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

Abstract

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 (η_p² = 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.

Fig. 1. Effect of overweight/obesity status on synaptic density.

Synaptic density is shown as estimated by [¹¹C]UCB-J volume of distribution (V_T) as it binds to synaptic vesicle protein 2A (SV2A) in the A dlPFC, B vmPFC, C OFC, D AMY, E HIP, and F CB. A MANCOVA revealed significantly reduced SV2A density in overweight or obese (OW; n = 40) subjects relative to normal weight (NW; n = 30) subjects, overall (η_p² = 0.193, F = 2.35, p = 0.042). Individual values are shown with the group mean ± SEM and p value associated with the main effect of weight group displayed above. **p ≤ 0.005 (Bonferroni) relative to NWPsy.

Fig. 2. Relationship between BMI and synaptic density and the influence of psychiatric morbidity.

No relationship between BMI and SV2A density ([¹¹C]UCB-J V_T) was observed among the mentally healthy control subjects (HC; n = 28), but there was a significant negative correlation among subjects with psychiatric disorders (Psy; n = 42) in the A dlPFC, B vmPFC, C OFC, D AMY, E HIP, and F CB. The best-fit line for each group is shown with the associated partial correlation (r; adjusting for age and sex) and p value. The BMI cutoff value for overweight/obesity (BMI = 25) is illustrated by the gray dashed vertical line.

Fig. 3. Relationship between synaptic density and mood symptoms in subjects with psychiatric disorders.

A Among clinical subjects (NWPsy + OWPsy), tendencies to worry, as measured by the Penn State Worry Questionnaire (PSWQ), were associated with lower dlPFC SV2A density ([¹¹C]UCB-J V_T). B Scores on the tension/anxiety and C fatigue subscales of the Profile of Mood States (POMS) scale were negatively correlated with dlPFC SV2A density, while D HIP SV2A density was positively correlated with scores on the vigor/vitality POMS subscale. The raw (uncorrected) individual values are shown with the best-fit line with the 95% confidence interval, but the correlation (r) and p values displayed represent the results of partial correlation analyses correcting for age and sex. Normal weight subjects with any psychiatric diagnosis (NWPsy) are represented by solid circles. Subjects with overweight/obesity with any psychiatric diagnosis (OWPsy) are represented by open circles.

Fig. 4. Relationships between synaptic density, BMI, and measures of cognitive function in clinical subjects.

A Among clinical subjects (NWPsy + OWPsy), worse visual attention (reaction time; IDN) was associated with lower SV2A density ([¹¹C]UCB-J V_T). B BMI was positively correlated with visual attention (reaction time; IDN) and C psychomotor function (response speed; DET). For both the IDN and DET, higher scores reflect poorer performance. The raw (uncorrected) individual values are shown with the best-fit line with the 95% confidence interval, but the correlation (r) and p values displayed represent the results of partial correlation analyses correcting for age and sex. Subjects with overweight/obesity with any psychiatric diagnosis (OWPsy) are represented by open circles.