Lack of an association between SCFD1 rs10139154 polymorphism and amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease. Through a genome‑wide association study (GWAS), the Sec1 family domain‑containing protein 1 (SCFD1) rs10139154 variant at 14q12 has emerged as a risk factor gene for ALS. Moreover, it has been reported to influence the age at onset (AAO) of patients with ALS. The aim of the present study was to assess the association of the SCFD1 rs10139154 polymorphism with the risk of developing ALS. For this purpose, 155 patients with sporadic ALS and 155 healthy controls were genotyped for the SCFD1 rs10139154. The effect of the SCFD1 rs10139154 polymorphism was then examined on the following parameters: i) The risk of developing ALS; ii) the AAO of ALS; iii) the site of ALS onset (patients with bulbar onset ALS vs. healthy controls; and patients with limb onset ALS vs. healthy controls); and iv) the AAO of ALS onset with subgroup analyses based on the site of onset (bulbar and limb, crude and adjusted for sex). The analysis of all the outcomes was performed assuming five genetic models. Crude and adjusted analyses were applied. The threshold for statistical significance was set at 0.05. The results revealed no association between SCFD1 rs10139154 and any of the examined phenotypes in any of the models examined. On the whole, based on the findings of the present study, SCFD1 rs10139154 does not appear to play a determining role in the risk of developing ALS

Unraveling the Possible Routes of SARS-COV-2 Invasion into the Central Nervous System

Purpose of Review: To describe the possible neuroinvasion pathways of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemic. Recent Findings: We present data regarding the family of Coronaviruses (CoVs) and the central nervous system (CNS), and describe parallels between SARS-CoV-2 and other members of the family, which have been investigated in more depth and combine these findings with the recent advancements regarding SARS-CoV-2. Summary: SARS-CoV-2 like other CoVs is neuroinvasive, neurotropic and neurovirulent. Two main pathways of CNS penetration seem to be the strongest candidates, the hematogenous and the neuronal. Τhe olfactory route in particular appears to play a significant role in neuroinvasion of coronaviruses and SARS-CoV-2, as well. However, existing data suggest that other routes, involving the nasal epithelium in general, lymphatic tissue and the CSF may also play roles in SARS-CoV-2 invasion into the CNS

MOBP rs616147 Polymorphism and Risk of Amyotrophic Lateral Sclerosis in a Greek Population: A Case-Control Study

Background and Objectives: To date, only one study has investigated the association between the rs616147 polymorphism of the Myelin-associated Oligodendrocyte Basic Protein (MOBP) locus and Amyotrophic Lateral Sclerosis (ALS). Materials and Methods: A case-control study was performed. Patients with definite sporadic ALS were prospectively and consecutively recruited from the inpatient and outpatient clinics of the Neurology Department of the General University Hospital of Larissa, Central Greece. Community based, age and sex matched healthy individuals with a free personal and family history constituted the control group. Results: A total of 155 patients with definite sporadic ALS and an equal number of healthy controls were genotyped. The power of our sample size was slightly above 80% and MOBP rs616147 was determined to be in Hardy-Weinberg Equilibrium among healthy participants (p = 1.00). According to the univariate analysis, there was no significant relationship between rs616147 and ALS [log-additive OR = 0.85 (0.61, 1.19), over-dominant OR = 0.73 (0.46, 1.15), recessive OR = 1.02 (0.50, 2.09), dominant OR = 0.74 (0.47, 1.16), co-dominant OR1 = 0.71 (0.44, 1.14) and co-dominant OR2 = 0.88 (0.42, 1.84). Additionally, the effect of rs616147 on the age of ALS onset was determined insignificant using both unadjusted and adjusted (sex, site of onset) cox-proportional models. Finally, rs616147 was not related to the site of ALS onset. Conclusions: Our study is the first to report the absence of an association between MOBP rs616147 and ALS among individuals of Greek ancestry. Additional, larger nationwide and multi-ethnic studies are warranted to shed light on the connection between rs616147 and ALS

