Effect of different oral anticoagulants on cognitive function in patients with atrial fibrillation: A Bayesian network meta-analysis.

BACKGROUND: Atrial fibrillation (AF) is 1 of the most common types of arrhythmias. At present, the treatment for patients with AF mainly includes oral anticoagulants (OACs). Studies have shown that OACs are associated with cognitive decline in patients with atrial fibrillation; however, there is a lack of relevant evidence. This study used Bayesian network meta-analysis (NMA) to investigate the effects of different oral anticoagulants on cognitive decline in patients with AF. METHODS: We systematically searched for clinical studies on oral anticoagulants in patients with AF in PubMed, Web of Science, Embase, and the Cochrane Library as of July 3, 2023. Cochrane's randomized controlled trial bias risk assessment tool and the Newcastle-Ottawa Scale were used to assess the bias risk of the included studies. The main outcome measure was decreased cognitive functioning. RESULTS: Ten studies were included, including 2 RCTs and 7 RCSs, including 882,847 patients with AF. Five oral anticoagulants and 2 anticoagulants were included: VKAs (especially warfarin), Dabigatran, Edoxaban, Rivaroxaban, Apixaban, and Aspirin, Clopidogrel. The results of the mesh meta-analysis showed that VKAs were superior to warfarin in reducing the risk of cognitive decline in patients with AF (OR = -1.19, 95% CI (-2.35, -0.06), P < .05) (Table 5). The top 3 drugs in terms of the probability of reducing the incidence of cognitive impairment in patients with AF with different oral anticoagulants were VKAs (87%), rivaroxaban (62.2%), and dabigatran (60.8%). CONCLUSION: Based on the results of this study, VKAs may be the best intervention measure for reducing the risk of cognitive decline in patients with AF. Owing to the limitations of this study, more high-quality randomized controlled trials with large sample sizes and multiple centers are required to provide more evidence.

Brain microstructural alterations in the left precuneus mediate the association between KIBRA polymorphism and working memory in healthy adults: a diffusion kurtosis imaging study.

Kidney and brain expressed protein (KIBRA) rs17070145 is associated with working memory function and cognitive processes. However, the neural mechanisms underlying these associations are not fully understood. This study aimed to explore the effect of KIBRA polymorphism on brain microstructure and blood oxygenation level dependent (BOLD) fluctuations using diffusion kurtosis imaging (DKI) and resting-state functional magnetic resonance imaging (fMRI) in 163 young adults. We also investigated that whether the imaging alterations mediated the association between KIBRA gene and working memory performance. Voxel-based analysis of DKI data showed that KIBRA C-allele carriers exhibited increased axial diffusivity (AD), radial diffusivity (RD) and mean diffusivity (MD) as well as decreased fractional anisotropy (FA), mean kurtosis (MK) and radial kurtosis (RK) compared with KIBRA TT homozygotes, primarily involving the prefrontal lobe, left precuneus and the left superior parietal white matter. Meanwhile, KIBRA C-allele carriers exhibited decreased amplitude of low-frequency fluctuation (ALFF) in the left precuneus compared to KIBRA TT homozygotes. Mediation analysis revealed that the DKI metrics (MK and RK) of the left precuneus mediated the effect of the KIBRA polymorphism on working memory performance. Moreover, the MK and RK in the left precuneus were positively correlated with ALFF in the same brain region. These findings suggest that abnormal DKI parameters may provide a gene-brain-behavior pathway in which KIBRA rs17070145 affects working memory by modulating brain microstructure in the left precuneus. This illustrates that DKI may provide additional biological information and reveal new insights into the neural mechanisms of the KIBRA polymorphism.

Disrupted Network Topology Contributed to Spatial Navigation Impairment in Patients With Mild Cognitive Impairment.

