Mental Health, Dementia and Neurodegeneration

Imaging techniques can enable the delineation and diagnosis of common conditions, scrutinise the pathophysiological processes underlying clinical presentations and identify biomarkers of disorders, treatment response and outcomes. The MHDN theme has strong links with the Centre of In Vivo Imaging and its state-of-the-art facilities, which include clinical and preclinical MRI platforms and PET-MR systems. Combined with clinical, neuropsychological, neurophysiological and neuropathological expertise, our work has led to high impact research of direct clinical relevance. 

The investigation of key imaging biomarkers, dopaminergic imaging using SPECT FPCIT and myocardial scintigraphy using MIBG, in people with cognitive decline at both the prodromal and dementia stages, comparing them with healthy older control subjects. 

The optimisation of a novel multinuclear MRI technique (⁷Li-MRI) capable of directly and non-invasively determining the distribution of brain lithium in vivo in a clinically acceptable scan time. We have demonstrated a relationship between lithium distribution and its effects on white matter. Co-localising the concentration of a drug and its tissue level actions. Combined with advanced neuropsychological analysis techniques such as intraindividual variability in attentional performance, we are exploring the impact of white matter disruption on phenotypic expression and treatment response in bipolar disorder. 

The development neurophysiological biomarkers to assist with diagnosis, prognostic, and response prediction in neurodegenerative diseases as well as providing mechanistic insight into the pathophysiology of these conditions. Examples include the use of electroencephalography spatio-temporal motifs to differentiate dementia with Lewy bodies from Alzheimer’s disease both at the dementia stage and prodromal stage and as markers of treatment response. Non-invasive brain stimulation, in conjunction with other investigative modalities has also been used to examine cortical (dys)function and perturbate cognitive processes to help understand underlying mechanisms. 

The Clinical Aging Research Unit (CARU) run by Newcastle University and Newcastle upon Tyne Hospitals NHS Foundation Trust is a site for the new Parkinson’s Progression Marker Initiative 2.0 (PPMI2.0). A landmark longitudinal clinical study that aims to identify biomarkers of Parkinson’s progression to facilitate the development of new and better treatments for this condition.

People

Our theme is heavily involved in clinical trials in all the disease areas we cover: neurodegeneration, dementia and mood disorders. In the Clinical Ageing Research Unit (CARU), we conduct cutting-edge academic research to understand the causes and the mechanisms of Parkinson’s disease (PD) and other uncurable diseases such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP). We collaborate with national and international companies to assess efficacy and safety of medications and non-pharmacological treatments, e.g. non-invasive vagus nerve stimulation for these conditions. We offer our patients the possibility to be involved in first-class research and to access new medications in the early clinical phases of their development.

Newcastle University, working with the Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle Hospitals NHS Foundation Trust have an extensive track record in undertaking pivotal trials in dementia, depression and bipolar disorder. These include studies investigating:

• re-purposing of existing medication
• novel pharmacological agents
• neurostimulatory treatments e.g. electroconvulsive therapy (ECT)
• transcranial magnetic stimulation (TMS)
• vagus nerve stimulation (VNS)
• determining clinical effectiveness of existing medications

We have experience of undertaking such studies in adolescents, adults and older people. Our studies use a range of outcome measures beyond simple symptom rating scales, including neuropsychological, neuroimaging and neurophysiological approaches. We are members of the National Institute for Health Research (NIHR) Translational Research Collaboration in Mental Health and NIHR Translational Research Collaboration in Dementia. Many of our studies are run in collaboration with other members from the UK, and international investigators.  Studies are largely funded by the NIHR Health Technology Appraisal (HTA) panel, or the NIHR/Medical Research Council (MRC) Efficacy and Mechanism Evaluation (EME) panel. We also run commercially funded studies in mood disorders and dementia that are on the NIHR Portfolio.

Newcastle hosts one of the three National Centres of Excellence in Dementia Care Research, as well as a NIHR Global Health Research Group on Dementia Care. 

People

Key to MHDN Theme research is the availability of specific patient cohorts and tissue resources. The Brains for Dementia Research (BDR) network is jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society. It was established in 2008, with Newcastle becoming the national Coordinating Centre in 2018. Collaborators are located in Manchester, Bristol, Cardiff, Oxford and London. The network has two major components. Firstly, an established clinical cohort of both healthy controls and people with dementia who have consented to brain tissue donation. This group have in principle agreed to participate in clinical studies to enhance the value of the brain tissue through deeper phenotyping. At the close of recruitment in 2016, 3,138 participants had joined the programme from throughout England and Wales. At the end of 2020 14,000 research assessments had been completed and the data is stored and available on request on the data portal Dementias Platform UK.

Secondly, BDR has a growing collection human brain tissue from individuals who have been deeply phenotyped through repeated clinical assessments. At the end of 2020 a total of 928 participants had donated their brains.  All BDR participants have full genotyping and we are now utilising donated brain cells to obtain patient specific, induced Pluripotent Stem Cells (iPSC) to be used in the future for the screening of new therapeutics.  Over 30,000 tissue samples have been distributed to dementia centres and over 500 peer-reviewed publications have resulted and this unique collection of resources. 

