Journal of Alzheimer's Disease - Volume 76, issue 4

Authors: Resende, Rosa | Ferreira-Marques, Marisa | Moreira, Patrícia | Coimbra, Judite R.M. | Baptista, Salete J. | Isidoro, Ciro | Salvador, Jorge A.R. | Dinis, Teresa C.P. | Pereira, Cláudia F. | Santos, Armanda E.

Article Type: Research Article

Abstract: Background: A disease-modifying therapy for Alzheimer’s disease (AD) is still an unmet clinical need. The formation of amyloid-β (Aβ) requires the initial cleavage of the amyloid-β protein precursor (AβPP) by BACE1 (beta-site AβPP cleaving enzyme 1), which is a prime therapeutic target for AD. Objective: We aimed to design and develop a selective BACE1 inhibitor suitable to AD treatment. Methods: The new BACE1 inhibitors consist on a chimeric peptide including a sequence related to the human Swedish mutant form of AβPP (AβPPswe) conjugated with the TAT carrier that facilitates cell membrane permeation and the crossing of …the blood-brain barrier. Additionally to the chimeric peptide in the L -form, we developed a D -retroinverso chimeric peptide. The latter strategy, never used with BACE1 inhibitors, is considered to favor a significantly higher half-life and lower immunogenicity. Results: We found that both chimeric peptides inhibit recombinant BACE1 activity and decrease Aβ40/42 production in Neuro-2a (N2A) cells expressing AβPPswe without inducing cytotoxicity. The intraperitoneal administration of these peptides to 3xTg-AD mice decreased plasma and brain Aβ40/42 levels, as well as brain soluble AβPPβ production. Also, a reduction of insoluble Aβ was observed in the brain after chronic treatment. Noteworthy, the chimeric peptides selectively inhibited the AβPP-β cleavage relatively to the proteolysis of other BACE1 substrates such as close homologue of L1 (CHL1) and seizure-related gene 6 (SEZ6). Conclusions: Overall these new BACE1 chimeric peptideshold promising potential as a selective disease-modifying therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, BACE1 inhibitor, chimeric peptide, CHL1, SEZ6

DOI: 10.3233/JAD-200381

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1317-1337, 2020

Authors: Li, Tengfei | Martin, Elodie | Abada, Yah-se | Boucher, Céline | Cès, Aurélia | Youssef, Ihsen | Fenaux, Grégory | Forand, Yona | Legrand, Annaelle | Nachiket, Nadkarni | Dhenain, Marc | Hermine, Olivier | Dubreuil, Patrice | Delarasse, Cécile | Delatour, Benoît

Article Type: Research Article

Abstract: Background: Masitinib is a selective tyrosine kinase inhibitor that modulates mast cells activity. A previous phase II study reported a cognitive effect of masitinib in patients with Alzheimer’s disease. Objective: We aimed to shed light on the mode of action of masitinib in Alzheimer’s disease. Methods/Results: We demonstrated here that chronic oral treatment of APPswe/PSEN1dE9 transgenic mice modeling Alzheimer’s disease restored normal spatial learning performance while having no impacts on amyloid-β loads nor on neuroinflammation. However, masitinib promoted a recovery of synaptic markers. Complete genetic depletion of mast cells in APPswe/PSEN1dE9 mice similarly rescued synaptic …impairments. Conclusion: These results underline that masitinib therapeutic efficacy might primarily be associated with a synapto-protective action in relation with mast cells inhibition. Show more

Keywords: Alzheimer’s disease, cognition, drug evaluation, masitinib, mast cells, preclinical, synapses

DOI: 10.3233/JAD-200466

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1339-1345, 2020

Authors: Mohan, Devi | Yap, Kwong Hsia | Reidpath, Daniel | Soh, Yee Chang | McGrattan, Andrea | Stephan, Blossom C.M. | Robinson, Louise | Chaiyakunapruk, Nathorn | Siervo, Mario | on behalf of DePEC team

Article Type: Research Article

Abstract: Background: A key focus for dementia risk-reduction is the prevention of socio-demographic, lifestyle, and nutritional risk factors. High sodium intake is associated with hypertension and cardiovascular disease (both are linked to dementia), generating numerous recommendations for salt reduction to improve cardiovascular health. Objective: This systematic review aimed to assess, in middle- and older-aged people, the relationship between dietary sodium intake and cognitive outcomes including cognitive function, risk of cognitive decline, or dementia. Methods: Six databases (PubMed, EMBASE, CINAHL, Psych info, Web of Science, and Cochrane Library) were searched from inception to 1 March 2020. Data extraction …included information on study design, population characteristics, sodium reduction strategy (trials) or assessment of dietary sodium intake (observational studies), measurement of cognitive function or dementia, and summary of main results. Risk-of-bias assessments were performed using the National Heart, Lung, and Blood Institute (NHLBI) assessment tool. Results: Fifteen studies met the inclusion criteria including one clinical trial, six cohorts, and eight cross-sectional studies. Studies reported mixed associations between sodium levels and cognition. Results from the only clinical trial showed that a lower sodium intake was associated with improved cognition over six months. In analysis restricted to only high-quality studies, three out of four studies found that higher sodium intake was associated with impaired cognitive function. Conclusion: There is some evidence that high salt intake is associated with poor cognition. However, findings are mixed, likely due to poor methodological quality, and heterogeneous dietary, analytical, and cognitive assessment methods and design of the studies. Reduced sodium intake may be a potential target for intervention. High quality prospective studies and clinical trials are needed. Show more

