Journal of Alzheimer's Disease - Volume Pre-press, issue Pre-press

Authors: Livny, Abigail | Schnaider Beeri, Michal | Heymann, Anthony | Moshier, Erin | Berman, Yuval | Mamistalov, Mary | Shahar, Danit-Rivka | Tsarfaty, Galia | Leroith, Derek | Preiss, Rachel | Soleimani, Laili | Silverman, Jeremy M. | Bendlin, Barbara B. | Levy, Andrew | Ravona-Springer, Ramit

Article Type: Research Article

Abstract: Backgrounds: The efficacy of vitamin E in prevention of diabetes-related complications differs by Haptoglobin (Hp) genotype. Objective: To examine the role of Hp genotype in the relationship of vitamin E intake with brain volume in cognitively normal elderly patients with type 2 diabetes. Methods: Brain volumes for the superior, middle, and inferior frontal gyri and for the middle temporal gyrus were generated from structural T1 MRI in 181 study participants (Hp 1-1: n  = 24, Hp 2-1: n  = 77, Hp 2-2: n  = 80). Daily vitamin E intake was assessed using the Food Frequency Questionnaire. Analyses of covariance, …controlling for demographic and cardiovascular variables was used to evaluate whether the association of daily vitamin E intake with brain volume was modified by Hp genotype. Results: Average age was 70.8 (SD = 4.2) with 40% females, and mean Mini-Mental State Examination score of 28.17 (SD = 1.90). A significant interaction was found between vitamin E intake and Hp genotype in inferior frontal gyrus’ volume; p  = 0.0108. For every 1 microgram increase in vitamin E intake, the volume of the inferior frontal gyrus decreased by 0.955% for Hp 1-1 (p  = 0.0348), increased by 0.429% for Hp 2-1 (p  = 0.0457), and by 0.077% for Hp 2-2 (p  = 0.6318). There were no significant interactions between vitamin E intake and Hp genotype for the middle (p  = 0.6011) and superior (p  = 0.2025) frontal gyri or for the middle temporal gyrus (p  = 0.503). Conclusions: The effect of dietary vitamin E on the brain may differ by Hp genotype. Studies examining the impact of vitamin E on brain-related outcomes should consider Hp genotype. Show more

Keywords: Brain volume, diabetes, haptoglobin genotype, vitamin E

DOI: 10.3233/JAD-191294

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Okafor, Maureen | Nye, Jonathon A. | Shokouhi, Mahsa | Shaw, Leslie | Goldstein, Felicia | Hajjar, Ihab

Article Type: Research Article

Abstract: Background: Tau positron emission tomography (PET) imaging is used in research, but its relation to cerebrospinal fluid (CSF) tau and other Alzheimer’s disease (AD)-related clinical measures is unclear in mild cognitive impairment with AD biomarkers (MCI-AD). Objective: To determine associations between 18 F-flortaucipir PET and CSF AD biomarkers, cognitive functioning, and neuroimaging measures in MCI-AD. Methods: In 29 participants 50 years or older with MCI-AD, 18 F-flortaucipir PET, CSF total tau (T-tau), phosphorylated tau181p (P-tau), amyloid-β (Aβ), structural MRI, and neuropsychological testing were collected as baseline assessments of an ongoing clinical trial. 11 C-Pittsburgh compound …B PET was simultaneously conducted in 20 participants. Associations between 18 F-flortaucipir PET and these measures were assessed by multiple linear regression adjusted for potential confounders and using global, lobar, and voxel-wise standardized uptake value ratio (SUVr). Results: Whole brain 18 F-flortaucipir SUVr was significantly associated with CSF T-tau (r  = 0.68, p  < 0.001) and P-tau (r  = 0.42, p  = 0.04) after adjusting for age, sex, race, and education, with strongest associations in the temporal region (T-tau: r  = 0.69, p  < 0.001; P-tau: r  = 0.49, p  = 0.02). Voxel-wise analysis confirmed these regional associations. 18 F-flortaucipir PET was also associated with CSF Aβ (r  = –0.45, p  = 0.03), episodic memory (r  = –0.61, p  = 0.001), visuospatial working memory (r  = –0.46, p  = 0.02), and brain cortical thickness (r  = –0.44, p  = 0.03) but not hippocampal volume. In the amyloid PET subset, although 11 C-PiB PET associated strongly with 18 F-flortaucipir (r  = 0.79, p ≤0.001), associations were stronger between 11 C-PiB and key outcomes, compared to 18 F-flortaucipir. Conclusion: 18 F-flortaucipir PET is moderately associated with CSF AD biomarkers and other AD-related phenotypes. The associations in this MCI-AD sample are stronger than previously described in other populations. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid biomarkers, cognitive function, cortical thickness, flortaucipir, mild cognitive impairment, positron emission tomography, tau PET

