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In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer's disease.

ABSTRACT: Synapse loss has been considered as a major pathological change in Alzheimer's disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using ¹⁸F-SynVesT-1 PET to evaluate synaptic alterations in 33 participants with AD, 31 with mild cognitive impairment (MCI), and 30 controls. We examined the correlation between synaptic density and cognitive function. Functional MRI was performed to analyze functional connectivity in lower synaptic density regions. We tracked the white matter tracts between impaired functional connectivity regions using Diffusion MRI. In AD group, lower synaptic density in bilateral cortex and hippocampus was found when compared with controls. The synaptic density changes in right insular cortex and bilateral caudal middle frontal gyrus (MFG) were correlated with cognitive decline. Among them, right MFG synaptic density was positively associated with right MFG - bilateral superior frontal gyrus (SFG) functional connectivity. AD had lower probability of tract (POT) between right MFG and SFG than controls, which was significantly associated with global cognition. These findings provide evidence supporting synapse loss contributes to functional and related structural connectivity alterations underlying cognitive impairment of AD.

SUBMITTER: Zhang J

PROVIDER: S-EPMC10196742 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer's disease.

Zhang Junfang J Wang Jie J Xu Xiaomeng X You Zhiwen Z Huang Qi Q Huang Yiyun Y Guo Qihao Q Guan Yihui Y Zhao Jun J Liu Jun J Xu Wei W Deng Yulei Y Xie Fang F Li Binyin B

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20230130 6

Synapse loss has been considered as a major pathological change in Alzheimer's disease (AD). It remains unclear about whether and how synapse loss relates to functional and structural connectivity dysfunction in AD. We measured synaptic vesicle glycoprotein 2 A (SV2A) binding using <sup>18</sup>F-SynVesT-1 PET to evaluate synaptic alterations in 33 participants with AD, 31 with mild cognitive impairment (MCI), and 30 controls. We examined the correlation between synaptic density and cognitive fu ...[more]

PMID: 36718002

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Project description:Alzheimer's disease (AD) is increasingly recognized as a disconnection syndrome, which leads to cognitive impairment due to the disruption of functional activity across large networks or systems of interconnected brain regions. We explored abnormal functional magnetic resonance imaging (fMRI) resting-state dynamics, functional connectivity, and weighted functional networks, in a sample of patients with severe AD (N = 18) and age-matched healthy volunteers (N = 21). We found that patients had reduced amplitude and regional homogeneity of low-frequency fMRI oscillations, and reduced the strength of functional connectivity, in several regions previously described as components of the default mode network, for example, medial posterior parietal cortex and dorsal medial prefrontal cortex. In patients with severe AD, functional connectivity was particularly attenuated between regions that were separated by a greater physical distance; and loss of long distance connectivity was associated with less efficient global and nodal network topology. This profile of functional abnormality in severe AD was consistent with the results of a comparable analysis of data on 2 additional groups of patients with mild AD (N = 17) and amnestic mild cognitive impairment (MCI; N = 18). A greater degree of cognitive impairment, measured by the mini-mental state examination across all patient groups, was correlated with greater attenuation of functional connectivity, particularly over long connection distances, for example, between anterior and posterior components of the default mode network, and greater reduction of global and nodal network efficiency. These results indicate that neurodegenerative disruption of fMRI oscillations and connectivity in AD affects long-distance connections to hub nodes, with the consequent loss of network efficiency. This profile was evident also to a lesser degree in the patients with less severe cognitive impairment, indicating that the potential of resting-state fMRI measures as biomarkers or predictors of disease progression in AD.

Project description:BackgroundBoth subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) have a high risk of progression to Alzheimer's disease (AD). While most of the available evidence described changes in functional connectivity (FC) in SCD and aMCI, there was no confirmation of changes in functional connectivity density (FCD) that have not been confirmed. Therefore, the purpose of this study was to investigate the specific alterations in resting-state FCD in SCD and aMCI and further assess the extent to which these changes can distinguish the preclinical and early-stage AD.MethodsA total of 57 patients with SCD, 59 patients with aMCI, and 78 healthy controls (HC) were included. The global FCD, local FCD, and long-range FCD were calculated for each voxel to identify brain regions with significant FCD alterations. The brain regions with abnormal FCD were then used as regions of interest for FC analysis. In addition, we calculated correlations between neuroimaging alterations and cognitive function and performed receiver-operating characteristic analyses to assess the diagnostic effect of the FCD and FC alterations on SCD and aMCI.ResultsFCD mapping revealed significantly increased global FCD in the left parahippocampal gyrus (PHG.L) and increased long-range FCD in the left hippocampus for patients with SCD when compared to HCs. However, when compared to SCD, patients with aMCI showed significantly decreased global FCD and long-range FCD in the PHG.L. The follow-up FC analysis further revealed significant variations between the PHG.L and the occipital lobe in patients with SCD and aMCI. In addition, patients with SCD also presented significant changes in FC between the left hippocampus, the left cerebellum anterior lobe, and the inferior temporal gyrus. Moreover, changes in abnormal indicators in the SCD and aMCI groups were significantly associated with cognitive function. Finally, combining FCD and FC abnormalities allowed for a more precise differentiation of the clinical stages.ConclusionTo our knowledge, this study is the first to investigate specific alterations in FCD and FC for both patients with SCD and aMCI and confirms differential abnormalities that can serve as potential imaging markers for preclinical and early-stage Alzheimer's disease (AD). Also, it adds a new dimension of understanding to the diagnosis of SCD and aMCI as well as the evaluation of disease progression.

Project description:BackgroundPremenstrual syndrome (PMS) is a menstrual-related disorder, characterized by physical, emotional, behavioral and cognitive symptoms. However, the neuropathological mechanisms of PMS remain unclear. This study aimed to investigate the frequency-specific functional connectivity density (FCD) and structural covariance in PMS.MethodsFunctional and T1-weighted structural data were obtained from 35 PMS patients and 36 healthy controls (HCs). This study was a cross-sectional and prospective design. The local/long-range FCD (LFCD/LRFCD) across slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) bands were computed, and two-way analysis of variance (ANOVA) was performed to ascertain the main effects of group and interaction effects between group and frequency band. Receiver operating characteristic (ROC) curve was performed to investigate reliable biomarkers for identifying PMS from HCs. Based on the ROC results, characterized the changes of whole-brain structural covariance patterns of striatum subregions in two groups. Correlation analysis was applied to examine relationships between the clinical symptoms and abnormal brain regions.ResultsCompared with HCs, PMS patients exhibited: (I) aberrant functional communication in the middle cingulate cortex and precentral gyrus; (II) significant frequency band-by-group interaction effects of the striatum, thalamus and orbitofrontal cortex; (III) the better classification ability of the LFCD in the striatum in ROC analysis (slow-5); (IV) decreased gray matter volumes in the caudate subregions and decreased structural associations of between the caudate subregions and frontal cortex; (V) the LFCD value in thalamus were significantly negatively correlated with the sleep problems (slow-5).ConclusionsBased on multi-modal magnetic resonance imaging (MRI) analysis, this study might imply the aberrant emotional regulation and cognitive function related to menstrual cycle in PMS and improve our understanding of the pathophysiologic mechanism in PMS from novel perspective.

Dataset Information

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer's disease.

Publications

In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer's disease.

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