Neurobiol Aging. 2015 Jun;36(6):2145-52. doi: 10.1016/j.neurobiolaging.2015.03.006.

Resting-state synchrony between the retrosplenial cortex and anterior medial cortical structures relates to memory complaints in subjective cognitive impairment.

Yasuno F1, Kazui H2, Yamamoto A3, Morita N4, Kajimoto K5, Ihara M5, Taguchi A6, Matsuoka K7, Kosaka J7, Tanaka T2, Kudo T8, Takeda M2, Nagatsuka K5, Iida H4, Kishimoto T7.
  • 1Department of Psychiatry, Nara Medical University, Kashihara, Japan; Department of Investigative Radiology, National Cerebral and Cardiovascular Center, Suita, Japan. Electronic address: ejm86rp@yahoo.co.jp.
  • 2Department of Neuropsychiatry, Osaka University Medical School, Suita, Japan.
  • 3Department of Investigative Radiology, National Cerebral and Cardiovascular Center, Suita, Japan.
  • 4Department of Radiology, National Cerebral and Cardiovascular Center, Suita, Japan.
  • 5Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan.
  • 6Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Japan; Department of Regenerative Medicine Research, Institute of Biomedical Research and Innovation, Kobe, Japan.
  • 7Department of Psychiatry, Nara Medical University, Kashihara, Japan.
  • 8Department of Psychiatry, Osaka University Health Care Center, Suita, Japan.

 

Abstract

Subjective cognitive impairment (SCI) is a clinical state characterized by subjective cognitive deficits without cognitive impairment. To test the hypothesis that this state might involve dysfunction of self-referential processing mediated by cortical midline structures, we investigated abnormalities of functional connectivity in these structures in individuals with SCI using resting-state functional magnetic resonance imaging. We performed functional connectivity analysis for 23 individuals with SCI and 30 individuals without SCI. To reveal the pathophysiological basis of the functional connectivity change, we performed magnetic resonance-diffusion tensor imaging. Positron emission tomography-amyloid imaging was conducted in 13 SCI and 15 nonSCI subjects. Individuals with SCI showed reduced functional connectivity in cortical midline structures. Reduction in white matter connections was related to reduced functional connectivity, but we found no amyloid deposition in individuals with SCI. The results do not necessarily contradict the possibility that SCI indicates initial cognitive decrements, but imply that reduced functional connectivity in cortical midline structures contributes to overestimation of the experience of forgetfulness.

PMID: 25862421

 

Supplement:

Introduction: Subjective cognitive impairment (SCI) is a clinical state characterized by an individual’s own perception that their cognitive abilities, including memory, are declining; importantly, individuals with SCI do not have overt cognitive deficits and their cognitive performance tends to be within the general normal range.

Given that self-overestimation of cognitive disturbance is a major factor influencing SCI, dysfunction in self-referential processing might contribute to this phenomenon. Converging evidence suggests that self-referential processing is mediated by cortical midline structures such as the ventromedial and dorsomedial prefrontal cortex and the anterior and posterior cingulate cortex (1). Therefore, we hypothesized that the resting-state functional connectivity among these regions in the cortical midline structures would be altered in SCI, and underlies these patients’ subjective memory complaints.

To test this hypothesis, we performed region of interest (ROI) seed-based functional connectivity analysis in order to investigate the intrinsic neural network related to self-referential processing in individuals with SCI and in those without SCI (nSCI). In addition, to reveal the pathophysiological basis of any observed differences in functional connectivity, we performed magnetic resonance-diffusion tensor imaging (MRI-DTI) and positron emission tomography (PET) imaging with the 11C-labeled Pittsburgh Compound-B ([11C]PIB), and examined the association of white matter connectivity and amyloid deposition with changes in resting functional connectivity in SCI.

 

Methods

Participants

23 SCI and 30 nSCI individuals with normal cognition were recruited in the analysis. Presence of subjective memory deficit was evaluated with a standardized questionnaire system based on the Everyday Memory Checklist (EMC) of Wilson et al. (1989). All individuals in the SCI group had EMC scores greater than the standardized cut-off score of 9.

MR image acquisition

All MRI examinations were performed using a 3-Tesla whole-body scanner. The resting-state fMRI scan images were obtained.

