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Background: Alzheimer's disease (AD), the most common cause of dementia, is a neurodegenerative disease resulting from extracellular and intracellular deposits of amyloid-β (Aβ) and neurofibrillary tangles in the brain. Although many clinical studies evaluating pharmacological approaches have been conducted, most have shown disappointing results; thus, innovative strategies other than drugs have been actively attempted. Objective: This study aims to explore low-dose radiation therapy (LDRT) for the treatment of patients with AD based on preclinical evidence, case reports, and a small pilot trial in humans. Methods: This study is a phase II, multicenter, prospective, single-blinded, randomized controlled trial that will evaluate the efficacy and safety of LDRT to the whole brain using a linear accelerator in patients with mild AD. Sixty participants will be randomly assigned to three groups: experimental I (24 cGy/6 fractions), experimental II (300 cGy/6 fractions), or sham RT group (0 cGy/6 fractions). During LDRT and follow-up visits after LDRT, possible adverse events will be assessed by the physician's interview and neurological examinations. Furthermore, the effectiveness of LDRT will be measured using neurocognitive function tests and imaging tools at 6 and 12 months after LDRT. We will also monitor the alterations in cytokines, Aβ42/Aβ40 ratio, and tau levels in plasma. Our primary endpoint is the change in cognitive function test scores estimated by the Alzheimer's Disease Assessment Scale-Korea compared to baseline after 6 months of LDRT. Conclusions: This study is registered at ClinicalTrials.gov [NCT05635968] and is currently recruiting patients. This study will provide evidence that LDRT is a new treatment strategy for AD. [ABSTRACT FROM AUTHOR]

Background: The previous studies reported increased concentrations of metallic ions, imbalanced Na+ and K+ ions, and the increased mobility of protons by microstructural disruptions in Alzheimer's disease (AD). Purpose: (1) to apply a high-frequency conductivity (HFC) mapping technique using a clinical 3T MRI system, (2) compare HFC values in the brains of participants with AD, amnestic mild cognitive impairment (MCI), and cognitively normal (CN) elderly people, (3) evaluate the relationship between HFC values and cognitive decline, and (4) explore usefulness of HFC values as an imaging biomarker to evaluate the differentiation of AD from CN. Materials and Methods: This prospective study included 74 participants (23 AD patients, 27 amnestic MCI patients, and 24 CN elderly people) to explore the clinical application of HFC mapping in the brain from March 2019 to August 2021. We performed statistical analyses to compare HFC maps between the three participant groups, evaluate the association of HFC maps with Mini-Mental State Examination (MMSE) scores, and to evaluate the differentiation between the participant groups for HFC values for some brain areas. Results: We obtained a good HFC map non-invasively. The HFC value was higher in the AD group than in the CN and MCI groups. MMSE scores were negatively associated with HFC values. Age was positively associated with HFC values. The HFC value in the insula has a high area under the receiver operating characteristic (ROC) curve (AUC) value to differentiate AD patients from the CN participants (Sensitivity [ SE ] = 82, Specificity [ SP ] =97, AUC = 0.902, p < 0.0001), better than gray matter volume (GMV) in hippocampus (SE = 79, SP = 83, AUC = 0.880, p < 0.0001). The classification for differentiating AD from CN was highest by adding the hippocampal GMV to the insular HFC value (SE = 87, SP = 87, AUC = 0.928, p < 0.0001). Conclusion: High-frequency conductivity values were significantly increased in the AD group compared to the CN group and increased with age and disease severity. HFC values of the insula along with the GMV of the hippocampus can be used as an imaging biomarker to improve the differentiation of AD from CN. [ABSTRACT FROM AUTHOR]

