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

Authors: Hayashi, Tetsuo | Shimonaka, Shotaro | Elahi, Montasir | Matsumoto, Shin-Ei | Ishiguro, Koichi | Takanashi, Masashi | Hattori, Nobutaka | Motoi, Yumiko

Article Type: Research Article

Abstract: Background: Human tauopathy brain injections into the mouse brain induce the development of tau aggregates, which spread to functionally connected brain regions; however, the features of this neurotoxicity remain unclear. One reason may be short observational periods because previous studies mostly used mutated-tau transgenic mice and needed to complete the study before these mice developed neurofibrillary tangles. Objective: To examine whether long-term incubation of Alzheimer’s disease (AD) brain in the mouse brain cause functional decline. Methods: We herein used Tg601 mice, which overexpress wild-type human tau, and non-transgenic littermates (NTg) and injected an insoluble fraction of …the AD brain into the unilateral hippocampus. Results: After a long-term (17–19 months) post-injection, mice exhibited learning deficits detected by the Barnes maze test. Aggregated tau pathology in the bilateral hippocampus was more prominent in Tg601 mice than in NTg mice. No significant changes were observed in the number of Neu-N positive cells or astrocytes in the hippocampus, whereas that of Iba-I-positive microglia increased after the AD brain injection. Conclusion: These results potentially implicate tau propagation in functional decline and indicate that long-term changes in non-mutated tau mice may reflect human pathological conditions. Show more

Keywords: Microglia, neurodegeneration, propagation, tau protein, tauopathies

DOI: 10.3233/JAD-201002

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2021

Authors: Lu, Yifei | Pike, James R. | Selvin, Elizabeth | Mosley, Thomas | Palta, Priya | Richey Sharrett, A. | Thomas, Alvin | Loehr, Laura | Sidney Barritt, A. | Hoogeveen, Ron C. | Heiss, Gerardo

Article Type: Research Article

Abstract: Background: Low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the low physiologic range, surrogate markers for reduced liver metabolic function, are associated with cerebral hypometabolism, impairment in neurotransmitter production and synaptic maintenance, and a higher prevalence of dementia. It is unknown whether a prospective association exists between low liver enzyme levels and incident dementia. Objective: To determine whether low levels of ALT and AST are associated with higher risk of incident dementia. Methods: Plasma ALT and AST were measured on 10,100 study participants (mean age 63.2 years, 55% female, 22% black) in 1996–1998. …Dementia was ascertained from comprehensive neuropsychological assessments, annual contact, and medical record surveillance. Cox proportional hazards regression was used to estimate the association. Results: During a median follow-up of 18.3 years (maximum 21.9 years), 1,857 individuals developed dementia. Adjusted for demographic factors, incidence rates of dementia were higher at the lower levels of ALT and AST. Compared to the second quintile, ALT values <10th percentile were associated with a higher risk of dementia (hazard ratio [HR] 1.34, 95% CI 1.08–1.65). The corresponding HR was 1.22 (0.99–1.51) for AST. Conclusion: Plasma aminotransferases <10th percentile of the physiologic range at mid-life, particularly ALT, were associated with greater long-term risk of dementia, advocating for attention to the putative role of hepatic function in the pathogenesis of dementia. Show more

Keywords: ALT, Alzheimer’s disease, AST, dementia, liver hypometabolism

DOI: 10.3233/JAD-201241

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021

Authors: Gnanaprakash, Madhumathi | Staniszewski, Agnieszka | Zhang, Hong | Pitstick, Rose | Kavanaugh, Michael P. | Arancio, Ottavio | Nicholls, Russell E.

Article Type: Research Article

Abstract: Background: The serine/threonine protein phosphatase, PP2A, is thought to play a central role in the molecular pathogenesis of Alzheimer’s disease (AD), and the activity and substrate specificity of PP2A is regulated, in part, through methylation and demethylation of its catalytic subunit. Previously, we found that transgenic overexpression of the PP2A methyltransferase, LCMT-1, or the PP2A methylesterase, PME-1, altered the sensitivity of mice to impairments caused by acute exposure to synthetic oligomeric amyloid-β (Aβ). Objective: Here we sought to test the possibility that these molecules also controlled sensitivity to impairments caused by chronically elevated levels of Aβ produced in …vivo . Methods: To do this, we examined the effects of transgenic LCMT-1, or PME-1 overexpression on cognitive and electrophysiological impairments caused by chronic overexpression of mutant human APP in Tg2576 mice. Results: We found that LCMT-1 overexpression prevented impairments in short-term spatial memory and synaptic plasticity in Tg2576 mice, without altering APP expression or soluble Aβ levels. While the magnitude of the effects of PME-1 overexpression in Tg2576 mice was small and potentially confounded by the emergence of non-cognitive impairments, Tg2576 mice that overexpressed PME-1 showed a trend toward earlier onset and/or increased severity of cognitive and electrophysiological impairments. Conclusion: These data suggest that the PP2A methyltransferase, LCMT-1, and the PP2A methylesterase, PME-1, may participate in the molecular pathogenesis of AD by regulating sensitivity to the pathogenic effects of chronically elevated levels of Aβ. Show more