Keywords: Cognitive dysfunction, dementia, salt, sodium, systematic review

DOI: 10.3233/JAD-191339

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1347-1373, 2020

Authors: Shi, Yun | Zhang, Lei | Gao, Xue | Zhang, Jing | Ben Abou, Matan | Liang, Ge | Meng, Qingcheng | Hepner, Adrian | Eckenhoff, Maryellen F. | Wei, Huafeng

Article Type: Research Article

Abstract: Background/Objective: This study compares the effectiveness and safety of intranasal versus subcutaneous administration of dantrolene in 5XFAD Alzheimer’s disease (AD) mice. Methods: 5XFAD and wild type (WT) B6SJLF1/J mice were treated with intranasal or subcutaneous dantrolene (5 mg/kg, 3×/wk), or vehicle. The early (ETG) and late (LTG) treatment groups began treatment at 2 or 6 months of age, respectively, and both treatment groups finished at12 months of age. Behavior was assessed for olfaction (buried food test), motor function (rotarod), and cognition (fear conditioning, Morris water maze). Liver histology (H & E staining) and function, synaptic proteins, and brain amyloid …immunohistochemistry were examined. Plasma and brain dantrolene concentrations were determined in a separate cohort after intranasal or subcutaneous administration. Results: Intranasal dantrolene achieved higher brain and lower plasma concentrations than subcutaneous administration. Dantrolene administration at both approaches significantly improved hippocampal-dependent and -independent memory in the ETG, whereas only intranasal dantrolene improved cognition in the LTG. Dantrolene treatment had no significant change in the amyloid burden or synaptic proteins and no significant side effects on mortality, olfaction, motor, or liver functions in 5XFAD mice. Intranasal dantrolene treatment significantly ameliorated memory loss when it was started either before or after the onset of AD symptoms in 5XFAD mice. Conclusions: The long-term intranasal administration of dantrolene had therapeutic effects on memory compared to the subcutaneous approach even started after onset of AD symptoms, suggesting use as a disease-modifying drug, without significant effects on amyloid plaques, side effects, or mortality. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dantrolene, intranasal administration

DOI: 10.3233/JAD-200227

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1375-1389, 2020

Authors: Joa, Kyung-Lim | Mankhong, Sakulrat | Kim, Sujin | Moon, Sohee | Lee, Kyoung-Hee | Yoo, Young-Hwan | Hwang, Byeong-Hun | Baek, Jong-Won | Kang, Ju-Hee

Article Type: Research Article

Abstract: Background: Recent evidence indicates brain ischemia is associated with accumulations of abnormal tau and related proteins. However, the effects of aerobic training on these proteins have not been evaluated. Objective: We aimed to evaluate the effect of aerobic exercise on the phosphorylation and acetylation of tau and on the expressions of tau related proteins in a rat stroke model and to compare the effects of aerobic exercise with those observed in our previous study on task specific training (TST). Methods: Twenty-four Sprague– Dawley rats with photothrombotic cortical infarction were used in the current study. The rehabilitation …group (RG) received treadmill training 40 min/day for 28 days, whereas the sedentary group (SG) did not receive any type of training. Functional tests such as the single pellet reaching task, rotarod, and radial arm maze tests were performed weekly for 4 weeks post-infarction. Results: Levels of p-taus396 and p-AMPK were found to be lower in ipsilateral cortices in the RG than in the SG (p  < 0.05). Levels of p-taus262 , Ac-tau, p-GSK3βS9 , p-Akt, p-Sin1, and p-P70-S6K were significantly lower in ipsilateral than in contralateral cortices in the RG (p  < 0.05). Aerobic training also improved motor, balance, and memory functions. Conclusion: Aerobic training inhibited the phosphorylation and acetylation of tau and modulated the expressions of tau related proteins after stroke by modifying the p70-S6K pathway and p-AMPK. By comparison with our previous study on the effects of TST, we have evidence to suggest that TST and aerobic exercise differ, although both types of rehabilitation inhibit tau phosphorylation and acetylation. Show more

Keywords: Aerobic training, dementia, phosphorylated tau, rehabilitation, stroke, tau

DOI: 10.3233/JAD-200250

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1391-1402, 2020

Authors: Nicoli, Charles D. | Howard, Virginia J. | Judd, Suzanne E. | Struck, Joachim | Manly, Jennifer J. | Cushman, Mary

