High Frequency of Cognitive and Behavioral Impairment in Amyotrophic Lateral Sclerosis Patients with SOD1 Pathogenic Variants.

OBJECTIVE: While the cognitive-behavioral characteristics of amyotrophic lateral sclerosis (ALS) patients carrying C9orf72 pathological repeat expansion have been extensively studied, our understanding of those carrying SOD1 variants is mostly based on case reports. The aim of this paper is to extensively explore the cognitive-behavioral characteristics of a cohort of ALS patients carrying pathogenetic variants of SOD1 gene, comparing them to patients without pathogenetic variants of 46 ALS-related genes (wild-type [WT]-ALS) and healthy controls. METHODS: All ALS patients seen at the Turin ALS expert center in the 2009-2021 period who underwent both cognitive/behavioral and extensive genetic testing were eligible to be included in the study. Only patients with SOD1 pathogenetic variants (n = 28) (SOD1-ALS) and WT-ALS (n = 829) were enrolled in the study. A series of 129 controls was also included. RESULTS: Among the 28 SOD1-ALS patients, 16 (57.1%) had normal cognitive function, 5 (17.9%) isolated cognitive impairment (ALSci) (17.9%), 6 (21.4%) isolated behavioral impairment (ALSbi), 1 (3.6%) cognitive and behavioral impairment (ALScbi), and no one ALS-FTD. SOD1-ALS performed worse than controls in all explored domains, in particular Social Cognition and Language domains. SOD1-ALS patients had similar scores in all tests compared to WT-ALS, except the Story-based Empathy Task (SET), where they performed worse. INTERPRETATION: Cognitive-behavioral impairment is much more common in SOD1 patients than previously assumed. SOD1-ALS are characterized by a more frequent impairment of Social Cognition and, less markedly, of Language domains. These findings have relevant implication both in the clinical and in the research setting, also considering recently approved treatment for SOD1-ALS. ANN NEUROL 2024;96:150-158.

Disentangling the relationship between social cognition, executive functions and behaviour changes in amyotrophic lateral sclerosis.

BACKGROUND: Social cognition (SC) deficits are included in the amyotrophic lateral sclerosis-frontotemporal spectrum disorder (ALS-FTDS) revised diagnostic criteria. However, the impact of SC assessment on cognitive classification and the cognitive-behavioural correlates of SC remain unclear. This cross-sectional study aimed to assess the impact of SC assessment on ALS-FTDS categorisation and explore the relationship of SC with executive functions (EF) and behaviour changes in a cohort of ALS patients. METHODS: 121 patients and 56 healthy controls from the Turin ALS Centre underwent cognitive/behavioural testing, including the SC subdomains of facial emotion recognition, and cognitive and affective theory of mind (ToM). RESULTS: Patients performed significantly worse than controls in all SC explored domains, and 45% of patients exhibited a deficit in at least one SC test, dissociated from the presence of EF deficits. In 13% of cases, the SC deficit was isolated and subclinical. SC assessment contributed to the attribution of cognitive impairment in 10% of patients. Through a statistical clustering approach, we found that ToM only partially overlaps with EF while behaviour changes are associated with emotional disorders (anxiety and depression). CONCLUSIONS: SC is overall independent of EF in ALS, with ToM only partially associated with specific EF measures, and behaviour changes associated with emotional disorders. The influence of SC on cognitive categorisation and the frequent identification of a subclinical SC impairment have implications in a clinical setting, considering the substantial impact of cognitive impairment on disease burden and therapeutic choices.

Prognostic communication in amyotrophic lateral sclerosis: findings from a Nationwide Italian survey.

