Neurofilament light chain in spinal fluid and plasma in multiple system atrophy: a prospective, longitudinal biomarker study.

PURPOSE: There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to cerebrospinal fluid (NfL-c) as a diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. METHODS: Well-characterized patients with early MSA (n = 32), Parkinson's disease (PD; n = 21), and matched controls (CON; n = 15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high-sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. RESULTS: Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson, r = 0.99), while correlation between NfL-c and -p was only moderate (r = 0.66). NfL was significantly higher in MSA compared with CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. CONCLUSIONS: These findings confirm NfL-c as a faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Neurofilament Light Chain in Spinal Fluid and Plasma in Multiple System Atrophy - A Prospective, Longitudinal Biomarker Study.

Purpose There is a critical need for reliable diagnostic biomarkers as well as surrogate markers of disease progression in multiple system atrophy (MSA). Neurofilament light chain (NfL) has been reported to potentially meet those needs. We therefore sought to explore the value of NfL in plasma (NfL-p) in contrast to CSF (NfL-c) as diagnostic marker of MSA, and to assess NfL-p and NfL-c as markers of clinical disease progression. Methods Well-characterized patients with early MSA (n=32), Parkinson's disease (PD, n=21), and matched controls (CON, n=15) were enrolled in a prospective, longitudinal study of synucleinopathies with serial annual evaluations. NfL was measured using a high sensitivity immunoassay, and findings were assessed by disease category and relationship with clinical measures of disease progression. Results Measurements of NfL-c were highly reproducible across immunoassay platforms (Pearson,r=0.99), while correlation between NfL-c and -p was only moderate (r=0.66). NfL was significantly higher in MSA compared to CON and PD; the separation was essentially perfect for NfL-c, but there was overlap, particularly with PD, for NfL-p. While clinical measures of disease severity progressively increased over time, NfL-c and -p remained at stable elevated levels within subjects across serial measurements. Neither change in NfL nor baseline NfL were significantly associated with changes in clinical markers of disease severity. Conclusions These findings confirm NfL-c as faithful diagnostic marker of MSA, while NfL-p showed less robust diagnostic value. The significant NfL elevation in MSA was found to be remarkably stable over time and was not predictive of clinical disease progression.

Word class and word frequency in the MMN looking glass.

The effects of lexical meaning and lexical familiarity on auditory deviance detection were investigated by presenting oddball sequences of words, while participants ignored the stimuli. Stimulus sequences were composed of words that were varied in word class (nouns vs. functions words) and frequency of language use (high vs. low frequency) in a factorial design with the roles of frequently presented stimuli (Standards) and infrequently presented ones (Deviants) were fully crossed. Deviants elicited the Mismatch Negativity component of the event-related brain potential. Modulating effects of lexical meaning were obtained, revealing processing advantages for denotationally meaningful items. However, no effect of word frequency was observed. These results demonstrate that an apparently low-level function, such as auditory deviance detection utilizes information from the mental lexicon even for task-irrelevant stimuli.

Suppression of the auditory N1 event-related potential component with unpredictable self-initiated tones: evidence for internal forward models with dynamic stimulation.

Internally operating forward model mechanisms enable the organism to discriminate the sensory consequences of one's own actions from other sensory events. The present event-related potential (ERP) study compared the processing of self-initiated tones with the processing of externally-initiated but otherwise identical tones. In different conditions, frequency and onset of the sound were either predictable or unpredictable. The amplitudes of the N1 component of the ERP for the self-initiated relative to the ones for externally-initiated sounds were significantly attenuated even when the particular frequency or sound onset could not be predicted by the subject. These results support internal forward model mechanisms which dynamically predict the sensorial consequences of ones own motor acts even in face of uncertainties with respect to the frequency of the sound and its onset. Moreover, the attenuation effect was reduced when the frequency was unpredictable suggesting that it is easier to discriminate a self-initiated sound with exact foreknowledge.

Optimizing the auditory distraction paradigm: behavioral and event-related potential effects in a lateralized multi-deviant approach.

OBJECTIVE: The present study aimed at adapting a multi-deviant auditory distraction paradigm for a comprehensive screening of functions of voluntary and involuntary auditory attention. METHODS: Subjects performed phonetic discrimination on lateralized consonant-vowel syllables in a distraction paradigm in which task-irrelevant deviances occurred on different syllable features. Behavioral performance and event-related potentials (ERPs) were measured within a multi-deviant (frequency, location, and duration deviants, p=0.11 each) and a classic single-deviant design (frequency deviants only, p=0.11). Additionally, ERP effects obtained in an active and a passive multi-deviant condition were compared. RESULTS: Behavioral and electrophysiological deviance-related effects were rather similar in the multi-deviant and the single-deviant paradigm. Furthermore, the comparison to the passive listening condition revealed a marked effect of voluntary attention on sensory processing of the syllables. CONCLUSIONS: The multi-deviant distraction paradigm provides a gain in time compared to the classic single-deviant distraction paradigm which is not accompanied by a loss in the strength of the effects. Inclusion of a passive listening condition enables the additional evaluation of effects of voluntary attention. SIGNIFICANCE: The present multi-deviant distraction paradigm creates an important step towards a tool suited to investigate involuntary and voluntary attention in selected groups of patients during the processing of task-relevant and task-irrelevant auditory information across different acoustic dimensions.