DOI: 10.3233/JAD-191330

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Patel, Hamel | Iniesta, Raquel | Stahl, Daniel | Dobson, Richard J.B. | Newhouse, Stephen J.

Article Type: Research Article

Abstract: Background: The typical approach to identify blood-derived gene expression signatures as a biomarker for Alzheimer’s disease (AD) have relied on training classification models using AD and healthy controls only. This may inadvertently result in the identification of markers for general illness rather than being disease-specific. Objective: Investigate whether incorporating additional related disorders in the classification model development process can lead to the discovery of an AD-specific gene expression signature. Methods: Two types of XGBoost classification models were developed. The first used 160 AD and 127 healthy controls and the second used the same 160 AD with …6,318 upsampled mixed controls consisting of Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, bipolar disorder, schizophrenia, coronary artery disease, rheumatoid arthritis, chronic obstructive pulmonary disease, and cognitively healthy subjects. Both classification models were evaluated in an independent cohort consisting of 127 AD and 687 mixed controls. Results: The AD versus healthy control models resulted in an average 48.7% sensitivity (95% CI = 34.7–64.6), 41.9% specificity (95% CI = 26.8–54.3), 13.6% PPV (95% CI = 9.9–18.5), and 81.1% NPV (95% CI = 73.3–87.7). In contrast, the mixed control models resulted in an average of 40.8% sensitivity (95% CI = 27.5–52.0), 95.3% specificity (95% CI = 93.3–97.1), 61.4% PPV (95% CI = 53.8–69.6), and 89.7% NPV (95% CI = 87.8–91.4). Conclusions: This early work demonstrates the value of incorporating additional related disorders into the classification model developmental process, which can result in models with improved ability to distinguish AD from a heterogeneous aging population. However, further improvement to the sensitivity of the test is still required. Show more

Keywords: Age-related memory disorders, Alzheimer’s disease, biomarkers, dementia, gene expression, human, machine learning, microarray analysis, neurodegenerative disorders

DOI: 10.3233/JAD-191163

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Cipollari, Eleonora | Szapary, Hannah J. | Picataggi, Antonino | Billheimer, Jeffrey T. | Lyssenko, Catherine A. | Ying, Gui-Shuang | Shaw, Leslie M. | Kling, Mitchel A. | Kaddurah-Daouk, Rima | Rader, Daniel J. | Praticò, Domenico | Lyssenko, Nicholas N. | for the Alzheimer’s Disease Metabolomics Consortium

