Old Age Psychiatry & Dementia

Consultancy in proteomics and protein biomarker research
Consultancy in proteomics
Mass spectrometry-based proteomics
Protein biomarker research for NIHR Biomedical Research Centres

Angela heads the Alzheimer’s disease RNA biomarker group that is part of a wider Alzheimer’s disease blood biomarker programme at the Institue of Psychiatry, headed by Professor Simon Lovestone.

The team aims to establish a robust panel of blood molecules within the next five years that together form a high performance biomarker, enabling early Alzheimer’s disease diagnosis and a way to accurately assess the rate of disease progression. A simple blood test for Alzheimer’s disease will ultimately enable personalised treatment strategies of individual patient response to treatments as they become available and enable treatment to begin at the earliest stage of disease where the greatest benefits can be achieved. It will also enable the effects of lifestyle and environmental factors to be monitored, which could lead to new health advice on how to prevent or slow progression of the disease.

In addition, the efficiency of a blood test would allow more drugs to be evaluated in clinical trials, thus increasing the chances of identifying and developing a desperately needed effective treatment for Alzheimer’s disease. Furthermore, this research could also have wider applications to other neurodegenerative disease, such as motor neurone disease and Parkinson’s disease, where common proteins to those implicated in Alzheimer’s disease are thought to be important in disease pathology.

Angela has also recently begun a pilot study to look for new ways to develop a treatment for Huntington’s disease. She is investigating how Dictyostelium discoideum (social amoeba) tolerate long polyglutamine-containing proteins that are found naturally in this organism which would be predicted to be disease-causing if produced in humans.

020 7848 0772

Dr Claudie Hooper currently holds a three year Alzheimer’s Society Fellowship to explore the role of inflammation in Alzheimer’s disease. Prior to this she worked on a Wellcome Trust project grant also at the Institute of Psychiatry and investigated the role of glycogen synthase kinase 3 (GSK3) in Alzheimer’s disease; particularly focusing on the Wnt and insulin signalling pathways (2004-2008).

020 7848 0547

020 7848 0547

My current research involves using multiple approaches to identify biomarkers for Alzheimer’s disease (AD) conversion, progression and treatment response. I am evaluating if smell identification test can be used as a treatment response marker in AD patients receiving cholinesterase inhibitors. I have further extended the project to establish whether smell identification has utility as a progression marker in AD. In a proteomics study in AD, I have identified plasma proteins differentiating rapid from non-rapid decliners, and validating them in larger samples for testing their robustness

Current research activity
My fellowship is allowing me to conduct research into how we monitor disease progression in Alzheimer’s Disease. We hope to devise a sensitive and reliable method using functional magnetic resonance imaging.

Other research interests
I am involved in a study looking at the role of certain stages of sleep in the process of memory consolidation.

020 7848 0346

Ricardo Sainz-Fuertes is a Specialist Registrar in General Adult Psychiatry at The South London and Maudsley Trust (Guy’s rotation).

Dr Sainz-Fuertes is currently working under the supervision of Professor Robin Murray and Professor Simon Lovestone analyzing protein expression in plasma samples of patients suffering from Schizophrenia using Proteomic techniques such as Two-Dimensional gel electrophoresis (2DGE) and mass spectrometry (LS/MS/MS).

020 7848 5245

Very late-onset schizophrenia-like psychosis. Psychosis that has onset after the age of 60 years is surprisingly common and our work has shown that this cannot be attributed to focal brain pathology or increased morbid risk among relatives but that increasing age, membership of a migrant group and difficulties with mentalisation can be added to the established risk factors of female gender and sensory impairment. We are continuing to explore how activity within the dopaminergic system changes with increasing age in females and investigating the utility of mentalising therapy, using film clips to train patients to understand social situations within which deception is involved. We are also about to begin recruitment to ATLAS (Antipsychotic treatment in very late-onset schizophrenia-like psychosis) which will be the first RCT to examine treatment in this group.

