Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients
Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was as...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-02-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996122003758 |
| _version_ | 1797942119369801728 |
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| author | Peng Ren Wencai Ding Siyang Li Guiyou Liu Meng Luo Wenyang Zhou Rui Cheng Yiqun Li Pingping Wang Zhipeng Li Lifen Yao Qinghua Jiang Xia Liang |
| author_facet | Peng Ren Wencai Ding Siyang Li Guiyou Liu Meng Luo Wenyang Zhou Rui Cheng Yiqun Li Pingping Wang Zhipeng Li Lifen Yao Qinghua Jiang Xia Liang |
| author_sort | Peng Ren |
| collection | DOAJ |
| description | Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM. |
| first_indexed | 2024-04-10T20:02:18Z |
| format | Article |
| id | doaj.art-34973b47cc104dcb9f200dd22d059ba3 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-04-10T20:02:18Z |
| publishDate | 2023-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-34973b47cc104dcb9f200dd22d059ba32023-01-27T04:18:25ZengElsevierNeurobiology of Disease1095-953X2023-02-01177105983Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patientsPeng Ren0Wencai Ding1Siyang Li2Guiyou Liu3Meng Luo4Wenyang Zhou5Rui Cheng6Yiqun Li7Pingping Wang8Zhipeng Li9Lifen Yao10Qinghua Jiang11Xia Liang12School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Laboratory for Space Environment and Physical Science, Harbin Institute of Technology, Harbin 150001, ChinaDepartment of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Laboratory for Space Environment and Physical Science, Harbin Institute of Technology, Harbin 150001, ChinaBeijing Institute for Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing 100069, China; Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing 100053, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Laboratory for Space Environment and Physical Science, Harbin Institute of Technology, Harbin 150001, ChinaDepartment of Neurology, First Affiliated Hospital of Harbin Medical University, Harbin 150001, ChinaSchool of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Key Laboratory of Biological Big Data (Harbin Institute of Technology), Ministry of Education, Harbin 150001, China; Corresponding authors at: Harbin Institute of Technology, Harbin, China.School of Life Science and Technology, Harbin Institute of Technology, Harbin 150001, China; Laboratory for Space Environment and Physical Science, Harbin Institute of Technology, Harbin 150001, China; Corresponding authors at: Harbin Institute of Technology, Harbin, China.Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.http://www.sciencedirect.com/science/article/pii/S0969996122003758Nucleus basalis of MeynertFunctional connectivityMild cognitive impairmentBasal forebrainTranscriptional vulnerabilityTissue-specific geneset risk score |
| spellingShingle | Peng Ren Wencai Ding Siyang Li Guiyou Liu Meng Luo Wenyang Zhou Rui Cheng Yiqun Li Pingping Wang Zhipeng Li Lifen Yao Qinghua Jiang Xia Liang Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients Neurobiology of Disease Nucleus basalis of Meynert Functional connectivity Mild cognitive impairment Basal forebrain Transcriptional vulnerability Tissue-specific geneset risk score |
| title | Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| title_full | Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| title_fullStr | Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| title_full_unstemmed | Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| title_short | Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| title_sort | regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients |
| topic | Nucleus basalis of Meynert Functional connectivity Mild cognitive impairment Basal forebrain Transcriptional vulnerability Tissue-specific geneset risk score |
| url | http://www.sciencedirect.com/science/article/pii/S0969996122003758 |
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