Article Type: Research Article

Abstract: Background: Basic research has implicated intracellular cholesterol in neurons, microglia, and astrocytes in the pathogenesis of Alzheimer’s disease (AD), but there is presently no assay to access intracellular cholesterol in neural cells in living people in the context of AD. Objective: To devise and characterize an assay that can access intracellular cholesterol and cholesterol efflux in neural cells in living subjects. Methods: We modified the protocol for high-density lipoprotein cholesterol efflux capacity (CEC) from macrophages, a biomarker that accesses cholesterol in macrophages in atherosclerosis. To measure cerebrospinal fluid (CSF) CECs from neurons, microglia, and astrocytes, CSF …was exposed to, correspondingly, neuronal, microglial, and astrocytic cholesterol source cells. Human neuroblastoma SH-SY5Y, mouse microglial N9, and human astroglial A172 cells were used as the cholesterol source cells. CSF samples were screened for contamination with blood. CSF CECs were measured in a small cohort of 22 individuals. Results: CSF CECs from neurons, microglia, and astrocytes were moderately to moderately strongly correlated with CSF concentrations of cholesterol, apolipoprotein A-I, apolipoprotein E, and clusterin (Pearson’s r  = 0.53–0.86), were in poor agreement with one another regarding CEC of the CSF samples (Lin’s concordance coefficient rc  = 0.71–0.76), and were best predicted by models consisting of, correspondingly, CSF phospholipid (R2  = 0.87, p  < 0.0001), CSF apolipoprotein A-I and clusterin (R2  = 0.90, p  < 0.0001), and CSF clusterin (R2  = 0.62, p  = 0.0005). Conclusion: Characteristics of the CSF CEC metrics suggest a potential for independent association with AD and provision of fresh insight into the role of cholesterol in AD pathogenesis. Show more

Keywords: ABCA1, ABCG1, Alzheimer’s disease biomarkers, apolipoprotein A-I, apolipoprotein E, cell cholesterol efflux, clusterin (apolipoprotein J), SR-BI

DOI: 10.3233/JAD-191246

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Xia, Wenqing | Luo, Yong | Chen, Yu-Chen | Chen, Huiyou | Ma, Jianhua | Yin, Xindao

Article Type: Research Article

Abstract: Background: Type 2 diabetes mellitus (T2DM) accelerates cognitive decline, which is believed to be triggered by aberrant neural activity. Objective: To explore how glucose fluctuations impact brain functional architecture and cognition in T2DM patients. Methods: T2DM patients were divided according to glycemic variability, forming two categories: patients with fluctuating glucose levels and patients with stable glucose levels. Degree centrality (DC) was calculated within the cerebral gray matter of each participant and was compared among the two patient groups and a healthy control group. The relationships between glucose fluctuations and aberrant DC and cognitive performance, as well …as the relationship between aberrant DC and cognitive performance, were further explored. Results: Compared with T2DM patients with stable glucose levels, T2DM patients with fluctuating glucose levels exhibited significantly worse performance on the Montreal Cognitive Assessment, Trail Making Test-B (TMT-B), and verbal fluency test (VFT), as well as significant decreases in DC in certain regions, most of which were within the default mode network. In the combined T2DM group, the mean amplitude of glycemic excursions (MAGE) was positively correlated with TMT-B scores and negatively correlated with VFT scores. Moreover, the MAGE was negatively correlated with DC in the left medial prefrontal cortex (mPFC). In addition, TMT-B scores were negatively correlated with reduced DC in the left mPFC. Conclusion: These findings further contribute to the mounting evidence of the effects of glycemic variability on the diabetic brain. Tightened control of glucose fluctuations might prevent cognitive decline and changes in brain functional architecture in T2DM individuals. Show more

Keywords: Brain, cognitive impairments, functional magnetic resonance imaging, type 2 diabetes mellitus

DOI: 10.3233/JAD-191217

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Sun, Lin | Cheng, Baoying | Zhou, Yuxun | Fan, Yating | Li, Wei | Qiu, Qi | Fang, Yuan | Xiao, Shifu | Zheng, Honghua | Li, Xia

