Abstract The surface of layered double hydroxide nanoparticles, a potential drug‐delivery nanovehicle, is modified with the cancer‐cell‐specific ligand, folic acid. The surface modification is successfully accomplished through step‐by‐step coupling reactions with aminopropyltriethoxysilane and 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐carbodiimide. In order to evaluate the cancer‐cell targeting effect of folic‐acid‐grafted layered double hydroxide utilizing fluorescence‐related assay, both layered double hydroxide with and without folic acid moiety are labeled with fluorescein 5′‐isothiocyanate. The uptake of layered double hydroxide and folic acid conjugated into KB and A549 cells is visualized using fluorescence microscopy and measured by flow cytometry. Both chemical and biological assay results demonstrate that the folic acid molecules are indeed conjugated to the surface of layered double hydroxide and thus the selectivity of nanovehicles to cancer cells overexpressing folate receptors increases. In this study, it is suggested that layered double hydroxide nanoparticles can be used as drug‐delivery carriers with a targeting function due to the chemical conjugation with specific ligand.
We recently developed a multiplex diagnostic kit, QPLEX™ Alz plus assay kit, which captures amyloid-β1-40, galectin-3 binding protein, angiotensin-converting enzyme, and periostin simultaneously using microliters of peripheral blood and utilizes an optimized algorithm for screening Alzheimer’s disease (AD) by correlating with cerebral amyloid deposition. Owing to the demand for early AD detection, we investigate the potential of our kit for the early clinical diagnosis of AD. A total of 1395 participants were recruited, and their blood samples were analyzed with the QPLEX™ kit. The average of QPLEX™ algorithm values in each group increased gradually in the order of the clinical progression continuum of AD: cognitively normal (0.382 ± 0.150), subjective cognitive decline (0.452 ± 0.130), mild cognitive impairment (0.484 ± 0.129), and AD (0.513 ± 0.136). The algorithm values between each group showed statistically significant differences among groups divided by Mini-Mental State Examination and Clinical Dementia Rating. The QPLEX™ algorithm values could be used to distinguish the clinical continuum of AD or cognitive function. Because blood-based diagnosis is more accessible, convenient, and cost- and time-effective than cerebral spinal fluid or positron emission tomography imaging-based diagnosis, the QPLEX™ kit can potentially be used for health checkups and the early clinical diagnosis of AD.
Abstract The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer’s disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEX TM Alz plus assay kit for the prescreening of Aβ accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aβ accumulation. We included a total of 221 CN participants with or without brain Aβ. The QPLEX TM biomarkers were characterized based on age groups (1 st –3 rd tertile) and across various brain regions with cerebral amyloid deposition. The 3 rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3 rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aβ1–42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEX TM Alz plus assay is useful for prescreening brain Aβ levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation.
Alzheimer's disease (AD), characterized by progressive cognitive decline, is the most prevalent neurodegenerative disease in the elderly. Cerebral β-amyloid (Aβ) deposition is the major pathological hallmark of AD. Recent studies also have shown that the serum level of phosphorus correlates to the risk of incident dementia. To date, however, the linkage between cerebral Aβ deposition and the serum phosphorus level or factors from routine blood test (FRBT) remains unknown. In this study, we analyzed the levels of serum phosphorus in 109 mild cognitive impairment (MCI) and 73 AD dementia (ADD) subjects. Also, other FRBT (triiodothyronine III, cholesterol, cortisol, ALT-S) were used as covariates. All subjects underwent Pittsburgh compound B positron emission tomography (PiB-PET) imaging to measure cerebral Aβ deposition. The results with Aβ deposition was compared with the serum levels of phosphorus or FRBT. The subjects with cerebral Aβ deposition showed significantly different levels of serum phosphorus, triiodothyronine III, cholesterol, cortisol, and ALT-S than those without Aβ deposition. Multiple regression analyses showed that a low level of serum phosphorus correlated with cerebral Aβ deposition, even when age, sex, apolipoprotein E ε4 genotype, and MMSE z-score were controlled for. Serum levels of other ions, including calcium, iron, zinc, and copper, showed no such correlation. Our results suggest that combined model of phosphorus with other FRBTs may be used as an easily accessible blood biomarker for cerebral Aβ deposition in a cognitively impaired population.
Alzheimer's disease (AD) is a common neurodegenerative disease characterized by amyloid plaques and impaired brain metabolism. Because women have a higher prevalence of AD than men, sex differences are of great interest. Using cross-sectional and longitudinal data, we showed sex-dependent metabolic dysregulations in the brains of AD patients. Cohort 1 (South Korean, n = 181) underwent Pittsburgh compound B-PET, fluorodeoxyglucose-PET, magnetic resonance imaging, and blood biomarker (plasma tau and beta-amyloid 42 and 40) measurements at baseline and two-year follow-ups. Transcriptome analysis of data from Cohorts 2 and 3 (European, n = 78; Singaporean, n = 18) revealed sex differences in AD-related alterations in brain metabolism. In women (but not in men), all imaging indicators displayed consistent correlation curves with AD progression. At the two-year follow-up, clear brain metabolic impairment was revealed only in women, and the plasma beta-amyloid 42/40 ratio was a possible biomarker for brain metabolism in women. Furthermore, our transcriptome analysis revealed sex differences in transcriptomes and metabolism in the brains of AD patients as well as a molecular network of 25 female-specific glucose metabolic genes (FGGs). We discovered four key-attractor FGG genes (ALDOA, ENO2, PRKACB, and PPP2R5D) that were associated with amyloid/tau-related genes (APP, MAPT, BACE1, and BACE2). Furthermore, these genes successfully distinguished amyloid positivity in women. Understanding sex differences in the pathogenesis of AD and considering these differences will improve development of effective diagnostics and therapeutic treatments for AD.
Abstract Background: Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by the hallmark finding of cerebral amyloid deposition. Many researchers have tried to predict the existence of cerebral amyloid deposition by using easily accessible blood plasma samples, but the effectiveness of such strategies remains controversial. Methods: We developed a new multiplex kit, the QPLEX TM Alz plus assay kit, which uses proteomics-based blood biomarkers to prescreen for cerebral amyloid deposition. A total of 300 participants who underwent Pittsburgh compound B (PiB)-positron emission tomography (PET) which allows imaging of cerebral amyloid deposition were included in this study. We compared the levels of QPLEX TM biomarkers between patients who were classified as PiB-negative or PiB-positive, regardless of their cognitive function. Logistic regression analysis followed by receiver operating characteristic (ROC) curve analysis was performed. The kit accuracy was tested using a randomized sample selection method. Results: The results obtained using our assay kit reached 89.1% area under curve (AUC) with 80.0% sensitivity and 83.0% specificity. Further validation of the QPLEX TM Alz plus assay kit using a randomized sample selection method showed an average accuracy of 81.5%. Conclusions: Our QPLEX TM Alz plus assay kit offers a highly effective way to predict cerebral amyloid deposition through a convenient blood test, and should enable easy prediction of AD in daily life.
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