Journal of Alzheimer's Disease - Volume 67, issue 1

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±7.4 μg/mL; control: 30.0±8.7 μg/mL; p  = 0.97) and women (preclinical AD 30.9±7.9 μg/mL; control: 31.7±8.5 μg/mL; p  = 0.72). Additionally, RBP4 levels were not related to body mass index or CSF AD biomarkers levels of amyloid-β42 , 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. 67, no. 1, pp. 257-263, 2019

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 Aβ42 and P-tau/Aβ42 for controls: 0.73 and 0.75, respectively; P-tau for MCI: 0.77 and total sample: 0.70; Aβ42 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. 67, no. 1, pp. 265-277, 2019

Authors: Mahinrad, Simin | Ferguson, Ian | Macfarlane, Peter W. | Clark, Elaine N. | Stott, David J. | Ford, Ian | Mooijaart, Simon P. | Trompet, Stella | van Heemst, Diana | Jukema, J. Wouter | Sabayan, Behnam

Article Type: Research Article

Abstract: Background: An abnormally wide spatial QRS-T angle on an ECG is a marker of heterogeneity in electrical activity of cardiac ventricles and is linked with cardiovascular events. Growing evidence suggests that cardiac dysfunction might signal future cognitive decline. Objective: In this study, we investigated whether spatial QRS-T angle associates with future cognitive decline in older subjects at high cardiovascular risk. Methods: We included 4,172 men and women (mean age 75.2±3.3 years) free of cardiac arrhythmias from the PROSPER cohort. Spatial QRS-T angle was calculated from baseline 12-lead ECGs using a matrix transformation method. Cognitive function …was assessed using 4 neuropsychological tests including Stroop test, letter-digit coding test, immediate and delayed picture word learning tests. Cognitive function was assessed at baseline and repeatedly during a mean follow-up time of 3.2 years. Using linear mixed models, we calculated the annual changes of cognitive scores in sex-specific thirds of spatial QRS-T angle. Results: Participants with wider spatial QRS-T angle had a steeper decline in letter-digit coding test (β = –0.0106, p  = 0.004), immediate picture-word learning test (β = –0.0049, p  = 0.001), and delayed picture-word learning test (β = –0.0055, p  = 0.013). All associations were independent of arrhythmias, cardiovascular risk factors, comorbidities, medication use, cardiovascular events, and other ECG abnormalities including QRS duration, QTc interval, T wave abnormalities, and left ventricular hypertrophy. Conclusion: Abnormal cardiac electrical activity characterized by wide spatial QRS-T angle associates with accelerated cognitive decline independent of conventional cardiovascular factors. These findings suggest a link between a non-traditional ECG measure of pre-clinical cardiac pathology and future cognitive decline. Show more

Keywords: Cardiac dysfunction, cognitive function, old age, spatial QRS-T angle

DOI: 10.3233/JAD-180633

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 279-289, 2019

Authors: Weissberger, Gali H. | Gollan, Tamar H. | Bondi, Mark W. | Nation, Daniel A. | Hansen, Lawrence A. | Galasko, Douglas | Salmon, David P.

Article Type: Research Article

Abstract:  This study aimed to determine if patterns of neuropsychological deficits, vascular risk factors, and neuropathology differ in Hispanic and Non-Hispanic patients with autopsy-confirmed Alzheimer’s disease (AD). Participants were enrolled in a longitudinal study at the Shiley-Marcos AD Research Center at the University of California, San Diego. Hispanic (n  = 14) and Non-Hispanic (n  = 20) patients with autopsy-confirmed AD who scored ≥95 on the Dementia Rating Scale (DRS) were included. Patient groups were matched on age, education, global mental status, and severity of functional decline; they were compared to Hispanic (n  = 14) or Non-Hispanic (n  = 20) cognitively-normal controls of similar age and …education. Ethnicity (Hispanic, Non-Hispanic) by disease state (autopsy-confirmed AD or cognitively normal) comparisons were made for cognitive test performance and vascular risk factors. Patient groups were further compared on measures of AD (Braak stage, neuritic plaques, neurofibrillary tangles), vascular neuropathology, and performance across cognitive domains of memory, language, attention, executive functions, and visuospatial abilities after scores were z-transformed based on respective culturally-appropriate control groups. Patient groups had similar overall AD pathology burden, whereas Hispanics with AD had more small parenchymal arteriolar disease and amyloid angiopathy than Non-Hispanics with AD. Despite largely similar pathology, Hispanics with AD were less cognitively impaired (relative to respective NC groups) than Non-Hispanics with AD, and exhibited a different pattern of deficits across cognitive domains. Findings suggest that cognitive deficits that are usually prominent in AD may be less salient in Hispanic patients and this may adversely impact the ability to clinically detect the disease in mild to moderate stages. Show more

Keywords: Alzheimer’s disease, autopsy, bilingualism, Hispanics, neuropsychology

DOI: 10.3233/JAD-180351

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 291-302, 2019

Authors: Frölich, Lutz | Atri, Alireza | Ballard, Clive | Tariot, Pierre N. | Molinuevo, José Luis | Boneva, Neli | Geist, Marie A. | Raket, Lars L. | Cummings, Jeffrey L.