BACKGROUND: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron disease with a highly variable prognosis. Among the proposed prognostic models, the European Network for the cure of ALS (ENCALS) survival model has demonstrated good predictive performance. However, few studies have examined prognostic communication and the diffusion of prognostic algorithms in ALS care. OBJECTIVE: To investigate neurologists' attitudes toward prognostic communication and their knowledge and utilization of the ENCALS survival model in clinical practice. METHODS: A web-based survey was administered between May 2021 and March 2022 to the 40 Italian ALS Centers members of the Motor Neuron Disease Study Group of the Italian Society of Neurology. RESULTS: Twenty-two out of 40 (55.0%) Italian ALS Centers responded to the survey, totaling 37 responses. The model was known by 27 (73.0%) respondents. However, it was predominantly utilized for research (81.1%) rather than for clinical prognostic communication (7.4%). Major obstacles to prognostic communication included the unpredictability of disease course, fear of a negative impact on patients or caregivers, dysfunctional reaction to diagnosis, and cognitive impairment. Nonetheless, the model was viewed as potentially useful for improving clinical management, increasing disease awareness, and facilitating care planning, especially end-of-life planning. CONCLUSIONS: Despite the widespread recognition and positive perceptions of the ENCALS survival model among Italian neurologists with expertise in ALS, its implementation in clinical practice remains limited. Addressing this disparity may require systematic investigations and targeted training to integrate tailored prognostic communication into ALS care protocols, aligning with the growing availability of prognostic tools for ALS.

Exploring the phenotype of Italian patients with ALS with intermediate ATXN2 polyQ repeats.

OBJECTIVE: To detect the clinical characteristics of patients with amyotrophic lateral sclerosis (ALS) carrying an intermediate ATXN2 polyQ number of repeats in a large population-based series of Italian patients with ALS. METHODS: The study population includes 1330 patients with ALS identified through the Piemonte and Valle d'Aosta Register for ALS, diagnosed between 2007 and 2019 and not carrying C9orf72, SOD1, TARDBP and FUS mutations. Controls were 1274 age, sex and geographically matched Italian subjects, identified through patients' general practitioners. RESULTS: We found 42 cases and 4 controls with≥31 polyQ repeats, corresponding to an estimated OR of 10.4 (95% CI 3.3 to 29.0). Patients with≥31 polyQ repeats (ATXN2+) compared with those without repeat expansion (ATXN2-) had more frequently a spinal onset (p=0.05), a shorter diagnostic delay (p=0.004), a faster rate of ALSFRS-R progression (p=0.004) and King's progression (p=0.004), and comorbid frontotemporal dementia (7 (28.0%) vs 121 (13.4%), p=0.037). ATXN2+ patients had a 1-year shorter survival (ATXN2+ patients 1.82 years, 95% CI 1.08 to 2.51; ATXN2- 2.84 years, 95% CI 1.67 to 5.58, p=0.0001). ATXN2 polyQ intermediate repeats was independently related to a worse outcome in Cox multivariable analysis (p=0.006). CONCLUSIONS: In our population-based cohort, ATXN2+ patients with ALS have a distinctive phenotype, characterised by a more rapid disease course and a shorter survival. In addition, ATXN2+ patients have a more severe impairment of cognitive functions. These findings have relevant implications on clinical practice, including the possibility of refining the individual prognostic prediction and improving the design of ALS clinical trials, in particular as regards as those targeted explicitly to ATXN2.

Social cognition deficits in amyotrophic lateral sclerosis: A pilot cross-sectional population-based study.

BACKGROUND AND PURPOSE: Social cognition (SC) deficits are included in amyotrophic lateral sclerosis (ALS)-frontotemporal spectrum disorder revised diagnostic criteria. However, SC performance among ALS patients is heterogeneous due to the phenotypic variability of the disease and the wide range of neuropsychological tools employed. The aim of the present study was to assess facial emotion recognition and theory of mind in ALS patients compared to controls and to evaluate correlations with the other cognitive domains and degree of motor impairment. METHODS: Eighty-three patients and 42 controls underwent a cognitive evaluation and SC assessment through the Ekman 60 Faces Test (EK-60F), the Reading the Mind in the Eyes Test-36 Faces (RMET-36), and the Story-Based Empathy Task (SET). RESULTS: ALS patients showed significantly worse performance compared to controls in EK-60F global score (p < 0.001), recognition of disgust (p = 0.032), anger (p = 0.038), fear (p < 0.001), and sadness (p < 0.001); RMET-36 (p < 0.001), and SET global score (p < 0.001). Also, cognitively normal patients (ALS-CN) showed significantly worse performance compared to controls in EK-60F global score (p < 0.001), recognition of fear (p = 0.002), sadness (p < 0.001), and SET (p < 0.001). RMET-36 showed a significant correlation with the Category Fluency Test (p = 0.041). SC tests showed no correlation with motor impairment expressed by Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised. CONCLUSIONS: ALS patients, also when categorized as ALS-CN, may show impairment in SC performance. The frequent identification of early SC impairment in ALS patients supports the need to routinely assess SC for its impact on end-of-life decisions and its potential influence on patients' quality of life.