Impairment in spatial navigation (SN) and structural network topology is not limited to patients with Alzheimer's disease (AD) dementia and can be detected earlier in patients with mild cognitive impairment (MCI). We recruited 32 MCI patients (65.91 ± 11.33 years old) and 28 normal cognition patients (NC; 69.68 ± 10.79 years old), all of whom underwent a computer-based battery of SN tests evaluating egocentric, allocentric, and mixed SN strategies and diffusion-weighted and T1-weighted Magnetic Resonance Imaging (MRI). To evaluate the topological features of the structural connectivity network, we calculated its measures such as the global efficiency, local efficiency, clustering coefficient, and shortest path length with GRETNA. We determined the correlation between SN accuracy and network topological properties. Compared to NC, MCI subjects demonstrated a lower egocentric navigation accuracy. Compared with NC, MCI subjects showed significantly decreased clustering coefficients in the left middle frontal gyrus, right rectus, right superior parietal gyrus, and right inferior parietal gyrus and decreased shortest path length in the left paracentral lobule. We observed significant positive correlations of the shortest path length in the left paracentral lobule with both the mixed allocentric-egocentric and the allocentric accuracy measured by the average total errors. A decreased clustering coefficient in the right inferior parietal gyrus was associated with a larger allocentric navigation error. White matter hyperintensities (WMH) did not affect the correlation between network properties and SN accuracy. This study demonstrated that structural connectivity network abnormalities, especially in the frontal and parietal gyri, are associated with a lower SN accuracy, independently of WMH, providing a new insight into the brain mechanisms associated with SN impairment in MCI.

Basal Forebrain Atrophy Is Associated With Allocentric Navigation Deficits in Subjective Cognitive Decline.

Individuals with subjective cognitive decline (SCD) are at higher risk of incipient Alzheimer's disease (AD). Spatial navigation (SN) impairments in AD dementia and mild cognitive impairment patients have been well-documented; however, studies investigating SN deficits in SCD subjects are still lacking. This study aimed to explore whether basal forebrain (BF) and entorhinal cortex (EC) atrophy contribute to spatial disorientation in the SCD stage. In total, 31 SCD subjects and 24 normal controls were enrolled and administered cognitive scales, a 2-dimensional computerized SN test, and structural magnetic resonance imaging (MRI) scanning. We computed the differences in navigation distance errors and volumes of BF subfields, EC, and hippocampus between the SCD and control groups. The correlations between MRI volumetry and navigation distance errors were also calculated. Compared with the controls, the SCD subjects performed worse in both egocentric and allocentric navigation. The SCD group showed volume reductions in the whole BF (p < 0.05, uncorrected) and the Ch4p subfield (p < 0.05, Bonferroni corrected), but comparable EC and hippocampal volumes with the controls. In the SCD cohort, the allocentric errors were negatively correlated with total BF (r = -0.625, p < 0.001), Ch4p (r = -0.625, p < 0.001), total EC (r = -0.423, p = 0.031), and left EC volumes (r = -0.442, p = 0.024), adjusting for age, gender, years of education, total intracranial volume, and hippocampal volume. This study demonstrates that SN deficits and BF atrophy may be promising indicators for the early detection of incipient AD patients. The reduced BF volume, especially in the Ch4p subfield, may serve as a structural basis for allocentric disorientation in SCD subjects independent of hippocampal atrophy. Our findings may have further implications for the preclinical diagnosis and intervention for potential AD patients.

Ego- and allo-network disconnection underlying spatial disorientation in subjective cognitive decline.

Patients with Alzheimer's disease (AD) related dementia and mild cognitive impairment experience difficulties with spatial navigation (SN). However, SN has rarely been investigated in individuals with subjective cognitive decline (SCD), a preclinical stage with elevated progression rate to symptomatic AD. In this study, 30 SCD subjects and 30 controls underwent cognitive scale (CS) evaluation, a 2D computerized SN test, and resting-state functional magnetic resonance imaging scanning. Two SN brain networks (ego-network and allo-network), each with 10 selected spherical regions, were defined. We calculated the average network functional connectivity (FC) and region-to-region FC within the two networks and evaluated correlations with SN performance. Compared with the controls, the SCD group performed worse in the SN test and showed decreased FC between the right retrosplenial and right prefrontal cortices in the ego-network, and between the right retrosplenial cortex and right hippocampus in the allo-network. The logistic regression model based on SN and FC measures revealed a high area under the curve of .880 in differentiating SCD individuals from controls. These results suggest that SN network disconnection contributes to spatial deficits in SCD, and SN and FC measures could benefit the preclinical detection of subjects with incipient AD dementia.

