Cognitive Reserve in Granulin-Related Frontotemporal Dementia: from Preclinical to Clinical Stages

Enrico Premi,Mara Cercignani,Marinella Turla,Barbara Borroni,Angelo Bianchetti,Carlo Caltagirone,Roberto Gasparotti,Silvana Archetti,Stefano Gazzina,Antonella Alberici,Marco Bozzali,Alessandro Padovani

doi:10.1371/journal.pone.0074762

Abstract

ObjectiveConsistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). MethodsEducation and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale.ResultsIn FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN.ConclusionsThis study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages.

Highlights

The cognitive reserve hypothesis posits that lifetime intellectual enrichment lessens the negative impact of neurological diseases on the cognitive status [1]
In this study we used resting state functional MRI (fMRI) to investigate the relationship between lifetime intellectual enrichment and patterns of brain functional connectivity in Frontotemporal Dementia (FTD) and in presymptomatic disease stages
We considered patients with and without pathogenetic GRN mutations, to assess the role of cognitive reserve in monogenic inherited disease, and asymptomatic subjects carrying GRN mutations, to evaluate how cognitive reserve acts on functional neuronal networks almost twenty years before the disease onset

Summary

Introduction

The cognitive reserve hypothesis posits that lifetime intellectual enrichment lessens the negative impact of neurological diseases on the cognitive status [1]. Resting state fMRI may contribute to clarify the interaction between genetic and environmental factors in modulating the occurrence of clinical symptoms and to define a theoretical model of disease progression, moving from the presymptomatic stage to clinical presentation. With these caveats in mind, the current study uses resting state fMRI to investigate the relationship between lifetime intellectual enrichment and patterns of brain connectivity in patients with FTD, with and without GRN pathogenetic mutations, and in presymptomatic GRN mutation carriers

Methods

Results

Discussion