Journal of Alzheimer's Disease - Volume 77, issue 2

Authors: Pedrini, Steve | Hone, Eugene | Gupta, Veer B. | James, Ian | Teimouri, Elham | Bush, Ashley I. | Rowe, Christopher C. | Villemagne, Victor L. | Ames, David | Masters, Colin L. | Rainey-Smith, Stephanie | Verdile, Giuseppe | Sohrabi, Hamid R. | Raida, Manfred R. | Wenk, Markus R. | Taddei, Kevin | Chatterjee, Pratishtha | Martins, Ian | Laws, Simon M. | Martins, Ralph N. | the AIBL Research Group

Article Type: Research Article

Abstract: Background: The link between cholesterol and Alzheimer’s disease (AD) has received much attention, as evidence suggests high levels of cholesterol might be an AD risk factor. The carriage of cholesterol and lipids through the body is mediated via lipoproteins, some of which, particularly apolipoprotein E (ApoE), are intimately linked with AD. In humans, high density lipoprotein (HDL) is regarded as a “good” lipid complex due to its ability to enable clearance of excess cholesterol via ‘cholesterol reverse transport’, although its activities in the pathogenesis of AD are poorly understood. There are several subclasses of HDL; these range from the newly …formed small HDL, to much larger HDL. Objective: We examined the major subclasses of HDL in healthy controls, mild cognitively impaired, and AD patients who were not taking statins to determine whether there were HDL profile differences between the groups, and whether HDL subclass levels correlated with plasma amyloid-β (Aβ) levels or brain Aβ deposition. Methods: Samples from AIBL cohort were used in this study. HDL subclass levels were assessed by Lipoprint while Aβ1–42 levels were assessed by ELISA. Brain Aβ deposition was assessed by PET scan. Statistical analysis was performed using parametric and non-parametric tests. Results: We found that small HDL subclass is reduced in AD patients and it correlates with cognitive performance while plasma Aβ concentrations do not correlate with lipid profile or HDL subfraction levels. Conclusion: Our data indicate that AD patients exhibit altered plasma HDL profile and that HDL subclasses correlate with cognitive performances. Show more

Keywords: Amyloid-β, apolipoprotein, blood, cholesterol, lipid transport

DOI: 10.3233/JAD-200291

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 733-744, 2020

Authors: Keleman, Audrey | Wisch, Julie K. | Bollinger, Rebecca M. | Grant, Elizabeth A. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M. | Stark, Susan L.

Article Type: Research Article

Abstract: Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n  = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, …and hippocampal volume were compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p  = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = –0.75, p  = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p  = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD. Show more

Keywords: Alzheimer’s disease, biomarkers, falls, resting state functional connectivity, volumetrics

DOI: 10.3233/JAD-200192

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 745-752, 2020

Authors: Rao, Shalini S. | Portbury, Stuart. D. | Lago, Larissa | Bush, Ashley I. | Adlard, Paul A.

Article Type: Research Article

Abstract: This article has been retracted, and the online PDF has been watermarked “RETRACTED”. A retraction notice is available at DOI: https://dx.doi.org/10.3233/JAD-239009 .

DOI: 10.3233/JAD-200551

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 753-771, 2020

Authors: Hasegawa, Tohru | Kosoku, Yoshinori | Sano, Yuka | Yoshida, Hiroshi | Kudoh, Chiaki | Tabira, Takeshi

