Current Alzheimer Research - Volume 18, Issue 1, 2021

Background: In a previous study on Alzheimer’s disease (AD), we showed that vestibular dysfunction derived from cerebral disorders contributes to balance disorders. No previous clinical study has attempted to prevent the progression of balance disorders in dementia patients through vestibular stimulation using an air caloric device. Objective: The purpose of this pilot study was to delay the progression of balance disorders by inducing vestibular compensation, specifically by utilizing the effect of vestibular stimulation to activate the cerebrum. Methods: Fifteen individuals were randomized and classified into a stimulation group or a nonstimulation group. Eight AD patients underwent vestibular stimulation every 2 weeks for 6 months in the stimulation group. Seven AD patients participated in the nonstimulation group (the control group). Both groups were subsequently evaluated using a Mini-Mental State Examination (MMSE), stepping test, caloric test, and smooth pursuit eye movement test just before starting the study and 6 months later. Results: For balance parameters, the various tests did not show any significant differences between the two groups. However, in the stepping test, the decline rate tended to be higher in the nonstimulation group than in the stimulation group. The stimulation group’s rate of decline in MMSE scores was lower than that of the nonstimulation group (p=0.015). No adverse events were tracked during the present study. Conclusion: Repeated vestibular stimulation might help patients retain greater balance and higher function. To prove these effects, the future clinical application will require an increased number of cases and longer periods of vestibular stimulation. This study showed that vestibular stimulation by air caloric device is safe and tolerable in patients with AD.

Background: White matter (WM) beta-amyloid uptake has been used as a reference region to calculate the cortical standard uptake value ratio (SUVr). However, white matter hyperintensities (WMH) may have an influence on WM beta-amyloid uptake. Our study aimed to investigate the associations between WMH and WM beta-amyloid deposition in cognitively unimpaired elderly. Methods: Data from 83 cognitively unimpaired individuals in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset were analyzed. All participants had complete baseline and four-year follow-up information about WMH volume, WM 18F-AV-45 SUVr, and cognitive function, including ADNI-Memory (ADNI-Mem) and ADNI-Executive function (ADNI-EF) scores. Cross-sectional and longitudinal linear regression analyses were used to determine the associations between WMH and WM SUVr and cognitive measures. Results: Lower WM 18F-AV-45 SUVr at baseline was associated with younger age (β=0.01, P=0.037) and larger WMH volume (β=-0.049, P=0.048). The longitudinal analysis found an annual increase in WM 18F-AV-45 SUVr was associated with an annual decrease in WMH volume (β=-0.016, P=0.041). An annual decrease in the ADNI-Mem score was associated with an annual increase in WMH volume (β=-0.070, P=0.001), an annual decrease in WM 18F-AV-45 SUVr (β=0.559, P=0.030), and fewer years of education (β=0.011, P=0.044). There was no significant association between WM 18F-AV-45 SUVr and ADNI-EF (P>0.05). Conclusion: Reduced beta-amyloid deposition in WM was associated with higher WMH load and memory decline in cognitively unimpaired elderly. WMH volume should be considered when WM 18F-AV-45 SUVr is used as a reference for evaluating cortical 18F-AV-45 SUVr.

Background: Environmental risk factors, including environmental noise stress, and genetic factors, have been associated with the occurrence and development of Alzheimer’s disease (AD). However, the exact role and mechanism of AD-like pathology induced by environment-gene interactions between environmental noise and APP/PS1 gene remain elusive. Methods: Herein, we investigated the impact of chronic noise exposure on AD-like neuropathology in APP/PS1 transgenic mice. The Morris water maze (MWM) task was conducted to evaluate AD-like changes. The hippocampal phosphorylated Tau, amyloid-β (Aβ), and neuroinflammation were assessed. We also assessed changes in positive feedback loop signaling of the voltage-dependent anion channel 1 (VDAC1) to explore the potential underlying mechanism linking AD-like neuropathology to noise-APP/PS1 interactions. Results: Long-term noise exposure significantly increased the escape latency and the number of platform crossings in the MWM task. The Aβ overproduction was induced in the hippocampus of APP/PS1 mice, along with the increase of Tau phosphorylation at Ser396 and Thr231 and the increase of the microglia and astrocytes markers expression. Moreover, the VDAC1-AKT (protein kinase B)-GSK3β (glycogen synthase kinase 3 beta)-VDAC1 signaling pathway was abnormally activated in the hippocampus of APP/PS1 mice after noise exposure. Conclusion: Chronic noise exposure and APP/PS1 overexpression may synergistically exacerbate cognitive impairment and neuropathological changes that occur in AD. This interaction may be mediated by the positive feedback loop of the VDAC1-AKT-GSK3β-VDAC1 signaling pathway.

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the research focus from Aβ to other pathological features of the disease. Objective: The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy. Methods: In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibiting different cell-membrane and BBB permeability were employed to assess BBB integrity and brain tissue redox status in the 5xFAD mouse model of AD. In vivo spin probe reduction decay was analyzed using a two-compartment pharmacokinetic model. Furthermore, 15 K EPR spectroscopy was employed to investigate the brain metal content. Results: This study has revealed an altered brain redox state, BBB breakdown, as well as ROS-mediated damage to mitochondrial iron-sulfur clusters, and up-regulation of MnSOD in the 5xFAD model. Conclusion: The EPR spin probes were shown to be excellent in vivo reporters of the 5xFAD neuronal tissue redox state, as well as the BBB integrity, indicating the importance of in vivo EPR spectroscopy application in preclinical studies of neurodegenerative diseases.