Article Type: Research Article

Abstract: Background: Amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) includes a large spectrum of neurodegenerative disorders. Objective: To identify the relationship of ErbB4 mutation and ALS/FTD. Methods: Here, we report an atypical case of frontal variant behavioral abnormalities at the initial stage, a stable plateau stage of 5 years, and paralysis involving both upper and lower motor neurons followed by progressive cognitive dysfunction at the advanced stage. The clinical findings suggested a diagnosis of ALS/FTD, and genetic testing revealed erb-b2 receptor tyrosine kinase 4 (ErbB4 ) heterozygous mutation (c.2136 T>G, p.I712M), identified in an ALS pedigree previously. …We modeled mutant ErbB4 protein through the SWISS-MODEL Server, and speculated on the structural change caused by the mutation. We also identified that ErbB4 (I712M) mutation led to reduced auto-phosphorylation of ErbB4 upon neuregulin-1 (NRG1) stimulation. Results: A functional analysis of ErbB4 mutation demonstrated an obviously decreased auto-phosphorylation of ErbB4 involving in the pathogenesis of ALS/FTD. Conclusion: We firstly found ErbB4 mutation to be identified in ALS/FTD. Show more

Keywords: Amyotrophic lateral sclerosis, ErbB4, frontotemporal dementia, I712M, neuregulin-1

DOI: 10.3233/JAD-191230

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Zhang, Wei | Luo, Peng

Article Type: Research Article

Abstract: Cardiovascular disorders, e.g., atherosclerosis and hypertension, increase susceptibility to neurodegenerative diseases, like dementia and Alzheimer’s disease (AD), with undetermined mechanisms. Moreover, whether myocardial infarction (MI) may similarly increases occurrence of AD is unknown. In the current study, we performed a MI model in wild-type and AD-prone APP/PS1 mice and assessed the development of AD in these mice. We found that MI-treated mice of both wild-type and APP/PS1 behaved poorer in a social recognition test, the Morris water maze, and the plus-maze discriminative avoidance task, compared to sham-treated controls. Mechanistically, MI significantly increased the levels of reactive oxygen species, as well …as increased deposition of amyloid-β peptide aggregates and phosphorylation of tau protein in mouse brain, two signature pathological features for AD. Moreover, the microglia in the MI-mice appeared to alter polarization to a more proinflammatory phenotype. Together, our data suggest that MI may be a predisposing factor for AD development. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide aggregates, microglia, myocardial infarction, reactive oxygen species, tau

DOI: 10.3233/JAD-191225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Gardner, Raquel C. | Rivera, Ernesto | O’Grady, Megan | Doherty, Colin | Yaffe, Kristine | Corrigan, John | Bogner, Jennifer | Kramer, Joel | Wilson, Fiona

Article Type: Research Article

Abstract: Background: Traumatic brain injury (TBI) is an established risk factor for dementia but mechanisms are uncertain. Accurate TBI exposure classification is critical for cognitive aging research studies seeking to discover mechanisms and treatments of post-TBI dementia. Brief TBI screens, commonly used in epidemiological studies of cognitive aging, are insensitive, leading to exposure mis-classification. Comprehensive TBI interviews, while more sensitive, may be impractical. Objective: We aimed to develop and validate a scalable, self-administered, comprehensive, web-based, TBI exposure survey for use in international cognitive aging research. Methods: We adapted a gold-standard comprehensive TBI interview (the Ohio State University …TBI Identification Method; OSU TBI-ID) into a self-administered web-based survey for older adults (Older Adult modification of the OSU TBI-ID; OA OSU TBI-ID). We assessed reliability of our web-based survey versus the gold-standard interview among 97 older adults with normal cognition and mild cognitive impairment (MCI). In addition, we assessed sensitivity of the National Alzheimer’s Coordinating Center Uniform Data Set (NACC UDS) brief TBI screen versus the interview among 70 older adults with normal cognition. Results: Our OA OSU TBI-ID web-based survey had good to excellent reliability versus the interview (κ 0.66–0.73; ICCs 0.68–0.81) even among the sub-set with MCI (κ 0.74–0.88; ICCs 0.76–0.85), except for several age-at-injury variables. The NACC UDS brief TBI screen missed 50% of TBI exposures identified using the OSU TBI-ID interview. Conclusion: The OSU TBI-ID interview and web-based survey may facilitate more accurate TBI exposure classification in cognitive aging research thereby accelerating discovery of targetable mechanisms of post-TBI dementia. Show more

