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

Authors: Xu, Mei | Zhang, Lin | Jiang, Ning | Zhou, Wenxia | Zhang, Yongxiang

Article Type: Research Article

Abstract: Microglia constitute the majority of innate immune cells in the brain, and their dysfunction is associated various central nervous system diseases. Human microglia are extremely difficult to obtain experimentally, thereby limiting studies on their role in complex diseases. Microglia derived from human stem cells provide new tools to assess the pathogenesis of complex diseases and to develop effective treatment methods. This study aimed to develop a reliable method to derive human microglial-like cells (iMGLs) from induced pluripotent stem cells (iPSCs) expressing microglia-specific markers IBA1 and TMEM119 and respond to lipopolysaccharide (LPS) stimulation. Thereafter, we compared iMGL functions from Alzheimer’s disease …(AD) patients and cognitive normal controls (CNCs). AD-iMGLs displayed stronger phagocytic ability with or without stimulation. High LPS concentrations (>2μ g/ml) caused death in CNC-iMGLs, while AD-iMGLs did not display significant cell death. Cytokine analysis revealed that TNF-α , IL-6, and IL-10 secreted by AD-iMGLs were significantly increased upon LPS stimulation compared to those in CNC-iMGLs. The present results indicate that AD-iMGLs exhibit significant inflammatory characteristics and can reflect some pathological changes in microglia in AD, thereby providing new valuable tools to screen candidate drugs for AD and to elucidate the mechanisms underlying AD pathogenesis. Show more

Keywords: Alzheimer’s disease, induced pluripotent stem cells, inflammation, microglia, phagocytosis

DOI: 10.3233/JAD-180722

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2018

Authors: Ishii, Makoto | Kamel, Hooman | Iadecola, Costantino

Article Type: Research Article

Abstract: Accumulating evidence suggests that disparate pathways from systemic metabolism to retinoic acid/vitamin A signaling can contribute to Alzheimer’s disease (AD) pathobiology. Retinol binding protein 4 (RBP4) is an adipocyte-secreted hormone (adipokine) that regulates insulin signaling and is also a key transporter of retinoic acid and its derivatives. While earlier studies found alterations in the brain and cerebrospinal fluid (CSF) levels of RBP4 in later stages of AD, it is not known if circulating RBP4 is altered in preclinical AD or if it can be a useful biomarker for cognitive decline and dementia. In this study, we used ELISA to measure …plasma RBP4 levels in cognitively normal individuals (Clinical Dementia Rating, CDR 0). Subjects with preclinical AD were identified by previously established CSF criteria (preclinical AD: 20 men, 18 women; control: 45 men, 73 women). Plasma RBP4 levels were similar between preclinical AD and control subjects in men (preclinical AD: 30.0±7.4μ g/mL; control: 30.0±8.7μ g/mL; p  = 0.97) and women (preclinical AD 30.9±7.9μ g/mL; control: 31.7±8.5μ g/mL; p  = 0.72). Additionally, RBP4 levels were not related to body mass index or CSF AD biomarkers levels of amyloid-β 42 , tau, or phosphorylated tau. Baseline plasma RBP4 levels were not associated with the incidence of CDR ≥0.5, all-cause dementia, or AD diagnosis. Collectively, these results do not support peripheral RBP4 as a clinical biomarker or therapeutic target in the early stages of AD. Show more

Keywords: Alzheimer’s disease, amyloid beta-peptides, enzyme-linked immunosorbent assay, metabolism, plasma, retinol binding proteins

DOI: 10.3233/JAD-180682

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2018

Authors: Pan, Kuan-Yu | Xu, Weili | Mangialasche, Francesca | Dekhtyar, Serhiy | Fratiglioni, Laura | Wang, Hui-Xin