Study of genetic polymorphisms in patients with motor neuron disease

Introduction: Although the majority of cases with amyotrophic lateral sclerosis (ALS) are sporadic, about 10% are familial. Regarding the remaining 90%, heritability is considered to play an important role as well, with about 50% of the total risk variance being explained by genetics. Only 10% of the genetic architecture of ALS has been captured to date. Published literature suggests that single nucleotide polymorphisms (SNPs) 1) MOBP rs616147 and 2) SCFD1 rs10139154 are associated with ALS in western European and (southern) American populations but not in Asian ones, whereas there has been no relevant research involving individuals of Greek ancestry. On the other hand, the role of 3) CD33 rs3865444 (which is implicated in the regulation of inflammatory responses) has never been explored in ALS, in any population. The purpose of the current thesis was to examine the relationship between the three aforementioned SNPs and ALS in a well-defined Greek population. Methods: A prospective case-control study that adheres to the principles of candidate gene analyses was conducted. Patients with ALS were recruited from the Neurology department of the University General Hospital of Larissa. Consecutive invitations were addressed to every adult patient with ALS that visited the Neurology department, until achieving the prespecified sample size. The diagnosis of ALS was established according to the El-Escorial criteria by an expert neurologist with experience in neuromuscular disorders. In parallel, community-based healthy controls were randomly selected via individualized matching based on age (±2 years) and sex. DNA was isolated from nucleated white blood cells through the salting out method. The primary outcomes of the current study were the relationship between the SNPs MOBP rs616147, CD33 rs3865444, and SCFD1 rs10139154 and ALS (chi-squared tests – odds ratios). The association of the aforementioned SNPs with the age of ALS onset were defined as secondary outcomes (Cox proportional hazards models). Results: A total of 155 patients with ALS as well as 155 age and sex (individually) matched healthy controls were included. Genotyping was successful in >98% of the cases, with respect to every SNP. The power of our sample was >80% with respect to every analysis. All SNPs were found in Hardy-Weinberg equilibrium in the group of healthy controls. Statistical analysis revealed that MOBP rs616147, CD33 rs3865444, and SCFD1 rs10139154 were not related to the presence of ALS based on any heritability pattern (dominant, recessive, co-dominant, over-dominant, additive). Moreover, using both unadjusted as well as sex-adjusted Cox models, none of the aforementioned SNPs was associated with the age of ALS onset. Discussion: MOBP rs616147, CD33 rs3865444, and SCFD1 rs10139154 are neither related to the presence of ALS nor to the age of ALS onset in individuals of Greek ancestry.