Neonatal CSF vasopressin concentration predicts later medical record diagnoses of autism spectrum disorder.

Autism spectrum disorder (ASD) is a brain disorder characterized by social impairments. ASD is currently diagnosed on the basis of behavioral criteria because no robust biomarkers have been identified. However, we recently found that cerebrospinal fluid (CSF) concentration of the "social" neuropeptide arginine vasopressin (AVP) is significantly lower in pediatric ASD cases vs. controls. As an initial step in establishing the direction of causation for this association, we capitalized upon a rare biomaterials collection of newborn CSF samples to conduct a quasi-prospective test of whether this association held before the developmental period when ASD first manifests. CSF samples had been collected in the course of medical care of 0- to 3-mo-old febrile infants (n = 913) and subsequently archived at -70 °C. We identified a subset of CSF samples from individuals later diagnosed with ASD, matched them 1:2 with appropriate controls (n = 33 total), and quantified their AVP and oxytocin (OXT) concentrations. Neonatal CSF AVP concentrations were significantly lower among ASD cases than controls and individually predicted case status, with highest precision when cases with comorbid attention-deficit/hyperactivity disorder were removed from the analysis. The associations were specific to AVP, as ASD cases and controls did not differ in neonatal CSF concentrations of the structurally related neuropeptide, OXT. These preliminary findings suggest that a neurochemical marker of ASD may be present very early in life, and if replicated in a larger, prospective study, this approach could transform how ASD is detected, both in behaviorally symptomatic children, and in infants at risk for developing it.

Cerebrospinal fluid vasopressin and symptom severity in children with autism.

Autism is a brain disorder characterized by social impairments. Progress in understanding autism has been hindered by difficulty in obtaining brain-relevant tissues (eg, cerebrospinal fluid [CSF]) by which to identify markers of disease and targets for treatment. Here, we overcome this barrier by providing evidence that mean CSF concentration of the "social" neuropeptide arginine vasopressin (AVP) is lower in children with autism versus controls. CSF AVP concentration also significantly differentiates individual cases from controls and is associated with greater social symptom severity in children with autism. These findings indicate that AVP may be a promising CSF marker of autism's social deficits. Ann Neurol 2018;84:611-615.

Arginine Vasopressin Is a Blood-Based Biomarker of Social Functioning in Children with Autism.

Brain arginine vasopressin (AVP) critically regulates normative social behavior in mammals, and experimental disruption of the AVP signaling pathway produces social impairments in rodent models. We therefore hypothesized that AVP signaling deficits may contribute to social impairments in children with autism spectrum disorder (ASD). Since blood measures (which are far easier to obtain than brain measures) of AVP are most meaningful if they are related to brain AVP activity, Study 1 tested the relationship between AVP concentrations in concomitantly collected blood and CSF samples from children and adults (N = 28) undergoing clinical procedures. Study 2 tested whether blood AVP concentrations: 1) differed between children with ASD (N = 57), their ASD discordant siblings (N = 47), and neurotypical controls (N = 55); and 2) predicted social functioning (using the NEPSY-II Theory of Mind and Affect Recognition tasks and the Social Responsiveness Scale) in this large, well-characterized child cohort. Blood AVP concentrations significantly and positively predicted CSF AVP concentrations (F1,26 = 7.17, r = 0.46, p = 0.0127) in Study 1. In Study 2, blood AVP concentrations did not differ between groups or by sex, but significantly and positively predicted Theory of Mind performance, specifically in children with ASD, but not in non-ASD children (F1,144 = 5.83, p = 0.017). Blood AVP concentrations can be used: 1) as a surrogate for brain AVP activity in humans; and 2) as a robust biomarker of theory of mind ability in children with ASD. These findings also suggest that AVP biology may be a promising therapeutic target by which to improve social cognition in individuals with ASD.

Increased intracranial pressure is associated with elevated cerebrospinal fluid ADH levels in closed-head injury.

OBJECTIVES: Head injury frequently results in increased intracranial pressure and brain edema. Investigators have demonstrated that ischemic injury causes an increase in cerebrospinal fluid (CSF) levels of antidiuretic hormone (ADH); increased CSF ADH levels exacerbate cerebral edema, and inhibition of the ADH system with specific ADH antagonists reduces cerebral edema. The current study was designed to test the hypothesis that elevated levels of ADH are present in the CSF of subjects with head injury. METHODS: Ventricular CSF and blood samples were taken from 11 subjects with head injury and 12 subjects with no known head trauma or injury. ADH levels were analyzed using radioimmunoassay. Severity of increased intracranial pressure (ICP) was rated in head-injured subjects using a four-point ordinal scale, based on which treatments were necessary to reduce ICP. RESULTS: Subjects with head injury had higher CSF (3.2 versus 1.2 pg/ml; P<0.02) and plasma (4.1 versus 1.4 pg/ml; P<0.02) levels of ADH than did control subjects. In head-injured subjects, CSF ADH levels positively correlated with severity of ICP. DISCUSSION: The results of this study suggest that ADH plays a role in brain edema associated with closed head injury.

