Dementia and A window of opportunity UCL SCHOOL OF LIFE AND MEDICAL SCIENCES Creating knowledge, achieving impact PREFACE

UCL has the expertise to have a Central to this new vision is the Leonard significant impact on the treatment of Wolfson Experimental and other neurodegenerative Centre, a site at which early proof- diseases – and the commitment to of-concept studies in people can be make it happen. carried out – overcoming one of the most important roadblocks in the UCL’s School of Life and Medical development of new therapeutics. Sciences is one of the largest centres With the associated progress in imaging of biomedical and health research in and biomarker development providing Europe, if not the world. Its speciality new tools for rapid assessment of areas span all levels from the smallest therapeutic agents, the Centre will play biomolecules to global populations. a critical role in bringing much-needed Similarly, in dementia and medicines to patients. Professor Alan Thompson neurodegeneration, the School can An important source of new Dean, UCL Faculty of Sciences. lay claim to world-leading expertise therapeutics will be UCL research across the full spectrum of research, itself, progressed through our from studies of the genetic causes of groundbreaking partnership with disease and their molecular modes the Eisai pharmaceutical company. of action through to evidence-based By creating interdisciplinary teams psychosocial treatments for patients combining academic and industry and carers. expertise, we will accelerate the We have identified dementia and development of new agents to the point neurodegeneration as a strategy at which they can be tested in people priority for the Faculty of Brain Sciences at the Leonard Wolfson Centre. for 2013–18. In part this reflects a Our extensive health research platform desire to build on our undoubted already contributes to clinical trials, strengths in this area. But it is also and has the potential to be involved a recognition that dementia and in later large-scale trials of promising neurodegeneration are a national and therapeutics. It also plays a vital role international priority. As populations in improving the quality of life of today’s age, dementia is inevitably going to patients and carers as research become more common. It is distressing continues on the next generation for patients and for those around of medicines. them, and imposes an immense cost on health systems. Currently, there is This document provides an insight very little we can do to tackle the root into some of the work on dementia causes of disease. and neurodegeneration being carried out in the Faculty of Brain Sciences, Yet there are reasons to be in collaboration with other Faculties optimistic. Mechanisms of disease within the School, other UCL Schools, are being elucidated, opening up national and international academic new opportunities for therapeutic collaborators, and our industrial intervention. And the realisation that partners. Over the next five years – neurodegeneration is a long-term and beyond – we aim to bring the process, an accumulation of damage unique strengths of UCL to bear on over many years, is opening up a these profoundly important health window of opportunity. There is the real problems. I am convinced our prospect that new disease-modifying collective efforts will make a very real treatments will be able to slow or even difference to the lives of patients and halt this accumulation, postponing their families in the years to come. the onset of symptoms and extending the duration of healthy life.

CONTENTS

Dementia and neurodegeneration: 2 Challenges and opportunities

Fundamental research: From molecules 4 to neural circuitry • John Collinge • Gipi Schiavo • Tony Schapira • Trevor Smart • Andrey Abramov • Eleanor Maguire • Patricia Salinas •

Profile: Huntington’s disease: from molecules to 9 (Sarah Tabrizi)

Translational research: Genetic insights, disease 10 models and intervention development

• John Hardy • • John Collinge • Helene Plun-Favreau • Francesca Cordeiro • Thomas Foltynie • Elizabeth Fisher • Mark Pepys Profile: The gene machine (John Hardy) 13

Patient-oriented research: Understanding, 18 and preventing, brain • Nick Fox • Sarah Tabrizi • Andre Strydom and • Seb Ourselin • Jason Warren LonDownS Consortium • Henrik Zetterberg • Jonathan Schott • Martin Rossor

Profile: A family affair (Nick Fox) 23

Social and health research: Essential support 24 for patients and carers

• Liz Sampson • Steve Iliffe • Marcus Richards • Martin Orrell • Bencie Woll • Gill Livingston, • Gill Livingston • Andrew Steptoe Martin Orrell, Sebastian Crutch

Profile: Dealing with dementia (Maggie and Andy Williams) 29

Facilities and resources: A platform for success 30

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 1 CHALLENGES AND OPPORTUNITIES

Neurodegeneration research at UCL spans all areas from the molecular and cellular to the social. World-class researchers are developing ways to improve the lives of patients and carers, as well as generating new insights into disease and laying the foundation for the development and testing of new treatments for these common and devastating conditions.

Dementia is one of the cellular and animal models. These principles underpin needed new treatments. greatest and growing Such models provide activities at the new Leonard In the meantime, there is challenges to health systems an ideal platform for the Wolfson Experimental still an urgent need to worldwide. In the UK, the development and testing Neurology Centre at UCL, support patients and carers. annual cost of dementia care of agents to interfere funded through a £20m UCL researchers have is £23bn, a figure projected with disease processes. grant from the Leonard played important roles to treble over the next 30 Wolfson Foundation. Perhaps most significant in documenting the years. Within a decade, The Centre will provide has been the growing belief surprisingly high incidence dementia is likely to affect facilities in which clinical that interventions need to be of undiagnosed dementia more than a million people. disease can be studied targeted as early as possible in emergency admissions further and, importantly, For individual patients, the in disease, and perhaps to hospital, as well as their emerging new treatments outlook is scarcely less even preventively. UCL very poor experience in can be tested for the first gloomy. Existing drugs researchers have played hospital and markedly worse time in people – a key provide only minor benefits a major role – particularly survival. The findings are stage in the development for a subset of patients, through brain imaging – in having practical impact, of new . and none tackle underlying demonstrating that damage underpinning a training causes of disease. An army to the brain is occurring well Equally important will be programme across UCL- of carers face the daily before clinical symptoms first the development of new associated hospitals to challenge of looking after appear. By intervening early, agents to test. A significant ensure sites are better people with dementia, often it may be possible to delay source will be the prepared to care for at great cost to their own or even prevent the onset development partnership people with dementia. mental health. of symptoms. established between UCL UCL research has also and the Eisai pharmaceutical Furthermore, brain imaging raised the important issue company. Industry expertise and biochemical markers of carer stress. A strategy New opportunities will help to develop promising of disease are providing to improve carers’ coping lines of research at UCL to Nevertheless, there are valuable new tools for strategy has been shown in a the stage at which clinical now exciting signs that clinical trials. Because of the to reduce the toll trials can begin. progress is being made. The sensitivity of these methods, of caring on mental health. mechanisms of disease are changes in the brain can be In addition, strong evidence gradually being unravelled, tracked in relatively small has been generated that Health and population and promising new targets numbers of patients over cognitive stimulation therapy research are being identified. Genetic manageable time periods, can have significant benefits studies are revealing key greatly enhancing the These exciting developments to patients. The programme disease processes, which opportunities for clinical trials in translational research is widely used in the UK and are being explored further in of disease-modifying agents. offer the prospect of much- many other countries.

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UNDERSTANDING DEMENTIA AND NEURODEGENERATION: THE KEY CHALLENGES

The hallmark of neurodegenerative disease is the death of cells. A key challenge is to understand how and why cells die.

The causes of neurodegeneration are poorly understood. Much insight has come from studies of rare families affected by neurodegenerative disease, which have revealed key genes and biochemical processes involved in Alzheimer’s disease, Parkinson’s disease and other conditions. These same processes are central to disease in the general population. A common feature of neurodegenerative disease is the build up of abnormal protein aggregates – including β- and in Alzheimer’s disease, α- in Parkinson’s disease, and protein in Creutzfeld–Jakob disease. Exactly how these aggregates contribute to disease is unclear, and the subject of intense research. Many cellular and physiological processes are disrupted in neurodegeneration. There is, for example, growing interest in the contribution of immune responses to disease progression. Mitochondrial function and disposal of defective mitochondria have been implicated in Parkinson’s disease, as has the ’s protein recycling systems. Given this complexity, it is conceivable that multiple abnormalities will be important in the development of disease. It will be important to tackle the conditions from many directions, and treatment may also ultimately require multiple lines of attack. A further challenge is to relate cellular changes to the Within a decade, dementia is likely to affect a million people. networks in which operate. For example, loss of synaptic connections as cells deteriorate may be critical to the onset of symptoms. The final link in the chain of understanding is to relate cellular changes to alterations in the activity of specific neural networks, and ultimately to the symptoms experienced by patients.

New imaging methods provide a detailed view of brain degeneration.

As well as patient groups, Cause for optimism breadth. Our goal is to exploit population cohorts are this unique resource to drive Dementia is undoubtedly also making increasing forward the development of one of the greatest health contributions to dementia interventions and diagnostics and social changes facing research. UCL is playing a that prevent disease, mitigate the UK and the rest of the leading role in several its effects or improve the world. Yet there are reasons cohorts, work on which will quality of life of those who to be optimistic. UCL is provide valuable new insight develop dementia or other ideally placed to exploit into the nature of disease neurodegenerative diseases. these opportunities, having progression and factors that established a portfolio may accelerate disease (or of research in dementia be protective) in the general and neurodegeneration of population. unmatched strength and

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 3 FUNDAMENTAL RESEARCH: FROM MOLECULES TO NEURAL CIRCUITRY

The development of new therapies will depend on a better understanding of the molecular and cellular basis of disease – and, in particular, which changes are most relevant to clinical symptoms.

Neurodegenerative diseases Even so, exactly how in mitochondrial function in have turned out to be b-amyloid accumulation neurodegeneration, and a hugely complex. Although leads to remains growing sense that cellular many changes have been unclear. As well as direct recycling mechanisms – of identified in molecular toxicity, recent work has mitochondria or abnormal and cellular processes, implicated inflammatory protein – may also be central it is unclear exactly which responses in the brain, to disease processes. have most bearing on suggesting that overactive UCL researchers are using the symptoms of disease immune responses could a variety of methods to and premature mortality. also contribute to neuronal understand the processes The question is of critical death. involved in these and other importance, as therapy On the other hand, cell forms of neurodegeneration. development needs to death may not be the critical Such work is also highlighting be focused on the most event in disease. Potentially, connections between disease-central pathways. an earlier stage – loss of different conditions, implying For Alzheimer’s disease, synaptic connections – may that some underlying cellular most attention has focused be instrumental in disease, and molecular processes on the b-amyloid pathway. leasing to a breakdown in may be shared between UCL researchers have been neural circuitry. diseases. instrumental in developing For Parkinson’s disease, As these pathways are the ‘b-amyloid cascade’ research is again providing unpicked, more possible theory of disease, which pieces of a jigsaw that are targets for pharmacological suggests that the pivotal beginning to slot together. intervention are being process in disease is the Genetic studies have revealed. accumulation of b-amyloid implicated abnormalities deposits.

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Prion protein aggregates. GABA receptor a-subunit showing neurosteroid-binding site.

CRACKING THE PRION ENIGMA THE BENEFITS OF INHIBITION As well as paving the way to new therapeutics, The inhibitory GABA could provide a better understanding of prion infections has a way to protect neurons from untimely death. implications for other neurodegenerative diseases. Many abnormalities in neurotransmitter signalling have been identified , infectious protein particles, cause a range of in Alzheimer’s disease, but it remains unclear exactly which contribute degenerative brain diseases, including Creutzfeld–Jakob to the condition’s complex constellation of cognitive and behavioural disease. In common with other neurodegenerative conditions, abnormalities. With a special interest in GABA (gamma-aminobutyric prion infections are characterised by the build up of abnormal acid) signalling, Professor Trevor Smart’s group is examining how protein aggregates. Understanding how such aggregates changes to inhibitory signalling through GABA receptors could be contribute to disease is a challenge across neurodegeneration. involved in disease. The work of Professor John Collinge and colleagues on the GABA is the brain’s main inhibitory neurotransmitter, helping to keep mechanisms of prion toxicity may therefore hold important neural excitation in check. But it also has a valuable neuroprotective role: lessons beyond prion disease. excitatory amino acids such as glutamate are toxic at high levels, and The infectious agent in prion diseases is a misfolded loss of GABA signalling can leave neurons vulnerable to overexcitation version of a cellular protein. This misfolded form, known as and cell death. Sc PrP , catalyses the conversion of the normal cellular protein, GABA signalling is mediated by two classes of GABA receptor, GABAA C PrP , into more copies of itself, which accumulate into protein and GABAB, both of which may play some role in neurodegeneration. aggregates. However, although this ultimately kills the cell, it Professor Smart’s work aims to establish links between the molecular is far from certain that the aggregates themselves are actually and cellular processes underlying GABA signalling and cognition, to most damaging to the cell – a phenomenon common across understand normal biological function and how it goes wrong in disease. neurodegenerative conditions. GABAA receptors are the targets of neurosteroids, and there is some Several key features of prion infection require explanation. evidence that neurosteroid levels are abnormally low in Alzheimer’s For example, prion infections show long incubation periods disease. Furthermore, boosting neurosteroid levels ameliorates the – decades in humans – but when clinical decline begins, it is symptoms of a severe childhood form of neurodegeneration, Niemann– extremely rapid, with death occurring within months. There Pick disease. To identify key mechanisms, Professor Smart is generating is also no obvious link between levels of PrPSc build up and transgenic mice lacking neurosteroid-binding sites in the α1, α2 and α4 Sc symptoms, and PrP is not toxic to cells unless they also subunits of the GABAA receptor, to see what impact reduced neurosteroid express PrPC. signalling has on neuronal function and survival, and on the animals’ These and other findings led Professor Collinge to propose cognitive abilities. a model in which infectivity and toxicity are dissociated. PrPSc Recently, Professor Smart and colleagues have looked in more detail at is the agent responsible for transmission, but some other state GABA and . Prolonged signalling through excitatory NMDA – perhaps an intermediate in the transition from PrPC to PrPSc – receptors – a possible downstream effect of β-amyloid accumulation – is the neurotoxic agent. Studies of experimental infections in was found to lead to reduced numbers of cell surface GABAB receptors, mice provided good evidence in support of this idea. whereas brief exposure to glutamate increased cell surface GABAB The model implies that PrPSc is not itself toxic but causes receptors, suggesting receptor numbers are determined by a highly harm through its effects on PrPC. Hence, maintaining PrPC in dynamic mechanism. These changes were dependent on phosphorylation its native state should prevent PrPSc from exerting its harmful of a critical site within one subunit of the receptor, which altered effects. This is the basis of therapeutic interventions being intracellular trafficking. Rather than being recycled to the cell surface after developed by Professor Collinge’s laboratory (see page internalisation, receptors underwent degradation in . 14). More generally, the results add to a growing body of Again using mouse models, Professor Smart aims to understand evidence that the characteristic large-scale aggregates seen more about these mechanisms and how they affect survival, in neurodegenerative conditions may not necessarily be the neural circuitry and ultimately cognitive symptoms. More generally, critical toxic entities. as GABA receptors are well-established targets for pharmaceutical interventions, these studies raise the prospect of therapies that interfere Collinge J, Clarke AR. A general model of prion strains and their with GABA receptors to maintain GABA inhibitory signalling and prevent pathogenicity. Science. 2007;318(5852):930–6. neurodegeneration. Sandberg MK et al. Prion propagation and toxicity in vivo occur in two distinct mechanistic phases. Nature. 2011;470(7335):540–2. Hosie AM et al. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature. 2006;444(7118):486–9.

Terunuma M et al. Prolonged activation of NMDA receptors promotes dephosphorylation and alters postendocytic sorting of GABAB receptors. Proc Natl Acad Sci USA. 2010;107(31):13918–23.

Hannan S, Wilkins ME, Smart TG. Sushi domains confer distinct trafficking profiles on GABAB receptors.Proc Natl Acad Sci USA. 2012;109(30): 12171–6.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 5 Tracking . Dr Andrey Abramov.

A MOVING STORY THE TWO SIDES OF DOPAMINE Might impaired transport of material along axons Under different circumstances, dopamine may be a critical factor in neurodegeneration? be either a harbinger of death or a guardian angel.

