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:

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:

Motor neuron diseases (MNDs), including amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA) and spinal and bulbar muscular atrophy (SBMA), are a heterogeneous group of neurodegenerative disorders characterized by motor neuron loss. Despite variability in onset, progression and genetic causes, these disorders share a common involvement of skeletal muscle that is suspected to have a relevant role in MND pathogenesis.

Due to the key role of muscle-specific microRNAs (myomiRs) in muscle development, here we investigated the expression of miR-206, miR-133a, miR-133b and miR-1 myomiRs, and their target genes, in G93A-SOD1 ALS, Δ7SMA and KI-SBMA mouse muscle during disease progression.

Methods:

MyomiRs and their putative target genes, PAX7, MYOD, MYOG, and MEF2, were analyzed by qPCR in ALS-G93A-SOD1, Δ7SMA-SMA and AR113Q-SBMA mice during disease progression. Sperman’s correlation analyses were performed to examine the myomiR/mRNA relationships. The corresponding myomiR target proteins were analysed by western blot. By qPCR, myomiRs were assessed in serum of 14 ALS-SOD1, 23 SMA pediatric, 10 SBMA patients, and 30 controls, including 19 pediatric patients with encephalitis.

Results:

We revealed myomiRs/mRNA target gene dysregulation as common pathogenic feature of the three MNDs. A similar myomiR signature was observed in serum from SOD1-mutated ALS, SMA and SBMA patients, with miR-206 up-regulation being identified in both animal muscle tissues and patients’sera.

Conclusions:

Our findings highlight the role of myomiRs as contributing factors and promising non-invasive biomarkers in ALS, SMA and SBMA, laying the groundwork for further investigations to explore myomiR potential as future therapeutic targets for MNDs.

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.