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Abstract
Type 2 diabetes mellitus (T2DM) patients show brain tissue changes in mood and cognitive regulatory sites, but the nature and extent of tissue injury and their associations with symptoms are unclear. Our aim was to examine brain tissue damage in T2DM over controls using mean diffusivity (MD) computed from diffusion tensor imaging (DTI), and assess correlations with mood and cognitive symptoms in T2DM. We collected DTI series (MRI), mood, and cognitive data, from 169 subjects (68 T2DM and 101 controls). Whole-brain MD-maps were calculated, normalized, smoothed, and compared between groups, as well as correlated with mood and cognition scores in T2DM subjects. Type 2 diabetes patients showed altered cognitive and mood functions over control subjects. Multiple brain sites in T2DM patients showed elevated MD values, indicating chronic tissue changes, including the cerebellum, insula, and frontal and prefrontal cortices, cingulate, and lingual gyrus. Associations between MD values and mood and cognition scores appeared in brain sites mediating these functions. Type 2 diabetes patients show predominantly chronic brain tissue changes in areas mediating mood and cognition functions, and tissue changes from those regions correlate with mood and cognitive symptoms suggesting that the microstructural brain changes may account for the observed functional deficits.

Widespread microstructural disruptions were observed in brain regions controlling cognitive and mood functions in people with T2D as compared to controls. Most of these changes were in the chronic stages, with only a few sites in the acute stage. Patients with T2D also exhibited impairments in visuospatial, language, and attention cognitive sub-domains, as well as greater depression and anxiety scores as compared to healthy controls.

Cognitive and mood regulatory networks are spread over a large area in the human brain. Thus, extensive microstructural tissue changes in these areas play a unique role in cognitive and mood deficits in T2D patients.

These findings provide important insights into those changes, as well as the microstructural neuropathological changes that can contribute to mood and cognitive dysfunctions in patients with T2D mellitus. Notably, all disruptions in the microstructural brain tissue integrity occurred predominantly in the temporal, parietal, temporal cortices, and subcortical regions.

Similar to previous studies, the regions that exhibited chronic tissue changes with increased MD values in T2D patients encompassed brain fibers joining the cerebellum to vermis and anterior crus to cortices, including the frontal, precentral, and superior parietal gyri.

Conclusions
The study findings demonstrate how MD can facilitate early detection of microstructural brain tissue changes in cognitive and mood regulatory regions in patients with T2D, which cause their altered mood and cognition deficits.

Background
T2D, a chronic metabolic disorder, has been shown to alter cognition and mood and, as a result, is often considered an early risk factor for Alzheimer's disease (AD) and vascular dementia. In fact, epidemiologic studies have shown that T2D increases the risk of

cognitive deficits and mood disorders by 1.5- and two-fold, respectively.

Structural magnetic resonance imaging (MRI), due to its inadequate sensitivity to tissue changes, cannot detect subtle brain tissue aberrations. However, DTI, a non-invasive procedure, shows changes in the brain's microstructural organization in gray and white matter. DTI also enables measuring MD, which reflects the movement of water molecules, thereby revealing the nature of the brain tissue injury and its extent in T2D patients.

To date, researchers have not examined direct correlations between tissue changes in brain sites mediating cognition and mood based on MD. Likewise, symptom scores for mood and cognition in T2D patients have not been reported.