The great length of many neurons poses a considerable challenge One of the puzzles of Parkinson’s disease is why such a specific set to communication between the cell body and nerve terminals. of neurons, cells of the , are affected. Intracellular transport systems are thus critical to neuron biology. The research of Dr Andrey Abramov and colleagues suggests that And, as Dr Gipi Schiavo and colleagues have discovered, dopamine itself may be the culprit. Yet, in other circumstances, abnormalities in such systems can spell the end of the cell. dopamine may actually protect neurons from premature death. Dr Schiavo has had a long-standing interest in both pathogens Familial forms of Parkinson’s disease have provided important and neuronal transport. In fact the two are connected, as several clues to the cellular mechanisms of disease. In PINK1 deficiency, pathogens and pathogen products have hijacked the uptake and for example, Dr Abramov’s work has highlighted important defects transport systems of neurons to enter cells and gain a free ride to in mitochondrial calcium storage, as well as damaging levels of the cell body. One such protein is tetanus toxin, and by adapting charged free radicals. Together, these changes render mitochondria this protein Dr Schiavo has been able to develop probes to explore unstable and vulnerable to premature death. the mechanisms of neuronal transport. Given the specific loss of dopaminergic cells, it has been Using mass spectrometry, he was able to show that transport suggested that dopamine itself may contribute to cell death in the from the nerve terminal to the cell body – axonal retrograde substantia nigra. Working with cells from PINK1 knockout mice, Dr transport – is dependent on a surprisingly complex organelle Abramov and colleagues recently found that this is indeed the case. containing many hundreds of proteins. At its heart is a molecular It turns out that, as well as its classic action on dopamine motor protein, . receptors, dopamine also has receptor-independent effects on In 2003, work with Professor Elizabeth Fisher identified cells. In particular, it generates additional calcium signals, while its in dynein in the ‘Legs at odd angles’ (Loa) mouse mutant, which enzymatic breakdown stimulates a burst of free radical production. shows late-onset neuromuscular degeneration. The mutant form of These triggers appear to be the final straw that pushes already dynein was less able to support rapid retrograde transport in motor vulnerable mitochondria over the edge, leading to the death of neurons. Since other genetic causes of neurodegeneration also the cell. affect retrograde transport, the results suggested that abnormal Significantly, these results argue that manipulation of calcium axonal transport could be important in a range of pathological signalling or targeting of the free radical system (to reduce free conditions affecting the . radical production or to increase levels of mitochondrial ) Indeed, work with Professor Linda Greensmith on another form of could be fruitful therapeutic strategies. Although therapy disease, amyotrophic lateral sclerosis (ALS), provided has not yet shown convincing results, this may be because it has further support for this idea. Using a newly developed assay, not been used early enough to have any beneficial effect. Dr Schiavo was able to visualise vesicle transport in living mice While dopamine may be the guilty party in Parkinson’s disease, engineered to express a human ALS-causing gene. Significantly, paradoxically it may also be a cellular life-safer. After oxygen defects in axonal retrograde transport were seen long before deprivation, a build up of extracellular glutamate can be lethal physical symptoms were apparent – implying that disruption of to neurons. However, through its action on calcium signalling, Dr transport was an early and perhaps causal event in disease. Abramov and colleagues have shown that dopamine can block the In 2013, Dr Schiavo moved from the CRUK Research neurotoxic effects of glutamate. Indeed, he suggests, dopamine may Institute to UCL, to forge closer links with Professor Fisher and have an important role as a ‘safety catch’ that prevents glutamate Professor Greensmith, as well as with UCL’s human geneticists from damaging cells during normal glutamate neurotransmission. and clinicians. Notably, components of neuronal transport systems identified in cellular studies have turned out to be involved in clinical Vaarmann A, Gandhi S, Abramov AY. Dopamine induces Ca2+ signaling conditions, and further analysis may reveal candidate causes of in through generated by monoamine oxidase. J Biol Chem. 2010;285(32):25018–23. other unexplained cases. Furthermore, transport abnormalities have also been seen in other neurodegenerative conditions, Gandhi S et al. Dopamine induced neurodegeneration in a PINK1 model including Alzheimer’s and Huntington’s disease, so the process of Parkinson’s disease. PLoS One. 2012;7(5):e37564. may be of even wider significance. Vaarmann A et al. Dopamine protects neurons against glutamate-induced excitotoxicity. Cell Death Dis. 2013;4:e455. Hafezparast M et al. Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science. 2003;300(5620):808–12.

Bilsland LG et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc Natl Acad Sci USA. 2010;107(47):20523–8.

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HUNTINGTON’S DISEASE: FROM MOLECULES TO BRAIN TRAINING

Professor Sarah Tabrizi is leading a highly varied programme of research in Huntington’s, ranging from genetic and cellular studies to advanced brain imaging and innovative interventions. And by maintaining regular contact with patients, she ensures this research is rooted in the realities of disease.

Huntington’s disease – which is common – or ‘neurofeedback’ techniques – such as muscle wasting may be less common research is proving tough, as a clinical intervention, to and weight loss – as well as than Alzheimer’s disease looking after patients helps boost compensation. While neurodegeneration, says but it strikes early and is me get a perspective.” undergoing functional MRI, Professor Tabrizi. “Targeting impossible to treat. “It’s patients are encouraged peripheral pathogenesis like “When I see patients in a truly dreadful disease,” to mentally envisage muscle wasting or immune clinic and witness the says Professor Tabrizi, who movement-related activity, dysregulation may be a more devastation that diseases manages both a major and receive real-time visual tractable therapeutic in the like Huntington’s disease multidisciplinary research feedback on activity in motor short term while we work on cause to families, I don’t programme and one of the areas of the brain. With the very challenging task of need any more motivation. UK’s leading clinical centres training, patients can learn modulating the brain.” It’s genuinely humbling.” for Huntington’s disease. to enhance this activity, even For the latter, Professor “Huntington’s affects people Professor Tabrizi’s research without visual feedback. Tabrizi is excited by the who are around 40, have is notably diverse, spanning Early results show promise potential of often nursed a parent with cellular and neurological that neurofeedback can technologies, which can the disease, and whose themes. The groundbreaking induce neural compensation selectively knockdown children are then also at risk.” TRACK-HD initiative, for with positive effects on levels of mutant example, has revealed behaviour. To support such families, protein in cells. Approval changes in brain structure Professor Tabrizi is Track-On is also focusing is being sought for human and other markers years committed to marrying on the extremes of the trials to be undertaken at before symptoms are clinical practice and patient sample – the ‘fast the Leonard Wolfson Centre, apparent, paving the way research, despite the progressors’ and ‘slow where Professor Tabrizi for clinical trials in early challenges. For a start, progressors’ – to identify is a principal investigator. and even presymptomatic clinical practice reveals what genetic factors that may patients (see page 20). Along with other charity- really matters to patients accelerate or protect Follow-up work, through the and industry-sponsored and shapes the direction against disease. One of the Track-On project, is aiming to work, she is optimistic that of laboratory research, most powerful modifiers is identify even more sensitive true disease-modifying while research generates the immune system, and markers for the latter group. treatments are a realistic advances that make a cellular studies in Professor prospect: “We have difference to patients’ lives. Track-On is also exploring Tabrizi’s laboratory have therapies that have ‘neural compensation’, identified key mechanisms But, she adds, patient enormous effects in mice. whereby patients recruit underlying the persistent contact has other benefits: But treating mice is not our other brain areas to carry activation of the immune “Seeing patients in clinic aim – our aim is translating out tasks and maintain system in Huntington’s always reminds me about that to humans, and that’s performance as brain tissue disease (see page 8). This why we do what we do, where we are now.” begins to be lost. An exciting may lead to new treatments and when things get tough spin-off from this work is that target the peripheral and experiments don’t work the possibility of using symptoms of the disease

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 7

Human neural stem cells. Professor Eleanor Maguire.

HUNTINGTON’S DISEASE: MAKING MEMORIES THE IMMUNE CONNECTION A better understanding of the mechanisms of memory Immune cells as well as brain cells are affected in may reveal more about the nature of dementia. Huntington’s disease – and the two may be closely connected. One of many challenges in Alzheimer’s disease is to understand the connection between pathological changes and clinical symptoms. The brain is the main focus of Huntington’s disease, but the mutant Brain imaging reveals the gross impact of neuronal death, yet protein that causes it is present in every cell of the body. Indeed, how these changes relate to symptoms will depend on a better abnormalities have been identified outside the brain, particularly in understanding of normal brain function. One of the earliest brain the immune system. Professor Sarah Tabrizi and colleagues have regions affected is the hippocampus, and Professor Eleanor identified a key mechanism by which the Huntington’s Maguire is generating fascinating insight into how this structure leads to overactive innate immune responses, a finding that could is involved in memory formation and retrieval. have consequences for the brain as well as peripheral tissues. The hippocampus has a well-established role in memory Huntington’s disease is caused by the expansion of a three- formation. A notable illustration has been Professor Maguire’s studies nucleotide repeat in the gene for huntingtin, a protein of poorly on London’s taxi drivers, whose hippocampus grows as they learn understood function. The mutation leads to a protein with a run ‘the knowledge’ – the names and locations of thousands of London of additional residues. As well as effects on the brain, streets and landmarks. mutant huntingtin is known to have a wider impact, causing muscle Of the different types of memory, the hippocampus plays a wasting and weight loss, despite increased calorie intake, and particular role in -centred or ‘episodic’ memory. Much of her work neuroendocrine changes. has been on patients with amnesia who have suffered focal damage Indeed, in 2008, Professor Tabrizi showed that Huntington’s to the hippocampus. One striking finding is that such damage not disease is associated with elevated levels of a particular cytokine, only affects memories of the past. People with amnesia also struggle IL-6, associated with activation of the innate immune response – to generate coherent visions of the future – suggesting that recalling the first-line, non-specific strand of the immune system. Human the past, imagining the future and spatial navigation may be macrophages were hyperresponsive, as were both macrophages underpinned by a common hippocampal-dependent mechanism. and (the brain’s immune cells) from Huntington’s disease A further line of research has been the use of high-resolution model mice. This hyperresponsiveness reflected huntingtin’s effect functional imaging to ‘decode’ neural signals from the brain. The within cells, rather than a response to external signals. ambitious goal is to use such recordings to identify traces of specific Recently, Professor Tabrizi’s group has extended these findings memories in the hippocampus and its associated cortical areas. significantly. Immune cells from Huntington’s disease patients were Decoding has achieved remarkable success in identifying which found to be releasing high levels of a range of cytokines involved virtual room a participant was in, and in identifying neural patterns in innate immune responses. These responses were due at least associated with specific memories of people’s life events. in part to the action of mutant huntingtin on the well-characterised Her recent studies have begun to explore the connections NF-κB intracellular signalling pathway. between the hippocampus and cortical areas, and the roles they Furthermore, using a novel gene-silencing technique – huntingtin- play in encoding memories of recent or distant events. Again using targeting small interfering RNA encased in polysaccharide shells high-resolution fMRI, Professor Maguire was able to detect signals that are readily taken up by phagocytic cells – the group was able associated with recent and distant memories, in both the cortex and to lower huntingtin levels and normalise cytokine production. the hippocampus – arguing that the hippocampus has an important Persistently high cytokine levels could underlie a range of role in accessing distant memories as well as storing new ones. health problems in Huntington’s disease, such as weight loss and More generally, these new techniques promise to provide a much depression. RNA-based methods targeting huntingtin in immune richer view of memory formation, storage and retrieval, and how cells could be a viable strategy for ameliorating these effects. and why memories decay across brain structures. Such knowledge Moreover, as evidence is accumulating that immune responses will ultimately shed light on how brain tissue loss affects memory influence disease progression in the brain, the findings also identify and other cognitive abilities in dementia. the NF-κB pathway as a possible target for interventions that have Woollett K, Maguire EA. Acquiring “the Knowledge” of London’s layout an impact on neurodegeneration. drives structural brain changes. Curr Biol. 2011;21(24):2109–14.

Björkqvist M et al. A novel pathogenic pathway of immune activation Hassabis D, Kumaran D, Vann SD, Maguire EA. Patients with hippocampal detectable before clinical onset in Huntington’s disease. J Exp Med. amnesia cannot imagine new experiences. Proc Natl Acad Sci USA. 2008;205(8):1869–77. 2007;104(5):1726–31.

Träger U et al. HTT-lowering reverses Huntington’s disease immune Chadwick MJ, Hassabis D, Weiskopf N, Maguire EA. Decoding dysfunction caused by NFκB-pathway dysregulation [submitted]. individual episodic memory traces in the human hippocampus. Curr Biol. 2010;20(6):544–7. Bonnici HM et al. Detecting representations of recent and remote autobiographical memories in vmPFC and hippocampus. J Neurosci. 2012;32(47):16982-91.

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Dendrites on cultured neurons. Professor Anthony Schapira.

SURVIVE AND PROSPER A CYCLE OF DEATH Could a better understanding of cell survival signals A rare metabolic disease is providing important clues be a route to new therapies for Alzheimer’s disease? to the mechanisms of Parkinson’s disease.

The 20 or so proteins of the Wnt family have been implicated in many People who inherit two copies of an abnormal aspects of embryonic development. Recently, though, Professor gene (GBA) develop Gaucher’s disease, suffering multiple Patricia Salinas has found that they also regulate the strength of symptoms due to the build up of toxic lipid molecules in their tissues. synaptic connections. And her most recent work suggests that Wnt They are also at significantly increased risk of Parkinson’s disease signalling could be playing a significant role in Alzheimer’s disease. – and Professor Anthony Schapira’s recent studies have revealed The idea that Wnt signalling might be important in Alzheimer’s how the conditions are connected. disease is actually an old one. Through its action on a critical The GBA gene codes for a lysosomal that digests certain kinase, GSK3β, Wnt signalling could potentially influence the build lipid molecules; in the complete absence of the enzyme, these up of phosphorylated tau, one of the hallmarks of the disease. The lipid molecules build up to toxic levels. However, although carriers evidence was not strong, however, until genomic studies identified with one abnormal gene are spared Gaucher’s disease, they are variants at a gene encoding a Wnt co-receptor as risk factors for still 20–30 times more likely to develop Parkinson’s disease than Alzheimer’s disease. the general population. Indeed, GBA is the most common gene Struck by this finding, Professor Salinas turned her attention to implicated in Parkinson’s disease. a secreted protein, known as Dickkopf or DKK1, which also binds By examining post-mortem tissue, Professor Schapira and to the co-receptor, competing with and antagonising the effects colleagues found that levels of glucocerebrosidase activity in of Wnt proteins. Indeed, adding DKK1 to mature cultured neurons Parkinson’s disease patients with GBA mutations were lower than had a dramatic effect, reducing numbers by 30 per cent those in normal , most markedly in the substantia nigra, – strongly suggesting that Wnt factors are important for maintaining the structure affected in Parkinson’s disease. in mature neurons. Furthermore, enzyme activity was also lower in the brains DKK1 levels are also increased in Alzheimer’s disease patients of sporadic Parkinson’s patients, even though they have two and some animal models of Alzheimer’s disease. Potentially, then, normal GBA genes. The likely explanation is that α-synuclein, DKK1-driven loss of synapses, rather than cell death per se, could the characteristic misfolded protein found in Parkinson’s disease, be contributing to the cognitive decline seen in patients. disrupts the function of glucocerebrosidase. To explore further, Professor Salinas examined the effect of These striking findings argue for a two-way interaction between β-amyloid on DKK1 levels in brain slice cultures. Sure enough, glucocerebrosidase and α-synuclein. When glucocerebrosidase β-amyloid triggered an increase in DKK1 levels, leading to loss of levels are abnormally low, lysosomal function is compromised and synapses. Most excitingly, though, antibodies against DKK1 blocked disposal of α-synuclein is disrupted; when glucocerebrosidase the toxic effect of β-amyloid on synapses. levels are normal, build up of α-synuclein inhibits enzyme function. Professor Salinas has recently extended this work, developing Hence there is potential for a vicious cycle, driven either by loss mice in which DKK1 can be selectively switched on in localised of glucocerebrosidase function or α-synuclein accumulation. regions of the brain in adulthood. In these animals, elevated DKK1 In vitro studies on glucocerebrosidase suggest a further possible in the hippocampus mimicked the effects of β-amyloid, reducing link to Parkinson’s disease processes. Inhibition of the enzyme the number of synaptic connections. And, although there was no leads to abnormal mitochondrial function and an increase in free sign of significant cell death, the animal’s cognitive abilities were radical levels – factors previously implicated in cell death in markedly impaired. Parkinson’s disease. The results therefore suggest that the impact of Wnt signalling The results suggest that targeting glucocerebrosidase could and DKK1 on synapse numbers could be playing an important be an effective strategy for patients with GBA mutations. Indeed, role in Alzheimer’s disease. Furthermore, they argue that targeting in mouse models Professor Schapira is investigating the potential DKK1 and Wnt signalling, to maintain synaptic integrity, could be a of ‘chaperone’-like drugs to promote the folding and intracellular therapeutic strategy to slow or prevent the loss of cognitive abilities. trafficking of abnormal glucocerebrosidase, as a way of boosting enzyme activity. Ciani L et al. Wnt7a signaling promotes dendritic spine growth and synaptic strength through Ca²+/Calmodulin-dependent protein kinase II. Proc Natl Gegg ME et al. Glucocerebrosidase deficiency in substantia nigra of Acad Sci USA. 2011;108(26):10732–7. Parkinson disease brains. Ann Neurol. 2012;72(3):455–63.