Objective: To investigate the association between plasma amyloid-β (Aβ) levels and neuropsychological performance in patients with cognitive decline using a highly sensitive nano-biosensing platform. Methods: We prospectively recruited 44 patients with cognitive decline who underwent plasma Aβ analysis, amyloid positron emission tomography (PET) scanning, and detailed neuropsychological tests. Patients were classified into a normal control (NC, n = 25) or Alzheimer's disease (AD, n = 19) group based on amyloid PET positivity. Multiple linear regression was performed to determine whether plasma Aβ (Aβ40, Aβ42, and Aβ42/40) levels were associated with neuropsychological test results. Results: The plasma levels of Aβ42/40 were significantly different between the NC and AD groups and were the best predictor of amyloid PET positivity by receiver operating characteristic curve analysis [area under the curve of 0.952 (95% confidence interval, 0.892–1.000)]. Although there were significant differences in the neuropsychological performance of cognitive domains (language, visuospatial, verbal/visual memory, and frontal/executive functions) between the NC and AD groups, higher levels of plasma Aβ42/40 were negatively correlated only with verbal and visual memory performance. Conclusion: Our results demonstrated that plasma Aβ analysis using a nano-biosensing platform could be a useful tool for diagnosing AD and assessing memory performance in patients with cognitive decline. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that alterations in cerebral microvasculature play a critical role in the pathogenesis of Alzheimer's disease (AD). The objective of this study was to characterize and evaluate the cerebral microvascular architecture of AD transgenic (Tg) mice and compare it with that of non‐Tg mice using brain microvascular indices obtained by MRI. Seven non‐Tg mice and 10 5xFAD Tg mice were scanned using a 7‐T animal MRI system to measure the transverse relaxation rates of R2 and R2* before and after the injection of the monocrystalline iron oxide nanoparticle contrast agent. After calculating ΔR2* and ΔR2, the vessel size index (VSI), mean vessel diameter (mVD), mean vessel density, mean vessel‐weighted image (MvWI) and blood volume fraction (BVf) were mapped. Voxel‐based analyses and region of interest (ROI)‐based analyses were performed to compare the indices of the non‐Tg and Tg groups. Voxel comparisons showed that BVf, mVD, VSI and MvWI were greater in the Tg group than in the non‐Tg group. Additionally, the ROI‐based analysis showed that ΔR2*, BVf, mVD, MvWI and VSI increased in several brain regions of the Tg group compared with those in the non‐Tg group. VSI and mVD increased in Tg mice; these findings indicated microvascular disruption in the brain that could be related to damage to the neurovascular unit in AD caused by cerebral amyloid angiopathy. [ABSTRACT FROM AUTHOR]

Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer's disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer's disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research. [ABSTRACT FROM AUTHOR]

Purpose: Although a number of studies have focused on finding anatomical regions in which iron concentrations are high, no study has been conducted to examine the overall variations in susceptibility maps of Alzheimer's disease (AD). The objective of this study, therefore, was to differentiate AD from cognitive normal (CN) and mild cognitive impairment (MCI) using a texture analysis of quantitative susceptibility maps (QSMs). Methods: The study was approved by the local institutional review board, and informed consent was obtained from all subjects. In each participant group--CN, MCI, and AD--18 elderly subjects were enrolled. A fully first-order flow-compensated 3D gradient-echo sequence was run to obtain axial magnitudes and phase images and to produce QSM data. Sagittal structural 3D T1-weighted (3DT1W) images were also obtained with the magnetization-prepared rapid acquisition of gradientecho sequence to obtain brain tissue images. The first- and second-order texture parameters of the QSMs and 3DT1W images were obtained to evaluate group differences using a one-way analysis of covariance. Results: For the first-order QSM analysis, mean, standard deviation, and covariance of signal intensity separated the subject groups (F = 5.191, p = 0.009). For the second-order analysis, angular second moment, contrast, and correlation separated the subject groups (F = 6.896, p = 0.002). Finally, a receiver operating characteristic curve analysis differentiated MCI from CN in white matter on the QSMs (z = 3.092, p = 0.0020). Conclusions: This was the first study to evaluate the textures of QSM in AD, which overcame the limitations of voxel-based analyses. The QSM texture analysis successfully distinguished both AD and MCI from CN and outperformed the voxel-based analysis using 3DT1-weighed images in separating MCI from CN. The first-order textures were more efficient in differentiating MCI from CN than did the second-order. [ABSTRACT FROM AUTHOR]

Background: The metabolite response during a memory task in Alzheimer's disease (AD) patients is unknown.Objective: To investigate the metabolite changes in subjects with AD, amnestic mild cognitive impairment (aMCI), and cognitively normal (CN) elderly during a memory task using functional magnetic resonance spectroscopy (fMRS).Methods: This study involved 23 young normal controls (YC), 24 CN elderly, 24 aMCI, and 24 mild and probable AD individuals. fMRS data were acquired at the precuneus and posterior cingulate brain regions during a face-name association task. Statistical analyses of quantified metabolites were performed to evaluate differences of the metabolite values between the stimulation conditions and among the four subject groups. Receiver operating curve analysis was performed to evaluate whether the metabolic changes after functional activations can differentiate the subject groups.Result: Glutamine and glutamate complex (Glx) was statistically significantly different between the fixation and repeat conditions in aMCI (p = 0.0492) as well as between the fixation and the novel conditions in the AD (p = 0.0412) group. The total N-acetylaspartate (tNAA) was statistically significantly different among the four subject groups in the fixation condition (DF = 3, F = 7.673, p <  0.001), the novel condition (DF = 3, F = 6.945, p <  0.001), and the repeat condition (DF = 3, F = 7.127, p <  0.001). tNAA, tCr, and mIns could be used to differentiate CN from aMCI. Furthermore, tNAA, tCr, Glx, and Glu could also differentiate CN from AD, and aMCI from AD.Conclusion: Glx was altered during a stimulation that may be used to evaluate neuronal dysfunction in a demented patient. tNAA and tCr were reduced in patients with AD. [ABSTRACT FROM AUTHOR]

