Value For Alzheimer's Disease Research Articles

Identification of immunogenic cell death-related genes involved in Alzheimer’s disease

Alzheimer's disease (AD) is the leading cause of dementia worldwide, with recent studies highlighting the potential role of immunogenic cell death (ICD) in the pathogenesis of this neurodegenerative disorder. A total of 52 healthy controls and 64 patients with AD were included. Compared to the controls, the patients with AD exhibited 2392 differentially expressed genes (DEGs), of which 1015 and 1377 were upregulated and downregulated genes, respectively. Among them, nine common genes were identified by intersecting the AD-related module genes with the DEGs and ICD-associated genes. Gene ontology (GO)analysis further revealed “positive regulation of cytokine production” as the most significant term. Moreover, the enriched molecular functions were primarily related to the inflammatory body complex, while the overlapping genes were significantly enriched in lipopolysaccharide binding. Kyoto encyclopedia of genes and genomes (KEGG) analysis also indicated that these overlapping genes were mainly enriched in immunity, inflammation, and lipid metabolism pathways. Furthermore, the following four hub genes were detected using machine learning algorithms: P2RX7, HSP90AA1, NT5E, and NLRP3. These genes demonstrated significant differences in expression between the AD and healthy control groups (P < 0.05). Additionally, the area under the curve values of these four genes were all > 0.7, indicating their potential diagnostic value for AD. We further validated the protein levels of these four genes in the hippocampus of 3xTg-AD and C57BL/6J mice, showing P2RX7 and HSP90AA1 expression levels consistent with the previously analyzed trends. Finally, the single-sample gene set enrichment analysis (ssGSEA) algorithm provided additional evidence by demonstrating the crucial role of immune cell infiltration and its link with the hub genes in AD progression. Our study results suggest that ICD-mediated elevation of HSP90AA1 and P2RX7 levels and the resulting induction of tau hyperphosphorylation and neuroinflammation are vital in the AD pathogenic mechanism.

Is blood pTau a reliable indicator of the CSF status? A narrative review.

The identification of biomarkers for the early diagnosis of Alzheimer's disease (AD) is a crucial goal of the current research. Blood biomarkers are less invasive, easier to obtain and achievable by a cheaper means than those on cerebrospinal fluid (CSF) and significantly more economic than functional neuroimaging investigations; thus, a great interest is focused on blood isoforms of the phosphorylated Tau protein (pTau), indicators of ongoing tau pathology (i.e. neurofibrillary tangles, NFTs, an AD neuropathological hallmark) in the central nervous system (CNS). However, current data often highlight discordant results about the ability of blood pTau to predict CSF status. We aim to synthesise the studies that compared pTau levels on CSF and blood to assess their correlation in AD continuum. We performed a narrative literature review using, first, MEDLINE (via PubMed) by means of MeSH terms, and then, we expanded the reults by means of Scopus and Web of Sciences to be as inclusive as possible. Finally, we added work following an expert opinion. Only papers presenting original data on pTau values on both blood and CSF were included. The 33 included studies show an extreme heterogeneity in terms of pTau isoform (pTau181, 217 and 231), laboratory methods, diagnostic criteria and choice of comparison groups. Most studies evaluated plasma pTau181, while data on other isoforms and serum are scarcer. Most papers identify a correlation between CSF and blood measurements. Furthermore, even when not specified, it is often possible to show an increase in blood pTau values as AD-related damage progresses in the AD continuum and higher values in AD than in other neurodegenerative diseases. Notably, plasma pTau231 seems the first biomarker to look for in the earliest and pre-clinical stages, quickly followed by pTau217 and, finally, by pTau181. Our results encourage the use of blood pTau for the early identification of patients with AD continuum.

In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [3H]1 provided KD (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [18F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Binding assays with [3H]21 provided KD (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [18F]21 demonstrated a higher brain penetration than [18F]1 and rapid clearance from normal brain tissues. We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.

Bioinformatics analysis and prediction of Alzheimer's disease and alcohol dependence based on Ferroptosis-related genes.