Purro SA, Dickins EM, Salinas PC. The secreted Wnt antagonist Cleeter MW et al. Glucocerebrosidase inhibition causes mitochondrial Dickkopf-1 is required for amyloid -mediated synaptic loss. J Neurosci. dysfunction and free radical damage. Neurochem Int. 2013 ; 62(1):1–7. 2012;32(10):3492–8. Schapira AH, Gegg ME. Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease. Proc Natl Acad Sci USA. 2013;110(9):3214–5.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 9 TRANSLATIONAL RESEARCH: GENETIC INSIGHTS, DISEASE MODELS AND INTERVENTION DEVELOPMENT

Cellular and animal models are providing platforms for understanding disease processes and testing of new diagnostics and treatments.

Genetic approaches of which has stimulated (iPS) cells derived from developed to prevent the have identified key great interest in the role of patients are increasingly accumulation of toxic protein processes involved in and the brain’s being used to gain insight assemblies. An existing neurodegeneration – an immune cells, microglia, in into disease processes. drug, exenatide, has shown area in which UCL has a Alzheimer’s disease. Patient skin cells are promise in a Parkinson’s long track record. Studies collected, reprogrammed disease trial. Genetics therefore provides of families have identified into a pluripotent state and a route into disease The landmark agreement rare single-gene causes then differentiated into the processes. Follow-up signed with the Eisai of Alzheimer’s disease, specific cell types affected functional studies can then pharmaceutical company Parkinson’s disease and |in neurodegenerative begin to reveal how they will also promote research other conditions. Genome- disease. exert their effects. into new therapeutics wide screens have revealed In collaboration with other targeting neurodegenerative genetic variants affecting Animal models of disease UK centres, UCL researchers disease processes. the risk of disease. Although have the advantage that are developing a suite of most have only small impact, they provide information on iPS cell lines with differing they highlight pathways likely abnormal function in the genetic abnormalities for to be involved in disease. context of whole-animal use in research. As well physiology (although good Increasingly, direct as tools in elucidating animal models of Alzheimer’s sequencing is likely to disease processes, cellular disease and Parkinson’s identify variants that are and animal models will be disease have been too rare to be picked up by valuable in the development difficult to generate). genome-wide analyses and, of new therapies. although having a significant Cellular studies are an Promising therapies effect on disease risk, do not important complement to are being explored in generate obvious patterns of animal studies. As well as Alzheimer’s disease and inheritance. A prime example cultured cells from patients, prion disease, with agents is TREM2, the identification induced pluripotent stem

10 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Genetic approaches are revealing the causes of neurodegeneration. Dr Helene Plun-Favreau.

AN INFLAMMATORY FINDING CELLS UNDER STRESS Work on two Turkish families with dementia led to the Cellular studies have implicated both defective discovery of one of the most important genetic risk factors disposal of mitochondria and abnormal mitochondrial yet identified in Alzheimer’s disease. function in Parkinson’s disease and other neurodegenerative conditions. Sequencing of coding regions of the genome has become a cost- effective way to identify the genes underlying inherited diseases, As with all neurodegenerative diseases, the underlying including familial . For Dr Rita Guerreiro in Professor John mechanisms of Parkinson’s disease remain poorly understood. Hardy’s lab, an analysis of Turkish families affected by early-onset Genes causing inherited forms of the disease provide a point of led to the identification of a risk factor access to disease processes, and by collaborating with human with the second biggest impact on disease after apolipoprotein E geneticists, Dr Helene Plun-Favreau is dissecting the function (ApoE) and sparked a flurry of interest in the role of inflammation in of these genes and their role in disease. Alzheimer’s disease. The power of this approach was illustrated by the discovery Through sequencing, Professor Hardy and colleagues discovered that two common causes of inherited Parkinson’s disease, PINK1 that three family members with dementia had mutations in a gene and , both affected mitochondria, placing this organelle known as TREM2. Notably, TREM2 was known to be involved in at the heart of studies into mechanisms of disease. PINK1 and regulating the activity of microglia, the brain’s immune cells. parkin physically interact with each other, and appear to be With evidence growing of an inflammatory component to Alzheimer’s involved in the controlled disposal of defective mitochondria disease, Dr Guerreiro then carried out a routine check on sequence (mitophagy). Defects in either lead to the persistence of defective data from sporadic Alzheimer’s disease cases. To her surprise, mitochondria, which ultimately lead to death of the cell. she discovered TREM2 variants in a significant number of patients. More recently, Dr Plun-Favreau and colleagues have Systematic genotyping of more than 1000 patients revealed TREM2 discovered that another Parkinson’s disease gene, Fbxo7, is variants in 22 cases but just five controls.TREM2 variants increase implicated in the PINK1–parkin pathway, further emphasising the the risk of developing Alzheimer’s disease around threefold, about importance of the defective removal of damaged mitochondria as much as the well-recognised ApoE4 risk factor (though TREM2 in Parkinson’s disease. variants are much less common). As well as abnormal mitochondrial recycling, loss of Perhaps most exciting is the insight the discovery provides into mitochondrial function may also play a role in Parkinson’s the mechanisms of disease. There has been growing interest in disease, and other forms of neurodegeneration, as well illustrated inflammation in Alzheimer’s disease, particularly as genome-wide by Dr Plun-Favreau and colleagues’ work on valosin-containing sweeps for genetic risk factors have implicated several genes involved protein (VCP). Mutations in VCP lead to a range of conditions, in immune responses. including muscle degeneration, frontotemporal dementia and Signalling through TREM2 is thought to dampen down microglia. amyotrophic lateral sclerosis. Notably, while the amount of Full mutations may leave it unable to prevent runaway inflammatory oxygen consumed by mitochondria in the cells of patients with responses, leading to rapid neurodegeneration and early-onset VCP mutations was dramatically increased, ATP production was dementia in people inheriting two copies of the faulty gene. The abnormally low – even though the two processes are usually Alzheimer’s-linked variants may mean that microglia are more active tightly coupled. than is ideal, and respond too aggressively to β-amyloid, increasing Because of this uncoupling, cells struggle to produce enough the risk of Alzheimer’s disease. ATP to cope with energy-intensive cellular processes. They are TREM2 is certainly the strongest hint yet that is thus highly vulnerable to further stresses, which can trigger an important feature of Alzheimer’s disease – and a potential route to processes leading to cell death. new therapies, perhaps by boosting TREM2 levels or more generally Cellular studies are therefore shedding important light on the by targeting other aspects of the inflammatory response. biochemical pathways and cellular processes that are disturbed when particular proteins are absent or abnormal. Looking Guerreiro R et al. TREM2 variants in Alzheimer’s disease. N Engl J Med. forward, Dr Plun-Favreau will be aiming to generate pluripotent 2013;368(2):117–27. stem cells from patients and differentiate them in culture – providing opportunities to study disease processes within critical cell types.

Burchell VS et al. The Parkinson’s disease genes Fbxo7 and Parkin interact to mediate mitophagy. Nat Neurosci. 2013;16(9):1257–65.

Plun-Favreau H et al. The mitochondrial protease HtrA2 is regulated by Parkinson’s disease-associated kinase PINK1. Nat Cell Biol. 2007;9(11):1243–52.

Bartolome F et al. Pathogenic VCP Mutations Induce Mitochondrial Uncoupling and Reduced ATP Levels. Neuron. 2013;78(1):57–64.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 11 Elizabeth Fisher (centre) with Frances Wiseman and Xun Choong. Monitoring of mitochondria (red) and Ca2+ (green) in neurons.

IN SEARCH OF THE PERFECT MODEL THE DEVIL IN THE DETAIL Increasingly sophisticated approaches are being used to Biology and biophysics are being combined to clarify generate mouse models of neurodegenerative disease. the role of α-synuclein in Parkinson’s disease.

For all neurodegenerative diseases, understanding mechanisms of The build up of α-synuclein is a hallmark of Parkinson’s disease, disease remains an important challenge. While cellular studies have but it is not absolutely clear how its detrimental effects are their place, there is also much to be gained from work on mouse models mediated. By teaming up with researchers in Cambridge of disease. Although none is perfect, collectively they provide key specialising in single-molecule studies of , insight into disease processes. As Professor Elizabeth Fisher’s work Dr Sonia Gandhi in Dr Andrey Abramov’s laboratory aims to illustrates, new technologies and insight from other studies are helping shed new light on this key question. to shape a new generation of mouse models more closely mimicking Professor , Professor Chris Dobson and human disease. colleagues in Cambridge have developed innovative biophysical With long-term collaborator Dr Victor Tybulewicz at the MRC National tools for tracking the aggregation of proteins, including Institute for Medical Research, Professor Fisher has been responsible α-synuclein. Fluorescent tags that are sensitive to the state of for one of the most remarkable feats of mouse engineering – a mouse aggregation are attached to the protein. By monitoring changing model of Down syndrome, Tc1, containing a near-complete version fluorescent signals in highly dilute solutions, the group can follow of human chromosome 21. Notably, people with Down syndrome are the aggregation of α-synuclein into oligomers and then fibrils – at high risk of developing Alzheimer’s disease at a relatively early age, as well as the reverse process, fibril disassembly – at essentially and show the characteristic Alzheimer’s brain pathology of β-amyloid single-molecule level. plaques and hyperphosphorylated tau tangles. Hence, alongside Recently, Professor Nick Wood and the Cambridge team insight into the cognitive and other abnormalities associated with showed that this process has profound biological consequences. Down syndrome, Tc1 mice may also shed light on the origins of The biophysical experiments confirmed thatα -synuclein Alzheimer’s disease. aggregates into oligomers, of varying sizes. Before aggregating Having developed the model, Professor Fisher and Dr Tybulewicz into fibrils, however, oligomers underwent a structural change also collaborate with other groups investigating its biology. Work into a protease-resistant form. Notably, when applied to cells, with Professor Tim Bliss, for example, identified distinctive memory protease-resistant oligomers generated far more damaging impairments in the mice. Recently, work with UCL’s Dr Frances reactive oxygen species, suggesting they are the most toxic form Wiseman revealed key features of tau phosphorylation in the ageing of α-synuclein. mouse brain. Recently awarded a four-year fellowship from the Wellcome The Tc1 mouse is trisomic for 200 genes, but some human Trust, Dr Gandhi will be following up these striking findings, chromosome 21 genes are missing. Notably, this includes the APP splitting her time between UCL and Cambridge. She will be gene, which codes for a precursor of β-amyloid protein. This can be an investigating the effects of the different aggregates of α-synuclein advantage – for example, it provides an opportunity to study tau in the on a range of cell types from patients with familial forms of absence of abnormal APP – but also has drawbacks. A recent detailed Parkinson’s disease and people with genetic variants increasing genetic analysis, carried out in collaboration with the Wellcome the risk of disease. The key readouts will be their effects on Trust Sanger Institute, provided a clearer view of the genetic make mitochondrial function and calcium signalling – processes up of the human chromosome, including other unsuspected genetic implicated in the death of neurons. rearrangements. As part of the LonDownS Consortium (see page 22), A further strand of research will make use of ‘nanobodies’ – Professor Fisher and Dr Tybulewicz aim to develop an improved ‘mark labelling reagents based on the unusual antibodies produced 2’ mouse. by members of the camel family. These are small and specific As well as Tc1, Professor Fisher has also generated models of other enough to visualise the location of different forms of α-synuclein neurodegenerative conditions, including amyotrophic lateral sclerosis, within the cell. which has a lifetime risk of up to one in 250. Her goal is to generate The work has important therapeutic implications. If the strains that include the precise genetic abnormality found in inherited protease-resistant form of α-synuclein is the most toxic, forms of disease, to ensure models are as similar as possible to the aggregation into fibrils may actually be a mechanism to human condition. sequester them and limit cell damage. Preventing conversion of α-synuclein into a toxic conformation could be a good therapeutic O’Doherty A et al. An aneuploid mouse strain carrying human chromosome 21 strategy – but promoting disaggregation of fibrils could be with Down syndrome phenotypes. Science. 2005;309(5743):2033–7. counterproductive, leading to the release of more toxic oligomers. Morice E et al. Preservation of long-term memory and synaptic plasticity despite Resolving this process with molecular precision should yield short-term impairments in the Tc1 mouse model of Down syndrome. Learn Mem. important insights for therapy. 2008;15(7):492–500. Cremades N et al. Direct observation of the interconversion of normal Sheppard O et al. Altered regulation of tau phosphorylation in a mouse model and toxic forms of -synuclein. Cell. 2012;149(5):1048–59. of Down syndrome aging. Neurobiol Aging. 2012;33(4):828.e31-44. α

12 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

THE GENE MACHINE

Professor John Hardy identified the first gene causing inherited Alzheimer’s disease and led the team that identified TREM2 as a major risk factor. Genetics has provided great insight into disease mechanisms but, he suggests, all the most critical genes may now have been found.

