Search

Objective: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).Methods: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.Results: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (rs=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.Conclusions: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS. [ABSTRACT FROM AUTHOR]

Background: There is an unmet need in amyotrophic lateral sclerosis (ALS) to provide specific biomarkers for the disease. Due to their easy availability, we aimed to investigate whether routine blood parameters provide useful clues for phenotypic classification and disease prognosis. Methods: We analyzed a large inpatient cohort of 836 ALS patients who underwent deep phenotyping with evaluation of the clinical and neurophysiological burden of upper (UMN) and lower (LMN) motor neuron signs. Disability and progression rate were measured through the revised ALS Functional Rating Scale (ALSFRS-R) and its changes during time. Cox regression analysis was performed to assess survival associations. Results: Creatinine significantly correlated with LMN damage (r = 0.38), active (r = 0.18) and chronic (r = 0.24) denervation and baseline ALSFRS-R (r = 0.33). Creatine kinase (CK), alanine (ALT) and aspartate (AST) transaminases correlated with active (r = 0.35, r = 0.27, r = 0.24) and chronic (r = 0.37, r = 0.20, r = 0.19) denervation, while albumin and C-reactive protein significantly correlated with LMN score (r = 0.20 and r = 0.17). Disease progression rate showed correlations with chloride (r = −0.19) and potassium levels (r = −0.16). After adjustment for known prognostic factors, total protein [HR 0.70 (95% CI 0.57–0.86)], creatinine [HR 0.86 (95% CI 0.81–0.92)], chloride [HR 0.95 (95% CI 0.92–0.99)], lactate dehydrogenase [HR 0.99 (95% CI 0.99–0.99)], and AST [HR 1.02 (95% CI 1.01–1.02)] were independently associated with survival. Conclusions: Creatinine is a reliable biomarker for ALS, associated with clinical features, disability and survival. Markers of nutrition/inflammation may offer additional prognostic information and partially correlate with clinical features. AST and chloride could further assist in predicting progression rate and survival. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder characterized by relentless and progressive loss of motor neurons. A molecular diagnosis, supported by the identification of specific biomarkers, might promote the definition of multiple biological subtypes of ALS, improving patient stratification and providing prognostic information. Here, we investigated the levels of neurofilament light chain (NfL), chitotriosidase (CHIT1) and microRNA-181b (miR-181b) in the cerebrospinal fluid (CSF) of ALS subjects (N = 210) as well as neurologically healthy and neurological disease controls (N = 218, including N = 74 with other neurodegenerative diseases) from a large European multicentric cohort, evaluating their specific or combined utility as diagnostic and prognostic biomarkers. NfL, CHIT1 and miR-181b all showed significantly higher levels in ALS subjects compared to controls, with NfL showing the most effective diagnostic performance. Importantly, all three biomarkers were increased compared to neurodegenerative disease controls and, specifically, to patients with Alzheimer's disease (AD; N = 44), with NfL and CHIT1 being also higher in ALS than in alpha-synucleinopathies (N = 22). Notably, ALS patients displayed increased CHIT1 levels despite having, compared to controls, a higher prevalence of a polymorphism lowering CHIT1 expression. While no relationship was found between CSF miR-181b and clinical measures in ALS (disease duration, functional disability, and disease progression rate), CSF NfL was the best independent predictor of disease progression and survival. This study deepens our knowledge of ALS biomarkers, highlighting the relative specificity of CHIT1 for ALS among neurodegenerative diseases and appraising the potential diagnostic utility of CSF miR-181b. [ABSTRACT FROM AUTHOR]

Background:. The present study aimed at deriving regression-based reliable change indices (RCIs) for the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented Parkinson's disease (PD) patients. Methods: N = 33 consecutive, non-demented PD patients were followed-up at a 5-to-8-month interval (M = 6.6; SD = 0.6) with the MoCA. Practice effects and test-retest reliability were assessed via dependent-sample t-tests and intra-class correlation (ICC) coefficients, respectively. RCIs were derived separately for raw and demographically adjusted MoCA scores according to a standardized regression-based approach by accounting for both baseline confounders (i.e., demographics, disease duration and Unified Parkinson's Disease Rating Scale scores) and retest interval. Results: No practice effects were found (t(32) = 0.29; p =.778), with acceptable test-retest reliability being detected (ICC = 0.67). MoCA scores at T0 proved to be the only significant predictor of T1 MoCA performances within both the model addressing raw scores and that addressing adjusted scores (ps < 0.001). Conclusions: The present study provides Italian practitioners and researchers with regression-based RCIs for the MoCA in non-demented PD patients, which can be reliably adopted for retest interval ≥ 5 and ≤ 8 months without encountering any practice effect. [ABSTRACT FROM AUTHOR]

Objective: To define the clinical usability of an affect recognition (AR) battery—the Comprehensive Affect Testing System (CATS)—in an Italian sample of patients with amyotrophic lateral sclerosis (ALS). Methods: 96 ALS patients and 116 healthy controls underwent a neuropsychological assessment including the AR subtests of the abbreviated version of the CATS (CATS-A). CATS-A AR subtests and their global score (CATS-A AR Quotient, ARQ) were assessed for their factorial, convergent, and divergent validity. The diagnostic accuracy of each CATS-A AR measure in discriminating ALS patients with cognitive impairment from cognitively normal controls and patients was tested via receiver-operating characteristics analyses. Optimal cut-offs were identified for CATS-A AR measures yielding an acceptable AUC value (≥.70). The ability of CATS-A ARQ to discriminate between different ALS cognitive phenotypes was also tested. Gray-matter (GM) volumes of controls, ALS with normal (ALS-nARQ), and impaired ARQ score (ALS-iARQ) were compared using ANCOVA models. Results: CATS-A AR subtests and ARQ proved to have moderate-to-strong convergent and divergent validity. Almost all considered CATS-A measures reached acceptable accuracy and diagnostic power (AUC range =.79–.83). ARQ showed to be the best diagnostic measure (sensitivity =.80; specificity =.75) and discriminated between different ALS cognitive phenotypes. Compared to ALS-nARQ, ALS-iARQ patients showed reduced GM volumes in the right anterior cingulate, right middle frontal, left inferior temporal, and superior occipital regions. Conclusions: The AR subtests of the CATS-A, and in particular the CATS-A ARQ, are sound measures of AR in ALS. AR deficits may be a valid marker of frontotemporal involvement in these patients. [ABSTRACT FROM AUTHOR]

Background: This study aimed at preliminarily assessing, in a cohort of non-demented amyotrophic lateral sclerosis (ALS) patients, the ecological validity, and more specifically the veridicality, of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioral Screen (ALS-CBS™), by relating their scores to caregiver-report ratings of cognitive changes. Methods: N = 147 patient-caregiver dyads were recruited. Patients were administered the ECAS and ALS-CBS™, whilst caregiver the Caregiver Behavioral Questionnaire (CBQ) and Beaumont Behavioural Inventory (BBI). An Ecological Cognitive Functioning Index (ECFI) was derived from those items of the CBQ and BBI that tap on executive and language changes. Ecological validity was assessed via both correlational and predictive analyses net of caregiver-rated behavioural changes (as assessed by the ECAS-Carer Interview). Results: The ECFI was associated with the total scores on both the ECAS (p =.014) and ALS-CBS™ (p =.017). When looking at ECAS and ALS-CBS™ subscales, those assessing verbal fluency were selectively associated with the ECFI. The ECFI was higher in patients performing defectively on the ECAS (p =.004) and on the ALS-CBS™ (p =.027). Discussion: This study suggests that both the ECAS and the ALS-CBS™ represent a valid estimate of non-demented ALS patients' cognitive status in the real world, also highlighting the clinical relevance of cognitive changes reported by caregivers. [ABSTRACT FROM AUTHOR]

