Connectome-based prediction of decreased trust propensity in older adults with mild cognitive impairment: A resting-state functional magnetic resonance imaging study.

Trust propensity (TP) relies more on social than economic rationality to transform the perceived probability of betrayal into positive reciprocity expectations in older adults with normal cognition. While deficits in social rationality have been observed in older adults with mild cognitive impairment (MCI), there is limited research on TP and its associated resting-state functional connectivity (RSFC) mechanisms in this population. To measure TP and related psychological functions (affect, motivation, executive cognition, and social cognition), MCI (n = 42) and normal healthy control (NHC, n = 115) groups completed a one-shot trust game and additional assessments of related psychological functions. RSFC associated with TP was analyzed using connectome-based predictive modeling (CPM) and lesion simulations. Our behavioral results showed that the MCI group trusted less (i.e., had lower TP) than the NHC group, with lower TP associated with higher sensitivity to the probability of betrayal in the MCI group. In the MCI group, only negative CPM models (RSFC negatively correlated with TP) significantly predicted TP, with a high salience network (SN) contribution. In contrast, in the NHC group, positive CPM models (RSFC positively correlated with TP) significantly predicted TP, with a high contribution from the default mode network (DMN). In addition, the total network strength of the NHC-specific positive network was lower in the MCI group than in the NHC group. Our findings demonstrated a decrease in TP in the MCI group compared to the NHC group, which is associated with deficits in social rationality (social cognition, associated with DMN) and increased sensitivity to betrayal (affect, associated with SN) in a trust dilemma. In conclusion, our study contributes to understanding MCI-related alterations in trust and their underlying neural mechanisms.

The connectome-based prediction of trust propensity in older adults: A resting-state functional magnetic resonance imaging study.

A recent neuropsychoeconomic model of trust propensity argues that an individual uses economic (executive functions) and social (social cognition) rationality strategies to transform the risk of treachery (affect) into positive expectations of reciprocity, promoting trust in another person. Previous studies have shown that the trust of older adults is associated with affect and social cognition. However, little is known about the intrinsic functional connectivity correlated with trust propensity or whether trust propensity is associated with executive functions in older adults. In this study, we examined the association between trust propensity (measured by a one-shot trust game [TG]), social preference (measured by a one-shot dictator game), and executive functions (measured by a battery of neuropsychological tests). We also performed connectome-based predictive modeling (CPM) and computational lesion analysis to identify the key large-scale resting-state functional connectivity (RSFC) underlying the prediction of trust propensity. Our behavioral results showed a lower trust propensity in older adults in our study than in younger adults in a previous meta-analysis. Furthermore, trust propensity was associated with social preference, but there was no significant relationship between trust propensity and executive functions. The neuroimaging results showed that the cingulo-opercular network (CON) and the default mode network (DMN), rather than the frontoparietal network (FPN), significantly contributed to the prediction of trust propensity in older adults. Our findings suggest that older adults rely less on economic rationality (executive functions, associated with FPN) in trust games. Rather, they are likely to depend more on social rationality (social cognition, associated with social preference and DMN) to resolve the risk of treachery (affect, associated with CON) in trust dilemmas. This study contributes to a better understanding of the neural underpinnings of older adults' trust propensity.

Altered functional coupling between the cerebellum and cerebrum in patients with amnestic mild cognitive impairment.

Cognitive processing relies on the functional coupling between the cerebrum and cerebellum. However, it remains unclear how the 2 collaborate in amnestic mild cognitive impairment (aMCI) patients. With functional magnetic resonance imaging techniques, we compared cerebrocerebellar functional connectivity during the resting state (rsFC) between the aMCI and healthy control (HC) groups. Additionally, we distinguished coupling between functionally corresponding and noncorresponding areas across the cerebrum and cerebellum. The results demonstrated decreased rsFC between both functionally corresponding and noncorresponding areas, suggesting distributed deficits of cerebrocerebellar connections in aMCI patients. Increased rsFC was also observed, which were between functionally noncorresponding areas. Moreover, the increased rsFC was positively correlated with attentional scores in the aMCI group, and this effect was absent in the HC group, supporting that there exists a compensatory mechanism in patients. The current study contributes to illustrating how the cerebellum adjusts its coupling with the cerebrum in individuals with cognitive impairment.

