Speakers
Melanie Hart
Tze How Mok
Ashvini Keshavan
Parallel session
Chair, Melanie Hart
Here in advances in diagnostic neurology session we will learn from three experts in the field of Prion, Parkinson's disease and dementia to give updates on diagnostic tests are being developed for in these conditions, including the ADAPT trial which uses the new blood dementia test phosphotau 217
Learning outcomes:
Prion diseases are transmissible and inevitably fatal neurodegenerative conditions characterized by recruitment of host-encoded cellular prion protein (PrP) into disease-associated polymeric assemblies which propagate by elongation and fission. Sporadic Creutzfeldt-Jakob disease (sCJD) is the commonest manifestation of human prion disease accounting for ~85% of cases. Inherited prion disease due to pathogenic mutations within the prion protein gene account for ~10-15%, while <1% are acquired due to dietary and medical exposures. Diagnosis of CJD has evolved significantly over the last 3 decades from the need for tissue diagnosis (brain biopsy or post-mortem examination), to highly accurate intra vitam diagnosis based on characteristic neuroimaging features and laboratory-based CSF assays. Here, we explore the protean clinical manifestations of CJD, and track the advances of neuroimaging (diffusion-weighted MRI) and laboratory techniques which have made CJD the easiest neurodegenerative disease to diagnose with high level of certainty in life.
Learning outcomes:
In this presentation I will focus on progress made in the ADAPT (Alzheimer's disease diagnosis and plasma p-tau217) study and some research developments regarding other blood biomarkers in this space.
Learning outcomes:
In the UK, approximately 150,000 people are living with Parkinson's disease (PD) and this is estimated to rise to around 175,000 people by 2030. Therefore, PD is a common and debilitating cause of morbidity and mortality in the UK.
In current clinical practice, the diagnosis of PD is made by a physician-led clinical examination as there are no objective tests that reliably diagnose the condition. However, achieving an early and accurate clinical diagnosis of PD is challenging because at that stage there is significant clinical overlap with Parkinson-plus disorders, including progressive supranuclear palsy (PSP) and multiple system atrophy (MSA), which also lack objective diagnostic tests. Being able to accurately diagnose Parkinsonian disorders at an early disease stage is important because it removes diagnostic uncertainty for patients. It also enables patients to be recruited to clinical trials at a stage in their disease when minimal irreversible damage has occurred, therefore representing a window of opportunity for effective drugs to stop or slow disease progression.
The primary neuropathology of PD and MSA is characterised by a build-up of pathological forms of alpha-synuclein protein (Lewy bodies) in brain cells which leads to progressive brain cell loss and associated symptoms of PD. Of note, secondary Lewy body co-pathology can be found in other neurodegenerative disorders. In contrast, brain cell loss in PSP is associated with a build-up of pathological 4-repeat tau (4RT) protein in brain cells, and this never occurs as a co-pathology in other neurodegenerative disorders.
Recently, an alpha-synuclein seed amplification assay (SAA) test has been developed. When applied to patient CSF samples, it reliably detects the presence of alpha-synuclein related PD pathology at the earliest stages of disease, and may even enable differentiation between PD- and MSA-type alpha-synuclein pathology. However, our own recent work has shown that the CSF alpha-synuclein SAA is also positive in a subset of PSP patient samples, likely due to alpha-synuclein co-pathology which may impact on disease trajectory.
Therefore, using alpha-synuclein SAA in isolation as a diagnostic biomarker cannot reliably differentiate between PD and PSP. Therefore, we have developed a 4-repeat tau SAA to use in combination with alpha-synuclein SAA for accurate diagnostic differentiation between PD, MSA and PSP. We have also shown that quantitative kinetic measures from the alpha-synuclein SAA at baseline are able to predict longitudinal clinical decline in PD, therefore highlighting its prognostic value. Finally, we envisage that SAA will have a role to play in upcoming PD and PSP clinical trials as a trial entry criterion, maker for target engagement, and surrogate marker for treatment response.
Learning outcomes:
Melanie Hart is a Consultant clinical scientist and Laboratory director of the Neuroimmunology and CSF Laboratory, based adjacent to the National Hospital for Neurology and Neurosurgery, at Queen Square (UCLH), with more than a decade of post doctorate experience in this field, having undertaken Grade A and B clinical scientist training in large NHS hospitals.
She holds fellowship of the Royal College of Pathologists, is a member of the NEQAS steering committee for Neuroimmunology and a member of the steering committee for the ADAPT trial.
She is supported by the UCLH Biomedical Research centre and holds an honorary contract with UCL and has a growing publication history in the field.
In addition to directing the laboratory service, she oversees the translation of novel neurological biomarkers into tests suitable for clinical use.
Tze How Mok is a Senior clinical research fellow at the MRC Prion Unit at UCL, a Honorary consultant neurologist at the UK NHS National Prion Clinic (NPC) at Queen Square, and a Consultant neurologist at East Surrey Hospital in the UK.
He has spent almost 10 years providing specialist clinical care at the NPC and researching various aspects of prion disease at the MRC Prion Unit.
His interests and expertise include assembling a CSF and blood biofluid archive particularly from asymptomatic at-risk individuals, and developing biomarkers capable of predicting proximity of clinical conversion, with special emphasis on prion seed amplification assays.
Ashvini Keshavan is a Senior clinical research fellow and Honorary consultant neurologist at the Dementia Research Centre UCL Queen Square Institute of Neurology.
A MBBChir graduate of Trinity College, Cambridge, she completed postgraduate medical and neurological training in London, and obtained her PhD in 2019 from University College London on Cerebrospinal fluid and blood biomarkers of Alzheimer’s disease.
Her ongoing work examines these biomarkers in clinical and pre-clinical cohorts, aiming toward application in more real-world settings, serving diverse populations.
She is the joint primary investigator for the UK-wide ADAPT (Alzheimer’s disease Diagnosis and Plasma p-Tau217) study, and the communications chair for the ISTAART Biofluid Biomarkers Professional Interest Area, and co-chair of its real World Translation work group.
Edwin Jabbari is a research group leader at the UCL Queen Square Institute of Neurology and Consultant Neurologist in the Movement Disorders Department at the National Hospital for Neurology and Neurosurgery.
His research is centred on the integration of fluid biomarker and genetic approaches to enhance the diagnostic accuracy of Parkinsonian disorders, refine clinical trial design, and discover novel treatment targets.
He has recently been awarded an MRC Clinician Scientist Fellowship which has enabled him to establish his research group at UCL to focus on the development of alpha-synuclein and tau seed amplification assays.