Article Type: Research Article

Abstract: Background: In the treatment of Alzheimer’s disease (AD), it is thought to be most effective to intervene at the earliest and mildest stages. For diagnosis at the earliest and mildest stages, it is desirable to use a biomarker that can be detected by a minimally invasive, cost-effective technique. Recent research indicates the potential clinical usefulness of plasma amyloid-β (Aβ ) biomarkers in predicting brain Aβ burden at an individual level. However, it is as yet unproven that accumulation of Aβ necessarily leads to the development of AD. Objective: Homocysteic acid (HCA) is useful as an …early diagnostic marker for mild cognitive impairment (MCI), a pre-stage of AD. Methods: We measured the concentration of HCA, tumor necrosis factor alpha, cortisol, tau, and phosphorylated tau (p-tau) in patients’ plasma of 22 AD, 23 MCI, and 9 negative control (NC) cases. Results: Plasma HCA was shown to be very high in areas under the receiver operating characteristic curves (AUC), distinguished between MCI and NC; when 0.116μ M was chosen as the analyte concentration cut-off, the sensitivity was 95.7% and the specificity was 70%. Conclusion: Our results suggest that plasma HCA may be a useful indicator as an early diagnostic marker for MCI. HCA seems to be upstream from neurodegeneration in the AD pathology because it is known that an overactive NMDA receptor promotes amyloid polymerization and tau phosphorylation in AD. Show more

Keywords: Alzheimer disease, homocysteic acid, mild cognitive impairment, plasma

DOI: 10.3233/JAD-200234

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 773-780, 2020

Authors: Zhang, Chenbo | Luo, Jianfeng | Yuan, Changzheng | Ding, Ding

Article Type: Research Article

Abstract: Background: Previous studies have indicated that B vitamin deficiencies are an essential cause of neurological pathology. There is a need to provide evidence of the benefit of B vitamins for the prevention of cognitive decline in community-dwelling older adults. Objective: To examine the association between intake and plasma levels of vitamins B12, B6, and folate and cognitive function in older populations through a systematic review and meta-analysis. Methods: Medline (PubMed), EMBASE, and Cochrane databases were used to search the literature though August 8, 2019. We included observational population-based studies evaluating the association between concentrations or intake …levels of vitamins B6, B12, or folate and cognition in older adults aged ≥45 years. The quality of all studies was assessed by the modified Newcastle-Ottawa Scale. Odds ratios (ORs) and hazard ratios (HRs) were analyzed by the random-effects model. Sensitivity analyses were conducted by excluding the studies with significant heterogeneity. Results: Twenty-one observational studies with sample sizes ranging from 155–7030 were included in the meta-analysis. Higher levels of vitamin B12 (OR = 0.77, 95% CI = 0.61–0.97) and folate concentration (OR = 0.68, 95% CI = 0.51–0.90) were associated with better cognition in cross-sectional studies, but not in sensitivity analyses or prospective studies. High vitamin B6 concentrations showed no significant benefit on cognition and dementia risk. Prospective studies did not provide substantial evidence for the relationship. Conclusion: The results from our meta-analysis suggest that vitamins B12, B6, and folate may not be modifiable risk factors for slowing cognitive decline among community-dwelling older individuals. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, folate, nutrition, vitamin B6, vitamin B12

DOI: 10.3233/JAD-200534

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 781-794, 2020

Authors: Furtado, André | Astaburuaga, Rosario | Costa, Ana | Duarte, Ana C. | Gonçalves, Isabel | Cipolla-Neto, José | Lemos, Manuel C. | Carro, Eva | Relógio, Angela | Santos, Cecília R.A. | Quintela, Telma

Article Type: Research Article

Abstract: Background: The choroid plexus (CP), which constitutes the blood-cerebrospinal fluid barrier, was recently identified as an important component of the circadian clock system. Objective: The fact that circadian rhythm disruption is closely associated to Alzheimer’s disease (AD) led us to investigate whether AD pathology can contribute to disturbances of the circadian clock in the CP. Methods: For this purpose, we evaluated the expression of core-clock genes at different time points, in 6- and 12-month-old female and male APP/PS1 mouse models of AD. In addition, we also assessed the effect of melatonin pre-treatment in vitro before …amyloid-β stimulus in the daily pattern of brain and muscle Arnt-like protein 1 (Bmal1) expression. Results: Our results showed a dysregulation of circadian rhythmicity of Bmal1 expression in female and male APP/PS1 transgenic 12-month-old mice and of Period 2 (Per2 ) expression in male mice. In addition, a significant circadian pattern of Bmal1 was measured the intermittent melatonin pre-treatment group, showing that melatonin can reset the CP circadian clock. Conclusion: These results demonstrated a connection between AD and the disruption of circadian rhythm in the CP, representing an attractive target for disease prevention and/or treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, blood-cerebrospinal fluid barrier, choroid plexus, circadian clock, melatonin