Brain imaging in dementia and psychosis. We were among the first groups to use functional brain imaging to locate activity associated with auditory and visual hallucinations and to investigate the substrate of visual imagery and motion perception and were the first to show that purely visual stimulation could activate auditory cortex and that hallucinatory activity was restricted to those brain areas whose activity supports perception. These findings have been used to explore the use of functional brain imaging to distinguish different dementia pathologies. Our main imaging approach to dementia has been to develop a paired associate learning stimulation paradigm which can be delivered to subjects during scanning at a number of different difficulty levels so that we can control for the confounds of performance success, relative and absolute difficulty. With this we have shown that young and old healthy subjects and patients with early Alzheimers disease all use the same brain areas to perform paired associate learning and that patients doing an easy task use the same brain regions that a healthy person would only have to use at a more difficult task level. These findings are currently being exploited to try and develop a robust biomarker of disease course progression in Alzheimers disease. To carry out more difficult levels of task, both patients and healthy comparison subjects recruit medial frontal regions - patients at easier levels than comparison subjects. We are currently investigating the sensitivity and reliability of just how early this frontal activation occurs and how it increases with increasing task difficulty in patients and healthy subjects scanned at 2 intervals separated by 6 months.

Independent large-scale randomised controlled trials. The evidence base used to support the use of most drug treatments in old age psychiatry is either modest or has been controlled by the pharmaceutical industry. Our work aims to change this situation through the identification of areas of genuine clinical uncertainty that can be tested through conduct of a trial. Some of the trials are still ongoing, but here is a sample with the questions that they hope to answer:

Is delirium preventable through training of general hospital staff to recognise and take steps to avoid emergence of symptoms? We carried out a trial of a staff education package within wards at Kings College Hospital and were able to halve the number of incident cases of delirium seen.

Is it possible to reduce the large proportion of nursing home residents with dementia who are routinely prescribed antipsychotic drugs? The FITS trial showed that provision of support to nursing homes in the form of 1 day per week of additional training reduced the proportion of residents prescribed antipsychotic drugs by 50%.

Do cholinesterase inhibitors have efficacy in the treatment of clinically significant agitated behaviour in people with Alzheimers disease? The CALM-AD trial showed unequivocally in 270 patients that these drugs were no better than placebo in the treatment of agitation although they did have a small positive effect on cognitive function.

Are the current NICE stopping rules for cholinesterase inhibitors correct? Should patients continue with their drugs once they have moderate to severe Alzheimers disease and do they benefit from adding memantine? The DOMINO trial begins recruitment in February 2008. To learn more about this trial visit http://neuroscience.iop.kcl.ac.uk/domino/
Are antipsychotic drugs superior to placebo in the treatment of patients with very late-onset schizophrenia-like psychosis? The ATLAS trial which commences recruitment in late 2010 will examine the effects of double-blind short-term (12 weeks) and longer term (26 weeks) treatment with amisulpride 100mg and placebo.

Can cognitive training improve cognition and slow down the rate of cognitive decline in mild Alzheimer’s disease? Together with Adrian Owen and colleagues in Cambridge we are developing an internet-deliverable cognitive training package based on the Cambridge Brain Gym (http://www.cambridgebraingym.com/tests.htm) which will be subject to a major RCT in the near future.

Can immunotherapy prevent or delay the appearance of Alzheimer’s disease in people with Downs Syndrome? Together with Tony Holland in Cambridge we are interested in investigating whether one of the current amyloid-based immunotherapy treatments can delay onset of symptomatic AD in this very high risk group.

Training and Standards in Psychiatry

As Dean of the Royal College of Psychiatrists (2008-13) I am the profession’s elected lead on training and professional standards. Within the College, I Chair the Education, Training and Standards Committee and the Heads of Schools Committee. Together with four Associate Deans, I have responsibility for the Curriculum, MRCPsych Examination and other assessments, Continuing Professional Development and Revalidation. As part of raising and maintaining standards in Psychiatry, I want us to attract the very brightest and best of trainees from all over the World to join us. In recent years, careers in Psychiatry have not been popular with UK medical school graduates. Changing undergraduate and foundation trainee perceptions about Psychiatry is an important ambition for the College and you can find out more about how we are doing this by visiting the College website.

020 7848 0545/0550

alison.sharpe@iop.kcl.ac.uk,r.howard@iop.kcl.ac.uk

My research
My research interests concentrate on understanding the molecular and cellular events that take place in the brain and especially the role of tau, in Alzheimer’s disease, together with the genetics and proteomics of late onset Alzheimer’s disease. This work is sponsored by the Wellcome Trust, the Medical research Council, The Alzheimer’s Research Trust, the Alzheimer’s Society and Research into Ageing.

