Older People & Complex Health Needs 2021

A list of ACF 2021 projects within the speciality of Neurology.

Project Lead: Dr Victoria Haunton vjh12@le.ac.uk

Project 1) Cerebral haemodynamics in ageing, mood, and cognitive disorders:

We have a strong track record in studies investigating the physiological changes to cerebral haemodynamics associated with ageing and age-related disorders (dementia, Parkinson’s disease, stroke). This project would seek to continue this work by exploring alterations in neurovascular coupling and dynamic cerebral autoregulation in chronic (i.e. mild cognitive impairment, Alzheimer’s disease, vascular dementia), and acute (i.e. delirium) cognitive disorders, and mood disorders in older people. Acute cognitive disorders such as delirium, significantly increase the risk of future dementia. This project would focus on identifying predictive physiological (haemodynamic) markers of future dementia in people with acute delirium. This will help further our understanding of the pathological mechanisms of conversion from acute to chronic cognitive disorders, but also highlight possible new therapeutic approaches to dementia risk reduction.

Disturbances of cerebral haemodynamics in depression have been demonstrated, but are poorly understood and research in this field has been limited. Furthermore, depression and cognitive function are closely linked, and depression can potentiate and exacerbate cognitive decline. This project will investigate the relationship between altered cerebral haemodynamics, mood disorders, and cognitive function. This will further our understanding of the complex interplay between these factors.

This post will provide an excellent grounding in translational research, and the opportunity to scale, via funded fellowship programmes, to projects investigating novel disease mechanisms, biomarkers, and potential therapeutic approaches through clinical trials.

Project 2) Cerebral Haemodynamics in Transient Ischaemic Attack: (Haunton, Robinson, Panerai, Minhas)

Transient Ischaemic Attack (TIA) affects 46,000 new patients each year in the UK, and is strongly predictive of future stroke.  Age is a strong risk factor.  Cerebral autoregulation (CA), which is the ability of the brain to maintain a relatively constant cerebral blood flow (CBF) in response to significant changes in perfusion pressure, is known to be altered in acute stroke (and is an important prognostic factor), but this is less well established in patients with TIA.  Our group has long standing research strengths in the use of Transcranial Doppler (TCD) ultrasound to study cerebral autoregulation and now plan to use this expertise to study TIA patients in a similar case-control study.  Participant recruitment will be from the specialist TIA clinic at University Hospitals of Leicester NHS Trust.

Project 3) Haemodynamic Mechanisms in Post-Stroke Cognitive Impairment (Haunton, Robinson, Panerai, Beishon)

30% of patients with stroke or TIA will be left with long term cognitive impairment.  Recent data from the Oxford Vascular Study suggests that TIA alone can bring forward the prevalence of dementia by two years, rising to 25 years with increasing stroke severity.  Impaired cognitive function is a key priority and un-met need for patients post-stroke, with patients experiencing loss of work and productivity, and poorer quality of life.  In a systematic review and meta-analysis we found clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at early stages of cognitive decline. Further work using Transcranial Doppler ultrasound is planned to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.  We hypothesise that we may be able to use cerebral haemodynamic data to identify those patients at risk of post-stroke cognitive impairment, and to trial novel therapeutic strategies.

Project Lead: Dr Mervyn Thomas, mt350@le.ac.uk

Two project areas are available within this ACF:

Project 1: Multi-modal imaging to predict risk and clinical sequelae in stroke

Studying the neurosensory retina and retinal vasculature offers a unique opportunity to non-invasively visualise and quantify vascular and central nervous system health. Changes in retinal microvasculature have been identified as independent predictors for hypertension, diabetes, coronary disease, renal disease, and stroke. Moreover, retinal microvascular changes can precede clinical manifestation of end organ damage (for example a cerebrovascular accident). Therefore, this has predictive value and potential window for aggressive risk reduction, thus reducing associated morbidity. Previous approaches have used qualitative descriptors (such as silver wiring, presence of A-V nipping) to assess retinal vascular changes. Differences in retinal vasculature have been described in different types of stroke, for example retinal venules are wider and arteriovenous ratios are smaller in patients with lacunar stroke compared with those in patients with cortical strokes. With deep learning approaches it is now possible to combine both qualitative descriptors (using qualitative coding) with retinal vascular morphometric parameters (from fundus photos) to develop novel risk prediction systems or surrogate biomarkers. This will be achieved in two phases, giving unique training opportunities for the ACF:


1)     Training dataset (retrospective): We will utilise UKBIOBANK data and our local dataset annotated with previously published and validated stroke prediction scores. This will form the basis of our training dataset for a novel convolutional neural network (CNN). In this phase of the project the ACF will be supervised by the Professor Yu-Dong Zhang and his team providing training on computational approaches to deal with large datasets, ground truth annotation and building CNNs.


