Validation and refinement of a predictive nomogram using artificial intelligence: assessing in-hospital mortality in patients with large hemispheric cerebral infarction.

Background: Large Hemispheric Infarction (LHI) poses significant mortality and morbidity risks, necessitating predictive models for in-hospital mortality. Previous studies have explored LHI progression to malignant cerebral edema (MCE) but have not comprehensively addressed in-hospital mortality risk, especially in non-decompressive hemicraniectomy (DHC) patients. Methods: Demographic, clinical, risk factor, and laboratory data were gathered. The population was randomly divided into Development and Validation Groups at a 3:1 ratio, with no statistically significant differences observed. Variable selection utilized the Bonferroni-corrected Boruta technique (p < 0.01). Logistic Regression retained essential variables, leading to the development of a nomogram. ROC and DCA curves were generated, and calibration was conducted based on the Validation Group. Results: This study included 314 patients with acute anterior-circulating LHI, with 29.6% in the Death group (n = 93). Significant variables, including Glasgow Coma Score, Collateral Score, NLR, Ventilation, Non-MCA territorial involvement, and Midline Shift, were identified through the Boruta algorithm. The final Logistic Regression model led to a nomogram creation, exhibiting excellent discriminative capacity. Calibration curves in the Validation Group showed a high degree of conformity with actual observations. DCA curve analysis indicated substantial clinical net benefit within the 5 to 85% threshold range. Conclusion: We have utilized NIHSS score, Collateral Score, NLR, mechanical ventilation, non-MCA territorial involvement, and midline shift to develop a highly accurate, user-friendly nomogram for predicting in-hospital mortality in LHI patients. This nomogram serves as valuable reference material for future studies on LHI patient prognosis and mortality prevention, while addressing previous research limitations.

Collaborative Care Model Based Telerehabilitation Exercise Training Program for Acute Stroke Patients in China: A Randomized Controlled Trial.

BACKGROUND: Early rehabilitation has been proved very important for stroke patients. However, the effective model of transitioning from early in-hospital rehabilitation to discharge rehabilitation using the collaborative remote rehabilitation nursing model has not been thoroughly studied. OBJECTIVE: To explore the feasibility and effectiveness of collaborative care model based telerehabilitation exercise training for acute stroke patients. METHODS: A randomized controlled clinical trial was conducted. Patients were recruited and randomly divided into intervention and control group. Both groups were given regular treatment and acute rehabilitation nursing instructions during hospitalization. The control group was followed by regular telephone follow-up after discharge. The intervention group received Internet-based remote rehabilitation project after discharge. Motor function, balance ability and quality of life were measured at the day of discharge, the 4th week, 8th week and 12th week after patients were discharged. The CONSORT checklist was used to check the procedure. RESULTS: A total of 61 patients completed the study, 30 cases in the intervention group and 31 cases in the control group. Both groups were significantly improved in terms of motor function and quality of life, but the intervention group showed greater improvement in Fugl-Meyer Motor Function Assessment (intervention group = 83.70 ± 4.44, control group = 75.29 ± 2.89), Berg Balance Scale (intervention group = 43.13 ± 2.32, control group = 38.29 ± 2.70) and Stroke-Specific Quality of Life Scale (intervention group = 190.57 ± 5.09, control group = 175.90 ± 5.78). Group-time interaction was significant in motor function and quality of life. CONCLUSION: Collaborative care model based telerehabilitation exercise training program can safely and effectively improve the recovery of motor function and improve the quality of life in patients with stroke.

Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly.

The apolipoprotein E (APOE) ε4 and ε2 alleles are acknowledged genetic factors modulating Alzheimer's disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM-related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE ε2, ε3, and ε4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 ε2 carriers, 44 ε3 homozygotes, and 49 ε4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the ε3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the ε4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the ε2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the ε4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles.

FTO is involved in Alzheimer's disease by targeting TSC1-mTOR-Tau signaling.

