1. Tracking the East Midlands contribution to PD-PROBAND Nin Bajaj Clinical Director NPF International Centre of Excellence in PD, East Midlands Trent CLRN PD Research Champion

2. PRoBAND: history Parkinson’s UK placed call for major biomarker study Joint scientific and clinical consortia formed PRoBaND was the clinical consortium to 2 of 3 studies Discovery Award went to Oxford group (£5m) Parkinson’s UK sought reactivation of PRoBaND PRoBaND funded by Parkinson’s UK (£1.6m)

3. PRoBAND: history Parkinson’s UK placed call for major biomarker study Joint scientific and clinical consortia formed PRoBaND was the clinical consortium to 2 of 3 studies Discovery Award went to Oxford group (£5m) Parkinson’s UK sought reactivation of PRoBaND PRoBaND funded by Parkinson’s UK (£1.6m) Jan 2011  Apr 2012 Public launch

4. PRoBaND: overview Prospective clinical study of PD patients and relatives DNA collected, tested, and stored Serum collected and stored

5. PRoBaND: recruitment of PD cases Around 2200 cases (PD diagnosed within last 3 years or <50 years) Study visits 6-monthly for 3 years (recent onset) Only 0 and 6 months for young onset Blood sample for DNA tests and biomarker analysis Clinical scoring: motor, non-motor, olfactory

6. PRoBaND: sample size Patients Recent onset PDDiagnosis under 50 2000 240 Gene tests 100 + 1900 – 12 + 228 –

7. PRoBaND: sample size Patients Recent onset PDDiagnosis under 50 2000 240 Gene tests 100 + 1900 – 12 + 228 – 150 600 750 Siblings

8. PRoBaND: sample size Patients Recent onset PDDiagnosis under 50 2000 240 Gene tests 100 + 1900 – 12 + 228 – 150 600 18 72 750 90 Siblings

9. PRoBaND: recruitment of siblings Around 800 subjects (sibs of PD cases recruited to main study) Visit schedule: 0, 36 months Blood sample for DNA tests and biomarker analysis Health questionnaires and clinical examination

10. PRoBaND: the detail Clinician scoring *Past, social and family history UPDRS - clinician Cognitive – MoCA, fluency *Response to medication Diagnostic evolution Patient scoring UPDRS – patient *Smell – UPSIT Depression – HADS Sleep – ESS, RBD, PDSS Autonomic – SCOPA QoL – EQ5D, PDQ8 ICDs – QUIP NMS scoring Wearing-off *Once during study

11. Basic plan for Parkinson gene tests LRRK2 GBA Recent onset PD Diagnosis under 50 Parkin (PARK 2) PINK-1 (PARK 6)

12. Basic plan for Parkinson gene tests LRRK2 GBA Recent onset PD Diagnosis under 50 Parkin (PARK 2) PINK-1 (PARK 6)  Extend to new techniques eg. immunochip analysis

14. Proteomics in Parkinson’s Disease- review of current work Nin Bajaj Nottingham

15. Key Points Most published studies in PD are CSF not plasma based LP hard to justify in PD patients Diagnosis in most PD is clinical (PDBBC) DaTSCAN is available for clinically challenging patients although expensive, high sensitivity/specificity not possible in all centres (95%) and not known in pre-motor disease, not universally available, not possible for community screening, cannot track disease progression in trials

16. Key Points Current biomarkers are pg/ml but although sensitive, have poor specificity to distinguish IPD from normals Using panel arrays is still in its infancy A number of biomarker projects in PD have funding from MJF foundation

17. Plasma Alpha-Syn Plasma α­synuclein difficult as numerous sources including platelets, RBCs, skin cells, vascular cells serum levels unlikely to be useful widespread distribution of α­synuclein also has implications for CsF re traumatic tap one small study found that the SNCA gene, upregulated in the skin fibroblasts of patients with PD, but not in controls or AD Recent paper (Foulds et al FASEB 2011) found mean level of phospho-alpha-syn higher in PD than controls, although no difference in total alpha syn or oligo alph syn or oligophosphoalphasyn

18. Plasma profiling Plasma metabolomic profiling (liquid chromatography electrochemical array detection) identified several markers that were predictive of IPD, including low uric acid and high glutathione levels, in a sample of 25 controls and 66 patients

19. Ttau or Ptau CSF ttau and ptau increased in AD v DLB or controls Use of CSF Ab42:t or ptau reliably distinguishes AD from DB with 90% accuracy CSF Abeta42 lower in AD or DLB v PD or controls

20. PSP v IPD CSF p or t tau no different between PSP and PD extended (55 kDa) and truncated (33 kDa) tau forms, proteolytic by-products of tau requiring immunoprecipitation, more time­ consuming and operator­dependent than ELISA Trunc tau:extended tau substantially reduced in patients with PsP compared with normal age­matched controls.

21. PSP v IPD 85% accuracy distinguishing PsP from all other neurodegenerations sensitivity of 96% and specificity of 85.7% were reported for comparing PsP with iPD or DlB sensitivity of 90% and specificity 76.2% for PSP v CBD but single centre (Borroni, B. et al. Tau forms in CSF as a reliable biomarker for progressive supranuclear palsy. Neurology 71, 1796–1803 (2008).)

22. CBD In one study, CSF t­tau significantly higher in patients with CBD v PSP-RS and controls (sensitivity of 81.5% and specificity of 80%- when ‘moderately severe’ cases analyzed separately, sensitivity of 92.3% and specificity of 100%) Contradicted by a smaller study, in which CSF t­tau and p­tau similar levels in control, PSP and CBD

23. MRI Imaging in PD Challenges Current technologies Nottingham contribution Proposed trial

24. PaMIR: Parkinson MR Imaging Repository MRI biomarker research in Parkinson’s is an emerging field with limited and often controversial findings To overcome this we propose to build a large dedicated MRI imaging repository in early Parkinson’s to assess the diagnostic accuracy and predictive power of novel MRI biomarkers Candidate MRI markers were selected from meta- analyses of published evidence and our own pilot and proof of concept studies We plan to collect neuromelanin, iron, diffusion tensor and resting state functional MRI at 3T in 300 people with early Parkinson’s co-recruited from the Tracking Parkinson’s study

25. PaMIR: Parkinson MR Imaging Repository Control data will be included from 100 age matched healthy controls 150 people with and 50 without the condition will be rescanned after 18 months to assess progression. This will allow creation of unique virtual Parkinson’s Brain Bank, which will be the largest repository of advanced MRI linked to clinical, genetic and potentially proteomic phenotyping