Journal of Alzheimer's Disease - Volume 70, issue 3

Authors: Cui, Yue | Dai, Sisi | Miao, Zupei | Zhong, Yu | Liu, Yang | Liu, Lin | Jing, Donglai | Bai, Yanyan | Kong, Yu | Sun, Wei | Li, Fang | Guo, Qihao | Rosa-Neto, Pedro | Gauthier, Serge | Wu, Liyong

Article Type: Research Article

Abstract: Background: The Mild Behavioral Impairment Checklist (MBI-C), a screening scale for neuropsychiatric symptom evaluation, facilitates Alzheimer’s disease (AD) screening. However, its validity and reliability for use as an AD screening tool have not been determined. Objective: To develop an AD screening scale suitable for the Chinese population. Methods: The MBI-C was translated into Chinese and back-translated with the original author’s consent. Forty-six AD patients, attending the Xuanwu hospital memory clinic, and 50 sex- and education-matched controls from the community underwent a full neuropsychological evaluation, including MBI-C assessment. Among them, 15 AD patients were evaluated repeatedly, and …eight were evaluated simultaneously by two different clinicians, to assess MBI-C reliability. Results: The MBI-C demonstrated good internal consistency reliability, test–retest reliability, and inter-rater reliability. Its optimal cutoff point was 6/7 for identifying AD dementia, with a sensitivity of 86.96% and specificity of 86.00%, and its detection rate for moderate–severe AD dementia was higher than that of the Neuropsychiatric Inventory Questionnaire (NPI-Q). Pearson’s correlation coefficients ranged from 0.702 to 0.831, indicating content validity. Seven factors were extracted during principal component analysis, with a cumulative contribution of 70.55%. Moreover, the Pearson’s correlation coefficient was 0.758, indicating its criterion validity. The MBI-C could also distinguish AD dementia severity. MBI-C scores were significantly negatively correlated with MMSE and MoCA scores, and positively correlated with ADL scores. Conclusion: This study showed that the Chinese version of MBI-C has high reliability and validity, and could replace the NPI-Q for AD dementia screening in the Chinese population. Show more

Keywords: Alzheimer’s disease, mild behavioral impairment checklist, neuropsychiatric inventory questionnaire, reliability, validity

DOI: 10.3233/JAD-190113

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 747-756, 2019

Authors: Lazarou, Ioulietta | Stavropoulos, Thanos G. | Meditskos, Georgios | Andreadis, Stelios | Kompatsiaris, Ioannis (Yiannis) | Tsolaki, Magda

Article Type: Research Article

Abstract: Background: Interactive smart home systems are particularly useful for people with cognitive impairment. Objective: To investigate the long-term effects of Assistive Technology (AT) combined with tailored non-pharmacological interventions for people with cognitive impairment. Methods: 18 participants (12 with mild cognitive impairment and 6 with Alzheimer’s disease) took part in the study that we evenly allocated in one of three groups: 1) experimental group (EG), 2) control group 1 (CG1), and 3) control group 2 (CG2). EG received the system installed at home for 4 to 12 months, during which they received tailored non-pharmacological interventions according to …system observations. CG1 received tailored interventions for the same period, but only according to state-of-the-art self-reporting methods. Finally, CG2 neither had a system installation nor received interventions. All groups underwent neuropsychological assessment before and after the observational period. Results: After several months of continuously monitoring at home and deployment of tailored interventions, the EG showed statistically significant improvement in cognitive function, compared to the CG1 and CG2. Moreover, EG participants, who received the sensor-based system, have shown improvement in domains such as sleep quality and daily activity, as measured by the multi-sensor system. In addition, the feedback collected from the participants concludes that the long-term use of the multi-sensor system by people with cognitive impairment can be both feasible and beneficial. Conclusion: Deploying a sensor-based system at real home settings of people with cognitive limitations living alone and maintaining its use long-term is not only possible, but also beneficial for clinical decision making in order to tackle cognitive, functional, and behavioral related problems. Show more

Keywords: Alzheimer’s disease, assistive technology, mild cognitive impairment, non-pharmacological interventions, patient engagement, remote monitoring, smart homes

DOI: 10.3233/JAD-190423

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 757-792, 2019

Authors: Bomba, Manuela | Granzotto, Alberto | Castelli, Vanessa | Onofrj, Marco | Lattanzio, Rossano | Cimini, Annamaria | Sensi, Stefano L.

