Introduction
Mild cognitive impairment (MCI) is a clinical construct that identifies individuals with cognitive impairment and a high risk of dementia [
1‐
3]. Although MCI is a heterogeneous condition, most MCI patients exhibit the amnestic phenotype with episodic memory deficits as the sole or most prominent characteristic [
4]. In those patients, Alzheimer’s disease (AD) is the most common clinical endpoint [
1,
5], and the amnestic deficits are considered to be the consequence of neuropathological changes affecting the medial temporal lobe (MTL) early in the disease process. While structural and functional MRI studies concerning memory functioning in MCI and AD, initially focused on the MTL or specifically hippocampus [
6], current neuroimaging studies examine patterns of deterioration in global functional and structural brain circuits or networks, e.g. the Papez circuit [
7,
8], or the more recently described default mode network (DMN) [
9‐
12]. Within these networks though, the effects of medial temporal lobe degeneration on network functioning, or functioning of specific network nodes, is still unclear [
8,
13].
The posterior cingulate cortex (PCC) is an important network node, showing hypometabolism and hypoperfusion in the MCI stage [
14‐
19], predictive for further cognitive decline into clinical AD [
14,
20,
21]. Given its network connection with the hippocampus, several studies debated whether changes in PCC functioning might reflect deterioration of the hippocampus in early disease stages [
13,
20,
22‐
30]. From these studies we can grossly deduce three theories, namely that PCC functioning in MCI might reflect: (1) functional changes in the hippocampus [
9,
24,
31‐
33]; (2) structural changes in the hippocampus [
13,
14,
24‐
28]; or (3) degeneration of white matter tracts subserving a part of the connection between the hippocampus and PCC [
29,
30,
34‐
36]. It is known that the hippocampus has multiple efferent connections, and communication between the hippocampus and PCC also runs through the thalamus [
8,
22], or several other nodes, as the functional path length between the hippocampus and PCC is shown to alter in MCI in relationship with cognitive decline [
37]. Meanwhile, there are a number of clinical studies that have specifically indicated cingulum disruption to subserve memory problems due to a disconnection between the hippocampus and PCC [
34,
38‐
40]. As the PCC is a key hub, and PCC dysfunctioning is shown to be an indicator for AD prodromal stages, examining the relationship between PCC functioning and hippocampus functioning, hippocampus structure and structural connectivity in MCI will provide further insight into the origin of PCC dysfunctioning in MCI. In this multimodal MRI study we performed analyses on the association between PCC functioning during task-related episodic memory fMRI and (1) hippocampus activation (episodic memory fMRI), (2) hippocampus volume (automatic segmentation of hippocampus), and (3) structural connections subserving partly the connection between the hippocampus and PCC (diffusion tensor imaging; DTI), in patients with MCI.
Discussion
Our results indicate an association between PCC activation and hippocampus activation during successful episodic memory encoding and correct recognition in MCI patients. We found no relationship between structural hippocampal predictors, such as the CGH subserving a part of the connection between the PCC and hippocampus or hippocampal volumes, and PCC activation. While this suggests that episodic memory decline in MCI can best be explained as a functional network disorder, structural and functional connectivity between the PCC and hippocampus is known to be quite complex in MCI and AD [
8,
37].
The finding of a relationship between hippocampal and PCC activation in the present study is supported by several functional neuroimaging studies in healthy individuals, MCI or dementia patients [
31,
55‐
57]. The absence of a relationship between structural hippocampal measures and PCC activation though, contrasts other studies. In these studies hippocampal volume was related to either perfusion within the PCC [
13,
25], fMRI task-induced PCC deactivation [
58] or functional connectivity between both structures [
27]. One reason for the difference in findings may be methodological, as our study was performed in an episodic memory-related fMRI setting, which enables us to investigate hippocampal and PCC activation while these structures are engaged in episodic memory. From the current clinical literature we can grossly deduce three theories that have been examined in previous studies, concerning the effects of disease-related changes in the hippocampus on PCC functioning. First, a theory concerning a relationship between PCC dysfunctioning and hippocampal grey matter atrophy via the degeneration of white matter bundles that subserve a part of the connections between the hippocampus and PCC [
26,
38,
59]. This is supported by several studies showing a relationship between hippocampal volume and PCC metabolism mediated through cingulum bundle disruption [
26,
59,
60]. Second, the theory that independent white matter tract degeneration disconnects the hippocampus from other structures, and subsequently affects episodic memory [
29,
30,
36,
39,
40,
61]. Third, a theory concerning the deterioration of functional networks, in which brain regions synchronically function less well [
12,
55]. As we found a relationship between hippocampal and PCC activation, our results can only support the functional network deterioration theory. However, we acknowledge that the structural and functional connectivity between the PCC and hippocampus subserving episodic memory in MCI is more complex [
8,
37].
