Study of altered functional connectivity in individuals at risk for Alzheimer’s Disease

1. Introduction

Alzheimer’s Disease (AD) is a wide prevalent neurodegenerative disease, which endangers the health of human all over the world. The accumulations of A β 1–42 and tau tangles have been considered as the biological markers of AD [1, 2]. Clinically, more extensive and serious cognitive impairments were detected in the later stage than early stage of AD, and patients with mild cognitive impairment (MCI) have a large chance to change AD [3, 4].

With the development of neuroimaging techniques, MRI has been widely applied to investigate the neurodegenerative diseases. Resting-state fMRI (rsfMRI) is an especially useful modality because it can be used easily in diverse patient populations to quantify functional network connectivity in terms of correlated, spontaneous MR signal fluctuations [5]. It is efficient to assess brain function connectivity among brain regions [6, 7]. Correlated brain regions have been divided into several resting-state networks (RSNs) [8, 9].

The research about RSNs offered a typical model for looking into the relationship between brain activity alterations and cognitive dysfunction in neurological disorders [10]. As for as AD and MCI concerned, convergence evidence on account of fMRI studies demonstrated that functional integration have disease severity related changes. For examples, recent studies have shown that functional connectivity and networks were influenced in the subjects with AD or at high risk for AD, especially in higher cognitive RSNs such as the default mode network (DMN), attention network (AN), executive control network (ECN) and salience network (SAL). All these preliminary research findings support the point that AD is a disconnection syndrome [11] and that the selective impairment patterns in the RSNs may describe the traits and states of AD.

However, most of these studies concentrate on the connectivity alterations within higher cognitive RSNs, the understanding of more RSNs still needs to explore. Inspired by the above studies, we hypothesized that the alteration of functional connectivity across more RSNs would happen in individuals with EMCI and LMCI, which are patients at high risk for AD. We expected that functional abnormalities would occur in several RSNs and that the cognitive impairments measured by mini-mental state examination (MMSE) would be correlated with rs-fMRI markers of abnormalities. To test these hypotheses, in this paper, altered functional connectivities based on a priori defined 246 regions of interest [12] were explored in participants of 26 patients with EMCI, 19 patients with LMCI, compared with 23 healthy control subjects.

2. Materials and methods

3. Results

For each group, a 246 × 246 functional connectivity matrix was computed.

At node level, significant differences between groups were detected, and these differences were widely separated in several RSNs. (1) Compared with EMCI group and LMCI group (Fig. 1), significant decrease integrity was showed in two regions of Posterior Salience Network (PCL_R_2_1, INS_R_6_1), and two regions of Language Network (pSTS_L_2_2, MTG_L_4_3), and two regions of dorsal Default Mode Network (CG_L_7_1, CG_L_7_6). (2) Compared with EMCI group and NC group (Fig. 2), significant decrease integrity was showed in the region of Dorsal Default Mode Network (Hipp_L_2_1). (3) Compared with LMCI group and NC group (Fig. 3), significant decrease integrity was showed in five regions of dorsal Default Mode Network (CG_L_7_6, CG_L_7_1, SFG_L_7_7, IPL_L_6_5, Hipp_L_2_1), and one region of Anterior Salience Network (IFG_R_6_3), three regions of Language Network (IFG_L_6_3, pSTS_L_2_2, MTG_L_4_3), one region of Posterior Salience Network (PCL_R_2_1), one region of Basal Ganglia Network (BG_L_6_6), one region of Left Executive Control Network (MFG_L_7_2), one region of Sensorimotor Network (PrG_L_6_4).

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At intra-network level (Fig. 4), compared with EMCI group, significant decreases were found in Auditory Network (AN) and Sensorimotor Network (SN) in the LMCI group. Compared with NC group, the LMCI group showed significant decreases in Auditory Network (AN), Language Network (LN), Sensorimotor Network (SN).

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At inter-network level (Fig. 5), compared with EMCI group, the connectivity strength difference between Auditory Network and Language Network (AN-LN) was found in LMCI. Compared with NC group, several connectivity strength differences were detected in LMCI group, such as Language Network and Left Executive Control Network (LN-LECN), Dorsal Default Mode Network and Language Network (dDMN-LN), Language Network and Anterior Salience Network (LN-ASN); Auditory Network-Language Network (AN-LN).

In the present study, impaired functional connectivity was detected widely in MCI which might be the basis of cognitive impairment. At node level, the differences were anchored in several networks (Figs 1–3), such as Posterior Salience Network, Language Network, dorsal Default Mode Network, Anterior Salience Network Basal Ganglia Network Left Executive Control Network, Sensorimotor Network.

At intra-network level, the significant decreases were anchored in Auditory Network (AN), Language Network (LN), Sensorimotor Network (SN) in MCI (Fig. 4). At inter-network level, the significant differences were anchored in between Auditory Network (AN) and Language Network (LN), between Language Network (LN) and Left Executive Control Network (LECN); between Dorsal Default Mode Network (dDMN) and Language Network (LN); between Language Network (LN) and Anterior Salience Network (ASN) in MCI (Fig. 5).

In this study, the altered function connectivity was detected in AN and SN, both of which were parts of SMN (sensory-motor network) [14]. Previous studies have found that the functional changes among olfaction, visual, hearing and motor systems (the major components of the SMN) might influence the onset of cognitive impairments, worsen as the disease progress, and be strong risk factors for AD [15]. The language network was anchored in Wernicke’s and Broca’s areas which was responsible for language comprehension and production. Our results provided additional convincing evidence that the dysfunction in SMN should be paid more attention.

In inter-network level, changes were aroused in between LN and LECN, as well as dDMN and LN. The Executive Control Network (ECN) was involved in goal-directed behavior and cognitive control. The DMN played a pivotal role in cognitive processes, especially in episodic memory processing [16, 17]. The impaired performance of episodic memory was one of the core features in the diagnosis of AD [18]. And the impaired functional connectivity within DMN was frequently identified in AD and MCI patients using multiple imaging techniques [18, 19, 20]. Our results also demonstrated that DMN might be one of the most affected networks in MCI patients.

Previous resting state fMRI studies demonstrated aberrant functional connectivity of DMN and SAL in AD [20, 21], aMCI [22] and even in normal cognition with amyloid burden [23]. It was suggested that the SAL was involved in the orientation of attention to the most homeostatically relevant (salient) of ongoing intrapersonal and extra personal events [24]. In this light, the present study prompted us to infer that the reduced connectivity between DMN and SAL might be one of the reasons for attention deficits in the early stages of AD and MCI.

These results provided insights into the dysfunction of more RSNs accompany the severity of subjects at high risk for AD. The aberrant intra- and inter-network dysfunctions might be potential biomarkers or predictors of MCI and AD progression.