Volume 76, Number 4, 2012

Pages 1179-1198

Ernesto Solis, Jr., Kevin N. Hascup, Erin R. Hascup
Alzheimer’s Disease: The Link Between Amyloid-β and Neurovascular Dysfunction
Abstract: While prevailing evidence supports that the amyloid cascade hypothesis is a key component of Alzheimer’s disease (AD) pathology, many recent studies indicate that the vascular system is also a major contributor to disease progression. Vascular dysfunction and reduced cerebral blood flow (CBF) occur prior to the accumulation and aggregation of amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles. Although research has predominantly focused on the cellular processes involved with Aβ-mediated neurodegeneration, effects of Aβ on CBF and neurovascular coupling are becoming more evident. This review will describe AD vascular disturbances as they relate to Aβ, including chronic cerebral hypoperfusion, hypertension, altered neurovascular coupling, and deterioration of the blood-brain barrier. In addition, we will describe recent findings about the relationship between these vascular defects and Aβ accumulation with emphasis on in vivo studies utilizing rodent AD models.


Ricardo B. Maccioni, Leonardo P. Navarrete, Andrea González, Alejandra González-Canacer, Leonardo Guzmán-Martínez, Nicole Cortés
Inflammation: A Major Target for Compounds to Control Alzheimer’s Disease
Abstract: Several hypotheses have been postulated to explain how Alzheimer’s disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmunomodulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer’s disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multitargeting compounds appear to provide a new pathway for Alzheimer’s disease treatment.

Pages 1215-1242

Kelly M. Bakulski*, Young Ah Seo*, Ruby C. Hickman, Daniel Brandt, Harita S. Vadari, Howard Hu, Sung Kyun Park *These authors contributed equally to this work.
Heavy Metals Exposure and Alzheimer’s Disease and Related Dementias
Abstract: Alzheimer’s disease and related dementias lack effective treatment or cures and are major public health challenges. Risk for Alzheimer’s disease and related dementias is partially attributable to environmental factors. The heavy metals lead, cadmium, and manganese are widespread and persistent in our environments. Once persons are exposed to these metals, they are adept at entering cells and reaching the brain. Lead and cadmium are associated with numerous health outcomes even at low levels of exposure. Although manganese is an essential metal, deficiency or environmental exposure or high levels of the metal can be toxic. In cell and animal model systems, lead, cadmium, and manganese are well documented neurotoxicants that contribute to canonical Alzheimer’s disease pathologies. Adult human epidemiologic studies have consistently shown lead, cadmium, and manganese are associated with impaired cognitive function and cognitive decline. No longitudinal human epidemiology study has assessed lead or manganese exposure on Alzheimer’s disease specifically though two studies have reported a link between cadmium and Alzheimer’s disease mortality. More longitudinal epidemiologic studies with high-quality time course exposure data and incident cases of Alzheimer’s disease and related dementias are warranted to confirm and estimate the proportion of risk attributable to these exposures. Given the widespread and global exposure to lead, cadmium, and manganese, even small increases in the risks of Alzheimer’s disease and related dementias would have a major population impact on the burden on disease. This article reviews the experimental and epidemiologic literature of the associations between lead, cadmium, and manganese on Alzheimer’s disease and related dementias and makes recommendations of critical areas of future investment.

Pages 1243-1248
Short Communication

Timo Pekkala, Anette Hall, Francesca Mangialasche, Nina Kemppainen, Patrizia Mecocci, Tiia Ngandu, Juha O. Rinne, Hilkka Soininen, Jaakko Tuomilehto, Miia Kivipelto, Alina Solomon (Handling Associate Editor: J. Wesson Ashford)
Association of Peripheral Insulin Resistance and Other Markers of Type 2 Diabetes Mellitus with Brain Amyloid Deposition in Healthy Individuals at Risk of Dementia
Abstract: We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with 12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE ε4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.

Pages 1249-1253

Masaaki Waragai, Gilbert Ho, Yoshiki Takamatsu, Ryoko Wada, Shuei Sugama, Takato Takenouchi, Eliezer Masliah, Makoto Hashimoto
Adiponectin Paradox as a Therapeutic Target in Alzheimer’s Disease
Abstract: Despite the apparent neurotoxicity of amyloid-β (Aβ), recent clinical trials of Aβ immunotherapy have not shown any clinical benefit in Alzheimer’s disease (AD). Given this, clarification of the next generation therapeutic strategy in AD is warranted. Hypothetically, adiponectin might be involved in promoting amyloidogenic evolvability in reproduction, which may result in the adiponectin paradox through antagonistic pleiotropy mechanism in aging, leading to AD. Accordingly, preventing the adiponectin paradox by suppressing adiponectin signaling might prove therapeutic in AD.

