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Altered Nucleus Basalis Connectivity Predicts Treatment Response in Mild Cognitive Impairment.

ABSTRACT: Purpose To determine whether functional connectivity (FC) mapping of nucleus basalis of Meynert (NBM) cholinergic network (hereafter, NBM FC) could provide a biomarker of central cholinergic deficits with predictive potential for response to cholinesterase inhibitor (ChEI) treatment. Materials and Methods The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All participants and their representatives gave written informed consent prior to data collection. NBM FC was examined in 33 healthy control participants, 102 patients with mild cognitive impairment (MCI), and 33 patients with AD by using resting-state functional MRI data from the ADNI database. NBM FC was compared between groups before and after 6 months of ChEI treatment in MCI. Associations between baseline NBM FC and baseline cognitive performance as well as cognitive outcomes after treatment were investigated. Results Compared with the healthy control group, NBM FC was decreased in patients with untreated MCI and increased in patients with AD treated with ChEI (corrected P ˂ .05). Global cognition (Alzheimer's Disease Assessment Scale-Cognitive subscale score) was associated with NBM FC (r = -0.349; P ˂ .001). NBM FC was higher 6 months after ChEI compared with before ChEI in treated MCI (corrected P ˂ .05), but did not change at 6 months in patients with untreated MCI (corrected P ˂ .05). Baseline NBM FC in MCI strongly predicted cognitive outcomes 6 months after ChEI (R² = 0.458; P = .001). Conclusion Functional dissociation of the nucleus basalis of Meynert from a cortical network may explain the cognitive deficits in dementia and allow for the selection of individuals who are more likely to respond to cholinesterase inhibitors at early disease stages. © RSNA, 2018 Online supplemental material is available for this article.

SUBMITTER: Meng D

PROVIDER: S-EPMC6283326 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: The spectrum of early Alzheimer's disease (AD) is thought to include subjective cognitive impairment, early mild cognitive impairment (eMCI), and late mild cognitive impairment (lMCI). Choline dysfunction affects the early progression of AD, in which the basal nucleus of Meynert (BNM) is primarily responsible for cortical cholinergic innervation. The aims of this study were to determine the abnormal patterns of BNM-functional connectivity (BNM-FC) in the preclinical AD spectrum (SCD, eMCI, and lMCI) and further explore the relationships between these alterations and neuropsychological measures. Methods: Resting-state functional magnetic resonance imaging (rs-fMRI) was used to investigate FC based on a seed mask (BNM mask) in 28 healthy controls (HC), 30 SCD, 24 eMCI, and 25 lMCI patients. Furthermore, the relationship between altered FC and neurocognitive performance was examined by a correlation analysis. The receiver operating characteristic (ROC) curve of abnormal BNM-FC was used to specifically determine the classification ability to differentiate the early AD disease spectrum relative to HC (SCD and HC, eMCI and HC, lMCI and HC) and pairs of groups in the AD disease spectrum (eMCI and SCD, lMCI and SCD, eMCI and lMCI). Results: Compared with HC, SCD patients showed increased FC in the bilateral SMA and decreased FC in the bilateral cerebellum and middle frontal gyrus (MFG), eMCI patients showed significantly decreased FC in the bilateral precuneus, and lMCI individuals showed decreased FC in the right lingual gyrus. Compared with the SCD group, the eMCI group showed decreased FC in the right superior frontal gyrus (SFG), while the lMCI group showed decreased FC in the left middle temporal gyrus (MTG). Compared with the eMCI group, the lMCI group showed decreased FC in the right hippocampus. Interestingly, abnormal FC was associated with certain cognitive domains and functions including episodic memory, executive function, information processing speed, and visuospatial function in the disease groups. BNM-FC of SFG in distinguishing eMCI from SCD; BNM-FC of MTG in distinguishing lMCI from SCD; BNM-FC of the MTG, hippocampus, and cerebellum in distinguishing SCD from HC; and BNM-FC of the hippocampus and MFG in distinguishing eMCI from lMCI have high sensitivity and specificity. Conclusions: The abnormal BNM-FC patterns can characterize the early disease spectrum of AD (SCD, eMCI, and lMCI) and are closely related to the cognitive domains. These new and reliable findings will provide a new perspective in identifying the early disease spectrum of AD and further strengthen the role of cholinergic theory in AD.