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a multifactorial condition in which, along with amyloid-β (Aβ) and tau-related pathology, the synergistic activity of co-morbidity factors promote the onset and progression of the disease. Epidemiological evidence indicates that glucose intolerance, deficits in insulin secretion, or type-2 diabetes mellitus (T2DM) participate in increasing cognitive impairment or dementia risk. Insulin plays a pivotal role in the process as the hormone critically regulates brain functioning. GLP-1, the glucagon-like peptide 1, facilitates insulin signaling, regulates glucose homeostasis, and modulates synaptic plasticity. Exenatide is a synthetic GLP-1 analog employed in T2DM. However, exenatide has also been shown to affect …the signaling of the brain-derived neurotrophic factor (BDNF), synaptic plasticity, and cognitive performances in animal models. In this study, we tested whether exenatide exerts neuroprotection in a preclinical AD model set to mimic the clinical complexity of the human disease. We investigated the effects of exenatide treatment in 3xTg-AD mice challenged with a high-fat diet (HFD). Endpoints of the study were variations in systemic metabolism, insulin and neurotrophic signaling, neuroinflammation, Aβ and tau pathology, and cognitive performances. Results of the study indicate that exenatide reverts the adverse changes of BDNF signaling and the neuroinflammation status of 3xTg-AD mice undergoing HFD without affecting systemic metabolism or promoting changes in cognitive performances. Show more

Keywords: Aging, BDNF, diabetes, exendin-4, insulin, insulin resistance, neurotrophic factors, dementia, T2DM

DOI: 10.3233/JAD-190237

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 793-810, 2019

Authors: Gagliardi, Geoffroy | Epelbaum, Stéphane | Houot, Marion | Bakardjian, Hovagim | Boukadida, Laurie | Revillon, Marie | Dubois, Bruno | Dalla Barba, Gianfranco | La Corte, Valentina | for the INSIGHT-preAD study group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology is found in the brain years before symptoms are usually detected. An episodic memory (EM) decline is considered to be the specific cognitive sign indicating a transition from the preclinical to the prodromal stage of AD. However, there is still no consensus on the most sensitive tool to detect it. Objective: The goal of our study was to determine which EM measures, among three clinically used EM tests and one research EM test, would be optimal to use for detection of early decline in elderly cognitive complainers. Methods: 318 healthy elderly …participants with subjective cognitive complaint were followed for two years. We applied generalized linear mixed models to investigate the effect of baseline brain amyloid and metabolism on the longitudinal evolution of four EM tests. Results: Our findings show that participants performed significantly worse in two out of four EM tests (i.e., the Memory Binding Test and the Delayed Matched Sample test 48 items) as their level of brain amyloid load increased. However, we did not find an association between EM measures and brain metabolism. An interaction of the two biomarkers was associated with the number of intrusions in the Memory Binding Test over two years. Conclusion: As most clinical trials in AD are now including patients at its early clinical stage, the precise delineation of the transition phase between the preclinical and prodromal stages of the disease is of crucial importance. Our study indicates that challenging EM tests and intrusions are valuable tools to identify this critical transition. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, episodic memory, preclinical

DOI: 10.3233/JAD-180966

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 811-824, 2019

Authors: Wells, Rebecca Erwin | Kerr, Catherine | Dossett, Michelle L. | Danhauer, Suzanne C. | Sohl, Stephanie J. | Sachs, Bonnie C. | Feeley, Jacquelyn Walsh | Wolkin, Jennifer | Wall, Robert | Kaptchuk, Ted | Press, Daniel Z. | Phillips, Russell S. | Yeh, Gloria Y.

