Background and Aims:

To investigate the relationship between respiratory failure and cognitive/behavioral impairment in ALS patients based on the stage of the disease.

Methods:

Data from 112 ALS patients were collected. Respiratory function was measured with ALS functional rating scale revised sub-score (RofALSFRS-R) and forced vital capacity value (FVC%). Disease stage was defined with the King’s Clinical Staging System (KCSS). Neuropsychological features were assessed by a comprehensive battery of tests according to current guidelines. Data were analysed using partial correlation corrected for KCSS, between group comparisons and the Jonckheere-Terpstra test.

Results:

62 (55%) patients had cognitive/behavioral impairment and 19 (17%) respiratory insufficiency (ALSr). No significant correlations were found between respiratory and neuropsychological parameters, except for the rate of quality of life being lower in ALSr. Across advancing disease stages, we detected a significant worsening of performances in language, fluency and memory domains (p<0.05), and respiratory function (FVC, RofALSFRS-R: p<0.001).

Conclusions:

Conclusion: Respiratory insufficiency and cognitive/behavioral impairment are not related, suggesting that motor and extra-motor features feed the heterogeneity of ALS clinical features with an independent prognostic value.

Background and Aims:

To date, mutations in the SOD1 gene of patients with amyotrophic lateral sclerosis (ALS) have been associated to peculiar clinical features and disease progression but rarely to cognitive and behavioural impairment. This report aims to address the occurrence of frontotemporal syndromes in ALS patients carrying SOD1 mutations

Methods:

We examined 423 consecutive Italian patients diagnosed with ALS between 2013 and 2020. All underwent clinical, neurophysiological, neurophysiological, neuroradiological assessment and targeted next generation sequencing of SOD1, FUS-TLS, TARDBP, VCP, PFN1, TUBA4A, OPTN, SQSTM1, UBQLN2 and C9orf72 genes. The occurrence of cognitive and behavioural impairment was defined according to current guidelines

Results:

Sixteen patients had mutation in SOD1 gene, four of whom had a variant of uncertain significant (VUS). All patients had spinal onset with predominant involvement of lower limbs. At diagnosis, 9 patients (3 VUS) had mild form of behavioural changes (ALSbi), one had cognitive and behavioural impairment (ALScbi), one patient had a profile of amnesic mild cognitive impairment and 5 (1 VUS) had cognitively-normal profile.

At follow up, three ALSbi patients (one with VUS) developed frank frontotemporal dementia (FTD) and one ALSbi developed cognitive impairment (ALScbi). The most common behavioural changes were apathy, mental rigidity and irritability.

Conclusions:

Our findings demonstrate that SOD1 patients have early behavioural impairment more commonly than previously reported, which might increase the risk to develop FTD

Background and Aims:

The two-month lockdown period during COVID-19 pandemic had a general impact on health treatments and care assistance. We wanted to assess Quality of life (QoL) of ALS patients and the burden of their caregivers during that period.

Methods:

60 patients and 59 caregivers, visited in telemedicine during March 2020, underwent the assessment of patients’ QoL (McGill QoL Questionnaire), general health status (EQ-5D-5L) and caregiver burden (Zarit Burden Interview [ZBI]). These phone scales were administered in April 2020 (T1) and repeated one month after the end of lockdown (T2), with the addition of a qualitative questionnaire (COVID-QoL-Questionnaire), exploring family reorganization and personal perception of lockdown.

Wilcoxon signed-rank test and the chi-squared test were used.

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 mildly inversely correlated at T1 (p<0.05, rho=-0.265); no significant correlations were found at T2. According to the COVID-QoL-Questionnaire, both patients and caregivers were able to consult their physicians while at home (60% and 66.1% respectively). Moreover, caregivers perceived lower family help compared to patients (p<0.001).

Conclusions:

In our cohort of ALS patients, QoL and caregiver burden were not compromised by restriction measures during COVID-19 pandemic, while caregiver burden significantly increased. Probably, this is due to the motor impairment in ALS patients, which did not perceive changing in life conditions. Instead, the reported increased burden for primary caregivers could be explained by the restriction of family help, reflecting the importance of a wide social support in ALS patients’ management.

Background and Aims:

Robust preclinical findings demonstrated that guanabenz selectively inhibits ER stress-induced eIF2α-phosphatase allowing misfolded protein clearance, reduces neuronal death and prolongs survival in in vitro and in vivo ALS models.

Methods:

In this multicentre RCT with futility design, ALS patients with onset <18 months were randomly assigned to receive in a 1:1:1:1 ratio guanabenz 64 mg, 32 mg, 16 mg or placebo daily for 6 months as add-on-therapy to riluzole. Primary outcome was the proportion of patients progressing to higher stages of disease measured by ALS-MITOs compared to a historical cohort of 200 patients. Secondary outcomes were rate of decline in ALSFRS-R, sVC change, time to death, tracheotomy or permanent ventilation and serum light neurofilament level. Primary analysis of efficacy was by intention-to-treat.

Results:

Guanabenz 64/32 mg arms reached the primary hypothesis of non-futility with proportions of patients progressing to higher stage of disease significantly lower than that expected and significantly lower difference in the median rate of change of the ALSFRS-R total score. This effect was driven by patients with bulbar onset, none of whom (0/18) progressed to higher stage of disease compared with those in guanabenz 16 mg (4/8; 50%), historical cohort alone (21/49; 43%; p=0.001) or plus placebo (25/60; 42%; p=0.001). The proportion of patients experiencing at least one adverse event was higher in any guanabenz than placebo arm, with higher dosing having significantly higher proportion of side effects and drop-out rate.

