Identification of biomarkers differentiating Alzheimer's disease from other neurodegenerative diseases by integrated bioinformatic analysis and machine-learning strategies.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disease, imposing huge mental and economic burdens on patients and society. The specific molecular pathway(s) and biomarker(s) that distinguish AD from other neurodegenerative diseases and reflect the disease progression are still not well studied. Methods: Four frontal cortical datasets of AD were integrated to conduct differentially expressed genes (DEGs) and functional gene enrichment analyses. The transcriptional changes after the integrated frontal cortical datasets subtracting the cerebellar dataset of AD were further compared with frontal cortical datasets of frontotemporal dementia and Huntingdon's disease to identify AD-frontal-associated gene expression. Integrated bioinformatic analysis and machine-learning strategies were applied for screening and determining diagnostic biomarkers, which were further validated in another two frontal cortical datasets of AD by receiver operating characteristic (ROC) curves. Results: Six hundred and twenty-six DEGs were identified as AD frontal associated, including 580 downregulated genes and 46 upregulated genes. The functional enrichment analysis revealed that immune response and oxidative stress were enriched in AD patients. Decorin (DCN) and regulator of G protein signaling 1 (RGS1) were screened as diagnostic biomarkers in distinguishing AD from frontotemporal dementia and Huntingdon's disease of AD. The diagnostic effects of DCN and RGS1 for AD were further validated in another two datasets of AD: the areas under the curve (AUCs) reached 0.8148 and 0.8262 in GSE33000, and 0.8595 and 0.8675 in GSE44770. There was a better value for AD diagnosis when combining performances of DCN and RGS1 with the AUCs of 0.863 and 0.869. Further, DCN mRNA level was correlated to CDR (Clinical Dementia Rating scale) score (r = 0.5066, p = 0.0058) and Braak staging (r = 0.3348, p = 0.0549). Conclusion: DCN and RGS1 associated with the immune response may be useful biomarkers for diagnosing AD and distinguishing the disease from frontotemporal dementia and Huntingdon's disease. DCN mRNA level reflects the development of the disease.

Identification of diagnostic biomarkers in Alzheimer's disease by integrated bioinformatic analysis and machine learning strategies.

Background: Alzheimer's disease (AD) is the most prevalent form of dementia, and is becoming one of the most burdening and lethal diseases. More useful biomarkers for diagnosing AD and reflecting the disease progression are in need and of significance. Methods: The integrated bioinformatic analysis combined with machine-learning strategies was applied for exploring crucial functional pathways and identifying diagnostic biomarkers of AD. Four datasets (GSE5281, GSE131617, GSE48350, and GSE84422) with samples of AD frontal cortex are integrated as experimental datasets, and another two datasets (GSE33000 and GSE44772) with samples of AD frontal cortex were used to perform validation analyses. Functional Correlation enrichment analyses were conducted based on Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and the Reactome database to reveal AD-associated biological functions and key pathways. Four models were employed to screen the potential diagnostic biomarkers, including one bioinformatic analysis of Weighted gene co-expression network analysis (WGCNA)and three machine-learning algorithms: Least absolute shrinkage and selection operator (LASSO), support vector machine-recursive feature elimination (SVM-RFE) and random forest (RF) analysis. The correlation analysis was performed to explore the correlation between the identified biomarkers with CDR scores and Braak staging. Results: The pathways of the immune response and oxidative stress were identified as playing a crucial role during AD. Thioredoxin interacting protein (TXNIP), early growth response 1 (EGR1), and insulin-like growth factor binding protein 5 (IGFBP5) were screened as diagnostic markers of AD. The diagnostic efficacy of TXNIP, EGR1, and IGFBP5 was validated with corresponding AUCs of 0.857, 0.888, and 0.856 in dataset GSE33000, 0.867, 0.909, and 0.841 in dataset GSE44770. And the AUCs of the combination of these three biomarkers as a diagnostic tool for AD were 0.954 and 0.938 in the two verification datasets. Conclusion: The pathways of immune response and oxidative stress can play a crucial role in the pathogenesis of AD. TXNIP, EGR1, and IGFBP5 are useful biomarkers for diagnosing AD and their mRNA level may reflect the development of the disease by correlation with the CDR scores and Breaking staging.