Diabetes and obesity are commonly associated with Alzheimer's disease (AD). Accumulating evidence show that insulin signaling defects are protentional upstream driver of AD. However, the mechanism by which diabetes and insulin signaling defects contribute to AD remains unknown. Here we show that Fat mass and obesity-associated protein (FTO) is involved the insulin defects-associated AD. Defective insulin signaling in diabetes and obesity in human and mice activated Fto in the brain tissues. Lentivirus-mediated knockdown of Fto reduced the phosphorylation of Tau protein whereas overexpression of FTO promoted the level of phosphorylated Tau in neurons. Mechanism study demonstrated that FTO activated the phosphorylation of Tau in a mTOR-dependent manner because FTO activated mTOR and its downstream signaling and rapamycin blocked FTO-mediated phosphorylation of Tau. FTO promoted the activation of mTOR by increasing the mRNA level of TSC1 but not TSC2, the upstream inhibitor of mTOR. Finally, we found that conditional knockout of Fto in the neurons reduced the cognitive deficits in 3xTg AD mice. Collectively, our evidence demonstrated that FTO is critically involved in insulin defects-related AD.

APOE Genotype Effects on Intrinsic Brain Network Connectivity in Patients with Amnestic Mild Cognitive Impairment.

Whether and how the apolipoprotein E (APOE) ε4 genotype specifically modulates brain network connectivity in patients with amnestic mild cognitive impairment (aMCI) remain largely unknown. Here, we employed resting-state ('task-free') functional MRI and network centrality approaches to investigate local (degree centrality, DC) and global (eigenvector centrality, EC) functional integrity in the whole-brain connectome in 156 older adults, including 66 aMCI patients (27 ε4-carriers and 39 non-carriers) and 90 healthy controls (45 ε4-carriers and 45 non-carriers). We observed diagnosis-by-genotype interactions on DC in the left superior/middle frontal gyrus, right middle temporal gyrus and cerebellum, with higher values in the ε4-carriers than non-carriers in the aMCI group. We further observed diagnosis-by-genotype interactions on EC, with higher values in the right middle temporal gyrus but lower values in the medial parts of default-mode network in the ε4-carriers than non-carriers in the aMCI group. Notably, these genotype differences in DC or EC were absent in the control group. Finally, the network connectivity DC values were negatively correlated with cognitive performance in the aMCI ε4-carriers. Our findings suggest that the APOE genotype selectively modulates the functional integration of brain networks in patients with aMCI, thus providing important insight into the gene-connectome interaction in this disease.

Opposite Neural Trajectories of Apolipoprotein E ϵ4 and ϵ2 Alleles with Aging Associated with Different Risks of Alzheimer's Disease.

The apolipoprotein E (APOE) ϵ4 allele is a confirmed genetic risk factor and the APOE ϵ2 allele is a protective factor related to late-onset Alzheimer's disease (AD). Intriguingly, recent studies demonstrated similar brain function alterations between APOE ϵ2 and ϵ4 alleles, despite their opposite susceptibilities to AD. To address this apparent discrepancy, we recruited 129 cognitively normal elderly subjects, including 36 ϵ2 carriers, 44 ϵ3 homozygotes, and 49 ϵ4 carriers. All subjects underwent resting-state functional MRI scans. We hypothesized that aging could influence the APOE ϵ2 and ϵ4 allele effects that contribute to their appropriate AD risks differently. Using the stepwise regression analysis, we demonstrated that although both ϵ2 and ϵ4 carriers showed decreased functional connectivity (FC) compared with ϵ3 homozygotes, they have opposite aging trajectories in the default mode network-primarily in the bilateral anterior cingulate cortex. As age increased, ϵ2 carriers showed elevated FC, whereas ϵ4 carriers exhibited decreased FC. Behaviorally, the altered DMN FC positively correlated with information processing speed in both ϵ2 and ϵ4 carriers. It is suggested that the opposite aging trajectories between APOE ϵ2 and ϵ4 alleles in the DMN may reflect the antagonistic pleiotropic properties and associate with their different AD risks.

