Abstract
Background Patients with Parkinson’s disease (PD) have variable rates of progression. More accurate prediction of progression could improve selection for clinical trials. Although some variance in clinical progression can be predicted by age at onset and phenotype, we hypothesise that this can be further improved by blood biomarkers.
Objective To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD.
Methods We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBA and APOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes .
Results 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia—HR 2.64; postural instability—HR 1.32; mortality—HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia—HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103).
Conclusions Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.
Objective To determine if blood biomarkers (serum neurofilament light (NfL) and genetic status (glucocerebrosidase, GBA and apolipoprotein E (APOE))) are useful in addition to clinical measures for prognostic modelling in PD.
Methods We evaluated the relationship between serum NfL and baseline and longitudinal clinical measures as well as patients’ genetic (GBA and APOE) status. We classified patients as having a favourable or an unfavourable outcome based on a previously validated model, and explored how blood biomarkers compared with clinical variables in distinguishing prognostic phenotypes .
Results 291 patients were assessed in this study. Baseline serum NfL was associated with baseline cognitive status. Nfl predicted a shorter time to dementia, postural instability and death (dementia—HR 2.64; postural instability—HR 1.32; mortality—HR 1.89) whereas APOEe4 status was associated with progression to dementia (dementia—HR 3.12, 95% CI 1.63 to 6.00). NfL levels and genetic variables predicted unfavourable progression to a similar extent as clinical predictors. The combination of clinical, NfL and genetic data produced a stronger prediction of unfavourable outcomes compared with age and gender (area under the curve: 0.74-age/gender vs 0.84-ALL p=0.0103).
Conclusions Clinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.
| Original language | English |
|---|---|
| Pages (from-to) | 707-715 |
| Number of pages | 9 |
| Journal | Journal of Neurology, Neurosurgery, and Psychiatry |
| Volume | 93 |
| Issue number | 7 |
| Early online date | 16 May 2022 |
| DOIs | |
| Publication status | E-pub ahead of print - 16 May 2022 |
Bibliographical note
Funding Information:HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018-02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C and #ADSF-21-831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE) and the UK Dementia Research Institute at UCL. DGG has received grant funding from the Neurosciences Foundation, Michael’s Movers, and Parkinson’s UK. VC has received grant funding from the Multiple System Atrophy Trust/ABN Clinical Research Training fellowship (Grant F84 ABN 540868) and The Guarantors of Brain (Grant 565908).
Funding Information:
NV has received unconditional educational grants from IPSEN and Biogen, travel grants from IPSEN, AbbVie and The International Parkinson’s Disease and Movement Disorders Society, speaker’s honorarium from AbbVie and STADA and served on advisory boards for Abbvie and Brittania outside of the submitted work. RAB receives consultancy monies from Novo Nordisk; UCB; BlueRock therapeutics; Aspen Neuroscience and FCDI. He also receives grant support from the MRC, Wellcome, ASAP, EU, NIHR, Cure Parkinson’s Trust, John Black Charitable Foundation, PUK, and Rosetrees Trust. He receives royalties from Wiley and Springer Nature. HZ has served at scientific advisory boards for Abbvie, Alector, Eisai, Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies and CogRx, has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). DGG has received honoraria from BIAL Pharma, GE Healthcare, and Vectura plc, and consultancy fees from the Glasgow Memory Clinic. TF has received grants from National Institute of Health Research, Michael J Fox Foundation, John Black Charitable Foundation, Cure Parkinson’s Trust, Innovate UK, Van Andel Research Institute and Defeat MSA. He has served on Advisory Boards for Voyager Therapeutics, Handl therapeutics, Living Cell Technologies, Bial, Profie Pharma. He has received honoraria for talks sponsored by Bial, Profile Pharma, Boston Scientific. HRM is employed by UCL. In the last 24 months he reports paid consultancy from Biogen, UCB, Abbvie, Denali, Biohaven, Lundbeck; lecture fees/honoraria from Biogen, UCB, C4X Discovery, GE-Healthcare, Wellcome Trust, Movement Disorders Society; Research Grants from ASAP, Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, CBD Solutions, Drake Foundation, Medical Research Council. Dr Morris is a coapplicant on a patent application related to C9ORF72—Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140).
Funding Information:
Cohort studies: Tracking Parkinson’s is primarily funded and supported by Parkinson’s UK. It is also supported by the National Institute for Health Research (NIHR) Dementias and Neurodegenerative Diseases Research Network (DeNDRoN). This research was supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre and Cambridge BRC. The UCL Movement Disorders Centre is supported by the Edmond J. Safra Philanthropic Foundation. Genetic and biomarker analysis: Work on the genetics and biomarkers of progression in Parkinson’s and related disorders is supported by Parkinson’s UK (PhD Studentship to Dr Tan H-1703, Understanding and predicting Parkinson's progression), and the PSP Association. The study is funded by the joint efforts of The Michael J. Fox Foundation for Parkinson’s Research (MJFF) and the Aligning Science Across Parkinson’s (ASAP) initiative. MJFF administers the grant [Grant ID: ASAP-000478] on behalf of ASAP and itself. For the purpose of open access, the author has applied a CC-BY public copyright license to the Author Accepted Manuscript (AAM) version arising from this submission.
Publisher Copyright:
© 2022 BMJ Publishing Group. All rights reserved.
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