Functional connectivity changes resemble patterns of pTDP-43 pathology in amyotrophic lateral sclerosis.

Ines Schulthess,Martin Gorges,Dorothée Lulé,Jan Kassubek,Kelly Del Tredici,Hans-Peter Müller,Albert C Ludolph

doi:10.1038/srep38391

Ines Schulthess, Martin Gorges + Show 5 more

Open Access

https://doi.org/10.1038/srep38391

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Journal: Scientific Reports	Publication Date: Dec 1, 2016
Citations: 65	License type: CC BY 4.0

Affiliation: University of Ulm

Abstract

‘Resting-state’ fMRI allows investigation of alterations in functional brain organization that are associated with an underlying pathological process. We determine whether abnormal connectivity in amyotrophic lateral sclerosis (ALS) in a priori-defined intrinsic functional connectivity networks, according to a neuropathological staging scheme and its DTI-based tract correlates, permits recognition of a sequential involvement of functional networks. ‘Resting-state’ fMRI data from 135 ALS patients and 56 matched healthy controls were investigated for the motor network (corresponding to neuropathological stage 1), brainstem (stage 2), ventral attention (stage 3), default mode/hippocampal network (stage 4), and primary visual network (as the control network) in a cross-sectional analysis and longitudinally in a subgroup of 27 patients after 6 months. Group comparison from cross-sectional and longitudinal data revealed significantly increased functional connectivity (p < 0.05, corrected) in all four investigated networks (but not in the control network), presenting as a network expansion that was correlated with physical disability. Increased connectivity of functional networks, as investigated in a hypothesis-driven approach, is characterized by network expansions and resembled the pattern of pTDP-43 pathology in ALS. However, our data did not allow for the recognition of a sequential involvement of functional connectivity networks at the individual level.

Highlights

Which, according to the pathoanatomical model5 and the diffusion tensor imaging (DTI)-based in vivo staging model3,17, we expected no functional connectivity alterations16
The functional connectivity patterns associated with the motor, brainstem, ventral attention, and default mode/hippocampal intrinsic connectivity network revealed increased connectivity maps in amyotrophic lateral sclerosis (ALS) patients (N = 135) compared with controls (N = 56) (Fig. 1a,b)
Using a hypothesis-guided MRI approach to investigate the network-based functional connectivity in ALS in vivo, this study demonstrated an increasing pattern of functional connectivity network expansions over time and signs of functional decoupling between major nodes of all investigated networks that were correlated with both DTI-based impairment in the corticospinal tract (CST) and with increasing physical disability

Summary

Introduction

Which, according to the pathoanatomical model and the DTI-based in vivo staging model, we expected no functional connectivity alterations. The functional networks cover functionally connected brain regions that are prone to develop ALS-associated pathology in a sequential fashion. We hypothesized that the functional network-associated regions become sequentially involved which may result in network-based abnormal functional connectivity patterns. Using ‘resting-state’ (rs-)fMRI, we compared the functional network organization in these four intrinsic connectivity networks between ALS patients and healthy controls over time to determine whether possible functional connectivity alterations permit recognition of abnormal BOLD synchronization. We used tractwise fractional anisotropy statistics, a DTI-based fiber tracking technique to determine tract-averaged FA-values, for correlation analysis between structural and functional connectivity measures

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