Alzheimer's disease (AD) is a neurodegenerative disease whose origins have not been universally accepted. Numerous studies have demonstrated the relationship between AD and alcohol dependence; however, few studies have combined the origins of AD, alcohol dependence, and programmed cell death (PCD) to analyze the mechanistic relationship between the development of this pair of diseases. We demonstrated in previous studies the relationship between psychiatric disorders and PCD, and in the same concerning neurodegeneration-related AD, we found an interesting link with the Ferroptosis pathway. In the present study, we explored the bioinformatic interactions between AD, alcohol dependence, and Ferroptosis and tried to elucidate and predict the development of AD from this aspect. We selected the Alzheimer's disease dataset GSE118553 and alcohol dependence dataset GSE44456 from the Gene Expression Omnibus (GEO) database. Ferroptosis-related genes were gathered through Gene Set Enrichment Analysis (GSEA), Kyoto Encyclopedia of Genes and Genomes (KEGG), and relevant literature, resulting in a total of 88 related genes. For the AD and alcohol dependence datasets, we conducted Limma analysis to identify differentially expressed genes (DEGs) and performed functional enrichment analysis on the intersection set. Furthermore, we used ferroptosis-related genes and the DEGs to perform machine learning crossover analysis, employing Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify candidate immune-related central genes. This analysis was also used to construct protein-protein interaction networks (PPI) and artificial neural networks (ANN), as well as to plot receiver operating characteristic (ROC) curves for diagnosing AD and alcohol dependence. We analyzed immune cell infiltration to explore the role of immune cell dysregulation in AD. Subsequently, we conducted consensus clustering analysis of AD using three relevant candidate gene models and examined the immune microenvironment and functional pathways between different subgroups. Finally, we generated a network of gene-gene interactions and miRNA-gene interactions using Networkanalyst. The crossover of AD and alcohol dependence DEG contains 278 genes, and functional enrichment analysis showed that both AD and alcohol dependence were strongly correlated with Ferroptosis, and then crossed them with Ferroptosis-related genes to obtain seven genes. Three candidate genes were finally identified by machine learning to build a diagnostic prediction model. After validation by ANN and PPI analysis, ROC curves were plotted to assess the diagnostic value of AD and alcohol dependence. The results showed a high diagnostic value of the predictive model. In the immune infiltration analysis, functional metabolism and immune microenvironment of AD patients were significantly associated with Ferroptosis. Finally, analysis of target genes and miRNA-gene interaction networks showed that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4. We obtained a diagnostic prediction model with good effect by comprehensive analysis, and validation of ROC in AD and alcohol dependence data sets showed good diagnostic, predictive value for both AD (AUC 0. 75, CI 0.91-0.60), and alcohol dependence (AUC 0.81, CI 0.95-0.68). In the consensus clustering grouping, we identified variability in the metabolic and immune microenvironment between subgroups as a likely cause of the different prognosis, which was all related to Ferroptosis function. Finally, we discovered that hsa-mir-34a-5p and has-mir-106b-5p could simultaneously regulate the expression of both CYBB and ACSL4.

Banks of the Superior Temporal Sulcus in Alzheimer's Disease: A Pilot Quantitative Susceptibility Mapping Study.

Brain iron homeostasis is disrupted in neurodegeneration and areas of iron overload partially overlap with regions of amyloid and tau burden in Alzheimer's disease (AD). Previous studies demonstrated alterations in brain iron accumulation in AD using quantitative susceptibility mapping (QSM). Here, we investigate brain alterations of QSM values in AD and non-AD patients as compared to healthy controls (HC) in the superior temporal sulcus and its banks (BANKSSTS), one of the top AD-affected regions. Thirty-four patients who underwent brain MRI including a multi-echo gradient-echo sequence were subdivided into AD (n = 19) and non-AD (n = 15) groups according to their clinical profile, CSF (Aβ42/40) and/or amyloid-PET status. Ten HC were also included. QSM values were extracted from left and right BANKSSTS and compared among groups. Correlation and binomial regression analyses between QSM values and CSF-AD biomarkers were conducted. QSM in left BANKSSTS was significantly different among groups (p = 0.003, H = 11.40), being higher in AD. QSM values in left BANKSSTS were correlated with Aβ42 (rho -0.55, p = 0.005), Aβ42/40 (rho -0.66, p < 0.001), pTau (rho 0.63, p < 0.001), tTau (rho 0.56, p = 0.005), tTau/Aβ42 (rho 0.68, p < 0.001) and pTau/Aβ42 (rho 0.71, p < 0.001). No correlations between QSM values and amyloid-PET SUVR in the left BANKSSTS were found. QSM values in left BANKSSTS showed good accuracy in discriminating AD (AUC = 0.80, CI95% [0.66-0.93]). Higher QSM values were independent predictors of Aβ42 (B = 0.63, p = 0.032), Aβ42/40 (B = 0.81, p = 0.028), pTau (B = 0.96, p = 0.046), tTau (B = 0.55, p = 0.027), and tTau/Aβ42 (B = 1.13, p = 0.042) positivity. Our preliminary data support the potential role of increased QSM values in the left BANKSSTS as an auxiliary imaging biomarker in AD diagnosis.