Εισαγωγή: Παρόλο που στην πλειοψηφία τους οι περιπτώσεις ασθενών με νόσο κινητικού νευρώνα (ΝΚΝ) είναι σποραδικές, ένα 10% του συνόλου των περιπτώσεων πάσχει από οικογενή ΝΚΝ. Στο υπόλοιπο 90% η κληρονομικότητα αποτελεί επίσης έναν ισχυρό προδιαθεσικό παράγοντα με περίπου 50% της μεταβλητότητας κινδύνου νόσησης να εξηγείται γενετικά. Μέχρι σήμερα έχει ανακαλυφθεί κατά προσέγγιση το 10% της γενετικής βάσης της ΝΚΝ. Στη δημοσιευμένη βιβλιογραφία οι μονονουκλεοτιδικοί πολυμορφισμοί (SNPs) 1) MOBP rs616147 και 2) SCFD1 rs10139154 έχουν συσχετιστεί με ΝΚΝ στον δυτικό-ευρωπαϊκό και αμερικάνικο πληθυσμό αλλά όχι στον ασιατικό (μη σημαντικά αποτελέσματα), ενώ απουσιάζει πλήρως η διερεύνηση αυτών των πολυμορφισμών στον ελληνικό πληθυσμό. Από την άλλη, ο ρόλος του 3) CD33 rs3865444 (υπεισέρχεται στη ρύθμιση και ισορροπία της φλεγμονώδους απόκρισης) δεν έχει μελετηθεί καθόλου στη NKN, σε κανέναν πληθυσμό. Σκοπός της παρούσας διατριβής είναι η διερεύνηση της συσχέτισης μεταξύ των εν λόγω πολυμορφισμών και της ΝΚΝ. Μεθοδολογία: Διενεργήθηκε μία προοπτική μελέτη πασχόντων-μαρτύρων που ακολουθεί της αρχές των candidate gene analyses (μελέτες υποψήφιων γονιδίων). Οι συμμετέχοντες εντοπίστηκαν προοπτικά στη Νευρολογική κλινική του Πανεπιστημιακού Γενικού Νοσοκομείου Λάρισας. Πρόταση συμμετοχής απευθύνθηκε διαδοχικά σε κάθε ενήλικα ασθενή με ΝΚΝ που παρουσιάστηκε στη Νευρολογική κλινική μέχρι την επίτευξη του επιθυμητού μεγέθους δείγματος. Η διάγνωση της νόσου βασίστηκε στα αναθεωρημένα κριτήρια El-Escorial και καθιερώθηκε από έναν ειδικό νευρολόγο με εμπειρία στις νευρομυικές διαταραχές. Παράλληλα, υγιείς μάρτυρες από την κοινότητα επιλέχθηκαν τυχαία, με τη διαδικασία της εξατομικευμένης αντιστοίχισης βάσει φύλου και ηλικίας (±2 έτη) με τους πάσχοντες. Η απομόνωση του DNA έγινε από εμπύρηνα λευκοκύτταρα με βάση τη μέθοδο της εξαλάτωσης. Ως πρωταρχικές εκβάσεις ορίστηκαν οι συσχετίσεις μεταξύ των πολυμορφισμών MOBP rs616147, CD33 rs3865444, και SCFD1 rs10139154 και της ΝΚΝ (chi-squared tests – odds ratios). Ως δευτερεύουσες εκβάσεις ορίστηκαν οι συσχετίσεις μεταξύ των εν λόγω SNPs και της ηλικίας έναρξης της ΝΚΝ (Cox proportional hazards models). Αποτελέσματα: Συνολικά, στην παρούσα μελέτη συμμετείχαν 155 ασθενείς με ΝΚΝ και 155 υγιείς μάρτυρες εξατομικευμένα αντιστοιχισμένοι βάσει ηλικίας και φύλου. Η γονοτύπηση ήταν επιτυχημένη σε >98% των περιπτώσεων, ως προς κάθε πολυμορφισμό. Επετεύχθη στατιστική ισχύς άνω του 80% για κάθε ανάλυση. Όλοι οι πολυμορφισμοί βρισκόταν σε ισορροπία κατά Hardy-Weinberg στους υγιείς μάρτυρες. Εκ της στατιστικής ανάλυσης, δεν προέκυψε στατιστικά σημαντική συσχέτιση μεταξύ των MOBP rs616147, CD33 rs3865444 και SCFD1 rs10139154 και της παρουσίας ΝΚΝ, σύμφωνα με όλα τα μοντέλα κληρονομικότητας (επικρατής-dominant, υπολειπόμενος-recessive, συν-επικρατής-co-dominant, υπερ-κυρίαρχος-over-dominant και συσσωρευτικός-additive τύπος). Επιπλέον, χρησιμοποιώντας τόσο μη σταθμισμένα – όσο και σταθμισμένα ως προς το φύλο μοντέλα επιβίωσης, οι αναλύσεις επιβίωσης ανέδειξαν πως οι εν λόγω πολυμορφισμοί δεν επιδρούν στην ηλικία έναρξης της νόσου. Συζήτηση: Στον ελληνικό πληθυσμό, οι πολυμορφισμοί MOBP rs616147, CD33 rs3865444 και SCFD1 rs10139154 δεν σχετίζονται με την παρουσία σποραδικής ΝΚΝ, ούτε επιδρούν στην ηλικία έναρξης της νόσου