Article Type: Research Article

Abstract: Background: The neuropeptide neurotensin (NT) has been linked to cardiometabolic disease. Cardiovascular risk factors are being recognized as risk factors for cognitive impairment. Objective: To examine the association of the stable precursor of NT, pro-neurotensin/neuromedin N (pro-NT/NMN), with incident cognitive impairment (ICI). Methods: We conducted a prospective nested case-control study in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. In 2003-2007, REGARDS enrolled 30,239 Black and White adults aged ≥45 years. ICI was identified using a 3-test cognitive battery administered biannually. Baseline pro-NT/NMN was measured by immunoassay in 393 cases of ICI and …490 controls after 3.4 years follow up. Multivariable logistic regression was used to calculate odds ratios (OR) of ICI by pro-NT/NMN quartiles. Race, age, and sex differences were studied with stratified models and interaction testing. Results: Pro-NT/NMN was higher in Black participants and those with hypertension and diabetes. Women with a 4th versus 1st-quartile pro-NT/NMN had 2.28-fold increased odds of ICI (95% CI 1.08–4.78) after adjusting for risk factors and incident stroke. There was no association of higher pro-NT/NMN quartiles with ICI in the overall group or men. There were no race or age differences in associations. Conclusion: In this biracial population-based study, elevated systemic pro-NT/NMN was associated with more than doubled risk of ICI in women but not men. Others reported sex-specific associations in women for cardiovascular mortality and diabetes with higher pro-NT/NMN, supporting a role for future research on sex differences in the neurotensinergic system. Show more

Keywords: Biomarkers, case-control studies, cognition disorders, cognitive dysfunction, neuropeptides, neurotensin, prospective studies

DOI: 10.3233/JAD-200456

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1403-1412, 2020

Authors: Falcon, Carles | Grau-Rivera, Oriol | Suárez-Calvet, Marc | Bosch, Beatriz | Sánchez-Valle, Raquel | Arenaza-Urquijo, Eider M. | González-de-Echavarri, José María | Gispert, Juan Domingo | Rami, Lorena | Molinuevo, José Luis

Article Type: Research Article

Abstract: Background: There is increasing evidence that AD progression differs by sex. Objective: The aim of this work was to determine sex differences in the association of baseline levels of cerebrospinal fluid (CSF) biomarkers (Aβ42 , p-tau, YKL-40, sTREM2) with longitudinal brain changes in cognitively unimpaired (CU) older adults. Methods: This pilot study included 36 CU subjects (age 66.5±5.5, 12 male) scanned twice, two years apart. Using a voxel-wise analysis, we determined the sex differences in the association maps between CSF biomarkers and atrophy rates. Results: We did not find differences related to Aβ42 . …We found a greater impact of the rest of CSF biomarkers in areas of the Papez circuit in women versus men. Men showed greater involvement in lateral parietal and paracentral areas. Discussion: Results suggest an early differential progression of brain atrophy between sexes. Further research will elucidate whether the mechanisms responsible for sex-specific atrophy patterns are biological and/or environmental. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitively unimpaired older adults, longitudinal VBM, sex differences, sTREM2, YKL-40

DOI: 10.3233/JAD-200293

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1413-1422, 2020

Authors: Hakim, Md A. | Behringer, Erik J.

Article Type: Research Article

Abstract: Background: Development of Alzheimer’s disease (AD) pathology is associated with impaired blood flow delivery of oxygen and nutrients throughout the brain. Cerebrovascular endothelium regulates vasoreactivity of blood vessel networks for optimal cerebral blood flow. Objective: We tested the hypothesis that cerebrovascular endothelial Gq -protein-coupled receptor (GPCR; purinergic and muscarinic) and K+ channel [Ca2+ -activated (KCa 2.3/SK3 and KCa 3.1/IK1) and inward-rectifying (KIR 2.x)] function declines during progressive AD pathology. Methods: We applied simultaneous measurements of intracellular Ca2+ ([Ca2+ ]i ) and membrane potential (Vm ) in freshly isolated endothelium from posterior cerebral arteries of …3×Tg-AD mice [young, no pathology (1– 2 mo), cognitive impairment (CI; 4– 5 mo), extracellular Aβ plaques (Aβ; 6– 8 mo), and Aβ plaques + neurofibrillary tangles (AβT; 12– 15 mo)]. Results: The coupling of Δ Vm -to-Δ [Ca2+ ]i during AβT pathology was lowest for both sexes but, overall, ATP-induced purinergic receptor function was stable throughout AD pathology. SKCa /IKCa channel function itself was enhanced by ∼20% during AD (Aβ+ AβT) versus pre-AD (Young + CI) in males while steady in females. Accordingly, hyperpolarization-induced [Ca2+ ]i increases following SKCa /IKCa channel activation and Δ [Ca2+ ]i -to-Δ Vm coupling was enhanced by ≥two-fold during AD pathology in males but not females. Further, KIR channel function decreased by ∼50% during AD conditions versus young regardless of sex. Finally, other than a ∼40% increase in females versus males during Aβ pathology, [Ca2+ ]i responses to the mitochondrial uncoupler FCCP were similar among AD versus pre-AD conditions. Conclusion: Altogether, AD pathology represents a condition of altered KCa and KIR channel function in cerebrovascular endothelium in a sex-dependent and sex-independent manner respectively. Show more

Keywords: Cerebral arteries, endothelial cells, potassium channels, sex characteristics

DOI: 10.3233/JAD-200085

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1423-1442, 2020

Authors: Goto, Tetsuya | Kuramoto, Eriko | Dhar, Ashis | Wang, Rachel Pei-Hsuan | Seki, Haruka | Iwai, Haruki | Yamanaka, Atsushi | Matsumoto, Shin-Ei | Hara, Hiromitsu | Michikawa, Makoto | Ohyagi, Yasumasa | Leung, Wai Keung | Chang, Raymond Chuen-Chung

