"Our overriding aim is to make a difference to patients and families – and accelerating the development of effective therapies is central to that aim." Nick Fox
UK DRI Group Leader
Prof Nick Fox is an expert in neuroimaging whose pioneering work in the development and application of magnetic resonance imaging (MRI) methods has had impacts on the detection, diagnosis and monitoring of progression in cognitive disorders and neurodegenerative dementias. He is currently Professor of Neurology and Director of the Dementia Research Centre at the Institute of Neurology, University College London. He has published over 400 papers, and is recognised as a “most highly cited” researcher by Thomson Reuters (top 1% of global citations in 2017). He has earned numerous prestigious awards, including election to the Fellowship of the Academy of Medical Sciences and NIHR Senior Investigator, and the 2017 Weston Brain Institute International Outstanding Achievement Award.
1. At a glance
Improving diagnosis, treatment and care for people living with dementia
Cellular and animal models have been vital to progressing our understanding of a multitude of diseases. However, in order to develop therapies for humans, there is no substitute for the real thing.
In this programme of work, Prof Nick Fox and his team working closely with his clinical colleagues at the Dementia Research Centre (DRC), will be collecting clinical, imaging and neuropsychological data and biological samples from groups of people attending clinics, particularly those at risk of developing neurodegenerative conditions such as Alzheimer’s disease. The group will principally be investigating individuals which have genetic mutations predisposing them to these conditions, but also those that develop them sporadically.
By studying these individuals over a long period of time, it is possible to track and quantify the biological changes that occur even before symptoms start. This provides unique opportunities to gain a deeper understanding of what causes these diseases, to develop new tests for diagnosing dementia earlier, and to design and trial new drugs targeting each disease’s specific molecular signature.
Additionally, the group will establish a specialist centre, offering support to people living with dementia and their families, including bespoke support groups and electronic resources addressing specific needs of different patient groups, and the latest clinical trials.
2. Scientific goals
The capacity to carry out experimental medicine and find therapies is critically dependent on understanding disease in the human – there is no substitute for this. Therefore, access to clinical cohorts and associated materials is invaluable to the success of the UK DRI in its mission to translate basic research into therapeutics for dementia-associated conditions.
Prof Nick Fox’s team and PIs at the DRC will support the effective integration of basic and clinical research by leveraging and building on ongoing studies and clinical expertise available at the DRC at UCL which hosts a number of longitudinal cohort studies including: (a) at-risk genetic populations of familial Alzheimer’s disease and frontotemporal dementia (FTD); (b) sporadic FTD, AD, and Lewy body dementias; and (c) biomarker (positive and negative) ageing birth cohorts where life course influences and genetics can be accounted for.
Specifically, this programme will: streamline and centralise the collection and storage of materials – DNA, RNA, serum, plasma, CSF, fibroblast- and blood-derived hiPSCs and brain tissue – from these cohorts, providing a vital resource to support the ground-breaking work of other groups at the DRI; and facilitate the identification of patients with familial forms of dementia throughout the UK, recruitment to research studies, and provide support to patients, family members and at-risk individuals.
The clinical cohorts available – and particularly individuals at risk of familial dementia – will be ideally placed to underpin first-in-human therapeutic studies, vital for translating basic research once viable drug targets are identified.
Main objectives and research goals:
1. Assess and offer research to every UK family with familial dementia, establishing a national centre, providing support to patients through specialist clinicians and support groups, and offering therapeutic trials at all stages of disease.
2. Establish a comprehensive collection of UK dementia samples: from blood & CSF to brain donation.
3. Establish novel dynamic markers at UCL, e.g. SILK (stable isotope labelling kinetics).
4. Use ex-vivo (e.g. iPSC) and in-vivo (imaging and biomarker) studies, to better define the relationships between mutation and effect on clinical manifestation and biomarkers.
5. Support multi-centre, multi-disciplinary familial dementia collaborations.
6. Establish a research programme to develop and test gene-based therapies in neurodegeneration.
7. Run at least one pilot therapeutic trial in genetic forms of dementia.
8. Conduct research into improving recruitment, acceptability and retention of clinical trials – including support for families and carers.