2)     Prospective testing: The ACF will subsequently work closely with the clinical teams performing an exploratory pilot study by recruiting and testing the new CNN on patients (independent dataset) from both rapid access TIA clinics, ophthalmology clinics and the hyperacute stroke unit (with range of stroke subtypes and severities). Thus overall, it will include a mixed cohort of patients with confirmed stroke and stroke mimics in addition to healthy individuals.


Project 2: Biomarkers of haemorrhagic stroke using high resolution enhanced depth imaging (EDI) of the optic nerve

Identification of stroke subtypes is important due to treatment and prognostic implications. Previous work using ultrasound has shown that the diameter of optic nerve sheath has moderate accuracy in differentiation of haemorrhagic and ischemic stroke. With the advent of optical coherence tomography (OCT) we are now able to obtain ultra-high resolution (<3µm) images of the retina and optic nerve. Moreover, the OCT scans are non-invasive and can be obtained in <5 seconds. Most OCT devices are table mounted thus making it inaccessible to bed bound and acutely unwell patients. In Leicester, we have developed fast acquisition and analysis protocols using a handheld OCT device. These have been developed for paediatric imaging; however, we anticipate it can have more widespread use. Recently, using our handheld OCT device we have developed methods to acquire enhanced depth imaging (EDI) thus improving measurements of optic nerve parameters in adults. In this pilot feasibility and diagnostic accuracy study the trainee will investigate the role of handheld OCT in differentiating haemorrhagic and ischaemic stroke. The trainee will also explore various optic nerve parameters including Bruch’s membrane complex orientation, optic nerve sheath diameter and optic nerve head morphology to monitor changes in intracranial pressure in haemorrhagic stroke.  Performing serial OCT-EDI scans to monitor optic nerve changes in relation to treatments could potentially provide a non-invasive objective measure of therapeutic response in haemorrhagic stroke.

Both projects will provide a strong foundation for a subsequent doctoral research fellowship application.

Dr Qadeer Arshad, Lecturer qa15@leicester.ac.uk

Professor Kevin Paterson, Professor of Experimental Psychology

Ms Sarah Gunn,

Dr Mark Lawden, Consultant Neurophysiologist/Honorary Senior Lecturer mark.lawden@uhl-tr.nhs.uk

Professor Elizabeta B. Mukaetova-Ladinska, Professor of Old Age Psychiatry eml12@le.ac.uk

Project 1 “The microvascular-brain interface in patients with small vessel disease- a beat by beat EEG study”

The number of people living longer than 65 years is rapidly increasing. As we age the risk of falling increases, directly impacting upon the elderly with respect to QoL (N.B. falls the elderly are a major cause of injury, disability and death) whilst simultaneously posing a considerable socio-economic burden upon already stretched healthcare resources. With increased life expectancy, the prevalence of neurodegenerative disorders such as dementia is also increasing (Vieira et al., 2016). It is well documented that people with dementia fall more often when compared to cognitively healthy older adults, but the risk factors associated with this increased risk remain to be elucidated. Identifying the factors that places patients with dementia at increased risk of falling forms the basis of the project (Fernando et al., 2017).


Two neurological functions consistently deteriorate with age:  cognition and balance.  Small vessel white matter disease (“SVD” or brain microangiopathy of the elderly) critically contributes to both these declines (Inzitari et al 2007).  We are currently investigating the contribution of SVD to the earliest possible balance symptom - postural imbalance (as reviewed in Kaski et al 2019).  However, two essentially related albeit un-addressed questions remain: (i) how does SVD disrupt brain activity and, (ii) can this disruption of brain activity be used for pre-clinical detection of dementia due to impaired balance and cognition?


With static MR images, there is considerable clinical-radiological dissociation in SVD and we postulate that variability in the microvascular-brain interaction is responsible for this dissociation.  In order to address this question, the academic trainee will investigate the blood pressure wave-central nervous system interface (BP-CNS Interface) in young participants, elderly controls and in patients with SVD.  We will be largely using EEG techniques we have recently piloted, including the simultaneous recording of beat-by-beat BP, ECG and EEG


The QRS or BP peak will be used to trigger beat-by-beat 4-D EEG spectrograms, sequentially and in averages, on a tilt table.  The results of these “vasculo-encephalic-coupling” experiments will be correlated with online measures (force platform) and cognitive measures (including assessment of executive function via the Posner task and anti-saccades).  We anticipate that the results of this project will allow us to understand how neurodegeneration (here modelled by SVD) disrupts brain function and why apparently identical scans can have different clinical impact on patients. Further, if successful, the results will yield potential early biomarkers of dementia, which the fellow can then utilise in obtaining further funding for a fellowship application.

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