Background: This study aimed at (1) delivering generalizable estimates of the prevalence of frontotemporal-spectrum disorders (FTSDs) in non-demented ALS patients and (2) exploring their motor-functional correlates. Methods: N = 808 ALS patients without FTD were assessed for motor-functional outcomes—i.e., disease duration, severity (ALSFRS-R), progression rate (ΔFS), and stage (King's and Milano–Torino—MiToS—systems)—cognition—via the cognitive section of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS)—and behaviour—via the ECAS-Carer Interview. Neuropsychological phenotypes were retrieved via Strong's revised criteria—i.e., ALS cognitively and behaviourally normal (ALScbn) or cognitively and/or behaviourally impaired (ALSci/bi/cbi). Results: Defective ECAS-Total performances were detected in ~ 29% of patients, with the ECAS-Executive being failed by the highest number of patients (~ 30%), followed by the ECAS-Language, -Fluency, and -Memory (~ 15–17%) and -Visuospatial (~ %8). Apathy was the most frequent behavioural change (~ 28%), followed by loss of sympathy/empathy (~ 13%); remaining symptoms were reported in < 4% of patients. The distribution of Strong's classifications was as follows: ALScbn: 46.7%; ALSci/bi/cbi: 22.9%/20.0%/10.4%. Multinomial regressions on Strong's classifications revealed that lower ALSFRS-R scores were associated with a higher probability of ALSbi and ALScbi classifications (p ≤.008). Higher King's and MiToS stages were associated with a higher probability of ALSbi classification (p ≤.031). Conclusions: FTSDs affect ~ 50% of non-demented ALS patients, with cognitive deficits being as frequent as behavioural changes. A higher degree of motor-functional involvement is associated with worse behavioural outcomes—with this link being weaker for cognitive deficits. [ABSTRACT FROM AUTHOR]

Introduction: Learning is a long-term memory process heavily influenced by the control processes implemented by working memory, including recognition of semantic properties of items by which subjects generate a semantic structure of engrams. Aim: The aim of this study is to investigate the verbal learning strategies of patients affected by a tumor in the left frontal lobe to highlight the role of area 9. Method: Ten patients with frontal low-grade gliomas and ten healthy control subjects, matched for age, sex and education, were recruited and then evaluated with a two-part verbal learning test: multi-trial word list learning in free recall, and multi-trial word list learning preceded by an explicit semantic strategy cue. Frontal patients were divided into two groups: those either with frontal lesions involving or sparing area 9. Results: In comparison to healthy control subjects, frontal patients with lesions involving area 9 memorized fewer words and displayed difficulty in using semantic strategies. When the strategy was suggested by the examiner, their performance improved, but to a lesser extent than the healthy control. Conversely, frontal patients with lesions sparing area 9 showed similar results to healthy control subjects. Conclusion: The results suggested that, while the identification of the categorical criterion requires the integrity of the entire dorsolateral prefrontal area, only area 9, and not the surrounding areas, could be responsible for the effective use of semantic strategies in learning tasks. [ABSTRACT FROM AUTHOR]

Background: Beyond memory deterioration, spatial disorientation may occur along the continuum of normal aging—dementia of Alzheimer's type. The present study aims at detecting behavioral disorders of spatial cognition in prodromal Alzheimer's disease (AD) and verifying the association between Apolipoprotein E-ε4 (ApoE-ε4) genotype and gait patterns during a real-world naturalistic task. Methods: A sample of 58 elderly participants, of which 20 patients with mild cognitive impairment with CFS biomarker evidence of AD, 23 individuals with subjective cognitive decline (SCD), and 15 healthy controls (HCs), was tested by a modified version of the Detour Navigation Test (DNT-mv). Generalized linear models were run to explore the association between group belonging and wrong turns (WTs)/moments of hesitation (MsH) as behavioral disorientation scores of the DNT-mv as well as the effect of ApoE-ε4 genotype on time and walking speed registered by a smartphone app providing GPS tracking of body movement around urban environments. Results: Patients with MCI due to AD reported more WTs than individuals with SCD and HCs. Further, the ApoE-ε4 genotype determined a lower capacity in spatial information processing, influencing gait during naturalistic spatial navigation tasks. Conclusions: Behavior alterations of spatial cognition can be detected ecologically in prodromal AD. The use of technological solutions supporting gait analysis may help in corroborating the experimental observation. [ABSTRACT FROM AUTHOR]

Neurological monogenic loss-of-function diseases are hereditary disorders resulting from gene mutations that decrease or abolish the normal function of the encoded protein. These conditions pose significant therapeutic challenges, which may be resolved through the development of innovative therapeutic strategies. RNA-based technologies, such as mRNA replacement therapy, have emerged as promising and increasingly viable treatments. Notably, mRNA therapy exhibits significant potential as a mutation-agnostic approach that can address virtually any monogenic loss-of-function disease. Therapeutic mRNA carries the information for a healthy copy of the defective protein, bypassing the problem of targeting specific genetic variants. Moreover, unlike conventional gene therapy, mRNA-based drugs are delivered through a simplified process that requires only transfer to the cytoplasm, thereby reducing the mutagenic risks related to DNA integration. Additionally, mRNA therapy exerts a transient effect on target cells, minimizing the risk of long-term unintended consequences. The remarkable success of mRNA technology for developing coronavirus disease 2019 vaccines has rekindled interest in mRNA as a cost-effective method for delivering therapeutic proteins. However, further optimization is required to enhance mRNA delivery, particularly to the CNS, while minimizing adverse drug reactions and toxicity. In this comprehensive review, we delve into past, present and ongoing applications of mRNA therapy for neurological monogenic loss-of-function diseases. We also discuss the promises and potential challenges presented by mRNA therapeutics in this rapidly advancing field. Ultimately, we underscore the full potential of mRNA therapy as a game-changing therapeutic approach for neurological disorders. [ABSTRACT FROM AUTHOR]

Background: Semantic behavioral variant frontotemporal dementia (sbvFTD) is a neurodegenerative condition presenting with specific behavioral and semantic derangements and predominant atrophy of the right anterior temporal lobe (ATL). The objective was to evaluate clinical, neuropsychological, neuroimaging, and genetic features of an Italian sbvFTD cohort, defined according to recently proposed guidelines, compared to semantic variant primary progressive aphasia (svPPA) and behavioral variant FTD (bvFTD) patients. Methods: Fifteen sbvFTD, sixty-three bvFTD, and twenty-five svPPA patients and forty controls were enrolled. Patients underwent clinical, cognitive evaluations, and brain MRI. Symptoms of bvFTD patients between onset and first visit were retrospectively recorded and classified as early and late. Grey matter atrophy was investigated using voxel-based morphometry. Results: sbvFTD experienced early criteria-specific symptoms: world, object and person-specific semantic loss (67%), complex compulsions and rigid thought (60%). Sequentially, more behavioral symptoms emerged (apathy/inertia, loss of empathy) along with non-criteria-specific symptoms (anxiety, suspiciousness). sbvFTD showed sparing of attentive/executive functions, especially compared to bvFTD and better language functions compared to svPPA. All sbvFTD patients failed at the famous face recognition test and more than 80% failed in understanding written metaphors and humor. At MRI, sbvFTD had predominant right ATL atrophy, almost specular to svPPA. Three sbvFTD patients presented pathogenic genetic variants. Conclusion: We replicated the application of sbvFTD diagnostic guidelines in an independent Italian cohort, demonstrating that the presence of person-specific semantic knowledge loss and mental rigidity, along with preserved executive functions and a predominant right ATL atrophy with sparing of frontal lobes, should prompt a diagnosis of sbvFTD. [ABSTRACT FROM AUTHOR]

