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Staff Profile

Dr Lauren Walker

Alzheimer's Research UK Fellow

  • Telephone: +44 (0) 191 208 1213
  • Address: Ageing Research Laboratories
    Edwardson Building
    Translational & Clinical Research Institute
    Newcastle University
    Campus for Ageing and Vitality
    Newcastle
    NE4 5PL
Background

My main research interests lie in investigating the effects of multiple pathological lesions on clinical phenotype in neurodegenerative disorders (e.g. Alzheimer's disease and Lewy body disease). Using a quantitative clinico-patholigical approach we aim to tease is distinct clinico-pathologcal phenotypes which may ultimately lead to tailored treatment options for patients.  


Neurodegenerative Pathology Research Group website:

https://research.ncl.ac.uk/ndprg/


Other roles

Editorial assistant Acta Neuropathologica

Alzheimer's Research UK ECR representative for the Northern network

Co-organisation and chair of Dementia and Neurodegenerative diseases (DemaNDs) seminar series


Qualifications:

PhD Neurodegenerative Pathology

MRes Medical and Molecular Bioscience 

BSc (Hons) Physiological Science 


Area of expertise

Neuroscience, Neuropathology of neurodegenerative diseases

Memberships:

British Neuropathological Society

Google scholar: Click here.

Research

Multi-morbidity in Lewy body diseases

Dementia with Lewy bodies (DLB) is neuropathologically defined by inclusions of α-synuclein (α-syn). However, concomitant Alzheimer’s disease (AD) pathologies, hyperphosphorylated tau (HP-T) and β amyloid, are observed frequently at post-mortem examination, with 50-70% of DLB cases found to have medium to high- level of AD neuropathologic change. Mixed pathologies are associated with an accelerated cognitive decline, which can make diagnosis challenging. An increased burden of all three pathologies in end- stage dementia suggests a potential synergistic interaction between these proteins and is supported by studies that demonstrate α-syn and HP-T are co-localised. Proteins can undergo numerous alterations, which can affect their structure and enhance toxicity, however little is known regarding which post-translational modifications (PTMs) of α-syn and tau are co-localised, and are associated with specific clinical symptoms. It seems paramount that we understand the interplay between these two pathological proteins, as presently there are no combination therapies to target both pathologies in clinical trials.

There are no specific clinical symptoms that can identify mixed pathology in individuals with DLB during life, as some patients present clinically with AD whilst others with DLB. I have observed that in cases that fulfill neuropathological criteria for both AD and DLB, individuals that present clinically with DLB have a lower mature tau load compared to those clinically diagnosed with AD, suggesting tau in these cases has been accumulating for a shorter period of time. Therefore, the timing of the onset of tau pathology in DLB can influence the clinical diagnosis which in individuals with DLB may prevent administration of appropriate disease modifying treatments when available.

I am investigating if a number of PTMs of α-syn and tau are frequently co-localised and are predictors of neuropathological spread and clinical disease progression in DLB by using human post-mortem brain tissue, and develop a novel model of mixed pathology to determine whether the temporal appearance of HP- T earlier in the disease course of a mouse model of α-synucleinopathy can alter clinical phenotype and other markers of neurodegeneration such as synaptic loss.

Pyroglutamylated amyloid-beta

Recent data has suggested a subspecies of Aβ, termed ‘pyroglutamylated Aβ’ (pAβ), may play a crucial role in pathology. pAβ is more abundant in AD and is cytotoxic in the presence of hyperphosphorylated tau (HP-T). pAβ expression also correlates with the presence of HP-T and clinical dementia.

To further investigate the role of pAβ in AD and LBD we are currently using brain tissue from the Newcastle Brain Tissue Resource to quantitatively assess pAβ, HP-T and α-syn, and will compare the results with clinical findings. Using immunohistochemical and biochemical techniques we aim to correlate pAβ with neurofibrillary tangle development, and assess its potential role in synaptic injury and inflammatory response. In addition, we will compare pAβ expression in cerebrospinal fluid (CSF) with parenchymal deposits in the brain. The results will clarify if pAβ plays a crucial role in the pathogenesis of both AD and LBD. If so, pAβ may represent a potential biomarker in CSF and imaging diagnostics, and therapeutic target.

High throughput tissue microarray

Tissue microarray (TMA) is a technique most commonly employed in tumour studies, involving the extraction and transfer of a large number of samples into a single block, allowing high throughput analysis. This technique has previously been adapted to investigate white matter disease in human brain tissue, highlighting its potential use in dementia research.  Our laboratory has developed a protocol to analyse 15 anatomically-distinct cortical and sub-cortical brain regions on one slide. Using an automated microscope and image analysis system we have accurately quantified a number of neuropathological lesions in human post-mortem brains from the Newcastle Brain Tissue Resource.  Current analysis of over 150 cases has demonstrated a large variation of pathology load in patients with severe neurodegenerative diseases, which has not been appreciated using internationally recognised semi-quantitative staging criteria.  This ongoing project will provide important information that can be used in clinico-pathological studies to assess the effect of single and multiple pathologies, on cognitive status.

TDP-43 in cerebral multi-morbidity

TDP-43 is the characteristic pathology of some types of motor neuron disease and frontal temporal dementia. However, recent studies have demonstrated TDP-43 is also found in Alzheimer's disease, where it follows a distinct topographic sequence of progression (Joseph et al, 2014; 2016). Using tissue from the Newcastle Brain Tissue Resource, we are currently investigating TDP-43 expression in other age-related neurodegenerative disorders.


Teaching

Undergraduate 

B940 BSc Biomedical Sciences Dissertation project supervisor

B940 BSc Biomedical Sciences - seminar leader, essay marking, practical skills lab, summer school workshop lecture

A100 Medicine and Surgery (MBBS) -  Lecture "Neuropathology of dementia and Movement Disorders". 

BMS3013 BSc Biomedical Sciences - Lecture "Neuropathology of dementia and Movement Disorders".

MPharm Pharmacy - Lecture "Pathophysiology and pharmacology of dementia".


Postgraduate

MRes Neuroscience Dissertation project supervisor

MRes Neuroscience Lecture - "Molecular Genetics of Parkinson's disease"

A101 Medicine and Surgery (MBBS), Accelerated Programme -  Lecture " Neuropathology of dementia and Movement Disorders"

Publications