Pages 1255-1265
Jing Jin, Jia Guo, Hongbin Cai, Chongchong Zhao, Huan Wang, Zhiyan Liu, Zhao-Ming Ge (Handling Associate Editor: Yuan Zhong)
M2-Like Microglia Polarization Attenuates Neuropathic Pain Associated with Alzheimer’s Disease
Abstract: Many Alzheimer’s disease (AD) patients suffer from persistent neuropathic pain (NP), which is mediated, at least partially, but microglia. Nevertheless, the exact underlying mechanism is unknown. Moreover, a clinically translatable approach through modulating microglia for treating AD-associated NP is not available. Here, in a doxycycline-induced mouse model (rTg4510) for AD, we showed development of NP. We found that the total number of microglia in the CA3 region was not increased, but polarized to pro-inflammatory M1-like phenotype, with concomitant increases in production and secretion of pro-inflammatory cytokines. To examine whether this microglia polarization plays an essential role in the AD-associated NP, we generated an adeno-associated virus (AAV) serotype PHP.B (capable of crossing the blood-brain barrier) carrying shRNA for DNA methyltransferase 1 (DNMT1) under a microglia-specific TMEM119 promoter (AAV-pTMEM119-shDNMT1), which specifically targeted microglia and induced a M2-like polarization in vitro and in vivo in doxycycline-treated rTg4510 mice. Intravenous infusion of AAV-pTMEM119-shDNMT1 induced M2-polarization of microglia and attenuated both AD-associated behavior impairment but also NP in the doxycycline-treated rTg4510 mice. Thus, our data suggest that AD-associated NP may be treated through M2-polarization of microglia.

Pages 1267-1280
Natalia Palacios, Jong Soo Lee, Tammy Scott, Rachel S. Kelly, Shilpa N. Bhupathiraju, Sherman J. Bigornia, Katherine L. Tucker (Handling Associate Editor: Wassim Tarraf)
Circulating Plasma Metabolites and Cognitive Function in a Puerto Rican Cohort
Abstract: Background: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer’s disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. Objective: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. Methods: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. Results: Of 621 metabolites, FDR corrected (p<0.05) multivariable linear regression identified 3 metabolites positively, and 10 negatively, associated with cognitive function in the BPRHS. In a combination of FDR-corrected linear regression, logistic regression regularized via LASSO, and sensitivity analyses restricted to participants without diabetes, and with good adherence to the Mediterranean diet, β-cryptoxanthin plasma concentration was consistently associated with better cognitive function and N-acetylisoleucine and tyramine O-sulfate concentrations were consistently associated with worse cognitive function. Conclusion: This untargeted metabolomics study identified potential biomarkers for cognitive function in a cohort of Puerto Rican older adults.

Pages 1281-1296
Dong Yeol Kim, Sung Hyun Choi, Jee Sun Lee, Hyoung Jun Kim, Ha Na Kim, Ji Eun Lee, Jin Young Shin, Phil Hyu Lee
Feasibility and Efficacy of Intra-Arterial Administration of Embryonic Stem Cell Derived-Mesenchymal Stem Cells in Animal Model of Alzheimer’s Disease
Abstract: Mesenchymal stem cells (MSCs) promote functional recoveries in pathological experimental models of the central nervous system and are currently being tested in clinical trials for neurological disorders. However, no studies have examined the various roles of embryonic stem cell derived (ES)-MSCs in eliciting therapeutic effects for Alzheimer’s disease (AD). In the present study, we investigated the neuroprotective effect of ES-MSCs in cellular and animal models of AD, as well as the safety of the intra-arterial administration of ES-MSCs in an AD animal model. ES-MSCs displayed higher cell viability than that of bone marrow (BM)-MSCs in amyloid-β (Aβ)-induced cellular models. Moreover, the efficacy of autophagy induction in ES-MSCs was comparable to that of BM-MSCs; however, intracellular Aβ levels were more significantly reduced in ES-MSCs than in BM-MSCs. In a rat model of AD, ES-MSCs significantly inhibited Aβ-induced cell death in the hippocampus and promoted autophagolysosomal clearance of Aβ, which was concomitantly followed by decreased levels of Aβ in the hippocampus. Furthermore, ES-MSC treatment in Aβ-treated rats featured a higher memory performance than that of rats injected solely with Aβ. Finally, intra-arterial administration of an appropriate cell density of ES-MSCs was safe and free from in situ occlusion or cerebral ischemia. These data support the therapeutic potential of ES-MSCs and clinical applications of the intra-arterial route of ES-MSC administration in AD.

