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.

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.

The role of peripheral immunity in ALS: a population-based study.

BACKGROUND: Systemic inflammation has been proposed as a relevant mechanism in amyotrophic lateral sclerosis (ALS). Still, comprehensive data on ALS patients' innate and adaptive immune responses and their effect on the clinical phenotype are lacking. Here, we investigate systemic immunity in a population-based ALS cohort using readily available hematological indexes. METHODS: We collected clinical data and the complete blood count (CBC) at diagnosis in ALS patients from the Piemonte and Valle d'Aosta Register for ALS (PARALS) from 2007 to 2019. Leukocytes populations, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic-immune-inflammation index (SII), and lymphocyte-to-monocyte ratio (LMR) were derived from CBC. All variables were analyzed for association with clinical features in the entire cohort and then in sex- and age-based subgroups. RESULTS: Neutrophils (P = 0.001) and markers of increased innate immunity (NLR, P = 0.008 and SII, P = 0.006) were associated with a faster disease progression. Similarly, elevated innate immunity correlated with worse pulmonary function and shorter survival. The prognosis in women also correlated with low lymphocytes (P = 0.045) and a decreased LMR (P = 0.013). ALS patients with cognitive impairment exhibited lower monocytes (P = 0.0415). CONCLUSIONS AND RELEVANCE: The dysregulation of the systemic immune system plays a multifaceted role in ALS. More specifically, an elevated innate immune response is associated with faster progression and reduced survival. Conversely, ALS patients with cognitive impairment showed a reduction in monocyte count. Additionally, immune response varied according to sex and age, thus suggesting that involved immune pathways are patient specific. Further studies will help translate those findings into clinical practice or targeted treatments.

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.

Telemedicine for patients with amyotrophic lateral sclerosis during COVID-19 pandemic: an Italian ALS referral center experience.

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.

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.

The Characteristics of Cognitive Impairment in ALS Patients Depend on the Lateralization of Motor Damage.

(1) Background: Cognitive features of patients with amyotrophic lateral sclerosis (ALS) have never been specifically analyzed according to the lateralization of motor impairment. In the present study we investigated the cognitive performances of ALS patients to describe the relationship between motor and cognitive dysfunction, according to site and side of disease onset. (2) Methods: Six-hundred and nine ALS patients underwent a comprehensive neuropsychological evaluation at diagnosis in Turin ALS Centre Tests included-mini-mental state examination (MMSE), frontal assessment battery (FAB), trail-making test A/B (TMT A-B), digit span forward and backward (digit span FW/digit span BW), letter fluency test (FAS), category fluency test (CAT), Rey auditory verbal learning test (RAVLT), Babcock story recall test (BSRT), Rey-Osterrieth complex figure test (ROCFT), Wisconsin card sorting test (WCST), Raven's coloured progressive matrices (CPM47). Cognitive performances of patients, grouped by side and site of onset, were statistically compared using z-scores, as appropriate. (3) Results: Bulbar patients and bilateral spinal onset patients (Sbil) were generally characterized by lower cognitive performances in most neuropsychological tests, when compared to patients with lateralized onset (right-side spinal onset, Sri and left-side spinal onset, Sle). Digit span backward and visual memory task (ROCFT) median z-scores were significantly higher, reflecting a better cognitive performance, in Sri patients when compared to bulbar/Sbil patients, while verbal memory tasks (RAVLT and BRST) resulted in significantly higher scores in Sle patients. Our results are in keeping with hemispheric functional lateralization of language and visuospatial abilities. (4) Conclusions: In ALS patients, as in other neurodegenerative diseases, we found a direct relationship between lateralized motor and cognitive features.

Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study.

OBJECTIVE: The lack of prognostic biomarkers in patients with amyotrophic lateral sclerosis (ALS) induced researchers to develop clinical evaluation tools for stratification and survival prediction. We assessed the correlation between patterns of functional involvement, considered as a cumulative number of body regions involved, and overall survival in a population-based series of patients with ALS (PARALS). METHODS: We derived the functional involvement of four body regions at diagnosis using ALSFRS-R subscores for bulbar, upper limbs, lower limbs and respiratory/thoracic regions. We analysed the effect of number of body regions involved (NBRI) at diagnosis on overall survival, adjusting for age at onset, sex, site of onset, diagnostic delay, forced vital capacity, body mass index, mutational status, cognition and comparing it with King's staging system. RESULTS: The NBRI was strongly related to survival, with a progressive increase of death/tracheostomy risk among groups (two body regions HR=1.24, 95% CI 1.06 to 1.45, p=0007; three body regions HR=1.65, 95% CI 1.38 to 1.98, p<0.001; four body regions HR=2.68, 95% CI 2.11 to 3.39, p<0.001). Using ALSFRS-R score, the consistency between the number of regions involved and King's clinical stage at diagnosis was very high (81%). The evaluation of respiratory/thoracic region and cognition allowed to subdivide patients into different prognostic categories. Regional spreading of the disease is associated with survival, independently from the initial region involved. CONCLUSIONS: The evaluation of NBRI, with the inclusion of initial respiratory/thoracic involvement and cognition, can be useful in many research fields, improving the stratification of patients. Our findings highlight the importance of the spatial spreading of functional impairment in the prediction of ALS outcome.