Article Type: Research Article

Abstract: While the importance of working conditions on cognitive function has been tentatively suggested previously, few studies have considered cumulative effects of exposure throughout the working life. We examined the association between job demand-control status and late-life cognitive decline, taking into account exposure durations. In the population-based cohort study, Swedish National Study on Aging and Care-Kungsholmen, 2,873 dementia-free participants aged 60+ were followed up to nine years. Cognitive function was measured using the Mini-Mental State Examination. The entire working life was outlined through interview and occupations were graded with a psychosocial job-exposure matrix. Multivariate linear mixed-effects models were used. Slower cognitive …decline was observed among people with high job control (β : 0.10, 95% CI: 0.03, 0.19) and demands (β : 0.15, 95% CI: 0.07, 0.22) in the longest-held job. Compared to active job, faster decline was shown in low strain (β : – 0.17, 95% CI: – 0.26, – 0.08), high strain (β : – 0.13, 95% CI: – 0.24, – 0.03), and passive job (β : – 0.22, 95% CI: – 0.34, – 0.11). Longer duration of active jobs was associated with slower cognitive decline (β : 0.24, 95% CI: 0.16, 0.32), whereas faster decline was associated with longer durations of low strain (β : – 0.12, 95% CI: – 0.19, – 0.05), high strain (β : – 0.13, 95% CI: – 0.21, – 0.04), and passive jobs (β : – 0.12, 95% CI: – 0.20, – 0.04). In conclusion, not only psychologically stressful jobs, but also low-stimulating and passive jobs are associated with faster cognitive decline in later life. Duration of exposure may play a role in the psychosocial working condition-cognitive decline association. Show more

Keywords: Cognition, cohort studies, epidemiology, psychosocial work condition, working life

DOI: 10.3233/JAD-180870

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018

Authors: Farlow, Martin R. | Thompson, Richard E. | Wei, Lee-Jen | Tuchman, Alan J. | Grenier, Elaine | Crockford, David | Wilke, Susanne | Benison, Jeffrey | Alkon, Daniel L.

Article Type: Research Article

Abstract: Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55–85) with MMSE-2 of 4–15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p  < 0.1 for primary efficacy, and 2-sided, p  < 0.05 for pre-specified and post hoc exploratory …analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p  = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p  < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant. Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified and post-hoc exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin— without memantine— to treat AD. Show more

Keywords: Bryostatin, memantine, neurorestorative, PKC (Protein Kinase C), severe Alzheimer’s disease, severe impairment battery, synaptic growth factors, synaptogenesis

DOI: 10.3233/JAD-180759

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2018

Authors: Torrealba, Eduardo | Garcia-Morales, Pilar | Cejudo, Juan Carlos | Diaz, Mario | Rodriguez-Esparragon, Francisco | Fabre, Oscar | Mesa-Herrera, Fatima | Marin, Raquel | Sanchez-Garcia, Florentino | Rodriguez-Perez, Aurelio | Gramunt, Nina

Article Type: Research Article

Abstract: Background: Assessment of hippocampal amnesia is helpful to distinguish between normal cognition and mild cognitive impairment (MCI), but not for identifying converters to dementia. Here biomarkers are useful but novel neuropsychological approaches are needed in their absence. The In-out-test assesses episodic memory using a new paradigm hypothesized to avoid reliance on executive function, which may compensate for damaged memory networks. Objective: To assess the validity of the In-out-test in identifying prodromal Alzheimer’s disease (PAD) in a clinical setting, by comparing this to the Free and Cued Selective Reminding Test (FCSRT) and cerebrospinal fluid biomarkers. …Methods: A cross-sectional study of 32 cognitively healthy, 32 MCI, and 30 progressive dementia subjects. All participants were given both the In-out-test and the FCSRT; 40 of them also received a lumbar puncture. Results: Internal consistency was demonstrated using Cronbach Alpha (r  = 0.81) and Inter-rater reliability with Kappa (k = 0.94). Intraclass correlation (ICC) for test-retest reliability: r  = 0.57 (p  = 0.57). ICC between the In-out-test and FCSRT r  = 0.87 (p  = 0.001). ICC between the In-out-test and Aβ 42 and P-tau/Aβ 42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ 42 for dementia: 0.71. All ICC measures between FCSRT and biomarkers were ≤0.264. AD diagnosis: In-out-test k = 0.71; FCSRT k = 0.49. PAD diagnosis (N = 35): In-out-test k = 0.69; FCSRT k = 0.44. Conclusions: The In-out-test detected prodromal AD with a higher degree of accuracy than a conventional hippocampal-based memory test. These results suggest that this new paradigm could be of value in clinical settings, predicting which patients with MCI will go on to develop AD. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, dementia, early diagnosis, episodic memory, mild cognitive impairment, neuropsychological tests, tau proteins