As a new postdoc in Inherited Alzheimer’s disease disease fivefold (see page intriguing discovery that all Newcastle in the 1980s, is rare, however, and in 11). TREM2 also places cases could be traced back Professor John Hardy sporadic cases no single microglia and the immune to a single origin, centred attended a talk from his lab gene triggers disease. Over system in the spotlight. on Scandinavia: “I thought head. “He said ‘there are the past decade, genome- “From our perspective it’s it was a Viking founder. two things we know about wide association studies a nice finding because it The mutation is incredibly Alzheimer’s disease: it’s not (GWAS) have identified gives a mechanisms straight common in Finland and genetic and it doesn’t involve dozens of genetic risk factors away,” says Professor Hardy, Sweden. It explains about inflammation’.” As Professor for Alzheimer’s and other “but also it’s the first high 30 per cent of motor neuron Hardy’s work has revealed, neurodegenerative diseases, risk gene to be found since disease in Finland.” he was wrong on both thanks to the efforts of large APOE in 1995.” Recent discoveries have counts. international collaborations. The root to further disease also shed interesting new Professor Hardy has Professor Hardy holds genes, he believes, will light on genetic contributions contributed to Alzheimer’s the distinction of being be through genome to disease. It has generally disease GWAS and led the world’s most highly sequencing: “The way you been thought that carriers of studies of frontotemporal cited Alzheimer’s disease find them is by brute force recessive disease-causing dementia (FTD) and researcher. His work, sequencing in cases and genes suffer no ill-effects, Parkinson’s disease (with and that of other human controls. That’s what we’ve but with TREM2 and the GBA Professor Nick Wood). geneticists, has arguably started to do in Alzheimer’s gene (see page 9), carriers provided the greatest insight While family studies reveal disease, with some success.” are at significantly increased into neurodegeneration, with rare genes of large effect, risk of an entirely different As more genetic causes of genetic discoveries revealing GWAS identify common disease (Alzheimer’s disease dementia are discovered, it biochemical pathways variants of small effect. Both and Parkinson’s disease, is proving possible to screen central to disease. approaches may be nearing respectively). patients with unexplained the limits of their usefulness, The genetic approach began dementia. Professor Hardy’s Professor Hardy is also, in Professor Hardy suggests: in earnest in the mid-1980s, colleague Dr Allan Pittman is his words, ‘grandfathering’ “I think we’ve discovered when Professor Hardy and developing new sequencing genetic components of other all the Mendelian genes for Professor Martin Rossor first tools to screen all known UCL projects, which are Alzheimer’s disease.” And began collecting families. dementia-causing mutations, looking for genetic modifiers for Alzheimer’s disease at At that time, mapping as a service to UCL influencing age of onset least, the genome may soon disease genes was a clinicians. More generally, or severity of symptoms. be mined out of common laborious process, but though, it is the insight into These include the LonDownS variants. It is the middle Professor Hardy and disease processes that consortium (see page 22) ground where the action now colleagues eventually nailed has been most helpful, and the 1946 Birth Cohort lies, with genes that have a down the first Alzheimer’s with functional follow up in (see page 28), as well big impact on disease risk disease gene, APP. The cells and animal models. as studies of early-onset but are not common enough gene codes for a precursor Alzheimer’s disease and to be picked up in GWAS Professor Hardy also worked of β-amyloid and was strong Huntington’s disease. While and not severe enough to on the curious evidence for the ‘β-amyloid the major genes may all have be obviously familial. gene, mutations in which can cascade theory’ – that been tracked down, genetics cause either a form of motor β-amyloid accumulation was This is precisely the territory has not entirely run its course neuron disease or FTD. a cause not a consequence of TREM2, which increases in dementia just yet. Professor Hardy made the of disease. the risk of Alzheimer’s

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 13 Detecting neuronal death in the retina. A molecular model of prion protein.

AN EYE ON ALZHEIMER’S THE SHAPE OF THINGS TO COME Imaging the retina may provide a novel way to diagnose Targeting cellular prion protein may be a way to prevent Alzheimer’s disease and other neurodegenerative conditions. pathogenic prions from harming the cell.

Thanks to the neural connections between them, the eye can provide Professor John Collinge has carried out groundbreaking work a window into the brain of living organisms. A new imaging technique on the mechanisms of action of infectious prion protein (see developed by ophthalmologist Professor Francesca Cordeiro is page 5). This work has suggested that the toxic prion entity may exploiting this opportunity to detect early signs of neuronal death in not be the infectious form itself but a species arising during the the retina – an approach that may lead to simple new diagnostic tests conversion of the cellular prion protein (PrPC) to its infectious for Alzheimer’s disease and other neurodegenerative conditions. form (PrPSc). This suggested a novel therapeutic strategy – Professor Cordeiro’s original interests lay in glaucoma, increased protecting PrPC so it cannot be converted into PrPSc. fluid pressure in the eye that can lead to blindness due to the death Other work suggested this approach was feasible. The of retinal ganglion cells (RGCs). Diagnosis of glaucoma is not function of PrPC remains unclear, but it does not appear to be straightforward and disease progression is difficult to track, relying essential – mice lacking PrPC show no obvious abnormalities. on monitoring of changes in vision. Perhaps most excitingly, Professor Collinge showed that when Death of RGCs followed an orderly pathway of programmed cell PrPC was turned off in infected adult mice, death, or , and leads to the appearance of characteristic disease processes were halted and the mice actually showed lipids on the surface of cells. Professor Cordeiro developed a signs of recovery. fluorescently labelled version of a protein known to bind these lipids, Professor Collinge and colleagues have been pursuing a two- annexin A5, and showed that the technique – called DARC (detection pronged approach, exploring the potential of both monoclonal of apoptosing retinal cells) – could sensitively detect RGCs undergoing antibodies and small molecules to protect PrPC. Many antibodies apoptosis using standard ophthalmological equipment. against prion protein block prion propagation in cellular and With translational funding from the , Professor Cordeiro animal models. Professor Collinge has shown that the potency has been preparing for first-in-human glaucoma trials. However, of such antibodies is dependent on their binding to PrPC, acting Professor Cordeiro also realised that DARC could find application in as ‘molecular chaperones’ to maintain their native conformation. neurodegenerative conditions, where loss of RGCs is also seen. Studies With MRC funding, Professor Collinge has shown that in a range of animal models of Alzheimer’s disease (and Parkinson’s monoclonal antibodies are highly effective at halting prion disease) have shown that there is a good correlation between the eye propagation in animal models. These antibodies have been damage detected by DARC and levels of brain pathology. ‘humanised’ for use in people, and discussions have begun with Symptom-based diagnosis of dementia is challenging. Brain imaging regulatory authorities about the possible format of clinical trials and biochemical biomarker analysis are also not entirely accurate, and with Creutzfeld–Jakob disease patients. not well suited to routine clinical use. A simple eye-based diagnostic In collaboration with GSK, Professor Collinge has also test could therefore have a significant impact on clinical practice. been developing small molecule inhibitors with chaperone-like Phase I trials with DARC will use intravenous injection to deliver properties. Past work has provided proof of principle, with a labelling agents. In the longer term, Professor Cordeiro is pinning her cationic tetrapyrrole molecule being shown to have potent anti- hopes on an innovative eye drop delivery system which could easily be prion activity by binding to and stabilising PrPC. Screens delivered by a technician. If phase I studies go according to plan, she of chemical libraries have revealed other promising hits. hopes to move to phase II studies for both glaucoma and Alzheimer’s Such agents may yet have further value. Recent work has disease, and has begun discussions with Dr Jonathan Schott in UCL’s suggested that prion protein may be a route through which Dementia Research Centre to explore the practicalities of studies in β-amyloid exerts its harmful effects in Alzheimer’s disease. Alzheimer’s patients. As well as confirming this effect using brain-derivedβ -amyloid, Professor Collinge has shown that PrPC antibodies can block Cordeiro MF et al. Real-time imaging of single nerve cell apoptosis in retinal interactions with β-amyloid and reduce its neurotoxic effects. neurodegeneration. Proc Natl Acad Sci USA. 2004;101(36):13352–6. If the prion therapies do prove safe and effective, they might Normando EM, Turner LA, Cordeiro MF. The potential of annexin-labelling for therefore also have application in Alzheimer’s disease. the diagnosis and follow-up of glaucoma. Cell Tissue Res. 2013;353(2):279–85. Mallucci GR et al. Targeting cellular prion protein reverses early Guo L, Duggan J, Cordeiro MF. Alzheimer’s disease and retinal cognitive deficits and neurophysiological dysfunction in prion-infected neurodegeneration. Curr Alzheimer Res. 2010;7(1):3–14. mice. Neuron. 2007;53(3):325–35. Antonyuk SV et al. Crystal structure of human prion protein bound to a therapeutic antibody. Proc Natl Acad Sci USA. 2009;106(8):2554–8. Nicoll AJ et al. Pharmacological chaperone for the structured domain of human prion protein. Proc Natl Acad Sci USA. 2010;107(41):17610–5. Freir DB et al. Interaction between prion protein and toxic amyloid β assemblies can be therapeutically targeted at multiple sites. Nat Commun. 2011;2:336.

14 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Exenatide may be a novel treatment for Parkinson’s disease. Cross-linking of serum amyloid P component by CPHPC (centre).

ACCELERATING DRUG TESTING ZAPSAP – TARGETED PROTEIN DEPLETION A drug used to treat diabetes has shown promising IN ALZHEIMER’S DISEASE effects in an innovative Parkinson’s disease trial. A unique mechanism of drug action may be applicable to Alzheimer’s disease, with work towards a clinical trial In recent years, evidence has been accumulating that the in progress. hormone glucagon-like -1 might be a good target for Parkinson’s disease. Furthermore, a drug targeting GLP-1, Professor Sir Mark Pepys FRS has worked on amyloid for 40 years with exenatide, a derivative of a compound found in the saliva of the a major focus on the normal blood protein, serum amyloid P component Gila monster, has already been licensed to treat type 2 diabetes. (SAP), which is always concentrated in amyloid deposits. Keen to test its effects in Parkinson’s disease, Dr Thomas Amyloid is an abnormal, insoluble, fibrous protein material which can Foltynie worked with the drug’s manufacturer and the Cure accumulate in body tissues, damaging their structure and function and Parkinson’s Trust to organise an innovative proof of concept trial, causing fatal disease. Amyloidosis, the disease caused by amyloid with positive results. deposits, is rare, affecting about 6,000 people in the UK. Alzheimer’s With safety data already available from earlier studies, a disease is very much more common; patients’ brains always contain randomised controlled trial could in theory have been organised a particular type of amyloid, Aβ, but it is not known whether these Aβ to test exenatide’s efficacy in Parkinson’s disease. However, amyloid deposits cause dementia. Nevertheless, Aβ amyloid is always such trials are expensive and there is inevitably a high risk of loaded with SAP, which binds avidly to Aβ amyloid fibres. failure. Exenatide’s makers were reluctant to commit to this Sir Mark has shown that SAP contributes to the formation and step without gathering further evidence of its likely impact persistence of amyloid and developed a drug, known by the initials of on disease. its chemical name, CPHPC, which uniquely removes all SAP from the Dr Foltynie and the Cure Parkinson’s Trust, however, were blood. CPHPC treatment and SAP depletion have no adverse effects. keen to move things along faster. A major challenge to a large SAP depletion alone does not cure amyloidosis. Sir Mark therefore trial would have been the need to develop a placebo version introduced a novel use of antibodies to target amyloid, which is only of the pen-like device used to inject exenatide. Dr Foltynie possible when patients have been treated with CPHPC. This invention therefore suggested running a single-blind randomised has now been developed in collaboration with GlaxoSmithKline and controlled – so patients would know whether or not they were the first clinical trial in amyloidosis patients is currently in progress. taking the drug but assessors would not. The main drawback Meanwhile Sir Mark and his colleagues have lately confirmed and of this trial design is that any positive impact might simply reflect extended earlier research showing that, unrelated to amyloid, SAP a placebo effect. itself is damaging to brain nerve cells. All Alzheimer’s disease patients The trial of 45 patients lasted a year, and generated highly have abnormally increased amounts of SAP in their brains. Removal of encouraging results. Not only did exenatide prevent the decline SAP from the brain is therefore a valid and very attractive new approach in motor and cognitive symptoms seen in control patients but to treatment and possibly prevention of Alzheimer’s disease. performance actually improved, suggesting exenatide is not In a preliminary small scale, 3 month, clinical study, Professor just neuroprotective but also has additional positive effects. Martin Rossor demonstrated that CPHPC removed all SAP from the While placebo effects cannot be excluded with certainty, there that bathes the brain – zapsap! The drug was well are reasons to believe they were not a key factor. For example, tolerated but the study was too short to show clinical benefit. improvement was gradual and sustained while a placebo effect Work is now in progress, funded by the NIHR UCL/UCLH BRC, in would typically be more immediate and then decline. preparation for a one year, double blind, placebo controlled, clinical trial Most importantly, quickly and at relatively low cost the trial has of CPHPC in Alzheimer’s disease. Sir Mark and Professor Rossor, with generated data suggesting that further studies of exenatide are GlaxoSmithKline’s participation, have been invited by the MRC to apply warranted. Its manufacturers and the Michael J Fox Foundation for funding of this trial, with a decision expected early in 2014. are now supporting a larger placebo-controlled trial which Dr Foltynie will be leading. More generally, the trial illustrates Pepys MB et al. Targeted pharmacological depletion of serum amyloid P how ‘mini-trials’ may act as cost-effective stepping stones in the component for treatment of human amyloidosis. Nature. 2002;417(6886):254–9. development of promising therapeutics, enabling more agents Bodin K et al. Antibodies to human serum amyloid P component eliminate to be tested in patients and reducing the risk of expensive visceral amyloid deposits. Nature. 2010;468(7320):93–7 . failure at phase III. Kolstoe SE et al. Molecular dissection of Alzheimer’s disease by depletion of serum amyloid P component. Proc Natl Acad Sci USA. Aviles-Olmos I et al. Exenatide and the treatment of patients with 2009;106(18):7619–23. Parkinson’s disease. J Clin Invest. 2013;123(6):2730–6.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 15 LEONARD WOLFSON The Leonard Wolfson Centre will play a pivotal EXPERIMENTAL role in testing the idea that early intervention is critical to the success NEUROLOGY CENTRE of treatments for neurodegeneration.

A strong theme Leonard Wolfson Foundation. RNA-based gene silencing numbers of patients – and, running across multiple Situated within the National approaches in Huntington’s crucially, in advance of the neurodegenerative Hospital for Neurology and disease, to be led by appearance of symptoms. conditions is that in Queen Professor Sarah Tabrizi. A further important disease is an extended Square, it is providing A further important factor theme at the Leonard process. Damage to cells facilities in which new is the increasingly close Wolfson Centre is training. accumulates over many experimental therapies for interaction with industry, Successful translation years, even if symptoms are neurodegenerative disease whose expertise will be of new therapeutics and not immediately apparent. can be tested in people. essential if effective drugs diagnostics will call for close Moreover, there is also The opening of the are to reach patients. integration of expertise in evidence that diseases Centre heralds a new era UCL’s pioneering partnership fundamental , accelerate over time, in therapeutic R&D in with Eisai Pharmaceuticals neurology and engineering. either through spreading neurodegenerative disease. (see Box) is an important With sponsorship from Eisai, of pathology or because Advances in understanding step towards this goal. the Centre has launched of positive feedback of disease mechanisms are a clinical fellowship and processes. Hence, there Other advances have revealing new targets for four-year PhD programme to are compelling arguments in laid the foundations drug development. A variety provide an interdisciplinary favour of early intervention, for this new venture. of different types of therapy grounding to both basic to halt or at least slow the Of paramount importance are under development. scientists and clinicians; damage that ultimately leads has been the development These range from small- a similar scheme exists to clinical symptoms – ideally of ‘biomarkers’ to assess chemical molecules, such for engineers. interventions would be the impact of treatment. as the ‘palindromic’ drug applied when the minimum Brain imaging and After a first year spent of developed by Professor of brain cells have been biochemical biomarkers formal tuition and laboratory Sir Mark Pepys (page 15), irreversibly lost. in cerebrospinal fluid rotations providing first- to the antibody-based now provide sensitive hand experience of a range This principle is the therapies being tested in ways to assess disease of techniques, students cornerstone of the the Dominantly Inherited progression and the impact undertake a three-year new Leonard Wolfson Alzheimer’s Network) of interventions, potentially PhD project with one Experimental Neurology DIAN trial (page 22). Other enabling proof-of-concept of UCL’s world-leading Centre, funded through innovative technologies are studies and trials to be , including the a £20m award from the in the pipeline, including carried out on much smaller eight principal investigators

16 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences associated with the Centre (see Box). Students also AN INNOVATION PARTNERSHIP CENTRE PRINCIPAL have the opportunity to gain INVESTIGATORS The pioneering partnership between UCL and industry experience through Eisai will bring together complementary expertise Professor John Collinge a placement with Eisai. in academia and industry to drive forward the Professor Nick Fox As well as trials of development of novel therapeutics for Professor John Hardy therapeutics, the Centre will neurodegenerative diseases. Professor Martin Rossor Professor Anthony Schapira also have an important role UCL and Eisai have had a long history of collaboration but in studies generating more the agreement signed in December 2012 to establish a Professor Sarah Tabrizi information about disease Therapeutic Innovation Group takes this to another level. Professor Alan Thompson processes. For example, By working together, the partnership aims to accelerate the Professor Nick Wood it will provide the facilities development of new agents, with the Leonard Wolfson Centre an important facility in which the most promising can be for studies on members of first tested in proof of concept studies in patients. ageing population cohorts The initiative reflects both UCL’s strong commitment to (page 27). working in partnership with industry and Eisai’s embracing of open innovation principles. While UCL provides unmatched The Leonard Wolfson scientific expertise and numerous leads for the development Centre will play a nationally of new therapeutics, Eisai brings the experience and important role in a critical expertise of drug development, including assay development phase in treatment and medicinal chemistry as well as regulatory and clinical expertise, that will be required to bring new products development – the first- to market. in-human studies of new Unusually, the initiative will see interdisciplinary teams therapeutics. It will help to of academic and industry researchers put together to work overcome a key bottleneck on promising areas of translational research. Over time, in the drug development a portfolio of development projects will be established. In line with commercial principles, projects will be subject process, and accelerate to ‘go/no-go’ decision making, with translational researchers the development of agents redeployed to alternative projects if a project is terminated. across a wide range of Work began on the first project in 2013, with Professor devastating conditions for Michael Duchen leading a project looking at mitochondrial which few if any disease- dysfunction in neurodegenerative disease. modifying treatments are currently available.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 17 PATIENT-ORIENTED RESEARCH: UNDERSTANDING, AND PREVENTING, BRAIN ATROPHY

Research on patients has provided a clearer view of disease progression, offering the possibility of therapeutic trials early in disease – or even before disease develops.