Keywords: Alzheimer’s disease, amyloid-β, cognitive impairment, leucine carboxyl methyltransferase, long-term potentiation, MAPT protein, protein phosphatase 2A, protein phosphatase methylesterase

DOI: 10.3233/JAD-200462

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Iliadou, Paraskevi | Paliokas, Ioannis | Zygouris, Stelios | Lazarou, Eftychia | Votis, Konstantinos | Tzovaras, Dimitrios | Tsolaki, Magdalini

Article Type: Research Article

Abstract: Background: Electroencephalography (EEG) has been used to assess brain activity while users are playing an immersive serious game. Objective: To assess differences in brain activation as measured with a non-intrusive wearable EEG device, differences in game performance and correlations between EEG power, game performance and global cognition, between cognitively impaired and non-impaired older adults, during the administration of a novel self-administered serious game-based test, the Virtual Supermarket Test (VST). Methods: 43 older adults with subjective cognitive decline (SCD) and 33 older adults with mild cognitive impairment (MCI) were recruited from day centers for cognitive disorders. Global …cognition was assessed with the Montreal Cognitive Assessment (MoCA). Brain activity was measured with a non-intrusive wearable EEG device in a resting state condition and while they were administered the VST. Results: During resting state condition, the MCI group showed increased alpha, beta, delta, and theta band power compared to the SCD group. During the administration of the VST, the MCI group showed increased beta and theta band power compared to the SCD group. Regarding game performance, alpha, beta, delta, and theta rhythms correlated with average duration, while delta rhythm was positively correlated with mean errors. MoCA correlated with alpha, beta, delta, and theta rhythms and with average game duration and mean game errors indicating that elevated EEG rhythms in MCI may be associated with an overall cognitive decline. Conclusion: VST performance can be used as a digital biomarker. Cheap commercially available wearable EEG devices can be used for obtaining brain activity biomarkers. Show more

Keywords: Age-related memory disorders, cognitive assessment screening instrument, computer games, dementia, EEG, mild cognitive impairment, neurocognitive tests, screening, self-evaluation

DOI: 10.3233/JAD-201300

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2021

Authors: Martínez-García, Ignacio | Hernández-Soto, Rebeca | Villasana-Salazar, Benjamín | Ordaz, Benito | Peña-Ortega, Fernando

Article Type: Research Article

Abstract: Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and …on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro . Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo . Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro . Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD. Show more

Keywords: Alzheimer’s disease, coherence, hyperexcitability, local field potential, main olfactory bulb, olfactory function, piriform cortex

DOI: 10.3233/JAD-201392

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2021

Authors: Ilango, Sindana D. | Gonzalez, Kevin | Gallo, Linda | Allison, Matthew A. | Cai, Jianwen | Isasi, Carmen R. | Hosgood, Dean H. | Vasquez, Priscilla M. | Zeng, Donglin | Mortamais, Marion | Gonzalez, Hector | Benmarhnia, Tarik

Article Type: Research Article

Abstract: Background: Hispanics/Latinos in the United States are more likely to live in neighborhoods with greater exposure to air pollution and are projected to have the largest increase in dementia among race/ethnic minority groups. Objective: We examined the associations of air pollution with performance on cognitive function tests in Hispanic/Latino adults. Methods: We used data from the San Diego site of the Hispanic Community Health Study/Study of Latinos, an ongoing cohort of Hispanics/Latinos. This analysis focused on individuals ≥45 years of age who completed a neurocognitive battery examining overall mental status, verbal learning, memory, verbal fluency, and …executive function (n  = 2,089). Air pollution (PM2.5 and O3 ) before study baseline was assigned to participants’ zip code. Logistic and linear regression were used to estimate the association of air pollution on overall mental status and domain-specific standardized test scores. Models accounted for complex survey design, demographic, and socioeconomic characteristics. Results: We found that for every 10μg/m3 increase in PM2.5 , verbal fluency worsened (β: –0.21 [95%CI: –0.68, 0.25]). For every 10 ppb increase in O3 , verbal fluency and executive function worsened (β: –0.19 [95%CI: –0.34, –0.03]; β: –0.01 [95%CI: –0.01, 0.09], respectively). We did not identify any detrimental effect of pollutants on other domains. Conclusion: Although we found suggestions that air pollution may impact verbal fluency and executive function, we observed no consistent or precise evidence to suggest an adverse impact of air pollution on cognitive level among this cohort of Hispanic/Latino adults. Show more

Keywords: Air pollution, cognitive dysfunction, cohort study, dementia, hispanics, latinos, particulate matter, ozone

DOI: 10.3233/JAD-200766

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2021

Authors: Lao, Kejing | Zhang, Ruisan | Luan, Jing | Zhang, Yuelin | Gou, Xingchun

