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Midlife risk factors such as type 2 diabetes mellitus (T2DM) confer a significantly increased risk of cognitive impairment in later life with executive function, memory, and attention domains often affected first. Spatiotemporal gait characteristics are emerging as important integrative biomarkers of neurocognitive function and of later dementia risk. We examined 24 spatiotemporal gait parameters across five domains of gait previously linked to cognitive function on usual-pace, maximal-pace, and cognitive dual-task gait conditions in 102 middle-aged adults with (57.5 ± 8.0 years; 40% female) and without (57.0 ± 8.3 years; 62.1% female) T2DM. Neurocognitive function was measured using a neuropsychological assessment battery. T2DM was associated with significant changes in gait phases and rhythm domains at usual pace, and greater gait variability observed during maximal pace and dual tasks. In the overall cohort, both the gait pace and rhythm domains were associated with memory and executive function during usual pace. At maximal pace, gait pace parameters were associated with reaction time and delayed memory. During the cognitive dual task, associations between gait variability and both delayed memory/executive function were observed. Associations persisted following covariate adjustment and did not differ by T2DM status. Principal components analysis identified a consistent association of slower gait pace (step/stride length) and increased gait variability during maximal-pace walking with poorer memory and executive function performance. These data support the use of spatiotemporal gait as an integrative biomarker of neurocognitive function in otherwise healthy middle-aged individuals and reveal discrete associations between both differing gait tasks and gait domains with domain-specific neuropsychological performance. Employing both maximal-pace and dual-task paradigms may be important in cognitively unimpaired populations with risk factors for later cognitive decline—with the aim of identifying individuals who may benefit from potential preventative interventions. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM. [ABSTRACT FROM AUTHOR]

Background: Midlife Type 2 Diabetes Mellitus (T2DM) is associated with an increased risk of dementia in later life. Despite this, few studies have examined the utility of midlife biomarkers to predict later cognitive decline in T2DM. We evaluated the association between dual‐task gait speed and cognitive performance in midlife T2DM as part of ENBIND Study. Method: Participants with midlife T2DM and matched healthy controls were recruited. Participants with T2DM only included if they had no micro/macrovascular complications of T2DM. Cognition was assessed using the Montreal Cognitive Assessment (MoCA) and computerised neuropsychological assessment battery (CANTAB®). Gait was assessed using both stopwatch and accelerometry across four tasks: (i) self‐selected (usual) gait speed, (ii) maximal gait speed and (iii) dual‐task gait speed (reciting alternate letters of the alphabet). Appropriate univariate statistics in addition to Poisson and linear models were used to analyse results. Results: 102 cognitively‐intact middle‐aged (52 ± 7.9 years) adults with (N = 71) and without (N = 31) T2DM were recruited. T2DM was associated with a greater likelihood of error on the MoCA (IRR = 2.36, 1.53‐3.64, p<0.001) which persisted after covariate adjustment. T2DM was associated with poorer performance on reaction/movement time, executive function, attention and visuospatial memory tasks, however results were attenuated by covariate adjustment. T2DM was associated with slower gait speed on all three tasks (all p<0.001). Overall, self‐selected, maximal and dual‐task speed were associated with greater likelihood of error on the MoCA (all p<0.001). However, after robust adjustment for covariates, only the association for Dual Task Cost (DTC) persisted (p = 0.021). A DTC*T2DM interaction was not significant. Conclusions: The current analysis showed diminished cognitive and gait performance in midlife T2DM vs. healthy controls. We observed significant associations between gait performance on the addition of a dual task and general cognitive function. This association, whilst greater in T2DM, was not T2DM specific and adds further evidence for the association between dual task‐gait and cognitive performance in midlife. Our findings support the ongoing exploration and use of gait as a physiological biomarker of overall cognitive function and warrants longitudinal investigation in this high risk group. [ABSTRACT FROM AUTHOR]

Background: Midlife Type 2 Diabetes Mellitus (T2DM) is a potent risk factor for later development of dementia. However, putative mechanisms mediating this risk are poorly understood. The NLRP3 inflammasome receptor, which drives strong pro‐inflammatory responses, has been implicated in both T2DM and Alzheimer's disease (AD) pathogenesis, and can be activated by Amyloid β1‐42 (Aβ42). Method: Peripheral Blood Mononuclear Cells (PBMCs) were isolated from participants with T2DM (N = 39; 52.04 ± 8.01 years) and matched controls (N = 21; 52.16 ± 7.82 years) without any evidence of cognitive impairment. PBMCs were incubated for 18 hours under the following conditions: (i) Lipopolysaccharide (LPS), (ii) Aβ42, (iii) LPS & Aβ42 and (iv) LPS & Nigericin (potent NLRP3 activator). Cytokine production was measured using ELISA and gene expression using qPCR. Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA). Gait speed was measured under normal and dual‐task conditions (reciting alternate letters of the alphabet). Wilcoxon rank‐sum tests were used for univariate analysis and Poisson and linear regression models used for multivariate analyses, adjusting for important covariates. Results: Treatment of PBMCs under all four conditions resulted in a significant production of the pro‐inflammatory cytokines IL‐1β and IL‐6, which did not differ between T2DM and healthy controls. Greater IL‐1β production (an NLRP3‐dependent cytokine) under both Aβ‐42 (ii) and LPS & Nigericin (iv) conditions was associated with greater likelihood of error on the MoCA (aIRR 1.01, p = 0.010; aIRR 1.01, p = 0.004). Further, greater IL‐1β production under both LPS & Aβ42 (iii) and LPS & Nigericin (iv) conditions was associated with a greater slowing effect (cost) on the dual‐task (adjusted: β = 0.31, 0.04‐0.58, p = 0.023; 0.029, 0.05 – 0.54, p = 0.019). Effects were seen in the cohort overall, regardless of T2DM status, but were stronger in those with T2DM. Conclusions: Greater activation of the NLRP3 inflamamsome by Aβ42 was associated with poorer cognitive and gait performance in midlife T2DM. Further work will follow this cohort longitudinally and assess the ability of innate immune NLRP3 activity to predict later cognitive trajectories in those with midlife T2DM. [ABSTRACT FROM AUTHOR]