Type 2 diabetes has been associated with cognitive decline, but its metabolic mechanism remains unclear. In the present study, we attempted to investigate brain region-specific metabolic changes in db/db mice with cognitive decline and explore the potential metabolic mechanism linking type 2 diabetes and cognitive decline. We analyzed the metabolic changes in seven brain regions of two types of mice (wild-type mice and db/db mice with cognitive decline) using a H NMR-based metabolomic approach. Then, a mixed-model analysis was used to evaluate the effects of mice type, brain region, and their interaction on metabolic changes. Compared with the wild-type mice, the db/db mice with cognitive decline had significant increases in lactate, glutamine (Gln) and taurine as well as significant decreases in alanine, aspartate, choline, succinate, γ-Aminobutyric acid (GABA), glutamate (Glu), glycine, N-acetylaspartate, inosine monophosphate, adenosine monophosphate, adenosine diphosphate, and nicotinamide adenine dinucleotide. Brain region-specific metabolic differences were also observed between these two mouse types. In addition, we found significant interaction effects of mice type and brain region on creatine/phosphocreatine, lactate, aspartate, GABA, N-acetylaspartate and taurine. Based on metabolic pathway analysis, the present study suggests that cognitive decline in db/db mice might be linked to a series of brain region-specific metabolic changes, involving an increase in anaerobic glycolysis, a decrease in tricarboxylic acid (TCA) and Gln-Glu/GABA cycles as well as a disturbance in lactate-alanine shuttle and membrane metabolism.

Mild traumatic brain injury (mTBI) is the most common neurological insult and leads to long-lasting cognitive impairments. The immune system modulates brain functions and plays a key role in cognitive deficits, however, the relationship between TBI-induced changes in inflammation-related cytokine levels and cognitive consequences is unclear. This was investigated in the present study in two cohorts of individuals within 1 week of mTBI (n = 52, n = 43) and 54 matched healthy control subjects. Patients with mTBI were also followed up at 1 and 3 months post-injury. Measures included cognitive assessments and a 9-plex panel of serum cytokines including interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, IL-12, chemokine ligand 2 (CCL2), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). The contribution of cytokine levels to cognitive function was evaluated by multivariate linear regression analysis. The results showed that serum levels of IL-1β, IL-6, and CCL2 were acutely elevated in mTBI patients relative to controls; CCL2 level was remained high over 3 months whereas IL-1β and IL-6 levels were declined by 3 months post-injury. A high level of CCL2 was associated with greater severity of post-concussion symptoms (which survived in the multiple testing correction); elevated IL-1β was associated with worse working memory in acute phase (which failed in correction); and acute high CCL2 level predicted higher information processing speed at 3 months post-injury (which failed in correction). Thus, acute serum cytokine levels are useful for evaluating post-concussion symptoms and predicting cognitive outcome in participants with mTBI.

The chronic consequences of traumatic brain injury (TBI) may contribute to the increased risk for early cognitive decline and dementia, primarily due to diffusion axonal injury. Previous studies in mild TBI (mTBI) have been controversial in describing the white matter tract integrity changes occurring at acute and subacute post-injury. In this prospective longitudinal study, we aim to investigate the longitudinal changes of white matter (WM) using diffusion tensor imaging (DTI) and their correlations with neuropsychological tests. Thirty-three patients with subacute mTBI and 31 matched healthy controls were studied with an extensive imaging and clinical battery. Neuroimaging was obtained within 7 days post-injury for acute scans and repeated at 1 and 3 months post-injury. Using a region-of-interest-based approach, tract-based spatial statistics was used to conduct voxel-wise analysis on diffusion changes in mTBI and was compared to those of healthy matched controls, scanned during the same time period and rescanned with an interval similar to that of patients. We found decreased fractional anisotropy (FA) values in the left anterior limb of internal capsule (ALIC) and right inferior fronto-occipital fasciculus (IFOF) during the 7 days post-injury, which showed longitudinal evidence of recovery following 1 month post-injury. Increased FA values in these two tracts at 1 month post-injury were positively associated with better performance on cognitive information processing speed at initial assessment. By contrast, there were also some tracts (right anterior corona radiata, forceps major, and body of corpus callosum) exhibiting the continuing loss of integrity sustaining even beyond 3 months, which can predict the persisting post-concussion syndromes. Continuing loss of structural integrity in some tracts may contribute to the persistent post-concussion syndromes in mTBI patients, suggesting certain tracts providing an objective biomarker for tracking the pathological recovery process following mTBI.

ObjectivePost-traumatic headache (PTH) is one of the most frequent and persistent physical symptoms following mild traumatic brain injury (mTBI) and develop in more than 50% of this population. This study aimed to investigate the periaqueductal grey (PAG)-seeded functional connectivity (FC) in patients with mTBI with acute post-traumatic headache (APTH) and further examine whether the FC can be used as a neural biomarker to identify patients developing chronic pain 3 months postinjury.Methods70 patients with mTBI underwent neuropsychological measurements and MRI scans within 7 days postinjury and 56 (80%) of patients were followed up at 3 months. 46 healthy controls completed the same protocol on recruitment to the study. PAG-seeded resting-state FC analysis was measured in 54 patients with mTBI with APTH, in comparison with 46 healthy volunteers.ResultsThe mTBI+APTH group presented significantly reduced PAG-seeded FC within the default mode network (DMN), compared with healthy volunteers group. The connectivity strength can also predict patients’ complaints on the impact of headache on their lives. Crucially, the initial FC strength between the PAG-right precuneus as well as the PAG-right inferior parietal lobule became the important predictor to identify patients with mTBI developing persistent PTH 3 months postinjury.ConclusionsPatients with mTBI+APTH exhibited significant PAG-related FC differences mainly within the DMN. These regions extended beyond traditional pain processing areas and may reflect the diminished top-down attention regulation of pain perception through antinociceptive descending modulation network. The disrupted PAG-DMN FC may be used as an early imaging biomarker to identify patients at risk of developing persistent PTH.

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