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Lower synaptic density is associated with psychiatric and cognitive alterations in obesity


Obesity is a serious medical condition that often co-occurs with stress-related psychiatric disorders. It is recognized that the brain plays a key role in the (patho)physiology of obesity and that there is a bidirectional relationship between obesity and psychopathology, yet molecular mechanisms altered in obesity have not been fully elucidated. Thus, we investigated relationships between obesity and synaptic density in vivo using the radioligand [11C]UCB-J (which binds to synaptic glycoprotein SV2A) and positron emission tomography in individuals with obesity, and with or without stress-related psychiatric disorders. Regions of interest were the dorsolateral prefrontal cortex, orbitofrontal cortex, ventromedial, amygdala, hippocampus, and cerebellum. Forty individuals with a body mass index (BMI) ≥ 25 kg/m2 (overweight/obese), with (n = 28) or without (n = 12) psychiatric diagnosis, were compared to 30 age- and sex-matched normal weight individuals (BMI < 25), with (n = 14) or without (n = 16) psychiatric diagnosis. Overall, significantly lower synaptic density was observed in overweight/obese relative to normal weight participants (ηp2 = 0.193, F = 2.35, p = 0.042). Importantly, in participants with stress-related psychiatric diagnoses, we found BMI to be negatively correlated with synaptic density in all regions of interest (p ≤ 0.03), but no such relationship observed for mentally healthy controls (p ≥ 0.68). In the stress-related psychiatric groups, dorsolateral prefrontal cortex synaptic density was negatively associated with measures of worry (r = −0.46, p = 0.01), tension/anxiety (r = −0.38, p = 0.04), fatigue (r = −0.44, p = 0.02), and attentional difficulties (r = −0.44, p = 0.02). In summary, the findings of this novel in vivo experiment suggest compounding effects of obesity and stress-related psychopathology on the brain and the associated symptomatology that may impact functioning. This offers a novel biological mechanism for the relationship between overweight/obesity and stress-related psychiatric disorders that may guide future intervention development efforts.

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Fig. 1: Effect of overweight/obesity status on synaptic density.
Fig. 2: Relationship between BMI and synaptic density and the influence of psychiatric morbidity.
Fig. 3: Relationship between synaptic density and mood symptoms in subjects with psychiatric disorders.
Fig. 4: Relationships between synaptic density, BMI, and measures of cognitive function in clinical subjects.


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This work was funded in part by the National Institute of Mental Health, the U.S. Department of Veterans Affairs National Center for PTSD, and the Nancy Taylor Foundation. RHA receives support from the NIMH (T32 MH014276). AMJ is consultant for Novo Nordisk, Eli Lilly, Boehringer Ingelheim, and receives research support from the American Diabetes Association, Eli Lilly, Novo Nordisk, and NIH/NIDDK. SEH, MNP, SRB, REC, RHP, and IE have no further conflicts of interest to disclose.

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RHA was responsible for data analysis and interpretation, in addition to drafting and revising the manuscript. SEH made substantial contributions to data acquisition and analysis, as well as manuscript revisions. AMJ, MNP, and SRB provided critically important intellectual content and manuscript revisions. REC and RHP advised data analysis and interpretation. IE was responsible for the study conception and design and oversaw all aspects of the work.

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Correspondence to Irina Esterlis.

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Asch, R.H., Holmes, S.E., Jastreboff, A.M. et al. Lower synaptic density is associated with psychiatric and cognitive alterations in obesity. Neuropsychopharmacol. (2021).

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