Plasma tau and neurofilament light chain as biomarkers of Alzheimer's disease and their relation to cognitive functions.

Alzheimer's disease (AD) dementia is the most frequent cause of neurodegenerative dementia. The cognitive and behavioral symptoms associated with this disorder often have overlapping characteristics, potentially resulting in delayed diagnosis or misdiagnosis. This study aimed to assess the level of peripheral blood neurofilament light chain (NfL) and total tau (t-tau) protein in AD patients and investigate their relationship with cognitive impairment. The study included 80 participants of both sexes between the ages of 60 to 85 years. The participants were divided into two groups, consisting of 40 individuals in the control group (mean age 75±6.6 years) who had no cognitive or functional impairments and 40 AD patients (mean age 74.98±5.03 years). This study utilized the DSM-5 diagnostic criteria for major or mild neurocognitive disorder attributed to Alzheimer's disease (AD). The clinical and biochemical features of all participants were documented, and the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-cog) scores were evaluated. Sandwich ELISA was employed to determine serum NfL and t-tau protein levels. The median serum NfL and t-tau protein levels in AD patients were significantly higher than those of the controls (47.84 pg/ml versus 17.66 pg/ml and 12.05 pg/ml versus 11.13 pg/ml, respectively). Age was positively correlated with NfL, t-tau levels, and ADAS-cog. Although elevated NfL and t-tau protein levels may play a role in disease progression, their diagnostic value for AD was limited.

The Inflammatory Gene PYCARD of the Entorhinal Cortex as an Early Diagnostic Target for Alzheimer's Disease.

The incidence of Alzheimer's disease (AD) is increasing year by year, which brings great challenges to human health. However, the pathogenesis of AD is still unclear, and it lacks early diagnostic targets. The entorhinal cortex (EC) is a key brain region for the occurrence of AD neurodegeneration, and neuroinflammation plays a significant role in EC degeneration in AD. This study aimed to reveal the close relationship between inflammation-related genes in the EC and AD by detecting key differentially expressed genes (DEGs) via gene function enrichment pathway analysis. GSE4757 and GSE21779 gene expression profiles of AD were downloaded from the Gene Expression Omnibus (GEO) database. R language was used for the standardization and differential analysis of DEGs. Then, significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed to predict the potential biological functions of the DEGs. Finally, the significant expressions of identified DEGs were verified, and the therapeutic values were detected by a receiver operating characteristic (ROC) curve. The results showed that eight up-regulated genes (SLC22A2, ITGB2-AS1, NIT1, FGF14-AS2, SEMA3E, PYCARD, PRORY, ADIRF) and two down-regulated genes (AKAIN1, TRMT2B) may have a potential diagnostic value for AD, and participate in inflammatory pathways. The area under curve (AUC) results of the ten genes showed that they had potential diagnostic value for AD. The AUC of PYCARD was 0.95, which had the most significant diagnostic value, and it is involved in inflammatory processes such as the inflammasome complex adaptor protein. The DEGs screened, and subsequent pathway analysis revealed a close relationship between inflammation-related PYCARD and AD, thus providing a new basis for an early diagnostic target for AD.

High cortisol and the risk of Alzheimer disease: A protocol for systematic review and meta-analysis.

