Functional network dynamics revealed by EEG microstates reflect cognitive decline in amyotrophic lateral sclerosis.

Recent electroencephalography (EEG) studies have shown that patterns of brain activity can be used to differentiate amyotrophic lateral sclerosis (ALS) and control groups. These differences can be interrogated by examining EEG microstates, which are distinct, reoccurring topographies of the scalp's electrical potentials. Quantifying the temporal properties of the four canonical microstates can elucidate how the dynamics of functional brain networks are altered in neurological conditions. Here we have analysed the properties of microstates to detect and quantify signal-based abnormality in ALS. High-density resting-state EEG data from 129 people with ALS and 78 HC were recorded longitudinally over a 24-month period. EEG topographies were extracted at instances of peak global field power to identify four microstate classes (labelled A-D) using K-means clustering. Each EEG topography was retrospectively associated with a microstate class based on global map dissimilarity. Changes in microstate properties over the course of the disease were assessed in people with ALS and compared with changes in clinical scores. The topographies of microstate classes remained consistent across participants and conditions. Differences were observed in coverage, occurrence, duration, and transition probabilities between ALS and control groups. The duration of microstate class B and coverage of microstate class C correlated with lower limb functional decline. The transition probabilities A to D, C to B and C to B also correlated with cognitive decline (total ECAS) in those with cognitive and behavioural impairments. Microstate characteristics also significantly changed over the course of the disease. Examining the temporal dependencies in the sequences of microstates revealed that the symmetry and stationarity of transition matrices were increased in people with late-stage ALS. These alterations in the properties of EEG microstates in ALS may reflect abnormalities within the sensory network and higher-order networks. Microstate properties could also prospectively predict symptom progression in those with cognitive impairments.

Epidemiologic Trends of Amyotrophic Lateral Sclerosis in Ireland, 1996-2021.

BACKGROUND AND OBJECTIVES: The objective of this study was to examine changes to the incidence, prevalence, age at onset, and survival of patients diagnosed with amyotrophic lateral sclerosis (ALS) in the Republic of Ireland over 25 years. METHODS: Incident and prevalent cases of ALS were estimated using the Irish population-based ALS Register, which has been in continuous operation since 1994. Incident cases were age standardized using the direct method and applied to 3 standard populations (Irish, European, and American). Survival was determined using Kaplan-Meier curves and Cox regression models. Non-normally distributed groups were compared using the Kruskal-Wallis test with a Bonferroni correction. RESULTS: A total of 2,771 patients with ALS were identified in the Republic of Ireland over 25 years. Incidence per 100,000 was determined for the population older than 15 years. Crude incidence increased from 2.64 to 5.46 per 100,000. Standardized incidence increased from 2.64 to 3.1 per 100,000. Prevalence increased from 5.83 to 8.10 per 100,000. The median age at onset increased from 64 to 67 years. The peak age of incidence increased from those between 70 and 74 years to those between 75 and 79 years. Overall, women had a consistently later median age at onset of 67 years compared with men at 65 years (p < 0.001). No significant difference in survival was noted between those captured across 3 different epochs (1996-2003, 2004-2012, 2013-2021). Older age at onset (hazard ratio [HR] 1.03, CI 1.02-1.04, p < 0.001) was a negative predictive factor of survival in multivariate Cox regression analysis. Riluzole use (HR 0.67, CI 0.50-0.90, p = 0.033) and diagnostic delay (HR 0.98, CI 0.98-0.99, p < 0.001) were positive predictive factors. DISCUSSION: Within the Republic of Ireland, the age-standardized overall incidence, peak incidence, prevalence, and age at onset of ALS have all increased over 25 years. Despite the widespread use of noninvasive ventilation, aggressive secretion management, and changes in ALS care, the mean survival within the Irish population has not changed.

The reading the mind in the eyes test short form (A & B): validation and outcomes in an amyotrophic lateral sclerosis cohort.

Objective: Deficits in social cognition are part of the cognitive phenotype of amyotrophic lateral sclerosis (ALS). This study investigated the psychometric properties and test-retest reliability of two short-form versions of the Reading the Mind in the Eyes Test. Method: Patients with ALS (n = 50), alongside age and IQ matched controls (n = 50) were recruited. The Reading the Mind in the Eyes Test (RMET) was apportioned according to previously published psychometric properties yielding two short forms. The internal consistency, test-retest reliability, item difficulty, and discrimination coefficient were computed to determine the utility of the short forms. Two one-sided t-test (TOST) assessed equivalency, and a ROC curve analysis determined a cutoff for impairment. Results: Cronbach's Alpha > 0.7 was observed for the RMET Short Form A and RMET Short Form B, indicating adequate internal consistency. Both RMET Short Forms had excellent psychometric properties when discriminating between ALS patients who performed well, compared to those who did not, with an overall medium difficulty coefficient observed. The TOST found the short forms to be equivalent. Conclusion: Social cognition is an important cognitive construct in ALS, as is its measurement. This study contributes not only to the psychometric knowledge of this measure, but also to the usability, efficacy, reliability, and repeatability of two short forms.

Xeroderma pigmentosum: overview of pharmacology and novel therapeutic strategies for neurological symptoms.

Xeroderma pigmentosum (XP) encompasses a group of rare diseases characterized in most cases by malfunction of nucleotide excision repair (NER), which results in an increased sensitivity to UV radiation in affected individuals. Approximately 25-30% of XP patients present with neurological symptoms, such as sensorineural deafness, mental deterioration and ataxia. Although it is known that dysfunctional DNA repair is the primary pathogenesis in XP, growing evidence suggests that mitochondrial pathophysiology may also occur. This appears to be secondary to dysfunctional NER but may contribute to the neurodegenerative process in these patients. The available pharmacological treatments in XP mostly target the dermal manifestations of the disease. In the present review, we outline how current understanding of the pathophysiology of XP could be used to develop novel therapies to counteract the neurological symptoms. Moreover, the coexistence of cancer and neurodegeneration present in XP led us to focus on possible new avenues targeting mitochondrial pathophysiology. LINKED ARTICLES: This article is part of a themed section on Mitochondrial Pharmacology: Featured Mechanisms and Approaches for Therapy Translation. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.22/issuetoc.