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In the absence of a definitive laboratory test to confirm a diagnosis of amyotrophic lateral sclerosis (ALS), neurologists have relied on clinical signs. In turn, these signs are taken to reflect disease involvement of upper and lower motor neurone compartments of the motor system. Over recent decades, diagnostic criteria have been developed to provide a degree of certainty to patients and their clinicians, from possible to probable and definite. This nomenclature implies a level of diagnostic confidence that is confusing to patients. Uncertainty about diagnosis constitutes a barrier for patient enrolment to clinical trials. To improve diagnostic clarity and to facilitate patient enrolment into clinical trials, a recent international consensus meeting was hosted on the Gold Coast in Australia. The meeting was supported by key stakeholders including the World Federation of Neurology, the International Federation of Clinical Neurophysiology, and key patient groups including the Motor Neurone Disease Association (UK) and the ALS Association (US). In adopting new streamlined consensus guidelines, the previous diagnostic categories of Definite, Probable and Possible were abandoned. In reality, virtually all patients diagnosed as possible disease, represent ALS with differing degrees of disease involvement. Separately, a diagnosis of possible ALS does not guarantee that patients will evolve through to probable and definite disease. Easier and earlier diagnosis of ALS will promote more focussed patient management, and will enable patients and carers to plan appropriately for the future. Finally, there is a further advantage of the new, simplified criteria: ALS patients can be fast-tracked into clinical trials.

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Clinical trials for amyotrophic lateral sclerosis (ALS) have failed, except for riluzole, which is expected to prolong survival by 3 months without effects to the symptoms, and edaravone, which was shown to be efficacious to slightly retard the progression of the disease without data of prolonging survival. This has at least two factors: ALS is diverse in its pathogenesis as exemplified by increasing number of causative genes, and treatment is started too late to rescue remaining motor neurons. Awaji criteria were developed for earlier diagnosis of ALS, to facilitate entry of patients at early stages.
Phase 1-2 trial of antisense oligonucleotide tofersen for ALS due to SOD1 mutations has been reported with promising results(Miller et al. NEJM 2020). This substance is an antisense oligonucleotide targeting at lowering concentration of mutant SOD1 mRNA, directly attacking pathogenesis.
The outcome of phase 3 high-dose intramuscular methylcobalamin (JETALS) has just come out with positive results, retarding the decline of ALSFRS-R(Izumi et al. 2021, fig.)

This trial was the first to adopt Awaji criteria, entering patients within 12 months after the onset. Its phase 2-3 trial (E0301) was not successful in those within 3 years after onset, but its subanalysis of those within 1 year of onset showed efficacy on ALSFRS-R decline and longer survival (>600 days) than control(Kaji et al. JNNP 2018). JETALS was designed to examine only ALSFRS-R, but according to E-0301 study, it likely prolongs the survival, if the patients started the therapy within 12 months after onset.

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Objective: to compare social cognition profile of patients with amyotrophic lateral sclerosis (ALS) and with behavioral variant frontotemporal dementia (bvFTD).

Methods: twenty-one patients with ALS, 20 patients with bvFTD and 21 healthy controls were recruited from two neurological clinics from Brazil and Chile, and underwent a cognitive battery. The assessment included: i) the abbreviated version of the Social Cognition and Emotional Assessment (Mini-SEA), composed by the faux pas test (theory of mind-ToM) and the Facial Emotion Recognition Test (FERT), ii) Mini-Mental State Examination (MMSE), iii) Frontal Assessment Battery (FAB), iv) lexical fluency (F-A-S), v) category fluency (animals/minute), vi) digit span (direct and backwards), and vii) Hayling test. A post hoc analysis was conducted to divide the ALS patients into two subgroups: patients with cognitive impairment ALSci (n=8) and patients without cognitive impairment ALScn (n=13).

Results: No significant difference was found between groups when comparing age, sex and education. Patients with ALS and bvFTD had similar disease duration. Patients with bvFTD performed worse than controls in executive and social cognition. By contrast, there was no significant difference between ALScn and controls.The ALSci subgroup performed poorly when compared with controls, in the total scores of Mini-SEA (p<0.002), including faux pas (p<0.004) and FERT (p<0.001).

Discussion: Our findings highlight the cognitive heterogeneity of ALS, supporting the existence of a cognitive continuum between ALS and bvFTD. While ALSci group performed similarly to bvFTD group, patients with ALScn performed similar to controls.