Chunxian Yue

Specifically Progressive Deficits of Brain Functional Marker in Amnestic Type Mild Cognitive Impairment

Background Deficits of the default mode network (DMN) have been demonstrated in subjects with amnestic type mild cognitive impairment (aMCI) who have a high risk of developing Alzheimer’s disease (AD). However, no longitudinal study of this network has been reported in aMCI. Identifying links between development of DMN and aMCI progression would be of considerable value in understanding brain changes underpinning aMCI and determining risk of conversion to AD. Methodology/Principal Findings Resting-state fMRI was acquired in aMCI subjects (n = 26) and controls (n = 18) at baseline and after approximately 20 months follow up. Independent component analysis was used to isolate the DMN in each participant. Differences in DMN between aMCI and controls were examined at baseline, and subsequent changes between baseline and follow-up were also assessed in the groups. Posterior cingulate cortex/precuneus (PCC/PCu) hyper-functional connectivity was observed at baseline in aMCI subjects, while a substantial decrement of these connections was evident at follow-up in aMCI subjects, compared to matched controls. Specifically, PCC/PCu dysfunction was positively related to the impairments of episodic memory from baseline to follow up in aMCI group. Conclusions/Significance The patterns of longitudinal deficits of DMN may assist investigators to identify and monitor the development of aMCI.

Abnormal whole-brain functional connection in amnestic mild cognitive impairment patients.

Amnestic mild cognitive impairment (aMCI) patients are thought to be particularly vulnerable to convert to clinical AD where functional disconnection is a major feature of the cortical neuropathology. However, the presence and extent of whole-brain connectivity disturbances is largely unknown in aMCI patients. Twenty-six aMCI patients and eighteen matched healthy subjects were evaluated at baseline and at mean 20 months follow up. Temporal correlations between spatially distinct regions were evaluated by using longitudinal resting-state fMRI. Compared to normal aging controls, patterns of abnormal interregional correlations in widely dispersed brain areas were identified in the patients, which also changed with disease progression. These disturbances were found particularly in subcortical regions and frontal cortex. Importantly, significantly decreased negative functional connection may be specifically associated with the development of aMCI patients. This suggests a compensatory mechanism is underway where local processing deficits are offset by recruitment of more dispersed cortical regions. In addition, the presence of this increased connectivity is seen to eventually weaken with disease progression. The results suggest that patterns of whole-brain functional connection may be a useful risk marker for conversion to AD in aMCI patients.

Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study.

Background Altered hippocampal structure and function is a valuable indicator of possible conversion from amnestic type mild cognitive impairment (aMCI) to Alzheimers disease (AD). However, little is known about the disrupted functional connectivity of hippocampus subregional networks in aMCI subjects. Methodology/Principal Findings aMCI group-1 (n = 26) and controls group-1 (n = 18) underwent baseline and after approximately 20 months follow up resting-state fMRI scans. Integrity of distributed functional connectivity networks incorporating six hippocampal subregions (i.e. cornu ammonis, dentate gyrus and subicular complex, bilaterally) was then explored over time and comparisons made between groups. The ability of these extent longitudinal changes to separate unrelated groups of 30 subjects (aMCI-converters, n = 6; aMCI group-2, n = 12; controls group-2, n = 12) were further assessed. Six longitudinal hippocampus subregional functional connectivity networks showed similar changes in aMCI subjects over time, which were mainly associated with medial frontal gyrus, lateral temporal cortex, insula, posterior cingulate cortex (PCC) and cerebellum. However, the disconnection of hippocampal subregions and PCC may be a key factor of impaired episodic memory in aMCI, and the functional index of these longitudinal changes allowed well classifying independent samples of aMCI converters from non-converters (sensitivity was 83.3%, specificity was 83.3%) and controls (sensitivity was 83.3%, specificity was 91.7%). Conclusions/Significance It demonstrated that the functional changes in resting-state hippocampus subregional networks could be an important and early indicator for dysfunction that may be particularly relevant to early stage changes and progression of aMCI subjects.

Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease

The apolipoprotein E (APOE) ϵ4 allele is a confirmed genetic risk factor and the APOE ϵ2 allele is a protective factor related to late-onset Alzheimers disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between APOE ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

Altered self-referential network in resting-state amnestic type mild cognitive impairment

INTRODUCTION Impaired capacity for self-reference has been observed in amnestic mild cognitive impairment (aMCI) subjects who are thought to be the likely to develop into clinical Alzheimers disease (AD). The altered pattern of self-referencing network (SRN) is not yet well understood in aMCI subjects particularly in resting state, and little is known about the relationship between SRN and other resting-state networks in aMCI subjects. METHODS The study was designed to administer longitudinal resting-state functional magnetic resonance imaging (fMRI) scanning to 26 aMCI subjects and 18 matched healthy controls. Independent component analysis was used to separate SRN, and a further cross-correlation approach was recruited to explore the relationship between SRN and other resting-state networks. RESULTS Compared to controls, selective changes of SRN regarding to the increased functional connectivity between ventromedial prefrontal cortex/medial orbital prefrontal cortex/gyrus rectus and the mean time series of SRN at baseline in aMCI, while these functional connections were associated with more extent of longitudinal diminish after follow up in the same subjects. In addition, greater decreased connectivity relationship between SRN and default mode network was observed in aMCI subjects. CONCLUSIONS Altered patterns of resting-state SRN were firstly explored in aMCI subjects, and it could help guide subsequent investigations designed to specify the precise functional implications of SRN in the progression of aMCI.

