Abstract
To evaluate the utility of mismatch negativity (MMN), a neurophysiologic marker of non-motor cognitive processing, in amyotrophic lateral sclerosis (ALS). 89 patients, stratified into 4 different phenotypic presentations of ALS (67 spinal-onset, 15 bulbar-onset, 7 ALS-FTD, 7 C9ORF72 gene careers), and 19 matched controls underwent 128-channel EEG data recording. Subjects were presented with standard auditory tones interleaved with pitch-deviant tones in three recording blocks. The MMN response was quantified by peak amplitude, peak delay, average amplitude, and average delay, 100-300 ms after stimuli. 64 patients underwent cognitive screening using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS), and 38 participants underwent contemporaneous cognitive assessment using the Stroop Color-Word Interference test (CWIT), which measures attention shift, inhibitory control, and error monitoring. The MMN response was observed in frontal and frontocentral regions of patient and control groups. Compared to controls, waveforms were attenuated in early onset, and the average delay was significantly increased in all of the ALS subgroups, with no significant difference between subgroups. Comparing with the control response, the ALS MMN response clustered into four new subgroups characterized by differences in response latency. The increased average delay correlated with changes in the Stroop CWIT; however, it did not show a direct relationship with age, gender, traditional phenotypes, revised ALS Functional Rating Scale, or ECAS scores. The MMN response in ALS patients reflects the cognitive dysfunction in specific sub-domains, as the new patient subgroups, identified by cluster analysis, do not segregate with existing clinical or cognitive classifications. Event-related potentials can provide additional quantitative neurophysiologic measures of impairment in specific cognitive sub-domains from which it may be possible to generate novel biologically relevant subgroups of ALS.
Highlights
Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder [1] characterized by a combination of upper and lower motor neuron impairment [2, 3]
For the ALS groups, the mismatch negativity (MMN) became significant from 127 ms and persisted up to 500 ms (Wilcoxon’s Signed Rank test, p < 0.05) (Figure 1)
We found that the N2a component of the event-related potentials (ERPs) responses discriminated between ALS and controls
Summary
Amyotrophic lateral sclerosis (ALS) is an age-related neurodegenerative disorder [1] characterized by a combination of upper and lower motor neuron impairment [2, 3]. Preclinical assessment of potential new therapeutics has been based primarily on the concept of selective vulnerability of individual motor neurons, and outcome metrics in human clinical trials have focused on survival, functional activity, and muscle strength [4]. The presence of patterns of progressive cognitive and behavioral changes suggest that different frontotemporal and frontostriatal neuroanatomical pathways can be affected in ALS, manifesting as executive impairment, and patterned behavioral change including apathy, rigidity, or disinhibition, respectively [7, 8]. Taken together with progressive motor decline, the clinical manifestations of ALS can be construed as a progressive disintegration of neural networking in motor and non-motor network domains [9]. Further elaboration of the nature, extent, and clinical correlates of network disruption is likely to provide useful data from which non-invasive biomarkers of disease pathophysiology could be discovered
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