to prove for a long time.…”