Background: This study is aimed at assessing the clinimetric properties and feasibility of the Italian version of the Montreal Cognitive Assessment (MoCA) in patients with Huntington's disease (HD). Methods: N = 39 motor-manifest HD patients, N = 74 Parkinson's disease (PD) patients and N = 92 matched HCs were administered the MoCA. HD patients further underwent the Unified Huntington's Disease Rating Scale (UHDRS), self-report questionnaires for anxiety and depression and a battery of first- and second-level cognitive tests. Construct validity was tested against cognitive and behavioural/psychiatric measures, whereas ecological validity against motor-functional subscales of the UHDRS. Sensitivity to disease severity was tested, via a logistic regression, by exploring whether the MoCA discriminated between patients in Shoulson-Fahn stage ≤ 2 vs. > 2. The same analysis was employed to test its ability to discriminate HD patients from HCs and PD patients. Results: The MoCA converged towards cognitive and behavioural measures but diverged from psychiatric ones, being also associated with motor/functional measures from the UHDRS. In identifying patients with cognitive impairment, adjusted MoCA scores were highly accurate (AUC =.92), yielding optimal diagnostics at the cut-off of < 19.945 (J =.78). The MoCA was able to discriminate patients in the middle-to-advanced from those in the early-to-middle stages of the disease (p =.037), as well as to differentiate HD patients from both HCs (p <.001) and PD patients (p <.001). Conclusions: The MoCA is a valid, diagnostically sound and feasible cognitive screener in motor-manifest HD patients, whose adoption is thus encouraged in clinical practice and research. [ABSTRACT FROM AUTHOR]

Introduction: The present study aimed at testing the longitudinal feasibility of the Montreal Cognitive Assessment (MoCA) in an Italian cohort of non-demented amyotrophic lateral sclerosis (ALS) patients. Methods:N = 39 non-demented ALS patients were followed-up at a 5-to-10-month interval (M = 6.8; SD = 1.4) with the MoCA and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS). Practice effects, test-retest reliability, and predictive validity (against follow-up ECAS scores) were assessed. Reliable change indices (RCIs) were derived via a regression-based approach by accounting for retest interval and baseline confounders (i.e., demographics, disease duration, and severity and progression rate). Results: At retest, 100% and 69.2% of patients completed the ECAS and the MoCA, respectively. Patients who could not complete the MoCA showed a slightly more severe and fast-progressing disease. The MoCA was not subject to practice effects (t[32] = −0.80; p = 0.429) and was reliable at retest (intra-class correlation = 0.82). Moreover, baseline MoCA scores predicted the ECAS at retest. RCIs were successfully derived – with baseline MoCA scores being the only significant predictor of retest performances (ps < 0.001). Conclusions: As long as motor disabilities do not undermine its applicability, the MoCA appears to be longitudinally feasible at a 5-to-10-month interval in non-demented ALS patients. However, ALS-specific screeners – such as the ECAS – should be preferred whenever possible. [ABSTRACT FROM AUTHOR]

Background: This study aimed at assessing the clinical usability of the Story-Based Empathy Task (SET) in non-demented amyotrophic lateral sclerosis (ALS) patients. Methods: N = 106 non-demented ALS patients and N = 101 healthy controls (HCs) were administered the SET, which includes three subtests assessing Emotion Attribution (SET-EA), Intention Attribution (SET-IA) and causal inference (SET-CI) — the latter being a control task. Patients also underwent the Reading the Mind in the Eyes Test (RMET), the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and a thorough behavioural and motor-functional evaluation. The diagnostics of the SET-EA and -IA were tested against a defective performance on the RMET. The association between SET subtests and cognitive/behavioural outcomes was examined net of demographic and motor-functional confounders. Case-control discrimination was explored for each SET subtest. Results: Demographically adjusted SET-EA and -IA scores accurately detected defective RMET performances at the optimal cutoffs of <3.04 (AUC =.84) and <3.61 (AUC =.88), respectively. By contrast, the SET-CI performed poorly in doing so (AUC =.58). The SET-EA converged with the RMET, as well as with ECAS-Executive and -Memory scores, whilst the SET-IA was unrelated to cognitive measures (including the RMET); the SET-CI was related to the ECAS-Language the ECAS-Executive. SET subscores were unrelated to behavioural outcomes. Only the SET-EA discriminated patients from HCs. Conclusions: The SET as a whole should not be addressed as a social-cognitive measure in this population. At variance, its subtest tapping on emotional processing — i.e., the SET-EA — is recommended for use as an estimate of social-cognitive abilities in non-demented ALS patients. [ABSTRACT FROM AUTHOR]

Background: The present study aimed at deriving equating norms to estimate scores on the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) based on those on the ALS Cognitive Behavioral Screen (ALS-CBS™) in an Italian cohort of non-demented ALS patients. Methods: ALS-CBS™ and ECAS scores of 293 ALS patients without frontotemporal dementia were retrospectively retrieved. Concurrent validity of the ALS-CBS™ towards the ECAS was tested by covarying for demographics, disease duration and severity, presence of C9orf72 hexanucleotide repeat expansion and behavioural features. A linear-smoothing equipercentile equating (LSEE) model was employed to derive ALS-CBS™-to-ECAS cross-walks. Gaps in LSEE-based estimation were managed via a linear regression-based equating approach. Equivalence between empirical and derived ECAS scores was tested via a two-one-sided test (TOST) procedure for the dependent sample. Results: The ALS-CBS™ predicted the ECAS (β = 0.75), accounting for the vast majority of its variance (60% out of an R2 = 0.71). Consistently, a strong, one-to-one linear association between ALS-CBS™ and ECAS scores was detected (r = 0.84; R2 = 0.73). The LSEE was able to estimate conversions for the full range of the ALS-CBS™, except for raw scores equal to 1 and 6 – for whom a linear equating-based equation was derived. Empirical ECAS scores were equivalent to those derived with both methods. Discussion: Italian practitioners and researchers have been herewith provided with valid, straightforward cross-walks to estimate the ECAS based on ALS-CBS™ scores in non-demented ALS patients. Conversions herewith provided will help avoid cross-sectional/longitudinal inconsistencies in test adoption within research, and possibly clinical, settings. [ABSTRACT FROM AUTHOR]

Background: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. Results: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion—amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. Conclusions: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS. [ABSTRACT FROM AUTHOR]

Background: This study aimed at assessing the cross-sectional and longitudinal clinimetrics and feasibility of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease (PD) patients. Methods: N = 109 PD patients underwent the FAB and the Montreal Cognitive Assessment (MoCA). A subsample of patients further underwent a thorough motor, functional and behavioral evaluation (the last including measures of anxiety, depression and apathy). A further subsample was administered a second-level cognitive battery tapping on attention, executive functioning, language, memory, praxis and visuo-spatial abilities. The following properties of the FAB were tested: (1) concurrent validity and diagnostics against the MoCA; (2) convergent validity against the second-level cognitive battery; (4) association with motor, functional and behavioral measures; (5) capability to discriminate patients from healthy controls (HCs; N = 96); (6) assessing its test–retest reliability, susceptibility to practice effects and predictive validity against the MoCA, as well as deriving reliable change indices (RCIs) for it, at a ≈ 6-month interval, within a subsample of patients (N = 33). Results: The FAB predicted MoCA scores at both T0 and T1, converged with the vast majority of second-level cognitive measures and was associated with functional independence and apathy. It accurately identified cognitive impairment (i.e., a below-cut-off MoCA score) in patients, also discriminating patients from HCs. The FAB was reliable at retest and free of practice effects; RCIs were derived according to a standardized regression-based approach. Discussion: The FAB is a clinimetrically sound and feasible screener for detecting dysexecutive-based cognitive impairment in non-demented PD patients. [ABSTRACT FROM AUTHOR]