The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice.

The ε4 allele of apolipoprotein E (APOE4) and aging are the major risk factors for Alzheimer's disease (AD). SUMOylation is intimately linked to the development of AD and the aging process. However, the SUMOylation status in APOE4 mice has not been uncovered. In this study, we investigated SENP1 and SUMOylation changes in the brains of aged APOE3 and APOE4 mice, aiming to understand their potential impact on mitochondrial metabolism and their contribution to cellular senescence in APOE4 mice. Concurrently, SUMO1-conjugated protein levels decreased, while SUMO2/3-conjugated protein levels increased relatively with the aging of APOE4 mice. This suggests that the equilibrium between the SUMOylation and deSUMOylation processes may be associated with senescence and longevity. Our findings highlight the significant roles of SENP1 and SUMOylation changes in APOE4-driven pathology and the aging process.

Comparative efficacy and acceptability of treatments for depressive symptoms in cognitive impairment: A systematic review and Bayesian network meta-analysis.

Background: Depressive symptoms play an essential role in cognition decline, while the benefit and acceptability of treatments for depressive symptoms in cognitive impairment are still unknown. Objective: To comprehensively evaluate the comparative efficacy and acceptability of treatments for depressive symptoms in cognitive impairment based on the quantitative Bayesian network meta-analysis method (NMA). Method: We searched MEDLINE, Embase, the Cochrane Library, CINAHL, and PsycINFO from inception until August 2022 to identify randomized clinical trials (RCTs) evaluating treatments for depressive symptoms in cognitive impairment. Efficacy was evaluated by the Cornell Scale for Depression in Dementia (CSDD), the Hamilton Depression Rating Scale (HDRS), and the Geriatric Depression Scale (GDS) for depression; the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfeld Agitation Inventory (CMAI) for behavior; and the Mini-Mental State Examination (MMSE) for cognition. Safety was evaluated by total adverse events (AEs), serious AEs, diarrhea, headache, and nausea. Results: In this study, 13,043 participants from 107 RCTs were included, involving 28 treatments and the discontinuation of antidepressants. On CSDD, aerobic exercise (MD -4.51, 95%CrI -8.60 to -0.37), aripiprazole (MD -1.85, 95%CrI -3.66 to -0.02), behavioral training (MD -1.14, 95%CrI -2.04 to -0.34), electrical current stimulation (MD -3.30, 95%CrI -5.94 to -0.73), massage (MD -12.67, 95%CrI -14.71 to -10.59), music therapy (MD -2.63, 95%CrI -4.72 to -0.58), and reminiscence therapy (MD -2.34, 95%CrI -3.51 to -1.25) significantly outperformed the placebo. On MMSE, cognitive stimulation therapy (MD 1.42, 95%CrI 0.49 to 2.39), electrical current stimulation (MD 4.08, 95%CrI 1.07 to 7.11), and reminiscence therapy (MD 1.31, 95%CrI 0.04 to 2.91) significantly outperformed the placebo. Additionally, no treatments showed a significantly higher risk than the placebo. Conclusion: Our NMAs indicated that non-pharmacological interventions were more efficacious and safe than pharmacological treatments for reducing depressive symptoms as well as improving cognitive impairment. Electrical current stimulation, aerobic exercise, and reminiscence therapy could be first recommended considering their beneficial performance on both depression and cognition. Hence, non-pharmacological treatments deserve more attention and extensive application and should at least be considered as an alternative or assistance in clinical settings. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021239621, identifier: CRD42021239621.

Unveiling the comparative efficacy and tolerability of comprehensive treatments for migraine: A protocol of systematic review and Bayesian network meta-analysis.