Pages 1297-1308
Martina Assogna, Elias Paolo Casula, Ilaria Borghi, Sonia Bonnì, Domenico Samà, Caterina Motta, Francesco Di Lorenzo, Alessia D'Acunto, Francesco Porrazzini, Marilena Minei, Carlo Caltagirone, Alessandro Martorana, Giacomo Koch (Handling Associate Editor: Marco Bozzali)
Effects of Palmitoylethanolamide Combined with Luteoline on Frontal Lobe Functions, High Frequency Oscillations, and GABAergic Transmission in Patients with Frontotemporal Dementia
Abstract: Background: Frontotemporal dementia (FTD) is a presenile neurodegenerative disease for which there is no effective pharmacological treatment. Recently, a link has been proposed between neuroinflammation and FTD. Objective: Here, we aim to investigate the effects of palmitoylethanolamide (PEA) combined with luteoline (PEA-LUT), an endocannabinoid with anti-inflammatory and neuroprotective effects, on behavior, cognition, and cortical activity in a sample of FTD patients. Methods: Seventeen patients with a diagnosis of probable FTD were enrolled. Cognitive and neurophysiological evaluations were performed at baseline and after 4 weeks of PEA-LUT 700 mgx2/day. Cognitive effects were assessed by Neuropsychiatric Inventory (NPI), Mini-Mental State Examination, Frontal Assessment Battery (FAB), Screening for Aphasia in Neurodegeneration, Activities of Daily Living-Instrumental Activities of Daily Living, and Frontotemporal Lobar Degeneration-modified Clinical Dementia Rating scale. To investigate in vivo neurophysiological effects of PEA-LUT, we used repetitive and paired-pulse transcranial magnetic stimulation (TMS) protocols assessing LTP-like cortical plasticity, short-interval intracortical inhibition, long-interval intracortical inhibition (LICI), and short-latency afferent inhibition. Moreover, we used TMS combined with EEG to evaluate the effects on frontal lobe cortical oscillatory activity. Results: Treatment with PEA-LUT was associated with an improvement in NPI and FAB scores. Neurophysiological evaluation showed a restoration of LICI, in particular at ISI 100 ms, suggesting a modulation of GABA(B) activity. TMS-EEG showed a remarkable increase of TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range. Conclusion: PEA-LUT could reduce behavioral disturbances and improve frontal lobe functions in FTD patients through the modulation of cortical oscillatory activity and GABA(B)ergic transmission.

Pages 1309-1316
Jeffrey J. Wing, Deborah A. Levine, Arun Ramamurthy, Carson Reider
Alzheimer’s Disease and Related Disorders Prevalence Differs by Appalachian Residence in Ohio
Abstract: Background: Areas within the Appalachian region may have a greater burden of underdiagnosed Alzheimer’s disease and related disorders (ADRD). Objective: To estimate the prevalence of ADRD in the Appalachian counties of Ohio, and to determine if differences exist by geographic location (Appalachian/non-Appalachian and rural/urban) and across time among Medicare beneficiaries. Methods: Centers for Medicare and Medicaid Services Public Use Files from 2007-2017 were used to estimate county-level ADRD prevalence among all fee-for-service beneficiaries in Ohio. Negative binomial regression was used to estimate prevalence overall, by Appalachian Regional Commission’s Appalachian/non-Appalachian designation, and by rural/urban (Rural-Urban Continuum Codes) classification. Models were repeated, adjusting for county-level demographics and comorbidities. Results: The prevalence of ADRD varied by both Appalachian residence and rural status (p = 0.008). Before adjustment by county-level demographics and comorbidities, the prevalence of ADRD in urban Appalachian counties was 1-3% lower than in urban non-Appalachian counties, while rural Appalachian counties had 2-3% higher prevalence compared to rural non-Appalachian counties. After adjustment, the differences between prevalence ratios were accentuated; the prevalence ratio was consistently higher for rural Appalachian counties, yet varied across the study period for urban counties (1.03 in 2007 to 0.97 in 2017). Conclusion: The results suggest a disparate burden of ADRD in Ohio with higher prevalence in rural Appalachian counties. This potential difference by Appalachian region is important to consider for availability of services and subsequent delivery of care. In order to better understand the disparity, further epidemiologic studies are necessary to better estimate the burden of ADRD.