Background: The present study aimed at (1) providing further validity and reliability evidence for the Italian version of the cognitive section of the ALS Cognitive Behavioral Screen (ALS-CBS™) and (2) testing its diagnostics within an Italian ALS cohort, as well as at (3) exploring its capability to discriminate patients from healthy controls (HCs). Methods: N = 293 non-demented ALS patients were administered the cognitive sections of the ALS-CBS™ and Edinburgh Cognitive and Behavioural ALS Screen (ECAS). N = 96 HCs demographically matched with N = 96 patients were also administered the cognitive section of the ALS-CBS™. In patients, factorial and construct validity, internal reliability, and diagnostics against a defective score on the cognitive section of the ECAS were tested. Case–control discrimination was assessed via a logistic regression. Results: ALS-CBS™ cognitive subscales were underpinned by a simple, unidimensional structure, internally reliable (McDonald's ω = 0.74), and mostly related with ECAS executive and fluency scores (rs = 0.54–0.71). Both raw and age- and education-adjusted scores on the cognitive section of the ALS-CBS™ accurately detected ECAS-defined cognitive impairment (AUC = 0.80 and.88, respectively), yielding optimal error-based, information-based and unitary diagnostics. A cut-off of < 15.374 was identified on adjusted scores. The test was able to discriminate patients from HCs (p < 0.001). Discussion: The cognitive section of the Italian ALS-CBS™ is a valid, reliable, and diagnostically sound ALS-specific screener for detecting frontotemporal, executive-/attentive-based cognitive inefficiency in non-demented ALS patients, being also able to discriminate them from normotypical individuals. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Clinimetrics and feasibility of the Italian version of the Frontal Assessment Battery (FAB) in non-demented Parkinson's disease patients" published in the Journal of Neural Transmission. The correction addresses an error in Table 5 of the original article, specifically in the column titled "Predicted score T1 (T1ˈ)". The corrected table is provided in the correction notice. The authors apologize for the error and any inconvenience caused. The document also includes the names of the authors involved in the article. [Extracted from the article]

Background: This study aimed at providing diagnostic properties and normative cut-offs for the Italian ECAS Carer Interview (ECAS-CI). Materials: N = 292 non-demented ALS patients and N = 107 healthy controls (HCs) underwent the ECAS-CI and the Frontal Behavioural Inventory (FBI). Two ECAS-CI measures were addressed: (1) the number of symptoms (NoS; range = 0–13) and (2) that of individual symptom clusters (SC; range = 0–6). Diagnostics were explored against an FBI score ≥ than the 95th percentile of the patients' distribution. Results: Both the NoS and SC discriminated patient from HCs. High accuracy, sensitivity, and specificity were detected for both the NoS and SC; however, at variance with SC, the NoS showed better post-test features and did not overestimate the occurrence of behavioural changes. The ECAS-CI converged with the FBI and diverged from the cognitive section of the ECAS. Discussion: The ECAS-CI is a suitable screener for behavioural changes in ALS patients, with the NoS being its best outcome measure (cut-off: ≥ 3). [ABSTRACT FROM AUTHOR]

Introduction: Amyotrophic lateral sclerosis (ALS) individuals carrying the hexanucleotide repeat expansion (HRE) in the C9orf72 gene (C9Pos) have been described as presenting distinct features compared to the general ALS population (C9Neg). We aim to identify the phenotypic traits more closely associated with the HRE and analyse the role of the repeat length as a modifier factor. Methods: We studied a cohort of 960 ALS patients (101 familial and 859 sporadic cases). Motor phenotype was determined using the MRC scale, the lower motor neuron score (LMNS) and the Penn upper motor neuron score (PUMNS). Neuropsychological profile was studied using the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS), the Frontal Behavioral Inventory (FBI), the Beck Depression Inventory-II (BDI-II) and the State-Trait Anxiety Inventory (STAI). A two-step PCR protocol and Southern blotting were performed to determine the presence and the size of C9orf72 HRE, respectively. Results: C9orf72 HRE was detected in 55/960 ALS patients. C9Pos patients showed a younger onset, higher odds of bulbar onset, increased burden of UMN signs, reduced survival and higher frequency of concurrent dementia. We found an inverse correlation between the HRE length and the performance at ECAS ALS-specific tasks (P = 0.031). Patients also showed higher burden of behavioural disinhibition (P = 1.6 × 10–4), lower degrees of depression (P = 0.015) and anxiety (P = 0.008) compared to C9Neg cases. Conclusions: Our study provides an extensive characterization of motor, cognitive and behavioural features of C9orf72-related ALS, indicating that the C9orf72 HRE size may represent a modifier of the cognitive phenotype. [ABSTRACT FROM AUTHOR]

Background : The cerebrospinal fluid (CSF)/serum albumin quotient (Q-Alb) is a marker of the blood-CSF barrier (BCSFB) and possibly of the blood–brain barrier (BBB). The latter is known to be altered in Alzheimer's disease (AD) based on neuropathological and neuroimaging studies. Following investigations performed on clinically diagnosed cohorts, we aimed at comparing Q-Alb in cognitively impaired patients with neurochemical demonstration of AD pathophysiology and neurological disease controls (NDCs). Methods: We evaluated N = 144 AD patients (MCI, N = 43; AD dementia — ADD, N = 101) and N = 132 NDCs. AD patients were all A + according to the A/T/N framework and were neurochemically classified based on T and N parameters. Results: Q-Alb did not significantly differ between AD patients and NDCs. Moreover, it was not associated with disease stage (MCI vs. ADD), MMSE score, or CSF AD biomarkers. Discussion: Our study indicates that BCSFB dysfunction is not a specific feature of AD. When interpreting Q-Alb as a marker of the BBB, the lack of difference from NDCs might be due to BBB dysfunction widely occurring in other neurological, non-degenerative, conditions or — more probably — to low sensitivity of this biochemical parameter towards subtle BBB alterations causing leakage of molecules smaller than albumin. Furthermore, Q-Alb is not associated with the degree of global cognitive deterioration in AD, nor with CSF AD neurochemical biomarkers. [ABSTRACT FROM AUTHOR]

Background: The present study aimed at evaluating the diagnostic properties of the Frontal Assessment Battery (FAB) in non-demented ALS patients by addressing the Edinburgh Cognitive Behavioural ALS Screen (ECAS) as the gold standard, as well as by examining the association between its administrability and scores with motor-functional measures. Materials: N = 348 consecutive patients were administered the ECAS and FAB. Disease severity (ALSFRS-R), duration, progression rate (ΔFS), and stages (via King's and Milano-Torino systems) were considered. Administrability rates and prevalence of below-cut-off FAB scores were compared across clinical stages; regression models allowed to test whether, net of the ECAS-Total, motor features predicted the probability of the FAB not being administrable and of a defective FAB score. Intrinsic and post-test diagnostics were explored against a combined defective ECAS-Executive and ECAS-Fluency scores. Results: 85.3% of patients managed to complete the FAB. FAB administrability rates decreased with advanced clinical stages, whereas the prevalence of below-cut-off FAB scores did not. The probability of the FAB not being administrable was predicted only by lower ALSFRS-R-bulbar and ALSFRS-R-upper-limb scores; no motor features, but the ECAS-Total, predicted a below-cut-off performance on the FAB. Raw and adjusted FAB scores showed high accuracy (AUC =.85 and.81, respectively) and good intrinsic and post-test properties. Discussion: The FAB is featured by optimal diagnostics for detecting executive deficits in ALS, provided that it can be administered according to its original, standardized procedure, and thus that patients have sufficiently spared motor abilities to complete the test. [ABSTRACT FROM AUTHOR]