Article Type: Research Article

Abstract: This open-label extension study evaluated the long-term safety and tolerability of idalopirdine 60 mg/day as adjunctive therapy in patients with mild-moderate Alzheimer’s disease (AD). This extension study was a continuation of Studies 1 and 2 of the Phase III development program for idalopirdine and comprised a 28-week open-label treatment period (“OLEX”) and a subsequent 24-week open-label treatment period with memantine (“MEMOLEX”) in selected patients. The previous studies had shown no evidence of efficacy with idalopirdine as adjunctive treatment to donepezil but with good tolerability (of 1,791 patients randomized, 1,609 [90%] completed the double-blind studies). Of those, 1,463 patients (91%) entered the …open-label extension study. During the 28-week OLEX period, the percentage of patients having treatment-emergent adverse events (TEAEs) ranged between 51% and 59% across the treatment groups originating from the lead-in studies. During the subsequent 24-week MEMOLEX period, 51% of the patients had TEAEs. Increases in liver enzymes (occurring in 1–3% of trial participants) were transient and no new safety signals were observed with longer term exposure. No consistent effects demonstrating benefits with idalopirdine were observed on efficacy parameters when patients transitioned to 60 mg in the extension study. Overall, idalopirdine was safe and well tolerated when added to donepezil, and when memantine was added to a prior combination of idalopirdine and donepezil. There were no new safety signals observed with up to 18 months of exposure at the described doses to idalopirdine. Show more

Keywords: 5-HT6 , Alzheimer’s disease, dementia, idalopirdine, treatment

DOI: 10.3233/JAD-180595

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 303-313, 2019

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. 67, no. 1, pp. 315-325, 2019

Authors: Iulita, M. Florencia | Ganesh, Aravind | Pentz, Rowan | Flores Aguilar, Lisi | Gubert, Palma | Ducatenzeiler, Adriana | Christie, Sharon | Wilcock, Gordon K. | Cuello, A. Claudio

Article Type: Research Article

Abstract: Biomarker discovery is a major need for earlier dementia diagnosis. We evaluated a plasma signature of amyloid, metallo-proteinases (MMPs), and inflammatory markers in a cohort of at-risk individuals and individuals clinically diagnosed with probable Alzheimer’s disease (pAD). Using multiplex arrays, we measured Aβ40 , Aβ42 , MMP-1, MMP-3, MMP-9, IFN-γ , TNF-α , IL-6, IL-8, and IL-10 in plasma from 107 individuals followed every 6 months for 3 years. Final diagnoses included: pAD (n = 28), mild cognitive impairment (MCI, n = 30), subjective memory impairment (SMI, n = 30), and asymptomatic (NCI, n = 19). …Blood was drawn at final follow-up. We used linear and logistic regressions to examine biomarker associations with prior known decline on the Montreal Cognitive Assessment (MoCA) and the Cambridge Cognitive Examination (CAMCOG); as well disease progression by the time of blood-draw. We derived a biomarker composite from the individual markers, and tested its association with a clinical diagnosis of pAD. Lower Aβ40 and Aβ42 and higher IL-8, IL-10, and TNF-α were associated with greater cognitive decline per the MoCA and CAMCOG. MMP-3 was higher in SMI, MCI, and pAD than NCI. Whereas the other investigative molecules did not differ between groups, composite scores—created using MoCA/CAMCOG-based trends in Aβ40 , Aβ42 , MMP-1, MMP-3, IL-8, IL-10, and TNF-α — were associated with a final diagnosis of pAD (c-statistic 0.732 versus 0.602 for age-sex alone). Thus, plasma amyloid, MMP, and inflammatory biomarkers demonstrated differences in individuals with cognitive deterioration and/or progression to MCI/pAD. Our findings support studying these markers earlier in the continuum of probable AD as well as in specific dementias. Show more

Keywords: Alzheimer’s disease, dementia, amyloid-β, biomarker, blood, cognitive decline, inflammation, metallo-proteinases, MMP-3, MMP-9, plasma

