Functional network resilience to pathology in presymptomatic genetic frontotemporal dementia

Abstract

The presymptomatic phase of neurodegenerative diseases are characterized by structural brain changes without significant clinical features. We set out to investigate the contribution of functional network resilience to preserved cognition in presymptomatic genetic frontotemporal dementia. We studied 172 people from families carrying genetic abnormalities in C9orf72, MAPT, or PGRN. Networks were extracted from functional MRI data and assessed using graph theoretical analysis. We found that despite loss of both brain volume and functional connections, there is maintenance of an efficient topological organization of the brain's functional network in the years leading up to the estimated age of frontotemporal dementia symptom onset. After this point, functional network efficiency declines markedly. Reduction in connectedness was most marked in highly connected hub regions. Measures of topological efficiency of the brain's functional network and organization predicted cognitive dysfunction in domains related to symptomatic frontotemporal dementia and connectivity correlated with brain volume loss in frontotemporal dementia. We propose that maintaining the efficient organization of the brain's functional network supports cognitive health even as atrophy and connectivity decline presymptomatically.

Longitudinal changes in resting state networks in early presymptomatic carriers of C9orf72 expansions

“…The mechanisms that could give rise to changes in circuit function, such as changes in synaptic strength or plasticity ( Benussi et al, 2016 ), may be more amenable to intervention than later stages after neuronal loss begins. Finding that C9+ carriers remain asymptomatic despite reduced connectivity is consistent with a graph theory analysis that reported that the efficiency of intracortical networks remains resilient to declining functional connectivity and focal atrophy until just prior to the onset of clinically manifest disease in carriers of FTD genes ( Rittman et al, 2019 ). Because the average age of our presymptomatic cohort was a decade younger than that of the symptomatic cohort, longer follow-up will be needed to determine whether the functional connectivity changes observed here are predictive of disease onset or allow identification of C9+ carriers at an earlier stage of disease.…”

Apathy is associated with reduced precision of prior beliefs about action outcomes.

“…We hypothesize that neuromodulatory deficits in patients can cause a loss of prior precision relative to the sensory input, which subsequently leads to apathy. Furthermore, higher order prior beliefs about desired outcomes may fail to appropriately contextualize lower level representations about sensory input due to structural and functional abnormalities in prefrontal and temporal brain regions ( Rittman et al, 2019 ). Further work is required to establish the synaptic and molecular basis of aberrant precision, aided by the parameterization of the precision of an individual’s prior.…”

Use of Multimodal Imaging and Clinical Biomarkers in Presymptomatic Carriers of C9orf72 Repeat Expansion

“… 10 , 11 Research in presymptomatic carriers of a hexanucleotide repeat expansion in the C9orf72 gene (preSxC9) reported the occurrence of cognitive and behavioral changes, neuropsychiatric symptoms, and degeneration of gray matter (GM) and white matter (WM). 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 …”