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
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: 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)
Jan 2011  Apr 2012 Public launch
Parkinson’s UK sought reactivation of
PRoBaND
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 onset
Blood sample for DNA tests and biomarker analysis
Clinical scoring: motor, non-motor, olfactory
PRoBaND: sample size
Patients
Recent onset PD
under 50
2000
Gene tests 100 + 1900 –
Diagnosis
240
12 + 228 –
PRoBaND: sample size
Patients
Recent onset PD
under 50
2000
Gene tests 100 + 1900 –
150
600
750
Siblings
Diagnosis
240
12 + 228 –
PRoBaND: sample size
Patients
Recent onset PD
under 50
2000
Gene tests 100 + 1900 –
150
600
750
Siblings
Diagnosis
240
12 + 228 –
18
72
90
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
PRoBaND: the detail
• Clinician scoring
• *Past, social and family
history
• UPDRS - clinician
• Cognitive – MoCA,
fluency
• *Response to
medication
• Diagnostic evolution
*Once during study
•
•
•
•
•
•
•
•
•
•
Patient scoring
UPDRS – patient
*Smell – UPSIT
Depression – HADS
Sleep – ESS, RBD, PDSS
Autonomic – SCOPA
QoL – EQ5D, PDQ8
ICDs – QUIP
NMS scoring
Wearing-off
Basic plan for Parkinson gene tests
LRRK2
GBA
Recent onset PD
Diagnosis under 50
Parkin (PARK 2)
PINK-1 (PARK 6)
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
Proteomics in Parkinson’s
Disease- review of current
work
Nin 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 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
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 operatordependent than
ELISA
• Trunc tau:extended tau substantially
reduced in patients with PsP compared
with normal agematched 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 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
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 metaanalyses 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