Mapping the Altered Patterns of Cerebellar Resting-State Function in Longitudinal Amnestic Mild Cognitive Impairment Patients

The cerebellum is known to be a relatively well preserved structure, but subtle alterations may occur early in the evolution of Alzheimers disease (AD). Amnestic mild cognitive impairment (aMCI) patients appear to be particularly vulnerable to AD. However, little is currently known whether altered patterns of cerebellar function occur in aMCI patients. 26 aMCI patients and 18 well-matched healthy controls underwent a baseline resting-state functional magnetic resonance imaging (fMRI) scan. After a mean follow-up period of 20 months, the subjects who successfully completed baseline fMRI scans underwent a further follow-up scan, while spontaneous activation and functional connectivity of the cerebellum were explored by using resting-state fMRI. Compared to controls, increased amplitude of low frequency fluctuation of the posterior cerebellar lobe may contribute to the underlying mechanisms affected, while greater decreased functional connections to the posterior cerebellar lobe were identified in the longitudinal study of aMCI patients. This suggests that abnormal functional connectivity of the cerebellum may offer a more sensitive and possibly preferred index of functional disturbance than regional activity measures in aMCI patients. The cerebellum may be partly related to the underlying mechanisms of aMCI, and it could help guide subsequent investigations designed to specify the precise functional role of cerebellum in aMCI patients.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD-those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

Association of the interleukin 1 beta gene and brain spontaneous activity in amnestic mild cognitive impairment

PurposeThe inflammatory response has been associated with the pathogenesis of Alzheimer’s disease (AD). The purpose of this study is to determine whether the rs1143627 polymorphism of the interleukin-1 beta (IL-1β) gene moderates functional magnetic resonance imaging (fMRI)-measured brain regional activity in amnestic mild cognitive impairment (aMCI).MethodsEighty older participants (47 with aMCI and 33 healthy controls) were recruited for this study. All of the participants were genotyped for variant rs1143627 in the IL1B gene and were scanned using resting-state fMRI. Brain activity was assessed by amplitude of low-frequency fluctuation (ALFF).ResultsaMCI patients had abnormal ALFF in many brain regions, including decreases in the inferior frontal gyrus, the superior temporal lobe and the middle temporal lobe, and increases in the occipital cortex (calcarine), parietal cortex (Pcu) and cerebellar cortex. The regions associated with an interaction of group X genotypes of rs1143627 C/T were the parietal cortex (left Pcu), frontal cortex (left superior, middle, and medial gyrus, right anterior cingulum), occipital cortex (left middle lobe, left cuneus) and the bilateral posterior lobes of the cerebellum. Regarding the behavioral significance, there were significant correlations between ALFF in different regions of the brain and with the cognitive scores of each genotype group.ConclusionsThe present study provided evidence that aMCI patients had abnormal ALFF in many brain regions. Specifically, the rs1143627 C/T polymorphism of the IL1B gene may modulate regional spontaneous brain activity in aMCI patients.

Genetics pathway-based imaging approaches in Chinese Han population with Alzheimer’s disease risk

The tau hypothesis has been raised with regard to the pathophysiology of Alzheimer’s disease (AD). Mild cognitive impairment (MCI) is associated with a high risk for developing AD. However, no study has directly examined the brain topological alterations based on combined effects of tau protein pathway genes in MCI population. Forty-three patients with MCI and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) in Chinese Han, and a tau protein pathway-based imaging approaches (7 candidate genes: 17 SNPs) were used to investigate changes in the topological organisation of brain activation associated with MCI. Impaired regional activation is related to tau protein pathway genes (5/7 candidate genes) in patients with MCI and likely in topologically convergent and divergent functional alterations patterns associated with genes, and combined effects of tau protein pathway genes disrupt the topological architecture of cortico-cerebellar loops. The associations between the loops and behaviours further suggest that tau protein pathway genes do play a significant role in non-episodic memory impairment. Tau pathway-based imaging approaches might strengthen the credibility in imaging genetic associations and generate pathway frameworks that might provide powerful new insights into the neural mechanisms that underlie MCI.

State-based functional connectivity changes associate with cognitive decline in amnestic mild cognitive impairment subjects

Episodic memory (EM) dysfunction is a central characteristic of amnestic mild cognitive impairment (aMCI) subjects, and has a high risk of converting to Alzheimers disease (AD). However, it is unknown how the EM network is modulated when a situation is switched. Twenty-six aMCI and twenty-two cognitively normal (CN) subjects were enrolled in this study. All of the subjects completed multi-dimensional neuropsychological tests and underwent functional magnetic resonance imaging scans during a resting-state and an episodic memory retrieval task state. The EM network was constructed using a seed-based functional connectivity (FC) approach. AMCI subjects showed poorer cognitive performances in the episodic memory and executive function. We demonstrated that connectivity of the left posterior parahippocampal gyrus (LpPHG) connected to the left ventral medial prefrontal cortex and the right postcentral gyrus (RPCG) was significantly decreased in aMCI subjects compared to CN subjects. Meanwhile, there was increased connectivity of the LpPHG to the right dorsal medial prefrontal cortex (RDMPFC), RPCG, left inferior parietal cortex, and bilateral superior parietal lobe in all of the subjects that changed from a resting-state to a task-state. Interestingly, the changed LpPHG-RDMPFC connectivity strength was significantly correlated with EM scores and executive function in the aMCI subjects. As a result, general brain regions are functionally organized and integrated into the EM network, and this strongly suggests that more cognitive resources are mobilized to meet the challenge of cognitive demand in the task state. These findings extend our understanding of the underlying mechanisms of EM deficits in aMCI subjects.