Background:Morning cortisol levels have been reported to be elevated among patients with Alzheimer disease (AD). We perform a protocol for systematic review and meta-analysis to assess morning central or peripheral cortisol levels in AD patients as compared with cognitively normal individuals.Methods:Studies were identified through systematic searches in August 2021 with no restrictions on date and time, language, and publication status using the following bibliographic databases: Embase, Medline, PubMed, Web of Science, Science Direct, and the Cochrane Library. Studies were identified using search terms related to cortisol, Alzheimer disease, and cognitive impairment. The study quality of included papers was evaluated using the “National Institutes of Health (NIH) quality assessment tool for observational cohort and cross-sectional studies.” Statistical analyses were performed using Stata (version 14, StataCorp, College Station, TX).Results:The findings of this study will be submitted to peer-reviewed journals for publication.Conclusion:Morning cortisol was elevated in AD patients and may have diagnostic and prognostic values for AD.

Reduced Resting-State Cortical Alpha Connectivity Reflects Distinct Functional Brain Dysconnectivity in Alzheimer's Disease and Mild Cognitive Impairment.

Background: Emerging evidence suggests distinct abnormal activity patterns during resting state in intrinsic functional brain networks in patients with neurodegenerative diseases, including Alzheimer's disease (AD) and mild cognitive impairment (MCI). This study aimed to identify the changes in the resting-state intracortical lagged phase synchronization derived from dense array electroencephalography (EEG) in AD and MCI. Methods: Resting-state current source density (CSD) and lagged phase synchronization between 84 regions of interest defined by Brodmann areas (BAs) for seven EEG frequency bands were investigated between the study groups (AD, MCI, and age-matched controls) using 128-channel EEG. Results: Reduced CSD and connectivity (large effect size, Cohen's d > 0.8) were found in AD and MCI compared with controls at alpha frequency. However, a positive correlation (r = 0.433; p = 0.044) of mini-mental state examination scores was found with BA 32-33 connectivity values in AD only. Conclusion: Reduced resting-state alpha 1 source connectivity in patient groups and correlation between attenuation of resting-state alpha 1 connectivity with cognitive decline in AD could indicate the disruption of inhibitory function of alpha rhythm leading to tonic unselective cortical excitation that affects attention and controlled access to stored information.

Antioxidative and antiapoptosis: Neuroprotective effects of dauricine in Alzheimer's disease models

AimsDauricine has been found that has significant neuroprotective effect on Alzheimer's disease (AD), but the mechanism is unclear, so we further investigated the possible mechanism of dauricine on AD. Main methodsCell counting kit-8 (CCK8) was applied to measure the cytotoxicity of dauricine on SH-SY5Y cells that overexpress the Swedish mutant form of human β-amyloid precursor protein (APPsw) and control cells (Neo). We used the Cu2+ to induce oxidative damage on APPsw cells, then tested the effect of dauricine on the damage and relative factors including reactive oxygen species (ROS), mitochondrial membrane potential (MMP) and superoxide dismutase (SOD) activity. The secretion level of amyloid beta 1–42(Aβ1–42), protein expression of apoptosis-related factors and the components of nuclear factor erythroid 2-related factor 2 (Nrf2) pathway were determined by western blotting. Aβ1–42-transgenic Caenorhabditis elegans GMC101, a model of AD, was applied to evaluate the neuroprotective effect of dauricine through the behavioral experiment and relative anti-oxidative tests. Key findingsIn vitro, dauricine decreased the secretion level of Aβ1–42, significantly reduced the level of Cu2+-induced ROS, and restored MMP and SOD activity in APPsw cells. Meanwhile, dauricine could suppress the activation of caspase-3 and to upregulate the expression of Bcl-2. Dauricine also regulated the proteins levels of Nrf2, and Kelch-like ECH-associated protein 1 (Keap1) that is necessary for the activation of Nrf2 in APPsw cell. As oxidative stress induced by Aβ or paraquat (PQ), dauricine showed protective effects in the survival experiment of GMC101 worms. SignificanceThose data revealed that dauricine has the pharmacological activity of anti-oxidative and anti-apoptosis, and shows the potential therapeutic value for AD.

MiR-133b is a potential diagnostic biomarker for Alzheimer's disease and has a neuroprotective role.