DOI: 10.3233/JAD-171007

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2018

Authors: Bonvicini, Cristian | Scassellati, Catia | Benussi, Luisa | Di Maria, Emilio | Maj, Carlo | Ciani, Miriam | Fostinelli, Silvia | Mega, Anna | Bocchetta, Martina | Lanzi, Gaetana | Giacopuzzi, Edoardo | Ferraboli, Sergio | Pievani, Michela | Fedi, Virginia | Defanti, Carlo Alberto | Giliani, Silvia | Frisoni, Giovanni Battista | Ghidoni, Roberta | Gennarelli, Massimo

Article Type: Research Article

Abstract: Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E (APOE ) and prion protein (PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation …Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants (APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% (n  = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% (n  = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% (n  = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD. Show more

Keywords: Alzheimer’s disease, common variants, early onset dementia, frontotemporal dementia, Lewy body dementia, next generation sequencing, rare mutations

DOI: 10.3233/JAD-180482

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: de Macêdo Medeiros, André | Silva, Regina Helena

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder that drastically compromises patients’ and relatives’ quality of life, besides being a significant economic burden to global public health. Its pathophysiology is not completely elucidated yet, hence, the current therapies are restricted to treating the symptoms. Over the years, several epidemiological studies have shown disproportionalities in AD when sex is considered, which has encouraged researchers to investigate the potentiality of sex as a risk factor. Studies in rodent models have been used to investigate mechanistic basis of sex differences in AD, as well as the development of possible new sex-specific therapeutic strategies. However, …full knowledge on factors related to this sexual dimorphism remains to be unraveled. Some findings point to differences in genetic and developmental backgrounds either earlier in life or in the aging brain. Herein we summarize the multisystemic framework behind the sex differences in AD and discuss the possible mechanisms involved in these differences raised by the literature so far in an integrative perspective. Show more

Keywords: Aging, animal models, hormones, humans, immune system, oxidative stress, stress

DOI: 10.3233/JAD-180213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-26, 2018

Authors: Hvidsten, Lara | Engedal, Knut | Selbæk, Geir | Wyller, Torgeir Bruun | Jūratė Šaltytė, Benth | Kersten, Hege

Article Type: Research Article

Abstract: Background: Cross-sectional studies of quality of life (QOL) of people with young-onset dementia shows diverging results. Objective: To identify factors associated with QOL in people with young-onset Alzheimer’s (AD) and frontotemporal dementia (FTD) and explore development in QOL over a two-year period, including differences between the two subtypes. Methods: A two-year cohort study of 88 community-dwelling people with young-onset AD and FTD recruited from Nordic memory clinics. QOL was assessed using the proxy version of the Quality of Life – Alzheimer’s Disease questionnaire, dementia severity was rated with the Clinical Dementia Rating scale, depressive symptoms by …the Cornell Scale for Depression in Dementia, awareness with the Reed anosognosia scale, and needs using the Camberwell Assessment of Needs in the Elderly questionnaire. Factors associated with QOL and development in QOL over time were explored with growth mixture model trajectories and mixed model analyses. Results: We identified two groups of people following trajectories with better (n  = 35) versus poorer (n  = 53) QOL. People with more depressive symptoms at baseline had higher odds of belonging to poorer QOL group, OR 1.2 (CI 1.1; 1.5, p  = 0.011). Having Alzheimer’s disease was associated with significantly better QOL (p  = 0.047 at baseline, p  = 0.009 at T1 and p  = 0.033 at T2). Increasing number of unmet needs was significantly associated with poorer QOL at baseline (p  = 0.007), but not later in follow-up. Conclusion: Early assessment and treatment based on dementia subtype, depression, and individual needs may enhance quality of life in young-onset dementia. Show more