DOI: 10.3233/JAD-200331

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 795-806, 2020

Authors: Wang, Yan-Juan | Gong, Wei-Gang | Ren, Qing-Guo | Zhang, Zhi-Jun

Article Type: Research Article

Abstract: Background: The inhibition of tau hyperphosphorylation is one of the most promising therapeutic targets for the development of Alzheimer’s disease (AD) modifying drugs. Escitalopram, a kind of selective serotonin reuptake inhibitor antidepressant, has been previously reported to ameliorate tau hyperphosphorylation in vitro . Objective: In this study, we determined whether escitalopram alleviates tau pathologies in the aged P301L mouse. Methods: Mice were intraperitoneal injected with either escitalopram or saline for 4 weeks, and a battery of behavioral tests were conducted before tissue collection and biochemical analyses of brain tissue with western blot and immunohistochemistry. …Results: Wild-type (Wt) mice statistically outperformed the aged pR5 mice in the Morris water maze, while escitalopram treatment did not significantly rescue learning and memory deficits of aged pR5 mice. Tau phosphorylation at different phosphorylation sites were enhanced in the hippocampus of aged pR5 mice, while escitalopram treatment significantly decreased tau phosphorylation. The levels of phosphorylated GSK-3β and phosphorylated Akt were significantly decreased in the hippocampus of aged pR5 mice, while escitalopram administration markedly increased the expression level. The aged pR5 mice showed significant decreases in PSD95 and PSD93, while the administration of escitalopram significantly increased PSD95 and PSD93 to levels comparable with the Wt mice. Conclusion: The protective effects of escitalopram exposure during advanced AD are mainly associated with significant decrease in tau hyperphosphorylation, increased numbers of neurons, and increased synaptic protein levels, which may via activation of the Akt/GSK-3β signaling pathway. Show more

Keywords: Alzheimer’s disease, selective serotonin reuptake inhibitor, synapse, tau hyperphosphorylation, transgenic mice

DOI: 10.3233/JAD-200401

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 807-819, 2020

Authors: Silverman, Hannah E. | Gazes, Yunglin | Barker, Megan S. | Manoochehri, Masood | Goldman, Jill S. | Wassermann, Eric M. | Tierney, Michael C. | Cosentino, Stephanie | Grafman, Jordan | Huey, Edward D.

Article Type: Research Article

Abstract: Background: Changes in sexual behaviors in frontotemporal dementia (FTD) are common and multifaceted, but not well characterized. Objective: To characterize changes in sexual behaviors and intimacy in FTD compared to corticobasal syndrome (CBS) and normal controls (NC), and to evaluate the neuroanatomical associations of these changes. Methods: Spouses of 30 FTD patients, 20 CBS patients, and 35 NC completed the Sexual Symptoms in Neurological Illness and Injury Questionnaire (SNIQ), which captures changes in sexual interest, inappropriate sexual behaviors, and prosocial sexual behaviors. 25 patients with FTD and 14 patients with CBS also received 18-flouorodeoxyglucose positron-emission topography …(18 FDG-PET) scans to determine the metabolic changes associated with these symptoms. Results: FTD patients showed a greater increase in inappropriate sexual behaviors than CBS patients [p  = 0.009] and NC [p  < 0.001] and a greater decrease in prosocial sexual behaviors than CBS patients [p  = 0.026] and NC [p  < 0.001]. Groups did not differ in change in sexual interest. Among both patient groups, the most common change was decreased prosocial sexual behaviors p  < 0.01. Hypometabolism in Brodmann’s Area 10 (BA10), within the right frontal pole, correlated with decreased prosocial sexual behaviors [p (FWE-corr) <0.05, k  = 44]. No anatomical associations were found with other sexual changes. Conclusion: Decreased prosocial sexual behavior was associated with hypometabolism in BA 10, an area tied to social knowledge and theory of mind, supporting the idea that changes reflect social-cognitive deficits due to frontal dysfunction. Show more

