CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET.

Determining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Predicting conversion of brain ß-amyloid positivity in amyloid-negative individuals.

BACKGROUND: Cortical deposition of ß-amyloid (Aß) plaque is one of the main hallmarks of Alzheimer's disease (AD). While Aß positivity has been the main concern so far, predicting whether Aß (-) individuals will convert to Aß (+) has become crucial in clinical and research aspects. In this study, we aimed to develop a classifier that predicts the conversion from Aß (-) to Aß (+) using artificial intelligence. METHODS: Data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort regarding patients who were initially Aß (-). We developed an artificial neural network-based classifier with baseline age, gender, APOE ε4 genotype, and global and regional standardized uptake value ratios (SUVRs) from positron emission tomography. Ten times repeated 10-fold cross-validation was performed for model measurement, and the feature importance was assessed. To validate the prediction model, we recruited subjects at the Samsung Medical Center (SMC). RESULTS: A total of 229 participants (53 converters) from the ADNI dataset and a total of 40 subjects (10 converters) from the SMC dataset were included. The average area under the receiver operating characteristic values of three developed models are as follows: Model 1 (age, gender, APOE ε4) of 0.674, Model 2 (age, gender, APOE ε4, global SUVR) of 0.814, and Model 3 (age, gender, APOE ε4, global and regional SUVR) of 0.841. External validation result showed an AUROC of 0.900. CONCLUSION: We developed prediction models regarding Aß positivity conversion. With the growing recognition of the need for earlier intervention in AD, the results of this study are expected to contribute to the screening of early treatment candidates.

Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer's disease dementia: a phase I clinical trial.

BACKGROUNDS: Alzheimer's disease is the most common cause of dementia, and currently, there is no disease-modifying treatment. Favorable functional outcomes and reduction of amyloid levels were observed following transplantation of mesenchymal stem cells (MSCs) in animal studies. OBJECTIVES: We conducted a phase I clinical trial in nine patients with mild-to-moderate Alzheimer's disease dementia to evaluate the safety and dose-limiting toxicity of three repeated intracerebroventricular injections of human umbilical cord blood-derived MSCs (hUCB-MSCs). METHODS: We recruited nine mild-to-moderate Alzheimer's disease dementia patients from Samsung Medical Center, Seoul, Republic of Korea. Four weeks prior to MSC administration, the Ommaya reservoir was implanted into the right lateral ventricle of the patients. Three patients received a low dose (1.0 × 107 cells/2 mL), and six patients received a high dose (3.0 × 107 cells/2 mL) of hUCB-MSCs. Three repeated injections of MSCs were performed (4-week intervals) in all nine patients. These patients were followed up to 12 weeks after the first hUCB-MSC injection and an additional 36 months in the extended observation study. RESULTS: After hUCB-MSC injection, the most common adverse event was fever (n = 9) followed by headache (n = 7), nausea (n = 5), and vomiting (n = 4), which all subsided within 36 h. There were three serious adverse events in two participants that were considered to have arisen from the investigational product. Fever in a low dose participant and nausea with vomiting in another low dose participant each required extended hospitalization by a day. There were no dose-limiting toxicities. Five participants completed the 36-month extended observation study, and no further serious adverse events were observed. CONCLUSIONS: Three repeated administrations of hUCB-MSCs into the lateral ventricle via an Ommaya reservoir were feasible, relatively and sufficiently safe, and well-tolerated. Currently, we are undergoing an extended follow-up study for those who participated in a phase IIa trial where upon completion, we hope to gain a deeper understanding of the clinical efficacy of MSC AD therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT02054208. Registered on 4 February 2014. ClinicalTrials.gov NCT03172117. Registered on 1 June 2017.

Possibility of undifferentiated human thigh adipose stem cells differentiating into functional hepatocytes.

BACKGROUND: This study aimed to investigate the possibility of isolating mesenchymal stem cells (MSCs) from human thigh adipose tissue and the ability of human thigh adipose stem cells (HTASCs) to differentiate into hepatocytes. METHODS: The adipose-derived stem cells (ADSCs) were isolated from thigh adipose tissue. Growth factors, cytokines, and hormones were added to the collagen coated dishes to induce the undifferentiated HTASCs to differentiate into hepatocyte-like cells. To confirm the experimental results, the expression of hepatocyte-specific markers on undifferentiated and differentiated HTASCs was analyzed using reverse transcription polymerase chain reaction and immunocytochemical staining. Differentiation efficiency was evaluated using functional tests such as periodic acid schiff (PAS) staining and detection of the albumin secretion level using enzyme-linked immunosorbent assay (ELISA). RESULTS: The majority of the undifferentiated HTASCs were changed into a more polygonal shape showing tight interactions between the cells. The differentiated HTASCs up-regulated mRNA of hepatocyte markers. Immunocytochemical analysis showed that they were intensely stained with anti-albumin antibody compared with undifferentiated HTASCs. PAS staining showed that HTASCs submitted to the hepatocyte differentiation protocol were able to more specifically store glycogen than undifferentiated HTASCs, displaying a purple color in the cytoplasm of the differentiated HTASCs. ELISA analyses showed that differentiated HTASCs could secrete albumin, which is one of the hepatocyte markers. CONCLUSIONS: MSCs were islolated from human thigh adipose tissue differentiate to heapatocytes. The source of ADSCs is not only abundant abdominal adipose tissue, but also thigh adipose tissue for cell therapy in liver regeneration and tissue regeneration.