Genetics pathway-based imaging approaches in Chinese Han population with Alzheimer's disease risk.

The tau hypothesis has been raised with regard to the pathophysiology of Alzheimer's disease (AD). Mild cognitive impairment (MCI) is associated with a high risk for developing AD. However, no study has directly examined the brain topological alterations based on combined effects of tau protein pathway genes in MCI population. Forty-three patients with MCI and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) in Chinese Han, and a tau protein pathway-based imaging approaches (7 candidate genes: 17 SNPs) were used to investigate changes in the topological organisation of brain activation associated with MCI. Impaired regional activation is related to tau protein pathway genes (5/7 candidate genes) in patients with MCI and likely in topologically convergent and divergent functional alterations patterns associated with genes, and combined effects of tau protein pathway genes disrupt the topological architecture of cortico-cerebellar loops. The associations between the loops and behaviours further suggest that tau protein pathway genes do play a significant role in non-episodic memory impairment. Tau pathway-based imaging approaches might strengthen the credibility in imaging genetic associations and generate pathway frameworks that might provide powerful new insights into the neural mechanisms that underlie MCI.

State-based functional connectivity changes associate with cognitive decline in amnestic mild cognitive impairment subjects.

Episodic memory (EM) dysfunction is a central characteristic of amnestic mild cognitive impairment (aMCI) subjects, and has a high risk of converting to Alzheimer's disease (AD). However, it is unknown how the EM network is modulated when a situation is switched. Twenty-six aMCI and twenty-two cognitively normal (CN) subjects were enrolled in this study. All of the subjects completed multi-dimensional neuropsychological tests and underwent functional magnetic resonance imaging scans during a resting-state and an episodic memory retrieval task state. The EM network was constructed using a seed-based functional connectivity (FC) approach. AMCI subjects showed poorer cognitive performances in the episodic memory and executive function. We demonstrated that connectivity of the left posterior parahippocampal gyrus (LpPHG) connected to the left ventral medial prefrontal cortex and the right postcentral gyrus (RPCG) was significantly decreased in aMCI subjects compared to CN subjects. Meanwhile, there was increased connectivity of the LpPHG to the right dorsal medial prefrontal cortex (RDMPFC), RPCG, left inferior parietal cortex, and bilateral superior parietal lobe in all of the subjects that changed from a resting-state to a task-state. Interestingly, the changed LpPHG-RDMPFC connectivity strength was significantly correlated with EM scores and executive function in the aMCI subjects. As a result, general brain regions are functionally organized and integrated into the EM network, and this strongly suggests that more cognitive resources are mobilized to meet the challenge of cognitive demand in the task state. These findings extend our understanding of the underlying mechanisms of EM deficits in aMCI subjects.

The association between TOMM40 gene polymorphism and spontaneous brain activity in amnestic mild cognitive impairment.

The outer mitochondria membrane 40 homolog (TOMM40) is thought to be involved in the mitochondrial function and to influence the susceptibility for the development of AD. To determine whether TOMM40 rs157581 polymorphism is a plausible modulator of spontaneous brain activity in amnestic mild cognitive impairment (aMCI) patients, 46 aMCI subjects and 21 healthy controls were recruited and explored. Each individual was firstly genotyped for TOMM40 rs157581 and was further assessed by resting-state functional MRI to evaluate regional brain activity using amplitude low-frequency fluctuation analysis (ALFF). aMCI patients showed decreased ALFF in the left inferior frontal gyrus and insula, and increased ALFF in right posterior cingulate, lingual gyrus and calcarine sulcus. A significant difference in the interaction of "groups × genotypes" was observed in the bilateral superior frontal gyrus, bilateral lingual gyrus, right calcarine sulcus and left cerebellum. These results demonstrated a pattern of change in ALFF values, in which increased and subsequently decreased ALFF values in parallel with the progression of aMCI symptoms. The present study shows for the first time that TOMM40 rs157581 polymorphism may modulate regional spontaneous brain activity and related to the progression of aMCI.