Brain metabolic correlates of apathy in amyotrophic lateral sclerosis: An 18F-FDG-positron emission tomography stud.

BACKGROUND AND PURPOSE: The aim of this study was to evaluate brain metabolic correlates of apathy in amyotrophic lateral sclerosis (ALS). METHODS: A total of 165 ALS patients underwent 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18 F-FDG-PET) and Frontal Systems Behaviour Scale (FrSBe) evaluation. FrSBe provides "before" and "after" apathy subscores, referring to premorbid and morbid conditions. "After" apathy subscore and "before-after" gap, i.e. the difference between "before" and "after" subscores, were regressed against whole-brain metabolism. Among patients with a pathological "after" apathy subscore (i.e., ≥65), we compared patients with "before" apathy subscores ≥65 and <65, and patients with "before-after" gaps of <22 and ≥22. RESULTS: In the whole sample, the "after" apathy subscore negatively correlated with metabolism in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), ventrolateral prefrontal cortex (VLPFC), premotor cortex (PMC) and anterior cingulate cortex (ACC), and insula bilaterally. A positive correlation was found in the cerebellum and pons. The "before-after" gap negatively correlated with metabolism in bilateral DLPFC, DMPFC and PMC, and left VLPFC and ACC, and positively correlated with cerebellar and pontine clusters. Among patients with an "after" apathy subscore ≥65, we found no difference between those with "before" apathy subscores ≥65 and <65. Patients with a "before-after" gap ≥22, compared to patients with a gap <22, showed relative hypometabolism in bilateral DLPFC and DMPFC, and left ACC and PMC, and relative cerebellar and pontine hypermetabolism. CONCLUSION: No studies on brain 18 F-2-fluoro-2-deoxy-D-glucose positron emission tomography correlates of apathy have been performed in ALS. We found that FrSBe "after" apathy subscore correlated with metabolic changes in brain regions known as neuroanatomical correlates of apathy. Furthermore, our findings support the relevance of the gap between premorbid and morbid conditions to detect behavioural changes due to the neurodegenerative process underlying ALS.

Metabolic brain changes across different levels of cognitive impairment in ALS: a 18F-FDG-PET study.

OBJECTIVE: To identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET) imaging. METHODS: 274 ALS patients underwent neuropsychological assessment and brain 18F-FDG-PET at diagnosis. According to the criteria published in 2017, cognitive status was classified as ALS with normal cognition (ALS-Cn, n=132), ALS with behavioural impairment (ALS-Bi, n=66), ALS with cognitive impairment (ALS-Ci, n=30), ALS with cognitive and behavioural impairment (ALS-Cbi, n=26), ALS with frontotemporal dementia (ALS-FTD, n=20). We compared each group displaying some degree of cognitive and/or behavioural impairment to ALS-Cn patients, including age at PET, sex and ALS Functional Rating Scale-Revised as covariates. RESULTS: We identified frontal lobe relative hypometabolism in cognitively impaired patients that resulted more extensive and significant across the continuum from ALS-Ci, through ALS-Cbi, to ALS-FTD. ALS-FTD patients also showed cerebellar relative hypermetabolism. ALS-Bi patients did not show any difference compared with ALS-Cn. CONCLUSIONS: These data support the concept that patients with cognitive impairment have a more widespread neurodegenerative process compared with patients with a pure motor disease: the more severe the cognitive impairment, the more diffuse the metabolic changes. Otherwise, metabolic changes related to pure behavioural impairment need further characterisation.