SUPERB Study

The SUPERB study is a longitudinal cohort study funded by Alzheimer’s Research UK which recruited 104 patients with Mild Cognitive Impairment (MCI) and 34 healthy comparison subjects. It investigates the diagnostic performance of Myocardial 123I-MIBG imaging as a biomarker to distinguish MCI with Lewy bodies from MCI due to Alzheimer’s disease.

SUPERB has assessed dopaminergic imaging of the nigrostriatal pathway using the established DLB biomarker FP-CIT SPECT. As well as the diagnostic performance of DLB clinical core diagnostic features: 

• cognitive fluctuations
• complex visual hallucinations
• parkinsonism
• REM sleep behaviour disorder

Patients and controls are now being reviewed every year. Other research assessments in SUPERB include:

• MRI
• EEG
• CSF
• blood
• neuropsychological measures and a range of additional clinical assessments  

Parkinson’s disease

Parkinson’s disease is progressive neurodegenerative condition with no cure. Dementia develops in up 80% of people with Parkinson’s disease. At the present time, it is difficult to know who will develop dementia in Parkinson’s, or when and why they do this. Within our theme, researchers lead key longitudinal studies in this area including the: 

• ICICLE-PD Study: Professor David Burn, Drs Alison Yarnall and Rachael Lawson
• ICICLE-Gait: Professor Lynn Rochester
• PPMI 2 Study: Professor Nicola Pavese

Participants perform a range of tests including motor assessments, cognitive tests, questionnaires, gait assessment blood tests and neuroimaging. 

People

Our research aims to provide a better understanding of the different cerebral pathologies underlying age-associated neurodegeneration. This will aid more accurate patient diagnosis during life, as well as the identification of novel targets for treatment.

Typically, the main forms of neurodegenerative diseases are characterised by the deposition of distinct protein aggregates:

• amyloid-beta and tau in Alzheimer's disease
• alpha-synuclein in Lewy body disease

However, multiple pathologies are frequently found in the brains of aged individuals. We use advanced neuropathological methods, such as automated quantification of pathological protein loads, to disentangle cerebral multimorbidity.  We also utilise advanced imaging, such as confocal fluorescent microscopy and imaging mass cytometry, to better elucidate cellular pathological changes. 

To provide a more mechanistic insight our neuropathological approach is complemented by other methods, e.g. biochemistry. We have strong collaborations with international leading basic science researchers as well as clinicians.

By taking a multi-disciplinary approach we hope to translate fundamental scientific knowledge into medical practice. Stratifying patient cohorts for future clinical trials, and ultimately identifying novel targets for diagnostics and therapeutic intervention.

We are active in the continuous development and update of neuropathological criteria for the diagnosis of neurodegenerative diseases, such as the recently published Lewy Pathology Consensus criteria. 

Other methods include: 

• biochemical and molecular biology methods for assessing and characterizing protein aggregation 
• microscopy- and nanoscopy-based techniques, using antibodies and nanobodies, to determine the distribution and molecular architecture of protein inclusions
• proteomic approaches for assessing posttranslational modifications in brain-derived proteins associated with neurodegeneration 

People 

Mobility loss is a key feature of dementia and neurodegenerative disease. Its impact is highly significant to the individual, e.g. loss of independence, quality of life, and society. Mobility loss therefore is both a target for intervention to aid independence and provides a read out , biomarker, of the health of the brain and body. 

The Brain and Movement (BAM) Research Group focuses on gait, the way someone walks, as the key feature of mobility. By understanding mobility loss, we have developed novel insights to connect brain and behaviour in health and disease. Our work has led to seminal insights into the role of gait: 

• as a biomarker in neurodegenerative disease to aid early and prodromal detection, e.g. in Parkinson’s disease (PD)
• to enhance disease classification in PD and dementia subtypes
• as a predictor of adverse clinical events, e.g. cognitive decline and falls risk 

The link between behavioural biomarkers and brain function is established though insights into neural networks and biological disease markers, e.g. CSF. Highlighting a role for different neurochemical pathological processes for more targeted intervention.

State of the art facilities underpin this work. The Human Movement Laboratory in the Clinical Ageing Research Unit (CARU) has facilities comprising: 

• a three-dimensional motion capture system
• an instrumented walkway
• cutting-edge wearable technology, e.g. Inertial Measurement Units 

A focus on digital healthcare has led to a translational programme of work. This has been funded through diverse streams including leadership of major public-private international consortia. It allows us to measure gait and mobility in the clinical and real-world, habitual, “at-home” conditions. Enabling us to translate knowledge of mobility loss into healthcare using digital technology and connected health – to modernise clinical care and research. 