Article Type: Research Article

Abstract: Background: The mesencephalic trigeminal nucleus (Vmes) is not only anatomically adjacent to the locus coeruleus (LC) but is also tightly associated with the function of the LC. The LC can be the first area in which Alzheimer’s disease (AD) develops, although it is unclear how LC neuronal loss occurs. Objective: We investigated whether neuronal death in the Vmes can be spread to adjacent LC in female triple transgenic (3×Tg)-AD mice, how amyloid-β (Aβ) is involved in LC neuronal loss, and how this neurodegeneration affects cognitive function. Methods: The molars of 3×Tg-AD mice were extracted, and the …mice were reared for one week to 4 months. Immunohistochemical analysis, and spatial learning/memory assessment using the Barnes maze were carried out. Results: In 4-month-old 3×Tg-AD mice, aggregated cytotoxic Aβ42 was found in granules in Vmes neurons. Neuronal death in the Vmes occurred after tooth extraction, resulting in the release of cytotoxic Aβ42 and an increase in CD86 immunoreactive microglia. Released Aβ42 damaged the LC, in turn inducing a significant reduction in hippocampal neurons in the CA1 and CA3 regions receiving projections from the LC. Based on spatial learning/memory assessment, after the tooth extraction in the 4-month-old 3×Tg-AD mice, increased latency was observed in 5-month-old 3×Tg-AD mice 1 month after tooth extraction, which is similar increase of latency observed in control 8-month-old 3×Tg-AD mice. Measures of cognitive deficits suggested an earlier shift to dementia-like behavior after tooth extraction. Conclusion: These findings suggest that tooth extraction in the predementia stage can trigger the spread of neurodegeneration from the Vmes, LC, and hippocampus and accelerate the onset of dementia. Show more

Keywords: Alzheimer’s disease, amyloid-β, behavior, locus coeruleus, neurodegeneration, tooth loss, trigeminal nuclei

DOI: 10.3233/JAD-200257

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1443-1459, 2020

Authors: Schwab, Simon | Afyouni, Soroosh | Chen, Yan | Han, Zaizhu | Guo, Qihao | Dierks, Thomas | Wahlund, Lars-Olof | Grieder, Matthias

Article Type: Research Article

Abstract: Background: Semantic memory impairments in semantic dementia are attributed to atrophy and functional disruption of the anterior temporal lobes. In contrast, the posterior medial temporal neurodegeneration found in Alzheimer’s disease is associated with episodic memory disturbance. The two dementia subtypes share hippocampal deterioration, despite a relatively spared episodic memory in semantic dementia. Objective: To unravel mutual and divergent functional alterations in Alzheimer’s disease and semantic dementia, we assessed functional connectivity between temporal lobe regions in Alzheimer’s disease (n  = 16), semantic dementia (n  = 23), and healthy controls (n  = 17). Methods: In an exploratory study, we used a …functional parcellation of the temporal cortex to extract time series from 66 regions for correlation analysis. Results: Apart from differing connections between Alzheimer’s disease and semantic dementia that yielded reduced functional connectivity, we identified a common pathway between the right anterior temporal lobe and the right orbitofrontal cortex in both dementia subtypes. This disconnectivity might be related to social knowledge deficits as part of semantic memory decline. However, such interpretations are preferably made in a holistic context of disease-specific semantic impairments and functional connectivity changes. Conclusion: Despite a major limitation owed to unbalanced databases between study groups, this study provides a preliminary picture of the brain’s functional disconnectivity in Alzheimer’s disease and semantic dementia. Future studies are needed to replicate findings of a common pathway with consistent diagnostic criteria and neuropsychological evaluation, balanced designs, and matched data MRI acquisition procedures. Show more

Keywords: Alzheimer’s disease, functional connectivity, semantic dementia, temporal lobe

DOI: 10.3233/JAD-191113

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1461-1475, 2020

Authors: Paul, Kimberly C. | Haan, Mary | Yu, Yu | Inoue, Kosuke | Mayeda, Elizabeth Rose | Dang, Kristina | Wu, Jun | Jerrett, Michael | Ritz, Beate

Article Type: Research Article

Abstract: Background: Ambient air pollution exposure has been associated with dementia. Additionally, epidemiologic evidence supports associations between air pollution and diabetes as well as diabetes and dementia. Thus, an indirect pathway between air pollution and dementia may exist through metabolic dysfunction. Objective: To investigate whether local traffic-related air pollution (TRAP) influences incident dementia and cognitive impairment, non-dementia (CIND) in a cohort of older Mexican Americans. We also assess how much of this estimated effect might be mediated through type 2 diabetes (T2DM). Methods: In a 10-year, prospective study of Latinos (n  = 1,564), we generated TRAP-NOx as …a surrogate for pollution from local traffic sources at participants’ residences during the year prior to enrollment. We used Cox proportional hazards modeling and mediation analysis to estimate the effects of TRAP-NOx on dementia and/or CIND and indirect pathways operating through T2DM. Results: Higher TRAP-NOx was associated with incident dementia (HR = 1.55 for the highest versus lower tertiles, 95% CI = 1.04, 2.55). Higher TRAP-NOx was also associated with T2DM (OR = 1.62, 95% CI = 1.27, 2.05); furthermore, T2DM was associated with dementia (HR = 1.94, 95% CI = 1.42, 2.66). Mediation analysis indicated that 20% of the estimated effect of TRAP-NOx on dementia/CIND was mediated through T2DM. Conclusion: Our results suggest that exposure to local traffic-related air pollution is associated with incident dementia. We also estimated that 20% of this effect is mediated through T2DM. Thus, ambient air pollution might affect brain health via direct damage as well as through indirect pathways related to diabetes and metabolic dysfunction. Show more