Introduction: Even if electromyography (EMG) is routinely used to confirm the diagnosis of amyotrophic lateral sclerosis (ALS), few studies have analysed the correlation between electrophysiological parameters and clinical characteristics of ALS. We assessed if the quantification of active denervation (AD) and chronic denervation (CD) provides clinicians with information about phenotype, disease progression and survival in ALS patients. Methods: We studied a cohort of 689 ALS patients recording the following parameters: age and site of onset, survival, MRC scale for muscle strength evaluation, burden of upper and lower motor signs as measured with specific scales (PUMNS and LMNS, respectively), ALSFRS-R, progression rate (ΔFS), MITOS and King's Staging systems (KSS). We performed EMG on 11 muscles, and calculated semiquantitative AD and CD scores for each limb, as well as for the bulbar and spinal regions. Results: We found a positive correlation between AD and CD scores with LMNS (respectively p = 4.4 × 10–37 and p = 2.8 × 10–45) and a negative correlation with MRC (respectively p = 4.5 × 10–35 and p = 3.0 × 10–35). Furthermore, patients with higher spinal AD and CD scores had significantly lower ALSFRS-R scores, and higher KSS and MITOS stages. Conversely, only AD was associated to higher ΔFS (p = 1.0 × 10–6) and shorter survival (p = 1.1 × 10–5). Conclusion: Our results confirmed that EMG examination represents not only a diagnostic instrument, but also a prognostic tool. In this context, AD seems to be a reliable predictor of disease's progression and survival while CD better describes functional disability. [ABSTRACT FROM AUTHOR]

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative condition affecting upper and/or lower motor neurons and characterized neuropathologically by TDP-43 proteinopathy. Given its role in ALS pathobiology, it is currently under debate whether TDP-43 might represent a suitable ALS biomarker to be measured in patients' biofluids. The rs12608932 A > C single nucleotide polymorphism in the UNC13A gene is a risk factor for ALS and patients homozygous for the high-risk C allele display a higher burden of TDP-43 neuropathology than homozygotes for the low-risk A allele, although the association with TDP-43 levels in biofluids has never been evaluated. In this study, we measured serum levels of TDP-43 and neurofilament light chain (NFL) by Simoa technology in a cohort of 69 ALS patients stratified according to the UNC13A rs12608932 genotype compared to 43 neurologically healthy controls. By multiple linear regression analysis, serum TDP-43 was significantly elevated in ALS patients compared to controls, with UNC13A AA and AC, but not CC, ALS patients showing higher serum TDP-43 levels than controls. We also confirmed that serum NFL concentration was increased in ALS patients, without any correlation with the UNC13A genotype. Our results indicate that serum TDP-43 is higher in ALS patients compared to controls and that, in contrast to NFL, this increase is specifically associated with the UNC13A rs12608932 AA and AC genotypes, but not with the high-risk CC genotype. Studies in larger cohorts will be needed to confirm these findings and to elucidate the biological link between serum TDP-43 levels and UNC13A genotype. • Serum TDP-43 levels are significantly elevated in ALS patients compared to controls. • ALS patients were stratified for the risk rs12608932 (A > C) genotype in UNC13A. • Patients with AA and AC genotypes have higher serum TDP-43 levels than controls. • Patients with the CC risk genotype have serum TDP-43 levels similar to controls. • Serum NFL was increased in ALS patients, with no correlation to the UNC13A genotype. [ABSTRACT FROM AUTHOR]

Background: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency – S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60”-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale – Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score – regardless of whether they presented or not with a below-cutoff NoW – reported worse ECAS-Executive scores than NoW + VFI + ones.The present reports support the use of the Italian VFI as a mean to validly assess ALS patients’ executive status by limiting the effect of motor disabilities that might undermine their speech rate.Methods: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency – S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60”-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale – Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score – regardless of whether they presented or not with a below-cutoff NoW – reported worse ECAS-Executive scores than NoW + VFI + ones.The present reports support the use of the Italian VFI as a mean to validly assess ALS patients’ executive status by limiting the effect of motor disabilities that might undermine their speech rate.Results: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency – S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60”-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale – Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score – regardless of whether they presented or not with a below-cutoff NoW – reported worse ECAS-Executive scores than NoW + VFI + ones.The present reports support the use of the Italian VFI as a mean to validly assess ALS patients’ executive status by limiting the effect of motor disabilities that might undermine their speech rate.Conclusions: This study aimed at assessing the clinical utility of the Verbal Fluency Index (VFI) over a classical phonemic verbal fluency test in Italian-speaking amyotrophic lateral sclerosis (ALS) patients.N = 343 non-demented ALS patients and N = 226 healthy controls (HCs) were administered the Verbal fluency – S task from the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). The associations between the number of words produced (NoW), the time to read words aloud (TRW) and the VFI (computed as [(60”-TRW)/NoW]) on one hand and both bulbar/respiratory scores from the ALS Functional Rating Scale – Revised (ALSFRS-R) and the ECAS-Executive on the other were tested. Italian norms for the NoW and the VFI were derived in HCs via the Equivalent Score method. Patients were classified based on their impaired/unimpaired performances on the NoW and the VFI (NoW-VFI-; NoW-VFI+; NoW + VFI-; NoW + VFI+), with these groups being compared on ECAS-Executive scores.The VFI, but neither the NoW nor the TRW, were related to ALSFRS-Bulbar/-Respiratory scores; VFI and NoW measures, but not the TRW, were related to the ECAS-Executive (p < .001). The NoW slightly overestimated the number of executively impaired patients when compared to the VFI (31.1% vs. 26.8%, respectively). Patients with a defective VFI score – regardless of whether they presented or not with a below-cutoff NoW – reported worse ECAS-Executive scores than NoW + VFI + ones.The present reports support the use of the Italian VFI as a mean to validly assess ALS patients’ executive status by limiting the effect of motor disabilities that might undermine their speech rate. [ABSTRACT FROM AUTHOR]

We describe 3 cases of solitary sclerosis (SS), a rare condition characterized by a single inflammatory demyelinating lesion in the white matter of the brain or spinal cord. All patients had progressive limb motor impairment (patient 1, 66-year-old female: left spastic hemiparesis; patient 2, 39-year-old male: right spastic hemiparesis; patient 3, 42-year-old female: proximally predominant left upper limb weakness with amyotrophy and fasciculations). In all patients, MRI disclosed a single small T2-hyperintense demyelinating lesion: in the right anterior paramedian upper medulla, in the median-left paramedian anterior lower medulla, and in the left paramedian anterior cervical spinal cord at C4 level, respectively. In patients 1 and 2, transcranial magnetic stimulation (TMS) demonstrated altered motor evoked potentials (MEPs) and increased central motor conduction time (CMCT) in the affected limbs; in patient 3, needle EMG revealed chronic neurogenic changes in C5–C7 muscles of left upper limb. Patients 1 and 2 had normal brain 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET). CSF analysis demonstrated IgG oligoclonal bands in all patients. In patients 2 and 3, levels of neurofilament light chain (NFL) in CSF and serum, respectively, were within normal limits. The three cases were consistent with the diagnosis of SS. Notably, while the first two cases mimicked Mills' syndrome (the hemiparetic variant of primary lateral sclerosis, PLS), the third one was rather reminiscent of amyotrophic lateral sclerosis (ALS). This suggests including SS in the differential diagnosis not only of PLS, but also of ALS. We also report the first quantification of NFL levels in SS. [ABSTRACT FROM AUTHOR]

