Effects of the Fasting-Postprandial State on Arterial Spin Labeling MRI-Based Cerebral Perfusion Quantification in Alzheimer's Disease.

BACKGROUND: The fasting-postprandial state remains an underrecognized confounding factor for quantifying cerebral blood flow (CBF) in the cognitive assessment and differential diagnosis of Alzheimer's disease (AD). PURPOSE: To investigate the effects of fasting-postprandial state on arterial spin labeling (ASL)-based CBF in AD patients. STUDY TYPE: Prospective. SUBJECTS: Ninety-two subjects (mean age = 62.5 ± 6.4 years; females 29.3%), including 30 with AD, 32 with mild cognitive impairment (MCI), and 30 healthy controls (HCs). Differential diagnostic models were developed with a 4:1 training to testing set ratio. FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted imaging using gradient echo and pseudocontinuous ASL imaging using turbo spin echo. ASSESSMENT: Two ASL scans were acquired to quantify fasting state and postprandial state regional CBFs based on an automated anatomical labeling atlas. Two-way ANOVA was used to assess the effects of fasting/postprandial state and disease state (AD, MCI, and HC) on regional CBF. Pearson's correlation analysis was conducted between regional CBF and cognitive scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). The diagnostic performances of the fasting state, postprandial state, and mixed state (random mixing of the fasting and postprandial state CBF) in differential diagnosis of AD were conducted using support vector machine and logistic regression models. STATISTICAL TESTS: Two-way ANOVA, Pearson's correlation, and area under the curve (AUC) of diagnostic model were performed. P values <0.05 indicated statistical significance. RESULTS: Fasting-state CBF was correlated with cognitive scores in more brain regions (17 vs. 4 [MMSE] and 15 vs. 9 [MoCA]) and had higher absolute correlation coefficients than postprandial-state CBF. In the differential diagnosis of AD patients from MCI patients and HCs, fasting-state CBF outperformed mixed-state CBF, which itself outperformed postprandial-state CBF. DATA CONCLUSION: Compared with postprandial CBF, fasting-state CBF performed better in terms of cognitive score correlations and in differentiating AD patients from MCI patients and HCs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Chain Mediation Analysis of the Effects of Nutrition and Cognition on the Association of Apolipoprotein E ɛ4 with Neuropsychiatric Symptoms in Alzheimer's Disease.

BACKGROUND: Apolipoprotein E (APOE) is the most recognized risk gene for cognitive decline and clinical progression of late-onset Alzheimer's disease (AD); nonetheless, its association with neuropsychiatric symptoms (NPSs) remains inconclusive. OBJECTIVE: To investigate the association of APOE ɛ4 with NPSs and explore nutritional status and cognition as joint mediators of this association. METHODS: Between June 2021 and October 2022, patients with amnestic mild cognitive impairment (aMCI) or AD were recruited from the Chinese Imaging, Biomarkers, and Lifestyle Study. NPSs were assessed using the Neuropsychiatric Inventory, while global cognition and nutritional status were evaluated using the Mini-Mental State Examination (MMSE) and Mini-Nutritional Assessment (MNA), respectively. Simple mediation and multiple chain mediation models were developed to examine the mediating effects of the MNA and MMSE scores on the relationship between APOE ɛ4 and specific neuropsychiatric symptom. RESULTS: Among 310 patients, 229 (73.87%) had NPSs, and 110 (35.48%) carried APOE ɛ4. Patients with APOE ɛ4 were more likely to have hallucinations (p = 0.014), apathy (p = 0.008), and aberrant motor activity (p = 0.018). MNA and MMSE scores mediated the association between APOE ɛ4 and hallucinations (17.97% and 37.13%, respectively), APOE ɛ4 and apathy (30.73% and 57.72%, respectively), and APOE ɛ4 and aberrant motor activity (17.82% and 34.24%), respectively. Chain-mediating effects of MNA and MMSE scores on the association of APOE ɛ4 with hallucinations, apathy, and aberrant motor activity after adjusting for confounding factors were 6.84%, 11.54%, and 6.19%, respectively. CONCLUSION: Nutritional status and cognition jointly mediate the association between APOE ɛ4 and neuropsychiatric symptoms in patients with aMCI or AD.

Corrigendum: miR-212/132-enriched extracellular vesicles promote differentiation of induced pluripotent stem cells into pancreatic beta cells.

[This corrects the article DOI: 10.3389/fcell.2021.673231.].

Nutrition in Alzheimer's disease: a review of an underappreciated pathophysiological mechanism.

