| Background and objective:Primary insomnia(PI)is a common type of sleep disorder that often occurs in elderly people with a prevalence of 3%-5%.The characteristics of PI patients including early wake-up,difficult sleep initiation and sleep maintenance,poor sleep quality and other symptoms that seriously impair the life quality of PI patients and even influence ordinary work or study during the daytime.Primary insomnia patients with cognitive dysfunction were involved in this study.Sleep quality was analyzed with the Pittsburgh sleep quality index scale(PSQI),and cognitive impairment was measured on a neuropsychological scale.The relations among the changes in the rs-f MRI ReHo brain function,topological properties of the brain networks,iron deposition,the changes in the volumes and shapes of the brain nuclei and cortex,and the changes in sleep and cognition were studied.The mechanism of cognitive dysfunction in patients with PI is discussed,and the neuropathologic knowledge of PI is deepened.Resting-state f MRI(rs-f MRI)detects spontaneous brain activities during the resting state to identify brain abnormities from the perspective of function and provide evidence about the pathogeneses of neurological diseases.Studies of whole-brain networks have suggested that the human brain is a complex dynamic network that has topological or ‘small world’ properties.According to graph theory,networks that have ‘small world’ properties usually possess a modified capability for global information exchange and processing.In 2005,the concept of ‘whole-brain functional network maps’ was first proposed,and these networks were acquired via the extraction of time signals from each functional region.Based on this theory,additional studies further discovered that the whole-brain network is closely related to higher cognitive functions.Analyses of the resting-state functional connectivity of the whole-brain were conducted to study the changes in the topological properties of the whole brain networks of PI patients with cognitive dysfunction.Spatial indexes,including the length of the shortest path,the ‘small world’ properties and the functional connections,were examined to estimate the topological properties of the brain networks and to analyze their relationships with cognitive function and insomnia.Most researches of MRI examinations focused on the volumes of the grey matter of the cerebral cortex in PI patients.We postulated that deep brain nuclei might play a significant role in cognitive dysfunction due to PI.Consequently,we further discovered differences in the deep brain nuclei between the patient group and the control group.Moreover,the correlations between the changes in the volumes and shapes of the brain nuclei and cortex,the degree of insomnia and the cognitive level were also analyzed.Susceptibility-weighted imaging(SWI)is a newly developed MRI technology in recent years.The mechanisms of SWI involve hemosiderin particles that change their local magnetic fields due to the paramagnetic effect,which leads to signal changes,and images are formed with the MRI equipment.In the nervous system,Fe is an important component in a variety of proteins and plays important roles in many physiological activities,such as oxidative phosphorylation,oxygen transportation and the synthesis of neurotransmitters.Disorders of the internal environment promote the formation of hydroxyl radicals that damage cells by impairing the synthesis of carbohydrates,proteins,lipids and DNA.Abnormal iron deposition in cells and even iron metabolism disorders can occur in many neurodegenerative diseases,including Alzheimer’s disease and Parkinson’s disease.The purposes of this study were to explore whether iron deposition in the brain is involved in PI with cognitive dysfunction and the relationship of iron deposition and cognitive dysfunction using SWI phase analysis.Materials and Methods:1.General information of the participants: Thirty-five primary insomnia patients with cognitive dysfunction and 30 comparable healthy subjects matched for gender,age and educational level were involved in this study.2.Neuropsychological cognitive assessment: The mental statuses and cognitive abilities were evaluated using the Montreal cognitive assessment(MoCA)scale,the mini-mental state examination(MMSE),the activity of daily living scale(ADL),Global deteriorate scale(GDS),Neuropsychiatric inventory(NPI),the Hamilton depression scale(HAMD)and the Hamilton anxiety scale(HAMA).Sleep quality was evaluated with the Pittsburgh sleep quality index scale with consideration for the patients’ histories of insomnia.3.MRI scanning: Images were acquired using a Siemens 3.0 T MRI apparatus in Germany.The subjects were required to be quiet,keep their eyes closed,stay clear,and reduce head movements during the MRI scanning.MRI scanning was conducted using the axis connecting the anterior and posterior commissures.Conventional MRI examinations,including T1 WI,T2WI,SWI,and a fluid-attenuated inversion recovery(FLAIR)sequence were conducted to eliminate patients with organic diseases of the brain.Resting state functional imaging was conducted using an echo planar imaging(EPI)sequence.Structural scanning was conducted using a three-dimensional magnetized to fast