3. Links with the Dementia Research Centre
The UK DRI at UCL works closely UCL’s Dementia Research Centre (DRC). The DRC is a hub for patient-centred research into dementias with particular expertise in young-onset, inherited and unusual dementias and is closely integrated with the NHS Cognitive Disorders Service at Queen Square. DRC clinical PIs include:
Dr Cath Mummery
Dr Jonathan Rohrer
Prof Martin Rossor
Prof Jonathan Schott
Prof Jason Warren
Dr Rimona Weil
Cohort studies relevant to the DRI that are run from the DRC include the Familial Alzheimer’s disease study run by Prof Fox, the Genetic FTD Initiative (GENFI), an international study of familial frontotemporal dementia run by Dr Jonathan Rohrer, and the Insight 1946 study run by Prof Jonathan Schott.
4. Team members
Emily Abel (Research Technician)
Dr David Cash (Senior Postdoctoral Research Associate - Imaging)
Prof Sebastian Crutch (Professor of Neuropsychology)
Ayesha Khatun (Research Co-ordinator FAD)
Claire Leckey (PhD Student)
Dr Antoinette O’Connor (Neurology Clinical Fellow)
Dr Ross Paterson (Neurologist – SILK lead)
Ivanna Pavisic (PhD Student)
Dr Natalie Ryan (Clinical Lecturer in Neurology)
Helen Rice (Research Nurse)
Imogen Swift (Research Technician)
Tom Veale (PhD Student)
Clinical trials, human imaging, neuropsychology, biomarkers, clinical phenotyping
Magnetic resonance imaging (MRI), biomarkers, Positron emission tomography (PET
7. Key publications
Fox NC, Black RS, Gilman S, Rossor MN, Griffith SG, Jenkins L, Koller M. Effects of Ab immunization (AN1792) on MRI measures of cerebral volume in AD. Neurology 2005;64(9):1563-72
Ridha BH, Barnes J, Bartlett JW, Godbolt A, Pepple T, Rossor MN, Fox NC. Tracking atrophy progression in familial Alzheimer’s disease: a serial MRI study. Lancet Neurol 2006;5(10):828-34.
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer disease. NEJM 2014;370:322-33
Ryan NS, Nicholas JM, Weston PSJ, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, de Strooper B, Revesz T, Holton J, Mead S, Rossor MN, Fox NC. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer's disease: a case series. Lancet Neurol. 2016 Dec;15(13):1326-1335. doi: 10.1016/S1474-4422(16)30193-4
Weston PSJ, Nicholas JM, Henley SMD, Liang Y, Macpherson K, Donnachie E, Schott JM, Rossor MN, Crutch SJ, Butler CR, Zeman AZ, Fox NC. (2018) Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study. Lancet Neurol;17(2):123-132. doi: 10.1016/S1474-4422(17)30434-9
Weston PSJ, Poole T, O'Connor A, Heslegrave A, Ryan NS, Liang Y, Druyeh R, Mead S, Blennow K, Schott JM, Frost C, Zetterberg H, Fox NC. (2019) Longitudinal measurement of serum neurofilament light in presymptomatic familial Alzheimer's disease. Alzheimers Res Ther. 2019 Feb 20;11(1):19. doi: 10.1186/s13195-019-0472-5
Arber C, Toombs J, Lovejoy C, Ryan NS, Paterson RW, Willumsen N, Gkanatsiou E, Portelius E, Blennow K, Heslegrave A, Schott JM, Hardy J, Lashley T, Fox NC, Zetterberg H, Wray S. (2019) Familial Alzheimer's disease patient-derived neurons reveal distinct mutation-specific effects on amyloid beta. Mol Psychiatry. doi: 10.1038/s41380-019-0410-8
Ross W. Paterson, Audrey Gabelle, Brendan P. Lucey, Nicolas R. Barthélemy, Claire A. Leckey, Christophe Hirtz, Sylvain Lehmann, Chihiro Sato, Bruce W. Patterson, Tim West, Kevin Yarasheski, Jonathan D. Rohrer, Norelle C. Wildburger, Jonathan M. Schott, Celeste M. Karch, Selina Wray, Timothy M. Miller, Donald L. Elbert, Henrik Zetterberg, Nick C. Fox & Randall J. Bateman. SILK studies — capturing the turnover of proteins linked to neurodegenerative diseases. Nat Rev Neurol. 2019 Jul;15(7):419-427. doi: 10.1038/s41582-019-0222-0.