We found that the most important predictor of PCC activation during successful episodic memory encoding was right hippocampal activation, whereas left hippocampal activation was a significant predictor for PCC functioning during episodic memory recognition. This pattern of hemispheric specialization for different phases of episodic memory has been presented in the literature, with right temporal lobe dysfunction having the greatest effect on acquisition of new learning, and left temporal lobe dysfunction on retention or retrieval [
62,
63]. In particular in case of verbal episodic memory engagement it was shown that other regions can be involved besides the PCC and hippocampus, like the medial and inferior frontal gyrus and the insula, and as stated below, the thalamus [
32,
64‐
67].
Increasing evidence suggests that while the hippocampus is an important node in memory functioning, other nodes within the mnemonic system or Papez circuit or DMN can also lead to memory dysfunctioning [
8]. As expected, the PCC is one of these nodes, but recent evidence shows that thalamus functioning is critical in memory functioning [
8]. With its numerous connections as a relay system, the thalamus subserves connections between the hippocampus and PCC. Through this interdependent relationship with the PCC, early thalamus damage or dysfunction may also be explanatory for the earliest PCC imaging evidence of early AD [
8]. In the current study one MCI patients showed a thalamus infarct in light of relatively mild medial temporal lobe atrophy (left MTA 1, right MTA 2) as evaluated on 2D T2 FLAIR. We acknowledge the limitations of T2 FLAIR to detect thalamic lesions [
47], and the possibility of underestimating the number and the role of thalamic lesions in the current study. Therefore, future studies should include (1) T2-weighted images in order to examine thalamic lesions, and (2) evaluate anterior thalamic functioning when elucidating influence on PCC functioning during memory tasks in MCI.
In this study we cannot rule out a direct relationship between PCC function and neuropathological changes within this region. One study suggested that amyloid burden disrupts functional networks in healthy elderly [
33]; however, PCC amyloid deposition in MCI was not found to be related to functional changes within the PCC region [
68] nor to clinical status or AD disease progression [
69‐
73]. Furthermore, the PCC region is relatively unaffected by neurofibrillary tangle (NFT) formation in early AD disease stages [
74,
75]. Hippocampal atrophy, on the other hand, is related to NFT formation [
76], directly reflected in episodic memory impairment at the MCI stage. As one study claims that PCC volume loss and cingulum bundle deterioration secondary to MTL atrophy both influence PCC functioning [
60], the role of PCC degeneration in the face of relative late NFT formation [
74,
75] could be obtained as a sequential process of functional decline followed by structural decline later in the disease process.
Strengths of our study are the use of an event-related fMRI design that enabled us to investigate PCC and hippocampus functioning during episodic memory component processes such as successful encoding and correct recognition. A drawback of the current study is the inability to use the research criteria for MCI due to AD in the present study [
1], as our participants were included in the years 2009–2011, before these criteria were established. All MCI patients though presented with amnestic MCI, which is known to have a high rate of conversion to clinical AD [
77‐
79]. We did not include AD biomarkers at the time, since PiB-PET was still in its infancy, and lumbar puncture was considered too invasive by our medical ethics committee for patients in a pre- or early clinical stage of dementia. Furthermore, although the number of MCI patients in this study was comparable to other studies using memory-related fMRI in MCI [
64], our study may suffer from a lack of power. This could explain the fact that hippocampus and PCC activation or deactivation in both the encoding and recognition tasks was minimal. This is an important limitation of our study, in which a priori hypotheses considered the relationship between PCC and hippocampus activation.
In the present study, we found a relationship between activation in the PCC and hippocampus during successful episodic memory encoding and correct recognition in MCI. We found no evidence for the influence of often referred structural hippocampal predictors, on PCC functioning. Our results suggest that in MCI, PCC functioning is foremost influenced by hippocampal functioning during episodic memory, reflecting possibly a pattern in which functional changes precede or exceed structural changes.
Acknowledgements
The scientific guarantor of this publication is Dr. Janne Papma, Erasmus MC. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This work was supported by the Brain Foundation of The Netherlands (project number H07.03 to Niels D. Prins). Janne M. Papma received financial support from the Netherlands Alzheimer Foundation. No complex statistical methods were necessary for this paper. Written informed consent was obtained from all subjects (patients) in this study. Institutional Review Board approval was obtained. Some of the study subjects have been previously reported in three previous studies:
- Papma JM et al. (2014) Cerebral small vessel disease affects white matter microstructure in mild cognitive impairment. Human Brain Mapping 35(6): 2836-2851
- IJsselstijn L et al. (2013) Serum proteomics in amnestic mild cognitive impairment. Proteomics 13 (16)
- Papma JM et al. (2012) The influence of cerebral small vessel disease on default mode network deactivation in mild cognitive impairment. Neuroimage: Clinical 16(2): 33-42
Methodology: prospective, case-control study, performed at one institution.