Genetic Alzheimer's Disease Risk Affects the Neural Mechanisms of Pattern Separation in Hippocampal Subfields.

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.

Brain Cortical Complexity and Subcortical Morphometrics in Lifelong Premature Ejaculation.

Premature ejaculation (PE) is the most common male sexual dysfunction. The brain disturbances that cause this disorder remain poorly understood. This study aimed to investigate how the morphology of cortical and subcortical brain structures differed in PE, how these morphologic differences were associated with severity measures of PE, such as intravaginal ejaculatory latency time (IELT), and how these cortical and subcortical structures were causally connected through mediation analysis. Anatomical MRI scans were acquired from 39 male participants, 23 with PE (28.78 ± 4.32 years), and 16 without PE (27.88 ± 3.65 years). We used a subcortical analysis package within FSL to perform subcortical shape segmentation and statistical analysis. The PE group was compared with the normal control (NC) group in the shapes of 15 subcortical structures with general linear models [p < 0.05, family-wise error (FWE)-corrected]. We analyzed the cortical complexity revealed by the gyrification index using the Computational Anatomy Toolbox (CAT12). Vertex-wise shape analyses revealed outward shape deformations (expansions) in the left hippocampus and bilateral thalamus. Gyrification index analyses revealed that the right orbital frontal cortex and the right nucleus accumbens had greater complexity in PE patients. The shape deformations were positively correlated with the IELTs in the NC group, while this relationship was interrupted in the PE group. PE is associated with outward deformations of the subcortical surfaces and more complexity of the cortical structures. These morphological differences may be the basis of the brain functional alterations underlying PE.

Interaction of Catechol-O-methyltransferase Val158 Met polymorphism and sex influences association of parietal intrinsic functional connectivity and immediate verbal memory.

INTRODUCTION: Sex differences modulate catechol-O-methyltransferase (COMT) genotype effect at a synaptic dopamine level, which influences brain function as well as cognitive performance. In this study, we investigated how COMT Val158 Met polymorphism and sex affect intrinsic functional connectivity and memory. METHODS: Intrinsic functional networks were extracted using independent component analysis of resting-state functional magnetic resonance imaging data from 186 healthy young COMT-genotyped participants. The association of these functional networks and memory function was tested to investigate whether the effect of COMT × sex interaction influences the association of intrinsic functional connectivity and memory performance. Quadratic curve fit estimation was used to examine the relationship between functional connectivity and speculative dopamine level among groups. RESULTS: COMT MM/MV carriers, relative to VV carriers, showed increased functional connectivity in left superior parietal lobule and right inferior frontal gyrus. Further, male MM/MV carriers showed significant higher mean functional connectivity in left inferior parietal lobule relative to male VV carriers and female MM/MV carriers, which was associated with worse immediate verbal recall performance. Additionally, the relationship between inferior parietal lobule functional connectivity and speculative dopamine level among groups fits the quadratic curve. CONCLUSIONS: These findings suggest that the interaction of COMT genotype and sex might regulate synaptic dopaminergic concentrations and influence the association of intrinsic functional connectivity and immediate verbal memory in left inferior parietal lobule.

Interaction of COMT and KIBRA modulates the association between hippocampal structure and episodic memory performance in healthy young adults.