Association of the interleukin 1 beta gene and brain spontaneous activity in amnestic mild cognitive impairment.

PURPOSE: The inflammatory response has been associated with the pathogenesis of Alzheimer's disease (AD). The purpose of this study is to determine whether the rs1143627 polymorphism of the interleukin-1 beta (IL-1ß) gene moderates functional magnetic resonance imaging (fMRI)-measured brain regional activity in amnestic mild cognitive impairment (aMCI). METHODS: Eighty older participants (47 with aMCI and 33 healthy controls) were recruited for this study. All of the participants were genotyped for variant rs1143627 in the IL1B gene and were scanned using resting-state fMRI. Brain activity was assessed by amplitude of low-frequency fluctuation (ALFF). RESULTS: aMCI patients had abnormal ALFF in many brain regions, including decreases in the inferior frontal gyrus, the superior temporal lobe and the middle temporal lobe, and increases in the occipital cortex (calcarine), parietal cortex (Pcu) and cerebellar cortex. The regions associated with an interaction of group X genotypes of rs1143627 C/T were the parietal cortex (left Pcu), frontal cortex (left superior, middle, and medial gyrus, right anterior cingulum), occipital cortex (left middle lobe, left cuneus) and the bilateral posterior lobes of the cerebellum. Regarding the behavioral significance, there were significant correlations between ALFF in different regions of the brain and with the cognitive scores of each genotype group. CONCLUSIONS: The present study provided evidence that aMCI patients had abnormal ALFF in many brain regions. Specifically, the rs1143627 C/T polymorphism of the IL1B gene may modulate regional spontaneous brain activity in aMCI patients.

Association study of candidate gene polymorphisms with amnestic mild cognitive impairment in a Chinese population.

To investigate the relationship between amnestic mild cognitive impairment (aMCI) and candidate gene polymorphisms in a Chinese population, 116 aMCI patients and 93 normal controls were recruited. Multi-dimensional neuropsychological tests were used to extensively assess the cognitive functions of the subjects. MassARRAY and iPLEX systems were used to measure candidate single nucleotide polymorohisms (SNPs) and analyse allelic, genotypic or haplotypic distributions. The scores of the neuropsychological tests were significantly lower for the aMCI patients than for the normal controls. The distributions of SNPs relating to the amyloid cascade hypothesis (TOMM40 rs157581 G and TOMM40 rs2075650 G), to the cholesterol metabolism hypothesis (ApoE rs429358 C, LDLR rs11668477 G and CH25H rs7091822 T and PLAU rs2227564 CT) and to the tau hypothesis (MAPT/STH rs242562 GG) in aMCI were significantly different than those in normal controls. Interactions were also found in aMCI amongst SNPs in LDLR rs11668477, PLAU rs2227564, and TOMM40 rs157581, between SNPs in TOMM40 rs157580 and BACE2 rs9975138. The study suggests that aMCI is characterised by memory impairment and associated with SNPs in three systems relating to the pathogenesis of AD--those of the amyloid cascade, tau and cholesterol metabolism pathways. Interactions were also observed between genes in the amyloid pathway and between the amyloid and cholesterol pathways.

Association of a GSK-3ß polymorphism with brain resting-state function in amnestic-type mild cognitive impairment.