MicroRNAs (miRNAs/miRs) are involved in post-transcriptional gene regulation and aberrant expression of miRNAs has been widely detected in various human diseases. The aim of the present study was to examine the serum levels of miR-133b in patients with Alzheimer's disease (AD), and to explore its diagnostic value and neuroprotective role in AD. Reverse transcription-quantitative PCR was applied to analyze the serum levels of miR-133b in 105 AD patients and 98 healthy controls. A cell model of AD was established by treating SH-SY5Y cells with amyloid β (Aβ)25-35, and the resulting effect on miR-133b expression was determined. Cell viability and apoptosis were also measured. A dual-luciferase assay was used to validate a target gene of miR-133b. Receiver operating characteristic (ROC) curve analysis was also applied to assess the specificity and sensitivity of miR-133b to diagnose AD. The results indicated that the serum levels of miR-133b were significantly downregulated in AD patients and SH-SY5Y cells treated with Aβ25-35 (all P<0.001). A positive correlation between the serum levels of miR-133b and the Mini-Mental State Examination score of AD patients was determined (r=0.8814, P<0.001). The area under the ROC curve for miR-133b regarding the diagnosis of AD was 0.907, with a sensitivity of 90.8% and specificity of 74.3% at the cutoff value of 1.70. Overexpression of miR-133b significantly attenuated the Aβ25-35-induced inhibition of cell viability (P<0.01) and induction of cell apoptosis (P<0.01). The luciferase reporter assay demonstrated that epidermal growth factor receptor (EGFR) is a target gene of miR-133b. In conclusion, miR-133b may serve as a novel diagnostic biomarker for AD and it may have a neuroprotective role in AD and targets EGFR.

Validation study of the Alzheimer's Disease Assessment Scale-Cognitive Subscale for people with mild cognitive impairment and Alzheimer's disease in Chinese communities.

Our study aimed to verify the validity of the Chinese version of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) for the community-dwelling older people in China. A total of 1276 individuals composed by 628 normal controls (NCs), 572 people living with mild cognitive impairment (MCI), and 76 people living with Alzheimer's disease (AD) were recruited for the current study. All of the participants underwent ADAS-Cog, clinical interview and examination, Quick Cognitive Screening Scale for the Elderly, and Activities of Daily Living Scale. The sensitivity and specificity of ADAS-Cog were calculated, and a receiver operating characteristic curve (ROC curve) was drawn to decide the optimal cutoff points of ADAS-Cog for screening MCI and AD. Statistically significant differences were observed among the three groups (P <. 001, NC < MCI <AD), in terms of the total and subtask scores of ADAS-Cog. The optimal cutoff value for MCI was 10 points with an area under the curve (AUC) of 0.824, sensitivity of 61.4%, and specificity of 93.2%. Comparatively, the best cutoff value for AD was 15 points with an AUC of 0.905, sensitivity of 73.7%, and specificity of 92.4%. The overall accuracy was 70.5%, and the accuracy of diagnosing cognitively healthy older people, MCI patients, and AD patients was 81.7%, 58.0%, and 71.1%, respectively. The present study illustrates that the Chinese version of the ADAS-Cog total score is able to detect cognitive impairment of AD patients in Chinese communities but has a lower efficacy for MCI.

Gray matter T1-w/T2-w ratios are higher in Alzheimer's disease.

Myelin determines the conduction of neuronal signals along axonal connections in networks of the brain. Loss of myelin integrity in neuronal circuits might result in cognitive decline in Alzheimer's disease (AD). Recently, the ratio of T1‐weighted by T2‐weighted MRI has been used as a proxy for myelin content in gray matter of the cortex. With this approach, we investigated whether AD dementia patients show lower cortical myelin content (i.e., a lower T1‐w/T2‐w ratio value). We selected structural T1‐w and T2‐w MR images of 293 AD patients and 172 participants with normal cognition (NC). T1‐w/T2‐w ratios were computed for the whole brain and within 90 automated anatomical labeling atlas regions using SPM12, compared between groups and correlated with the neuronal injury marker tau in cerebrospinal fluid (CSF) and Mini Mental State Examination (MMSE). In contrast to our hypothesis, AD patients showed higher whole brain T1‐w/T2‐w ratios than NC, and regionally in 31 anatomical areas (p < .0005; d = 0.21 to 0.48), predominantly in the inferior parietal lobule, angular gyrus, anterior cingulate, and precuneus. Regional higher T1‐w/T2‐w values were associated with higher CSF tau concentrations (p < .0005; r = .16 to .22) and worse MMSE scores (p < .0005; r = −.16 to −.21). These higher T1‐w/T2‐w values in AD seem to contradict previous pathological findings of demyelination and disconnectivity in AD. Future research should further investigate the biological processes reflected by increases in T1‐w/T2‐w values.

