Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurological disease which causes a very rapid form of dementia. Most people with the disease die within 6 months of having their first symptoms. The brains of people with sCJD are full of an abnormally twisted form of a protein called prion protein. This abnormal prion protein forms large clumps which are found throughout the brain and stop it functioning normally. The diagnosis of sCJD is made in life by doctors examining the patient for the presence of neurological features of sCJD and the results of investigations such as EEG, MRI and the presence of a protein called 14-3-3 in the fluid surrounding the brain (cerebrospinal fluid-CSF). However each of these investigations may be positive in other diseases and a definite diagnosis of sCJD can only be made by examining the brain tissue either after death or by a brain biopsy. Recently a new test, called real-time quaking-induced-conversion (RT-QuIC), has been developed which can detect the presence the abnormal prion protein in CSF. Scientific studies have shown RT-QuIC can identify patients with sCJD more accurately than CSF 14-3-3. There is a lot of interest in establishing this test in many laboratories throughout Europe and the aim of this project is to make sure that all laboratories performing RT-QuIC do it in a similar way and get comparable results. This is important as it ensures that the diagnosis of sCJD throughout Europe is as consistent as possible.

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.

GBA1 mutation increases PD risk by 20-30x. The UK group has established the largest published cohort of GBA1 mutation carriers with 100 followed longitudinally and has developed a protocol for their clinical and biochemical phenotyping to identify the prodromal features of PD in this genetically stratified high risk group. This application will build on the existing strong links between the applicants to increase and integrate this UK cohort with existing cohorts of GBA1 mutation carriers in Italy and Canada. Harmonised international longitudinal evaluation of GBA1 carriers in the established clinic based cohorts to determine prodromal clinical features , cognition, anxiety, depression), biochemical phenotype and identify those at high risk for conversion to PD. Genetically stratified group of individuals suitable for future clinical trials of agents targeted for those with GBA1 mutations with PD or at risk of PD.