The glycogen synthase kinase-3ß (GSK-3ß) gene has been implicated in Alzheimer's disease (AD). Polymorphisms in this gene are plausible modulators of brain function. However, little is known about the potential role of the GSK-3ß rs334558 polymorphism, which has been associated with amnestic mild cognitive impairment (aMCI), which is itself associated with a high risk of AD. In this study, 43 aMCI patients and 30 healthy controls underwent resting-state functional magnetic resonance imaging, and their GSK-3ß rs334558 genotypes were evaluated to determine the effect of the risk variant on regional brain activity and functional networks in these subjects. Then, gene-brain-behavior relationships were examined. Compared with the controls, aMCI subjects with the higher risk T allele had more deficits in regional activation of the right superior frontal gyrus (rSFG), while a higher functional connectivity of the rSFG was observed in TT/CT carriers. Further correlative analyses revealed that the increase in rSFG connectivity was robustly positively correlated with non-memory performance in aMCI GSK-3ß rs334558 TT/CT carriers. Our findings are the first to show that a clinically significant proportion of resting-state brain function variation in aMCI patients may be explained by genetic variation at the GSK-3ßrs334558 locus in ways that are distinguishable from controls.

Altered self-referential network in resting-state amnestic type mild cognitive impairment.

INTRODUCTION: Impaired capacity for self-reference has been observed in amnestic mild cognitive impairment (aMCI) subjects who are thought to be the likely to develop into clinical Alzheimer's disease (AD). The altered pattern of self-referencing network (SRN) is not yet well understood in aMCI subjects particularly in resting state, and little is known about the relationship between SRN and other resting-state networks in aMCI subjects. METHODS: The study was designed to administer longitudinal resting-state functional magnetic resonance imaging (fMRI) scanning to 26 aMCI subjects and 18 matched healthy controls. Independent component analysis was used to separate SRN, and a further cross-correlation approach was recruited to explore the relationship between SRN and other resting-state networks. RESULTS: Compared to controls, selective changes of SRN regarding to the increased functional connectivity between ventromedial prefrontal cortex/medial orbital prefrontal cortex/gyrus rectus and the mean time series of SRN at baseline in aMCI, while these functional connections were associated with more extent of longitudinal diminish after follow up in the same subjects. In addition, greater decreased connectivity relationship between SRN and default mode network was observed in aMCI subjects. CONCLUSIONS: Altered patterns of resting-state SRN were firstly explored in aMCI subjects, and it could help guide subsequent investigations designed to specify the precise functional implications of SRN in the progression of aMCI.

Specifically progressive deficits of brain functional marker in amnestic type mild cognitive impairment.

BACKGROUND: Deficits of the default mode network (DMN) have been demonstrated in subjects with amnestic type mild cognitive impairment (aMCI) who have a high risk of developing Alzheimer's disease (AD). However, no longitudinal study of this network has been reported in aMCI. Identifying links between development of DMN and aMCI progression would be of considerable value in understanding brain changes underpinning aMCI and determining risk of conversion to AD. METHODOLOGY/PRINCIPAL FINDINGS: Resting-state fMRI was acquired in aMCI subjects (n = 26) and controls (n = 18) at baseline and after approximately 20 months follow up. Independent component analysis was used to isolate the DMN in each participant. Differences in DMN between aMCI and controls were examined at baseline, and subsequent changes between baseline and follow-up were also assessed in the groups. Posterior cingulate cortex/precuneus (PCC/PCu) hyper-functional connectivity was observed at baseline in aMCI subjects, while a substantial decrement of these connections was evident at follow-up in aMCI subjects, compared to matched controls. Specifically, PCC/PCu dysfunction was positively related to the impairments of episodic memory from baseline to follow up in aMCI group. CONCLUSIONS/SIGNIFICANCE: The patterns of longitudinal deficits of DMN may assist investigators to identify and monitor the development of aMCI.

Mapping the altered patterns of cerebellar resting-state function in longitudinal amnestic mild cognitive impairment patients.