Abstract: Few studies have examined white matter hyperintensities (WMH) along the cognitive continuum between single-domain amnestic mild cognitive impairment (sd-aMCI) and Alzheimer’s disease (AD). The aims of our study were to explore relationships between the extent and location of WMH and disease severity along the cognitive continuum and to determine whether differences in the distribution of WMH could be predictive of specific patterns of cognitive impairment. We compared cognitive function, vascular risk factors, and regional (frontal lobe, parieto-occipital [PO] lobe, temporal lobe, periventricular [PV] white matter and deep white matter) WMH volume in 37 patients with mild AD, 23 patients with sd-aMCI, and 24 age-matched and education-matched normal controls. A quantitative volumetric method was applied to measure WMH burden. Total and regional WMH burdens, except for those in the temporal lobe, were significantly correlated with age (p <0.01). We found a trend toward increasing WMH volume with disease severity, higher in AD than in sd-aMCI and lowest in the controls. Total WMH volume was associated with the global cognitive test score. In multiple linear regression analysis, PV WMH volume, but not deep WMH volume, strongly predicted performances on the Controlled Oral Word Association test and the Color Word Stroop test after adjusting for important demographic variables. Only PO WMH volume was a significant predictor of a cognitive test score when frontal and temporal WMH volumes were simultaneously entered into the regression model. The extent and distribution of WMH, especially in the PV and PO regions, were associated with disease severity and reduced cognition. [Copyright &y& Elsevier]

The purpose of this study was to investigate myelin loss in both AD and mild cognitive impairment (MCI) patients with a new myelin water mapping technique within reasonable scan time and evaluate the clinical relevance of the apparent myelin water fraction (MWF) values by assessing the relationship between decreases in myelin water and the degree of memory decline or aging. Twenty-nine individuals were assigned to the cognitively normal (CN) elderly group, 32 participants were assigned to the MCI group, and 31 patients were assigned to the AD group. A 3D visualization of the short transverse relaxation time component (ViSTa)-gradient and spin-echo (GraSE) sequence was developed to map apparent MWF. Then, the MWF values were compared between the three participant groups and was evaluated the relationship with the degree of memory loss. The AD group showed a reduced apparent MWF compared to the CN and MCI groups. The largest AUC (area under the curve) value was in the corpus callosum and used to classify the CN and AD groups using the apparent MWF. The ViSTa-GraSE sequence can be a useful tool to map the MWF in a reasonable scan time. Combining the MWF in the corpus callosum with the detection of atrophy in the hippocampus can be valuable for group classification. [ABSTRACT FROM AUTHOR]

Cyclophilin A (CypA), heme oxygenase-1 (HO-1), and inositol-requiring enzyme 1 (IRE1) are believed to be associated with Alzheimer's disease (AD). In this study, we investigated the association between gray matter volume (GMV) changes and blood levels of CypA, HO-1, and IRE1 in cognitively normal (CN) subjects and those with amnestic mild cognitive impairment (aMCI) and AD. Forty-five elderly CN, 34 aMCI, and 39 AD subjects were enrolled in this study. The results of voxel-based multiple regression analysis showed that blood levels of CypA, HO-1, and IRE1 were correlated with GMV on brain magnetic resonance imaging (MRI) in the entire population (p = 0.0005). The three serum protein levels were correlated with GMV of signature AD regions in the population as a whole. CypA values increased with increasing GMV in the occipital gyrus (r = 0.387, p < 0.0001) and posterior cingulate (r = 0.196, p = 0.034). HO-1 values increased with increasing GMV at the uncus (r = 0.307, p = 0.0008), lateral globus pallidus and putamen (r = 0.287, p = 0.002), and hippocampus (r = 0.197, p = 0.034). IRE1 values decreased with increasing GMV at the uncus (r = −0.239, p = 0.010) and lateral globus pallidus and putamen (r = −0.335, p = 0.0002). Associations between the three serum protein levels and regional GMV indicate that the blood levels of these biomarkers may reflect the pathological mechanism of AD in the brain. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common type of dementia. AD involves major pathologies such as amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. During the progression of AD, microglia can be polarized from anti-inflammatory M2 to pro-inflammatory M1 phenotype. The activation of triggering receptor expressed on myeloid cells 2 (TREM2) may result in microglia phenotype switching from M1 to M2, which finally attenuated Aβ deposition and memory loss in AD. Low-dose ionizing radiation (LDIR) is known to ameliorate Aβ pathology and cognitive deficits in AD; however, the therapeutic mechanisms of LDIR against AD-related pathology have been little studied. First, we reconfirm that LDIR (two Gy per fraction for five times)-treated six-month 5XFAD mice exhibited (1) the reduction of Aβ deposition, as reflected by thioflavins S staining, and (2) the improvement of cognitive deficits, as revealed by Morris water maze test, compared to sham-exposed 5XFAD mice. To elucidate the mechanisms of LDIR-induced inhibition of Aβ accumulation and memory loss in AD, we examined whether LDIR regulates the microglial phenotype through the examination of levels of M1 and M2 cytokines in 5XFAD mice. In addition, we investigated the direct effects of LDIR on lipopolysaccharide (LPS)-induced production and secretion of M1/M2 cytokines in the BV-2 microglial cells. In the LPS- and LDIR-treated BV-2 cells, the M2 phenotypic marker CD206 was significantly increased, compared with LPS- and sham-treated BV-2 cells. Finally, the effect of LDIR on M2 polarization was confirmed by detection of increased expression of TREM2 in LPS-induced BV2 cells. These results suggest that LDIR directly induced phenotype switching from M1 to M2 in the brain with AD. Taken together, our results indicated that LDIR modulates LPS- and Aβ-induced neuroinflammation by promoting M2 polarization via TREM2 expression, and has beneficial effects in the AD-related pathology such as Aβ deposition and memory loss. [ABSTRACT FROM AUTHOR]