BACKGROUND: Migraine is a chronic paroxysmal incapacitating neurological disorder, which endangers the health of human worldwide ranking as the third most prevalent medical condition. There are no comprehensive estimates of treatments for migraine. We will conduct this systematic review and Bayesian network meta-analysis (NMA) to synthesis quantitative and comparative evidence on the efficacy and tolerability of all the known pharmacological and non-pharmacological interventions for migraine. METHOD: We will perform the systematic electronic search of the literature utilizing MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cumulative Index to Nursing & Allied Health (CINAHL), and PsycINFO. We will only include randomized controlled trials (RCTs) of high quality which appraise the efficacy or safety of any potential pharmacological or non-pharmacological interventions in the treatment of patients with migraine. The traditional pairwise meta-analyses will be performed to anticipate the heterogeneities and publication bias and the NMA will be conducted within a Bayesian hierarchical model framework to obtain estimates for all valuable treatments for migraine. The entire heterogeneity will be quantified by Q statistic and I2 index. Other analyses included sensitivity analyses, meta-regression, and subgroup analyses will also be conducted. The whole process will be conducted using in R-3.6.0 software. RESULTS: This study will obtain the efficacy and tolerability of all potential treatments for migraine, aiming at providing consolidated evidence to help make the best choice of interventions. The results will be published in a peer-reviewed journal. DISCUSSION: This Bayesian network meta-analysis may be the first attempt to quantitatively synthesize the efficacy and tolerability of all potential treatments for migraine. And this method can ensure us to fully utilize both the direct and indirect evidence as well as gain the comparative estimates displayed in the derived hierarchies. Besides, we have registered this protocol on the international prospective register of systematic review (PROSPERO) (CRD42020157278).

Dynamic Change of Intracellular Metabolism of Microglia Evaluated by Transcriptomics in an Alzheimer's Mouse Model.

BACKGROUND: Microglia play diverse roles in Alzheimer's disease (AD). Intracellular metabolism has been indicated an important factor in modulating the function of microglia. However, it is not clear whether the intracellular metabolism of microglia changes dynamically in different stages of AD. OBJECTIVE: To determine whether microglia intracellular metabolism changes dynamically in different stages of AD. METHODS: Microglia were extracted from APPSwe/PS1dE9 (APP/PS1) mice and wild-type littermates at 2, 4, and 8 months old by fluorescence-activated cell sorting and used for RNA-sequencing analysis and quantitative PCR. Morphologies of amyloid plaques and microglia were detected by immunofluorescence staining. RESULTS: Compared with control littermates, the microglia of APP/PS1 mice exhibited significant transcriptional changes at 2-month-old before microglia morphological alterations and the plaque formation. The changes continued drastically following age with defined morphological shift of microglia and amyloid plaque enhancement in brains. Further analysis of those genotype and age dependent transcriptomic changes revealed that differentially expressed genes were enriched in pathways related to energy metabolism. Compared with wild-type mice, there were changes of some vital genes related to glucose metabolism and lipid metabolism pathways in APP/PS1 mice at different ages. Glucose metabolism may play a major role in early activation of microglia, and lipid metabolism may be more important in later activation period. CONCLUSION: Our results showed that microglia actively participate in the pathological progress of AD. The intracellular metabolism of microglia changed significantly in different stages of AD, even preceding amyloid-ß deposition.

Comparative efficacy and safety of therapy for the behavioral and psychological symptoms of dementia: a systemic review and Bayesian network meta-analysis.

