Tracking the East Midlands contribution to PD-PROBAND

Nin BajajClinical Director NPF International Centre of

Excellence in PD,East Midlands

Trent CLRN PD Research Champion

PRoBAND: historyParkinson’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)

PRoBAND: historyParkinson’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

PRoBaND: overview

• Prospective clinical study of PD patients and relatives

• DNA collected, tested, and stored

• Serum collected and stored

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 onsetBlood sample for DNA tests and biomarker analysisClinical scoring: motor, non-motor, olfactory

PRoBaND: sample size Patients

Recent onset PD Diagnosis under 50

2000 240

Gene tests 100 + 1900 – 12 + 228 –

PRoBaND: sample size Patients

Recent onset PD Diagnosis under 50

2000 240

Gene tests 100 + 1900 – 12 + 228 –

150 600

750  

Siblings

PRoBaND: sample size Patients

Recent onset PD Diagnosis under 50

2000 240

Gene tests 100 + 1900 – 12 + 228 –

150 600 18 72

750 90 

Siblings

PRoBaND: recruitment of siblings

Around 800 subjects (sibs of PD cases recruited to main study)

Visit schedule: 0, 36 monthsBlood sample for DNA tests and biomarker analysisHealth questionnaires and clinical examination

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

Basic plan for Parkinson gene tests

LRRK2GBA

Recent onset PD

Diagnosis under 50

Parkin (PARK 2)PINK-1 (PARK 6)

Basic plan for Parkinson gene tests

LRRK2GBA

Recent onset PD

Diagnosis under 50

Parkin (PARK 2)PINK-1 (PARK 6)

Extend to new techniques eg. immunochip analysis

Proteomics in Parkinson’s Disease- review of current

workNin Bajaj

Nottingham

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

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

Plasma Alpha-Syn

• Plasma α synuclein difficult as numerous sources including platelets, RBCs, skin cells, vascular cells

• serum levels unlikely to be useful

• widespread distribution of α synuclein 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

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

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

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 operator dependent than ELISA

• Trunc tau:extended tau substantially reduced in patients with PsP compared with normal age matched controls.

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).)

CBD

• In one study, CSF t tau 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 t tau and p tau similar levels in control, PSP and CBD

MRI Imaging in PD

• Challenges

• Current technologies

• Nottingham contribution

• Proposed trial

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

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