gradient echo(3D-MPRAGE)sequence.4.Data analysis and Statistical analysis of ReHo: The data in the DICOM format were transformed using MRIcron software and then processed using statistical parametric mapping(SPM)on the MATLAB 2013 platform.The statistical analysis was conducted using SPSS 17.0 software.General information and scale test results were analyzed.The data are presented as the means ± the SDs.The data between two groups were compared using Student’s t tests,and count data were compared between two groups using Pearson’s χ2 tests.Because the individual differences,including age,gender and educational level,might have led to biased results,we defined age,gender and educational level as covariates.The correlation between the ReHo values of the different brain regions from the two groups and the neuropsychological cognitive scores was evaluated with partial correlation analysis.P < 0.05 was considered significant.5.Data analysis and Statistical analysis of brain network: The resting state signals from 90 brain regions were extracted using an automated anatomical labeling(AAL)template,and noise was then eliminated.The levels of functional connectivity from each pair of brain regions were analyzed,and the whole-brain networks were established.The clustering coefficient,the length of the shortest path and the indexes of the ‘small world’ properties of the subjects’ brain networks with a sparse rate ranging from 0.01 to 0.6 were analyzed and tested using displacement tests.Two-sample t tests were employed to test the levels of functional connectivity between the two groups.Age,gender and educational level were defined as covariates,and the correlations of the indexes of the aberrantly functional connectivity and the brain network and the neuropsychological cognitive scores were evaluated with partial correlation analysis.P < 0.05 was considered significant.6.Data analysis and Statistical analysis of morphology: The data processing was conducted with SPM based on the voxel-based morphology(VBM)method.After standardization of the MRI data,various brain regions were separated using brain structure templates,and smoothing was conducted using a 6-mm full-width at half-maximum(FWHM)kernel for size measurements.The statistical analyses were conducted with SPSS 17.0 software.Two-sample t tests were employed to examine the volumes of the brain regions of the subjects.Age,gender and educational level were defined as covariates,and the correlations of the percentages of the volumes of the different brain regions with the whole brains were then analyzed in the two groups,and the neuropsychological cognitive scores were evaluated with partial correlation analysis.P < 0.05 was considered significant.7.Data analysis and Statistical analysis of SWI: SPIN software was employed to conduct the SWI data analysis,to draw the ROIs around the nuclei,to measure the phase values of the nuclei and to convert these values to radians.The statistical analyses were conducted with SPSS 17.0 software.Two-sample t tests were employed to test the radians of the nuclei of the subjects.Age,gender and educational level were defined as covariates,and the correlations of the radians of the different brain regions in the PI groups and the neuropsychological cognitive scores were then evaluated with partial correlation analyses.P < 0.05 was considered significant.Correlation analyses were conducted to examine the relationships between the SWI radian values of the nuclei of the control group and the iron concentrations of the nuclei of the autopsy group to correct the accuracy of the SWI values.Results:1.Thirty-five primary insomnia patients with cognitive dysfunction and 30 healthy comparable subjects were involved in this study.The genders,ages and educational levels between the two groups were not significantly different(P>0.05).The PSQI,HAMA and HAMD scores were significantly higher,and the MMSE and MoCA scores were significantly lower in the patient group than in the control group.2.The ReHo values of the left middle and inferior temporal gyri,the right inferior temporal gyrus and the left limbic parahippocampal gyrus in the patient group were significantly greater than those in the control group.However,the ReHo values of the right superior temporal gyrus,right temporal fusiform gyrus,superior temporal gyrus,left inferior frontal gyrus,right limbic anterior cingulate gyrus,left parietal angular gyrus and left superior parietal lobule in the patient group were significantly lower than those in the control group.The brain regions of the two groups with different ReHo values were marked,and the Reho values were separated for further analysis.Age,gender and educational level were defined as covariates,and partial correlation analysis was employed with Bonferroni correction.The results demonstrated that the ReHo value of the left limbic parahippocampal gyrus was significantly negatively correlated with the MoCA score(r=-0.424,P<0.05),the ReHo value of the right limbic anterior cingulate gyrus was significantly positively correlated with the MoCA score(r=0.397,P<0.05)and significantly negatively correlated with the PSQI score(r=-0.372,P<0.05).The ReHo values of the other abnormal brain regions were not significantly