Early assessment, diagnosis and treatment of Parkinson's Plus Related Syndromes (ExPRESS)

Progressive supranuclear palsy (PSP), Multiple System Atrophy (MSA) and Corticobasal syndrome (CBS) are rare brain disorders, which cause rapidly progressive disability. The last decade has seen rapid progress and recognition that PPS are not only tractable disorders in their own right, but also provide ideal conditions in which to evaluate therapeutic strategies which will potentially have a wide impact in the treatment of more common dementias and movement disorders.

Here, we plan to build on scientific and organisational opportunities in the UK, to improve early diagnosis and treatment for PPS. We will do so in partnership with the NHS and a network of collaborating clinicians, and charities supporting families affected by PPS including the Progressive Supranuclear Palsy Association (PSPA) and Multiple System Atrophy Trust (MSAT). We will engage with national research platforms for discovery science and translation, including the Dementia Research Institute (DRI), Dementia Platform UK (DPUK), and National Institute for Health Research - Clinical Research Network and Biomedical Research Centres (NIHR - CRN/BRC). In addition, a number of drug companies have indicated that they would like to collaborate in this initiative.

A major challenge for the development of PPS research has been to build the infrastructure required to enable national network activities and nationally-representative patient recruitment. UK charities helped to establish a skeleton network of UK sites (the PSPA and MSAT funded PROSPECT-M study), which has been successful in proof-of-concept for recruitment and coordination across specialist clinics. There is significant interest from both pharmaceutical industry and university researchers in developing new trials of disease modifying therapies. Early diagnosis will require new diagnostic markers (for example specialist blood tests, spinal fluid tests, and pathology-specific brain scans), likely developed with industry.

To maximise the impact of forthcoming trials, we need to meet the challenge of recruiting patients with early stage disease, improving diagnostic and prognostic accuracy and developing new trajectory models for individualised approaches. Within our proposed ExPRESS (Early assessment, diagnosis and treatment of Parkinson's Plus Related Syndromes) study we will link together clinicians and therapists who see patients with early stage disease and establish collaborative links with disease charities (PSP Association, MSA Trust). We will link together with professional bodies (Association of British Neurologists Movement Disorders Group, British Geriatric Society Movement Disorders Group), industry partners, and linked UK scientific research consortia such as the UK Dementia Research Institute (DRI), Dementia Platform UK (DPUK), UK Brain Bank Network (BBN) and Health Data Research UK (HDRUK) to maximise the scientific potential of the UK's activity in this area and to improve the potential to develop new treatments.

We will recruit patients who have been referred from primary care with suspected Parkinson's disease and develop a clinical algorithm which will enable early detection and recruitment of patients likely to have Parkinson's Plus Syndromes (PPS). This will improve clinical diagnostic pathways and early disease diagnosis. However, we envisage that emerging technologies such as protein based brain scans, advanced MRI scans, specialist spinal fluid and blood tests, and digital tests, for example delivered through smartphone apps, will rapidly accelerate our ability to identify patients with these rare movement disorders. Ultimately, we hope that these early stage patients will be recruited to clinical trials which slow down or stop the progression of these disabling conditions.

We have established the PROSPECT-M study, funded by UK charities. This has grown from an initial network of 7 sites to 29 sites in the UK, and we have recruited patients with established Parkinson's Plus syndromes (PPS). This network has been successful in that it has attracted external funding, facilitated the establishment of ~ 10 commercial therapeutic trials in PPS including antisense oligonucleotide and monoclonal therapies.

However a major barrier to development in this area has been delay to diagnosis of these rare diseases, with an average delay to diagnosis of over 3 years, which relates to lack of awareness of these rare conditions and clinical uncertainty in patients with early stage disease. In this study we plan to build a new clinical research network for these rare movement disorders.

We plan to initiate a unique study to enable the development of biomarker studies in patients with early disease and to enable the recruitment of these patients to clinical trials.

- We will review available information from existing longitudinal studies and publicly available datasets to define clinical data that will guide the development of a clinical strategy for the identification of patients with early PPS
- We will expand our network to increase the number investigators who assess primary care referrals of participants with suspected PPS
- We will develop a patient information sheet, consent form and data collection questionnaire for early PPS in conjunction with our expert panel, and patient/carer/charity review and input.
- We will develop a pilot platform for recruitment of early stage patients and recruit 500 incident parkinsonism cases
- Contingent on external funding we will store biomarkers and carry out face to face assessments in a subset of participants
- We will evaluate MRI and digital biomarker data which has been previously collected to enable future implementation of a multimodal approach to early diagnosis.