UCL’s Dementia Research be given as earlier for tracking the progression therapeutics will emerge Centre has pioneered the as possible, to prevent or of Alzheimer’s disease. from the drug development use of brain imaging, notably delay the neuronal death partnership established As well as Alzheimer’s magnetic resonance imaging that ultimately leads to loss with Eisai. disease, imaging has (MRI), to characterise the of cognitive function. provided key insight into Finally, work continues to changes in brain structure Furthermore, they have had the development of brain characterise Alzheimer’s in people with all kinds a further important benefit. degeneration in Huntington’s disease and other of dementia, particularly Advances in the sensitivity disease. The landmark dementias, in particular Alzheimer’s disease. of brain imaging and image TRACK-HD study, led from to identify genetic or other Importantly, by working with processing enable even UCL, has provided clear factors that accelerate or families affected by inherited small changes in brain evidence of early brain protect against disease. forms of the condition, volume to be detected over atrophy years in advance researchers have been able a period of a year or so. of clinical symptoms. to document significant Brain imaging can therefore changes to the brain well in Most excitingly, these be used as a ‘biomarker’ to advance of any symptoms biomarkers are opening the track disease progression. appearing. doors to new clinical trials As well as being far more of therapeutics. The new These findings have led sensitive than cognitive Leonard Wolfson Centre to the idea that overt tests, imaging can also be for Experimental Neurology Alzheimer’s disease is a used at early stages before provides an exceptional late stage in a process symptoms are apparent. platform for such studies. of neurodegeneration In addition, detection of It will hosts trials of agents that begins years or even characteristic molecules targeting β-amyloid, as well decades earlier. They have in cerebrospinal fluid as planned tests of innovative provided strong support for is providing additional gene silencing therapy for the notion that treatments for biochemical biomarkers Huntington’s disease. Further Alzheimer’s disease should

18 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

MRI has revealed much about the processes of neurodegeneration. Tracking changes in pre-symptomatic patients.

INSIDE THE BRAIN ENGINEERING A BETTER SCAN The ability to study the structure of the brain in living Large-scale imaging studies of neurodegeneration people has yielded new insights disease, and provided rely on engineering expertise. a crucial platform for clinical trials. For patient and clinician, symptoms are the critical feature of a Although post-mortem analysis long ago revealed the brain neurodegenerative disease. Yet, although standard cognitive abnormalities associated with Alzheimer’s disease, only with the imaging tests exist, they are not a particularly sensitive way of assessing techniques of CT and, in particular, MRI have changes in living brain neurodegeneration. This presents challenges to clinical trials, tissue been visualised. Professor Nick Fox has pioneered studies to which would need to assess thousands of patients in order to characterise brain pathology in dementia, and in individuals in advance detect an effect reliably. These numbers can be reduced by of disease. His work has not only established that brain changes occur an order of magnitude through use of brain imaging, thanks to well in advance of clinical disease, but has also provided a platform input from engineers such as Professor Seb Ourselin. for reliably assessing the impact of interventions in clinical trials. Although based in the Faculty of Engineering, Professor In the mid-1990s, Professor Fox and Professor Martin Rossor realised Ourselin spends much of his time at the Dementia Research that advances in MRI were providing opportunities to characterise the Centre. Over the past decade, he has worked with several brains of dementia patients, and to distinguish pathological effects from members of the Centre to refine methods of MRI scanning and those seen in normal ageing. Furthermore, they recognised that families to gather an ever more detailed picture of brain anatomy and with inherited forms of the disease, although rare, provided unique function in Alzheimer’s disease and other dementias. opportunities to study the onset of disease. Because dementia was The work is technically challenging. Brain imaging is far more likely to develop in this group than in the general population, attempting to characterise changes in brain volume of just and at earlier ages, it was practical to study them intensively in advance 1–2 per cent per year. But being able to achieve such sensitivity of disease onset. and accuracy means that trials can be carried out on just a Over the next 20 years, Professor Fox and colleagues conducted few hundred patients. As the need grows for more trials multiple studies to track brain atrophy in Alzheimer’s disease and other of therapeutic agents on targeted patient groups, such dementias. One of the most profound conclusions was that loss of brain methodologies will be essential to ensure that clinical trials tissue was occurring before cognitive symptoms are apparent. This do not become a bottleneck in the development pathway. influential discovery has driven a radical reappraisal of Alzheimer’s Furthermore, unlike cognitive tests, measures of brain loss disease, to encompass both a ‘pre-dementia’ phase, with minor can be used in trials on pre-symptomatic patients. cognitive deterioration, and a ‘pre-clinical phase’ – potentially decades To date, Professor Ourselin’s work has focused on total long – when the pathology of Alzheimer’s is accumulating in advance brain volume or areas such as the hippocampus, a site of of symptoms of cognitive decline. early neurodegeneration. His group develops image-analysis Furthermore, this idea has emphasised the need to treat Alzheimer’s algorithms to extract information from scan data. A major disease as early as possible. By the time serious symptoms are challenge is to ensure that the results gathered from multiple apparent, the brain may already be beyond repair. This emphasis on international sites are compatible, with shared protocols for early intervention is a central principle of the new Leonard Wolfson imaging and for data analysis. For effective translation, imaging Experimental Neurology Centre. technologies must also be integrated into the clinical environment. Significantly, thanks to the exquisite sensitivity with which brain There is also growing interest in the use of PET imaging, which imaging can track changes in brain structure, clinical trials are can reveal β-amyloid build up but does not yet have the spatial now feasible on relatively small numbers of patients. Nevertheless, sensitivity of MRI. Professor Ourselin also plans to make more Professor Fox is continuing to characterise patterns of tissue loss and use of methods such as diffusion imaging, which characterises other changes, such as the build up of β-amyloid using PET imaging, white matter microstructure, and functional MRI. Such studies will for example in groups showing early onset of disease. This deep provide complementary information to that obtained by structural understanding will reveal more about the biology of disease, but will MRI, and bring imaging closer to the biological function of neural also be a critical way to stratify patients in trials. circuitry. Ultimately, the range of methods will provide a more detailed characterisation of patients, and may allow correlations Rossor MN et al. Incomplete penetrance of familial Alzheimer’s disease in a to be drawn between patient traits and response to therapies. pedigree with a novel presenilin-1 gene mutation. Lancet. 1996;347(9014):1560. Leung KK et al. Robust atrophy rate measurement in Alzheimer’s disease Fox NC, Scahill RI, Crum WR, Rossor MN. Correlation between rates of brain using multi-site serial MRI: tissue-specific intensity normalization and atrophy and cognitive decline in AD. Neurology. 1999;52(8):1687–9. parameter selection. Neuroimage. 2010;50(2):516–23. Fox NC et al. Imaging of onset and progression of Alzheimer’s disease with Keihaninejad S et al. The importance of group-wise registration in tract voxel-compression mapping of serial magnetic resonance images. Lancet. based spatial statistics study of neurodegeneration: a simulation study 2001;358(9277):201–5. in Alzheimer’s disease. PLoS One. 2012;7(11):e45996. Ryan NS et al. Magnetic resonance imaging evidence for presymptomatic Ryan NS et al. Magnetic resonance imaging evidence for change in thalamus and caudate in familial Alzheimer’s disease. Brain. presymptomatic change in thalamus and caudate in familial Alzheimer’s 2013;136(Pt 5):1399–414 disease. Brain. 2013;136(Pt 5):1399–414.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 19 Professor Henrik Zetterberg. Tracking white matter atrophy in Huntington’s disease.

MARKERS FOR LIFE TRACKING HUNTINGTON’S DISEASE Cerebrospinal fluid biomarkers can track Alzheimer’s disease A landmark long-term study of Huntington’s disease progression – but also provide clues to disease mechanisms. has identified brain and other changes years before symptoms appear. Tracking neurodegeneration, particularly before symptoms appear, is a key challenge in dementia research. Alongside brain imaging, If treatment of neurodegenerative disease is to begin early there is growing interest in measurement of biochemical markers in – possibly, even before symptoms appear – methods will be cerebrospinal fluid – which, suggests new UCL recruitProfessor Henrik needed to track disease progression over time. In the short Zetterberg, may also provide insight into the cellular changes occurring term, such tools will be required to assess the impact of in the brain. new therapeutics in clinical trials. For Huntington’s disease, It is now clear that the origins of Alzheimer’s disease go back Professor Sarah Tabrizi has led a groundbreaking international decades, as neurons accumulate abnormal proteins and die, collaboration, TRACK-HD, that has identified a suite of suitable even before symptoms appear. Measurement of key proteins in markers, for patients early in disease and even those yet to cerebrospinal fluid provides a window into these critical changes. experience symptoms. Of great interest, levels of a truncated form of β-amyloid (Aβ42) fall Huntington’s disease provides a rare opportunity to study markedly in people destined to develop Alzheimer’s disease. Other neurodegeneration preclinically. Because it is caused by a single characteristic changes include an increase in levels of both total tau faulty gene, and everyone with the gene will get the disease, protein and phosphorylated tau. These markers have recently been affected individuals can be identified using genetic tests and incorporated into diagnostic criteria for Alzheimer’s disease and the then followed over time. mild cognitive impairment that precedes it. The TRACK-HD study has been following some 300 Furthermore, they may also provide insight into disease mechanisms, Huntington’s disease gene carriers in four North American and as they reflect different aspects of disease. The drop in Aβ42 probably European countries. As well as tests of motor and coordination reflects the sequestration of β-amyloid into plaques, total tau assays skills, and assessments of mood and other neuropsychiatric neuronal death, which leads to the release of intracellular tau, while indicators, TRACK-HD has undertaken detailed imaging of the phospho-tau levels track the formation of fibrillary tangles. Notably, brain’s white and grey matter. the decline in Aβ42 precedes changes in tau, arguing that it represents Recently published third year results have provided a wealth of an earlier stage in the disease process. valuable information. Perhaps most striking was the identification As well as diagnosis, cerebrospinal fluid biomarkers also provide a of several signs of neurodegeneration years before individuals complementary tool to brain imaging for tracking disease progression. are likely to experience symptoms. These included loss of grey Since changes are apparent years before symptoms appear, they can matter in particular regions of the brain, as well as changes in be used in trials of therapies targeting early, pre-symptomatic phases simple behavioural tests such as finger tapping regularity. of disease. Moreover, certain molecular biomarkers will be highly Furthermore, some baseline measures – primarily low grey relevant to particular therapeutic strategies – Aβ42, for example, matter volumes in certain areas of the brain – were predictive of for therapies targeting β-amyloid. later clinical decline, providing markers of those most vulnerable Professor Zetterberg has taken up a position at UCL while to the disease. The trial had further benefits, providing new maintaining his group in Gothenburg, Sweden – a centre with renowned insights into the patterns and dynamics of neural circuitry expertise in biomarker research. As well as these well-characterised breakdown as disease progresses, and the data are being used biomarkers, he will also be studying the potential of other metabolites to look for genetic modifiers of the speed of disease progression. – first example, of markers of inflammation or loss of synapses – which Crucially, the changes identified will provide biomarkers for may reflect important disease processes. He will also be undertaking clinical trials in presymptomatic gene carriers. In addition, the proteomic studies to identify new components of cerebrospinal fluid baseline markers of susceptibility will enable patients to be of potential relevance to neurodegeneration. stratified according to their underlying vulnerability. With new As well as disease groups, Professor Zetterberg will also be studying agents for Huntington’s disease close to human use, TRACK- members of the 1946 Birth Cohort (see page 28). Such studies will HD’s findings will ensure that they can be tested in patients yet to reveal the ‘natural history’ of biomarker change, and allow comparisons experience symptoms, when they are likely to be most beneficial. between those who develop Alzheimer’s disease and those who do not. Tabrizi SJ et al. Predictors of phenotypic progression and disease Rosén C, Zetterberg H. Cerebrospinal fluid biomarkers for pathological onset in premanifest and early-stage Huntington’s disease in the TRACK- processes in Alzheimer’s disease. Curr Opin . 2013;26(3):276-82. HD study: analysis of 36-month observational data. Lancet Neurol. 2013;12(7):637–49. Hölttä M et al. Peptidome analysis of cerebrospinal fluid by LC-MALDI MS. PLoS One. 2012;7(8):e42555. Tabrizi SJ et al. Potential endpoints for clinical trials in premanifest and early Huntington’s disease in the TRACK-HD study: analysis of Buchhave P et al. Cerebrospinal fluid levels of β-amyloid 1-42, but not of tau, 24 month observational data. Lancet Neurol. 2012;11(1):42–53. are fully changed already 5 to 10 years before the onset of Alzheimer dementia. Arch Gen Psychiatry. 2012;69(1):98-106. Tabrizi SJ et al. Biological and clinical changes in premanifest and early stage Huntington’s disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol. 2011;10(1):31–42.

20 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Areas of contraction (green) and expansion (red) in FTD brains. Dr Jonathan Schott.