Genetic variations of COMT and KIBRA, which were reported to be expressed in the hippocampus, have been linked to memory function. However, their interaction on the hippocampal structure remains unknown. This study aimed to explore the interaction effects of COMT rs4680 and KIBRA rs17070145 on the hippocampal subfield volumes and test their associations with hippocampus-memory relationship in 187 healthy young adults. Two-way analysis of covariance was applied to the alterations in hippocampal subfield volumes among COMT and KIBRA genotypes. Significant interaction effects of these two genes were found in the right CA1 and CA3 subfields. Among KIBRA C-allele carriers, COMT Val/Val homozygotes showed greater volume in these regions than COMT Met-allele carriers. Furthermore, the slope of the correlation between right CA1 volume and immediate recall on the California Verbal Learning Test-II (CVLT-II) (F = 4.36, p = 0.041) as well as CVLT-II delayed recall (F = 6.44, p = 0.014) were significantly different between COMT Val/Val homozygotes and Met-allele carriers, which were positive or tend to be positive in COMT Val/Val group (CVLT immediate recall, r = 0.319, p = 0.040; CVLT delayed recall, r = 0.304, p = 0.051), but absent in COMT Met-allele carriers (CVLT immediate recall, r = -0.263, p = 0.205; CVLT delayed recall, r = -0.351, p = 0.086). These findings may provide a novel insight into the genetic effects upon the hippocampal structure and suggest that the conjoint effects of COMT and KIBRA played a modulatory role in the hippocampus-episodic memory correlation.

The Impact of Spatial Normalization Strategies on the Temporal Features of the Resting-State Functional MRI: Spatial Normalization Before rs-fMRI Features Calculation May Reduce the Reliability.

Previous resting-state functional magnetic resonance imaging (rs-fMRI) studies frequently applied the spatial normalization on fMRI time series before the calculation of temporal features (here referred to as "Prenorm"). We hypothesized that calculating the rs-fMRI features, for example, functional connectivity (FC), regional homogeneity (ReHo), or amplitude of low-frequency fluctuation (ALFF) in individual space, before the spatial normalization (referred to as "Postnorm") can be an improvement to avoid artifacts and increase the results' reliability. We utilized two datasets: (1) simulated images where temporal signal-to-noise ratio (tSNR) is kept a constant and (2) an empirical fMRI dataset with 50 healthy young subjects. For simulated images, the tSNR is constant as generated in individual space but increased after Prenorm and intersubject variability of tSNR was induced. In contrast, tSNR was kept constant after Postnorm. Consistently, for empirical images, higher tSNR, ReHo, and FC (default mode network, seed in precuneus) and lower ALFF were found after Prenorm compared to those of Postnorm. Coefficient of variability of tSNR and ALFF was higher after Prenorm compared to those of Postnorm. Moreover, the significant correlation was found between simulated tSNR after Prenorm and empirical tSNR, ALFF, and ReHo after Prenorm, indicating algorithmic variation in empirical rs-fMRI features. Furthermore, comparing to Prenorm, ALFF and ReHo showed higher intraclass correlation coefficients between two serial scans after Postnorm. Our results indicated that Prenorm may induce algorithmic intersubject variability on tSNR and reduce its reliability, which also significantly affected ALFF and ReHo. We suggest using Postnorm instead of Prenorm for future rs-fMRI studies using ALFF/ReHo.

Disruptions of the olfactory and default mode networks in Alzheimer's disease.

INTRODUCTION: Olfactory deficits are prevalent in early Alzheimer's disease (AD) and are predictive of progressive memory loss and dementia. However, direct neural evidence to relate AD neurodegeneration to deficits in olfaction and memory is limited. METHODS: We combined the University of Pennsylvania Smell Identification Test (UPSIT) with olfactory functional magnetic resonance imaging (fMRI) to investigate links between neurodegeneration, the olfactory network (ON) and the default mode network (DMN) in AD. RESULTS: Behaviorally, olfactory and memory scores showed a strong positive correlation in the study cohorts. During olfactory fMRI, the ON showed reduced task-related activation and the DMN showed reduced task-related suppression in mild cognitive impairment (MCI) and AD subjects compared to age-matched cognitively normal subjects. CONCLUSIONS: The results provide in vivo evidence for selective vulnerability of ON and DMN in AD and significantly improves the viable clinical applications of olfactory testing. A network-based approach, focusing on network integrity rather than focal pathology, seems beneficial to olfactory prediction of dementia in AD.

Abnormal brain functional connectivity coupled with hypoperfusion measured by Resting-State fMRI: An additional contributing factor for cognitive impairment in patients with Alzheimer's disease.