• Skeletal muscle channelopathies are rare genetic diseases. • NGS screening is a powerful tool in the diagnostic workflow for skeletal muscle channelopathies. • The CLCN1 and SCN4A are mainly genes associated with non-dystrophic myotonia. • Collaboration between clinicians and molecular geneticists to make a diagnosis of SMC. Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A , 3 in both CLCN1 and SCN4A , 1 in ATP2A1 , 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1 , p.K1302R in SCN4A , p.L208P in ATP2A1 and c.280–1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis. [ABSTRACT FROM AUTHOR]

SP 3 sp "Dino Ferrari Center", Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, 20122 Milan, Italy. SP 2 sp Neurology Residency Program, Universita degli Studi di Milano, Via Festa del Perdono 7, 20122 Milan, Italy. SP 2 sp "Dino Ferrari Center", Department of Pathophysiology and Transplantation, Universita degli Studi di Milano, 20122 Milan, Italy. [Extracted from the article]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder and the most common motor neuron disease. ALS shows substantial clinical and molecular heterogeneity. In vitro and in vivo models coupled with multiomic techniques have provided important contributions to unraveling the pathomechanisms underlying ALS. To date, despite promising results and accumulating knowledge, an effective treatment is still lacking. Here, we provide an overview of the literature on the use of genomics, epigenomics, transcriptomics and microRNAs to deeply investigate the molecular mechanisms developing and sustaining ALS. We report the most relevant genes implicated in ALS pathogenesis, discussing the use of different high-throughput sequencing techniques and the role of epigenomic modifications. Furthermore, we present transcriptomic studies discussing the most recent advances, from microarrays to bulk and single-cell RNA sequencing. Finally, we discuss the use of microRNAs as potential biomarkers and promising tools for molecular intervention. The integration of data from multiple omic approaches may provide new insights into pathogenic pathways in ALS by shedding light on diagnostic and prognostic biomarkers, helping to stratify patients into clinically relevant subgroups, revealing novel therapeutic targets and supporting the development of new effective therapies. • ALS is a multifactorial disease resulting from a time-locked exposure of genetic, epigenetic, and environmental factors. • Transcriptomics offers pathogenesis insights for the development of new therapeutic strategies. • microRNAs regulate post-transcriptional gene expression, serving as disease biomarkers and tools for molecular intervention. • Integrating multiple omics approaches unveils potential therapeutic targets, guiding the development of effective therapies. [ABSTRACT FROM AUTHOR]

Repeat expansions in the C9orf72 gene are the most common genetic cause of (ALS) and frontotemporal dementia (FTD). Like other genetic forms of neurodegeneration, pinpointing the precise mechanism(s) by which this mutation leads to neuronal death remains elusive, and this lack of knowledge hampers the development of therapy for C9orf72-related disease. We used an agnostic approach based on genomic data (n = 41,273 ALS and healthy samples, and n = 1,516 C9orf72 carriers) to overcome these bottlenecks. Our drug-repurposing screen, based on gene- and expression-pattern matching and information about the genetic variants influencing onset age among C9orf72 carriers, identified acamprosate, a γ-aminobutyric acid analog, as a potentially repurposable treatment for patients carrying C9orf72 repeat expansions. We validated its neuroprotective effect in cell models and showed comparable efficacy to riluzole, the current standard of care. Our work highlights the potential value of genomics in repurposing drugs in situations where the underlying pathomechanisms are inherently complex. VIDEO ABSTRACT., Competing Interests: Declaration of interests B.J.T. holds patents on clinical testing and therapeutic intervention for the hexanucleotide repeat expansion of C9orf72., (Published by Elsevier Inc.)

The advent of computerized medical recording systems in healthcare facilities has made data retrieval tasks easier, compared to manual recording. Nevertheless, the potential of the information contained within medical records remains largely untapped, mostly due to the time and effort required to extract data from unstructured documents. Natural Language Processing (NLP) represents a promising solution to this challenge, as it enables the use of automated text-mining tools for clinical practitioners. In this work, we present the architecture of the Virtual Dementia Institute (IVD), a consortium of sixteen Italian hospitals, using the NLP Extraction and Management Tool (NEMT), a (semi-) automated end-to-end pipeline that extracts relevant information from clinical documents and stores it in a centralized REDCap database. After defining a common Case Report Form (CRF) across the IVD hospitals, we implemented NEMT, the core of which is a Question Answering Bot (QABot) based on a modern NLP model. This QABot is fine-tuned on thousands of examples from IVD centers. Detailed descriptions of the process to define a common minimum dataset, Inter-Annotator Agreement calculated on clinical documents, and NEMT results are provided. The best QABot performance show an Exact Match score (EM) of 78.1%, a F1-score of 84.7%, a Lenient Accuracy (LAcc) of 0.834, and a Mean Reciprocal Rank (MRR) of 0.810. EM and F1 scores outperform the same metrics obtained with ChatGPTv3.5 (68.9% and 52.5%, respectively). With NEMT the IVD has been able to populate a database that will contain data from thousands of Italian patients, all screened with the same procedure. NEMT represents an efficient tool that paves the way for medical information extraction and exploitation for new research studies.

Background and Objectives: Vascular risk factors (VRFs) and cerebral small vessel disease (cSVD) are common in patients with Alzheimer disease (AD). It remains unclear whether this coexistence reflects shared risk factors or a mechanistic relationship and whether vascular and amyloid pathologies have independent or synergistic influence on subsequent AD pathophysiology in preclinical stages. We investigated links between VRFs, cSVD, and amyloid levels (Aβ 1-42 ) and their combined effect on downstream AD biomarkers, that is, CSF hyperphosphorylated tau (P-tau 181 ), atrophy, and cognition., Methods: This retrospective study included nondemented participants (Clinical Dementia Rating < 1) from the European Prevention of Alzheimer's Dementia (EPAD) cohort and assessed VRFs with the Framingham risk score (FRS) and cSVD features on MRI using visual scales and white matter hyperintensity volumes. After preliminary linear analysis, we used structural equation modeling (SEM) to create a "cSVD severity" latent variable and assess the direct and indirect effects of FRS and cSVD severity on Aβ 1-42 , P-tau 181 , gray matter volume (baseline and longitudinal), and cognitive performance (baseline and longitudinal)., Results: A total cohort of 1,592 participants were evaluated (mean age = 65.5 ± 7.4 years; 56.16% F). We observed positive associations between FRS and all cSVD features (all p < 0.05) and a negative association between FRS and Aβ 1-42 (β = -0.04 ± 0.01). All cSVD features were negatively associated with CSF Aβ 1-42 (all p < 0.05). Using SEM, the cSVD severity fully mediated the association between FRS and CSF Aβ 1-42 (indirect effect: β = -0.03 ± 0.01), also when omitting vascular amyloid-related markers. We observed a significant indirect effect of cSVD severity on P-tau 181 (indirect effect: β = 0.12 ± 0.03), baseline and longitudinal gray matter volume (indirect effect: β = -0.10 ± 0.03; β = -0.12 ± 0.05), and baseline cognitive performance (indirect effect: β = -0.16 ± 0.03) through CSF Aβ 1-42 ., Discussion: In a large nondemented population, our findings suggest that cSVD is a mediator of the relationship between VRFs and CSF Aβ 1-42 and affects downstream neurodegeneration and cognitive impairment. We provide evidence of VRFs indirectly affecting the pathogenesis of AD, highlighting the importance of considering cSVD burden in memory clinics for AD risk evaluation and as an early window for intervention. These results stress the role of VRFs and cerebrovascular pathology as key biomarkers for accurate design of anti-amyloid clinical trials and offer new perspectives for patient stratification.

