Professor Roxana Carare, Lead for Interdisciplinary Ageing and Dementia Centre (IDEAC), University of Southampton – Written evidence (INQ0083)

Scientific Basis

How complete is the scientific understanding of the biological processes of ageing and their epidemiologies? (including the relative roles of genetics, epigentitics, lifestyle, environment, etc.)?

It is well recognised that deteriorating brain function with aging is one of the primary factors that will impact upon quality of life not just for the individual growing old but also for their carers.

Much of the science behind efficient brain function remains unknown. Essential physiological mechanisms such as how the blood flow is regulated, and how waste products are cleared are poorly understood, particularly at a system level. We need to increase our understanding of the healthy brain, and develop methods to measure and monitor the mechanisms that are eroded with age. Then we will be able to address the role of genetics, epigenetics, lifestyles and environment on these mechanisms.

3 Which developments in biomedical science are anticipated in the coming years, in time to contribute to the Government’s aim of five more years of healthy and independent life by 2035?

Biomarkers for diagnostics and for monitoring effectiveness of treatments.

Imaging biomarkers are going to become increasingly more targeted; currently, in clinical practice, the main metrics that are measured are brain volume, brain perfusion (blood flow) and poorly characterised signs such as white matter hyperintensities on MRI images. These are all markers of later stages of the disease and often lack sensitivity and specificity and the ability to distinguish between different types of dementia. New radiopharmaceuticals and tracers should be able to more precisely identify pathological changes associated with disease and these (and existing ones) should be more widely available. In addition, new MRI techniques are being developed that provide quantitative information about brain function, including blood-brain barrier dysfunction, CSF flow, brain connectivity and iron accumulation. The advantage of MRI over other imaging techniques is that it produces data (spatially localised in the brain) that can be quantified and also uses non-ionising radiation, so can be used to monitor a disease over long periods of time and accurately assess the effect of an intervention. The key concept going forward is how data from many sources can be combined to provide metrics that are more sensitive to disease changes and could provide earlier diagnostic information – for example pattern recognition, machine learning and modelling techniques. Imaging data is ideal for the application of such techniques and these techniques will enable us to extract the most ‘value’ from this data.
Vascular changes are closely associated with deteriorating brain function; while it remains unknown if this is a cause or an effect it is widely accepted that these changes are likely to begin at an early stage of the disease process. Developments are anticipated in the measurement of cerebral fluid dynamics, both blood flow and cerebrospinal fluid. These include developments of MR imaging, ultrasonic and infrared techniques. It is

anticipated that these developments will lead to earlier detection of age related diseases of the brain.

Technologies

What technologies will be needed to facilitate treatments for ageing and ageing-related diseases, and what is their current state of readiness? For example:

Technologies for monitoring conditions and providing personalised medical advice.

Imaging technologies that can accurately measure and track the effect of a treatment or other intervention will be essential. The ideas around this are described above (see answer to question 3). More sophisticated analysis of this data could lead to better personalisation of treatments/interventions (eg machine learning). These are probably at TRL 5-6 currently (testing/validation stage).

Technologies for monitoring healthy living e.g. fitness diet, etc

The concept of brain health is likely to develop, perhaps as the most important health related determinant of life quality. There will be questions asked about what factors influence brain health and how best to optimise them. These include sleeping, diet and exercise. As the physiological basis of a healthy brain function become better understood objective measurements are likely to develop of “brain health.” There is no such technology that is close to ready for this at the moment, we don’t even know what should be measured, however it is likely to emerge in the next 10 – 20 years depending on how funding is allocated. There will be positive and sociologically negative effects from this. The positive will not be fully realised unless there is a successful treatment for “poor” brain health. The sociologically negative impacts will be particularly extreme if the treatment is prohibitively expensive for a section of society.

What are the barriers to the development and implementation of these various technologies (considered in 5 -7)?

One barrier to development of technologies in this field is a lack of a well-defined pathway from concept to practical implementation. A definition of progress along a pathway that is sometimes adopted is the TRL Technology Readiness Level. An adaptation of this for medical device applications with clear methodologies for demonstrating each advance in readiness would be helpful. It would also highlight significant gaps that exist between the different government funding schemes where technologies can become trapped.