A WORLD WITHOUT MEANING ENIGMA OF THE VARIATION Can specific symptoms of dementia be linked Why does the time-course of Alzheimer’s disease to abnormal neural networks, and perhaps even vary so greatly? to underlying molecular causes? Sporadic Alzheimer’s disease can differ markedly in its age of A major challenge in dementia research is to establish connections onset. Although typically a disease of later life, it can strike while between symptoms and changes in the brain. Ideally, it would be people are in their sixties or even earlier. Dr Jonathan Schott valuable to drill down still further to relate these abnormalities to aims to identify factors influencing age of onset, which calls for underlying molecular mechanisms, as these will be the target of an integration of multiple ways of assessing disease. pharmacological interventions. Dr Jason Warren is attempting to Alzheimer’s symptoms are difficult to quantify sensitively and, develop a better understanding of this ‘chain of causation’, using moreover, may not easily distinguish Alzheimer’s disease from complex sound, taste and smell processing as model systems. other conditions, particularly early in disease. Researchers A major focus of Dr Warren’s research is frontotemporal dementia have therefore adopted a range of other techniques to probe (FTD). FTD strikes relatively early in life, generally from the late 40s the underlying biological changes occurring during Alzheimer’s onwards, and is characterised by a variety of symptoms including disease, and to gauge disease progression. behavioural changes, speech difficulties, and loss of the meanings Different forms of brain imaging, particularly MRI, can reveal of words and objects (semantic dementia). As its name suggests, characteristic changes in brain structure – importantly, even FTD is associated with loss of tissue in the frontal lobes. before symptoms are apparent. Similarly, PET imaging of Notably, specific genetic causes are relatively common in FTD, β-amyloid can now reveal the tell-tale signs of amyloid plaque offering hope that it may be possible to track the chain of events from formation in the brains of living people. Biochemical markers, molecular defect through cellular and neural network abnormalities particularly in cerebrospinal fluid, can also provide an early to symptoms. Unfortunately, although some links can be made, there warning sign of cellular damage. appears to be no simple correlation between a gene defect and clinical Combining these measures with detailed clinical assessments symptoms. Indeed, mutations in the newly discovered C9ORF72 gene and cognitive tests provides a means of characterising can cause either FTD or a form of . patients, and tracking changes over time. Key challenges are The behavioural changes seen in FTD reflect the loss of particular to understand precisely which markers of disease are most cognitive abilities. Dr Warren is using brain imaging and other relevant to cognitive decline, to aid diagnosis and risk prediction, techniques to pin down more precisely which aspects of cognition to gain a better understanding of the course of disease, and for are affected and the neural basis of these changes, and to link these monitoring changes during clinical trials. where possible to molecular defects. Working with Professor Nick Fox and others, Dr Schott has For example, patients often appear unemotional, reflecting an been involved in several studies characterising changes in effect on emotion-processing brain pathways. Unusual eating habits, the brain, and the influence of factors such as genetic variants such as strange food combinations, hint at defects in flavour or taste implicated in risk of disease. His latest research is extending this processing. Simple tools such as flavoured jellybeans, including characterisation to two contrasting populations. combinations with either congruent or clashing flavour combinations, The first is a large group of individuals with young-onset are helping to reveal which aspects of flavour processing are disrupted. Alzheimer’s disease. The key challenge is to understand why This work has shown that these behavioural processes have specific this group has turned out to be vulnerable to dementia decades neuroanatomical associations. before the disease becomes common. Similarly, extensive work on complex sound processing, including By contrast, Dr Schott’s second group is, in effect, an entirely speech and music, has generated important into the nature of deficits random population sample – of people all born in the same week (as well as shedding light on music processing in the brain). Music in March 1946. Members of the MRC National Survey of Health may be a useful model for understanding how the brain interprets and Development 1946 Birth Cohort (see page 28) are reaching ambiguous social signals, and how this goes so catastrophically wrong the age at which dementia is starting to become apparent. in FTD. Ultimately, by connecting the dots from molecular abnormality Dr Schott, Professor Fox, Professor Richards and others are to network disturbance to manifest symptom, this intensive multilevel beginning a detailed assessment of some study members to characterisation may make it possible to identify the most appropriate try to identify those at risk of Alzheimer’s and those who will be interventions for particular classes of patient. spared. Comparisons between these groups may reveal factors that influence if and when individuals will develop the disease. Omar R, Mahoney CJ, Buckley AH, Warren JD. Flavour identification in frontotemporal lobar degeneration. J Neurol Neurosurg Psychiatry. Schott JM et al. Neuropsychological correlates of whole brain atrophy 2013;84(1):88–93. in Alzheimer’s disease. Neuropsychologia. 2008;46(6):1732–7.

Goll JC et al. Nonverbal sound processing in semantic dementia: a functional Schott JM et al. Increased brain atrophy rates in cognitively normal MRI study. Neuroimage. 2012;61(1):170–80. older adults with low cerebrospinal fluid Aβ1-42. Ann Neurol. 2010;68(6):825–34. Rohrer JD et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain. 2011;134(Pt 9):2565–81. Andrews KA et al. Atrophy rates in asymptomatic amyloidosis: implications for Alzheimer prevention trials. PLoS One. 2013;8(3):e58816.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 21 Dr Andre Strydom, who is leading the LonDownS Consortium. Professor Martin Rossor.

DECIPHERING THE DOWN DEMENTIA LINK TRIALS AND TRIBULATIONS A major new programme is examining why people with Families with inherited forms of Alzheimer’s disease Down syndrome are often protected against dementia have made huge contributions to dementia research. despite showing neuropathology of Alzheimer’s disease. Now they may finally be gaining the rewards.

Down syndrome, the most common chromosomal abnormality, is With Professor Nick Fox, Professor Martin Rossor has caused by an additional copy of chromosome 21. As well as a range pioneered the involvement of families affected by inherited of cognitive and health issues, people with Down syndrome are prone Alzheimer’s disease in research. Ironically, though, clinical trials to develop Alzheimer’s disease, and at relative early ages. LonDownS, of interventions have typically excluded such individuals. With a new multicentre collaboration being led by UCL’s Dr Andre Strydom, the emphasis shifting to early treatment, however, such families aims to get to the root of this susceptibility – knowledge that could will now be participating in an exciting new wave of trials. benefit both people with Down syndrome and others with dementia. For more than 20 years, Professor Rossor has worked with Funded through a £2.5m Strategic Award from the Wellcome Trust, families affected by inherited forms of dementia, helping to track the LonDownS Consortium brings together clinical assessment, human down the genes affected and mapping changes in the brain as genetics, mouse modelling, cellular studies and cognitive profiling. disease progresses. Such work has provided enormous insight The main aim is to understand how the additional copy of chromosome into both the molecular mechanisms of disease and the natural 21 affects cells, circuitry and cognition, and ultimately leads to history of disease progression. Alzheimer’s disease. Professor Rossor has also been involved in key international Genetic work will be lead by Professor John Hardy. Chromosome 21 trials testing new interventions. Among the most exciting was includes the APP gene, which Professor Hardy identified as a major a trial of antibody therapy targeted at β-amyloid. Unfortunately, risk factor for Alzheimer’s disease. The additional copy of APP, although the trial showed positive effects on brain β-amyloid which codes for a precursor of the β-amyloid protein that builds up in levels and cerebrospinal fluid biomarkers, the therapies had Alzheimer’s disease, is likely to be key to disease, but additional factors little impact on cognitive performance. on chromosome 21 (or elsewhere in the genome) could explain why However, the results do not necessarily imply that the not all people with Down syndrome are affected by dementia (even therapeutic strategy is wrong. It has been argued that the trial’s when they have high levels of β-amyloid in their brains). The main focus patients, all of whom had well-established Alzheimer’s disease, will be on ‘extremes’ – those with very early onset and those showing had already incurred too much tissue damage for the therapy relatively little change in old age. to be effective. Given what is now known about the trajectory of Professor Elizabeth Fisher and Dr Victor Tybulewicz will investigate β-amyloid build-up, and the appearance of symptoms, a window biological processes in their mouse model of Down syndrome (see of opportunity exists in presymptomatic or early-stage individuals page 12). This work will be complemented by the cellular studies of to block or delay β-amyloid-induced damage. Professor Dean Nizetic at Queen Mary, University of London. He will This idea is now being tested in the international DIAN be generating induced pluripotent stem cells from people with Down (Dominantly Inherited Alzheimer Network) trial, the UK arm of syndrome and differentiating them into neural cells, to investigate which is being led by Professor Rossor. The 13 DIAN centres in pathological process in key cell types. the USA, Europe and Australia, led from Washington University Finally, Professor Annette Karmiloff-Smith of Birkbeck University School of Medicine, St Louis, have previously collaborated to of London will be undertaking cognitive profiling of infants with Down establish joint systems for tracking brain atrophy and assessing syndrome, using similar tests used by Dr Strydom in young adults biomarkers. The latest trial will enroll 240 members of affected before the onset of dementia. The aim will be to see if the risk factors families and will initially compare three existing , identified in older patients with dementia correlate with any traits seen using their impact on biomarkers to identify which would be best in infants and young people – which would provide a way to identify to take forward into trials assessing effects on cognition. early in life those at risk of dementia in adulthood. The UK arm will be one of several studies making use of The unusual background to Down syndrome provides a unique facilities in the new Leonard Wolfson Experimental Neurology set of circumstances in which to study the mechanisms underlying Centre. Professor Rossor has also been involved in other trials Alzheimer’s disease. As the disease is essentially the same as that of novel therapies, including the innovative therapy developed seen in the general population, the findings will be of benefit not just by Professor Sir Mark Pepys (see page 15). to those with Down syndrome but also patients more widely. Bateman RJ et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med. 2012;367(9):795–804.

11C-PiB PET assessment of change in fibrillar Rinne JO et al. amyloid-beta load in patients with Alzheimer’s disease treated with bapineuzumab: a phase 2, double-blind, placebo-controlled, ascending-dose study. Lancet Neurol. 2010;9(4):363–72.

Kolstoe SE et al. Molecular dissection of Alzheimer’s disease neuropathology by depletion of serum amyloid P component. Proc Natl Acad Sci USA. 2009;106(18):7619–23.

22 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

A FAMILY AFFAIR

Professor Nick Fox has worked for many years with families affected by inherited Alzheimer’s disease. Through the Leonard Wolfson Centre, they will now finally be able to take part in trials of new therapeutics.

The Leonard Wolfson targeting specific disease been revolutionary, that will undergo scanning and Experimental Neurology processes, such as have been truly disease- biomarker assessment. Centre will play a critical β-amyloid accumulation. modifying, those therapies “That will allow us to have role in testing promising Yet, despite Professor Fox’s initially failed in more severe imaging, biomarker, clinical new therapeutics for best efforts, for a variety disease.” Benefits came only assessments including Alzheimer’s disease and of reasons trials have when they were used early markers of presymptomatic other neurodegenerative routinely excluded families. in disease. “With familial Alzheimer’s disease and disorders. Professor Nick “Which is bizarre, because Alzheimer’s disease we know subclinical vascular damage Fox has played a significant they’re the ones closest with certainty somebody in a truly representative role in developing plans for to the transgenic models will be affected, so we can cohort who’ve been followed the Centre, and the vision and they’re the ones go really quite early.” since birth, which is unique.” behind it draws heavily on where therapy is most As well as establishing the This work will also draw on the idea that interventions likely to work.” Leonard Wolfson Centre, the facilities of the Leonard need to be given early. Now, however, through Professor Fox is also involved Wolfson Centre, which Furthermore, clinical initiatives such as the in initiatives to characterise will provide a platform trials will depend upon Dominantly Inherited further the ‘natural history’ of for much future work. For the advances in imaging Alzheimer’s Network (DIAN) Alzheimer’s disease, which Professor Fox there is a developed by Professor Fox trial (see page 22), families shows considerable variation pleasing symmetry that the and colleagues. are finally being enrolled: in age of inset and speed of first beneficiaries may be Yet this progress, Professor “I’m really pleased that, decline. In part this will come those whose participation in Fox is at to point after 20 years, the first trials from studies of young-onset research made it all possible. out, has relied on the have been approved.” Alzheimer’s disease, where “It’s the coming together of contributions made by symptoms are manifest work that people like Martin The DIAN trial marks a affected families. “We’ve while people are in their Rossor and John Hardy did profound shift in strategy: been following families 50s or 60s. in the 1980s, finding the “The revolutionary step is where Alzheimer’s disease first families, finding the first that this will include people “There must be something occurred early and genes, all coming full circle who are not affected, who that means that disease frequently, even before with the facility and the are presymptomatic.” comes on 20–30 years the first genes were found. first trials.” Clinical trials of antibody- earlier,” says Professor Gradually those families based therapies have been Fox. “How do these people have yielded really important disappointing but, points differ, what is it about them, genetic discoveries. That has out Professor Fox, they were is it something about their been a remarkable stimulus carried out in patients with genetic make-up or is it to research.” advanced disease: “A lot something that imaging As well as providing clues of us feel it may have been or biomarkers will give to disease mechanisms, too little too late.” us a clue to?” genetic discoveries have He draws an analogy with A further exciting initiative allowed the development of : “The is work with the 1946 Birth transgenic disease models. lesson from MS is that a lot Cohort (see page 28), These have formed the of the therapies that have where some 500 people test bed of new therapies

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 23 POPULATION AND HEALTH RESEARCH: ESSENTIAL SUPPORT FOR PATIENTS AND CARERS

The School’s research has identified psychosocial therapies that benefit dementia patients and their carers.

Dementia imposes a huge evidence of the problems A new coping strategy burden on patients, their they face in hospital, work developed at UCL has been carers and health systems. that is underpinning a new shown in trials both to help The number of people with training programme for those with depression and dementia is projected to emergency admissions staff prevent its development. rise to a million by 2025. across UCL-associated Population-based studies One in three people over 65 hospitals. are also providing new are likely to have dementia In the absence of truly insight into disease. UCL at the time of their death. effective pharmacological is responsible for a unique Dementia presents great treatments, there is collection of population challenges to health systems. a valuable role for cohorts, including the 1946 An influential study by UCL psychosocial interventions. Birth Cohort (the National researchers, tracking 600 UCL researchers have Survey of Health and consecutive unplanned generated compelling Development), the English admissions to a London evidence of the effectiveness Longitudinal Study of Ageing hospital, found that 42 of a cognitive stimulation and the Whitehall II study. per cent of patients had therapy which is now in As these cohorts reach dementia, many of whom widespread use in the UK the age at which cognitive had not previously been and many other countries. decline and early signs of diagnosed. Patients with dementia are apparent, they In addition, important dementia were more likely are providing rich information forms of support are being to die during admission and on the nature of changes in developed for carers. Caring had worse survival after the general population and for someone with dementia discharge. A follow-up study factors that may accelerate can be highly demanding, of a cohort of dementia or protect against disease. leading to high levels of patients provided more stress and depression.

24 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Dr Liz Sampson. Professor Martin Orrell.

TOWARDS ‘DEMENTIA-FRIENDLY’ HOSPITALS STIMULATING SUCCESS Shocking statistics on the experience of dementia patients An enjoyable programme of cognitive stimulation in hospitals are catalysing major changes in practice. improves both cognitive skills and the quality of life of dementia patients. Hospitals can be intimidating places at the best of times. For patients with dementia, they can be highly distressing. Having documented the With pharmaceutical approaches yet to deliver substantial enormous difficulties dementia patients experience in hospitals,Dr Liz benefits to dementia patients, psychosocial interventions may Sampson’s research is feeding into a training programme across north offer an alternative route to protect memory and other cognitive London to raise awareness among acute care staff at all levels – from skills. Indeed, a cognitive stimulation programme developed porters to chief executives – of the needs of dementia patients. by Professor Martin Orrell, Dr Aimee Spector and colleagues The impact of emergency admission to hospital was graphically has been shown to provide multiple benefits, and has now been illustrated in a prospective study of more than 600 acute admissions widely implemented in the UK and internationally. of people aged over 70. Some 42 per cent were suffering from Professor Orrell became interested in cognitive stimulation dementia, though only half had previously been diagnosed. Perhaps therapy while undertaking a systematic review of mental most striking, they suffered markedly higher mortality – 24 per cent of stimulation approaches in dementia. The evidence suggested patients with cognitive impairment died during admission, five times that such approaches had a positive impact on cognitive skills the proportion of those without impairment. and quality of life, and were also cost-effective. What was Their long-term survival was also much worse. Median survival was lacking, however, were large-scale multicentre trials to confirm 2.7 years for those without dementia but just 1.1 years for those with these promising findings. dementia. Drawing on best practice from these studies, Professor Additional studies on a cohort of 230 patients with dementia, Orrell went on to develop a seven-week cognitive stimulation followed through their hospital stay, have provided more detail on the programme, delivered in groups, with accompanying manual difficulties such patients face. Behavioural disturbances are extremely and DVD. Randomised controlled trials confirmed that the common, but this was strongly associated with undiagnosed – programme improved cognition and quality of life at least as well patients struggling to communicate that they are in pain often become as pharmaceutical interventions. It was positively received by agitated. patients and carers, was practical to deliver and cost-effective. The key issue is that hospital systems are simply not geared to the The programme aims to be engaging and enjoyable. It makes special needs of dementia patients. To help remedy this, Dr Sampson extensive use of puzzles to get mental juices flowing, touching has developed a training package designed to help acute care upon areas such as money management, current affairs and staff provide better support for patients with dementia. Working with diet. The programme, Making a Difference, now in its second ‘dementia champions’ across UCL Partners – which provides services incarnation, has been endorsed by the National Institute for to six million people – Dr Sampson has helped to train more than 1000 Health and Care Excellence (NICE) and recommended by members of staff. Having real data to draw upon, she suggests, has a Alzheimer’s Disease International. It is in widespread use across profound impact – one chief executive was visibly shocked to discover the UK and has been adapted for other cultures, being used in that 75 per cent of dementia patients showed some form of aggressive at least 15 other countries. or agitated behaviour during admission. Professor Orrell is continuing to work on cognitive stimulation As well as evaluating the training programme, Dr Sampson is also therapy. Recent studies have suggested that longer-term use of investigating other ways in which health systems may need to adapt to six months delivers additional benefits, and notably that it acts accommodate dementia patients. The standard way of assessing pain synergistically with drug treatments for Alzheimer’s disease. levels, for example, using a series of faces showing varying levels of As well as additional work on the training needs of programme distress, is impossible for many patients to use, owing to their cognitive facilitators, he has also begun a major programme to examine impairments. With the numbers of dementia patients certain to rise the effectiveness of individual cognitive stimulation therapy – sharply, there is an urgent need to ensure hospital facilities offer a more flexible approach that carers could use with people with a more suitable service to this highly vulnerable group of patients. dementia. As group therapy is not suitable for all patients, the individual course could bring the benefits of cognitive stimulation Sampson EL et al. Dementia in the acute hospital: prospective cohort study therapy to much larger numbers of people. of prevalence and mortality. Br J Psychiatry. 2009;195(1):61–6. Watkin L, Blanchard MR, Tookman A, Sampson EL. Prospective cohort study Spector A et al. Efficacy of an evidence-based cognitive stimulation of adverse events in older people admitted to the acute general hospital: risk therapy programme for people with dementia: randomised controlled factors and the impact of dementia. Int J Geriatr Psychiatry. 2012;27(1):76–82. trial. Br J Psychiatry. 2003;183:248–54.