Validation of the revised classification of cognitive and behavioural impairment in ALS.

OBJECTIVE: In 2017, the diagnostic criteria for cognitive and behavioural impairment in amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (ALSFTD-1) have been modified (ALSFTD-2) with the inclusion of a novel category (ALS with combined cognitive and behavioural impairment, ALScbi) and with changes of operational criteria of the other categories (ALS with cognitive impairment (ALSci), ALS with behavioural impairment (ALSbi) and ALS with frontotemporal dementia (ALS-FTD)). We compared the two sets of criteria to assess the effect of the revised criteria on the cognitive classification of patients with ALS. METHODS: Two cohorts of patients with ALS were included in this study: a population-based cohort including patients identified through the Piemonte/Valle d'Aosta register for ALS in the 2014-2017 period (n=321), and a referral cohort recruited at the Turin ALS centre and at the ALS centre of the Maugeri Institute in Milan in the same period (n=205). Cognitive function was classified in blind by two neuropsychologists expert in ALS. RESULTS: ALSFTD-2 criteria determined a shift of about 15% of patients from their original category to a new one. In both cohorts, about 9% of patients were reclassified to the novel category ALScbi. Among patients previously classified as cognitively normal, 14 (4.3%, population-based cohort) and 19 (9.3%, referral cohort) were reclassified as ALSbi or ALSci. The median survival of the different categories was significantly different with both with sets of criteria. CONCLUSIONS: The new ALSFTD-2 criteria, compared with the old ones, have positive effects on the clinical practice being more sensitive to the early cognitive impairment and having a better prognostic yield.

Cognitive correlates in amyotrophic lateral sclerosis: a population-based study in Italy.

BACKGROUND: There is less data available regarding the characteristics of cognitive impairment in patients with amyotrophic lateral sclerosis (ALS) in a population-based series. METHODOLOGY: Patients with ALS incident in Piemonte, Italy, between 2009 and 2011 underwent an extensive neuropsychological battery. Cognitive status was classified as follows: normal cognition, frontotemporal dementia (ALS-FTD), executive cognitive impairment (ALS-ECI), non-executive cognitive impairment (ALS-NECI), behavioural impairment (ALS-Bi), non-classifiable cognitive impairment. We also assessed 127 age-matched and gender-matched controls identified through patients' general practitioners. RESULTS: Out of the 281 incident patients, 207 (71.9%) underwent the neuropsychological testing; of these, 19 were excluded from the analysis due previous conditions affecting cognition. Ninety-one (49.7%) patients were cognitively normal, 23 (12.6%) had ALS-FTD, 36 (19.7%) ALS-ECI, 10 (5.5%) ALS-NECI, 11 (6.0%) ALS-Bi and 11 (6.0%) non-classifiable cognitive impairment, 1 had comorbid Alzheimer's disease. Patients with ALS-FTD were older, had a lower education level, and had a shorter survival than any other cognitive group. Of the nine cases with C9ORF72 mutation, six had ALS-FTD, two ALS-ECI and one was cognitively normal; one of the five patients with SOD1 mutations and one of the five patients with TARBDP mutations had ALS-Bi. CONCLUSIONS: About 50% of Italian patients with ALS had some degree of cognitive impairment, in keeping with a previous Irish study, despite the largely different genetic background of the two populations. The lower educational attainment in patients with ALS-FTD indicated a possible role of cognitive reserve in ALS-related cognitive impairment. ALS-ECI and ALS-NECI may represent discrete cognitive syndromes in the continuum of ALS and FTD.

High serum uric acid levels are protective against cognitive impairment in amyotrophic lateral sclerosis.