Another barrier is the resource required to develop appropriate imaging/diagnostic techniques and the ability to test these in large populations. We would like to gather as much imaging data as possible from our ageing population in a robust and safe way, and this requires specialist expertise and access to the right equipment and techniques, at the right time. This ideally needs to happen in an NHS setting, so that this data gathering can all be linked together efficiently, and this will require this resource to be available within the NHS and not just in academic centres. This will require clinical scientists (ie medical physicists), computer scientists, radiologists, radiographers, neurologists, and other clinicians and technologists, as well as equipment resource (ie imaging capacity and capability).

i) What is needed to help overcome these barriers?

A pathway definition for technology development, perhaps with different arms for diagnostic devices and therapeutic. A review of how often and why research project applications are passed between the research councils to assess if there are common themes that illustrate the gaps. An NIHR framework for evidence-based imaging and diagnostics would help identify the resources that are required and highlight the demand for dedicated funding streams for these projects – this is currently being discussed within the NIHR.

The NHS scientific workforce needs to be developed and trained appropriately to act as the conduit between academic (basic) scientists and clinicians, and healthcare professionals. Ultimately there will need to be an increase in numbers, to tackle the questions and issues in a quantitative and measurable way, to enable all aspects of the problem to be addressed and assessed (from mechanism, to diagnosis, to treatment and management).

This will also require collaboration with industry, ie imaging and pharma sectors, to ensure that new techniques are developed, optimised and validated using the appropriate patient cohorts and in the right clinical settings.

Industrial Strategy

What opportunities are there for industry in the development of new technologies to help increase health span? In which areas of medical research and technology development does the UK excel?

The UK has a strong academic medical imaging sector and this should be harnessed alongside clinical imaging expertise and commercial links to develop clinically applicable diagnostic and prognostic (multi-modality) imaging approaches, which can be tested in our well defined and accessible patient cohorts.

What more is required for the UK to benefit from commercialisation of its discoveries and inventions relating to healthy ageing, as envisioned by the Government’s Industrial Strategy?

Better links between the NHS and the commercial sector to ensure robust translation of imaging innovations, with appropriamte funding.

Interdisciplinary Ageing and Dementia Centre (IDEAC)

University of Southampton, UK

There are 850,000 cases of dementia in the UK and this number is rising in line with the increased life expectancy of the population. The most common form of dementia is Alzheimer’s disease and over 95% of cases are sporadic, not familial. Over the last 20 years, sophisticated genetic studies have highlighted some important genes that are associated with the increased risk of developing dementia. Apart from increasing age, the strongest risk factors for developing dementia are possession of Apolipoprotein E4 (APOE4) genotype. The APOE gene is responsible for transport of cholesterol and the APOE4 subtype is associated with an earlier and more severe form of dementia, as well as heart attacks. Large and carefully designed epidemiological studies have established the firm connection between cardiovascular risk factors such as smoking, obesity, diabetes with the risk of developing dementia. As the tools for laboratory investigations are improving (from microscopy at nanoscale resolution, to lab on a chip, genetic studies, milifluidics, transgenic animals), we are now able to determine that changes in the walls of the blood vessels and a failure of eliminating toxic waste from the ageing brain are responsible for the development of dementia. The University of Southampton has led the international research into how toxic waste is eliminated from the brain and why immunization against the proteins that accumulate in the brain leads to worsening of the condition. The National Institute of Health in USA has already set the research agenda and funding budget for the next 5 years to address the role of vascular factors in the prevention and new therapeutic strategies for dementia.

The Committee should also prioritise the areas that require investigation in the underlying vascular factors of dementia, while also promoting lifestyle measures that could prevent or delay the onset of dementia. There are many international studies funded by Alzheimer’s International Association in how diet and exercise are fundamental to the process of dementia but the UK has the advantage of addressing the epigenetic factors that are acting from gestation and lactation and predisposing newborn for dementia in later life. The Barker hypothesis “maternal origins of adult disease” originated in Southampton and there is already some firm experimental basic science evidence of changes that occur in the brains of pups born from mothers on a high fat diet. This could be expanded to epipdemiological studies- for example Southampton Women Survey.

6 January 2020