COG-01 Phenotypic variation in 
ALS-FTD and effect on survival

Background: Within the Amyotrophic Lateral Sclerosis (ALS)-Frontotemporal dementia (FTD) spectrum there is considerable heterogeneity in clinical presentation and survival.Objectives: The current study aimed to examine how initial symptoms (motor compared to cognitive) may affect survival, with specific focus on structural cognitive and behavioural differences between ALS-FTD and bvFTD 
cohorts.Methods: Cognitive and behavioural profiles were examined in 98 patients (59 ALS-FTD and 39 bvFTD patients). The initial presentation of ALS-FTD was categorized into either motor or cognitive, based on symptoms combined with carer reports. Survival was calculated from initial symptom onset. Brain atrophy patterns on MRI were examined using a verified visual rating scale.Results: In the ALS-FTD group, 69% were categorized as having an initial cognitive presentation and 31% a motor presentation. Those patients with motor presentation of ALS-FTD experienced a significantly shorter survival of 33 months, compared to 63 months (p<0.007) in those with a cognitive presentation of ALS-FTD. On cognitive testing there were no differences between motor versus cognitive onset ALS-FTD. When compared to bvFTD, ALS-FTD, particularly the cognitive presentation, was characterized by reduced language function (p<0.001), verbal fluency (p = 0.001), and naming (p = 0.007). Both cognitive and motor presentation ALS-FTD had poorer emotion processing (p = 0.01) compared to bvFTD. On structural imaging analyses both motor and cognitive onset ALS-FTD patients had greater motor cortex and dorsal lateral prefrontal cortex atrophy compared to bvFTD patients. Increased motor cortex atrophy was associated with 1.5-fold reduction in survival.Discussion and conclusions: In ALS-FTD those with an initial motor presentation have a much faster progression than those with a cognitive presentation, despite having similar overall cognitive impairment, suggesting that disease progression in ALS-FTD may be critically linked to physiological and motor changes. Survival is also associated with motor cortex atrophy which is increased in ALS-FTD.These results provide further suggestions in relation to the categorization of clinical trial patients into fast and slow progressors.