Background: This study aimed to assess whether quantitative susceptibility imaging (QSM)-based measures of iron accumulation in the cerebellum predict cognitive and behavioral features in non-demented amyotrophic lateral sclerosis (ALS) patients., Methods: A total of ALS patients underwent 3-T MRI and a clinical assessment using the ALS Functional Rating Scale-Revised (ALSFRS-R) and the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Regression models were applied to each subscale of the cognitive section of the ECAS and the ECAS-Carer Interview to examine the effect of QSM-based measures in white and gray matter (WM; GM) of the cerebellum, separately for right, left, and bilateral cerebellar regions of interest (ROIs). These effects were compared to those of cerebellar volumetrics in WM/GM, right and left hemispheres while controlling for demographics, disease status, and total intracranial volume., Results: Higher QSM measures of the cerebellar GM on the left, right, and bilateral sides significantly predicted ( p s ≤ 0.003) a greater number of errors on the executive functioning (EF) subscale of the ECAS (ECAS-EF). Moreover, higher GM-related, QSM measures of the cerebellum were associated with an increased probability of a below-cut-off performance on the ECAS-EF ( p s ≤ 0.024). No significant effects were observed for QSM measures of the cerebellar WM or for volumetric measures on the ECAS-EF. Other ECAS measures showed no significant effects. Bilateral QSM measures of the cerebellar GM also selectively predicted performance on backward digit span and social cognition tasks., Discussion: Iron accumulation within the cerebellar GM, particularly in the cerebellar cortices, may be associated with executive functioning deficits in non-demented ALS patients. Therefore, QSM-based measures could be useful for identifying the neural correlates of extra-motor cognitive deficits in ALS patients., Competing Interests: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., and Novartis Pharma AG, receives or has received research supports from the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology. BP received compensation for consulting services and/or speaking activities from Liquidweb S.r.l. She is Associate Editor for Frontier in Neuroscience. NT received compensation for consulting services from Amylyx Pharmaceuticals and Zambon Biotech SA. He is Associate Editor for Frontiers in Aging Neuroscience. ENA serves as an Editorial Board Member for BMC Neurology. FV is Associated Editor for Journal of Alzheimer’s Disease. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Aiello, Contarino, Conte, Solca, Curti, Maranzano, Torre, Casale, Doretti, Colombo, Verde, Silani, Liu, Cinnante, Triulzi, Morelli, Poletti and Ticozzi.)

Background: Anti-IgLON5 disease is an autoimmune encephalitis overlapping with neurodegenerative disorders due to pathological accumulation of hyperphosphorylated tau. It is characterized by several clinical manifestations determined by involvement of different brain areas, and mild response to first-line immunotherapies. We report a case of anti-IgLON5 disease with a multifaceted semiology and an unusually good response to glucocorticoid monotherapy., Case Presentation: A 68-year-old man with type 2 diabetes was evaluated for an 8-month history of progressive gait disorder causing frequent falls. He also suffered from obstructive sleep apneas and complained of dysphonia, dysarthria, occasional dysphagia, urinary incontinence, and upper limb action tremor. Neurological examination demonstrated bilateral eyelid ptosis, limitation of ocular horizontal smooth pursuit movements, slow horizontal saccades, and lack of inhibition of the vestibulo-ocular reflex during rapid horizontal head torsions. The patient also displayed involuntary, slow, rhythmic movements of the left periorbital and perioral muscles, spreading to the ipsilateral hemipalate and hemitongue, along with bilateral negative upper limb myoclonus. There were proximal muscle wasting in the upper limbs, proximal weakness of the four limbs, and diffuse fasciculations. Ataxia of stance and gait and of the four limbs was noted. MRI of the brain and spine was unremarkable; nerve conduction studies revealed a chronic, predominantly demyelinating, sensory-motor polyneuropathy, probably due to diabetes. Routine CSF examination was unrevealing and serum GFAP level was 89.6 pg/mL; however, the autoimmunity tests revealed a high-titer positivity for anti-IgLON5 autoantibodies in both CSF and serum, leading to the diagnosis of anti-IgLON5 disease. Symptoms improved significantly after intravenous methylprednisolone., Conclusions: Hemifacial and hemiorolingual myorhythmia along with peculiar oculomotor abnormalities characterizes the multifaceted clinical picture of our case. The complex semiology of our patient may reflect multifocal targeting of the autoimmune process or sequential spreading of tau inclusions in different brain areas. Our patient's optimal response to glucocorticoid monotherapy could be underpinned by a slightly different phenotype in which autoimmunity plays a greater pathogenic role than tauopathy, with a lower burden of tau deposition. In such patients, neurodegeneration and tau accumulation could be merely secondary to immune-mediated neuronal dysfunction, supporting the existence of a group of glucocorticoid-responsive patients., (© 2024. The Author(s).)

Background: Bibrachial amyotrophy associated with an extradural CSF collection and infratentorial superficial siderosis (SS) are rare conditions that may occasionally mimic ALS. Both disorders are assumed to be due to dural tears., Case Presentation: A 53-year-old man presented with a 7-year history of slowly progressive asymmetric bibrachial amyotrophy. Initially, a diagnosis of atypical motor neuron disease (MND) was made. At re-evaluation 11 years later, upper limb wasting and weakness had further progressed and were accompanied by sensorineural hearing loss. MRI of the brain and spine demonstrated extensive supra- and infratentorial SS (including the surface of the whole spinal cord) as well as a ventral longitudinal intraspinal fluid collection (VLISFC) extending along almost the entire thoracic spine. Osteodegenerative changes were observed at C5-C7 level, with osteophytes protruding posteriorly. The bony spurs at C6-C7 level were hypothesized to have lesioned the dura, causing a CSF leak and thus a VLISFC. Review of the MRI acquired at first evaluation showed that the VLISFC was already present at that time (actually beginning at C7 level), whereas the SS was not. 19 years after the onset of upper limb weakness, the patient additionally developed parkinsonism. Response to levodopa, brain scintigraphy with 123 I-ioflupane and brain MRI with nigrosome 1 evaluation were consistent with idiopathic Parkinson's disease (PD). On the latest follow-up 21 years after symptom onset, the VLISFC was unchanged, as were upper arm weakness and wasting., Conclusions: Based on the long-term follow-up, we could establish that, while the evidence of the VLISFC was concomitant with the clinical presentation of upper limb amyotrophy and weakness, the radiological signs of SS appeared later. This suggests that SS was not per se the cause of the ALS-like clinical picture, but rather a long-term sequela of a dural leak. The latter was instead the causative lesion, giving rise to a VLISFC which compressed the cervical motor roots. Dural tears can actually cause several symptoms, and further studies are needed to elucidate the pathophysiological correlates of "duropathies". Finally, as iron metabolism has been implicated in PD, the co-occurrence of PD with SS deserves further investigation., (© 2024. The Author(s).)

Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research. Experimentally, the creation of vascularized brain organoids has primarily focused on the fusion of vascular and brain organoids, on organoid transplantation in vivo, and on the use of microfluidic devices to replicate the intricate microenvironment of the human brain in vitro. This review summarizes these efforts and highlights the importance of studying the neurovascular unit in a forward-looking perspective of leveraging their use for understanding and treating neurological disorders., (© 2024. The Author(s).)