A new perspective for understanding the contributions of the cerebellum to reading: The cerebro-cerebellar mapping hypothesis.

Extensive studies have reported significant activation of the cerebellum in reading and reading-related tasks. However, it has remained unclear how the cerebellum contributes to reading and how reading-related regions in the cerebrum are related to those in the cerebellum. In this review, by summarizing previous literature, we observe that multiple cerebellar areas are engaged in reading and vary in their contributions to reading. Moreover, the cerebellar reading-related areas are selectively connected with the cerebral areas with the same functional specificity. Abnormalities in the cerebro-cerebellar connection are also associated with reading impairments. We thus propose the cerebro-cerebellar mapping hypothesis, which suggests that the cerebellum might have another reading-related network rather than serving as a neural hub. This network maps to and collaborates with its functionally corresponding network in the cerebrum. This framework heightens the importance of the cerebellum to reading and provides new insights into the relationship between the cerebellum, cerebrum, and reading development.

Functional mapping and cooperation between the cerebellum and cerebrum during word reading.

Multiple areas in the cerebellum have been reported to be engaged in reading. However, how these regions cooperate with the reading-related areas in the cerebrum remains unclear. Here, brain images of fifty-two adults were acquired via functional magnetic resonance imaging. By comparing the cerebellar activation across three localization tasks targeting orthographic, phonological, and semantic processing, we first identified three different reading-related areas in the cerebellum, biased toward orthography, phonology, and semantics, respectively. Then, functional connectivity (FC) analyses demonstrated that the mean FC between functionally corresponding areas across the cerebrum and cerebellum was greater than that between noncorresponding areas during silent word reading. FC patterns of functionally corresponding areas could significantly predict reading speed, with the FC driven from orthographic and semantic areas contributing the most. Effective FC analyses further showed that orthographic and semantic areas in the cerebellum had selective and direct connectivity to areas in the cerebrum with similar functional specificity. These results suggest that reading-related areas vary in their functions to reading, and cooperation between areas with corresponding functions was greater than that between noncorresponding areas. These findings emphasize the importance of functional cooperation between the cerebrum and cerebellum during reading from a new perspective.

Dengzhanxixin Injection Ameliorates Cognitive Impairment Through a Neuroprotective Mechanism Based on Mitochondrial Preservation in Patients With Acute Ischemic Stroke.

Acute ischemic stroke (AIS) is a global health burden and cognitive impairment is one of its most serious complication. Adequate interventions for AIS may have the potential to improve cognitive outcomes. In the present study, we selected Erigeron breviscapus (Vaniot) Hand.-Mazz. injection (Dengzhanxixin injection, DZXI), a widely used Chinese herbal injection, in contrast to edaravone as the positive control drug to test its potential to ameliorates neurological and cognitive impairments caused by AIS. We performed a 2-week randomized trial with these two drugs in AIS patients presenting mild to moderate cognitive impairments. Neuropsychological tests and MRI examinations showed that DZXI attenuated the neurological and cognitive impairments of patients and protected the grey matter in specific regions from ischemic damage. Notably, DZXI exerted better effects than edaravone in some neuropsychological tests, probably due to the protective effect of DZXI on grey matter. To explore the therapeutic mechanisms, we carried out an experiment with a middle cerebral artery occlusion rat model. We found that DZXI decreased the infarct volume and increased the survival of neuronal cells in the ischemic penumbra; furthermore, DZXI modulated the mitochondrial respiratory chain process and preserved the mitochondrial structure in the brain tissue. Overall, our data suggested that the administration of DZXI is effective at ameliorating neurological and cognitive impairments in AIS, and the underlying mechanisms are related to the protective effects of DZXI on cerebral neurons and neuronal mitochondria.