Article Type: Research Article

Abstract: Background/Objective: High levels of chronic stress negatively impact the hippocampus and are associated with increased incidence of mild cognitive impairment (MCI) and Alzheimer’s disease. While mindfulness meditation may mitigate the effects of chronic stress, it is uncertain if adults with MCI have the capacity to learn mindfulness meditation. Methods: 14 adults with MCI were randomized 2:1 to Mindfulness Based Stress Reduction (MBSR) or a wait-list control group. We conducted qualitative interviews with those who completed MBSR. Transcribed interviews were: a) coded using an emergent themes inductive approach informed by grounded theory; b) rated 0–10, with higher scores reflecting …greater perceived benefit from, and understanding of, mindfulness meditation. Ratings were correlated with daily home practice times and baseline level of cognitive function. Results: Seven themes emerged from the interviews: positive perceptions of class; development of mindfulness skills, including meta-cognition; importance of the group experience; enhanced well-being; shift in MCI perspective; decreased stress reactivity and increased relaxation; improvement in interpersonal skills. Ratings of perceived benefit and understanding ranged from 2–10 (mean = 7) and of 0–9.5 (mean = 6), respectively. Many participants experienced substantial benefit/understanding, some had moderate, and a few had minimal benefit/understanding. Understanding the key concepts of mindfulness was highly positively correlated with ≥20 minutes/day of home practice (r  = 0.90) but not with baseline cognitive function (r  = 0.13). Conclusions: Most adults with MCI were able to learn mindfulness meditation and had improved MCI acceptance, self-efficacy, and social engagement. Cognitive reserve may be enhanced through a mindfulness meditation program even in patients with MCI. Show more

Keywords: Alzheimer’s disease, meditation, mild cognitive impairment, mindfulness, randomized clinical trial, yoga

DOI: 10.3233/JAD-190191

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 825-842, 2019

Authors: Zhu, Yao | Gong, Liang | He, Cancan | Wang, Qing | Ren, Qingguo | Xie, Chunming | on behalf of Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Although previous studies have investigated the effects of the apolipoprotein E (APOE ) ɛ 4 genotype on the default mode network (DMN) in the Alzheimer’s disease (AD) spectrum, it is still unclear how the APOE genotype regulates the DMN and subsequently affects cognitive decline in the AD spectrum. One hundred sixty-nine subjects with resting-state functional magnetic resonance imaging data and neuropsychological test scores were selected from the Alzheimer’s Disease Neuroimaging Initiative. The main effects and interaction of the APOE genotype and disease status on the DMN were explored. A moderation analysis was performed to investigate the relationship among …the APOE genotype, DMN connectivity, and cognition. Additionally, the pair-wised DMN connectivity was used to classify AD spectrum, and the classification accuracy was validated. Compared to APOE ɛ 4 non-carriers, APOE ɛ 4 carriers showed the opposite trajectory of DMN connectivity across the AD spectrum. Specifically, the strengths in the posterior cingulate cortex (PCC) connecting with the right precuneus, insular, and fusiform area (FFA) were positively correlated with Mini-Mental State Examination (MMSE) scores in APOE ɛ 4 non-carriers but not in APOE ɛ 4 carriers. Furthermore, PCC-right FFA connectivity could moderate the effects of the APOE genotype on MMSE scores across the disease groups. More importantly, using a receiver operating characteristic analysis, these altered connectivities yielded strong classification powers in a pathological stage-dependent manner in the AD spectrum. These findings first identified the intrinsic DMN connectivity moderating the effect of the APOE genotype on cognition and provided a pathological stage-dependent neuroimaging biomarker for early differentiation of the AD spectrum. Show more

Keywords: Alzheimer’s disease, apolipoprotein E, classification, moderation analysis, resting-state functional magnetic resonance imaging

DOI: 10.3233/JAD-190254

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 843-860, 2019

Authors: Simonovitch, Shira | Schmukler, Eran | Masliah, Eliezer | Pinkas-Kramarski, Ronit | Michaelson, Daniel M.

Article Type: Research Article

Abstract: This study examined the effects of apolipoprotein E4 (APOE4 ), the most prevalent genetic risk factor for Alzheimer’s disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial …proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4 -related therapeutic targets. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, autophagy, mitochondrial dynamics, mitophagy

