Intraindividual Neurofilament Dynamics in Serum Mark the Conversion to Sporadic Parkinson's Disease

Abstract

Background and Objectives: With disease-modifying treatment strategies on the horizon, stratification of individual patients at the earliest stages of Parkinson's disease (PD) is key-ideally already at clinical disease onset. Blood levels of neurofilament light chain (NfL) provide an easily accessible fluid biomarker that might allow capturing the conversion from prodromal to manifest PD. Methods: We assessed longitudinal serum NfL levels in subjects converting from prodromal to manifest sporadic PD (converters), at-risk subjects, and matched controls (72 participants with ≈4 visits), using single-molecule array (Simoa) technique. Results: While NfL levels were not increased at the prodromal stage, subjects converting to the manifest motor stage showed a significant intraindividual acceleration of the age-dependent increase of NfL levels. Conclusions: The temporal dynamics of intraindividual NfL blood levels might mark the conversion to clinically manifest PD, providing a potential stratification biomarker for individual disease onset in the advent of precision medicine for PD.

Serum neurofilament light as a biomarker for prognosis in patients with newly diagnosed Parkinson’s disease

“…We noted a negative main effect of higher baseline NfL levels on progression scores in mixed modelling. This novel finding is potentially consistent with NfL levels peaking prior to the onset of appreciable clinical features [28]. Our observation of higher baseline NfL levels predicting more rapid motor and functional progression mirrors several other studies [12–14,29,30] and could potentially be explained by NfL’s ability to reflect baseline pathological characteristics which predict a more malignant progression such as the magnitude of alpha synuclein deposition and anatomical dysfunction present [35–37].…”

“…Our enrolment of HC without a history of neurological disorders potentially explains the significant difference noted in comparison to PD. A further potential explanation for this discrepancy could be our measurement of NfL in the earlier stages of symptomatic PD (mean disease duration of 1.3 years), since NfL levels appear to peak in the stages of conversion to clinically manifest PD before gradually declining [28,29]. Taken together these findings support the potential use of NfL as a biomarker for clinical trial recruitment in early PD.…”

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study

“…21 Thus, the combination of both biomarkers -NfL and pNfHmight be clinically relevant in the early and late stages of neurodegenerative diseases. 28 Although neurofilament increases are specific in that they signal axonal decay rate (rather than merely unspecific cell damage), their value in genetic FTD does not primarily consist in their use as diagnostic biomarkers, as neurofilament levels are increased in various neurodegenerative and non-neurodegenerative conditions 12,14,21,22,[29][30][31] and as assessment of mutations and altered disease-specific proteins already meets such a diagnostic purpose. [32][33][34] For preparing future FTD intervention trials, however, the biomarker value of neurofilament levels rather consists in their potential use as stratification, disease severity, and treatment response biomarkers.…”

“…To characterize the disease stages of genetic FTD in terms of both neurofilament levels and their change rates, we used linear mixed-effects models of longitudinal neurofilament data, thus considering the covariance between repeated measurements of each subject. 16,22 In the models, we included clinical status (presymptomatic stage, conversion stage, symptomatic stage, and controls as the reference group), age (centered at the mean baseline age of all subjects), and time from baseline (ie, the first serum sample) as fixed effects, the interaction of clinical status and time from baseline, and the random variable subject, modeled by random intercepts (R packages: lme4 and effects). The addition of random slopes did not improve the model fit.…”

Blood Neurofilament Light Chain in Parkinson’s Disease: Comparability between Parkinson’s Progression Markers Initiative (PPMI) and Asian Cohorts

“…[ 28 ]. Furthermore, another study found that the temporal dynamics of serum NfL levels in individuals were associated with the conversion from prodromal to PD, suggesting that NfL may not be an early, PD-specific diagnostic biomarker [ 29 ]. These remaining questions necessitate sophisticated global data-pooling with consideration of background demographic data to fully assess the role of blood NfL as a reliable diagnostic biomarker in persons at high risk of PD.…”