correlated with the MMSE,MoCA or PSQI scores(P>0.05).3.The levels of connection between the right dorsolateral frontal gyrus and the right superior temporal gyrus,the connection between left temporal pole and the right transverse temporal gyrus,the connection between the right middle frontal gyrus and the right inferior frontal gyrus,the connection between the left lingual gyrus and the right thalamus,and the connection between the left thalamus and the right-middle temporal gyrus were greater in the patients than in the control group.However,the levels of the connections between the left inferior occipital gyrus and the right temporal pole,the connection between the right middle frontal gyrus and the right orbital middle frontal gyrus,the connection between right cingulate gyrus and the left caudate nucleus and the connection between the right parahippocampal gyrus and the left caudate nucleus were lower in the patients than in the control group.The level of the connection between the right cingulate gyrus and the left caudate nucleus was correlated with the MMSE score(r=0.362,P<0.05).The ‘small world’ properties and clustering coefficient of the patient group were smaller than those of the control group at a sparse rate ranging from 0.1 to 0.4.The correlation analysis demonstrated that the sigma value of the ‘small world’ properties of the whole-brain networks was positively correlated with the MMSE score(r=0.367,P<0.05,)and the MoCA score(r=0.408,P<0.05)but was not correlated with the PSQI score.4.The white matter volume was greater in the patient group than in the control group.However,the total gray matter volume was smaller,and the volumes of many ventricles,the occipital white matter,the midbrain and the globus pallidus were increased,whereas the volumes of the left hippocampus,left frontal lobe,bilateral parietal lobe,right occipital lobe,left temporal lobe and bilateral cingulate were decreased.The results of the correlation analysis demonstrated that the volume of the right hippocampus was positively correlated with the MoCA score(r=0.267,P<0.05),the volume of the gray matter in the right parietal lobe was also positively correlated with the MoCA score(r=0.457,P<0.05).No correlations were found between the other brain regions and the scores.5.The radian values of the hippocampus,substantia nigra,red nucleus,putamen,caudate nucleus,globus pallidus,thalamus and frontal white matter in control group were significantly positively correlated with the iron concentrations of the autopsy brains(r = 0.771,P<0.05).The radian values of the left caudate nucleus,left putamen,bilateral thalami and left hippocampus of the primary insomnia patients with cognitive dysfunction were significantly increased compared with the control group(P<0.05),whereas no significant differences were detected in the other brain regions between the two groups(P > 0.05).The radian value of the left hippocampus was negatively correlated with the MMSE score(R=-0.447,P<0.05).The radian values of the other nuclei were not correlated with the PI values or the scores of the psychological tests.Conclusion:1.Primary insomnia with cognitive dysfunction is a complex pathological process that includes disorders of several brain regions.The decline in the ReHo value of the right limbic anterior cingulate reflected the level of sleep disorder and cognitive dysfunction.The increased ReHo value of the left limbic parahippocampal gyrus may be associated with the compensation of the brain for sleep disorders.2.The thalamus,hippocampus and cingulate gyrus were the main regions that formed aberrant functional connections according to our analysis of the whole-brain resting functional networks.The level of the connection between the right cingulate gyrus and the left caudate nucleus was correlated with cognitive dysfunction.The ‘small world’ properties of the whole-brain networks in the patient group were positively correlated with the cognitive scores but were not correlated with the insomnia scale scores.Our results indicated that significant differences in the whole-brain networks of PI patients appeared at a sparse rate ranging from 0.1 to 0.4,which suggests that a sparse rate of 0.1-0.4 might be the proper range to study the whole-brain networks of PI patients.3.Our results indicated that the primary insomnia patients with cognitive dysfunction exhibited different degrees of brain atrophy compared with the healthy people based on an MRI study of the whole-brain structure.The atrophies of the hippocampus and parietal lobe were correlated with cognitive dysfunction but not with insomnia.4.The iron concentration in the left hippocampus was correlated with the cognitive function of the primary insomnia patients with cognitive dysfunction based on SWI analysis.Our results demonstrated that neurodegeneration occurred in the hippocampi of the patients with chronic insomnia and led to cognitive dysfunction during the daytime.5.Our results might deepen the understanding of cognitive dysfunction after PI and provide a method for the early detection of the disease and its progression.Moreover,our study provides pathophysiologic clues and evidence about PI with cognitive dysfunction. |
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