Progressive Brain Degeneration From Subjective Cognitive Decline to Amnestic Mild Cognitive Impairment: Evidence From Large-Scale Anatomical Connection Classification Analysis.

People with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are both at high risk for Alzheimer's disease (AD). Behaviorally, both SCD and aMCI have subjective reports of cognitive decline, but the latter suffers a more severe objective cognitive impairment than the former. However, it remains unclear how the brain develops from SCD to aMCI. In the current study, we aimed to investigate the topological characteristics of the white matter (WM) network that can successfully identify individuals with SCD or aMCI from healthy control (HC) and to describe the relationship of pathological changes between these two stages. To this end, three groups were recruited, including 22 SCD, 22 aMCI, and 22 healthy control (HC) subjects. We constructed WM network for each subject and compared large-scale topological organization between groups at both network and nodal levels. At the network level, the combined network indexes had the best performance in discriminating aMCI from HC. However, no indexes at the network level can significantly identify SCD from HC. These results suggested that aMCI but not SCD was associated with anatomical impairments at the network level. At the nodal level, we found that the short-path length can best differentiate between aMCI and HC subjects, whereas the global efficiency has the best performance in differentiating between SCD and HC subjects, suggesting that both SCD and aMCI had significant functional integration alteration compared to HC subjects. These results converged on the idea that the neural degeneration from SCD to aMCI follows a gradual process, from abnormalities at the nodal level to those at both nodal and network levels.

Early prevention of cognitive impairment in the community population: The Beijing Aging Brain Rejuvenation Initiative.

Facing considerable challenges associated with aging and dementia, China urgently needs an evidence-based health-care system for prevention and management of dementia. The Beijing Aging Brain Rejuvenation Initiative (BABRI) is a community-based cohort study initiated in 2008 that focuses on asymptomatic stages of dementia, aims to develop community-based prevention strategies for cognitive impairment, and provides a platform for scientific research and clinical trials. Thus far, BABRI has recruited 10,255 participants (aged 50 and over, 60.3% female), 2021 of whom have been followed up at least once at a 2- or 3-year interval. This article presents aims and study design of BABRI; summarizes preliminary behavioral and neuroimaging findings on mild cognitive impairment (MCI) and results of clinical trials on MCI; and discusses issues concerning early prevention in community, MCI diagnosis methods, and applications of database of aging and dementia. BABRI is proposed to build a systematic framework on brain health in old age.

Disrupted White Matter Networks from Subjective Memory Impairment to Amnestic Mild Cognitive Impairment.

BACKGROUND AND OBJECTIVE: Subjective memory impairment (SMI) is a preclinical stage prior to amnestic mild cognitive impairment (aMCI) along with the Alzheimer's disease (AD) continuum. We hypothesized that SMI patients had white matter (WM) network disruptions similar to those in aMCI patients. METHODS: We used diffusion-tensor magnetic resonance imaging and graph theory to construct, analyze, and compare the WM networks among 20 normal controls (NC), 20 SMI patients, and 20 aMCI patients. RESULTS: Compared with the NC group, the SMI group had significantly decreased global and local efficiency and an increased shortest path length. Moreover, similar to the aMCI group, the SMI group had lower nodal efficiency in regions located in the frontal and parietal lobes, limbic systems, and caudate nucleus compared to that of the NC group. CONCLUSION: Similar to aMCI patient, SMI patients exhibited WM network disruptions, and detection of these disruptions could facilitate the early detection of SMI.

The Anterior-posterior Functional Connectivity Disconnection in the Elderly with Subjective Memory Impairment and Amnestic Mild Cognitive Impairment.