Increased Iron Deposition on Brain Quantitative Susceptibility Mapping Correlates with Decreased Cognitive Function in Alzheimer's Disease.

The excessive accumulation of iron in deep gray structures is an important pathological characteristic in patients with Alzheimer's disease (AD). Quantitative susceptibility mapping (QSM) is more specific than other imaging-based iron measurement modalities and allows noninvasive assessment of tissue magnetic susceptibility, which has been shown to correlate well with brain iron levels. This study aimed to investigate the correlations between the magnetic susceptibility values of deep gray matter nuclei and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) in patients with mild and moderate AD. Thirty subjects with mild and moderate AD and 30 age- and sex-matched healthy controls were scanned with a 3.0 T magnetic resonance imaging (MRI) scanner. The magnetic susceptibilities of the regions of interest (ROIs), including caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), red nucleus (Rn), substantia nigra (Sn), and dentate nucleus (Dn), were quantified by QSM. We found that the susceptibility values of the bilateral Cd and Pt were significantly higher in AD patients than the controls ( P < 0.05). In contrast, bilateral Rn had significantly lower susceptibility values in AD than the controls. Regardless of gender and age, the increase of magnetic susceptibility in the left Cd was significantly correlated with the decrease of MMSE scores and MoCA scores ( P < 0.05). Our study indicated that magnetic susceptibility value of left Cd could be potentially used as a biomarker of disease severity in mild and moderate AD.

Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging.

Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.

RKIP-Mediated NF-κB Signaling is involved in ELF-MF-mediated improvement in AD rat

In a previous study, we reported the positive effects of extremely low frequency electromagnetic field (ELF-MF) exposure on Alzheimer's disease (AD) rats; however, the underlying mechanism remains unclear. In addition, we found that Raf-1 kinase inhibitor protein (RKIP) was downregulated by microwave exposure in the rat hippocampus. Our hypothesis was that RKIP-mediated NF-κB pathway signaling is involved in the effect of ELF-MF on the AD rat. In this study, D-galactose intraperitoneal (50 mg/kg/d for 42 d) and Aβ25-35 hippocampal (5 μL/unilateral, bilateral, single-dose) injection were implemented to establish an AD rat model. Animals were exposed to 50 Hz and 400 µT ELF-MF for 60 continuous days. The spatial memory ability of the rat was then tested using the Morris water maze. Protein expression and interaction were detected by western blotting and co-immunoprecipitation for RKIP-mediated NF-κB pathway factors. The results showed that ELF-MF exposure partially improved the cognitive disorder, upregulated the levels of RKIP, TAK1, and the RKIP/TAK1 interaction, but downregulated p-IKK levels in AD rats. These results indicated that RKIP-mediated NF-κB pathway signaling plays an important role in the ELF-MF exposure-mediated improvements in the AD rat. Our study suggested that ELF-MF exposure might have a potential therapeutic value for AD. Further in depth studies are required in the future.

Discovery of novel brain permeable and G protein-biased beta-1 adrenergic receptor partial agonists for the treatment of neurocognitive disorders.

The beta-1 adrenergic receptor (ADRB1) is a promising therapeutic target intrinsically involved in the cognitive deficits and pathological features associated with Alzheimer’s disease (AD). Evidence indicates that ADRB1 plays an important role in regulating neuroinflammatory processes, and activation of ADRB1 may produce neuroprotective effects in neuroinflammatory diseases. Novel small molecule modulators of ADRB1, engineered to be highly brain permeable and functionally selective for the G protein with partial agonistic activity, could have tremendous value both as pharmacological tools and potential lead molecules for further preclinical development. The present study describes our ongoing efforts toward the discovery of functionally selective partial agonists of ADRB1 that have potential therapeutic value for AD and neuroinflammatory disorders, which has led to the identification of the molecule STD-101-D1. As a functionally selective agonist of ADRB1, STD-101-D1 produces partial agonistic activity on G protein signaling with an EC50 value in the low nanomolar range, but engages very little beta-arrestin recruitment compared to the unbiased agonist isoproterenol. STD-101-D1 also inhibits the tumor necrosis factor α (TNFα) response induced by lipopolysaccharide (LPS) both in vitro and in vivo, and shows high brain penetration. Other than the therapeutic role, this newly identified, functionally selective, partial agonist of ADRB1 is an invaluable research tool to study mechanisms of G protein-coupled receptor signal transduction.