Functional connectivity analysis

Functional images were imported into the conn tool-box. A series of ROIs were defined on the cortical midline structures, and we performed an ROI-to-ROI seed-based functional connectivity analysis in the cortical midline area in order to compare the intrinsic neural networks related to self-referential processing between the SCI and nSCI subjects.

DTI analysis

DTI-Fractional anisotropy (FA) maps were generated from each individual using FMRIB software. Voxel-based analysis was performed using SPM8 software.

PET acquisition and data analysis

[11C]PIB PET examinations were performed on 17 individuals from the nSCI group and 11 individuals from the SCI group using a Biograph mCT (Siemens, Knoxville, USA).

 

Fig1Figure 1

 

Results

1. We found reduced functional connectivity in individuals with SCI between group analysis

  1. Seed-based region of interest drawn around the hubs within the cortical midline structures [Fig.1: Purple: orbitomedial prefrontal cortex (OMPFC) (BA11), yellow: dorsal medial prefrontal cortex (DMPFC) (BA10), green: anterior cingulate cortex (ACC) (BA32), red: posterior cingulate cortex (PCC) (BA31), and blue: retrosplenial cortex (RSC) (BA29)].
  2. ROI-to-ROI in the cortical midline structure exhibited significantly reduced connectivity in individuals with SCI between RSC and DMPFC/ACC (Fig.2a)
  3. Whole-brain connectivity from the seed of RSC confirmed that SCI group had reduced connectivity between the RSC and bilateral cortical medial structures of the DMPFC and ACC, as indicated by the ROI-to-ROI analysis (Fig.2b).

Fig2

Figure 2

2. There was significant correlation between subjective memory complaints as reflected by the EMC score and functional connectivity

Higher EMC scores (SCI) correlated with more reduced functional connectivity between the RSC and other cortical midline structure of ACC/DLPFC (Fig.3)

Fig3

Figure 3

 

3. We found group difference of FA values and its association with the functional connectivity

  1. Voxel-based comparison of FA values between the SCI and nSCI groups.

Results revealed significantly lower FA of the superior longitudinal fasciculus (SLF) at the left external capsule and higher FA in the left cingulum (CG) near the hippocampus (Fig.4)

b. Figure showed the correlation plot of SLF-FA / CG-FA and the functional connectivity of RSC and other cortical midline structures of ACC/DLPFC (Fig.5)

Fig4

Figure 4

 

4. We found no significant differences of PIB-BPND between the SCI and nSCI in the whole-brain voxel-based analysis.

 

Conclusion: Our study demonstrates that individuals with SCI have less functional connectivity between the posterior cortical midline structures of RSC and the anterior cortical midline structures, namely, the DMPFC and ACC. The reduction in functional connectivity between the two cortical midline structures might contribute to the overestimation of their experience of benign forgetfulness, due to dysfunction of self-referential processing. The decrease of white matter connections in the SLF manifested as reduced functional connectivity between the RSC and ACC/DMPFC. The increase in white matter connectivity in the CG near the hippocampus might facilitate the role of the hippocampus and compensate for the decreased functional connectivity between the two systems due to the reduction in white matter connectivity in the SLF in the SCI group. We found no relationship between amyloid depositions and reduced functional and white matter connections in SCI subjects. Our results do not necessarily contradict the possibility that SCI indicates initial cognitive decrements due to AD pathology, but they do indicate that reduced functional connectivity in cortical midline structures due to the decrease of white matter connections contribute to SCI.

Fig5

Figure 5

 

References

  1. Northoff, G., Heinzel, A., de Greck, M., Bermpohl, F., Dobrowolny, H., Panksepp, J. 2006. Self-referential processing in our brain–a meta-analysis of imaging studies on the self. Neuroimage 31, 440-57.

 

Acknowledgements: This research was supported by Grants-in-Aid for Scientific Research (C) 24591740 and 24591708 from the Japan Society for the Promotion of Science, and by the Health and Labor Sciences Research Grants, Research on Dementia (H25-01).

 

Contact: Fumihiko Yasuno, M.D., Ph.D.

Department of Psychiatry, Nara Medical University, 840 Shijocho, Kashihara, Nara, 634-8522, Japan. Tel.: +81-744-22-3051; Fax: +81-744-22-3854; E-mail address: ejm86rp@yahoo.co.jp

 

 

 

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