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) is a chronic neurodegenerative disease that has been recognized as one of the most intractable medical problems with heavy social and economic costs. Amyloid-β (Aβ) has been identified as a major factor that participates in AD progression through its neurotoxic effects. The major mechanism of Aβ-induced neurotoxicity is by interacting with membrane receptors and subsequent triggering of aberrant cellular signaling. Besides, Aβ transporters also plays an important role by affecting Aβ homeostasis. Thus, these Aβ receptors and transporters are potential targets for the development of AD therapies. Here, we summarize the reported therapeutic strategies targeting Aβ receptors …and transporters to provide a molecular basis for future rational design of anti-AD agents. Show more

Keywords: Aβ receptors, Aβ transporter, EphB2, LilrB2, LRP-1, NgR, p75NTR, PrPc, RAGE

DOI: 10.3233/JAD-200851

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2021

Authors: Loeffler, David A.

Article Type: Research Article

Abstract: There is an extensive literature relating to factors associated with the development of Alzheimer’s disease (AD), but less is known about factors which may contribute to its progression. This review examined the literature with regard to 15 factors which were suggested by PubMed search to be positively associated with the cognitive and/or neuropathological progression of AD. The factors were grouped as potentially modifiable (vascular risk factors, comorbidities, malnutrition, educational level, inflammation, and oxidative stress), non-modifiable (age at clinical onset, family history of dementia, gender, Apolipoprotein E ɛ4, genetic variants, and altered gene regulation), and clinical (baseline cognitive level, neuropsychiatric symptoms, …and extrapyramidal signs). Although conflicting results were found for the majority of factors, a positive association was found in nearly all studies which investigated the relationship of six factors to AD progression: malnutrition, genetic variants, altered gene regulation, baseline cognitive level, neuropsychiatric symptoms, and extrapyramidal signs. Whether these or other factors which have been suggested to be associated with AD progression actually influence the rate of decline of AD patients is unclear. Therapeutic approaches which include addressing of modifiable factors associated with AD progression should be considered. Show more

Keywords: Alzheimer’s disease, baseline cognition, extrapyramidal signs, genetic factors, malnutrition, neuropsychiatric symptoms, progression

DOI: 10.3233/JAD-201182

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-27, 2021

Authors: Ferini-Strambi, Luigi | Hensley, Michael | Salsone, Maria

Article Type: Research Article

Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are two common chronic diseases with a well-documented association. Whether the association is causal has been highlighted by recent evidence reporting a neurobiological link between these disorders. This narrative review discusses the brain regions and networks involved in OSA as potential vulnerable areas for the development of AD neuropathology with a particular focus on gender-related implications. Using a neuroimaging perspective supported by neuropathological investigations, we provide a new model of neurodegeneration common to OSA and AD, that we have called OSA-AD neurodegeneration in order to decode the causal links between these two …chronic conditions. Show more

Keywords: Alzheimer’s disease, amygdala, cingulate gyrus, hippocampus, insula, magnetic resonance imaging, obstructive sleep apnea

DOI: 10.3233/JAD-201066

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2021

Authors: Borda, Miguel Germán | Ayala Copete, Ana María | Tovar-Rios, Diego Alejandro | Jaramillo-Jimenez, Alberto | Giil, Lasse Melvær | Soennesyn, Hogne | Gómez-Arteaga, Camilo | Venegas-Sanabria, Luis Carlos | Kristiansen, Ida | Chavarro-Carvajal, Diego Andrés | Caicedo, Sandra | Cano-Gutierrez, Carlos Alberto | Vik-Mo, Audun | Aarsland, Dag

Article Type: Research Article

Abstract: Background: In dementia, functional status depends on multiple factors in addition to cognition. Nutritional status is a potentially modifiable factor related to homeostasis and proper functioning of body systems and may contribute to cognitive and functional decline. Objective: This paper aims to analyze the association of malnutrition with the course of cognitive and functional decline in people living with dementia. Methods: This is an analysis of a longitudinal cohort study, the Dementia Study of Western Norway. Data of 202 patients diagnosed with mild dementia were analyzed; Alzheimer’s disease (AD) (n  = 103), Lewy body dementia (LBD) (n … = 74), and other dementias (OD) (n  = 25). Cognition was assessed with the Mini-Mental State Examination and functional decline through the activities of daily living included in the Rapid Disability Rating Scale. The Global Leadership Initiative on Malnutrition Index was used to determine nutritional status. Associations of nutritional status with cognitive and functional decline were evaluated through adjusted linear mixed models. Results: At baseline, the prevalence of general malnutrition was 28.7%; 17.32% were classified as moderate malnutrition and 11.38% as severe malnutrition (there were no significant differences between AD and LBD). Malnutrition at diagnosis and over follow-up was a significant predictor of functional-decline, but not of cognitive decline. Conclusion: According to our results malnutrition was associated with faster functional loss but, not cognitive decline in older adults with dementia. A more comprehensive dementia approach including nutritional assessments could improve prognosis. Show more

Keywords: Activities of daily living, Alzheimer’s disease, dementia, Lewy body dementia, malnutrition

DOI: 10.3233/JAD-200961

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2021