Understanding the heterogeneity of pathology in dementia with Lewy bodies to aid the interpretation of biomarkers

The primary pathology of dementia with Lewy bodies (DLB) is alpha-synuclein, however multiple studies have demonstrated that Alzheimer’s disease (AD) related pathologies (tau and beta amyloid) play an important role in disease progression driving spread of pathology and accelerating cognitive decline. Clinically, it is difficult to diagnose patients with both AD and DLB pathologies and therefore finding biomarkers for assessing cognitive impairment in individuals with high levels of all 3 pathologies would be extremely beneficial. Tau biomarkers in plasma, particularly, are proven as an accurate biomarker for AD, providing a cost effective and minimally invasive alternative to cerebrospinal fluid and positron emission tomography biomarkers. Plasma tau levels in patients with a clinical diagnosis of probable DLB are higher than in healthy control cases, but lower than AD. There is though, considerable heterogeneity across the DLB spectrum, particularly regarding the burden of AD related neuropathology, and studies have confirmed that multiple pathologies can alter the typical pattern of clinical progression. Work from our lab and others has suggested that tau pathology is atypical, potentially sparing the hippocampus in Lewy body disease individuals. Tau exists in many conformational states and can be post translationally modified, and data on the topographical distribution of tau species in DLB cases with considerable AD related pathology is lacking. Data from this study will provide pathological groundwork to aid the assessment of candidate plasma biomarkers.

Question/hypothesis

We will investigate an extremely well neuropathologically and clinically characterised cohort of DLB cases and assess the burden and spread of different tau species and compare this to AD cases and healthy controls. We hypothesise the burden and spread of tau species will differ across DLB cases with differing tau burdens and between AD and DLB cases, which may need to be considered when assessing plasma biomarker data.

Methods

Using quantitative neuropathological and biochemical techniques we will fully characterise a DLB cohort to assess pathology burden and topographical distribution of tau species using our novel tissue microarray platform incorporating 15 distinct brain regions, and analyse how this relates to other markers of neurodegeneration including amyloid beta, alpha-synuclein, activated astrocytes and microglia, and clinical scores collected from patients during life.

Potential impact

To fully understand and accurately interpret biomarker data from patients with DLB we need to understand the underlying pathological burden and clinical correlates. Data from this study will also shed light on other markers of neurodegeneration that may be useful in parallel with plasma tau species to increase the accuracy of clinical diagnosis of DLB.

Supervisory team

Dr Lauren Walker holds an excellent track record for neuropathological studies of neurodegenerative diseases in particular assessing multiple pathologies in DLB. With the support of Professor Johannes Attems and Dr Chris Morris who both have extensive experience in the field of neurodegeneration and have supervised many PhD students, we have both the enthusiasm and experience necessary to deliver this successful PhD project. Come join us at Newcastle University, a world renowned centre for DLB research with a multidisciplinary team, and home of the NIHR Newcastle Biomedical Research Centre (BRC), where developing the next generation of researchers and giving the knowledge and skills to undertake high quality experimental medicine and translational research is a key priority.

How to Apply:

FURTHER DETAILS AND A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/ . Please read the information there before submitting your application. Applications not meeting these criteria may be rejected.

Applications should be made by emailing [Email Address Removed] with:

• a completed copy of the Application Form. A blank copy of the form can be found at: https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/
• a CV (including contact details of two academic referees).
• a covering letter. This should explain your particular interest in the projects selected, and include any additional information you feel is pertinent to your application
• copies of your degree transcripts and certificates
• a copy of your passport (photo page).
• your English language certificate (IELTS or TOEFL certificate, where applicable)

Informal enquiries may be made to the supervisors.