BACKGROUND: Uric acid (UA) has emerged as a factor that can modify cognitive function both in the general population and in people with neurodegenerative disorders. Since very few data are available concerning amyotrophic lateral sclerosis (ALS), we explored the correlation of UA levels and cognitive impairment in a large cohort of ALS patients. METHODS: We enrolled ALS patients consecutively seen at the Turin ALS expert center in the 2007-2018 period who underwent both cognitive/behavioral and UA evaluation at diagnosis. Patients were classified in 5 categories: normal cognition (ALS-CN), isolated cognitive impairment (ALSci), isolated behavioural impairment (ALSbi), cognitive and behavioural impairment (ALScbi), frontotemporal dementia (ALS-FTD). For this study, ALSci, ALSbi and ALScbi were merged as ALS with intermediate cognitive impairment (ALS-INT). RESULTS: Out of the 841 ALS patients, 422 had ALS-CN, 271 ALS-INT and 148 ALS-FTD. The mean values of UA were significantly different among the cognitive subgroups of patients, with the lowest values in the ALS-FTD (ALS-CN, 288.5 ± 78.0 (µmol/L; ALS-INT, 289.7 ± 75.5 µmol/L; ALS-FTD, 271.8 ± 74.9 µmol/L; p = 0.046). The frequency of ALS-FTD was significantly higher in the 1st tertile of UA. Lower UA levels were independently associated with FTD (OR 1.32, 95% c.i. 1.01-1.43; p = 0.038) in binary logistic regression. CONCLUSIONS: We found that in ALS lower UA serum levels are correlated with reduced frequency of co-morbid FTD. Patients with intermediate cognitive impairment showed UA levels similar to ALS-CN but higher than ALS-FTD, implying that higher UA levels can prevent or delay cognitive function deterioration.

Cognitive and Behavioral Features of Patients With Amyotrophic Lateral Sclerosis Who Are Carriers of the TARDBP Pathogenic Variant.

BACKGROUND AND OBJECTIVES: TARDBP patients are considered particularly prone to cognitive involvement, but no systematic studies of cognitive impairment in TARDBP patients are available. The aim of this article was to depict in depth the cognitive-behavioral characteristics of a cohort of patients with amyotrophic lateral sclerosis (ALS) carrying TARDBP pathogenetic variants followed by an ALS referral center. METHODS: We enrolled all patients with ALS seen at the Turin ALS expert center in the 2009-2021 period who underwent extensive genetic testing and a neuropsychological battery encompassing executive function, verbal memory, language, visual memory, visuoconstructive abilities, attention/working memory, psychomotor speed, nonverbal intelligence, cognitive flexibility, social cognition, and behavior. Tests were compared with the Mann-Whitney U test on age-corrected, sex-corrected, and education-corrected scores. Cognition was classified as normal (ALS-CN); isolated cognitive impairment (ALSci), that is, evidence of executive and/or language dysfunction; isolated behavioral impairment (ALSbi), that is, identification of apathy; cognitive and behavioral impairment (ALScbi), that is, evidence meeting the criteria for both ALSci and ALSbi; and frontotemporal dementia (ALS-FTD). RESULTS: This study includes 33 patients with TARDBP pathogenetic variants (TARDBP-ALS) (median age 61 years [interquartile range (IQR) 53-67], 8 female [24.2%]) and 928 patients with ALS not carrying the pathogenic variant (WT-ALS) (median age 67 years [IQR 59-74], 386 female [41.6%]). TARDBP-ALS cases were also compared with 129 matched controls (median age 66 years [IQR 57.5-71.5], 55 female [42.6%]). TARDBP-ALS and WT-ALS patients were cognitively classified as ALS-CN (54% vs 58.8%, respectively), ALSci (21.2% vs 18.3%), ALSci (9.1% vs 9.5%), ALScbi (6.1% vs 6.0%), and ALS-FTD (9.1 vs 6.7%), with no significant difference (p = 0.623). Compared with controls, TARDBP-ALS had a worse performance in executive functions, visual memory, visuoconstructive abilities, verbal fluency, and the apathy behavioral component of FrSBe. The scores of performed tests, including all Edinburgh Cognitive and Behavioral ALS Screen subdomains, were similar in TARDBP-ALS and WT-ALS. DISCUSSION: TARDBP-ALS patients were significantly more impaired than controls in most examined domains but do not show any specific pattern of cognitive impairment compared with WT-ALS. Our findings are relevant both clinically, considering the effect of cognitive impairment on patients' decision-making and caregivers' burden, and in designing clinical trials for the treatment of patients carrying TARDBP pathogenetic variants.

