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Proper brain development requires coordinated glycosylation, and in particular correct glycosylation of neural cell adhesion molecule (NCAM). The polysialylated version of NCAM (PolySia-NCAM) is vital in neurogenesis, playing a role in axon and dendritic outgrowth, and important for synaptic plasticity and normal neural development.
These were some of the key points made during a preclinical research track symposium entitled “Merging mouse and human data on the role of PolySia-NCAM in neurodevelopment and schizophrenia”, jointly chaired by Professor Herbert Hildenbrandt, of the Institute of cellular Chemistry, Hannover University, Germany and Professor Jean Mariani, of the Pierre and Marie Curie University, Paris, France.
In presentations by Dr Juan Nacher, of the University of Valencia, Spain and Dr Marta Barabara Wisniewska of the University of Warsaw, Poland, delegates learned of some of the latest research involving cultured immature neurones, animal models of neurodevelopment, imaging studies and research involving transgenic mice that point to the importance of normal polysialyation of NCAM in neurodevelopment. Dr Wiseniewska showed histological evidence of the impact of abnormal, or poly-Sia-free-NCAM, seen as demyelination and abnormal on neuronal structure and morphology.
Professor Hildebrandt described preclinical studies which suggest that in knock-out mice lacking an enzyme (ST8SIA2) responsible for modifying NCAM to PolySia-NCAM, the resulting reduced polysialyation leads to pathological brain development and schizophrenia-like behaviour. According to Professor Hildebrandt, a genetic variation in ST8SIA2 is not associated per se with schizophrenia but has been associated with schizophrenia where cognitive function is particularly poor, and he suggested that lacking ST8SIA2 has the potential to confer a neurodevelopmental predisposition to schizophrenia. He then went on to describe research suggesting that having this genetic deficiency, coupled with juvenile exposure to cannabis was linked with synergistic, negative effects on cognition in adulthood.
There has been inconsistent data regarding whether NCAM levels are increased or decreased in schizophrenia.
The final speaker at the symposium, Professor Gianfranco Spalletta, of the IRCCS Santa Lucia Foundation and Laboratory of Clinical and Behavioural Neurology in Rome, Italy, presented research findings relating to NCAM and polysialic acid serum levels in patients with schizophrenia. He said that there has been inconsistent data regarding whether NCAM levels are increased or decreased in schizophrenia. He reported his own, as yet unpublished data suggesting that PolySia-NCAM serum levels are significantly raised in schizophrenia and appear to be modifiable – as shown by lower levels in patients receiving treatment for the condition. He also reported that levels of this marker appear higher in patients with disease characterized by predominantly negative symptoms. Professor Spalletta said that brain neuroimaging studies may help with further understanding of the role of this intriguing molecule in subtypes of schizophrenia.
One of the first symposia on Day One ECNP 2015 was a research-track-focus on the possible roles of polysialylated neural cell adhesion molecule (PolySia-NCAM) in neurodevelopment and schizophrenia.
People with schizophrenia aged 55 years and above are about to become 25% of the total population with the disease. Yet only 1% of the schizophrenia research budget relates to older adults. So it is not surprising that much about the natural history of schizophrenia in this group remains unclear. To what extent is it really a quiescent disease at this stage in life? How does cognitive function change with time?
Data from New York City, presented by Carl Cohen (SUNY Downstate Medical Center, Brooklyn, New York, USA) casts light on what is happening in people with schizophrenia in mid to late life (55 years plus) and living in the community.
The starting point was a group of 250 who had developed schizophrenia before the age of 45. They were outpatients and did not have moderate or severe cognitive deficits or complicating factors such as a history of head trauma at baseline. Those living independently represented 39% of the sample: the others were in some form of supported residence. They were matched at baseline with 113 controls matched for age and income.
The cognition situation in older people is dynamic: some improve, others decline
At the start of the study, people with schizophrenia had a mean Dementia Rating Scale (DRS) score of 128, not far below the score of 138 among controls, but perhaps indicative of mild cognitive impairment.
As expected, there was considerable loss to follow-up, not least because of death. But those lost were similar to those who could be re-contacted. After a median follow-up of 4.5 years, the mean score of 127 among 104 people with schizophrenia showed no change. But this did not mean that no px had changed. While 59% showed essentially the same score at follow-up, 21% had experienced a decline in cognition – defined as a fall of 0.5 SD per year – and 19% had shown improvement -- defined as an increase in score of 0.5 SD per year. So the cognition the situation is actually quite dynamic.
On multivariate analysis, those whose cognition scores improved had had poorer scores at baseline. So there may be some regression to the mean. Though pxs living independently had better cognition at baseline, those living in supported housing were less likely to show decline over the period of follow-up, perhaps because of greater access to services.
Although an estimated 8% of the human genome is of retroviral origin, acquired during millions of years of primate evolution, most of it is now junk. It has been inactivated by mutation or epigenetic processes such as methylation. But what if some of it is capable of re-activation, perhaps by infections during embryonic development?
Though he repeatedly acknowledged that the idea is highly speculative, Awais Aftab (Case Western Reserve University, Cleveland, Ohio, USA) presented the argument that Human Endogenous Retroviruses (HERVS), particularly the HERV-W family, may play a malign role in the causation of schizophrenia.
There is evidence that HERV-W nucleotide sequences are more common in those affected with schizophrenia than in controls. The HERV-W envelope protein seems to activate production of inflammatory cytokines, which might contribute to the inflammation story in schizophrenia. And infections linked to schizophrenia can activate HERV-W elements, perhaps through demethylation of relevant genes.
In combination with genetic predisposition and environmental factors, archaeological remnants of millennia-old viral RNA could set the developing brain on the path towards schizophrenia and so provide a missing link in causation, at least in some patients. It is a suggestion worth considering.