Pathogenesis of Alzheimer’s disease and the role of Glycogen Synthase Kinase-3 in the brain
In Alzheimer’s disease, the neuronal protein tau is more highly phosphorylated than in normal brain. Searching for the enzyme responsible for this phosphorylation led our group, and others, to the enzyme glycogen synthase kinase-3 (GSK-3). It is clear now that GSK-3 is not the only tau-kinase but it is perhaps the predominant kinase and we have shown that it is altered in Alzheimer’s disease and that it regulates long term potentiation (the closest model we have at a cellular level of memory). In cells we have shown that GSK-3 regulates tau binding to and stabilisation of microtubules and in Drosophila altering tau phosphorylation through GSK-3 inhibition restored axonal transport – a property of neurons essential for their normal function. All of this suggests that inhibition of GSK-3 might be a possible therapeutic option in Alzheimer’s disease.

We are now concentrating on understanding the regulation of GSK-3 in the brain. Our evidence suggests that GSK-3 regulation is altered in Alzheimer’s disease and possibly also in other neuropsychiatric conditions such as schizophrenia.

Biomarkers of Alzheimer’s disease
A biomarker, or test, for Alzheimer’s disease is urgently sought. Biomarkers are used elsewhere in medicine for improved diagnosis, for pre-symptomatic diagnosis, for risk evaluation, to monitor disease progression or the results of therapy. There are no fully confirmed biomarkers for AD although neuroimaging comes the closest and is widely used in both clinical practice and in research. For biochemical markers there is best evidence for CSF (spinal fluid) assays for tau protein or amyloid – both known to be involved in AD.

We have concentrated instead on trying to find a blood-based biomarker for AD. Using a candidate based approach and using proteomics we have found a range of changes in the blood of people with AD. This demonstrates that a blood based approach is feasible and we have confirmed some of these changes in large numbers of patients. We are now using these and related methods to find biomarkers that might be used in clinical trials and in clinical practice.

This research includes AddNeuroMed, one of the two related InnoMed projects that are pilots for the Innovative Medicines Initiative (IMI). Further details of IMI and AddNeuroMed can be found here.

Genetics of Alzheimer’s disease and other disorders
Together with John Powell at the IoP and collaborators in Cardiff I have been involved with large collaborative studies seeking to find genetic susceptibility factors for Alzheimer’s disease. Together this group has published many papers including a sibling-pair study finding a region on chromosome 10 linked to AD and a number of possible association findings including the first report of an association with Angiotensin Converting Enzyme. The IoP group has also reported associations of genetic factors with behavioural symptoms in AD and, in studies linking with our interest in intracellular signalling (see above), associations of genes involved in regulation of GSK-3 via wnt and insulin signalling with both Alzheimer’s and Schizophrenia.

My group
Many students, post-doctoral researchers and fellows have contributed to this work over the years. My current group are, in no particular order Richard Killick, Claudie Hooper, Graham Cocks, Anna Kinsey, Mirsada Causevic, Nicola Archer, Catherine Tunnard, Nicola Dunlop, Andreas Guntert, Madhav Thambisetty, Paul Hopkins and Ricardo Sainz Fuertes. Recent and much valued colleagues include Rejith Dayanadan, Amritpal Mudher, Eirini Meimaridou, Danae Liolitsa, Fiona Kerr, Abdul Hye and many others.

020 7848 0239

The main focus of my research interest is the neurochemistry of neuropsychiatric disorders in later life, with a view to understanding their pathophysiology and optimizing treatment strategies. I have a primary interest in psychosis within the context of neurodegeneration. My work to date has focussed upon the dopaminergic system of neurotransmission and has provided evidence that dopaminergic dysregulation is intimately associated with psychosis in Alzheimer’s Disease, similar to young adults with schizophrenia. Future PET studies aim to differentiate between age- and disease-related mechanisms of antipsychotic sensitivity in older people.

In addition to my own research, I oversee clinical trials in dementia, as part of my role within the Mental Health of Older Adults and Dementia Clinical Academic Group (CAG). We are also in the process of setting up an MSc in Dementia Care