Enhancement of sensitivity using hybrid stimulus for the diagnosis of prostate cancer based on polydiacetylene (PDA) supramolecules.

In this study, hybrid stimulus was initially introduced to improve the sensitivity of PDA vesicle chip for detection of prostate-specific antigen-α1-antichymotrypsin (PSA-ACT) complex. The strategy of hybrid stimulus on PDA vesicle chip offers the amplification method of fluorescent signal which combines a primary response by the immune reaction of antigen-antibody and a secondary response by the mechanical pressure of pAb-conjugated magnetic beads. As the primary response result on PDA vesicle chip, the PSA-ACT complex in PBS buffer was detected at 10 ng/mL. However, this detection sensitivity was insufficient for diagnosis of prostate cancer because the normal human PSA concentration is less than 4.0 ng/mL. To solve this problem, polyclonal PSA antibody-conjugated magnetic beads were used as an amplifying agent after primary immunoresponse. As a result, the PSA-ACT complex concentrations (as low as 0.1 ng/mL) could be detected in the PBS buffer sample. Therefore, this result can be applied to various fields, such as the detection of cells, proteins, and DNA for sensitive and specific biosensing based on PDA supramolecules.

Enhancement of sensitivity and specificity by surface modification of carbon nanotubes in diagnosis of prostate cancer based on carbon nanotube field effect transistors.

This paper presents a simple and sensitive method for the real-time detection of a prostate cancer marker (PSA-ACT complex) through label-free protein biosensors based on a carbon nanotube field effect transistor (CNT-FET). Herein, the CNT-FET was functionalized with a solution containing various linker-to-spacer ratios, the binding event of the target PSA-ACT complex onto the receptor detected by monitoring the gating effect caused by charges in the target PSA-ACT complex. Since the biosensors were used in a buffer solution, it was crucial to control the distance between the receptors through introduction of linkers and spacers so that the charged target PSA-ACT complex could easily approach the CNT surface within the Debye length to give a large gating effect. The results show that CNT-FET biosensors modified with only linkers could not detect target proteins unless a very high concentration of the PSA-ACT complex solution (approximately 500 ng/ml) was injected, while those modified with a 1:3 ratio of linker-to-spacer could detect 1.0 ng/ml without any pretreatment. Moreover, our linker and spacer-modified CNT-FET could successfully block non-target proteins and selectively detect the target protein in human serum. Significantly, this strategy can be applied to general antibody-based detection schemes and enables production of very simple and sensitive electronic biosensors to detect clinically important biomarkers for disease diagnosis.

A strategy for sensitivity and specificity enhancements in prostate specific antigen-alpha1-antichymotrypsin detection based on surface plasmon resonance.

A biochip based on surface plasmon resonance was fabricated to detect prostate specific antigen-alpha(1)-antichymotrypsin (PSA-ACT complex) in both HBS buffer and human serum. To reduce non-specific binding and steric hindrance effect, the chemical surface of the sensor chips was constructed by using various oligo(ethylene glycol) mixtures of different molar ratios of HS(CH2)11(OCH2CH2)6OCH2COOH and HS(CH2)11(OCH2CH2)3OH. The self-assembled monolayers were biotinylated to facilitate the immobilization of streptavidin. Using the chip surfaces, PSA-ACT complex in HBS buffer and human serum was detected at 20.7 and 47.5 ng/ml by primary immunoresponse, respectively. However, the limit of detection could be simply enhanced by a sandwich strategy to improve the sensitivity and specificity of the immunoassay. An intact PSA polyclonal antibody was used as an amplifying agent in the strategy. As a result, PSA-ACT complex concentrations as low as 10.2 and 18.1 ng/ml were found in the HBS buffer and human serum sample, respectively. The result indicates that this approach could satisfy our goal without modifying the secondary interactant.