DOI: 10.3233/JAD-190074

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 861-875, 2019

Authors: Schaeffer, Morgan J. | Callahan, Brandy L. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The percentage of verbal forgetting (VF%) measure of the Rey Auditory Verbal Learning Test (RAVLT) has been proposed to differentiate patients diagnosed clinically with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: To determine if VF% aligns with gold-standard biomarker and autopsy evidence of AD and DLB neuropathology. Methods: Clinical, cognitive, sociodemographic, and biomarker data were collected from 315 patients with baseline cognitive impairment and 485 normal controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). AD markers included reduced cerebrospinal fluid (CSF) amyloid-β, elevated total-tau and phosphorylated-tau, hippocampal atrophy, and the presence of …amyloid plaques and neurofibrillary tangles at autopsy. DLB markers included reduced CSF α -synuclein, preserved hippocampus, atrophied putamen, occipital glucose metabolism, and the presence of Lewy bodies at autopsy. Cognitively impaired participants were classified as ADVF% (n  = 190) or DLBVF% (n  = 125) based on their RAVLT VF% scores using a 75% cut-off (≥75%  = ADVF% , <75%  = DLBVF% ). Postmortem data were available for 13 ADVF% participants, 13 DLBVF% patients, and six healthy controls. Results: ADVF% and DLBVF% participants did not differ on CSF or neuroimaging biomarkers, with the exception of total tau levels which were higher in ADVF% . In the subset of participants with autopsy data, comorbid AD and DLB pathology was most frequent in ADVF% participants, and pure DLB pathology was most frequent in DLBVF% participants, however, these differences were not statistically significant. Conclusion: The RAVLT VF% measure does not reliably align with AD and DLB neuropathology in ADNI participants. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive assessment, Lewy body disease, memory, neuropathology

DOI: 10.3233/JAD-180962

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 877-887, 2019

Authors: Molad, Jeremy | Hallevi, Hen | Korczyn, Amos D. | Kliper, Efrat | Auriel, Eitan | Bornstein, Natan M. | Ben Assayag, Einor

Article Type: Research Article

Abstract: Background: Stroke is a major cause of cognitive impairment and dementia. However, the underlying mechanisms beyond post-stroke cognitive impairment (PSCI) are not fully explained to date. Objective: We studied the contribution of vascular pathology measures to PSCI, separate from and in conjunction with pathologic markers associated with Alzheimer’s disease (AD). Methods: Data from 397 cognitively intact ischemic stroke patients were available. All patients underwent 3T MRI and evaluated for white matter hyperintensity volume (WMHV) and integrity, ischemic lesions, small vessel disease (SVD) markers and grey matter (GM), hippocampal and cerebrospinal fluid (CSF) volumes. Comprehensive cognitive tests …were performed on admission and after two years. We used multiple regression to evaluate the contributions of vascular pathology measures (Framingham risk score, WMHV, and existence of SVD) and AD-associated markers (apolipoprotein E4 status and hippocampal volume). Results: During two years follow-up, 80 participants (20.2%) developed PSCI. Low GM and cortex volume and high WMHV and CSF volume, but not the new lesion volume, predicted the development of PSCI in a dose-dependent relationship (p  = 0.001). Vascular related imaging markers and risk factors predicted PSCI better than AD related markers (p  < 0.001). Conclusions: Brain structural measures, including total GM volume, WMHV, and CSF volume were independently associated with PSCI and may serve as early biomarkers for risk prediction. In our sample, vascular pathology measures contributed significantly better to PSCI prediction than markers associated with AD. The newly detected ischemic lesion has not emerged as biomarker for PSCI risk, thus maybe a part of the ongoing vascular pathology. Show more

Keywords: Cognitive impairment, neuroimaging, predictors, stroke

DOI: 10.3233/JAD-190339

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 889-898, 2019

Authors: Kostev, Karel | Kurylo, Pawel | Kosik, Joanna | Jacob, Louis

Article Type: Research Article

Abstract: Background: Previous studies have suggested that there are substantial differences between countries in terms of persistence with antidementia drugs and that the management of dementia is likely to be population-specific. Objective: The aim of this study was to analyze the one-year persistence with donepezil, memantine, and rivastigmine in more than 66,000 elderly patients followed in Poland. Methods: This study included patients who were prescribed donepezil, memantine, or rivastigmine for the first time in general and neuropsychiatric practices in Poland between September 2016 and December 2017 (index date; N  = 66,030). The primary outcome of the study was …the one-year persistence with donepezil, memantine, and rivastigmine. Non-persistence was defined as a gap of at least 90 days without anti-dementia therapy. The secondary outcome was the identification of variables significantly associated with treatment non-persistence. Results: After 12 months of follow-up, 42.2% of donepezil users, 46.0% of rivastigmine users, and 65.9% of memantine users were persistent (log-rank p -value <0.001). Memantine (hazard ratio [HR] = 0.58) and rivastigmine users (HR = 0.92) were less likely to discontinue treatment one year after initiation than donepezil users. Furthermore, a younger age (60–64 years: HR = 1.32; 65–74 years: HR = 1.13) and therapy initiated by a neuropsychiatrist (HR = 1.11) were positively associated with therapy discontinuation, while we observed a negative association between the prescription of anti-psychotic drugs and non-persistence (HR = 0.81). Conclusion: One-year persistence with donepezil, memantine, and rivastigmine was low in elderly patients followed in Poland, and was influenced by age, physician specialty, and co-therapy. Show more