The cerebellum is known to be a relatively well preserved structure, but subtle alterations may occur early in the evolution of Alzheimer's disease (AD). Amnestic mild cognitive impairment (aMCI) patients appear to be particularly vulnerable to AD. However, little is currently known whether altered patterns of cerebellar function occur in aMCI patients. 26 aMCI patients and 18 well-matched healthy controls underwent a baseline resting-state functional magnetic resonance imaging (fMRI) scan. After a mean follow-up period of 20 months, the subjects who successfully completed baseline fMRI scans underwent a further follow-up scan, while spontaneous activation and functional connectivity of the cerebellum were explored by using resting-state fMRI. Compared to controls, increased amplitude of low frequency fluctuation of the posterior cerebellar lobe may contribute to the underlying mechanisms affected, while greater decreased functional connections to the posterior cerebellar lobe were identified in the longitudinal study of aMCI patients. This suggests that abnormal functional connectivity of the cerebellum may offer a more sensitive and possibly preferred index of functional disturbance than regional activity measures in aMCI patients. The cerebellum may be partly related to the underlying mechanisms of aMCI, and it could help guide subsequent investigations designed to specify the precise functional role of cerebellum in aMCI patients.

Abnormal whole-brain functional connection in amnestic mild cognitive impairment patients.

Amnestic mild cognitive impairment (aMCI) patients are thought to be particularly vulnerable to convert to clinical AD where functional disconnection is a major feature of the cortical neuropathology. However, the presence and extent of whole-brain connectivity disturbances is largely unknown in aMCI patients. Twenty-six aMCI patients and eighteen matched healthy subjects were evaluated at baseline and at mean 20 months follow up. Temporal correlations between spatially distinct regions were evaluated by using longitudinal resting-state fMRI. Compared to normal aging controls, patterns of abnormal interregional correlations in widely dispersed brain areas were identified in the patients, which also changed with disease progression. These disturbances were found particularly in subcortical regions and frontal cortex. Importantly, significantly decreased negative functional connection may be specifically associated with the development of aMCI patients. This suggests a compensatory mechanism is underway where local processing deficits are offset by recruitment of more dispersed cortical regions. In addition, the presence of this increased connectivity is seen to eventually weaken with disease progression. The results suggest that patterns of whole-brain functional connection may be a useful risk marker for conversion to AD in aMCI patients.

Aberrant hippocampal subregion networks associated with the classifications of aMCI subjects: a longitudinal resting-state study.

BACKGROUND: Altered hippocampal structure and function is a valuable indicator of possible conversion from amnestic type mild cognitive impairment (aMCI) to Alzheimer's disease (AD). However, little is known about the disrupted functional connectivity of hippocampus subregional networks in aMCI subjects. METHODOLOGY/PRINCIPAL FINDINGS: aMCI group-1 (n=26) and controls group-1 (n=18) underwent baseline and after approximately 20 months follow up resting-state fMRI scans. Integrity of distributed functional connectivity networks incorporating six hippocampal subregions (i.e. cornu ammonis, dentate gyrus and subicular complex, bilaterally) was then explored over time and comparisons made between groups. The ability of these extent longitudinal changes to separate unrelated groups of 30 subjects (aMCI-converters, n=6; aMCI group-2, n=12; controls group-2, n=12) were further assessed. Six longitudinal hippocampus subregional functional connectivity networks showed similar changes in aMCI subjects over time, which were mainly associated with medial frontal gyrus, lateral temporal cortex, insula, posterior cingulate cortex (PCC) and cerebellum. However, the disconnection of hippocampal subregions and PCC may be a key factor of impaired episodic memory in aMCI, and the functional index of these longitudinal changes allowed well classifying independent samples of aMCI converters from non-converters (sensitivity was 83.3%, specificity was 83.3%) and controls (sensitivity was 83.3%, specificity was 91.7%). CONCLUSIONS/SIGNIFICANCE: It demonstrated that the functional changes in resting-state hippocampus subregional networks could be an important and early indicator for dysfunction that may be particularly relevant to early stage changes and progression of aMCI subjects.