The Relationship between Neuropsychiatric Symptoms and Cognitive Performance in Older Adults with Normal Cognition

Background and Objectives: To explore whether specific Neuropsychiatric Symptoms (NPS) are related to worse performance in particular cognitive domains. Materials and Methods: A cross-sectional analysis of the baseline evaluations of older (≥60 years), cognitively unimpaired (CU) participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set was performed. Data were derived from 43 Alzheimer’s Disease Research Centers. Cognitively impaired individuals, participants with psychiatric disorders and/or under treatment with antipsychotic, anxiolytic, sedative, or hypnotic agents were excluded. NPS were assessed using the Neuropsychiatric Inventory Questionnaire. The association of NPS with participants’ performance on episodic memory, semantic memory, language, attention, processing speed and executive function was analysed using an adjusted (considering important demographic and medical factors) multivariate general linear model. Results: A total of 7179 CU, older, predominantly female, Caucasian, and well-educated participants were included in the present analysis. Among them, 1856 individuals had one or more NPS. Our analysis revealed that moderate/severe anxiety was related to worse performance on semantic memory, attention and executive function, the presence of hallucinations was linked to worse processing speed and executive function scores, while the presence of elation/euphoria and aberrant motor behaviour were associated with poorer attention and language performance, respectively. In the context of a secondary, exploratory analysis, the presence of moderate/severe delusions was related to worse processing speed and executive function performance. Conclusions: The relationship between specific NPS and worse performance in particular cognitive domains could inform the formulation of individualized preventive strategies directed to the ‘‘fortification’’ of specific cognitive functions in CU individuals with NPS

Association between Motor Signs and Cognitive Performance in Cognitively Unimpaired Older Adults: A Cross-Sectional Study Using the NACC Database

Aiming to examine whether specific motor signs are associated with worse performance in specific cognitive domains among cognitively unimpaired (CU) individuals, we performed a cross-sectional analysis of data from the baseline evaluations of older, CU participants from the National Alzheimer’s Coordinating Center (NACC) Uniform Data Set. In total, 8149 CU (≥60 years) participants were included. Of these, 905 individuals scored ≥ 2 on at least one of the motor domains of the Unified Parkinson’s Disease Rating Scale part III (UPDRSIII). Cognitively impaired individuals, participants with psychiatric disorders and/or under treatment with antipsychotic, anxiolytic, sedative or hypnotic agents were excluded. Nine motor signs were examined: hypophonia, masked facies, resting tremor, action/postural tremor, rigidity, bradykinesia, impaired chair rise, impaired posture/gait and postural instability. Their association with performance on episodic memory, semantic memory, language, attention, processing speed or executive function was assessed using crude and adjusted linear regression models. Individuals with impaired chair rise had worse episodic memory, semantic memory, processing speed and executive function, while those with bradykinesia had worse language, processing speed and executive function. Sensitivity analyses, by excluding participants with cerebrovascular disease or PD, or other Parkinsonism, produced similar results with the exception of the relationship between bradykinesia and language performance