Keywords: Anti-dementia drugs, older adults, one-year persistence, Poland, predictors

DOI: 10.3233/JAD-190508

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 899-905, 2019

Authors: Nazarian, Alireza | Kulminski, Alexander M.

Article Type: Research Article

Abstract: Heritability analysis of complex traits/diseases is commonly performed to obtain illustrative information about the potential contribution of the genetic factors to their phenotypic variances. In this study, we investigated the narrow-sense heritability (h 2 ) of Alzheimer’s disease (AD) using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent studies in the linear mixed models framework. Our meta-analyses demonstrated that the estimated h 2 values (and their standard errors) of AD in liability scale were 0.280 (0.091), 0.348 (0.113), and 0.389 (0.126) assuming AD prevalence rates of 10%, 20%, or 30% at ages of 65+, 75+, and 85+ years, respectively. …We also found that chromosomal regions containing two or more AD-associated SNPs at p  < 5E-08 could collectively explain 37% of the additive genetic variance of AD in our samples. AD-associated regions in which at least one SNP had attained p  < 5E-08 explained 56% of the additive genetic variance of AD. These regions harbored 3% and 11% of SNPs in our analyses. Also, the chromosomal regions containing two or more and one or more AD-associated SNPs at p  < 5E-06 accounted for 72% and 94% of the additive genetic variance of AD, respectively. These regions harbored 27% and 44% of SNPs in our analyses. Our findings showed that the overall contribution of the additive genetic effects to the AD liability was moderate and age-dependent. Also, they supported the importance of focusing on known AD-associated chromosomal regions to investigate the genetic basis of AD, e.g., through haplotype analysis, analysis of heterogeneity, and functional studies. Show more

Keywords: Aging, complex disorders, dementia, missing heritability, narrow-sense heritability, neurodegenerative disorders, polygenic inheritance

DOI: 10.3233/JAD-190168

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 907-915, 2019

Authors: Pandey, Janardan P. | Kothera, Ronald T. | Liu, Shufeng | Costa, Andrea Saul | Mancuso, Roberta | Agostini, Simone

Article Type: Research Article

Abstract: Although genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (AD) have identified numerous genes that influence the risk for disease, the majority of the genetic variance of AD remains uncharacterized. Furthermore, current GWAS, despite their name, do not evaluate all genes in the human genome. One such gene complex is immunoglobulin GM (γ marker) genes on chromosome 14. GM genes are excellent candidate genes for AD because they influence immunity to herpes simplex virus type 1 (HSV1), which has been implicated in AD pathology by an increasing number of reports. The aim of this investigation was to determine if …particular GM genotypes were associated with AD and mild cognitive impairment (MCI), and whether they contributed to the interindividual differences in the level of anti-HSV1 IgG antibodies. A total of 141 HSV1 seropositive individuals—56 AD patients, 48 MCI individuals, and 37 sex- and age-matched healthy controls—were characterized for GM alleles 3, 17, and 23. The homozygosity for the GM 3 allele was significantly associated with MCI (p  = 0.025). GM 3/17 heterozygous AD patients had significantly higher levels of anti-HSV1 antibodies than the healthy controls expressing the same genotype (p  = 0.0004). Among MCI subjects, the GM 3/17 genotype was associated with significantly higher level of anti-HSV1 antibodies as compared to the GM 17/17 homozygous genotype (pc  = 0.040). Among AD patients, the GM 23+/–genotype was significantly associated with anti-HSV1 antibody responses (pc  = 0.025). These results suggest that GM genes could act as potential unifiers of the genetic and viral etiology of AD. Show more

