Combining biomarkers for prognostic modelling of Parkinson’s disease

Abstract

BackgroundPatients 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.ObjectiveTo 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.MethodsWe 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 .Results291 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).ConclusionsClinical trials of disease-modifying therapies might usefully stratify patients using clinical, genetic and NfL status at the time of recruitment.

Blood based biomarkers for movement disorders

“…Nf-L is an axonal structural protein which is highly expressed in large cases as compared to controls, with some authors suggesting that the strong association between Nf-L and age in healthy controls may confound comparisons. [41][42][43][44][45] A meta-analysis of CSF Nf-L showed a slight increase in PD cases, which did not reach statistical significance. 46 If there is an elevation of Nf-L in PD, it is likely to be to a small extent and is unlikely to be helpful as an isolated measure in the early diagnosis of PD.…”

“…Serum/plasma Nf-L has been consistently shown to be elevated in the Parkinson's plus syndromes PSP, MSA, and CBS, and elevated Nf-L levels are helpful in distinguishing these conditions from PD. 20,42,44,46 Area under the sensitivity, versus 1-specificity curve survive correction for age and disease duration, implying that this is an independent marker of disease state. 47,48 As well as being associated with clinical severity at baseline, in serial measures, Nf-L progressively increases with time, suggesting that it tracks disease progression.…”

“…CSF and plasma/serum Nf‐L are strongly correlated. There have been inconsistent reports of raised CSF and plasma Nf‐L in PD cases as compared to controls, with some authors suggesting that the strong association between Nf‐L and age in healthy controls may confound comparisons 41–45 . A meta‐analysis of CSF Nf‐L showed a slight increase in PD cases, which did not reach statistical significance 46 .…”

“…Blood and CSF Nf‐L appears to be a useful prognostic biomarker in PD, i.e., cross‐sectional or baseline levels predict the rate of progression and adverse future outcomes. In most but not all PD cohort studies, baseline CSF or blood Nf‐L is associated with motor progression measured by the Hoehn and Yahr or MDS‐UPDRS scale, functional progression measured with the Schwab and England activities of daily living scale (SEADL) and mortality 44,45,51,52 . Variation between studies may relate to the age at cohort baseline and duration of follow‐up, with older study cohorts and longer duration of follow‐up providing higher event rates for correlation with prognostic biomarker measurements.…”

Diabetes and Neuroaxonal Damage in Parkinson's Disease

“…Considering the authors' novel findings of an association between diabetes and neuroaxonal damage, we explored the relationship between serum NfL and diabetes in our previously defined subgroup of the Tracking Parkinson's study. 4 The analysis was performed using Stata V.17.0 (Stata, RRID:SCR_012763), and differences were compared using Kruskal-Wallis tests for continuous data and χ2 tests for categorical data, whereas the association between NfL and diabetes was further explored using univariate and multivariate (age, BMI, and vascular risk factors) linear regression analysis.…”