Tracking the East Midlands contribution to PD-PROBAND

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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

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PRoBAND history

• Parkinsons 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)
• Parkinsons UK sought reactivation of PRoBaND
• PRoBaND funded by Parkinsons UK (1.6m)

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PRoBAND history

• Parkinsons 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)
• Parkinsons UK sought reactivation of PRoBaND
• PRoBaND funded by Parkinsons UK (1.6m)

Jan 2011 ? Apr 2012 Public launch
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PRoBaND overview

• Prospective clinical study of PD patients and
  relatives
• DNA collected, tested, and stored
• Serum collected and stored

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PRoBaND recruitment of PD cases

• Around 2200 cases
• (PD diagnosed within last 3 years or lt50 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
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PRoBaND sample size

•   Patients
• Recent onset PD Diagnosis under 50
• 2000 240

Gene tests 100 1900 12 228
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PRoBaND sample size

•   Patients
• Recent onset PD Diagnosis under 50
• 2000 240

Gene tests 100 1900 12 228
150 600
750  
Siblings
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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
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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
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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
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Basic plan for Parkinson gene tests
  Recent onset PD Diagnosis under 50

• LRRK2
• GBA

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

• LRRK2
• GBA

Parkin (PARK 2) PINK-1 (PARK 6)
? Extend to new techniques eg. immunochip analysis
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Proteomics in Parkinsons Disease- review of
current work

• Nin Bajaj
• Nottingham

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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

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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

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Plasma Alpha-Syn

• Plasma asynuclein difficult as numerous sources
  including platelets, RBCs, skin cells, vascular
  cells
• serum levels unlikely to be useful
• widespread distribution of asynuclein 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

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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

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Ttau or Ptau

• CSF ttau and ptau increased in AD v DLB or
  controls
• Use of CSF Ab42t or ptau reliably distinguishes
  AD from DB with 90 accuracy
• CSF Abeta42 lower in AD or DLB v PD or controls

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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 tauextended tau substantially reduced in
  patients with PsP compared with normal
  agematched controls.

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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,
  17961803 (2008).)

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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

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MRI Imaging in PD

• Challenges
• Current technologies
• Nottingham contribution
• Proposed trial

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PaMIR Parkinson MR Imaging Repository

• MRI biomarker research in Parkinsons 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
  Parkinsons 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 Parkinsons co-recruited
  from the Tracking Parkinsons study

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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
  Parkinsons Brain Bank, which will be the largest
  repository of advanced MRI linked to clinical,
  genetic and potentially proteomic phenotyping