Hippocampal connectivity in Amyotrophic Lateral Sclerosis (ALS): more than Papez circuit impairment

Francesca Trojsi,Carla Passaniti,Sabrina Esposito,Gioacchino Tedeschi,Luigi Lavorgna,Dario Ricciardi,Gabriella Santangelo,Federica Di Nardo,Simona Bonavita,Giuseppina Caiazzo,Fabrizio Esposito,Teresa Ferrantino,Mattia Siciliano,Mario Cirillo,Giulia D’Alvano,Antonio Russo

doi:10.1007/s11682-020-00408-1

Abstract

Emerging evidence suggests that memory deficit in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease with varying impairment of motor abilities and cognitive profile, may be independent from executive dysfunction. Our multimodal magnetic resonance imaging (MRI) approach, including resting state functional MRI (RS-fMRI), diffusion tensor imaging (DTI) and voxel-based morphometry (VBM), aimed to investigate structural and functional changes within and beyond the Papez circuit in non-demented ALS patients (n = 32) compared with healthy controls (HCs, n = 21), and whether these changes correlated with neuropsychological measures of verbal and non-verbal memory. We revealed a decreased functional connectivity between bilateral hippocampus, bilateral parahippocampal gyri and cerebellum in ALS patients compared with HCs. Between-group comparisons revealed white matter abnormalities in the genu and body of the corpus callosum and bilateral cortico-spinal tracts, superior longitudinal and uncinate fasciculi in ALS patients (p < .05, family-wise error corrected). Interestingly, changes of Digit Span forward performance were inversely related to RS-fMRI signal fluctuations in the cerebellum, while changes of both episodic and visual memory scores were inversely related to mean and radial diffusivity abnormalities in several WM fiber tracts, including middle cerebellar peduncles. Our findings revealed that ALS patients showed significant functional and structural connectivity changes across the regions comprising the Papez circuit, as well as more extended areas including cerebellum and frontal, temporal and parietal areas, supporting the theory of a multi-system pathology in ALS that spreads from cortical to subcortical structures.

Highlights

Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease (MND), is a rapidly progressive neurodegenerative disorder primary involving upper and lower motor neurons (Hardiman et al 2017)
A specific focus of interest in histopathological studies was represented by the perforant pathway (PP) zone, which has been associated in ALS with detection of phosphorylated TAR DNA-binding protein 43 deposits (Geser et al 2008; Brettschneider et al 2013), as confirmed in vivo by magnetic resonance imaging (MRI) data (Kassubek et al 2014; Schmidt et al 2016; Gorges et al 2018)
We investigated the structural integrity of gray and white matter (GM, WM) within and beyond several areas comprising the Papez circuit, by performing wholebrain voxel-based morphometry (VBM) and diffusion tensor imaging (DTI) analyses and seed-based resting state functional MRI (RS-fMRI) analysis

Summary

Introduction

A specific focus of interest in histopathological studies was represented by the perforant pathway (PP) zone, which has been associated in ALS with detection of phosphorylated TAR DNA-binding protein 43 (pTDP43) deposits (Geser et al 2008; Brettschneider et al 2013), as confirmed in vivo by magnetic resonance imaging (MRI) data (Kassubek et al 2014; Schmidt et al 2016; Gorges et al 2018) In this regard, advanced neuroimaging techniques, such as structural and functional MRI techniques, offered unprecedented opportunities to characterize hippocampal changes (Bede et al 2013b, 2018; Abdulla et al 2014; Stoppel et al 2014; Westeneng et al 2015; Machts et al 2018; Christidi et al 2018, 2019)

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Results

Conclusion