PRoBaND | Tracking Parkinson’s Investigator Meeting Thursday , 16 May 2019 Barnes Wallis Building, University of Manchester 12:00 Registration & lunch 13 :00 Welcome & overview Donald Grosset, Chief investigator 1 3:15 Summary of study data & queries Sofia Kanavou, University of Bristol 1 3:30 Heterogeneity in Parkinson's disease cognitive impairment Callum Smith , University of Glasgow 13:50 Update on genetics Huw Morris , University College London 1 4:15 Break 14: 30 A GWAS of pain in Parkinson’s disease Nigel Williams , Cardiff University 1 5 :00 The L-dopa response in Parkinson's disease Vanessa Pitz , University of Glasgow 1 5 : 2 0 Administration issues and updates Donald Grosset, Chief Investigator 1 5 : 4 0 Discussion , Q&A 1 6 :00 Meeting closes
Tracking Parkinson’s A Brief Summary of Study data Sofia Kanavou Medical Statistician Bristol Medical School: Population Health Sciences
Outline • Data collection • Form completion rates • Withdrawals & cases with change in diagnosis • Common errors / things to avoid • Queries • Resolution rates • Database lockdown • Timeline Bristol Medical School: Population Health Sciences
Data collection Form completion rates* %CRFs on %CRFs on Follow – up visits Database Database (inc. withdrawn) (exc. withdrawn) Baseline (V0/1) 100% 100% 6 months (V2) 93.75% 97.5% 12 months (V3) 90.9% 98.3% Locked-down visits; 18 months (V4) 86.45% 97.85% no further changes are expected up until V7 24 months (V5) 79.3% 95.2% 30 months (V6) 74.9% 93.8% 36 months (V7) 70.7% 92.6% 42 months (V8) 49.3% 80.65% Extended follow-up 54 months (V9) 41.25% 71.8% (ongoing) 72 months (V10) 7.1% 14.2% *Rates are calculated based on the Medication forms
Data collection Withdrawals • 50.1% of recruited patients have withdrawn from the study (06/05/19). • Out of 1002 withdrawn subjects: • 817 (81.5%) have all relevant information recorded on the Registration form. • 18.4% missing withdrawal date– all come from 10/68 Centres (14.7%). • 34 (3.4%) had a change in their initial diagnosis • Approximately 1/3 of withdrawals are due to patients decline of follow-up extension or Site’s difficulty to support it
Data collection Withdrawals Reasons (N= 1002) N (%) Change in diagnosis 34 (3.4%) Developed dementia 10 (1%) Patient died 124 (12.4%) Did not consent to study extension 111 (11.1%) Entered nursing/residential home 9 (0.9%) Intercurrent illness 75 (7.5%) Moved out of area 11 (1.1%) 968 cases (96.6%) Patient choice 177 (17.6%) Site closed 218 (21.75%) Too disabled to attend 11 (1.1%) Withdrew consent 32 (3.2%) Other 190 (18.95%)
Data collection Change in diagnosis “Other diagnosis” category includes: • MS • Corticobasal degeneration • Post polio syndrome • Spinal cord syndrome • SWEDD • SWEDD subdural haematoma • SWEDD and cerebrovascular tremor
Data collection Common errors / things to avoid • Some interesting cases initially recorded under “Other” reasons: • Patient finds study unacceptable • Patient not on Parkinson’s medication • Patient choice – not entering study extension (2 cases) • Unspecified diagnosis change • Misdiagnosed - patient does not have PD
Data collection Common errors / things to avoid • Cases initially recorded under “Other” reasons: • Patient finds study unacceptable • Withdrew after Baseline visit; would be good to have a few more details on memo (i.e. why patient found the study to be unacceptable?) • Patient not on Parkinson’s medication • This could trigger a re-evaluation of patient’s diagnosis, but should not be a reason to withdraw from study • Patient choice – not entering study extension (2 cases) • Subject I: Patient had already completed Visit 10 – conflicting information
Data collection Common errors / things to avoid • Cases initially recorded under “Other” reasons: • Patient choice – not entering study extension (2 cases) • Subject II: Patient had a new diagnosis recorded on the form; reason for withdrawal should have been “change in diagnosis” • Unspecified diagnosis change • Even with unspecified new diagnosis, this should have been recorded as “change in diagnosis” • Misdiagnosed - patient does not have PD • This should have been recorded as “change in diagnosis”
Queries Resolution rates • 3616 queries have been recorded so far - 90.4% have been resolved. • Majority of queries were with regards to Medication (34.9%), Diagnostic factors (9.3%), Registration (7.4%) and UPDRS Clinician form (7%). • So far 70% of all participating centres dealt with ≥90% of their queries.