An evaluation of human neurophysin production in Alzheimer's disease: preliminary observations.

The concentrations of human neurophysins in the cerebrospinal fluid (CSF) of nine patients with Alzheimer's disease: Preliminary observations. (AD), and one patients with Pick's disease, were determined using specific radioimmunoassays (RIAs). Concentrations of vasopressin and oxytocin were also measured. Values were compared with those from 20 age-matched mentally normal individuals who were being treated for back pain. CSF levels of vasopressin-associated human neurophysin (VP-HNP) and oxytocin-associated human neurophysin (OT-HNP) in patients with AD (22 +/- 4 fmol/ml and 104 +/- 17 fmol/ml) were only 42% and 58% of those in the control subjects (p less than 0.0001, p less than 0.0004). Vasopressin levels for these patients (3.6 +/- 0.4 fmol/ml) were also significantly reduced to 51% of controls (p less than 0.007) and oxytocin levels were marginally (p = 0.092) reduced to 70% of controls. Because neurophysins and neuropeptides are gene-related products of vasopressin-neurons and oxytocin-neurons, the data indicate that these neurons are functionally impaired in patients with AD. Plasma neurophysin values suggest this impairment is confined to neurons with centrally-directed axons. Data from the one patient with Pick's disease demonstrates that reduced CSF levels of neurophysins and hormones is not confined to Alzheimer-type dementia.

Cerebrospinal fluid neurophysins in affective illness and in schizophrenia.

We studied the concentration of neurophysin I (hNPI) and II (hNPII), the hypothalamo-pituitary carriers of vasopressin and oxytocin, in CSF of depressed and schizophrenic patients and age matched controls. Mean hNPI values were lower and mean hNPII values greater in schizophrenics than in controls. Lower hNPI values were observed in unipolar patients than in controls. In bipolar patients however, higher hNPI values were present. Significantly higher hNPII values were observed in bipolar patients than in controls; no difference was present between unipolars and controls. A positive correlation was observed with age in controls and bipolars for hNPII. These data emphasize the interest of studying the neurohypophysal function in affective illness and in schizophrenia.

A time-dependent peak of oxytocin exists in cerebrospinal fluid but not in plasma of humans.

Oxytocin (OT) and the oxytocin-neurophysin (OT-Np) were measured by RIA in samples of cerebrospinal fluid (CSF) obtained sequentially at 0600, 1200, 1800, and 2400 h from six patients in whom intrathecal catheters were temporarily placed for CSF rhinorrhea. The highest levels of OT in CSF were found at 1200 h. An analysis of variance of sequential measures of the concentration of OT in samples of CSF obtained every 6 h over a 30-h period showed the mean levels (+/- SEM) of OT at 1200 h, 6.41 +/- 1.13 microU/ml and 5.06 +/- 0.58 microU/ml, to be significantly higher (p less than 0.05) than mean levels of OT at 0600 h, 2.50 +/- 0.65 microU/ml; 1800 h, 2.63 +/- 0.61 microU/ml and 2.64 +/- 1.21 microU/ml; and 2400 h, 2.86 +/- 1.13 microU/ml. The levels of OT-Np in CSF did not show a similar peak. In three of the patients simultaneous samples of blood were obtained for measurement of the same peptides, but no corresponding peak of OT or its Np was found in plasma of these three patients. The level of OT in CSF at all times was also significantly higher (p less than 0.05) than the level of OT in plasma of these three patients. Levels of OT and OT-Np were measured by RIA of samples of plasma obtained hourly for a 24-h period from six healthy men and six healthy women. No diurnal variation of OT or its Np in the plasma of men or women was found. This pattern of OT in the CSF of humans is similar to the pattern of OT in the CSF of the Rhesus monkey, but in contrast to the lack of a clearly defined peak of OT in the CSF of the cat or the rat. These observations in humans reinforce the differences among species of the secretion of OT in the CSF.

Neuropeptides in cerebrospinal fluid.

Most neuropeptides can now be assayed in human cerebrospinal fluid (CSF). Some, such as beta-endorphin and arginine vasopressin, seem to be secreted directly into CSF. Others may reach CSF from plasma either by passage through the blood-brain barrier or by absorption through the circumventricular organs, which lack a blood-brain barrier. The role of neuropeptides in CSF is still unclear. Thyrotropin-releasing hormone, somatostatin, arginine vasopressin, angiotensin II, substance P, vasoactive intestinal polypeptide, beta-endorphin, gastrin, and cholecystokinin are all present in assayable quantities in human CSF. Their functions in this fluid are liable to be as diverse as their functions elsewhere in the body. The release of hypothalamic releasing factors into the CSF may be part of the pathway of pituitary hormone release. Pituitary hormones may function in CSF as part of a feedback loop from the hypothalamus. Other neuropeptides may affect receptors in the central nervous system far away from their release site. Intraventricular neuropeptide injection, anatomical and physiological ablation experiments, receptor studies, and neurobiological techniques now being developed will allow a more complete understanding of CSF neuropeptide function in the future.