Prevalence and motor-functional correlates of frontotemporal-spectrum disorders in a large cohort of non-demented ALS patients.

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.

Plasma CHI3L1 in Amyotrophic Lateral Sclerosis: A Potential Differential Diagnostic Biomarker.

(1) Background: Motor neuron diseases (MNDs) are fatal neurodegenerative diseases. Biomarkers could help with defining patients' prognoses and stratifications. Besides neurofilaments, chitinases are a promising family of possible biomarkers which correlate with neuroinflammatory status. We evaluated the plasmatic levels of CHI3L1 in MNDs, MND mimics, and healthy controls (HCs). (2) Methods: We used a sandwich ELISA to quantify the CHI3L1 in plasma samples from 44 MND patients, 7 hereditary spastic paraplegia (HSP) patients, 9 MND mimics, and 19 HCs. We also collected a ALSFRSr scale, MRC scale, spirometry, mutational status, progression rate (PR), blood sampling, and neuropsychological evaluation. (3) Results: The plasma levels of the CHI3L1 were different among groups (p = 0.005). Particularly, the MND mimics showed higher CHI3L1 levels compared with the MND patients and HCs. The CHI3L1 levels did not differ among PMA, PLS, and ALS, and we did not find a correlation among the CHI3L1 levels and clinical scores, spirometry parameters, PR, and neuropsychological features. Of note, the red blood cell count and haemoglobin was correlated with the CHI3L1 levels (respectively, p < 0.001, r = 0.63; p = 0.022, and r = 0.52). (4) Conclusions: The CHI3L1 plasma levels were increased in the MND mimics cohort compared with MNDs group. The increase of CHI3L1 in neuroinflammatory processes could explain our findings. We confirmed that the CHI3L1 plasma levels did not allow for differentiation between ALS and HCs, nor were they correlated with neuropsychological impairment.

Association of Copresence of Pathogenic Variants Related to Amyotrophic Lateral Sclerosis and Prognosis.

BACKGROUND AND OBJECTIVES: Despite recent advances, it is not clear whether the various genes/genetic variants related to amyotrophic lateral sclerosis (ALS) interact in modifying patients' phenotype. The aim of this study was to determine whether the copresence of genetic variants related to ALS has interactive effects on the course of the disease. METHODS: The study population includes 1,245 patients with ALS identified through the Piemonte Register for ALS between 2007 and 2016 and not carrying superoxide dismutase type 1, TAR DNA binding protein, and fused in sarcoma pathogenic variants. Controls were 766 Italian participants age-matched, sex-matched, and geographically matched to cases. We considered Unc-13 homolog A (UNC13A) (rs12608932), calmodulin binding transcription activator 1 (CAMTA1) (rs2412208), solute carrier family 11 member 2 (SLC11A2) (rs407135), and zinc finger protein 512B (ZNF512B) (rs2275294) variants, as well as ataxin-2 (ATXN2) polyQ intermediate repeats (≥31) and chromosome 9 open reading frame 72 (C9orf72) GGGGCC intronic expansions (≥30). RESULTS: The median survival time of the whole cohort was 2.67 years (interquartile range [IQR] 1.67-5.25). In univariate analysis, only C9orf72 (2.51 years, IQR 1.74-3.82; p = 0.016), ATXN2 (1.82 years, IQR 1.08-2.33; p < 0.001), and UNC13A C/C (2.3 years, IQR 1.3-3.9; p < 0.001) significantly reduced survival. In Cox multivariable analysis, CAMTA1 also emerged to be independently related to survival (hazard ratio 1.13, 95% CI 1.001-1.30, p = 0.048). The copresence of 2 detrimental alleles/expansions was correlated with shorter survival. In particular, the median survival of patients with CAMTA1 G/G+G/T and UNC13A C/C alleles was 1.67 years (1.16-3.08) compared with 2.75 years (1.67-5.26) of the patients not carrying these variants (p < 0.001); the survival of patients with CAMTA1 G/G+G/T alleles and ATXN2 ≥31 intermediate polyQ repeats was 1.75 years (0.84-2.18) (p < 0.001); the survival of patients with ATXN2 ≥31 polyQ repeats and UNC13A C/C allele was 1.33 years (0.84-1.75) (p < 0.001); the survival of patients with C9ORF72 ≥30 and UNC13A C/C allele was 1.66 years (1.41-2.16). Each pair of detrimental alleles/expansions was associated to specific clinical phenotypes. DISCUSSION: We showed that gene variants acting as modifiers of ALS survival or phenotype can act on their own or in unison. Overall, 54% of patients carried at least 1 detrimental common variant or repeat expansion, emphasizing the clinical impact of our findings. In addition, the identification of the interactive effects of modifier genes represents a crucial clue for explaining ALS clinical heterogeneity and should be considered when designing and interpreting clinical trials results.