Keywords: Frontal lobe, frontotemporal dementia, neurodegenerative disorders, prefrontal cortex, sexual behavior

DOI: 10.3233/JAD-200346

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 821-830, 2020

Authors: Aksnes, Mari | Müller, Ebba Glersen | Tiiman, Ann | Edwin, Trine Holt | Terenius, Lars | Revheim, Mona-Elisabeth | Vukojević, Vladana | Bogdanović, Nenad | Knapskog, Anne-Brita

Article Type: Research Article

Abstract: Background: Aggregation of amyloid-β (Aβ) is an early pathological event in Alzheimer’s disease (AD). Consequently, measures of pathogenic aggregated Aβ are attractive biomarkers for AD. Here, we use a recently developed Thioflavin-T-Fluorescence Correlation Spectroscopy (ThT-FCS) assay to quantify structured ThT-responsive protein aggregates, so-called nanoplaques, in the cerebrospinal fluid (CSF). Objective: The overall aim of this work was to assess whether ThT-FCS determined CSF nanoplaque levels could predict amyloid brain uptake as determined by 18 F-Flutemetamol PET analysis. Further, we assess whether nanoplaque levels could predict clinical AD. Methods: Nanoplaque levels in the CSF from 54 memory …clinic patients were compared between sub-groups classified by 18 F-Flutemetamol PET as amyloid-positive or amyloid-negative, and by clinical assessment as AD or non-AD. Results: Nanoplaque levels did not differ between amyloid groups and could not predict brain amyloid uptake. However, nanoplaque levels were significantly increased in patients with clinical AD, and were significant predictors for AD when adjusting for age, sex, cognitive function, and apolipoprotein E (APOE) genotype. Conclusion: The concentration of nanoplaques in the CSF differentiates patients with clinical AD from non-AD patients. Show more

Keywords: Alzheimer’s disease, amyloid, amyloid-β peptides, amyloidogenic proteins, biomarkers, cerebrospinal fluid, fluorescence spectrometry, positron-emission tomography, Thioflavin T

DOI: 10.3233/JAD-200237

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 831-842, 2020

Authors: Trammell, Antoine R. | McDaniel, Darius J. | Obideen, Malik | Okafor, Maureen | Thomas, Tiffany L. | Goldstein, Felicia C. | Shaw, Leslie M. | Hajjar, Ihab M.

Article Type: Research Article

Abstract: Background: African Americans (AA) have a higher Alzheimer’s disease (AD) prevalence and report more perceived stress than White Americans. The biological basis of the stress-AD link is unclear. This study investigates the connection between stress and AD biomarkers in a biracial cohort. Objective: Establish biomarker evidence for the observed association between stress and AD, especially in AA. Methods: A cross-sectional study (n  = 364, 41.8% AA) administering cognitive tests and the perceived stress scale (PSS) questionnaire. A subset (n  = 309) provided cerebrospinal fluid for measurement of Aβ42 , Tau, Ptau, Tau/Aβ42 (TAR), and Ptau/Aβ42 (PTAR). …Multivariate linear regression, including factors that confound racial differences in AD, was performed. Results: Higher PSS scores were associated with higher Ptau (β= 0.43, p  = 0.01) and PTAR (β= 0.005, p  = 0.03) in AA with impaired cognition (mild cognitive impairment). Conclusion: Higher PSS scores were associated with Tau-related AD biomarker indices in AA/MCI, suggesting a potential biological connection for stress with AD and its racial disparity. Show more

Keywords: African Americans, Alzheimer’s disease, tauopathy, amyloid-β peptides, cognitive function, mild cognitive impairment, neurocognitive tests, psychological stress

DOI: 10.3233/JAD-200089

Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 843-853, 2020