Project description:Background: Mild cognitive impairment (MCI) is the prodromal phase of Alzheimer's disease (AD) and has a high risk of progression to AD. Cigarette smoking is one of the important modifiable risk factors in AD progression. Cholinergic dysfunction, especially the nucleus basalis of Meynert (NBM), is the converging target connecting smoking and AD. However, how cigarette smoking affects NBM connectivity in MCI remains unclear. Objective: This study aimed to evaluate the interaction effects of condition (non-smoking vs. smoking) and diagnosis [cognitively normal (CN) vs. MCI] based on the resting-state functional connectivity (rsFC) of the NBM. Methods: After propensity score matching, we included 86 non-smoking CN, 44 smoking CN, 62 non-smoking MCI, and 32 smoking MCI. All subjects underwent structural and functional magnetic resonance imaging scans and neuropsychological tests. The seed-based rsFC of the NBM with the whole-brain voxel was calculated. Furthermore, the mixed effect analysis was performed to explore the interaction effects between condition and diagnosis on rsFC of the NBM. Results: The interaction effects of condition × diagnosis on rsFC of the NBM were observed in the bilateral prefrontal cortex (PFC), bilateral supplementary motor area (SMA), and right precuneus/middle occipital gyrus (MOG). Specifically, the smoking CN showed decreased rsFC between left NBM and PFC and increased rsFC between left NBM and SMA compared with non-smoking CN and smoking MCI. The smoking MCI showed reduced rsFC between right NBM and precuneus/MOG compared with non-smoking MCI. Additionally, rsFC between the NBM and SMA showed a significant negative correlation with Wechsler Memory Scale-Logical Memory (WMS-LM) immediate recall in smoking CN (r = -0.321, p = 0.041). Conclusion: Our findings indicate that chronic nicotine exposure through smoking may lead to functional connectivity disruption between the NBM and precuneus in MCI patients. The distinct alteration patterns on NBM connectivity in CN smokers and MCI smokers suggest that cigarette smoking has different influences on normal and impaired cognition.

Project description:(1) Background: Alzheimer's disease (AD), an age-progressive neurodegenerative disease that affects cognitive function, causes changes in the functional connectivity of the default-mode network (DMN). However, the question of whether AD-related changes occur in the functional connectivity of the basal ganglia has rarely been specifically analyzed. This study aimed to measure the changes in basal ganglia functional connectivity among patients with AD and mild cognitive impairment (MCI) in their resting state using the functional connectivity density (FCD) value, the functional connectivity (FC) intensity, and the graph theory index, and to confirm their influence on clinical manifestations. (2) Methods: Resting-state functional MRI (rs-fMRI) and neuropsychological data from 48 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were used for analyses. The 48 ADNI participants comprised 16 patients with AD, 16 patients with MCI, and 16 normal controls (NCs). The functional connectivity of basal ganglia was evaluated by FCDs, FC strength, and graph theory index. We compared voxel-based FCD values between groups to show specific regions with significant variation and significant connectivity from ROI conduction to ROI analysis. Pearson's correlation analyses between functional connectivity and several simultaneous clinical variables were also conducted. Additionally, receiver operating characteristic (ROC) analyses associated with classification were conducted for both FCD values and graph theory indices. (3) Results: The level of FCD in patients with cognitive impairment showed obvious abnormalities (including short-range and long-range FCD). In addition to DMN-related regions, aberrant functional connectivity was also found to be present in the basal ganglia, especially in the caudate and amygdala. The FCD values of the basal ganglia (involving the caudate and amygdala) were closely related to scores from the Mini-Mental State Examination (MMSE) and the Functional Activities Questionnaire (FAQ); meanwhile, the graph theory indices (involving global efficiency and degree) of the basal ganglia (involving the caudate, amygdala, and putamen) were also found to be closely correlated with MMSE scores. In ROC analyses of both FCD and graph theory, the amygdala was of the utmost importance in the early-stage detection of MCI; additionally, the caudate nucleus was found to be crucial in the progression of cognitive decline and AD diagnosis. (4) Conclusions: It was systematically confirmed that there is a phenomenon of change in the functional connections in the basal ganglia during cognitive decline. The findings of this study could improve our understanding of AD and MCI pathology in the basal ganglia and make it possible to propose new targets for AD treatment in further studies.

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Altered Nucleus Basalis Connectivity Predicts Treatment Response in Mild Cognitive Impairment.

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