White Matter Integrity Disruptions Associated With Cognitive Impairments in Type 2 Diabetic Patients

Abstract

Type 2 diabetes mellitus (T2DM) is associated with a twofold increased risk of dementia and can affect many cognitive abilities, but its underlying cause is still unclear. In this study, we used a combination of a battery of neuropsychological tests and diffusion tensor imaging (DTI) to explore how T2DM affects white matter (WM) integrity and cognition in 38 T2DM patients and 34 age-, sex-, and education-matched normal control subjects. A battery of neuropsychological tests was used to assess a wide range of cognitive functions. Tract-based spatial statistics combined with region of interest-wise (ROI-wise) analysis of mean values of DTI metrics in ROIs was used to compare group differences of DTI metrics on WM skeletons to identify severely disrupted WM tracts in T2DM. We found that T2DM patients showed 1) various cognitive impairments, including executive function, spatial processing, attention, and working memory deficits; 2) widespread WM disruptions, especially in the whole corpus callosum, the left anterior limb of the internal capsule (ALIC.L), and external capsule (EC); and 3) a positive correlation between executive function and WM integrity in the ALIC.L and the left EC.In conclusion, T2DM patients show various cognitive impairments and widespread WM integrity disruptions, which we attribute to demyelination. Moreover, executive dysfunction closely correlates with WM abnormalities.Type 2 diabetes mellitus (T2DM) in the elderly is a major public health problem. In China, .20.4% of the elderly population has diabetes, among which T2DM accounts for ;90% (1). As a risk factor for cognitive decline, T2DM is associated with a twofold increased risk of dementia (2) and can affect a wide range of cognitive abilities (3,4). However, its underlying cause is still unclear.A number of studies were carried out to investigate the mechanisms of T2DM-induced dementia and attributed the cognition decline to cerebral microstructure impairments, which included gray matter (GM) and white matter (WM) destruction (5,6). Despite the importance of GM atrophy in T2DM, WM microstructure abnormalities played a distinct and irreplaceable role in cognition impairments induced by T2DM (7,8). WM has a vital role for transferring information between GM regions, and its efficiency depends on WM microstructural integrity (9). However, the relationship between WM microstructural changes and T2DM is debated and contradictory. Many studies suggested a close correlation between T2DM and WM lesion (WML) severity or progression (5,10), but others did not (11,12). This uncertainty could be partly due to the insufficient sensitivity of conventional MRI modalities in detecting subtle brain WM changes or assessing the severity of WM hyperintensities (WMH) (7).Diffusion tensor imaging (DTI), a new type of MRI, has been developed as a powerful noninvasive technique to investigate WM microstructures and integrity (13,14). Fractional anisotropy (FA) and mean diffusivity (MD)

Disrupted White Matter Network and Cognitive Decline in Type 2 Diabetes Patients

“…We found similar results from Reijmer et al's study that WMN parameters were associated with worse cognitive performances in patients with T2DM [12]. Besides, studies in T2DM patients showed that executive function impairment was related to WM integrity decline including internal and external capsules [7]. These findings also support the idea that the decreased nodal efficiency of ROL connects with executive function impairment in T2DM patients.…”

“…These abnormal phenomena maybe attributed to reduced WM integrity and increased disconnection; some microvascular lesions and enlarged perivascular spaces would induce possible neuropathology changes in T2DM [30]. Previous studies provide direct evidence for disrupted structural integrity in various WM tracts in diabetic patients, such as the corpus callosum [7,31]. Overall, our findings provide additional evidence for the imbalanced topological organizations and reduced efficiency for signal propagation in patients with diabetes.…”

“…Cerebral atrophy and WM lesions, which were commonly observed structural anomalies, are believed to be modestly associated with diabetes-related cognitive dysfunction [4,5]. Recent studies have shown that T2DM patients exhibited reduced WM integrity in the whole brain [4] and that specific tracts such as the cingulum bundle and the uncinate fasciculus exhibited lower fractional anisotropy (FA) in T2DM patients [6,7]. These studies suggest that WM structural disconnections play a potential part in the cognitive decline of diabetic patients.…”

Altered Brain Activation Patterns Under Different Working Memory Loads in Patients With Type 2 Diabetes

“…Studies on middleaged adults with cognitive complaints also have shown that lower activation in the SFG is related to poorer WM performance (42). Moreover, in light of recent white matter studies, increased impairments in the frontal fiber tracts were associated with reduced executive function (43) and information processing speed (16) in T2DM patients. Demyelination of axons, loss of glial cells, expanded microvascular lesions, enlarged perivascular spaces, and even bloodbrain barrier disruptions possibly induce neuropathological changes in brain structure and function in T2DM patients (44).…”

Thalamic resting-state functional connectivity: disruption in patients with type 2 diabetes

“…Structural MRI studies on T2DM have revealed the aberrant hyperintensity in the thalamus associated with impaired speed of mental processes and memory (Akisaki et al 2006). Zhang et al reported decreased fractional anisotropy and increased mean diffusivity in widespread WM tracts in T2DM compared with controls, including the posterior thalamic radiation (Zhang et al 2014). Furthermore, impaired macromolecular protein pools in fronto-striato-thalamic circuits were demonstrated in T2DM using magnetization transfer imaging (Yang et al 2014).…”