Sampson EL et al. Survival of people with dementia after unplanned acute Knapp M et al. Cognitive stimulation therapy for people with dementia: hospital admission: a prospective cohort study. Int J Geriatr Psychiatry. cost-effectiveness analysis. Br J Psychiatry. 2006;188:574–80. 2013;28(10):1015–22. Spector A, Gardner C, Orrell M. The impact of Cognitive Stimulation Therapy groups on people with dementia: views from participants, their carers and group facilitators. Aging Ment Health. 2011;15(8):945 –9.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 25 Professor Gill Livingston. Professor Steve Iliffe.

CARING FOR CARERS IN PURSUIT OF TIMELY DIAGNOSIS A simple intervention, delivered by psychology graduates, An educational package helps GPs spot early signs of can improve the quality of life of people caring for dementia, but has no impact on their clinical behaviour. dementia patients. The English National Dementia Strategy, published in 2009, Two-thirds of people with dementia live at home, so the bulk of the included a focus on timely diagnosis. However, distinguishing caring burden falls on family members. Without such carers, the between the inevitable decline associated with ageing and economic impact of dementia would be even higher than the current early signs of dementia is not straightforward. An educational £23bn a year, but this saving has its own health impact: some 40 per programme for GPs developed by Professor Steve Iliffe and cent of family carers suffer from clinical anxiety or depression. To colleagues has been successful at one level, helping GPs make help such individuals, Professor Gill Livingston and colleagues have this distinction. Strikingly, though, it has not actually changed adapted a US programme designed to boost carers’ coping skills – what they document about their everyday practice with people and a recent randomised controlled trial confirmed it is both effective with dementia. and cost-effective. Timely diagnosis is important as it relieves uncertainty, allowing With Dr Claudia Cooper, Professor Livingston led a programme that patients and carers to plan for the future and be prepared for uncovered alarmingly high levels of abuse of people with dementia by changes in mood and behaviour. Treatment can also be initiated carers. Most cases reflected the inability of family members to cope in a timely fashion. with the challenges of caring. The findings led her to consider what Nevertheless, there is good evidence that dementia is not well could be done to help carers, and by extension the people they were recognised in primary care. In part, this reflects the diagnostic caring for. challenge. But there are other more subtle influences at work. People’s coping strategies vary. Some approaches may offer Dementia still carries a stigma, and GPs may be reluctant short-term relief but store up long-term problems. Encouraging more to attach the label to patients. With few effective therapies positive coping strategies may therefore better prepare carers for the available, they may feel a diagnosis offers few positives but challenges they will inevitably face. plenty of negatives. In the USA, the ‘Coping with Caring’ programme, a manual-based In an initial study, Professor Iliffe and colleagues compared the group intervention, has been shown to reduce depression in carers. effectiveness of three approaches designed to improve timely However, the use of groups and need for trained clinical psychologists diagnosis: a CD-ROM, practice-based workshops and decision- would make it difficult to implement widely in the UK. Professor support software. While the latter two clearly helped GPs spot Livingston therefore modified the programme so it could be delivered dementia better, they had no impact on practice behaviour. to individuals by graduates (under supervision). Building on this trial, Professor Iliffe developed the ‘EVIDEM’ The ‘START’ programme is based on sound cognitive psychological educational package, drawing on both multidisciplinary expert principles. It helps carers accept that patients will show difficult input on dementia diagnosis and adult educational theory, and behaviours, which they will not be able to influence, and encourages integrating practice-based workshops and electronic resources. them to look for things to enjoy, even small moments like shared cups The trial included detailed needs assessment in practices, and of tea, and to find ways to do more of them. materials geared to doctors of varying degrees of experience. A trial of 260 carers found that the START programme significantly Everything was done to ensure that new knowledge could reduced anxiety and depression, and improved carers’ quality of life. readily be applied during doctors’ routine work. This pragmatic, There were also hints of a fall in levels of abuse, something that will practice-based approach was designed to minimise the barriers be examined further in follow up. Notably, the intervention had both to implementation. preventive effects and therapeutic benefits for those already depressed. However, results from this larger EVIDEM-ED trial, based on Health economic analyses suggested it is also cost-effective. 23 primary care practices, mirrored those from the earlier study. This is the first evidence that a cost-effective psychosocial Diagnostic skills were enhanced, but there was no increase in intervention can benefit carers of dementia patients. Professor diagnoses and management practice with patients remained Livingston is helping to implement the programme locally, and unchanged. Professor Iliffe is now undertaking qualitative encouraging its take up more widely. research with practices to try to uncover the factors that prevent them from adhering to clinical guidelines. Cooper C et al. The determinants of family carers’ abusive behaviour to people with dementia: results of the CARDstudy. J Affect Disord. 2010;121(1-2):136–42. Downs M et al. Effectiveness of educational interventions in improving detection and management of dementia in primary care: cluster Livingston G et al. Clinical effectiveness of a manual based coping strategy randomised controlled study. BMJ. 2006;332(7543):692-6. programme (START, STrAtegies for RelaTives) in promoting the mental health of carers of family members with dementia: pragmatic randomised controlled trial. Iliffe S et al. Evidence-based interventions in dementia: A pragmatic BMJ. 2013;347:f6276. cluster-randomised trial of an educational intervention to promote earlier recognition and response to dementia in primary care (EVIDEM-ED). Knapp M et al. Cost effectiveness of a manual based coping strategy programme Trials. 2010;11:13. in promoting the mental health of family carers of people with dementia (the START (STrAtegies for RelaTives) study): a pragmatic randomised controlled trial. BMJ. 2013;347:f6342.

26 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Dementia may be difficult to diagnose in those who use sign language. Social contact may protect against cognitive decline.

DEAFNESS AND DEMENTIA A TWO-WAY STREET A new screening tool tailored to deaf people who An ageing cohort is providing insight into both are sign language users may lead to more timely the causes and consequences of cognitive decline, diagnosis of dementia. with implications for both health and social policy.

The early stages of dementia are difficult to distinguish from normal The English Longitudinal Study of Ageing has been tracking ageing, and it is recognised that dementia is not well diagnosed in more than 10,000 people aged 50 or more since 2002. primary care. Patients who are deaf are even less likely to receive a Unusually, it captures data across a wide range of social, timely diagnosis. Through the Deaf with Dementia project, Professor economic and health indicators, an interdisciplinary perspective Bencie Woll and colleagues are developing tools to enhance detection that allows links to be made between health and wellbeing and of dementia among deaf people, so they receive better support and social circumstances. care at this critical phase. Management of the cohort is coordinated by Professor The first signs of dementia are typically memory loss or other Andrew Steptoe at UCL in partnership with the Institute of cognitive difficulties. Communicating such problems can be difficult Fiscal Studies and other academic groups. Unusually, data for a deaf person, unless a doctor is familiar with sign language (which are released as rapidly as possible to other researchers, to few are). In particular, lack of interaction may be put down to a difficulty encourage their use in evidence-based policy-making. with communication rather than a sign of dementia. Furthermore, Among the data collected are measures of cognitive ability. standard screening tools are not suitable for people who have been Given that cognitive decline is a well-recognised staging post on deaf since birth, whose cognitive skills will be different in significant the path to dementia, any factors influencing this decline could respects from those of hearing people. As a result, diagnosis and early have later implications for disease. For example, if disease onset management of dementia in deaf individuals is generally poor. could be delayed by five years, some 30,000 fewer people would The Deaf with Dementia project – a partnership between the die from dementia each year. ESRC Deafness, Cognition and Language Research Centre at UCL One factor that could influence the decline of cognitive skills (DCAL), the University of Manchester, City University London and the is social isolation. Recently, Professor Steptoe and colleagues Royal Association for Deaf People – aims to rectify this situation. In have explored the potential impact of both isolation – an particular, DCAL has led the development of culturally and linguistically objective measure of people’s social networks – and loneliness, appropriate tools for diagnosis. a subjective assessment of connectedness (which may not A team of neuropsychologists and linguists, several of whom are necessarily reflect actual degree of isolation). themselves deaf, has adapted existing assessments and created new Notably, the degree of cognitive decline was more closely ones to develop a tool that better reflects the differing cognitive abilities related with isolation than loneliness. Such studies suggest and experiences of deaf people. Memory tests, for example, include possible strategies for intervention, for example by promoting events of particular resonance to deaf people, such as the death of social network development in vulnerable populations. Diana, Princess of Wales, Patron of the British Deaf Association. The cognitive data have also provided an unusual opportunity To provide a yardstick against which cognitive deterioration can be to explore its impact on real-life financial decision-making. This assessed, data have been collected from more than 200 healthy older is of particular interest to policy-makers, for example to guide members of the deaf community aged 50–89, attendees at an annual pension policy. One use of ELSA data has been to examine how Darby and Joan Club outing to a seaside holiday camp. cognitive performance and numeracy affect savings behaviour In collaboration with DCAL, the National Hospital for Neurology and around retirement. Neurosurgery has established a special memory clinic for deaf patients Finally, ELSA has been modelled on the US Health and that uses the tool in its assessment. More generally, Professor Woll Retirement Survey, enabling international comparisons to be and DCAL are aiming to improve the assessment and management made. As well as revealing that US seniors cognitively outperform of the estimated 6–8000 sign language users in the UK with a their UK peers (despite typically being less healthy), cross- neurological condition. country comparisons also suggest that cognitive skills in old age are strongly influenced by life course – the elders in industrialised Atkinson J, Woll B et al. The health of deaf people. Lancet. countries are cognitively healthier because of the better living 2012;379(9833):2239. standards they enjoyed when younger.

Shankar A, Hamer M, McMunn A, Steptoe A. Social isolation and loneliness: relationships with cognitive function during 4 years of follow-up in the English Longitudinal Study of Ageing. Psychosom Med. 2013;75(2):161–70.

Langa KM et al. Cognitive health among older adults in the United States and in England. BMC Geriatr. 2009;9:23.

Skirbekk V, Loichinger E, Weber D. Variation in cognitive functioning as a refined approach to comparing aging across countries.Proc Natl Acad Sci USA. 2012;109(3):770–4.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 27 A historic birth cohort is now contributing to dementia research. New research will benefit those living with dementia.

THE CLASS OF 46 IMPROVING EVERYDAY LIFE The 1946 birth cohort will shed light on the emergence Three UCL research teams have been awarded of dementia in the general population. multimillion pound funding for programmes that could make a significant difference to patients’ and carers’ In 1946 a remarkable experiment began. All infants born during a single quality of life. week in March were enrolled in a national maternity survey, generating invaluable data on early health and the cost of childbirth. Subsequently, In 2013, three UCL groups launched major new research researchers have continued to follow a subset of these infants, who programmes designed to generate rapid benefits for dementia became the 1946 birth cohort and have gone on to provide unique patients and their carers. insight into factors affecting health and wellbeing across the life course. The MARQUE (Managing Agitation and Raising Quality of Life) And as cohort members reach their later years, they are yet again programme, led by Professor Gill Livingston, is focusing on the contributing to our understanding of disease – this time, early signs distressing and common agitation experienced by patients with of dementia. moderate to severe dementia. Generally linked to the inability to The 1946 cohort, the world’s longest running birth cohort, is express an unmet need, agitation has a great impact on quality coordinated by the MRC Unit for Lifelong Health and Ageing (LHA), of life and is highly challenging for carers. An interdisciplinary led by Professor Diana Kuh. From the 5000 or so infants, more team is carrying out a trial of an intervention developed to ensure than half are still contributing regularly, undergoing periodic health that the culture of care homes minimises agitation, as well as checkups, taking tests of cognition, and contributing medical and pilot studies of an approach designed to improve quality of life lifestyle data. for carers and patients in the last six months of life. As participants reach their late 60s, they have become of increasing The PRIDE (Promoting Independence in Dementia) study, interest to the field of healthy ageing. Uniquely, the wealth of data led by Professor Martin Orrell, targets those in early stages of collected over their lifetime can reveal factors influencing health and dementia. One aim is to use data from the English Longitudinal wellbeing in old age. Study on Ageing (ELSA) to investigate the social and lifestyle Furthermore, for dementia researchers, the cohort is a golden factors associated with cognitive decline and its consequences opportunity to study an entirely unbiased population sample as they for individuals’ sense of wellbeing. New questions will be added begin to show signs of cognitive impairment. Even if symptoms are not to future rounds of ELSA data collection, to capture additional apparent, their brains may still be showing the distinctive changes that information about cognitive decline, and people’s expectations precede overt loss of cognitive function. and experiences. A complementary aim is to develop a social To gain insight into the changes, 500 cohort members are being intervention to promote behaviours found to protect against invited to participate in a dementia substudy, being led by Professor cognitive decline, identified by consultation with people with Marcus Richards at the LHA and Dr Jonathan Schott and Professor dementia and their carers and by review of published evidence. Nick Fox in UCL’s Dementia Research Centre. Participants will undergo The intervention will be evaluated in a multicentre clinical trial. combined PET–MRI scanning, to characterise brain structure and The ‘Seeing what they see’ study, led by Dr Sebastian Crutch, levels of β-amyloid. They will also provide biological samples for is addressing an underappreciated aspect of Alzheimer’s biomarker assessment and genetic analysis, and undertake various disease – loss of visual skills. Impaired visual perception performance tests. After a baseline scan, study members will be can significantly interfere with everyday life, and lead to falls, scanned again in two to three years’ time. hallucinations and poor diet. The interdisciplinary project will The study is a rare opportunity to collect data from large numbers of focus on patients with posterior cortical atrophy, a form of healthy individuals and to relate them to the subsequent development Alzheimer’s disease in which vision is particularly affected. of disease. In addition, analysis of historical data will also shed light By characterising these and other Alzheimer’s patients in an on multiple other factors, from education to blood pressure, that could artificial domestic environment, developed by UCL’s Engineering conceivably affect the onset of symptoms. This most intensively studied Department, the project aims to identify practical adaptations group of individuals therefore look set to benefit medicine all the way and coping strategies that can be then be evaluated in a trial from cradle to grave. based in patients’ homes and care homes.

28 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

DEALING WITH DEMENTIA

Maggie Williams’s husband Andy was diagnosed with posterior cortical atrophy (PCA) in 2011. The PCA Support Group run by UCL’s Dementia Research Centre has helped them both adjust to the implications of this life-changing diagnosis.