Alzheimer's disease (AD) is the leading cause of dementia in older individuals and is an escalating challenge to global public health. Pharmacy therapy of AD is one of the well-funded areas; however, little progress has been made due to the complex pathogenesis. Recent evidence has demonstrated that modifying risk factors and lifestyle may prevent or delay the incidence of AD by 40%, which suggests that the management should pivot from single pharmacotherapy toward a multipronged approach because AD is a complex and multifaceted disease. Recently, the gut-microbiota-brain axis has gained tremendous traction in the pathogenesis of AD through bidirectional communication with multiple neural, immune, and metabolic pathways, providing new insights into novel therapeutic strategies. Dietary nutrition is an important and profound environmental factor that influences the composition and function of the microbiota. The Nutrition for Dementia Prevention Working Group recently found that dietary nutrition can affect cognition in AD-related dementia directly or indirectly through complex interactions of behavioral, genetic, systemic, and brain factors. Thus, considering the multiple etiologies of AD, nutrition represents a multidimensional factor that has a profound effect on AD onset and development. However, mechanistically, the effect of nutrition on AD is uncertain; therefore, optimal strategies or the timing of nutritional intervention to prevent or treat AD has not been established.Thus, this review summarizes the current state of knowledge concerning nutritional disorders, AD patient and caregiver burden, and the roles of nutrition in the pathophysiology of AD. We aim to emphasize knowledge gaps to provide direction for future research and to establish optimal nutrition-based intervention strategies for AD.

miR-212/132-Enriched Extracellular Vesicles Promote Differentiation of Induced Pluripotent Stem Cells Into Pancreatic Beta Cells.

Pancreatic beta cell transplantation is the ideal method for treatment of type 1 diabetes mellitus (T1DM), and the generation of beta cells from induced pluripotent stem cells (iPSCs) of patients is a promising strategy. In this study, we improved a previous strategy to produce beta cells using extracellular vesicles (EVs) derived from mature beta cells and differentiated beta cells from iPSCs (i-Beta cells), which secreted insulin under glucose stimulation in vitro and ameliorated hyperglycemia in vivo. Mechanistic analyses revealed that EV-carried microRNA (miR)-212/132 (EV-miR-212/132) directly bound to the 3' UTR of FBW7 to prevent its translation and FBW7 combined with NGN3 to accelerate its proteasomal degradation. EV-miR-212/132 stabilized NGN3 expression to promote differentiation of endocrine cells from induced iPSCs. Moreover, NGN3 bound to PDX1 to enhance transcription of endogenous miR-212/132 and formed a positive regulatory circuit that maintained the functions of mature pancreatic beta cells. CONCLUSION: This study describes a novel approach for beta cell production and supports the use of iPSCs for cell replacement therapy of T1DM.

A highly CMOS compatible hafnia-based ferroelectric diode.

Memory devices with high speed and high density are highly desired to address the 'memory wall' issue. Here we demonstrated a highly scalable, three-dimensional stackable ferroelectric diode, with its rectifying polarity modulated by the polarization reversal of Hf0.5Zr0.5O2 films. By visualizing the hafnium/zirconium lattice order and oxygen lattice order with atomic-resolution spherical aberration-corrected STEM, we revealed the correlation between the spontaneous polarization of Hf0.5Zr0.5O2 film and the displacement of oxygen atom, thus unambiguously identified the non-centrosymmetric Pca21 orthorhombic phase in Hf0.5Zr0.5O2 film. We further implemented this ferroelectric diode in an 8 layers 3D array. Operation speed as high as 20 ns and robust endurance of more than 109 were demonstrated. The built-in nonlinearity of more than 100 guarantees its self-selective property that eliminates the need for external selectors to suppress the leakage current in large array. This work opens up new opportunities for future memory hierarchy evolution.

P53 gene mutation and expression of MDM2, P53, P16 protein and their relationship in human glioma.

To investigate the effect of P53 protein accumulation and p53 gene mutation in the pathogenesis of glioma and to study the role of MDM2, P53 and P16 protein in glioma formation and progression and their relationship with each other, LSAB immunohistochemical staining method and non-isotopic PCR-SSCP techniques were used to detect the expression of MDM2, P53 and P16 protein and p53 gene mutation in 48 cases of gliomas. The results showed that the positive expression rate of MDM2, P53 and the negative rate of P16 was 22.9%, 41.7% and 60.4%, respectively. The latter two in high grade (grade III, IV) gliomas had a significantly higher rate than in the low grade (grade II) gliomas. Moreover, the co-expression of MDM2 and P53 protein was confirmed in only 1 of 48 cases. No significant difference was found in the rate of the expression of MDM2 between high grade and low grade gliomas (P > 0.1). PCR-SSCP results showed that mutation of 5-8 exons of p53 gene was detected in 17 out of 48 cases (35.42%). Mutation was detected in 16 of 20 cases of positive p53 expression, and another one was detected in 28 cases of negative expression cases. The correlation between p53 mutation and p53 immunopositivity was observed in 89.6% of the cases. P53 gene mutation and the level of MDM2, P53 and P16 protein were not related to age, gender of the patients, tumor location and size. It is concluded that the mutation of p53 and deletion of p16 might play important roles in the tumorigenesis of gliomas and it was significantly associated with the grade of tumor differentiation. P53 protein accumulation can indirectly reflect p53 mutation. MDM2 amplification and overexpression might be an early event in the growth of human gliomas.