OBJECTIVE: To assess the comparative efficacy and safety of both pharmacological and non-pharmacological therapies for the behavioral and psychological symptoms of dementia, using direct and indirect evidence from randomized data. METHOD: A systematic review and Bayesian network meta-analysis was conducted on only randomized controlled trials (RCTs) of all the available interventions for BPSD. RCTs were selected from Pubmed, EMBASE, the Cochrane library, and CINAHL. The efficacy outcomes were Neuropsychiatric Inventory (NPI) and Cohen-Mansfield Agitation Inventory (CMAI). The outcomes of safety were total adverse events (AEs), diarrhea, dizziness, headache, falls, nausea, vomiting, and cerebrovascular diseases. RESULT: 146 RCTs comprising 44,873 patients with BPSD were included in this study. On NPI, aripiprazole (MD - 3.65, 95% credible interval (CrI) = - 6.92 to - 0.42), escitalopram (MD - 6.79, 95% CrI - 12.91 to - 0.60), donepezil (MD - 1.45, 95% CrI - 2.70 to - 0.20), galantamine (MD - 1.80, 95% CrI - 3.29 to - 0.32), memantine (MD - 2.14, 95% CrI - 3.46 to - 0.78), and risperidone (MD - 3.20, 95% CrI - 6.08 to - 0.31) were superior to placebo. On CMAI, aripiprazole (MD - 4.00, 95% CrI - 7.39 to - 0.54) and risperidone (MD - 2.58, 95% CrI - 5.20 to - 0.6) showed superiority to placebo. On the risk of total AEs, donepezil (OR 1.27, 95% CrI 1.07-1.50), galantamine (OR 1.91, 95% CrI 1.58-2.36), risperidone (OR 1.47, 95% CrI 1.13-1.97), and rivastigmine (OR 2.02, 95% CrI 1.53-2.70) owned higher risk than placebo. CONCLUSION: Pharmacological therapies should be the first choice for BPSD. Aripiprazole, haloperidol, quetiapine, and risperidone of antipsychotics showed the significant efficacy, while memantine, galantine, and donepezil may provide the modest effectiveness. The safety of all was thought to be acceptable.

Comparative efficacy and safety of cognitive enhancers for treating vascular cognitive impairment: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To assess and compare the clinical efficacy and safety of cognitive enhancers (donepezil, galantamine, rivastigmine, and memantine) on cognition, behavior, function, and global status in patients with vascular cognitive impairment. DATA SOURCES: The initial literature search was performed with PubMed, EMBASE, the Cochrane Methodology Register, the Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing & Allied Health (CINAHL) from inception to January 2018 for studies regarding donepezil, galantamine, rivastigmine, and memantine for treatment of vascular cognitive impairment. DATA SELECTION: Randomized controlled trials on donepezil, galantamine, rivastigmine, and memantine as monotherapy in the treatment of vascular cognitive impairment were included. A Bayesian network meta-analysis was conducted. OUTCOME MEASURES: Efficacy was assessed by changes in scores of the Alzheimer's Disease Assessment Scale, cognitive subscale, Mini-Mental State Examination, Neuropsychiatric Inventory scores and Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input, Activities of Daily Living, the Clinical Dementia Rating scale. Safety was evaluated by mortality, total adverse events (TAEs), serious adverse events (SAEs), nausea, vomiting. diarrhea, or cerebrovascular accidents (CVAs). RESULTS: After screening 1717 citations, 12 randomized controlled trials were included. Donepezil and rivastigmine (mean difference (e) = -0.77, 95% confidence interval (CI): 0.25-1.32; MD = 1.05, 95% CI: 0.18-1.79) were significantly more effective than placebo in reducing Mini-Mental State Examination scores. Donepezil, galantamine, and memantine (MD = -1.30, 95% CI: -2.27 to -0.42; MD = -1.67, 95% CI: -3.36 to -0.06; MD = -2.27, 95% CI: -3.91 to -0.53) showed superior benefits on the Alzheimer's Disease Assessment Scale-cognitive scores compared with placebo. Memantine (MD = 2.71, 95% CI: 1.05-7.29) improved global status (Clinician's Interview-Based Impression of Change Scale Plus Caregiver's Input) more than the placebo. Safety results revealed that donepezil 10 mg (odds ratio (OR) = 3.04, 95% CI: 1.86-5.41) contributed to higer risk of adverse events than placebo. Galantamine (OR = 5.64, 95% CI: 1.31-26.71) increased the risk of nausea. Rivastigmine (OR = 16.80, 95% CI: 1.78-319.26) increased the risk of vomiting. No agents displayed a significant risk of serious adverse events, mortality, cerebrovascular accidents, or diarrhea. CONCLUSION: We found significant efficacy of donepezil, galantamine, and memantine on cognition. Memantine can provide significant efficacy in global status. They are all safe and well tolerated.