People

Dementia with Lewy bodies (DLB) is a major cause of cognitive impairment in older persons and shows similarities to both Alzheimer’s disease and Parkinson’s. Individuals experience a wide range of differing symptoms including memory decline, depression, anxiety and hallucinations. Why these symptoms occur and the brain areas that lead to them is unknown. It is likely that the underlying cause is specific biochemical and pathological changes due to the presence of aggregated α-synuclein protein in key nerve cells. Our research seeks to identify those specific regions of the brain that are involved with particular symptoms. By identifying these regions, we would then hope to investigate potential targets for treatment. 

Novel treatments for DLB are needed and it is widely accepted that these will be more successful if started earlier in the course of the disease. A major research theme is the detection of specific biomarkers that allow earlier and simplified detection of DLB. These biomarkers allow accurate identification of DLB at earlier, potentially prodromal and preclinical stages of disease, where novel therapeutics could be beneficial. 

We use tissue samples obtained during life or at post mortem to identify changes in biochemistry that are specific to DLB. These patient cohorts are clinically well characterised. We use RNA sequencing approaches to identify unbiased changes in function coupled with quantitative RNA and protein methods. High resolution microscopy (STED) is used to complement the biochemical and neurochemical approaches for target and biomarker identification. Functional studies complement these investigations. We have access to an extensive bank of well characterised patient cell lines including induced pluripotent stem cells. 

People

• Lina Gliaudelyté 

Our research aims to understand the brain mechanisms underlying mental health and well-being to develop and assess new preventive and therapeutic interventions. We use a combination of behavioural, electrophysiological and neuroimaging approaches in human participants and animal models.

Past and current projects include: 

• investigating the effect of moods on brain structure and function using neuroimaging in a non-human primate model
• identifying brain networks modified by early life adversity in humans
• exploring cortical interneuron function and mitochondrial deficits in mouse transgenic models of dementia 

People 

MHDN theme members led the publication of updated global consensus criteria for the diagnosis and management of DLB (McKeith et al, 2017) which were incorporated into DSM5. The 2017 consensus criteria were also cited in the most recent NICE dementia guideline (NG 57, section 1.2.12, published June 2018). Including specific recommendations about the use of 123I FP CIT SPECT and 123I MIBG cardiac scintigraphy in cases of diagnostic uncertainty (NG 57, sections 1.2.20 - 1.2.22 ). Guidance is also given about pharmacological management based upon primary research data collected in Newcastle. This includes the use of cholinesterase inhibitors (NG 57, sections 1.5.10 - 1.5.14) and the judicious use of antipsychotics (NG 57, sections 1.7.3, 1.7.4 & 1.7.14).  

In 2020 the first set of research diagnostic criteria for prodromal DLB were published (McKeith et al, 2020). As a final stage in the diagnostic consensus process updated pathological staging criteria for LB disease have also recently been published (Attems et al 2021).  Theme member, Louise Robinson was the primary care lead for the NICE dementia care guidelines (Pink et al. 2018). Clinical academics have developed robust diagnostic assessment toolkits and a comprehensive management guideline for Lewy body dementia as part of the NIHR Diamond Lewy programme. As well as UK based professional guidelines for managing driving with dementia/mild cognitive impairment.

Theme members working in mood disorders have led, or been involved in, numerous national and international guidelines and consensus statements. Providing expert input into NICE Clinical Guidelines and Health Technology Appraisals, and UK Department of Health guidance regarding various medications. Theme members have been heavily involved in the production of influential British Association for Psychopharmacology (BAP) guidelines. Including those on the management of depression (Clear et al. 2015), bipolar disorder (Goodwin et al. 2016) and use of medication in the perinatal period (McAllister-Williams et al. 2017). They have led on a UK consensus defining Multi-Therapy Resistant Major Depressive Disorder (MTR-MDD) and its management (McAllister-Williams et al. 2018). Collaborated on the related consensus for Multi-Therapy Resistant Bipolar Disorder (Hidalgo-Mazzei et al. 2019).  Our Clinical Academics work in an internationally recognised highly specialised clinic for patients with difficult to treat mood disorders. They have produced the world’s first guidance on selection of patients for implanted vagus nerve stimulation (McAllister-Williams et al. 2020). They have led an International consensus reconceptualising “treatment resistant depression” as “difficult to treat depression”. Providing a model of care for patients with such difficulties (McAllister-Williams et al. 2020). 

INCLUDE is a national project commissioned by the National Institute for Health Research (NIHR) led through Newcastle University. It aims to improve the inclusion of under-served groups in clinical research. The project provides a suggested framework of questions to guide the deliberations of funders, researchers and delivery teams as they design and assess clinical research proposals. It gives examples of good practice and resources to guide teams seeking to engage with and include under-served groups in clinical research. 

People

We have strong links with several other Faculty research themes:

Our theme works with a number of organisations:

• Newcastle Health Innovation Partners 
• Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust
• Newcastle upon Tyne Hospitals NHS Foundation Trust
• NIHR Clinical Research Network North East and North Cumbria 
• Northern Centre for Mood Disorders 
• National Innovation Centre for Ageing 
• Dementia Innovation hub 
• NIHR Newcastle Biomedical Research Centre
• Centre for In Vivo Imaging