Cognitive inhibition impairments in presymptomatic C9orf72 carriers

Abstract

ObjectiveTo investigate cognitive inhibition in presymptomatic C9orf72 mutation carriers (C9+) and its associated neuroanatomical correlates.MethodsThirty-eight presymptomatic C9orf72 mutation carriers (C9+, mean age 38.2±8.0 years) and 22 C9− controls from the PREV-DEMALS cohort were included in this study. They underwent a cognitive inhibition assessment with the Hayling Sentence Completion Test (HSCT; time to completion (part B−part A); error score in part B) as well as a 3D MRI.ResultsC9+ individuals younger than 40 years had higher error scores (part B) but equivalent HSCT time to completion (part B−part A) compared to C9− individuals. C9+ individuals older than 40 years had both higher error scores and longer time to completion. HSCT time to completion significantly predicted the proximity to estimated clinical conversion from presymptomatic to symptomatic phase in C9+ individuals (based on the average age at onset of affected relatives in the family). Anatomically, we found that HSCT time to completion was associated with the integrity of the cerebellum.ConclusionThe HSCT represents a good marker of cognitive inhibition impairments in C9+ and of proximity to clinical conversion. This study also highlights the key role of the cerebellum in cognitive inhibition.

Structural MRI Signatures in Genetic Presentations of the Frontotemporal Dementia/Motor Neuron Disease Spectrum

“…When looking at single genetic alterations, we identified gMND and, particularly, C9-MND as driving these results, which are consistent with recent studies indicating the involvement of the cognitive/affective regions of the posterior cerebellum (particularly, lobule VII and crus regions, involved in the modulation of emotions and social behaviors) as indicative of the presence of a C9orf72 mutation, 7 possibly as a consequence of the close structural and functional connections with the thalami through cerebello-thalamo-cortical networks. 42 , 45 Similar alterations have been demonstrated in presymptomatic C9orf72 mutation carriers, 37 , 38 , 46 correlating with cognitive inhibition deficits. 46 Although the role in cognition and the topologic organization of the cerebellar cortex has started being elucidated only in recent years, 45 this is an exciting area of developing research for biomarkers of disease pathology in the FTLD spectrum (including MND) that might be combined with other more established measures of cortical damage.…”

“… 42 , 45 Similar alterations have been demonstrated in presymptomatic C9orf72 mutation carriers, 37 , 38 , 46 correlating with cognitive inhibition deficits. 46 Although the role in cognition and the topologic organization of the cerebellar cortex has started being elucidated only in recent years, 45 this is an exciting area of developing research for biomarkers of disease pathology in the FTLD spectrum (including MND) that might be combined with other more established measures of cortical damage.…”

Frontotemporal dementia subtypes based on behavioral inhibition deficits

“…In the HSCT, participants are asked to complete 15 sentences using the appropriate word, as fast as possible (automatic condition, Part A), and 15 sentences using a completely unrelated word (inhibition condition, Part B). Recently, it has been demonstrated that this test is a reliable measure of cognitive inhibition impairments in pre‐symptomatic C9orf72 mutation carriers and their proximity to clinical conversion to bvFTD 14 . We used the Hayling error score (number of errors in Part B) as a measure of the difficulty to inhibit a prepotent response, as in Flanagan et al 15 .…”

Biomarkers for C9orf7-ALS in Symptomatic and Pre-symptomatic Patients: State-of-the-art in the New Era of Clinical Trials

“…An example of specific C9orf72 -related impairment is the presence, in pre-symptomatic carriers, of deficits in cognitive inhibition (i.e., the ability to resist to interference from irrelevant stimuli) which seems to become more evident in individuals who are closer to symptom onset [ 40 ]. Some other studies have shown the presence of deficits in semantic access [ 41 ] as well as early involvement of praxis, which has been observed already in subjects younger than 40 years of age, supporting the hypothesis that frontal and prefrontal structures are early involved in degeneration [ 42 ].…”