DOI: 10.3233/JAD-180970

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 327-341, 2019

Authors: Gavilan, Javiera | Mennickent, Daniela | Ramirez-Molina, Oscar | Triviño, Sergio | Perez, Claudia | Silva-Grecchi, Tiare | Godoy, Pamela A. | Becerra, Jose | Aguayo, Luis G. | Moraga-Cid, Gustavo | Martin, Victoria San | Yevenes, Gonzalo E. | Castro, Patricio A. | Guzman, Leonardo | Fuentealba, Jorge

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a neurodegenerative pathology, which is characterized by progressive and irreversible cognitive impairment. Most of the neuronal perturbations described in AD can be associated with soluble amyloid– β oligomers (SO-Aβ). There is a large amount of evidence demonstrating the neuroprotective effect of Nicotine neurotransmission in AD, mainly through nicotinic acetylcholine receptor (nAChR) activation and antiapoptotic PI3K/Akt/Bcl–2 pathway signaling. Using HPLC and GC/MS, we isolated and characterized two alkaloids obtained from C. scoparius , Lupanine (Lup), and 17– oxo-sparteine (17– ox), and examined their neuroprotective properties in a cellular model of SO-Aβ toxicity. Our results showed that Lup …and 17– ox (both at 0.03μ M) prevented SO-Aβ-induced toxicity in PC12 cells (Lup: 64±7%; 17– ox: 57±6%). Similar results were seen in hippocampal neurons where these alkaloids prevented SO-Aβ neurotoxicity (Lup: 57±2%; 17– ox: 52±3%) and increased the frequency of spontaneous calcium transients (Lup: 60±4%; 17– Ox: 40±3%), suggesting an enhancing effect on neural network activity and synaptic activity potentiation. All of the neuroprotective effects elicited by both alkaloids were completely blocked by α -bungarotoxin. Additionally, we observed that the presence of both Lup and 17– ox increased Akt phosphorylation levels (52±4% and 35±7%, respectively) in cells treated with SO-Aβ (3 h). Taken together, our results suggest that the activation of nAChR by Lup and 17– ox induces neuroprotection in different cellular models, and appears to be an interesting target for the development of new pharmacological tools and strategies against AD. Show more

Keywords: Alzheimer’s disease, 17– oxo-sparteine, Lupanine, neuroprotection, nicotinic receptor

DOI: 10.3233/JAD-180945

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 343-356, 2019

Authors: Xu, Mei | Zhang, Lin | Liu, Gang | 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 with 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. 67, no. 1, pp. 357-368, 2019

Authors: Islamoska, Sabrina | Ishtiak-Ahmed, Kazi | Hansen, Åse Marie | Grynderup, Matias Brødsgaard | Mortensen, Erik Lykke | Garde, Anne Helene | Gyntelberg, Finn | Prescott, Eva Irene Bossano | Török, Eszter | Waldemar, Gunhild | Nabe-Nielsen, Kirsten

Article Type: Research Article

Abstract: Background: Psychological distress is potentially linked to the risk of dementia through neurologic and cardiovascular mechanisms. Vital exhaustion (VE) is a mental state of psychological distress, which could be a risk factor for dementia. Objective: To investigate whether VE is a risk factor for dementia in later life. Methods: We used data from 6,807 participants attending the third survey of the Copenhagen City Heart Study in 1991–1994. VE was assessed by 17 symptoms (score: 0–17) from the Maastricht Questionnaire. Information on dementia was obtained from national registers. Risk time for dementia was counted from five …years after VE assessment for participants > 55 years at the time of VE assessment. For younger participants, risk time for dementia was counted from the year they turned 60 years and onwards. Participants were followed until 2016. We used Poisson regression to calculate incidence rate ratios (IRR) and their 95% confidence intervals (CI). Results: During an average follow-up of 10 years, 872 participants were registered with dementia. We found a dose-response relation between the number of VE symptoms and the incidence of dementia. For every additional VE symptom, the dementia incidence increased by 2% (IRR = 1.024; 95% CI: 1.004–1.043). Adjustment for socio-demographic and health-related factors did not change the results substantially. Neither did stratification by age, sex, educational level, and marital status. Conclusion: We found evidence that VE is a risk factor for dementia. Our sensitivity analyses supported that this association was not only due to VE being a potential prodromal sign of dementia. Show more

Keywords: Dementia, mental health, psychological stress, subjective health complaint

DOI: 10.3233/JAD-180478

Citation: Journal of Alzheimer's Disease, vol. 67, no. 1, pp. 369-379, 2019