Keywords: Air pollution, CALINE4, cognitive decline, dementia, diabetes, Latino, mediation, nitrogen oxide, traffic-related air pollution

DOI: 10.3233/JAD-200320

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1477-1491, 2020

Authors: Garcia, Marc A. | Ortiz, Kasim | Arévalo, Sandra P. | Diminich, Erica D. | Briceño, Emily | Vega, Irving E. | Tarraf, Wassim

Article Type: Research Article

Abstract: Background: Age of migration has been shown to have a robust association with Latino immigrant health outcomes; however, the relationship between timing of migration and cognition is less understood. Objective: To examine associations between race/ethnicity, nativity, age of migration, and cognitive aging among US-born (USB) non-Latino Whites (NLW) and USB and foreign-born Latinos 50 years and older. Methods: We used longitudinal biennial data from the Health and Retirement Study (HRS; 2006-2014) to fit generalized linear and linear latent growth curve models for: 1) global cognition (Modified Telephone Interview for Cognitive Status; TICS-M); 2) memory and attention …subdomains of TICS-M; and 3) cognitive dysfunction. We also tested for sex modifications. Results: In age and sex adjusted models, all Latino subgroups, independent of nativity and age of migration, had lower global and domain-specific cognitive scores and higher propensity of cognitive impairment classification compared to USB-NLWs. Differences between USB Latinos, but not other Latino subgroups, and USB-NLWs remained after full covariate adjustment. Latinas, independent of nativity or age of migration, had poorer cognitive scores relative to NLW females. Differences between all Latinos and USB-NLWs were principally expressed at baseline. Racial/ethnic, nativity, and age of migration grouping was not associated with slope (nor explained variance) of cognitive decline. Conclusion: Older US-born Latinos, regardless of sex exhibit poorer cognitive function than older USB-NLWs and foreign-born Latinos. Social determinants that differentially affect cognitive function, particularly those that compensate for education and sex differences among US-born Latinos and foreign-born Latinos, require further exploration. Show more

Keywords: Alzheimer’s disease and related dementias, cognitive function, immigration, Latino, nativity, sex differences

DOI: 10.3233/JAD-191296

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1493-1511, 2020

Authors: Sun, Zhiqing | Sun, Lei | Tu, Lixiang

Article Type: Research Article

Abstract: Background: Oxidative stress has been implicated in Alzheimer’s disease (AD) as a common pathway underlying neuronal damage causing huge impacts on cognitive functions in the AD process. Objective: Reduction and remodeling of γ -aminobutyric acid (GABA) signaling in AD may promote neuronal survival by regulating PI3K/Akt axis. Moreover, its activation exerts beneficial effects on AD by alleviating the neuronal oxidative stress injury. Considering these facts, we hypothesized the GABAB receptor as a novel therapeutic target for AD. Methods: To evaluate this hypothesis, a rat AD model was established by intraperitoneal injection of the GABAB …receptor agonist (baclofen), PI3K/Akt signaling pathway agonist (740 Y-P), and antagonist (LY294002), respectively. The effects of GABAB activation on spatial memory and learning ability in the AD rats were measured by Morris water maze. Whereas the effects of GABAB and PI3K/Akt signaling pathway on apoptosis and oxidative stress injury were determined in vivo and in vitro using primary neuronal cultures. Results: We found that GABAB receptor activation restored spatial memory and learning ability of AD rats and suppressed the neuronal apoptosis and hippocampal atrophy by activating the PI3K/Akt signaling pathway. Additionally, GABAB receptor activation reduced the oxidative stress injury by lowering the MDA levels and increased the SOD, GSH-Px, and CAT levels via activation of the PI3K/Akt signaling pathway. Conclusion: Taken together, our results suggest that GABAB receptor activation repressed the oxidative stress injury implicated in neurons in AD rats via PI3K/Akt signaling pathway activation which may suggest a potential new therapeutic target for AD. Show more

Keywords: Alzheimer’s disease, GABAB receptor, oxidative stress injury, PI3K/Akt signaling pathway

DOI: 10.3233/JAD-191032

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1513-1526, 2020

Authors: Gárate-Vélez, Lorena | Escudero-Lourdes, Claudia | Salado-Leza, Daniela | González-Sánchez, Armando | Alvarado-Morales, Ildemar | Bahena, Daniel | Labrada-Delgado, Gladis Judith | Rodríguez-López, José Luis

