Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD.

Fig. 1.. Biological measurements that differentiate low- and high-social monkeys in the discovery cohort.

(A) The logistic regression model [which, in this panel, includes the four combined biological measures that are plotted separately in (B) to (E)] correctly classified 24 of 27 monkeys (89%). (B to E) Each panel depicts a regression line that represents the effect of an individual biological measure. Each biological variable on the x axis is plotted against the probability of being low-social on the y axis and is corrected for the other variables in the analysis. Low-social monkeys (blue circles) plotted above, and high-social monkeys (orange circles) plotted beneath, the dashed lines (which represent 50% probability) are correctly classified. P values from LR χ² tests are reported to indicate the strength of the plotted relationships, and the biological measures are presented in order of their contribution to the predictive power of the logistic regression model.

Fig. 2.. Group comparisons for three biological measurements in the monkey discovery cohort.

General linear model F tests were used to evaluate whether the low- and high-social monkey groups differed in the three biological measurements (A to C) that were found to significantly predict monkey social group classification (as shown in Fig.1). Data are presented as least-squares means ± SEM. Only CSF AVP concentration differed significantly between the low-social (blue bars) and high-social (orange bars) monkey groups [n = 30 (CSF AVP); n = 28 (PTEN and AKT)].

Fig. 3.. CSF AVP concentration is positively associated with social grooming in the monkey discovery cohort and is a stable, trait-like measure in an additional monkey cohort.

(A) The relationship between CSF AVP concentration and percentage of time spent in social grooming was tested with a general linear model F test (n = 30). The resulting regression line is plotted, corrected for the other variables in the analysis. Low-social monkeys are depicted in blue circles, and high-social monkeys are depicted in orange circles. (B) Within-individual consistency of CSF AVP concentrations across the four measurement time points was evaluated with intraclass correlation coefficients calculated from a mixed model. Least-squares means ± SEM CSF AVP concentrations are presented for each monkey (labeled M01 to M10; n = 10) and ordered on the x axis by ascending average CSF AVP concentration.

Fig. 4.. CSF AVP concentration distinguishes low- and high-social monkeys and differs between social groups in the monkey replication cohort.

(A) The logistic regression model correctly classified 28 of 30 monkeys (93%) and was evaluated for significance using LR χ². CSF AVP concentration is plotted against the probability of being low-social; the resulting regression line is corrected for the other variables in the analysis. Low-social monkeys (blue circles) plotted above, and high-social monkeys (orange circles) plotted beneath, the dashed line (which represents 50% probability) are correctly classified. (B) A general linear model F test was used to test whether CSF AVP concentration was lower in low-social (blue bars) compared to high-social (orange bars) monkey groups in this replication cohort. Data are presented as least-squares means ± SEM.

Fig. 5.. CSF AVP concentration distinguishes ASD cases from medical controls.

(A) The logistic regression model correctly classified 13 of 14 children (93%) in a small patient cohort comprising seven children with ASD and seven medical control children without ASD (but with other medical conditions) and was evaluated for significance using LR χ². CSF AVP concentration is plotted against the probability of being diagnosed with ASD; the resulting regression line is corrected for the other variables in the analysis. Children with ASD (blue circles) plotted above, and medical control children (orange circles) plotted beneath, the dashed line (which represents 50% probability) are correctly classified. (B) A general linear model F test was used to test whether children with and without ASD differed in CSF AVP concentrations. Similar to low-social monkeys studied in our preclinical model (that is, as shown in Figs. 2A and 4B), CSF AVP concentration was found to be lower in children with ASD (blue bars) compared to medical control children without ASD (orange bars). Data are presented as least-squares means ± SEM.