'Molecular and Cellular Neuroscience': Impacts of Eight Highly Cited Articles Published in This Section of Brain Sciences in 2024.

Therapeutic Translation of iPSCs for Treating Neurological Disease

INFLUENCE OF DISCHARGE OF MOTONEURONS UPON EXCITATION OF NEIGHBORING MOTONEURONS

Activation of Nrf2 signaling as a common treatment of neurodegenerative diseases.

He investigates mitochondrial dysfunction in adult neurodegenerative diseases.He holds multiple

Background: Amyotrophic lateral sclerosis (ALS) is a rare neurological disease that leads to impairment of both lower and upper motor neurons, resulting in progressive weakness, muscle atrophy and respiratory and swallowing dysfunction. Despite well-documented motor symptoms, non-motor manifestations remain underexplored. Objective: To investigate the cognitive function in individuals with ALS in both sporadic and familial forms and its relationship with disease progression. Methods: Observational, cross-sectional, controlled study based on primary data of ALS patients over 18 years old, without a prior diagnosis of dementia. Functionality and neuropsychological assessment battery were measured by the following instruments: ALS Functional Rating Scale Revised (ALS-FRS-R), ALS Cognitive Behavioral Screen (ALSCBS), semantic verbal fluency test, phonemic verbal fluency test, digit span subtest from the Wais III scale, Hopkins Verbal Learning Test-Revised (HVLT-R), five-point test, and Mini-Mental State Examination (MMSE). We also applied the social cognition/theory of mind tests of Faux Pas and Theory of Mind – 15 (ToM-15). Results: Twenty-two ALS patients and 24 healthy controls were recruited. Among the patients, nine (40.9%) had the sporadic form and 13 (59.1%) had the familial form. Significant differences were observed in MMSE and ALSCBS scores between the ALS and control groups, with worse scores associated with the ALS group, and these differences were more evident among those with the familial form when compared to controls. Digit span, HVLT-R (total recall), five-point test, and ALSCBS were inversely related to ALS-FRS-R scores suggesting worse cognitive impairment in individuals with greater functional impairment related to ALS. Significant differences were also observed between the ALS and control groups in the performance of social cognition tasks measured by the Faux-Pas intention, comprehension, false beliefs, empathy, and total score. The ALS group (more evidently the familial ALS patients) had worse performance in social cognition tasks. This same pattern was also observed in the ability to detect false beliefs using the ToM-15 test with no evidence of significant relationship between ALS-FRS-R and social cognition impairment, suggesting a possible early compromise of theory of mind abilities. Conclusion: Individuals with ALS tend to show alterations in multiple cognitive domains, not all of them directly related to functional decline. Cognitive impairment was more pronounced in individuals with the familial form compared to the sporadic form, and there is evidence that social cognition impairment may occur early in the disease in this population.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. There is heterogeneity of the clinical features of ALS including site of onset and rate of progression. Previously, ALS was considered to be a disease of the motor system. However, there is evidence that ALS patients can have cognitive impairment. Some patients meet the diagnostic criteria for Frontotemporal dementia (FTD). It is now thought that FTD and ALS are related neurodegenerative disorders, which fall on the same disease spectrum. A reliable biomarker is needed to monitor the progression of the disease and assess the effects of potential therapies. Sequential Window Acquisition of all theoretical fragment-ion spectra analysis (SWATHTM) is a reliable and powerful proteomic approach to investigate the biomarker proteins in complex samples such as blood. Method: The aim of the first study is to evaluate the utility of neurofilament levels as blood or cerebrospinal fluid (CSF) biomarker in patients with ALS by using a systematic search of Pubmed, Embase and Scopus databases. Meta-analysis of the data was performed. The aim of the second study is to screen for cognitive and behavioural impairment in people with ALS and controls with neuromuscular disease and to correlate these with clinical features. 