The contribution of hypoperfusion to abnormal functional connectivity in Alzheimer's disease (AD) and mild cognitive impairment (MCI) remains unclear. In this study, we investigated the potential association between brain perfusion and functional connectivity (FC), and its effects on the cognitive impairment among AD, MCI, and normal controls (NC). One-time acquisition of resting-state functional magnetic resonance imaging (rs-fMRI) was used to study brain perfusion and FC. Compared to the NC, the perfusion in the left temporal lobe showed significantly lower in AD, and bilateral hypoperfusion in the frontal lobe showed in MCI. Using these hypoperfusion areas as seed regions, we found that FC between the left inferior temporal gyrus and medial frontal-cingulate regions in AD patients was significantly lower than that in NCs. The FC between the right medial superior frontal gyrus and left parietal lobe in MCI patients was significantly higher than that in NCs. Additionally, the FC between the right medial superior frontal gyrus and the left superior parietal gyrus were found to be correlated significantly and negatively with mini-mental state examination (MMSE) scores in MCI patients. In conclusion, hypoperfusion may affect cognitive states via abnormal FC as an additional factor contributing to cognitive impairment.

The Role of MRI Biomarkers and Their Interactions with Cognitive Status and APOE ε4 in Nondemented Elderly Subjects.

PURPOSE: (1) To investigate atrophy patterns of hippocampal subfield volume and Alzheimer's disease (AD)-signature cortical thickness in mild cognitive impairment (MCI) patients; (2) to explore the association between the neuropsychological (NP) and the brain structure in the MCI and older normal cognition group; (3) to determine whether these associations were modified by the apolipoprotein E (APOE) ε4 gene and cognitive status. METHODS: The FreeSurfer software was used for automated segmentation of hippocampal subfields and AD-signature cortical thickness for 22 MCI patients and 23 cognitive normal controls (NC). The volume, cortical thickness, and the neuropsychological scale were compared with two-sample t tests. Linear regression models were used to determine the association between the NP and the brain structure. RESULTS: Compared with the NC group, MCI patients showed a decreased volume of the left presubiculum, subiculum and right CA2_3 and CA4_DG (p < 0.05, FDR corrected). The volume of these regions was positively correlated with NP scores. Of note, these associations depended on the cognitive status but not on the APOE ε4 status. The left subiculum and presubiculum volume were positively correlated with the Montreal Cognitive Assessment (MoCA) scores only in the MCI patients. CONCLUSION: Atrophy of the hippocampal subfields may be a powerful biomarker for MCI in the Chinese population.

Subregional Structural Alterations in Hippocampus and Nucleus Accumbens Correlate with the Clinical Impairment in Patients with Alzheimer's Disease Clinical Spectrum: Parallel Combining Volume and Vertex-Based Approach.

Deep gray matter structures are associated with memory and other important functions that are impaired in Alzheimer's disease (AD) and mild cognitive impairment (MCI). However, systematic characterization of the subregional atrophy and deformations in these structures in AD and MCI still need more investigations. In this article, we combined complex volumetry- and vertex-based analysis to investigate the pattern of subregional structural alterations in deep gray matter structures and its association with global clinical scores in AD (n = 30) and MCI patients (n = 30), compared to normal controls (NCs, n = 30). Among all seven pairs of structures, the bilateral hippocampi and nucleus accumbens showed significant atrophy in AD compared with NCs (p < 0.05). But only the subregional atrophy in the dorsal-medial part of the left hippocampus, the ventral part of right hippocampus, and the left nucleus accumbens, the posterior part of the right nucleus accumbens correlated with the worse clinical scores of MMSE and MOCA (p < 0.05). Furthermore, the medial-ventral part of right thalamus significantly shrank and correlated with clinical scores without decreasing in its whole volume (p > 0.05). In conclusion, the atrophy of these four subregions in bilateral hippocampi and nucleus accumbens was associated with cognitive impairment of patients, which might be potential target regions of treatment in AD. The surface analysis could provide additional information to volume comparison in finding the early pathological progress in deep gray matter structures.