Familial risk for mood disorder and the personality risk factor, neuroticism, interact in their association with frontolimbic serotonin 2A receptor binding.

Life stress is a robust risk factor for later development of mood disorders, particularly for individuals at familial risk. Likewise, scoring high on the personality trait neuroticism is associated with an increased risk for mood disorders. Neuroticism partly reflects stress vulnerability and is positively correlated to frontolimbic serotonin 2A (5-HT(2A)) receptor binding. Here, we investigate whether neuroticism interacts with familial risk in relation to frontolimbic 5-HT(2A) receptor binding. Twenty-one healthy twins with a co-twin history of mood disorder and 16 healthy twins without a co-twin history of mood disorder were included. They answered self-report personality questionnaires and underwent [(18)F]altanserin positron emission tomography. We found a significant interaction between neuroticism and familial risk in predicting the frontolimbic 5-HT(2A) receptor binding (p=0.026) in an analysis adjusting for age and body mass index. Within the high-risk group only, neuroticism and frontolimbic 5-HT(2A) receptor binding was positively associated (p=0.0037). In conclusion, our data indicate that familial risk and neuroticism interact in their relation to frontolimbic 5-HT(2A) receptor binding. These findings point at a plausible neurobiological link between genetic and personality risk factors and vulnerability to developing mood disorders. It contributes to our understanding of why some people at high risk develop mood disorders while others do not. We speculate that an increased stress reactivity in individuals at high familial risk for mood disorders might enhance the effect of neuroticism in shaping the impact of potential environmental stress and thereby influence serotonergic neurotransmission.

The 5-HT2A receptor binding pattern in the human brain is strongly genetically determined.

With the appropriate radiolabeled tracers, positron emission tomography (PET) enables in vivo human brain imaging of markers for neurotransmission, including neurotransmitter synthesis, receptors, and transporters. Whereas structural imaging studies have provided compelling evidence that the human brain anatomy is largely genetically determined, it is currently unknown to what degree neuromodulatory markers are subjected to genetic and environmental influence. Changes in serotonin 2A (5-HT(2A)) receptors have been reported to occur in various neuropsychiatric disorders and an association between 5-HT(2A) receptor gene variants and neuropsychiatric illness susceptibility also exists. In a classical twin design involving 24 healthy male subjects (6 monozygotic twin pairs and 6 dizygotic twin pairs), we examined the relative contribution of genetic and environmental factors to interindividual variability in cortical 5-HT(2A) receptor binding as measured with [(18)F]altanserin PET imaging. The intraclass correlation coefficients were 0.67 for dizygotic and 0.87 for monozygotic twin pairs. For comparison, the intraclass correlation coefficient was 0.93 in a group of six male healthy subjects examined twice within two weeks with an identical experimental setup. Multivariate analysis was used to separate the phenotypic variance of individuals into additive genetic (heritability) effect (A), shared (family) environment (C), and non-shared (individual-specific) environment (E). Irrespective of whether a full ACE model or a reduced AE model was used to fit the data, the variance due to non-shared environment was below 10% indicating that the contribution of individual specific environmental factors to 5-HT(2A) receptor binding is limited.

Reproducibility of 5-HT2A receptor measurements and sample size estimations with [18F]altanserin PET using a bolus/infusion approach.

PURPOSE: To determine the reproducibility of measurements of brain 5-HT2A receptors with an [18F]altanserin PET bolus/infusion approach. Further, to estimate the sample size needed to detect regional differences between two groups and, finally, to evaluate how partial volume correction affects reproducibility and the required sample size. METHODS: For assessment of the variability, six subjects were investigated with [18F]altanserin PET twice, at an interval of less than 2 weeks. The sample size required to detect a 20% difference was estimated from [18F]altanserin PET studies in 84 healthy subjects. Regions of interest were automatically delineated on co-registered MR and PET images. RESULTS: In cortical brain regions with a high density of 5-HT2A receptors, the outcome parameter (binding potential, BP1) showed high reproducibility, with a median difference between the two group measurements of 6% (range 5-12%), whereas in regions with a low receptor density, BP1 reproducibility was lower, with a median difference of 17% (range 11-39%). Partial volume correction reduced the variability in the sample considerably. The sample size required to detect a 20% difference in brain regions with high receptor density is approximately 27, whereas for low receptor binding regions the required sample size is substantially higher. CONCLUSION: This study demonstrates that [18F]altanserin PET with a bolus/infusion design has very low variability, particularly in larger brain regions with high 5-HT2A receptor density. Moreover, partial volume correction considerably reduces the sample size required to detect regional changes between groups.