Keywords: Clinical research, cognitive aging, reliability, screening, traumatic brain injury, validation

DOI: 10.3233/JAD-191138

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Hou, Ting-ting | Han, Yun-Dan | Cong, Lin | Liu, Cui-cui | Liang, Xiao-Yan | Xue, Fu-zhong | Du, Yi-feng

Article Type: Research Article

Abstract: Hyperphosphorylated tau is one of the key characteristics of Alzheimer’s disease (AD), and tau pathology correlates with cognitive impairment in AD better than amyloid-β (Aβ) pathology. Thus, a complete understanding of the relevant factors involved in tau phosphorylation is important for AD treatment. APOE ɛ 4 , the strongest genetic risk factor for AD, was found to be involved in tau pathology in frontotemporal dementia. This result indicated that apolipoprotein E (ApoE) may also participate in tau phosphorylation in AD. In the present study, we injected Aβ oligomer (AβO) into the lateral ventricles of wild-type (WT) mice and apoE-/- …mice to test the process of tau phosphorylation in the acute phase. We found that the phosphorylated tau and phosphokinase levels were higher in WT mice than in apoE-/- mice. These phenomena were also confirmed in vitro . ApoE ɛ 4-treated apoE-/- neurons exhibited more phosphorylated tau than ApoE ɛ 2- and ApoE ɛ 3-treated neurons. We also found that AβO induced more serious inflammation in WT mice and in ApoE-positive cultured neurons. Anti-inflammatory treatment reduced the phosphorylated tau level induced by AβOs in ApoE-positive neurons. These results suggest that ApoE may facilitate the phosphorylation of tau induced by AβO via inflammation. Show more

Keywords: Alzheimer’s disease, amyloid-β apolipoprotein E, inflammation, oligomer, phosphorylated tau

DOI: 10.3233/JAD-190711

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: James, Hailey J. | Van Houtven, Courtney Harold | Lippmann, Steven | Burke, James R. | Shepherd-Banigan, Megan | Belanger, Emmanuelle | Wetle, Terrie Fox | Plassman, Brenda L.

Article Type: Research Article

Abstract: Background: Amyloid-β PET scans will likely become an integral part of the diagnostic evaluation for Alzheimer’s disease if Medicare approves reimbursement for the scans. However, little is known about patients’ and their care partners’ interpretation of scan results. Objective: This study seeks to understand how accurately patients with mild cognitive impairment (MCI) or dementia and their care partners report results of amyloid-β PET scans and factors related to correct reporting. Methods: A mixed-methods approach was used to analyze survey data from 1,845 patient-care partner dyads and responses to open-ended questions about interpretation of scan results from …a sub-sample of 200 dyads. Results: Eighty-three percent of patients and 85% of care partners correctly reported amyloid-β PET scan results. Patients’ higher cognitive function was associated with a small but significant decrease in the predicted probability of not only patients accurately reporting scan results (ME: –0.004, 95% CI: –0.007, –0.000), but also care partners accurately reporting scan results (ME: –0.006, 95% CI: –0.007, –0.001), as well as decreased concordance between patient and care partner reports (ME: –0.004, 95% CI: –0.007, –0.001). Content analysis of open-ended responses found that participants who reported the scan results incorrectly exhibited more confusion about diagnostic terminology than those who correctly reported the scan results. Conclusion: Overall, patients with MCI or dementia showed high rates of accurate reporting of amyloid-β PET scan results. However, responses to questions about the meaning of the scan results highlight the need for improved provider communication, including providing written explanations and better prognostic information. Show more

Keywords: Alzheimer’s disease, amyloid PET, caregivers, dementia, mild cognitive impairment

DOI: 10.3233/JAD-190922

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020