Pages 1317-1337
Rosa Resende, Marisa Ferreira-Marques, Patrícia Moreira, Judite R.M. Coimbra, Salete J. Baptista, Ciro Isidoro, Jorge A.R. Salvador, Teresa C.P. Dinis, Cláudia F. Pereira, Armanda E. Santos
New BACE1 Chimeric Peptide Inhibitors Selectively Prevent AβPPβ Cleavage Decreasing Amyloid-β Production and Accumulation in Alzheimer’s Disease Models
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 AβPPβ 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 peptides hold promising potential as a selective disease-modifying therapy for AD.

Pages 1339-1345
Tengfei Li*, Elodie Martin*, Yah-se Abada, Céline Boucher, Aurélia Cès, Ihsen Youssef, Grégory Fenaux, Yona Forand, Annaelle Legrand, Nadkarni Nachiket, Marc Dhenain, Olivier Hermine, Patrice Dubreuil, Cécile Delarasse, Benoît Delatour *These authors contributed equally to this work.
Effects of Chronic Masitinib Treatment in APPPS1dE9 Transgenic Mice Modeling Alzheimer’s Disease
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 APPPS1dE9 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 APPPS1dE9 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.

Pages 1347-1373
Devi Mohan*, Kwong Hsia Yap*, Daniel Reidpath, Yee Chang Soh, Andrea McGrattan, Blossom C.M. Stephan, Louise Robinson, Nathorn Chaiyakunapruk**, Mario Siervo**, on behalf of DePEC team (Handling Associate Editor: Matthew Pase) *,**These authors contributed equally to this work.
Link Between Dietary Sodium Intake, Cognitive Function, and Dementia Risk in Middle-Aged and Older Adults: A Systematic Review
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, Psychinfo, 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.

Pages 1375-1389
Yun Shi, Lei Zhang, Xue Gao, Jing Zhang, Matan Ben Abou, Ge Liang, Qingcheng Meng, Adrian Hepner, Maryellen F. Eckenhoff, Huafeng Wei (Handling Associate Editor: Tao Ma)
Intranasal Dantrolene as a Disease-Modifying Drug in Alzheimer 5XFAD Mice
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, 3x/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 at 12 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.

Pages 1391-1402
Kyung-Lim Joa, Sakulrat Mankhong, Sujin Kim, Sohee Moon, Kyoung-Hee Lee, Young-Hwan Yoo, Byeong-Hun Hwang, Jong-Won Beak, Ju-Hee Kang
Effects of Aerobic Exercise on Tau and Related Proteins in Rats with Photochemically-Induced Infarction
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.

Pages 1403-1412
Charles D. Nicoli, Virginia J. Howard, Suzanne E. Judd, Joachim Struck, Jennifer J. Manly, Mary Cushman (Handling Associate Editor: Karel Kostev)
Pro-Neurotensin/Neuromedin N and Risk of Cognitive Impairment in a Prospective Study
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. 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 Blacks 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.

Pages 1413-1422
Carles Falcon, Oriol Grau-Rivera, Marc Suárez-Calvet, Beatriz Bosch, Raquel Sánchez-Valle, Eider M. Arenaza-Urquijo, José María González-de-Echavarri, Juan Domingo Gispert, Lorena Rami, José Luis Molinuevo
Sex Differences of Longitudinal Brain Changes in Cognitively Unimpaired Adults
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.

Pages 1423-1442
Md A. Hakim, Erik J. Behringer (Handling Associate Editor: Luis Aguayo)
Development of Alzheimer’s Disease Progressively Alters Sex-Dependent KCa and Sex-Independent KIR Channel Function in Cerebrovascular Endothelium
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 (KCa2.3/SK3 and KCa3.1/IK1) and inward-rectifying (KIR2.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 3xTg-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 ∆Vm-to-∆[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 ∆[Ca2+]i-to-∆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.

Pages 1443-1459
Tetsuya Goto, Eriko Kuramoto, Ashis Dhar, Rachel P.-H. Wang, Haruka Seki, Haruki Iwai, Atsushi Yamanaka, Shin-Ei Matsumoto, Hiromitsu Hara, Makoto Michikawa, Yasumasa Ohyagi, Wai K. Leung, Raymond C.-C. Chang
Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3×Tg-AD Model Mice
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 projecting 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.