108 people with ALS and 60 controls were recruited and assessed with the Addenbrooke’s cognitive examination-III (ACE-III), the Frontal assessment battery (FAB), and the executive function component of the Edinburgh cognitive and behavioural ALS screen (ECAS). The Amyotrophic lateral sclerosis-Frontotemporal dementia questionnaire (ALS-FTD-Q) and the Motor Neuron Disease Behavioural instrument (MiND-B) were administered to the caregivers of people with ALS. Longitudinal studies of cognition were performed in 37 ALS patients. The aim of the third study is to search for plasma biomarkers in ALS patients compared to healthy controls by using SWATH™ quantification analysis and to compare proteomic analysis of ALS patients with and without cognitive impairment (CI). 42 patients with ALS and 18 healthy controls were recruited. Western blot analysis was used to confirm the results of analysis and in an independent set of samples. Ingenuity pathway analysis (IPA) was performed. Results: The systematic review found that levels of NF heavy chain and light chains were significantly elevated in the CSF of ALS patients compared to healthy controls/controls without parenchymal central nervous system (CNS) involvement and ALS mimic disease patients. NF light chain level in CSF was higher in ALS patients than in neurological patients with CNS involvement (SMD=1.352, P=0.001). NF light chain concentration in blood was higher in ALS patients than in healthy controls/controls without CNS involvement (SMD=1.448, P<0.0001). NF heavy chain levels in CSF were negatively correlated disease duration and ALSFRS-R (r=-0.447, P<0.0001; r=-0.279, P=0.011). NF light chain levels in CSF were negatively correlated with disease duration (r=-0.486, P<0.0001). In the patient cohort, the frequencies of cognitive impairment based on the ACE-III and FAB were 30.0% and 14.0%, in ALS and 11.7% and 3.3% in controls, respectively. In ALS, the frequencies of behavioural impairment based on ALS-FTD-Q and MiND-B were 32.1% and 39.4 %, respectively. ALS participants with cognitive impairment measured with ACE-III had significantly shorter survival time than those without. ALS participants with behavioural impairment measured with ALS-FTD-Q had worse prognosis than those without. No significant difference was found between the first two serial cognitive tests based on ACE-III and FAB by using a generalized estimating equation. Between ALS and controls, there were significant differences in the expression of 30 proteins. Of these, plasma gelsolin concentration was 1.2 fold higher in controls than ALS patients (P=0.006). Between controls and ALS with CI, there was significant difference in expression of 32 proteins. The clusterin level was 1.2 fold downregulated in patients with CI compared with controls (P=0.03). The observed changes in levels of gelsolin, clusterin, CD5L and ficolin 3 were validated by using western blot. Pathway analysis showed that the LXR/RXR pathway, complement pathway and coagulation pathway are regulated in ALS. Conclusions: The results of the first study shows that NF heavy and light chain levels have potential to be used as markers of neural degeneration in ALS, but are not specific for the disease, and are more likely to be used as measures of disease progression. The results of second study indicate that there is a greater frequency of cognitive impairment in people with ALS than in patients with other neuromuscular diseases. The cognitive and behavioural tests are potential biomarkers of the prognosis of ALS. The results of cognitive tests are stable over 6 months and possibly longer. The results of the third study illustrate that clusterin, gelsolin and ficolin 3 are novel potential biomarkers to differentiate the ALS patients from healthy controls. Abnormalities in the LXR/RXR pathway suggest that lipid metabolism is involved in ALS. There are widespread changes in immune function and coagulation in ALS.