Keywords: Alzheimer’s disease, depression, frontotemporal dementia, quality of life, young-onset

DOI: 10.3233/JAD-180479

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2018

Authors: Almansoub, Hasan A.M.M. | Tang, Hui | Wu, Ying | Wang, Ding-Qi | Mahaman, Yacoubou Abdoul Razak | Wei, Na | Almansob, Yusra A. M. | He, Wei | Liu, Dan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative diseases that is characterized by progressive memory loss and two main pathological hallmarks, including the extracellular amyloid plaques and intracellular neurofibrillary tangles. The microtubule-related protein tau is involved in the pathogenesis of many neurological diseases commonly known as tauopathies and is found to be abnormally hyperphosphorylated in AD and accumulated in neurons. Besides hyperphosphorylation, tau also undergoes abnormal glycosylation, ubiquitination, glycation, and other posttranslational modifications. These abnormalities lead to the aberrant aggregation of tau in the synaptic loci in AD. In this review, we highlighted the most recent studies about …how tau is abnormally regulated and how those abnormalities play important roles in the pathogenesis of AD. Show more

Keywords: Aggregation, Alzheimer’s disease, hyperphosphorylation, post-translational modifications, tau

DOI: 10.3233/JAD-180868

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2018

Authors: Zammit, Andrea R. | Muniz-Terrera, Graciela | Katz, Mindy J. | Hall, Charles B. | Ezzati, Ali | Bennett, David A. | Lipton, Richard B.

Article Type: Research Article

Abstract: Background: In a previous report, we used latent class analysis (LCA) to identify natural subgroups of older adults in the Einstein Aging Study (EAS) based on neuropsychological performance. These subgroups differed in demographics, genetic profile, and prognosis. Herein, we assess the generalizability of these findings to an independent sample, the Rush Memory and Aging Project (MAP), which used an overlapping, but distinct neuropsychological battery. Objective: Our aim was to identify the association of natural subgroups based on neuropsychological performance in the MAP cohort with incident dementia and compare them with the associations identified in the EAS. …Methods: MAP is a community-dwelling cohort of older adults living in the northeastern Illinois, Chicago. Latent class models were applied to baseline scores of 10 neuropsychological measures across 1,662 dementia-free MAP participants. Results were compared to prior findings from the EAS. Results: LCA resulted in a 5-class model: Mixed-Domain Impairment (n  = 71, 4.3%), Memory-specific-Impairment (n  = 274, 16.5%), Average (n  = 767, 46.1%), Frontal Impairment (n  = 222, 13.4%), and a class of Superior Cognition (n  = 328, 19.7%). Similar to the EAS, the Mixed-Domain Impairment, the Memory-Specific Impairment, and the Frontal Impairment classes had higher risk of incident Alzheimer’s disease when compared to the Average class. By contrast, the Superior Cognition had a lower risk of Alzheimer’s disease when compared to the Average class. Conclusions: Natural cognitive subgroups in MAP are similar to those identified in EAS. These similarities, despite study differences in geography, sampling strategy, and cognitive tests, suggest that LCA is capable of identifying classes that are not limited to a single sample or a set of cognitive tests. Show more

Keywords: Alzheimer’s disease, dementia, latent class analysis, neuropsychological profiles

DOI: 10.3233/JAD-180737

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2018