Before his diagnosis, “To get a diagnosis was a have been able to find out score having improved on his Andy had been enduring relief. We knew then what practical information about last clinical assessment. tough times. He had been we were dealing with. As the benefit system and other She laments the lack made redundant twice horrible as it is, we knew support that is available. of funding for dementia and had recently lost his then what it was.” Hearing first hand from research, which bears little brother. When he began to people who have navigated Since then, the family has relation to the enormous experience other problems, the system has been been adjusting to the new clinical and economic particularly with driving, invaluable. circumstances. Andy is in impact of the condition. it was initially put down the early stages of disease The social contacts they And attitudes more generally to stress. As is often the and Maggie is able to leave have made have also been still need to change, she case with PCA – a form of him on his own, continuing enormously helpful, though suggests: “It’s still got dementia that affects the to work part-time. Perhaps tinged with sadness. a stigma attached to it. visual areas of the brain – the biggest blow to Andy has “You see people that are Alzheimer’s disease and it was problems with vision been the fact that he can no further on in the journey, dementia in general, it’s like that proved the key to longer drive, as much of his and it’s heartbreaking. cancer was 10–15 years ago. diagnosis. working life had been spent But you need to be aware You mention that and people “We went and had an eye on the road. “That was a of what is ahead.” just run away. Which is test done,” says Maggie, shock for him,” says Maggie. very sad.” Through the PCA Support “and the optician picked up With their children returning Group, Maggie and Andy Information about the PCA Support early stage cataracts. We to live at home, it is, says met Dr Sebastian Crutch, Group, run in partnership with the then got referred on to an National Hospital for Neurology Maggie, “a busy house”, and and volunteered to take ophthalmic surgeon. He was and Neurosurgery and with support the family tries to minimise part in research being from the Myrtle Ellis Fund, can very much on the ball, and the impact of Andy’s carried out at the DRC. be found at www.ucl.ac.uk/drc/ he picked up that there was pcasupport. The website includes diagnosis. “At the time it was Both have been taking part something else going on. information for patients and families awful,” says Maggie, “but you in studies examining their We had a brain scan and and for healthcare professionals, just accept it. You live your vision and visual memory, and includes short films of patients it just went from there.” life around it. You carry on as an experience both have discussing their experience, including well-known fantasy Andy was formally diagnosed best you can. Though I have enjoyed. “It’s lovely, the staff novelist Terry Pratchett, who in December 2011, yet in a good sob most days, out there are very helpful, you was diagnosed with PCA in 2007. retrospect Maggie believes of earshot of anyone else!’ meet like-minded people.” the signs were present years What has been a great For people like Andy, few earlier: “Looking back, we help, she adds, is the PCA therapeutic options are saw the start of symptoms Support Group. Through available. He has been in 2008. As you do, you just regular meetings in London, prescribed Aricept, which think it is something else.” a newsletter and other may slow the decline of By the time all the tests had mechanisms, she has been Alzheimer’s and other forms been completed, Maggie able to make contact with of dementia in some patients. already had an inkling of other families in a similar “We think it’s helping,” says what Andy’s problem was: situation. She and Andy Maggie, Andy’s memory

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 29 FACILITIES AND RESOURCES: A PLATFORM FOR SUCCESS

UCL has the intellectual firepower and infrastructure to make a real difference in dementia research. Our future ambitions are to build on this foundation to further understand the disease, accelerate the development of new treatments, and improve the healthcare delivered to patients.

The UK is a global leader in and internationally significant include studies of molecular The Reta Lila Weston Institute the dementia field, publishing contributions to research structure, genetics, within the Department is nine per cent of the world’s across the spectrum from biochemistry, immunology, a world-renowned centre research in this area in basic to health research. cell and animal models, in the study of movement 2008/09, second only to Outstanding research and clinical research, disorders. the USA. UCL is the leading and clinical resources are including treatment trials. Institute of Neurology UK institution in dementia available to support this Institute of Neurology Department of research, contributing more research. Department of Molecular Neurodegeneration: than 15 per cent of the UK Dementia Research Centre: Neuroscience: The The Department’s research output. Given the breadth Based at the National Department’s research encompasses prion and depth of neuroscience Hospital for Neurology portfolio encompasses diseases (predominantly research and, in particular, and Neurosurgery in Queen the full range of within the embedded MRC our clinical strengths, we Square, the Centre is one neurodegenerative Prion Unit), Alzheimer’s are well positioned to be of the UK’s leading sites disorders. It houses the disease and other at the forefront of dementia for clinical research into Queen Square Brain neurodegenerative disorders research and healthcare, and dementia, and the hospital Bank, which has Europe’s including Huntington’s to respond to future research is the lead centre for trialling largest collection of frozen disease, frontotemporal funding opportunities. Our new drugs to slow the Parkinson’s disease brains as dementia and studies of aim is to consolidate our progression of Alzheimer’s well as extensive collections the pathways of cellular position as the leading UK disease. of rare disorders and of senescence. It includes centre for dementia research progressive supranuclear studies of the genetic basis and to establish ourselves MRC Prion Unit: The Unit palsy and multisystem of two disorders that involve as an international leader. is a national centre of atrophy. The collection also neurodegeneration, motor excellence undertaking includes donated brains neuron diseases and Down Facilities and resources research in prions and from prospectively studied syndrome, using mouse related diseases. Research UCL includes a range of people with familial models. programmes within the Unit centres making nationally dementias.

30 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

Leonard Wolfson Wolfson Drug Discovery NIHR Bioresource: Neuroscience Domain: Experimental Neurology Unit: Based at the Royal UCL/UCLH leads one of The Domain provides a Centre: A dedicated, Free Hospital Campus, the the Biomedical Research mechanism to draw together specialist centre for the Unit has a major programme Centres involved in the UCL’s world-leading conduct of first-in-human of drug development for national NIHR Bioresource community of neuroscientists studies of novel therapies amyloidosis and potentially and is the lead institution working across all the for the treatment of Alzheimer’s disease and for the neurological theme. School’s Faculties, as well neurodegenerative diseases. other dementias, supported The Bioresource will enable as researchers working in by the MRC, the NIHR via the recruitment of patients UCL’s other two Schools. Wolfson Biomarker the UCLH/UCL Biomedical for stratified experimental Core: The Core provides Research Centre and GSK. medicine studies, as well Industrial collaboration biobanking resources and as providing the potential facilities for biomarker In addition, UCL manages or The involvement of the to study the molecular bases analyses and research. has access to a wide range pharmaceutical sector will be of disease, identify the most The Core collaborates with of resources and platforms essential for the development appropriate biomarkers Professor Henrik Zetterberg’s that support and facilitate of new therapeutics. UCL for diagnosis and drug laboratory in Sweden and dementia research. These has an outstanding tradition discovery, and test the with the proteomics and include: of working with industry, mechanism of action metabolomics unit at the and well-established Clinical and population and effects of new drugs. Institute of Child Health. partnerships with companies cohorts: UCL has access Rare Disease Initiative: such as GSK and others. NIHR Queen Square to a large number of This new UCL initiative will Of particular significance Dementia Biomedical unique patient cohorts that develop a comprehensive is the drug discovery and Research Unit: The unit can be used for both the rare disease portfolio development partnership is one of four NIHR BRUs understanding of dementia that connects databases, established with Eisai, which which undertake translational and the testing of new registries, biobanks and will see researchers from clinical research in dementia. therapeutic strategies. It also clinical bioinformatics for rare both organisations working It focuses on early-onset and plays a key role in several disease research, including together to develop new familial disease to improve population cohorts, including neurodegeneration. ways to treat neurological diagnosis and facilitate the MRC National Survey of diseases such as Alzheimer’s early-phase trials of novel Health and Development (the Sainsbury Wellcome and Parkinson’s disease. interventions. 1946 Birth Cohort) and the Centre for Neurocircuits: English Longitudinal Study The Centre will use state- UCL/UCLH NIHR Training of Ageing, which are making of-the-art molecular and Biomedical Research increasing contributions cellular biology, imaging, Training is an integral Centre: The centre has to cognitive ageing and electrophysiology and component of the Leonard four major programmes, dementia research. behavioural techniques, Wolfson Experimental including . supported by computational Neurology Centre, which The neurosciences DeNDRoN: UCL is one modelling, to investigate will provide clinical and basic programme has four strategic of two national hosts how brain circuits process scientists with insight into objectives, which align well of the NIHR Dementia information to create neural different diseases areas with the Faculty strategy and Neurodegenerative representations and guide and experimental techniques for dementia: (1) aligning Diseases Research Network behaviour. in neurodegeneration. human imaging to redefine (DeNDRoN), which aims to More generally, UCL offers diseases, improve diagnosis facilitate clinical research Francis Crick Institute: unrivalled opportunities for and facilitate the discovery into dementia and related The partnership with the PhD research in all aspects of effective treatments; (2) diseases. Frances Crick Institute, an of neuroscience, basic identifying and studying interdisciplinary medical CHAPTER: The Centre and clinical. This training is early-stage disease; (3) data research institute supported for Health Service and provided in the laboratories handling and bioinformatics; by a consortium of six Academic Partnership of researchers who are (4) biomarkers. scientific and academic in Translational E-Health among the leaders of their organisations (the MRC, Queen Square Clinical Research is one of four fields, using the most modern Cancer Research UK, Trials Unit: The Unit aims E-Health Informatics techniques to address the Wellcome Trust, UCL, to increase clinical trial Research Centres funded important problems of basic Imperial College London activity in neuroscience by by the MRC. The aim is to and . and King’s College London), supporting and facilitating maximise translational impact will further add to the research and by linking from discovery through trials strength of basic biological with the UCL Clinical Trials to clinical practice, service research in neuroscience. Unit and the Central and delivery, patient outcomes East London (CEL) Clinical and public health. Research Network.

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 31 LEADING THE WAY

UCL is one of the world’s leading multifaculty interdisciplinary universities, with a breadth and depth of research expertise that, when brought together, will have a major impact on the health issues facing our society. In order to achieve impact in tackling dementia, and to ensure that UCL maintains and builds its position as an internationally leading centre for dementia, the different strands of research from basic through to clinical, combined with cutting-edge technologies, will become integrated into a coherent strategy. We have identified a number of research challenges that will be addressed over the next five years, and beyond, and which will lead to the development of new therapeutics and treatment strategies for dementia. We will further develop our relationships and dialogue with the funding bodies, charities, government departments, and with patient groups, to ensure that UCL both informs on, and responds to, the latest developments in dementia research.

Basic: Clinical: Furthermore, we will also: • improve our understanding of the • increase the number of early-phase • improve communication and molecular mechanisms resulting and phase III trials and accelerate interaction between researchers, in dementia recruitment into trials to achieve better translation between basic and clinical • understand the changes in neural • develop presymptomatic markers sciences circuitry underpinning dementia to improve early diagnosis and that are sensitive to change in first-in- • expand our programmes to train Translational: human studies the next generation of researchers • develop better animal models such as the built environment Social: of dementia and economics • improve our understanding of • explore the use of stem cells as • increase public engagement cognitive health and its changes a therapeutic strategy and public/patient involvement. over the entire life course • use cellular models of disease • develop and enhance interventions to screen for new therapeutics to improve the health and quality diagnosis, including metabolomic of life of patients and their carers and proteomic approaches

32 DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences

UCL FACULTY OF BRAIN SCIENCES

The UCL Faculty of Brain Sciences brings together world- leading expertise at the forefront of neurology, ophthalmology, audiology, and mental health sciences. The Faculty seeks to understand and solve the greatest health and wellbeing problems in the brain sciences, in order to transform society and reduce the global burden of disease. Research within the Faculty addresses all the major conditions affecting the brain and nervous system. For 2013–18, the Faculty has identified four strategic research priorities: • Neurodegeneration and • Mental health • Sensory systems and therapies • Cognitive ageing The Faculty of Brain Sciences is one of the four component faculties of the UCL School of Life and Medical Sciences, arguably the greatest concentration of expertise in biomedical science and population health in Europe. By drawing on the expertise in other Faculties and in other UCL Schools, the Faculty of Brain Sciences can develop genuinely interdisciplinary programmes of research from the level of single molecules to global populations.

CREDITS

Cover: Professor Nick Fox; p. 2: Dr Sion Lewis; p. 3: Lea Paterson/SPL; p. 3: Dr Rachael Scahill (from Scahill RI et al. Genetic influences on atrophy patterns in familial Alzheimer’s Disease: a comparison of APP and PSEN1 mutations. J Alzheimers Dis. 2013;35(1):199–212); p. 3 (box): Pasieka/SPL; p. 4: Xun Choong; p. 5 (left): Eye of Science/SPL; p. 5 (right): Professor Trevor Smart; p. 6: Dr Gipi Schiavo (left); p. 6 (right), p. 7: David Bishop; p. 8 (left): Professor Sarah Tabrizi; p. 8 (right): Wellcome Library, London; p. 9 (left): Professor Patricia Salinas; p. 9 (right): David Bishop; p. 10: David Scharf/SPL; p. 11 (left): Pablo Rojas/Wellcome Images; p. 11 (right), p. 12 (left): David Bishop; p. 12 (right): Dr Sonia Gandhi; p. 13: David Bishop; p. 14 (left): Professor Francesca Cordeiro; p. 14 (right): Emw; p. 15 (left): iStockphoto/FredFroese; p. 15 (right): Professor Sir Mark Pepys; p. 16 (left): Professor Nick Fox; p. 16 (right); Dr Rachael Scahill (from Scahill RI et all. Genetic influences on atrophy patterns in familial Alzheimer’s Disease: a comparison of APP and PSEN1 mutations. J Alzheimers Dis. 2013;35(1):199–212); p. 17: iStockphoto/AlexRaths; p. 18: Dr Rachael Scahill (from Scahill RI et al. Genetic influences on atrophy patterns in familial Alzheimer’s Disease: a comparison of APP and PSEN1 mutations. J Alzheimers Dis. 2013;35(1):199–212); p. 19 (left): Spencer Grant/ SPL; p. 19 (right): from Ryan NS et al. Magnetic resonance imaging evidence for presymptomatic change in thalamus and caudate in familial Alzheimer’s disease. Brain. 2013;136(Pt 5):1399–414); p. 20 (left): David Bishop); p. 20 (right): Dr Rachael Scahill; p. 21 (left): Dr Jason Warren (from Rohrer JD et al. Clinical and neuroanatomical signatures of tissue pathology in frontotemporal lobar degeneration. Brain. 2011;134(Pt 9):2565–81); p. 21 (right), p. 22 (left and right), p. 23: David Bishop; p. 24: iStockphoto/Yuri_Arcurs; p. 25 (left and right), p. 26 (left and right): David Bishop; p. 27 (left) iStockphoto/lawcain; p. 27 (right): iStockphoto; p. 28 (left): iStockphoto/filizturk7; p. 28 (right): iStockphoto/ SarahlWard; p. 29 Maggie Williams; p. 30, p. 32: Dr Jamie Kawadler.

Text: Ian Jones, Jinja Publishing Ltd

Design: Jag Matharu, Thin Air Productions Ltd

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TAP1989/08-11-13/V1J

DEMENTIA AND NEURODEGENERATION UCL School of Life and Medical Sciences 33 About UCL UCL is one of the world’s top universities. Based in the heart of London it is a modern, outward-looking institution. At its establishment in 1826 UCL was radical and responsive to the needs of society, and this ethos – that excellence should go hand-in-hand with enriching society – continues today. UCL’s excellence extends across all academic disciplines; from one of Europe’s largest and most productive hubs for biomedical science interacting with several leading London hospitals, to world-renowned centres for architecture (UCL Bartlett) and fine art (UCL Slade School). UCL is in practice a university in its own right, although constitutionally a college within the federal University of London. With an annual turnover exceeding £800 million, it is financially and managerially independent of the University of London. UCL’s staff and former students have included 21 Nobel prizewinners. It is a truly international community: more than one-third of our student body – around 25,000 strong – come from nearly 140 countries and nearly one-third of staff are from outside the UK. www.ucl.ac.uk

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