The diagnostic value of the Italian version of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS).

Objectives: The diagnostic capabilities of specific cognitive screeners are clinically crucial for an early detection of frontotemporal features in amyotrophic lateral sclerosis (ALS) patients. This study aimed at providing diagnostic properties of the cognitive section of the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) in Italian ALS patients.Methods: Eighty-nine consecutive Italian ALS patients were classified according to Strong et al. (2017) criteria with a comprehensive neuropsychological assessment. The Italian version of ECAS was also administered, and its accuracy, sensitivity (SE), specificity (SP), negative and positive predictive values (PPV; NPV) and likelihood ratios (LR+; LR-) were computed against clinical diagnoses.Results: The ECAS and its subscales yielded moderate-to-high accuracy (AUC = .7-.87). High SP was overall found (81.8%-100%). The most sensitive measures were ALS-specific and Executive (73.9-78.3%) subscales, while the least were the ALS-non-specific subscales (8.7-17.4%). ECAS measures showed good PPVs (60%-100%) and NPVs (75.9%-91.5%). Acceptable LRs were found (LR+: 6.97-4.3; LR-: .29-.91), with total and ALS-specific measures yielding the best estimates.Conclusions: This is the first study demonstrating the diagnostic value of the ECAS against a thorough neuropsychological assessment in Italy. ECAS-total and -ALS-specific scores are diagnostically sound as to both intrinsic and post-test features, whereas ALS-non-specific measures perform slightly worse.

Italian adaptation of the Beaumont Behavioral Inventory (BBI): psychometric properties and clinical usability.

Objective. Up to 50% of patients affected by amyotrophic lateral sclerosis (ALS) show behavioral changes within the spectrum of frontotemporal degeneration (FTD). Behavioral dysfunctions in ALS patients negatively impact on management, prognosis and survival. It is, thus, crucial to develop ALS-specific psychometric tools for early detecting alterations in behavior. This study aimed at investigating psychometric properties and feasibility of the Beaumont Behavioral Impairment (BBI), a proxy-report questionnaire designed to screen for FTD-like behavioral symptoms in ALS patients.Methods. Ninety ALS patients were compared to 100 healthy participants (HPs) on the BBI. ALS patients underwent clinical, cognitive, mood/anxiety and further behavioral (Frontal System Behavior Scale, FrSBe; Frontal Behavioral Inventory, FBI) evaluation. Validity, reliability, sensitivity and specificity of the BBI were assessed.Results. The BBI was significantly related to FrSBe and FBI scores, whereas not to other measures. A Principal Component Analysis yielded a mono-component structure; Cronbach's α was .93. The BBI proved to be sensitive to changes in behavior as well as to discriminate between different degrees of dysfunction. By addressing the FrSBe as the gold standard, the BBI reached optimal sensitivity (85.7%) and specificity (79.7%) at a cutoff of 10.5. Moreover, the BBI proved to be more accurate than the FrSBe and the FBI in clinical classifications.Conclusion. The BBI showed high internal consistency, as well as good construct, convergent and divergent validity. Its clinical usability is encouraged in ALS patients as being able to sensitively and specifically detect FTD-like behavioral changes.

Amyotrophic lateral sclerosis caregiver burden and patients' quality of life during COVID-19 pandemic.