Keywords: Antibody dependent cellular cytotoxicity, APOE4, Fcγ receptor, γ marker (GM) allotypes, HSV1, immunoevasion

DOI: 10.3233/JAD-190265

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 917-924, 2019

Authors: Yu, Qian | Dai, Chun-Ling | Zhang, Yongli | Chen, Yanxing | Wu, Zhe | Iqbal, Khalid | Liu, Fei | Gong, Cheng-Xin

Article Type: Research Article

Abstract: General anesthesia increases the risk for cognitive impairment and Alzheimer’s disease (AD) in vulnerable individuals such as the elderly. We previously reported that prior administration of insulin through intranasal delivery can prevent the anesthesia-induced cognitive impairment and biochemical changes in the brain. However, little is known about the underlying molecular mechanisms. Here, we report that general anesthesia resulted in downregulation of mammalian/mechanistic target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the brain along with reduction of presynaptic proteins and brain-derived neurotrophic factor and cognitive impairment in aged mice. Prior administration of intranasal insulin prevented these anesthesia-induced changes. …These results suggest the involvement of the mTOR-eEF2 signaling pathway in the anesthesia-induced brain changes and cognitive impairment and in the prevention of these changes with insulin. Correlation analyses and the use of eEF2 kinase inhibitor further support our conclusions. These studies shed light on the molecular mechanism by which anesthesia and insulin could act on synaptic proteins and cognitive function. Show more

Keywords: Anesthesia, cognitive impairment, eEF2, insulin, intranasal delivery, mTOR, synaptic proteins

DOI: 10.3233/JAD-190280

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 925-936, 2019

Authors: Taniguchi, Kaori | Yamamoto, Fumiko | Arai, Takuya | Yang, Jinwei | Sakai, Yusuke | Itoh, Masayuki | Mamada, Naomi | Sekiguchi, Masayuki | Yamada, Daisuke | Saitoh, Akiyoshi | Kametani, Fuyuki | Tamaoka, Akira | Araki, Yumiko M. | Wada, Keiji | Mizusawa, Hidehiro | Araki, Wataru

Article Type: Research Article

Abstract: Soluble amyloid-β (Aβ) oligomers (AβOs), which elicit neurotoxicity and synaptotoxicity, are thought to play an initiating role in the pathology of Alzheimer’s disease (AD). Since AβOs are a key therapeutic target, we attempted to identify natural agents that reduce AβO neurotoxicity. Using an assay system in which primary cultured neurons are treated with AβOs, we found that Rhodiola rosea extracts and one of its main constituents, tyrosol, significantly inhibited AβO-induced caspase-3 activation. We then assessed the in vivo efficacy of tyrosol by oral administration of the compound into AD model (5XFAD) transgenic and non-transgenic mice from either 2 …or 4 to 7 months of age. In both paradigms, tyrosol treatment did not affect body weights of mice. Immunohistochemical analysis revealed that the immunoreactivity of spinophilin, a dendritic synaptic protein, was significantly reduced in three hippocampal subregions of vehicle-treated AD mice compared with non-transgenic mice, which was reversed in tyrosol-treated AD mice. Tyrosol treatment also prevented the enhancement of 4-hydroxy-2-nonenal immunoreactivity in the hippocampal CA3 region of AD mice. By contrast, tyrosol administration did not affect Aβ accumulation, as evaluated by immunohistochemical and biochemical analyses. Moreover, the Barnes maze test showed that tyrosol administration modestly mitigated spatial memory impairment in AD mice. These findings collectively indicate that the natural agent tyrosol protects neurons against AβO neurotoxicity in vitro and ameliorates synaptic disturbance, oxidative stress responses, and cognitive impairment in vivo . We thus suggest that tyrosol is potentially an effective, safe, and unique drug candidate for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, neuron, oligomer, oxidative stress, synapse

DOI: 10.3233/JAD-190098

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 937-952, 2019

Authors: Low, Audrey | Ng, Kok Pin | Chander, Russell Jude | Wong, Benjamin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Objective: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. Methods: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, …controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. Results: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. Conclusion: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4 -negative cognitive impairment, compared to APOE4 -positive which may be driven primarily by AD pathology. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cerebral small vessel diseases, cognitive aging, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-190159

Citation: Journal of Alzheimer's Disease, vol. 70, no. 3, pp. 953-964, 2019