Carrier-mediated blood-brain barrier transport of short-chain monocarboxylic organic acids

Background:Adult-onset neurodegenerative diseases affect millions and negatively impact health care systems worldwide. Evidence suggests that air pollution may contribute to aggravation of neurodegeneration, but studies have been limited.Objective:We examined the potential association between long-term exposure to particulate matter in aerodynamic diameter [fine particulate matter ()] and disease aggravation in Alzheimer’s (AD) and Parkinson’s (PD) diseases and amyotrophic lateral sclerosis (ALS), using first hospitalization as a surrogate of clinical aggravation.Methods:We used data from the New York Department of Health Statewide Planning and Research Cooperative System (SPARCS 2000–2014) to construct annual county counts of first hospitalizations with a diagnosis of AD, PD, or ALS (total, urbanicity-, sex-, and age-stratified). We used annual concentrations estimated by a prediction model at a resolution, which we aggregated to population-weighted county averages to assign exposure to cases based on county of residence. We used outcome-specific mixed quasi-Poisson models with county-specific random intercepts to estimate rate ratios (RRs) for a 1-y exposure. We allowed for nonlinear exposure–outcome relationships using penalized splines and accounted for potential confounders.Results:We found a positive nonlinear association that plateaued above (, 95% CI: 1.04, 1.14 for a increase from 8.1 to ). We also found a linear positive association (, 95% CI: 1.01, 1.09 per increase), and suggestive evidence of an association with AD. We found effect modification by age for PD and ALS with a stronger positive association in patients of age but found insufficient evidence of effect modification by sex or urbanization level for any of the outcomes.Conclusion:Our findings suggest that annual increase in county-level concentrations may contribute to clinical aggravation of PD and ALS. Importantly, the average annual concentration in our study was , below the current American national standards, suggesting the standards may not adequately protect the aging population. https://doi.org/10.1289/EHP7425

BackgroundDespite considerable interest, the population-based frequency, clinical characteristics and natural history of cognitive impairment in amyotrophic lateral sclerosis (ALS) are not known.MethodologyThe authors undertook a prospective population-based study of cognitive...

Complex Genetics of Amyotrophic Lateral Sclerosis

A Long Shot? Could neurodegenerative disease be caused by a cyanobacterial toxin?

Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in patients with ALS and to correlate such findings with cognitive-behavioral data. Three consecutive inpatient cohorts of Italian patients with ALS and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided into a discovery cohort and a replication cohort. Controls included a cohort of cognitively impaired individuals and patients with Alzheimer disease (AD). Participants underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed with a standard neuropsychological battery (discovery ALS cohort and AD cohort) and the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS) (replication ALS cohort). We recruited 864 individuals with ALS (635 discovery, 229 replication), 798 who were cognitively unimpaired and 171 with AD. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p = 1.2 × 10-14) and 11.4% of patients with AD (p = NS). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMA frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts (p = 1.1 × 10-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathologic scores at the ECAS ALS-specific domains. Last, OMAs could be observed in 35.0% of cognitively impaired patients with ALS vs 11.4% of patients with AD (p = 6.4 × 10-7), suggesting a possible involvement of frontal oculomotor areas in ALS. Patients with ALS showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration, and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.

BackgroundCerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear.ObjectivesThe aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them.MethodsCSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software.ResultsCompared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment.ConclusionsThe CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS.

Quantitative Proteomics Identifies Surfactant-Resistant α-Synuclein in Cerebral Cortex of Parkinsonism-Dementia Complex of Guam but Not Alzheimer's Disease or Progressive Supranuclear Palsy

Despite an early understanding of amyotrophic lateral sclerosis (ALS) as a disease affecting the motor system, including motoneurons in the motor cortex, brainstem, and spinal cord, today, many cases involving dementia and behavioral disorders are reported. Therefore, we currently divide ALS not only based on genetic predisposition into the most common sporadic variant (90% of cases) and the familial variant (10%), but also based on cognitive and/or behavioral symptoms, with five specific subgroups of clinical manifestation—ALS with cognitive impairment, ALS with behavioral impairment, ALS with combined cognitive and behavioral impairment, the fully developed behavioral variant of frontotemporal dementia in combination with ALS, and comorbid ALS and Alzheimer’s disease (AD). Generally, these cases are referred to as amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTSD). Clinical behaviors and the presence of the same pathognomonic deposits suggest that FTLD and ALS could be a continuum of one entity. This review was designed primarily to compare neuropathological findings in different types of ALS relative to their characteristic locations as well as the immunoreactivity of the inclusions, and thus, foster a better understanding of the immunoreactivity, distribution, and morphology of the pathological deposits in relation to genetic mutations, which can be useful in specifying the final diagnosis.