Objective: Little is known about amyotrophic lateral sclerosis (ALS)-nonspecific cognitive deficits - most notably memory disturbance - and their biological underpinnings. We investigated the associations of the Alzheimer's disease (AD) genetic risk factor APOE and cerebrospinal fluid (CSF) biomarkers Aβ and tau proteins with cognitive and motor phenotype in ALS., Methods: APOE haplotype was determined in 281 ALS patients; for 105 of these, CSF levels of Aβ42, Aβ40, total tau (T-tau), and phosphorylated tau (P-tau181) were quantified by chemiluminescence enzyme immunoassay (CLEIA). The Edinburgh Cognitive and Behavioural ALS Screen (ECAS) was employed to evaluate the neuropsychological phenotype., Results: APOE-E4 allele was associated with worse ECAS memory score (median, 14.0 in carriers vs. 16.0 in non-carriers) and lower CSF Aβ42 (-0.8 vs. 0.1, log-transformed values) and Aβ42/40 ratio (-0.1 vs. 0.3). Some 37.1% of ALS patients showed low Aβ42 levels, possibly reflecting cerebral Aβ deposition. While lower Aβ42/40 correlated with lower memory score (β = 0.20), Aβ42 positively correlated with both ALS-specific (β = 0.24) and ALS-nonspecific (β = 0.24) scores. Although Aβ42/40 negatively correlated with T-tau (β = -0.29) and P-tau181 (β = -0.33), we found an unexpected positive association of Aβ42 and Aβ40 with both tau proteins. Regarding motor phenotype, lower levels of Aβ species were associated with lower motor neuron (LMN) signs (Aβ40: β = 0.34; Aβ42: β = 0.22)., Conclusions: APOE haplotype and CSF Aβ biomarkers are associated with cognitive deficits in ALS and particularly with memory impairment. This might partly reflect AD-like pathophysiological processes, but additional ALS-specific mechanisms could be involved., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: Plasma levels of phosphorylated tau (P-tau181) have been recently reported to be increased in amyotrophic lateral sclerosis (ALS) and associated with lower motor neuron (LMN) impairment., Patients and Methods: We quantified plasma P-tau181 (pP-tau181) in a cohort of 29 deeply phenotyped ALS patients using the new fully automated Lumipulse assay and analysed phenotype-biomarker correlations., Results: pP-tau181 levels correlated positively with a clinical LMN score (r = 0.3803) and negatively, albeit not significantly, with a composite index of muscle strength (r =  - 0.3416; p = 0.0811), but not with Penn Upper Motor Neuron (UMN) Score. Accordingly, pP-tau181 correlated with electromyographic indices of spinal active and chronic denervation (r = 0.4507 and r = 0.3864, respectively) but not with transcranial magnetic stimulation parameters of UMN dysfunction. pP-tau181 levels did not correlate with those in the cerebrospinal fluid (CSF), serum NFL, serum GFAP, CSF/serum albumin ratio, or estimated glomerular filtration rate, but correlated with plasma creatine kinase levels (r = 0.4661). Finally, while not being associated with neuropsychological phenotype, pP-tau181 correlated negatively with pH (r =  - 0.5632) and positively with partial pressure of carbon dioxide (PaCO 2 ; r = 0.7092), bicarbonate (sHCO 3 - ; r = 0.6667) and base excess (r = 0.6611) on arterial blood gas analysis., Discussion: pP-tau181 has potential as ALS biomarker and could be associated with LMN impairment. Its raised levels might reflect pathophysiological processes (tau hyperphosphorylation and/or release) occurring in the axons of LMNs distantly from the CNS and the CSF. pP-tau181 could also be associated with respiratory dysfunction., (© 2023. Fondazione Società Italiana di Neurologia.)

Introduction: Alzheimer's disease  (AD) is characterized by decreased cerebrospinal fluid (CSF) Aβ42 and Aβ42/Aβ40 ratio. Aβ peptides can now be measured also in plasma and are promising peripheral biomarkers for AD. We evaluated the relationships of plasma Aβ species with their CSF counterparts, kidney function, and serum/CSF albumin ratio (Q-Alb) in AD patients., Materials and Methods: We measured plasma Aβ42 and Aβ40, as well as CSF AD biomarkers, with the fully automated Lumipulse platform in a cohort of N = 30 patients with clinical and neurochemical diagnosis of AD., Results: The two plasma Aβ peptides correlated strongly with each other (r = 0.7449), as did the corresponding CSF biomarkers (r = 0.7670). On the contrary, the positive correlations of plasma Aβ42, Aβ40, and Aβ42/Aβ40 ratio with their CSF counterparts and the negative correlation of plasma Aβ42/Aβ40 ratio with CSF P-tau181 were not statistically significant. Plasma levels of both Aβ species negatively correlated with estimated glomerular filtration rate (eGFR) (Aβ42: r = -0.4138; Aβ40: r = -0.6015), but plasma Aβ42/Aβ40 ratio did not. Q-Alb did not correlate with any plasma Aβ parameter., Discussion: Plasma Aβ42 and Aβ40 are critically influenced by kidney function; however, their ratio is advantageously spared from this effect. The lack of significant correlations between plasma Aβ species and their CSF counterparts is probably mainly due to small sample size and inclusion of only Aβ + individuals. Q-Alb is not a major determinant of plasma Aβ concentrations, highlighting the uncertainties about mechanisms of Aβ transfer between CNS and periphery., (© 2023. Fondazione Società Italiana di Neurologia.)

Background and Objectives: A variety of neurologic disorders have been reported as presentations or complications of coronavirus disease 2019 (COVID-19) infection. The objective of this study was to determine their incidence dynamics and long-term functional outcome., Methods: The Neuro-COVID Italy study was a multicenter, observational, cohort study with ambispective recruitment and prospective follow-up. Consecutive hospitalized patients presenting new neurologic disorders associated with COVID-19 infection (neuro-COVID), independently from respiratory severity, were systematically screened and actively recruited by neurology specialists in 38 centers in Italy and the Republic of San Marino. The primary outcomes were incidence of neuro-COVID cases during the first 70 weeks of the pandemic (March 2020-June 2021) and long-term functional outcome at 6 months, categorized as full recovery, mild symptoms, disabling symptoms, or death., Results: Among 52,759 hospitalized patients with COVID-19, 1,865 patients presenting 2,881 new neurologic disorders associated with COVID-19 infection (neuro-COVID) were recruited. The incidence of neuro-COVID cases significantly declined over time, comparing the first 3 pandemic waves (8.4%, 95% CI 7.9-8.9; 5.0%, 95% CI 4.7-5.3; 3.3%, 95% CI 3.0-3.6, respectively; p = 0.027). The most frequent neurologic disorders were acute encephalopathy (25.2%), hyposmia-hypogeusia (20.2%), acute ischemic stroke (18.4%), and cognitive impairment (13.7%). The onset of neurologic disorders was more common in the prodromic phase (44.3%) or during the acute respiratory illness (40.9%), except for cognitive impairment whose onset prevailed during recovery (48.4%). A good functional outcome was achieved by most patients with neuro-COVID (64.6%) during follow-up (median 6.7 months), and the proportion of good outcome increased throughout the study period ( r = 0.29, 95% CI 0.05-0.50; p = 0.019). Mild residual symptoms were frequently reported (28.1%) while disabling symptoms were common only in stroke survivors (47.6%)., Discussion: Incidence of COVID-associated neurologic disorders decreased during the prevaccination phase of the pandemic. Long-term functional outcome was favorable in most neuro-COVID disorders, although mild symptoms commonly lasted more than 6 months after infection., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)