The effects of pre-natal alcohol on adolescent learning and memory

Foetal alcohol spectrum disorders (FASD) are a result of prenatal exposure to ethanol and are characterised by impaired learning and memory, growth retardation, structural brain abnormalities and facial anomalies: they affect close to 1% of births in Europe. Diagnosis of FASD is often extremely difficult as the learning deficits may present at 10 years of age or older when details of prenatal alcohol exposure are long forgotten and unobtainable.  This leaves many children without a clear diagnosis and thus without correctly targeted interventions. Currently maternal hair analysis or the presence of elevated fatty acid ethyl esters in meconium at the time of birth are the only biochemical markers for intra-uterine alcohol exposure. These markers are of no value shortly after the birth and do not allow for retrospective diagnosis when a child presents later in life.

Our animal studies lead us to believe that prenatal exposure to ethanol may cause long-lasting alteration to a group of aminopeptidase enzymes, and that this change in enzyme activity may be associated with impaired learning and memory. We now wish to explore the potential of these plasma enzymes as enduring markers of prenatal alcohol exposure / FASD in a human population.

Project timeframes

This project began in 2013 and is ongoing.

Project aims

The projects aims to identify the biochemical changes associated with FASD in order to develop a definitive diagnostic method and possible methods of prevention and treatment.

Project findings and impact

Diagnostic criteria for FASD are controversial, and under-diagnosis is believed to be common. It is likely that there are many more children with FASD in schools than records suggest. In early life, differential diagnosis of FASD, autistic spectrum disorder and attention deficit hyperactivity disorder is problematic, although distinct intervention strategies with differential degrees of success have been identified.

This research will determine whether plasma aminopeptidase activity is measureable in neonates and will assess the potential of plasma aminopeptidase activity to identify prenatal alcohol exposure and possible FASD in neonates. Only follow-up later in life would allow differentiation of prenatal alcohol exposure and FASD.

The research will also determine whether any observed changes in neonates endure into adolescents, and whether there is a clear association of enzyme activity with FASD, rather than prenatal alcohol exposure. The biochemical parameter may also correlate with severity of learning disability. The predictive validity of any correlation would allow assessment of the usefulness of this biochemical assay as a selective diagnostic tool for FASD, to allow appropriate intervention.

Research team

Professor Paul Gard

 

Output

Mechaeil R, Lewis M, Pepple R, Jackson A, Gard P, RustedJ (2007) The effect of losartan on cognition in healthy young adults. J Psychopharmacology 21, supplement A50.

Golding, B.J., Overall, A.D.J., Gard, P.R. (2008)  The role of IRAP in the effect of angiotensin IV on cognition in the mouse.  Fundamental and Clinical Pharmacology 22, Suppl 2, p103.

Gard, P.R. (2008)  Animal models of cognition and putative novel therapies.  J. Pharm. Pharmacol. suppl 1, A71

Mechaeil, R., Ahmed, O., Hussein, A., Pressney, I., Young, A., Yu, D., King, S.L., Gard, P., Jackson, A., Rusted, J. (2008)  The separate and combined effects of losartan and scopolamine on cognitive performance of healthy young adults Abstract788.4/SS54 Neuroscience 2008; Washington DC

Golding, B.J., Overall, A.D.J., Brown, G., Gard, P.R. (2010)  Strain differences in the effects of angiotensin IV on mouse cognition.  Eur. J. Pharmacol. 641 154-159

Mechaeil, R., Lewis, M., Grice, J., Gard, P.R., Jackson, A., Rusted,J. (2011)  Angiotensin receptor antagonists as potential cognitive enhancing agents.  Psychopharmacol. 217 51-60

Gard, P.R., Naylor, C., Ali, S., Partington, C. (2012)  Blockade of pro-cognitive effects of angiotensin IV and physostigmine in mice by oxytocin antagonism.  Eur. J. Pharmacol. 683 155-160

Fidalgo, S., Onaji, V., Gard, P.R., Effect of acute administration of angiotensin IV in a mouse model of Foetal Alcohol syndrome. For presentation to 9th FENS forum of neuroscience, July 5-9th 2014 Milan, Italy,

Gard, P.R.,  Fidalgo, S. Lotter, I., Richardson, C., Farina, C., Tabet, N., Rusted, J.(2015). Changes of IRAP-related aminopeptidases in early stage Alzheimer’s disease and a model of foetal alcohol syndrome. Presented to the 2nd IRAP Symposium, Uppsala, Sweden, September 2015

Fidalgo, S.,Tucker, R., Tsiligkaridis, T., Takyi, A., Murphy, D., Silva, N.M., Sadiq, W., Gard, P.R. (2015)  Effect of acute administration of angiotensin IV in a mouse model of Foetal Alcohol syndrome.  Presented to the 2nd IRAP Symposium, Uppsala, Sweden, September 2015

Fidalgo, S., Tucker, R., Payne, R., Linsdall, S., McIver, A., Sadiq, W., Patel, M., Gard, P.R. (Submitted for publication)  Sex differences in the effects of angiotensin IV and oxytocin on insulin-regulated aminopeptidase function and mouse cognition in different paradigms of novel object recognition.  International Journal of Neuropsychopharmacology

Partners

Dr Raja Mukherjee, Consultant Psychiatrist/Lead Clinical National Specialist FASD, Surrey and Borders Partnership NHS Foundation Trust

Dr Neil Aiton, Consultant Neonatologist, Royal Sussex County Hospital, Brighton