Lead Research Organisation: University of Edinburgh
Department Name: CJD Surveillance Unit-DCN


Here, we propose the establishment of a large European and global collaboration to include national
surveillance units from both within and outside the European Union. This collaboration will facilitate
cooperation between neurologists, epidemiologists and neuropathologists 1) to harmonize the
protocols involved in patient documentation, biomaterial sampling/ storage, biomarker testing/assay
analysis and data sharing; and 2) to standardise a more precise diagnosis in patients with RPD by
analysis of the biochemical markers in the cerebrospinal fluid and blood. We will work on
standardisation of tests that are currently available and harmonise their use between centers
worldwide. We will define standards for biochemically based diagnosis in most relevant rapid
progressive dementia such as CJD and rpAD. As an add-on value, we will define criteria for early
differential diagnosis between rapid progressive neurodegenerative or potentially reversible dementia.

Technical Summary

Rapidly progressive dementia (RPD), in contrast to the more common forms of dementia, is a subset that follows an accelerated course of cognitive, behavioural and motor decline over a period of less than 2 years. An important cause of RPD is sporadic Creutzfeldt-Jakob Disease (sCJD). The clinical diagnosis of sCJD is supported by detection of biomarkers in blood or CSF, including the indirect markers 14-3-3, AB-amyloid 1-40 AB-amyloid 1-42, and the direct marker PrPSc, abnormal disease specific prion protein. In the differential diagnosis of neurodegenerative disorders, elevated levels of 14-3-3 and/or tau support the diagnosis of sCJD with a sensitivity of 85-94% and specificity of 80%. The availability of a reliable assay for the sensitive detection of PrPSc in human body fluids would provide a much needed disease specific test during the patient lifetime. Assays based on initial amplification of PrPSc protein aggregates show great promise for achieving specific and sensitive premortem testing for CJD.
Studies on prion disease diagnosis have shown that rapidly progressive Alzheimers dementia (rpAD) as a major differential diagnosis. In addition, about one third of the referred cases actually suffer from a potentially treatable and reversible dementia caused by autoimmune, metabolic or (para)neoplastic conditions. Thus, achieving a correct diagnosis in RPD cases has important implications for distinguishing prion disease from other, potentially treatable diseases, preventing infectious material from being distributed via blood transfusions, surgery or organ donations and selecting homogeneous population for upcoming drug trials in AD and prion diseases.

Planned Impact

Our major motivation to study CSF biomarkers in RPD is to achieve an early correct diagnosis in this
important subgroups of patients. This goal has to be seen in light of data on the differential diagnostic
spectrum of RPD patients, which are usually referred for prion diagnostics at national registries and
reference laboratories. As only a small fraction of these patients (1-2%) is diagnosed with prion
disease, we target here a much larger population, namely patients with "non-classical" and rapidly
progressive dementia. Three major neurodegenerative diagnoses are made in these populations:
CJD, AD and DLB (17, 18, 19, 20). In patients with a prion disease/CJD, an early premortem
diagnosis is important to select patients for upcoming trials (for example like the multicenter trials on
doxycyclin in Germany, Italy and France or antibody based compounds in UK). Also, an early
molecular based diagnosis (= ealy clinical diagnosis of human strains, (21) will become important for
stratification of patient cohorts, as has been seen recently in Germany in patients treated with
doxycyclin, showing a clear codon 129 genotype, and thus molecular strain dependent treatment
response (unpublished data).
A substantial number of patients suffer from rapid progressive AD (rpAD), which represent various
atypical AD forms. Questions on disease heterogeneity in AD have been raised recently and a
definition of diagnostic standards for these atypical AD forms, which are characterized by rapid
disease progression, poor prognosis, distinct clinical and neuropsychological syndrome and possibly
specific genetic background, becomes important for clinical diagnosis as well as potential selection
and stratification of patients for therapeutic trials. Some biomarker pattern has been suggested to
define endophenotypes (22). Moreover, improved diagnosis in these patients will allow us to study the
effect of treatment and to understand risk factors for disease progression.


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Title CSF tau checklist 
Description Checklist to ensure harmonisation of methodology 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact Improvement in comparability between laboratories 
Title database 
Description Standardised database for data collection in relation to CSF analyses in early onset dementia 
Type Of Material Biological samples 
Provided To Others? No  
Impact Systematic analysis of outcome of CSF analyses 
Description DEMTEST 
Organisation University of Göttingen
Country Germany 
Sector Academic/University 
PI Contribution Attendance at launch meeting in June 2012
Collaborator Contribution Lecture on CSF markers (Dr Alison Green)
Impact None as yet. The project has just started
Start Year 2012
Description DEMTEST Ann Rowling 
Organisation Neurology DEMTEST Edinburgh
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of CSF samples for tau, phosphorylated tau and beta amyloid
Collaborator Contribution Supply of CSF samples form cases of early onset dementia
Impact Ongoing
Start Year 2012
Description DEMTEST Dundee 
Organisation Ninewells Hospital
Department Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Analysis of CSF samples for tau, phosphorylated tau and beta amyloid
Collaborator Contribution Supply of samples from cases of early onset dementia
Impact Ongoing
Start Year 2012
Description DEMTEST Glasgow 
Organisation Queen Elizabeth Hospital (Malaysia)
Country Malaysia 
Sector Hospitals 
PI Contribution We have analysed 12 CSF samples for tau protein, p-tau and AB42 from patients with young onset dementia.
Collaborator Contribution These partners have sent us CSF samples for analysis and provided clinical information regarding the differential diagnosis, severity and duration of illness. In addition they have given information regarding the usefulness of CSF biomarkers in the clinical process.
Impact Results of this collaboration were presented at the Dementia in Younger Adults: Science, Services & Supports meeting funded by Mental Heath NHS Services Fife held in Stirling on 30th October 2015
Start Year 2015
Description DEMTEST Kirkcaldy 
Organisation Victoria Hospital
Department Neurology Service
Country United Kingdom 
Sector Hospitals 
PI Contribution Analysis of CSF samples for tau. phosphorylated tau and beta amyloid
Collaborator Contribution Supply ios CSF samoples form patients with early onset dementia
Impact Ongoing
Start Year 2012
Organisation Royal Devon and Exeter NHS Foundation Trust
Country United Kingdom 
Sector Public 
PI Contribution We analysed 8 CSF samples for CSF tau protein, p-tau and AB42 from patients with young onset dementia
Collaborator Contribution The partners provided clinical information concerning the differential diagnosis, severity and duration of disease on the patients whose CSF samples we received. In addition the partner also provided information regarding how useful the CSF biomarkers had been in the clinical evaluation of patients with cognitive problems.
Impact The results of this collaboration were presented at the Dementia in Younger Adults: Science, Services & Supports meeting funded by the Mental Health NHS Services Fife at Stirling on 30th October 2015. This meeting was open to patients, carers, supportive staff as well as clinical and scientific professionals. In addition these results were discussed at the Scottish Young Onset Cognitive Disorders Network meeting held in Perth on the 30th January 2015
Start Year 2013
Description Presentation of scientific research to dementia carers, patients and supportive staff 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The results of research into the use of CSF biomarkers in the investigation of young patients with suspected dementia were presented to an audience of approximately 50 people which included patients, carers and other professional bodies. The results presented discussions regarding the difficulty in getting early accurate diagnosis for dementia in patients younger than 65 years old.
Year(s) Of Engagement Activity 2015