Objective: To assess patients Quality of life (QoL) and the burden of their caregivers during Covid-19 pandemic and specifically the impact of two-month lockdown period. Methods: In April 2020, a total of 60 patients and 59 caregivers were administered by phone scales assessing patients' QoL (McGill QoL Questionnaire), general health status (EQ-5D-5L), and caregiver burden (Zarit Burden Interview). The administration was repeated one month after the end of lockdown measures, with the addition of a qualitative questionnaire (COVID-QoL Questionnaire) exploring family reorganization and personal perception of lock down. Results: QoL and perceived health status did not worsen during lockdown, while caregiver burden increased (p = 0.01). Patient's QoL and caregiver burden were inversely correlated at T1 (ZBI total score mildly correlated with Mc Gill existential subscore, p = 0.02, rho = 0.30 and with Mc Gill total score, p = 0.05, rho = 0.265). No significant correlations were found at T2. According to the COVID-QoL questionnaire, caregivers perceived lower family help compared to patients (p < 0.001). Conclusions: Restricted measures of lockdown period during COVID-19 pandemic did not result in a significant reduction of QoL in our cohort of ALS patients, while caregiver burden significantly increased. ALS motor impairment may have played a role in the unchanged life conditions of patients. Instead, the restriction of family help for primary caregivers could be responsible of their increased burden, reflecting the importance of a wide social support in the management of this clinical condition.

Differential Neuropsychological Profile of Patients With Amyotrophic Lateral Sclerosis With and Without C9orf72 Mutation.

OBJECTIVE: To determine whether the neuropsychological profiles of patients with amyotrophic lateral sclerosis (ALS) with (ALSC9+) and without (ALSC9-) C9orf72 expansion are different, we administered a battery of neuropsychological tests to 741 patients with ALS (68 ALSC9+ and 673 ALSC9-) and 129 controls. METHODS: The study population includes 741 patients with ALS who were consecutively diagnosed at the Turin ALS expert center in the 2010-2018 period and who underwent both cognitive/behavioral and genetic testing. Patients' neuropsychological patterns were compared (1) at the same degree of cognitive and behavioral deficit according to the revised ALS-Frontotemporal Dementia Consensus Criteria and (2) at the same level of motor impairment according to the King staging system. RESULTS: Despite being about 7 years younger, ALSC9+ patients had significantly lower scores in tests exploring executive function and verbal memory both when classified as cognitively normal and when diagnosed in the intermediate cognitive categories. Considering the clinical perspective, ALSC9+ patients showed significantly lower scores compared to ALSC9- patients at King stage 1 and 3 in almost all the examined neuropsychological domains; at King stage 2, ALSC9+ patients were more severely affected only in the verbal memory domain. Behavioral function was comparably impaired in the 2 cohorts. CONCLUSIONS: ALSC9+ patients show a different neuropsychological profile compared to ALSC9- patients, being more impaired in executive functions and verbal memory domains at all King stages. Verbal memory emerged as a particularly vulnerable function in ALSC9+, with worse performances even when patients were still classified as cognitively normal.

Validation of the Italian version of self-administered ALSFRS-R scale.

OBJECTIVES: To validate and assess the reliability of the Italian version of self-administered ALSFRS-R, considering patients' clinical and cognitive features and caregiver's help. Methods: During the COVID-19 pandemic, by analyzing the results of 70 paired self-administered vs standard telephone-administered ALSFRS-R, we calculated overall score, single item scores, ALSFRS-R domain scores, King's and MiToS stage inter-rater agreement and reliability using different validated methods. We created the Italian version of self-administered ALSFRS-R following ENCALS recommendation. Results: Correlation between the two scales was 0.94 and no systematic directional bias was found. The intraclass correlation coefficient (ICC) was very high (>0.90) for the vast majority of the considered classification criteria, especially King's total score (0.96) and MiToS score (0.94). A higher ICC was found when the patients answered the questionnaire with the caregiver's help (0.95). Conclusions: Online self-administered ALSFRS-R scale is a valid tool to stratify ALS patients into clinical stages and to implement telemedicine monitoring.