BACKGROUND: Subjective Memory Impairment (SMI) may tremendously increase the risk of Alzheimer's Disease (AD). The full understanding of the neuromechanism of SMI will shed light on the early intervention of AD. METHODS: In the current study, 23 Healthy Controls (HC), 22 SMI subjects and 24 amnestic Mild Cognitive Impairment (aMCI) subjects underwent the comprehensive neuropsychological assessment and the resting-state functional magnetic resonance imaging scan. The difference in the connectivity of the Default Mode Network (DMN) and Functional Connectivity (FC) from the Region of Interest (ROI) to the whole brain were compared, respectively. RESULTS: The results showed that HC and SMI subjects had significantly higher connectivity in the region of the precuneus area compared to aMCI subjects. However, from this region to the whole brain, SMI and aMCI subjects had significant FC decrease in the right anterior cingulum, left superior frontal and left medial superior frontal gyrus compared to HC. In addition, this FC change was significantly correlated with the cognitive function decline in participants. CONCLUSION: Our study indicated that SMI subjects had relatively intact DMN connectivity but impaired FC between the anterior and posterior brain. The findings suggest that long-distance FC is more vulnerable than the short ones in the people with SMI.

The Contribution of Genetic Factors to Cognitive Impairment and Dementia: Apolipoprotein E Gene, Gene Interactions, and Polygenic Risk.

Alzheimer's disease (AD) is a progressive neurodegenerative disease. Although it has been studied for years, the pathogenesis of AD is still controversial. Genetic factors may play an important role in pathogenesis, with the apolipoprotein E (APOE) gene among the greatest risk factors for AD. In this review, we focus on the influence of genetic factors, including the APOE gene, the interaction between APOE and other genes, and the polygenic risk factors for cognitive function and dementia. The presence of the APOE ε4 allele is associated with increased AD risk and reduced age of AD onset. Accelerated cognitive decline and abnormal internal environment, structure, and function of the brain were also found in ε4 carriers. The effect of the APOE promoter on cognition and the brain was confirmed by some studies, but further investigation is still needed. We also describe the effects of the associations between APOE and other genetic risk factors on cognition and the brain that exhibit a complex gene⁻gene interaction, and we consider the importance of using a polygenic risk score to investigate the association between genetic variance and phenotype.

APOE influences working memory in non-demented elderly through an interaction with SPON1 rs2618516.

Exploring how risk genes cumulatively impair brain function in preclinical phase (i.e., in cognitively normal elderly) could provide critical insights into the pathophysiology of Alzheimer's disease (AD). Working memory impairment has always been a considerable cognitive deficit in AD, which is likely under complex genetic control. Though, the APOE ɛ4 allele could damage the working memory performance in normal elderly, dissociable results have been reported. This allele may exert specific effects in contexts with other genetic variants. The rs2618516 in the spondin 1 gene (SPON1) has been associated with AD risk and brain structure in the elderly. SPON1 may interact with APOE through processing the amyloid precursor protein and suppressing amyloid-ß levels. Using neuropsychological tasks from 710 individuals, we found significant SPON1 × APOE genotype interactions in working memory and executive function performances. Moreover, such interaction was also found in regional brain activations based on functional magnetic resonance imaging data with the n-back working memory task performed in a sub-cohort of 64 subjects. The effects of ɛ4 allele on activation of right inferior frontal gyrus, triangular part (IFGtriang.R) were modulated by rs2618516 in a working memory task. Furthermore, lower IFGtriang.R activation was associated with better cognitive functions. Moreover, the IFGtriang.R activation could mediate the impacts of SPON1 × APOE interactions on working memory performance. These findings suggested the importance of weighing APOE effects on brain activation under the working memory task within the context of the SPON1 genotype.

Inflection Point in Course of Mild Cognitive Impairment: Increased Functional Connectivity of Default Mode Network.

