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WIN Wednesday Works In Progress

Identifying the neuroimaging fingerprint of hippocampal insulin resistance in depression: a pilot study

Presented by Antoine Cherix

Abstract: Depression is a leading cause of disability worldwide and a major public health issue but little is known about the etiological factors and its underlying pathophysiology. Recently, metabolic syndrome (MetS) and insulin resistance (IR) in particular, have been proposed as potential causes of a subset of depression due to their high co-morbidity. The hippocampus is a well-recognised insulin-sensitive tissue which might be key in this pathophysiological process, but tools are lacking to assess insulin signalling efficiency non-invasively in the brain. Disrupting brain insulin signalling in mice allowed us to identify a neuroimaging fingerprint (using 1H, 31P and 13C-MRS) of insulin resistance in preclinical models of depression. We observed that a reduction of hippocampal lactate (end-product of glycolysis) and reduction of excitatory/inhibitory (E/I) balance (Glu/GABA) was linked with animal’s depressive-like behaviour.

We are now investigating whether a similar hippocampal ‘trace’ can be identified in a pilot group of participants with depression and known disruption of insulin signalling. To do so, we will conduct a cross-sectional pilot study using edited MRS at 7 Tesla in the hippocampus of people with depression and controls. We will test whether low levels of lactate and Glu/GABA can be detected in people with depression and whether they correlate with ‘systemic’ insulin resistance (HbA1C) and/or with specific cognitive/memory functions.

Overall, we anticipate that our findings will provide preliminary data to capture the role of IR in depression and bring forward a useful imaging fingerprint with high clinical potential in the field of psychiatry.





WIN Wednesday Works In ProgressMultimodal MRI characterisation of impact of metformin treatment on adult brain structure and function in Four Core Genotype (FCG) mice

Presented by Kamila Szulc-Lerch

Abstract: Metformin, a commonly prescribed medication for managing type 2 diabetes, has recently gained attention for its potential as an anti-aging drug. While its primary role is to regulate blood sugar levels, studies have revealed that individuals taking metformin may experience a range of health benefits beyond glycaemic control. These potential benefits include an extension of both healthspan and lifespan, making metformin an exciting subject in the field of longevity science. Nonetheless, it's essential to highlight that further research and clinical trials are necessary to fully understand its long-term impact and safety when used for anti-aging purposes in the general population. In particular, our recent analysis of UK Biobank data, inspired by preclinical findings showing brain volume loss in mice following metformin treatment, investigated the impact of metformin on the human brain. This analysis revealed exacerbated brain volume loss in patients with diabetes who were taking metformin in an age and sex dependent manner. Recent studies in humans have shown that metformin also has the potential to lower testosterone levels. Given the overall association of testosterone levels with brain volume, it is plausible that metformin exerts its effects on the brain via its impact on testosterone. In this study, we will use Four Core Genotype mice to test this hypothesis. The use of this model will allow us to separate the impact of sex hormones (testosterone and oestrogen) from sex chromosomes by studying the response to metformin in XY and XX mice both having either male or female gonads. Our hypothesis is that the brain volume lowering effects of metformin are mediated by testosterone. We expect that this response will be diminished in XY mice with female gonads. We also expect that XX mice with male gonads will display a similar brain response to metformin as the standard male mice (XY mice with male gonads).