EEG in Neurorehabilitation: A Bibliometric Analysis and Content Review

Background: There is increasing interest in the role of EEG in neurorehabilitation. We primarily aimed to identify the knowledge base through highly influential studies. Our secondary aims were to imprint the relevant thematic hotspots, research trends, and social networks within the scientific community. Methods: We performed an electronic search in Scopus, looking for studies reporting on rehabilitation in patients with neurological disabilities. We used the most influential papers to outline the knowledge base and carried out a word co-occurrence analysis to identify the research hotspots. We also used depicted collaboration networks between universities, authors, and countries after analyzing the cocitations. The results were presented in summary tables, plots, and maps. Finally, a content review based on the top-20 most cited articles completed our study. Results: Our current bibliometric study was based on 874 records from 420 sources. There was vivid research interest in EEG use for neurorehabilitation, with an annual growth rate as high as 14.3%. The most influential paper was the study titled “Brain-computer interfaces, a review” by L.F. Nicolas-Alfonso and J. Gomez-Gill, with 997 citations, followed by “Brain-computer interfaces in neurological rehabilitation” by J. Daly and J.R. Wolpaw (708 citations). The US, Italy, and Germany were among the most productive countries. The research hotspots shifted with time from the use of functional magnetic imaging to EEG-based brain–machine interface, motor imagery, and deep learning. Conclusions: EEG constitutes the most significant input in brain–computer interfaces (BCIs) and can be successfully used in the neurorehabilitation of patients with stroke symptoms, amyotrophic lateral sclerosis, and traumatic brain and spinal injuries. EEG-based BCI facilitates the training, communication, and control of wheelchair and exoskeletons. However, research is limited to specific scientific groups from developed countries. Evidence is expected to change with the broader availability of BCI and improvement in EEG-filtering algorithms

Objective Physical Function in the Alzheimer’s Disease Continuum: Association with Cerebrospinal Fluid Biomarkers in the ALBION Study

Cognitive and physical decline, both indicators of aging, seem to be associated with each other. The aim of the present study was to investigate whether physical function parameters (walking time and handgrip strength) are related to cerebrospinal fluid (CSF) biomarkers (amyloid-beta Aβ42, Tau, PhTau) in individuals in the Alzheimer’s disease (AD) continuum. The sample was drawn from the Aiginition Longitudinal Biomarker Investigation of Neurodegeneration study, comprising 163 individuals aged 40–75 years: 112 cognitively normal (CN) and 51 with mild cognitive impairment (MCI). Physical function parameters were measured at baseline, a lumbar puncture was performed the same day and CSF biomarkers were analyzed using automated methods. The association between walking time, handgrip strength and CSF biomarkers was evaluated by linear correlation, followed by multivariate linear regression models adjusted for age, sex, education and APOEe4 genotype. Walking time was inversely related to CSF Aβ42 (lower CSF values correspond to increased brain deposition) in all participants (p < 0.05). Subgroup analysis showed that this association was stronger in individuals with MCI and participants older than 60 years old, a result which remained statistically significant after adjustment for the aforementioned confounding factors. These findings may open new perspectives regarding the role of mobility in the AD continuum

Qualitative Verbal Fluency Components as Prognostic Factors for Developing Alzheimer&rsquo;s Dementia and Mild Cognitive Impairment: Results from the Population-Based HELIAD Cohort

Background and Objectives: The aim of the present study was to investigate the prognostic value of the qualitative components of verbal fluency (clustering, switching, intrusions, and perseverations) on the development of mild cognitive impairment (MCI) and dementia. Materials and Methods: Participants were drawn from the multidisciplinary, population-based, prospective HELIAD (Hellenic Longitudinal Investigation of Aging and Diet) cohort. Two participant sets were separately analysed: those with normal cognition and MCI at baseline. Verbal fluency was assessed via one category and one letter fluency task. Separate Cox proportional hazards regressions adjusted for important sociodemographic parameters were performed for each qualitative semantic and phonemic verbal fluency component. Results: There were 955 cognitively normal (CN), older (72.9 years &plusmn;4.9), predominantly female (~60%) individuals with available follow-up assessments after a mean of 3.09 years (&plusmn;0.83). Among them, 34 developed dementia at follow-up (29 of whom progressed to Alzheimer&rsquo;s dementia (AD)), 160 developed MCI, and 761 remained CN. Each additional perseveration on the semantic condition increased the risk of developing all-cause dementia and AD by 52% and 55%, respectively. Of note, participants with two or more perseverations on the semantic task presented a much more prominent risk for incident dementia compared to those with one or no perseverations. Among the remaining qualitative indices, none were associated with the hazard of developing all-cause dementia, AD, and MCI at follow-up. Conclusions: Perseverations on the semantic fluency condition were related to an increased risk of incident all-cause dementia or AD in older, CN individuals