Emerging Trends: Neurofilament Biomarkers in Precision Neurology

The primary treatment for Parkinson’s disease (PD) is supplementation of levodopa (L-dopa). With disease progression, people may experience motor and non-motor fluctuations, whereby the PD symptoms return before the next dose of medication. Paradoxically, in order to prevent wearing-off, one must take the next dose while still feeling well, as the upcoming off episodes can be unpredictable. Waiting until feeling wearing-off and then taking the next dose of medication is a sub-optimal strategy, as the medication can take up to an hour to be absorbed. Ultimately, early detection of wearing-off before people are consciously aware would be ideal. Towards this goal, we examined whether or not a wearable sensor recording autonomic nervous system (ANS) activity could be used to predict wearing-off in people on L-dopa. We had PD subjects on L-dopa record a diary of their on/off status over 24 hours while wearing a wearable sensor (E4 wristband®) that recorded ANS dynamics, including electrodermal activity (EDA), heart rate (HR), blood volume pulse (BVP), and skin temperature (TEMP). A joint empirical mode decomposition (EMD) / regression analysis was used to predict wearing-off (WO) time. When we used individually specific models assessed with cross-validation, we obtained > 90% correlation between the original OFF state logged by the patients and the reconstructed signal. However, a pooled model using the same combination of ASR measures across subjects was not statistically significant. This proof-of-principle study suggests that ANS dynamics can be used to assess the on/off phenomenon in people with PD taking L-dopa, but must be individually calibrated. More work is required to determine if individual wearing-off detection can take place before people become consciously aware of it.

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An Individualized Multi-Modal Approach for Detection of Medication “Off” Episodes in Parkinson’s Disease via Wearable Sensors

Abstract Digital biomarkers that remotely monitor symptoms have the potential to revolutionize outcome assessments in future disease-modifying trials in Parkinson’s disease (PD), by allowing objective and recurrent measurement of symptoms and signs collected in the participant’s own living environment. This biomarker field is developing rapidly for assessing the motor features of PD, but the non-motor domain lags behind. Here, we systematically review and assess digital biomarkers under development for measuring non-motor symptoms of PD. We also consider relevant developments outside the PD field. We focus on technological readiness level and evaluate whether the identified digital non-motor biomarkers have potential for measuring disease progression, covering the spectrum from prodromal to advanced disease stages. Furthermore, we provide perspectives for future deployment of these biomarkers in trials. We found that various wearables show high promise for measuring autonomic function, constipation and sleep characteristics, including REM sleep behavior disorder. Biomarkers for neuropsychiatric symptoms are less well-developed, but show increasing accuracy in non-PD populations. Most biomarkers have not been validated for specific use in PD, and their sensitivity to capture disease progression remains untested for prodromal PD where the need for digital progression biomarkers is greatest. External validation in real-world environments and large longitudinal cohorts remains necessary for integrating non-motor biomarkers into research, and ultimately also into daily clinical practice. 

Digital biomarkers for non-motor symptoms in Parkinson’s disease: the state of the art

Parkinson's disease (PD) presents with decreased heart rate variability (HRV) from its early stages. However, most of its evidence originates from HRV measurements in parasympathetic dominant states. In this study, we aimed to examine whether HRV in sympathetic dominant states during the head-up tilt table test (HUT) serves as a marker of autonomic dysfunction in PD and isolated REM sleep behavior disorder (iRBD). 

Decreased Heart Rate Variability in Sympathetic Dominant States in Parkinson’s Disease and Isolated REM Sleep Behavior Disorder

Acute neuroaxonal remodelling after electroconvulsive treatment in patients with major depressive disorder: a pilot study

Wearable sensor device-based detection of decreased heart rate variability in Parkinson’s disease

BACKGROUND
The neurofilament light chain (NfL) is receiving increased attention as a biomarker of neurological diseases, as NfL concentration is elevated in the blood and cerebrospinal fluid after neuronal damage. However, few studies have addressed NfL in epilepsy. We aimed to investigate alteration of serum NfL in adult patients with epilepsy, and the association between this biomarker and cognitive impairment.


METHODS
A total of 38 consecutive epilepsy patients and 24 controls underwent cross-sectional measurement of serum NfL levels and cognitive testing using the Mini-Mental State Examination (MMSE), the Japanese version of the Montreal Cognitive Assessment (MoCA-J), the Frontal Assessment Battery (FAB), the Trail-Making Test, and the Stroop Colour-Word Test. Statistical analysis was performed with the Student's t-test to compare serum NfL levels between the epilepsy group and the control group, and with Spearman's correlation and age-corrected partial correlation analyses to evaluate the association between serum NfL level and cognitive impairment in epilepsy patients.


RESULTS
There was no difference in serum NfL levels between the epilepsy and control groups (epilepsy [mean ± SD]: 17.3 ± 13.9 pg/mL; control: 17.7 ± 11.5 pig/mL; p = 0.92), however, the MoCA-J scores were lower in the epilepsy group (26.6 ± 3.1 vs. 28.1 ± 1.6; p = 0.03). The age-corrected partial correlation analysis showed a correlation between serum NfL level and cognitive test scores in the epilepsy group (MMSE: rs = -0.63, p < 0.01; MoCA-J: rs = -0.54, p < 0.01; FAB: rs = -0.68, p < 0.01), whereas serum NfL levels were correlated exclusively with MMSE scores in the control group (rs = 0.44, p = 0.04).


SIGNIFICANCE
In adult epilepsy patients, the serum NfL level was not significantly elevated, but was correlated with cognitive test scores. Our findings suggest that serum NfL concentration could be an indicator of cognitive function in epilepsy patients.

Serum neurofilament light chain in patients with epilepsy and cognitive impairment.

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Wearable sensor device-based detection of decreased heart rate variability in Parkinson’s disease

Serum neurofilament light chain in patients with epilepsy and cognitive impairment.