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The Challenge
Neurodegenerative diseases (NDD) are the 6th leading cause of death, a major cause of disability
and residential care placement, and the main cause of dementia in the UK. By 2025, one million
people will be affected by dementia – unless effective disease modifying therapies are found.
Dementia alone costs the UK economy £23bn a year – more than cancer and heart disease
combined – yet UK government and charitable investment in dementia research is 12 times lower
than spending on cancer research (source – Alzheimer‟s Research UK).
NDD encompass highly prevalent disorders such as Alzheimer‟s disease (AD) and Parkinson‟s
disease (PD), as well as less common but equally devastating conditions including frontotemporal
lobar degeneration (FTLD), Huntington‟s disease (HD), motor neurone disease (MND) and prion
diseases. There is emerging consensus that although such disorders have very different clinical
presentations, there are some common themes – in pathology and progression, as well as ethical
and trial design issues – that apply across conditions. These and other commonalities argue for a
sharing of expertise, resources and approaches for advances in one area to benefit another.
Symptomatic treatments, where available, are of only modest benefit for any of these diseases and
there is a desperate need for novel treatments that slow or delay progression. There is increasing
recognition that the most – and potentially the only – effective therapies will be those applied at the
earliest stages. A „self-perpetuating‟ aspect to neurodegeneration that is difficult to slow once
established, may account in part for notable trial failures. It is also clear that for many of the NDD
there is a long latency period before symptoms appear during which there is progressive
accumulation of molecular pathology, followed by increasing and inexorable neuronal damage. Our
best chance of maintaining CNS function is to slow neurodegeneration when the minimum of
irretrievable neuronal loss has occurred. Experience across medicine is that treatment of advanced
disease may come too late and this is of particular relevance in degeneration of post-mitotic nondividing
cells. Investment in other previously “untreatable” chronic conditions has shown that
preserved function and greatly improved survival are possible if effective interventions are instituted
as early as possible.
This approach also provides the greatest benefit to families, carers and society. Effective
intervention at the pre-symptomatic stage has the potential to slow or delay progression preserving
useful clinical and cognitive function rather than prolonging late stage survival with significant
disability and low quality of life. Thus intervention should occur when there is most to save in terms
of function; individuals gain disease-free quality years, and there is a major impact on prevalence.
For AD, a delay in dementia onset by five years would halve prevalence (2). Comparable benefits
accrue in other diseases.
Our improved understanding of disease pathophysiology, combined with recent clinical, imaging and
other biomarkers advances, opens a new window of therapeutic opportunity, which we are ideally
placed to exploit. Key challenges are therefore to identify and characterise suitable at-risk cohorts;
to develop disease modification therapies that can be applied as early as possible in NDD; and to
establish the most effective methods of evaluating these therapies.
Aims
To address these challenges we will establish the Leonard Wolfson Experimental Neurology Centre
(LWENC), a dedicated, specialist centre for the conduct of first-in-human studies of novel therapies.
The LWENC will be embedded within a substantive research programme to advance our
understanding of NDD and our ability to diagnose and intervene at the earliest possible stage. This
proposal is led by eight principal researchers (Nick Fox together with John Collinge, John Hardy,
Martin Rossor, Anthony Schapira, Sarah Tabrizi, Alan Thompson and Nick Wood) but importantly it
also draws on a broad range of resources and exceptional collaborators who share an ambitious
vision of accelerating the search for disease-modifying therapies in NDD and instituting these
therapies early enough to delay onset and slow progression. Specifically, we will:
(1) establish and comprehensively characterise at-risk cohorts from which presymptomatic
individuals could be offered promising therapies;
(2) facilitate basic neuroscience research in NDDs and accelerate promising therapeutic leads
into translational stages;
(3) support academic groups in taking innovative therapeutic concepts safely and costeffectively
into first-in-human or proof-of-concept (POC) studies;
(4) perform quicker and more effective triage of compounds for late-stage clinical trials;
(5) improve and validate the methods (from biomarkers to ethics and trial design) needed to
evaluate promising treatments in very early stage disease; and
(6) initiate POC studies in presymptomatic disease and accelerate international efforts to
establish prevention trials in NDD.
Hypotheses
Over the next five years we will undertake studies that will address a large number of hypotheses
amongst which are:
Earliest pathophysiological change
(1) There are disease-specific patterns of progression that run from the accumulation of
molecular pathology, cellular dysfunction and neuronal loss to symptoms that can be tested
by multi-modal longitudinal studies of at-risk groups
(2) Neuronal dysfunction in the earliest pre-clinical phase of NDD is potentially reversible and
this can be tested by very early intervention with disease-modifying agents
(3) Compensatory neural network changes coupled with synaptic plasticity allow at-risk
individuals to function at a relatively high level despite demonstrable ongoing functional and
structural brain imaging changes
(4) Clinical manifestation that follows (up to a decade of) progressive accumulation of molecular
pathology involves gradually accelerating neuronal loss and dysfunction
Multi-modality assessment of progression and network vulnerability
(5) Patterns of progression, reflecting selective vulnerability of neuronal populations and
networks, can define NDD and subgroups of disease
(6) Modality-specific markers will predict symptoms and diagnosis in different NDD and will
reflect molecular pathology (e.g. amyloid imaging for AD, dopaminergic loss in PD; and
topography of loss/dysfunction (e.g. caudate atrophy in HD)
(7) Novel CSF markers (e.g. 4/3 repeat tau ratios; Aβ
NDD
(8) Within-subject change using the individual as their own control will be more sensitive to
pathological loss than cross-sectional measures
(9) Novel neuropsychological tests developed from cognitive neuroscience can improve
measurement of therapy-related change in symptomatic NDD; sensitive tests adjusted for
practice effects will provide proximity markers of subtle cognitive change in at-risk individuals
(10) Quantitative timing- and variability-based metrics will provide more precise measures of
cognitive change than traditional accuracy-based tests
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Translation to therapy
(11) Response to therapies, both side effects and efficacy, will be influenced by genetic factors:
candidates from GWAS studies will influence phenotypic expression and therapeutic
response
(12) Rate of progression in NDD is very variable and limits power in trials; determinants of this
heterogeneity are largely unknown: genetic, epigenetic and/or innate immune system factors
will determine a large proportion of variance and may be used to optimise trial designs