Conclusions:

A larger trial with a molecule targeting the UPR pathway without alpha-2 adrenergic related side-effect profile is warranted.

Background and Aims:

In pure-motor ALS patients, we recently observed that smaller volume of the left pallidum was related with impaired recognition of disgust. In the present study, we investigated the resting-state functional connectivity (RS-FC) of the pallidum in ALS, and the relationship between RS-FC changes and disgust recognition.

Methods:

19 pure-motor ALS patients and 52 matched healthy controls underwent RS functional MRI and a neuropsychological assessment including the Comprehensive Affect Testing System (CATS), investigating emotion recognition. A seed-based RS-FC analysis was run between the left and right pallidum and the rest of the brain, and compared between groups. Correlation analyses were run between the RS-FC significant changes and patients’ performance in recognizing disgust.

Results:

Compared to controls, ALS presented reduced RS-FC between bilateral pallidum and right superior and middle frontal gyri, and increased RS-FC between bilateral pallidum and left superior temporal and postcentral gyri, and left Rolandic operculum. Increased RS-FC was observed between left pallidum and left supramarginal gyrus and between right pallidum and contralateral insula and thalamus. In patients, lower performance in recognizing disgust was related with reduced RS-FC between bilateral pallidum and right middle and superior frontal gyri, and with increased RS-FC between bilateral pallidum and left postcentral gyrus and Rolandic operculum.

Conclusions:

In a cognitively unimpaired ALS patients, reduced pallidum-frontal RS-FC and increased pallidum-insular-thalamic RS-FC may suggest a fronto-striatal functional disconnection, which could have a role in the lower ability of patients in recognizing disgust.

Funding: Italian Ministry of Health (GR-2013-02357415); European Research Council (StG-2016_714388_NeuroTRACK).

Background and Aims:

ALS phenotype widely vary across patients. It is unclear if different etiologies could justify this variability. Spatial epidemiology could give some hints on the etiology of diseases by identifying clusters and looking for their genetic or environmental causes. The aim of the study was to perform a spatial analysis of ALS cases stratified by their clinical presentation.

Methods:

All patients included in the Piemonte and Valle d’Aosta ALS Register who received an ALS diagnosis between 2007 and 2014 and who were resident in Piemonte at the time of diagnosis were considered. Cluster analysis was performed stratifying patients by sex, age at diagnosis, onset site and phenotype (classified as classic, flail arm, flail leg, predominant UMN, bulbar and respiratory). All analyses were performed both including and excluding genetic cases to consider a possible different susceptibility to environmental exposure. Cluster analyses were assessed using the Kulldorff spatial scan statistic.

Results:

A total of 943 patients were included. No significant clusters were revealed for any of the subgroups considered with the only exception of a small low-incidence cluster of flail arm patients located in Northern Piedmont (over 201 municipalities with 655537 residents, 7.86 cases were expected and none was observed, relative risk=0.0, p=0.024). Analyses excluding genetic cases did not modify the results.

Conclusions:

Our data, based on the geographical distribution of cases, do not indicate that different ecological factors underlie the diversity of ALS clinical presentation. A stratification based on genetics could be considered when looking for susceptibility to different environmental factors.

Background and Aims:

Spirometry is commonly used to monitor respiratory function in Amyotrophic Lateral Sclerosis (ALS). However, its use is poorly accurate in patients with bulbar or cognitive impairment. Arterial blood gas analysis (ABG) correlates moderately with forced vital capacity (FVC).

We aimed at investigating if the assessment of the ALSFRS-r respiratory items (10 and 11) increases the correlation between ABG and FVC in a cohort of ALS patients.

Methods:

We selected the first ABG performed before non-invasive ventilation by ALS patients. The best combination to predict FVC was assessed by studying the correlations of different combinations of FVC% with ABG parameters (carbon dioxide, pCO2; carbonate, HCO3-) and respiratory symptoms (dyspnea and orthopnea were considered present if ALSFRS-R items 10 and 11 were <4, respectively). Clinical and epidemiological characteristics were compared between patients with and without respiratory symptoms, grouped according to ABG values.

Results:

A total of 488 ABGs were collected. The best combination to predict FVC was: pCO2 plus HCO3- plus ALSFRS-R item 10 (R=0.430, p <0.001). Patients with dyspnea showed a more severe motor impairment, a higher disease progression rate and lower FVC values. Patients with normal ABG and dyspnea had a reduced survival than patients without dyspnea (0.91 years, IQR 0.46-1.91 vs 1.46 years, IQR 0.89-2.29, p=0.002). Cognitive dysfunction did not influence the complaining of dyspnea (OR 1.009, 95% CI 0.837-1.215, p=0.927).

Conclusions:

Combining ABG with clinical evaluation of dyspnea improves the ability to assess early respiratory dysfunction in ALS, especially in patients with bulbar or cognitive impairment.

Background and Aims:

Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in ALS patients and to correlate such findings with cognitive-behavioral data.

Methods:

Two inpatient cohorts of Italian ALS patients and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided in a discovery and a replication cohort. Subjects underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed using a standard neuropsychological battery (discovery cohort), and the Italian Edinburgh Cognitive and Behavioural ALS Screen – ECAS (replication cohort).

Results:

OMAs were detected in 10.5% of our ALS cohort and in 1.6% of controls (p=1.2x10^-14). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMAs frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both cohorts (p=1.1x10^-25). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathological scores at the ECAS ALS-specific domains.

Conclusions:

ALS patients showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.