Article Type: Research Article

Abstract: Background: Iron nanoparticles, mainly in magnetite phase (Fe3 O4 NPs), are released to the environment in areas with high traffic density and braking frequency. Fe3 O4 NPs were found in postmortem human brains and are assumed to get directly into the brain through the olfactory nerve. However, these pollution-derived NPs may also translocate from the lungs to the bloodstream and then, through the blood-brain barrier (BBB), into the brain inducing oxidative and inflammatory responses that contribute to neurodegeneration. Objective: To describe the interaction and toxicity of pollution-derived Fe3 O4 NPs on primary rat brain microvascular …endothelial cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3 O4 NPs that mimic the environmental ones (miFe3 O4 ) were synthesized by co-precipitation and characterized using complementary techniques. The rBMECs were cultured in Transwell® plates. The NPs-cell interaction was evaluated through transmission electron microscopy and standard colorimetric in vitro assays. Results: The miFe3 O4 NPs, with a mean diameter of 8.45±0.14 nm, presented both magnetite and maghemite phases, and showed super-paramagnetic properties. Results suggest that miFe3 O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3 O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3 O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage. Show more

Keywords: Blood-brain barrier, cytotoxicity, in vitro , magnetite nanoparticles

DOI: 10.3233/JAD-190929

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1527-1539, 2020

Authors: Ferguson, Amy C. | Tank, Rachana | Lyall, Laura M. | Ward, Joey | Celis-Morales, Carlos | Strawbridge, Rona | Ho, Frederick | Whelan, Christopher D. | Gill, Jason | Welsh, Paul | Anderson, Jana J. | Mark, Patrick B. | Mackay, Daniel F. | Smith, Daniel J. | Pell, Jill P. | Cavanagh, Jonathan | Sattar, Naveed | Lyall, Donald M.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a neurodegenerative condition where the underlying etiology is still unclear. Investigating the potential influence of apolipoprotein E (APOE ), a major genetic risk factor, on common blood biomarkers could provide a greater understanding of the mechanisms of AD and dementia risk. Objective: Our objective was to conduct the largest (to date) single-protocol investigation of blood biomarkers in the context of APOE genotype, in UK Biobank. Methods: After quality control and exclusions, data on 395,769 participants of White European ancestry were available for analysis. Linear regressions were used to test potential …associations between APOE genotypes and biomarkers. Results: Several biomarkers significantly associated with APOE ɛ 4 ‘risk’ and ɛ 2 ‘protective’ genotypes (versus neutral ɛ 3/ɛ 3). Most associations supported previous data: for example, ɛ 4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b] = 0.150 standard deviations [SDs] per allele, p  < 0.001) and ɛ 2 with lower LDL (b  = –0.456 SDs, p  < 0.001). There were however instances of associations found in unexpected directions: e.g., ɛ 4 and increased insulin-like growth factor (IGF-1) (b  = 0.017, p  < 0.001) where lower levels have been previously suggested as an AD risk factor. Conclusion: These findings highlight biomarker differences in non-demented people at genetic risk for dementia. The evidence herein supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways. Show more

Keywords: Alzheimer’s disease, APOE, cholesterol, dementia, UK Biobank

DOI: 10.3233/JAD-200338

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1541-1551, 2020

Authors: Fan, Kang-Hsien | Feingold, Eleanor | Rosenthal, Samantha L. | Demirci, F. Yesim | Ganguli, Mary | Lopez, Oscar L. | Kamboh, M. Ilyas

Article Type: Research Article

Abstract: The genetics of late-onset Alzheimer’s disease (AD) is complex due to the heterogeneous nature of the disorder. APOE*4 is the strongest genetic risk factor for AD. Genome-wide association studies have identified more than 30 additional loci, each having relatively small effect size. Known AD loci explain only about 30% of the genetic variance, and thus much of the genetic variance remains unexplained. To identify some of the missing heritability of AD, we analyzed whole-exome sequencing (WES) data focusing on non-APOE*4 carriers from two WES datasets: 720 cases and controls from the University of Pittsburgh and 7,252 cases and …controls from the Alzheimer’s Disease Sequencing Project. Following separate WES analyses in each dataset, we performed meta-analysis for overlapping markers present in both datasets. Among the four variants reaching the exome-wide significance threshold, three were from known AD loci: APOE /rs7412 (odds ratio (OR) = 0.40; p  = 5.46E–24), TOMM40 /rs157581 (OR = 1.49; p  = 4.04E–07), and TREM2 /rs75932628 (OR = 4.00; p  = 1.15E–07). The fourth significant variant, rs199533, was from a novel locus on chromosome 17 in the NSF gene (OR = 0.78; p  = 2.88E–07). NSF was also significant in the gene-based analysis (p  = 1.20E–05). In the GTEx data, NSF /rs199533 is a cis-eQTL for multiple genes in the brain and blood, including NSF that is highly expressed across all brain tissues, including regions that typically show amyloid-β accumulation. Further characterization of genes that are affected by NSF /rs199533 may help to shed light on the roles of these genes in AD etiology. Show more

Keywords: Alzheimer’s disease, genetics, NSF gene, whole-exome sequencing

DOI: 10.3233/JAD-200037

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1553-1565, 2020

Authors: Coppalle, Renaud | Mauger, Caroline | Quernet, Sophie | Dewald, Axel | Letortu, Odile | Desgranges, Béatrice | Groussard, Mathilde | Platel, Hervé