The alteration of the default mode network (DMN) functional connectivity (FC) has been reported in patients with amnestic mild cognitive impairment (aMCI) as a predictor of Alzheimer's disease (AD). However, no studies exist that examined stage-dependent DMN FC changes throughout the course of aMCI. The present study aims to characterize patterns of DMN FC over three aMCI stages as first defined. Utilizing the extreme groups approach on the performance of memory tasks, aMCI subjects were divided into mild, moderate, and severe stages. Independent component analysis was used to assess DMN for individual patients in each of the three cross-sectionally defined stages. Instead of finding that continued monotonic decline was the case for the hippocampus volume, which we also investigated in this study, we observed an increase in DMN functional connectivity from mild aMCI to moderate aMCI and a decrease to severe aMCI, mainly in the left precuneus and superior parietal lobe. Moreover, the FC was significantly associated with cognitive performance. Though a longitudinal study is needed to confirm these results, our cross-sectional finding is that non-linear FC changes in DMN could be a characteristic of prodromal early disease development.

Vulnerability of the frontal and parietal regions in hypertensive patients during working memory task.

BACKGROUND: Hypertension is related with cognitive decline in the elderly. The frontal-parietal executive system plays an important role in cognitive aging and is also vulnerable to damage in elderly patients with hypertension. Examination of the brain's functional characteristics in frontal-parietal regions of hypertension is likely to be important for understanding the neural mechanisms of hypertension's effect on cognitive aging. METHODS: We address this issue by comparing hypertension and control-performers in a functional MRI study. Twenty-eight hypertensive patients and 32 elderly controls were tested with n-back task with two load levels. RESULTS: The hypertensive patients exhibited worse executive and memory abilities than control subjects. The patterns of brain activation changed under different working memory loads in the hypertensive patients, who exhibited reduced activation only in the precentral gyrus under low loads and reduced activation in the middle frontal gyrus, left medial superior frontal gyrus and right precuneus under high loads. Thus, more regions of diminished activation were observed in the frontal and parietal regions with increasing task difficulty. More importantly, we found that lower activation in changed frontal and parietal regions was associated with worse cognitive function in high loads. CONCLUSION: The results demonstrate the relationship between cognitive function and frontoparietal functional activation in hypertension and their relevance to cognitive aging risk. Our findings provide a better understanding of the mechanism of cognitive decline in hypertension and highlight the importance of brain protection in hypertension.

Multistage Grading of Amnestic Mild Cognitive Impairment: The Associated Brain Gray Matter Volume and Cognitive Behavior Characterization.

Background and Purpose: It is well known that there is a wide range of different pathological stages related to Alzheimer's disease (AD) among patients with amnestic mild cognitive impairment (aMCI). Further refinement of the stages based on neuropsychological and neuroimaging methods is important for earlier disease detection, as well as for the development and evaluation of disease-modifying interventions. Materials and Methods: In this cross-sectional study, 125 aMCI patients were classified into declined progressively three stages of mild, moderate and severe, utilizing the extreme groups approach (EGA) based on their memory function. Fifty-two patients, in addition to 24 cognitively normal subjects, were included in further structural MRI analyses. Characteristics of cognitive functions and brain structures across these newly defined stages were explored through general linear models. Results: Almost all the non-memory cognitive functions showed progressive decline as memory function deteriorated. In addition, medial structures including the right hippocampus, right lingual and left fusiform gyrus, presented with greater gray matter (GM) atrophy during the later stages of aMCI (corrected p < 0.05). Correlations were found between GM volume of the lingual gyrus and processing speed (r = 0.419, p = 0.003) and between the fusiform gyrus and general cognitive function (r = 0.281, p = 0.046). Moreover, both cognitive function and GM volume presented non-linear trajectories over stages of aMCI. Conclusion: Our study characterized the cognitive profiles along with the degree of episodic memory impairment, and these three stages of aMCI showed non-linear progressive decline in cognitive functions and GM volumes.