Queries Bristol Medical School: Population Health Sciences
Queries Bristol Medical School: Population Health Sciences
Queries Last 2 years in the study • July 2017 - March 2019 → 592 queries entered on database • 66.6% were resolved • Out of 198 outstanding queries: • 35.9% refer to 18-month visit • 17.2% refer to 36-month visit • Queries focus mostly on: • Medications (46.6%); UPDRS Clinician (12.8%); MoCA (12.5%) Bristol Medical School: Population Health Sciences
Database lockdown Timeline Follow-up visit First visit* Last visit* Database Lockdown 18 months (V4) 03/05/2013 01/12/2016 12/01/2018 24 months (V5) 21/01/2014 14/02/2018 01/03/2019 30 months (V6) 06/06/2014 06/06/2018 01/03/2019 36 months (V7) 05/01/2015 12/09/2018 01/03/2019 *Taken from Medication form extracted in March 2019 Bristol Medical School: Population Health Sciences
Database lockdown Timeline Follow-up visit First visit* Last visit* Database Lockdown Done; datasets 18 months (V4) 10/01/2013 04/12/2016 12/01/2018 annually amended 24 months (V5) 26/03/2013 05/12/2017 01/03/2019 based on any updates recorded 30 months (V6) 10/01/2014 01/12/2017 01/03/2019 throughout the year 36 months (V7) 04/01/2015 04/12/2017 01/03/2019 42 months (V8) 22/09/2015 (ongoing) 01/09/2019 Estimated 54 months (V9) 29/06/2016 (ongoing) 01/03/2020 (likely to change) 72 months (V10) 17/01/2018 (ongoing) 01/03/2021 *Taken from Medication form extracted in March 2019 Bristol Medical School: Population Health Sciences
Summary • Based on Medications forms recorded on Database • ≥90% forms entered in 3 years of follow-up • similar rates expected for forms completed at the clinic ( UPDRS, MoCa) • Rates drop in follow-up extension • Around 1/3 did not participate after 3-year follow-up Bristol Medical School: Population Health Sciences
Summary • Withdrawals & changed diagnosis always recorded on relevant fields the Registration form • Queries are being handled more quickly • Few specific centres that are not very responsive • Lock-down of 3 year follow-up period • Data will be reviewed and amended annually • Current data version 1 Bristol Medical School: Population Health Sciences
Heterogeneity in Parkinson’s disease cognitive impairment Callum Smith 3 rd year Ph.D. student Dr. Donald Grosset Dr. Breda Cullen Prof. Jonathan Cavanagh Dr. Matthew Sheridan
Cognitive decline in PD • Parkinson’s disease (PD) is primarily a movement disorder. • However, non-motor symptoms are common. • Cognitive decline, including dementia, is especially common and debilitating. • In many respects, cognitive impairment is highly variable in PD.
Variation in cognitive decline in PD Genetic Clinical Neuropathological
Variation in cognitive decline in PD Genetic Clinical Neuropathological
Systematic review (1) Major protein pathologies: • Alpha-synuclein (Parkinson’s) • Amyloid-beta (Alzheimer’s; top image ) • Tau (Alzheimer’s; bottom image ) • TDP-43 (frontotemporal dementia, LATE) Vascular pathology (e.g. stroke). All of these pathologies are common autopsy findings in people with PD.
Systematic review (2) Objective : To describe the neuropathology of dementia in PD using a systematic review of autopsy studies. • Five databases were systematically searched for relevant articles. 1566 potentially eligible articles were found. • Of these, 44 reports met inclusion criteria. • These involved 2002 PD cases, 57.2% with dementia.
Systematic review (3) TDP-43 and cerebrovascular pathologies were not significantly more common in PD cases with dementia compared to those without. However… Aarsland, n=18 Aarsland, n=18 Ballard, n=28 Ballard, n=28 Braak, n=79 Braak, n=79 Compta, n=29 de Vos, n=12 Horvath, n=109 Horvath, n=109 Irwin, n=92 Irwin, n=92 ᵇJellinger 2002, n=66 ᵇJellinger 2008, n=32 ᵇJellinger 2008, n=32 ᵇJellinger 2002, n=66 Jendroska, n=23 Jendroska, n=23 Kalaitzakis, n=12 ᵃKempster, n=69 ᵃKotzbauer, n=32 ᵃKotzbauer, n=32 ᵃRuffmann, n=55 Sierra, n=10 Sierra, n=10 All studies, n=538 All studies, n=535 0% 20% 40% 60% 80% 100% 0% 20% 40% 60% 80% 100% Absent Mild Moderate Severe Absent Mild Moderate Severe Figure 2. Severity of tau pathology in PD Figure 1. Severity of amyloid-beta pathology in PD cases with dementia. cases with dementia.
Variation in cognitive decline in PD Genetic Clinical Neuropathological
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