Oxytocin, vasopressin, and estrogen-stimulated neurophysin: daily patterns of concentration in cerebrospinal fluid.

The concentrations of oxytocin, arginine vasopressin, and estrogen stimulated neurophysin in cerebrospinal fluid of monkeys showed a daily fluctuation with high concentrations occurring during the light period. The patterns of oxytocin and estrogen-stimulated neurophysin in the cerebrospinal fluid were not observed in the plasma nor were they altered after the administration of a dose of estradiol that increased concentrations of estrogen-stimulated neurophysin in plasma. The disassociation between these cerebrospinal fluid and plasma patterns and values suggests that the secretory activity of neurons that release estrogen-stimulated neurophysin and oxytocin into the cerebrospinal fluid is controlled by mechanisms different from those that control their release into the plasma.

Differential clearance of neurophysin and neurohypophysial peptides from the cerebrospinal fluid in conscious guinea pigs.

The clearance of neurohypophysial peptides from cerebrospinal fluid (CSF) in conscious unrestrained guinea pigs. 125I-labelled peptides were detectable in the cisterna magna within 2 min of their intracerebroventricular injection, reaching peak concentrations 10-15 min post-injection and declining exponentially over the next hour. 125I-oxytocin (125I-OT) and 125I-vasopressin (125(I-AVP) were cleared at similar rates, whereas 125I-labelled neurophysin (125I-NP) disappeared significantly more slowly; mean half-times of clearance (t1/2) from cisternal CSF were 28, 24 and 46 min, respectively. 125I-NP was cleared at the same rate as 3H-inulin (t1/2 40 min), as was an antibody to OT (anti-OT, t1/2 37 min). Intracerebroventricular infusions of iodinated peptides produced constant levels in CSF within 3 h. 125I-AVP reached lower plateau levels and disappeared twice as fast as 125I-NP, although the apparent equilibrium distribution space was the same for both peptides. Although NP was cleared half as fast as OT or AVP, this difference was not sufficient to account for the large molar excess of NP over the nonapeptides in guinea pig CSF. There is an effective blood/CSF barrier to neurohypophysial peptides in the guinea pig; intravenous infusions of OT or porcine NP did not raise the CSF levels of these peptides (measured by specific radioimmunoassays) except when very high concentrations were maintained in peripheral plasma. However, single intravenous injections of anti-OT produced low but significant titres in CSF, persisting for several days.

[Incidence of inappropriate secretion of antidiuretic hormone in patients with severe head injuries]. / Incidence du syndrome de sécrétion inappropriée d'hormone antidiurétique chez le traumatisé crânien grave.

Eight patients with severe craniocerebral trauma were studied prospectively to assess the effects of the injury on sodium and water balance. Hyponatremic hypo-osmolar states occurred in 5 of the 8 patients. The cause was an inappropriate secretion of antidiuretic hormone (I.S.A.D.H.). We found an early I.S.A.D.H. (appearing within 2-3 days post trauma) whose presence was related to the craniocerebral injury (2 cases). We also found a late I.S.A.D.H. which may represent a response to positive-pressure ventilation, semi-recumbent position and centrally acting drugs. This tardive I.S.A.D.H. appeared 9-10 days after admission (3 cases). Radioimmunoassay for circulating and ventricular C.S.F. neurophysins shows an early and transitory increase of hNpI (the carrier of A.D.H.). hNpI was detectable during the hyponatremic hypo-osmolar states, thus demonstrating an inappropriate secretion of A.D.H.

Oxytocin and neurophysin in plasma and CSF during suckling in the guinea-pig.

Cerebrospinal fluid (CSF) obtained from the cisterna magna of conscious unrestrained guinea-pigs was assayed for oxytocin (OT), vasopressin (AVP) and neurophysin (NP). Basal levels of OT and AVP were approximately 5 and 15 fmol/ml, respectively, whereas NP levels were considerably higher (around 1 pmol/ml); there was no significant differences between males, females and lactating females. In lactating females, simultaneous samples of blood and CSF were obtained during suckling episodes. Despite large increases in plasma OT and NP at milk ejection, CSF levels remained unchanged throughout. Intracerebroventricular injection of 100 fmol OT produced an 8-fold rise in the concentration of this peptide in cisternal fluid within 10 min. Since CSF levels of OT and NP do not change when these peptides are released from the pituitary, we conclude that the presence of these peptides in CSF reflects activity of extrapituitary terminals and that these terminals are not activated during suckling.