Article Type: Research Article

Abstract: Background: Encoding of new information is considered to be impossible in people with Alzheimer’s disease (PWAD) at a moderate to severe stage. However, a few case studies reported new learning under special circumstances, especially with music. Objective: This article aims at clarifying PWAD’s learning capacities toward unknown material under more ecological settings, which is repeated exposure without encoding instruction. Methods: Twenty-three PWAD (Age: m = 84.6(5.2), 5≤MMSE≤19) underwent presentations of unknown artistic pieces (targets) through 8 daily individual sessions. These sessions were followed by a test session, during which their knowledge of the targets was assessed through a …verbal and behavioral scale (the sense of familiarity scale) against a series of unknown items (distractors). Results: Through this design, we were able to objectify encoding of three types of targets (verses, paintings, and music) against distractors the day after exposure sessions, and 2 months after the last presentation (study 1). Music and paintings were eventually well-encoded by most participants, whereas poems encoding was poorer. When compared to distractors, target items were significantly better recognized. We then compared the recognition of target paintings against two types of painting distractors, either perceptually or semantically related (study 2). The targets were better recognized than all three painting distractors, even when they were very close to the targets. Conclusion: Despite massive anterograde amnesia, our results clearly showed that recognition-based learning without conscious memory of the encoding context is preserved in PWAD at a severe stage, revealed through an increasing sense of familiarity following repeated exposure. These findings could open new perspective both for researchers and clinicians and improve the way we understand and care for PWAD living in healthcare facilities. Show more

Keywords: Alzheimer’s disease, familiarity, learning, music, recognition-based memory

DOI: 10.3233/JAD-191318

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1567-1579, 2020

Authors: Secnik, Juraj | Xu, Hong | Schwertner, Emilia | Hammar, Niklas | Alvarsson, Michael | Winblad, Bengt | Eriksdotter, Maria | Garcia-Ptacek, Sara | Religa, Dorota

Article Type: Research Article

Abstract: Background: Care individualization dominates in clinical guidelines for cognitively impaired patients with diabetes; however, few studies examined such adaptations. Objective: Describe long-term pharmacological changes in diabetes treatment in subjects with and without dementia. Methods: We performed a registry-based cohort study on 133,318 Swedish subjects (12,284 [9.2%] with dementia) with type 2 or other/unspecified diabetes. Dementia status originated from the Swedish Dementia Registry, while the National Patient Register, Prescribed Drug Register, and Cause of Death Register provided data on diabetes, comorbidities, drug dispensation, and mortality. Drug dispensation interval comprised years between 2005 and 2018 and the dispensation …was assessed relative to index date (dementia diagnosis) in full cohort and propensity-score (PS) matched cohorts. Annual changes of drug dispensation were analyzed by linear regression, while Cox and competing-risk regression were used to determine the probability of drug dispensation after index date in naïve subjects. Studied medications included insulin, metformin, sulfonylureas, thiazolidinediones, dipeptidyl-peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 agonists (GLP-1a), and sodium-glucose cotransporter-2 inhibitors (SGLT-2i). Results: Dementia patients had higher probability of insulin dispensation (hazard ratio 1.21 [95% CI 1.11–1.31] and lower probability of DPP-4i (0.72 [0.66–0.79]), GLP-1a (0.51 [0.41–0.63]), and SGLT-2i dispensation (0.44 [0.36–0.54]) after index date. PS-matched analyses showed increased annual insulin dispensation (β difference 0.97%) and lower increase in DPP-4i (–0.58%), GLP-1a (–0.13%), and SGLT-2i (–0.21%) dispensation in dementia patients compared to dementia-free controls. Conclusion: Dementia patients had lower probability of receiving newer antidiabetic drugs, with simultaneous higher insulin dispensation compared to dementia-free subjects. Show more

Keywords: Dementia, diabetes mellitus, hypoglycemic agents, pharmacoepidemiology

DOI: 10.3233/JAD-200618

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1581-1594, 2020

Authors: Luiu, Anna Laura | Favez, Nicolas | Betrancourt, Mireille | Szilas, Nicolas | Ehrler, Frederic

Article Type: Research Article

Abstract: Background: Family caregivers of people with Alzheimer’s disease are the most important support in concrete personal and economic terms. Family dynamics play a fundamental role in the provision of informal caregiving benefits. Objective: This review aims to identify factors related to the family caregiving of relatives with Alzheimer’s disease, taking specifically into account the construct of coping and expressed emotion. Methods: This is a systematic review including articles selected using search terms including “caregivers,” “Alzheimer’s,” “family,” and “relationship” in research databases. Findings were synthesized and categorized into themes. Results: A total of 454 abstracts …were identified. Following screening, lateral searches, and quality appraisal, 36 studies were included for synthesis. A total of 5 themes were identified: burden; demographics; coping strategies; caregiver mental health; and family dynamics and expressed emotions. Conclusion: The quality and level of evidence supporting each theme varied. We need further research into family dynamics ameliorating the caregiving and how to measure it. Show more

Keywords: Alzheimer’s disease, family caregivers, family relationship, systematic review

DOI: 10.3233/JAD-200125

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1595-1608, 2020

Authors: Muzambi, Rutendo | Bhaskaran, Krishnan | Brayne, Carol | Davidson, Jennifer A. | Smeeth, Liam | Warren-Gash, Charlotte