Cerebrospinal Fluid Biomarkers for the Diagnosis of Alzheimer Disease in South Korea.

Laboratory-specific reference values for cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers are necessary. Our objective was to apply well-known CSF biomarkers and redetermine their diagnostic cutoff values for AD in South Korea. CSF samples from matched control subjects (n=71), patients with AD dementia (ADD, n=76), and other neurological disorders with cognitive decline (OND, n=47) were obtained from 6 Korean dementia clinics according to a standardized protocol. CSF biomarker concentrations were measured using enzyme-linked immunosorbent assay. CSF biomarkers differed significantly between the ADD and control groups (P<0.001 for all), and between the ADD and OND groups (P<0.001 for all). The areas under the curve in differentiation of ADD from control subjects were 0.97 for Aβ42, 0.93 for total tau (tTau), 0.86 for pTau, and 0.99 for both tTau/Aβ42 and pTau/Aβ42 ratios. Our revised cutoff value for Aβ42 was higher than our previous one, whereas the values for the Tau proteins were similar. The tTau/Aβ42 ratio had the highest accuracy, 97%. Our findings highlight the usefulness of CSF AD biomarkers in South Korea, and the necessity of continually testing the reliability of cutoff values.

Determining appropriate screening tools and cut-points for cognitive impairment in an elderly Chinese sample.

The establishment of normative data and screening cut-points for cognitive tasks is important to ensure the effective and timely detection of mild cognitive impairment (MCI) and Alzheimer's disease (AD). These need to be culturally relevant and account for known factors that impact on cognition such as age, education, and gender. In this study, 1,068 elderly Chinese residents of Shanghai completed a comprehensive series of cognitive tasks as part of a community screening study with 1027 meeting criteria for analysis, age M(SD) = 72.54 (8.40). MCI was detected in 267 individuals, AD in 50, and 710 had normal cognition. Receiver Operator Characteristic curve analysis indicated that the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) best differentiated normal cognition from MCI and AD. We present suggested cut-points to differentiate between normal cognition and MCI and AD for the total sample, and when split according to education levels, age, and gender. Trends suggest that the MoCA was better suited to detecting MCI, and the MMSE was better for detecting AD. For younger and more educated participants, only a slight impairment was necessary to meet screening criteria, while a larger impairment was necessary for older and less educated participants. Both tasks had a high negative predictive values for MCI and AD, and variable positive predictive values. The cut-points presented can be used to inform future work using the MMSE and MoCA to screen for MCI and AD in older Chinese people. (PsycINFO Database Record

A Delayed Recall Battery as a Sensitive Screening for Mild Cognitive Impairment: Follow-up Study of Memory Clinic Patients after 10 years

I examined the predictive value of the combination of three delayed recall tests to distinguish (1) those with probable Alzheimer's disease (AD) from those within normal range, and (2) those with Mild cognitive impairment (MCI) from those within normal range. The data from 90 visitors to a memory clinic in Tokyo was used. I first examined patients clinically, neuroradiologically, and excluded the mental and neurological illness. AD was diagnosed according to the NINCDS-ADRDA criteria, MCI according to the criteria of Petersen et al.. Normal must be free from any disease examined above. After the diagnosis, the baseline neuropsychological tests were performed for all participants; the Mini Mental State Examination, Raven's Colored Progressive Matrices, the Stroop Test, a 10-words list learning and recall test, a story recall test, and the Rey-Osterrieth Complex Figure Test. After 10 years, all patients were reassessed and diagnosed again. Of the MCI patients for follow-up (n=29), 19 were converted to AD, while 5 not. One died. 4 lost. All AD patients (n=30) remained as AD. The combination of 3 delayed recall battery provides clinically useful predictive values for both AD and MCI in a memory clinics and dementia research clinics.