• Extra-neurite conductivity (EC) was higher in patients with Alzheimer's disease than cognitively normal elderly people. • EC values in the insula and middle temporal gyrus decreased with increasing the mini-mental state examination (MMSE) scores, after adjusting for age, but intra-neurite conductivity (IC) in the corpus callosum increased with increasing MMSE scores. • At the ROC curve, EC in the hippocampus and insula had high AUC values with high sensitivity and specificity. The objectives of this study were to investigate how the extra-neurite conductivity (EC) and intra-neurite conductivity (IC) were reflected in Alzheimer's disease (AD) patients compared with old cognitively normal (CN) people and patients with amnestic mild cognitive impairment (MCI) and to evaluate the association between those conductivity values and cognitive decline. To do this, high-frequency conductivity (HFC) at the Larmor frequency was obtained using MRI-based electrical property tomography (MREPT) and was decomposed into EC and IC using information of multi-shell multi-gradient direction diffusion tensor images. This prospective single-center study included 20 patients with mild or moderate AD, 25 patients with amnestic MCI, and 21 old CN participants. After decomposing EC and IC from HFC for all participants, we performed voxel-based and regions-of-interest analyses to compare conductivity between the three participant groups and to evaluate the association with either age or the Mini-Mental State Examination (MMSE) scores. We found increased EC in AD compared to CN and MCI. EC was significantly negatively associated with MMSE scores in the insula, and middle temporal gyrus. EC might be used as an imaging biomarker for helping to monitor cognitive function. [ABSTRACT FROM AUTHOR]

Progressive aggregation and protein misfolding are the initial fundamental indicators of neurodegenerative disorders such as Alzheimer's disease (AD). In this study, a highly sensitive and novel method to detect amyloid beta (Aβ) biomarkers, which are a hallmark of AD, using an immunoassay platform-based interdigitated capacitive biosensor, has been explored. For several decades, aptamers have classified as a novel class of molecular recognition probes comprising single-stranded complementary DNA sequences that bind to their identified targets with high specificity and affinity by an in vitro technique called SELEX (systematic evolution of exponential and enrichment). Aptamers, often referred to as "chemical antibodies", possess several highly obvious features for clinical use. The proposed sensing bio-device was fabricated and glazed with oligomeric Aβ (oAβ) aptamer and anti-oAβ antibody, functionalized onto a Pt/Ti-featured SiO 2 substrate. Subsequently, analytical studies were conducted to confirm that the specificity, sensitivity, and selective detection of the oAβ-based bioengineered surfaces facilitate a label-free approach. The bionic capacitive sensor achieved real-time detection within 5 s (faster response than ELISA) under the femto-molar range concentrations of oAβ peptide in plasma using anti-oAβ antibody and oAβ aptamer with ultra-high affinity. Furthermore, the prepared capacitive biochip was selective against plasma-borne antigens and standby for 100 days at 4 °C. The developed biosensor is suitable for point-of-care (POC) diagnostic applications owing to its portability and scalability. Furthermore, the superior efficacy of oAβ in identifying AD has huge potential for biomedical applications. [Display omitted] • Interdigitated Electrodes executed oAβ aptamer-switched biosensors. • Ultrasensitive Probeless Capacitive Biosensor (oAβ aptamer-APTS-Pt/Ti–SiO 2 IDCs) for Amyloid Beta (Aβ 1-42) Detection in Human Plasma. • SELEX (systematic evolution of exponential and enrichment) based Ultrasensitive Probeless Capacitive Biosensor. • Faster response times (5 s) than conventional diagnostic methods. • Point-of-care (POC) diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]