Article Type: Research Article

Abstract: Background: Bacterial infections may be associated with dementia, but the temporality of any relationship remains unclear. Objectives: To summarize existing literature on the association between common bacterial infections and the risk of dementia and cognitive decline in longitudinal studies. Methods: We performed a comprehensive search of 10 databases of published and grey literature from inception to 18 March 2019 using search terms for common bacterial infections, dementia, cognitive decline, and longitudinal study designs. Two reviewers independently performed the study selection, data extraction, risk of bias and overall quality assessment. Data were summarized through a narrative synthesis …as high heterogeneity precluded a meta-analysis. Results: We identified 3,488 studies. 9 met the eligibility criteria; 6 were conducted in the United States and 3 in Taiwan. 7 studies reported on dementia and 2 investigated cognitive decline. Multiple infections were assessed in two studies. All studies found sepsis (n  = 6), pneumonia (n  = 3), urinary tract infection (n  = 1), and cellulitis (n  = 1) increased dementia risk (HR 1.10; 95% CI 1.02–1.19) to (OR 2.60; 95% CI 1.84–3.66). The range of effect estimates was similar when limited to three studies with no domains at high risk of bias. However, the overall quality of evidence was rated very low. Studies on cognitive decline found no association with infection but had low power. Conclusion: Our review suggests common bacterial infections may be associated with an increased risk of subsequent dementia, after adjustment for multiple confounders, but further high-quality, large-scale longitudinal studies, across different healthcare settings, are recommended to further explore this association. Show more

Keywords: Cognition, dementia, infections, prevention, systematic review, Systematic review registration number: CRD42018119294, registered in December 2018

DOI: 10.3233/JAD-200303

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1609-1626, 2020

Authors: Mei, Xinchun | Zheng, Hai-Lin | Li, Cheng | Ma, Xin | Zheng, Hui | Marcantonio, Edward | Xie, Zhongcong | Shen, Yuan

Article Type: Research Article

Abstract: Background: Postoperative delirium is associated with adverse postoperative outcomes. However, whether intravenous and inhalation anesthetics are associated with different risks of postoperative delirium remains unknown. Objective: We set up to determine the incidence and duration of postoperative delirium in older patients who had surgery under the intravenous anesthetic propofol or the inhalational anesthetic sevoflurane. Methods: Participants were patients who had total hip/knee replacements and were randomized to propofol (N = 106) or sevoflurane (N = 103) anesthesia group. The Confusion Assessment Method was employed by investigators who were blinded to the anesthesia regimen to assess the incidence and duration (days …of postoperative delirium per person) of postoperative delirium on postoperative days 1, 2, and 3. Results: A total of 209 participants (71.2±6.7 years old, 29.2% male) were included in the final data analysis. The incidence of postoperative delirium was 33.0% with propofol anesthesia and 23.3% with sevoflurane anesthesia (p  = 0.119, Chi-square test ), and we estimated that we would need 316 participants in each arm to detect a potential statistically significant difference. Days of postoperative delirium per person were higher in the propofol (0.5±0.8) anesthesia group compared to the sevoflurane anesthesia group (0.3±0.5, p  = 0.049, Student ’s t-test ). Conclusion: This pilot study established a system to compare effects of different anesthetics and generated a hypothesis that propofol trended to have a higher incidence and had longer duration of postoperative delirium than sevoflurane. Additional studies with a larger sample size are needed to test this hypothesis. Show more

Keywords: Anesthesia, delirium, postoperative, propofol, sevoflurane

DOI: 10.3233/JAD-200322

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1627-1636, 2020

Authors: Guan, Qing | Hu, Xiaohui | Ma, Ning | He, Hao | Duan, Feiyan | Li, Xin | Luo, Yuejia | Zhang, Haobo

Article Type: Research Article

Abstract: Background: Both sleep quality and depression could affect cognitive performance in older adults. Previous studies have suggested that there are bi-directional relationships between sleep quality and depression. Possibly, the influence of sleep quality on cognition is partly mediated by depression, and vice versa. Objective: We aimed to assess the mediation effects of sleep quality and depression on each other’s relationship with various cognitive functions in non-demented older adults. Methods: Correlations were examined among sleep quality indices, depressive severity score, and five cognitive functions in 206 cognitively normal (CN) older adults and all participants that included these …CN and 40 mild cognitive impairment (MCI) individuals. We then analyzed the mediation effects for the significant cognitive correlations of sleep disturbance and depression using the bias-corrected Bootstrap method in the two populations. Results: Both sleep disturbance and depression were significantly correlated with memory recall and processing speed. In CN, depression could mediate the relationships of sleep disturbance with both cognitive functions, while sleep disturbance could only mediate the relationship of depression with processing speed, but not memory recall. However, in all participants, sleep disturbance could mediate the relationships of depression with both cognitive functions. Conclusion: Different mediation effects in the two models in CN older adults might suggest differential mechanisms underlying the pathways from sleep disturbance and depression to various cognitive functions. The mediation results in all participants might indicate that the mechanisms underlying the pathways from sleep disturbance and depression to memory recall were different between MCI and CN older adults. Show more

Keywords: Cognitive function, depression, mediation, mild cognitive impairment, older adults, sleep quality

DOI: 10.3233/JAD-190990

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1637-1650, 2020

Authors: Liu, Yanyong | Aisa, Haji Akber | Ji, Chao | Yang, Nan | Zhu, Haibo | Zuo, Pingping

Article Type: Correction

DOI: 10.3233/JAD-209006

Citation: Journal of Alzheimer's Disease, vol. 76, no. 4, pp. 1651-1652, 2020