Background: As a potential brain imaging biomarker, amplitude of low frequency fluctuation (ALFF) has been used as a feature to distinguish patients with Alzheimer’s disease (AD) and amnestic mild cognitive impairment (aMCI) from normal controls (NC). However, it remains unclear whether the frequency-dependent pattern of ALFF alterations can effectively distinguish the different phases of the disease. Methods: In the present study, 52 AD and 50 aMCI patients were enrolled together with 43 NC in total. The ALFF values were calculated in the following three frequency bands: classical (0.01-0.08 Hz), slow-4 (0.027-0.073 Hz) and slow-5 (0.01-0.027 Hz) for the three different groups. Subsequently, the local functional abnormalities were employed as features to examine the effect of classification among AD, aMCI and NC using a support vector machine (SVM). Results: We found that the among-group differences of ALFF in the different frequency bands were mainly located in the left hippocampus (HP), right HP, bilateral posterior cingulate cortex (PCC) and bilateral precuneus (PCu), left angular gyrus (AG) and left medial prefrontal cortex (mPFC). When the local functional abnormalities were employed as features, we identified that the ALFF in the slow-5 frequency band showed the highest accuracy to distinguish among the three groups. Conclusion: These findings may deepen our understanding of the pathogenesis of AD and suggest that slow-5 frequency band may be helpful to explore the pathogenesis and distinguish the phases of this disease.

Background: Sufficient attention was not paid to the effects of microtubule-associated protein tau (MAPT) and plasma tau protein on cognition. Objective: A total of 3072 people in rural China were recruited. They were provided with questionnaires, and blood samples were obtained. Methods: The MMSE score was used to divide the population into cognitive impairment group and control group. First, logistic regression analysis was used to explore the possible factors influencing cognitive function. Second, 1837 samples were selected for SNP detection through stratified sampling. Third, 288 samples were selected to test three plasma biomarkers (tau, phosphorylated tau, and Aβ-42). Results: For the MAPT rs242557, people with AG genotypes were 1.32 times more likely to develop cognitive impairment than those with AA genotypes, and people with GG genotypes were 1.47 times more likely to develop cognitive impairment than those with AG phenotypes. The plasma tau protein concentration was also increased in the population carrying G (P = 0.020). The plasma tau protein was negatively correlated with the MMSE score (P = 0.004). Conclusion: The mutation of MAPT rs242557 (A > G) increased the risk of cognitive impairment and the concentration of plasma tau protein.

Background: APOE ε4 is the best-known risk factor for late-onset alzheimer’s disease (AD). Population studies have demonstrated a relatively low prevalence of APOE ε4 among Chinese population, implying additional risk factors that are Chinese-specific may exist. Apart from - alleles, genetic variation profile along the full-length APOE has rarely been investigated. Objective: In this study, we filled this gap by comprehensively determining all genetic variations in APOE and investigated their potential associations with late-onset AD and mild cognitive impairment (MCI) in southern Chinese. Methods: Two hundred and fifty-seven southern Chinese participants were recruited, of whom 69 were AD patients, 83 had MCI, and 105 were normal controls. Full-length APOE from promoter to 3′UTR regions were sequenced. Genetic variants were identified and compared among the three groups. Results: While APOE ε4 was more significantly found in AD patients, the prevalence of APOE ε4 in southern Chinese AD patients was the lowest when compared to other areas of China and nearby regions, as well as other countries worldwide. We further identified 13 rare non-singleton variants in APOE. Significantly more AD patients carried any of the rare non-singleton variants than MCI and normal subjects. Such difference was observed in the non-carriers of ε4-allele only. Among the identified rare variants, the potential functional impact was predicted for rs532314089, rs553874843, rs533904656 and rs370594287. Conclusion: Our study suggests an ethnic difference in genetic risk composition of AD in southern Chinese. Rare variants on APOE are a potential candidate for AD risk stratification biomarker in addition to APOE-ε4.

Background: In Alzheimer’s disease, accumulation of beta amyloid (Aβ) triggers amyloidogenesis and hyperphosphorylation of tau protein leading to neuronal cell death. Piper sarmentosum Roxb. (PS) is a traditional medicinal herb used by Malay to treat rheumatism, headache and boost memory. It possesses various biological effects, such as anti-cholinergic, anti-inflammatory, anti-oxidant and anti-depressant-like effects. Objective: The present study aimed to investigate neuroprotective properties of PS against Aβ-induced neurotoxicity and to evaluate its potential mechanism of action. Methods: Neuroprotective effects of hexane (HXN), dichloromethane (DCM), ethyl acetate (EA) and methanol (MEOH) extracts from leaves (L) and roots (R) of PS against Aβ-induced neurotoxicity were investigated in SH-SY5Y human neuroblastoma cells. Cells were pre-treated with PS for 24 h followed by 24 h of induction with Aβ. The neuroprotective effects of PS were studied using cell viability and cellular reactive oxygen species (ROS) assays. The levels of extracellular Aβ and tau proteins phosphorylated at threonine 231 (pT231) were determined. Gene and protein expressions were assessed using qRT-PCR analyses and western blot analyses, respectively. Results: Hexane extracts of PS (LHXN and RHXN) protected SH-SY5Y cells against Aβ-induced neurotoxicity, and decreased levels of extracellular Aβ and phosphorylated tau (pT231). Although extracts of PS inhibited Aβ-induced ROS production, it was unlikely that neuroprotective effects were simply due to the anti-oxidant capacity of PS. Further, mechanistic study suggested that the neuroprotective effects of PS might be due to its capability to regulate amyloidogenesis through the downregulation of BACE and APP. Conclusion: These findings suggest that hexane extracts of PS confer neuroprotection against Aβ- induced neurotoxicity in SH-SY5Y cells by attenuating amyloidogenesis and tau hyperphosphorylation. Due to its neuroprotective properties, PS might be a potential therapeutic agent for Alzheimer’s disease.