Pages 1461-1475
Simon Schwab, Soroosh Afyouni, Yan Chen, Zaizhu Han, Qihao Guo, Thomas Dierks, Lars-Olof Wahlund, Matthias Grieder (Handling Associate Editor: Claudio Babiloni)
Functional Connectivity Alterations of the Temporal Lobe and Hippocampus in Semantic Dementia and Alzheimer’s Disease
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.

Pages 1477-1491
Kimberly C. Paul, Mary Haan, Yu Yu, Kosuke Inoue, Elizabeth Rose Mayeda, Kristina Dang, Jun Wu, Michael Jerrett, Beate Ritz
Traffic-Related Air Pollution and Incident Dementia: Direct and Indirect Pathways Through Metabolic Dysfunction
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.

Pages 1493-1511
Marc A. Garcia, Kasim Ortiz, Sandra P. Arévalo, Erica D. Diminich, Emily Briceño, Irving E. Vega, Wassim Tarraf (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Age of Migration and Cognitive Function Among Older Latinos in the United States
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.

Pages 1513-1526
Zhiqing Sun, Lei Sun, Lixiang Tu
GABAB Receptor-Mediated PI3K/Akt Signaling Pathway Alleviates Oxidative Stress and Neuronal Cell Injury in a Rat Model of Alzheimer’s Disease
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.

Pages 1527-1539
Lorena Gárate-Vélez, Claudia Escudero-Lourdes, Daniela Salado-Leza, Armando González-Sánchez, Ildemar Alvarado-Morales, Daniel Bahena, Gladis Judith Labrada-Delgado, José Luis Rodríguez-López (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Anthropogenic Iron Oxide Nanoparticles Induce Damage to Brain Microvascular Endothelial Cells Forming the Blood-Brain Barrier
Abstract: Background: Iron nanoparticles, mainly in magnetite phase (Fe3O4 NPs), are released to the environment in areas with high traffic density and braking frequency. Fe3O4 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 Fe3O4 NPs on primary rat brain microvascular endothelial cells (rBMECs), main constituents of in vitro BBB models. Methods: Synthetic bare Fe3O4 NPs that mimic the environmental ones (miFe3O4) 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 miFe3O4 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 miFe3O4 NPs are internalized by rBMECs through endocytosis and that they are able to cross the cells monolayer. The lowest miFe3O4 NPs concentration tested induced mid cytotoxicity in terms of 1) membrane integrity (LDH release) and 2) metabolic activity (MTS transformation). Conclusion: Pollution-derived Fe3O4 NPs may interact and cross the microvascular endothelial cells forming the BBB and cause biological damage.

Pages 1541-1551
Amy C. Ferguson, Rachana Tank, Laura M. Lyall, Joey Ward, Carlos Celis-Morales, Rona Strawbridge, Frederick Ho, Christopher D. Whelan, Jason Gill, Paul Welsh, Jana J. Anderson, Patrick B. Mark, Daniel F. Mackay, Daniel J. Smith, Jill P. Pell, Jonathan Cavanagh, Naveed Sattar, Donald M. Lyall (Handling Associate Editor: Lori Beason-Held)
Alzheimer’s Disease Susceptibility Gene Apolipoprotein E (APOE) and Blood Biomarkers in UK Biobank (N=395,769)
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 ε4 ‘risk’ and ε2 ‘protective’ genotypes (versus neutral ε3/ε3). Most associations supported previous data: for example, ε4 genotype was associated with elevated low-density lipoprotein cholesterol (LDL) (standardized beta [b]=0.150 standard deviations [SDs] per allele, p<0.001) and ε2 with lower LDL (b=-0.456 SDs, p<0.001). There were however instances of associations found in unexpected directions: e.g., ε4 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 here in supports previous hypotheses of involvement from cardiometabolic and neuroinflammatory pathways.

Pages 1553-1565
Kang-Hsien Fan, Eleanor Feingold, Samantha L. Rosenthal, F. Yesim Demirci, Mary Ganguli, Oscar L. Lopez, M. Ilyas Kamboh
Whole-Exome Sequencing Analysis of Alzheimer’s Disease in Non-APOE*4 Carriers
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.

Pages 1567-1579
Renaud Coppalle, Caroline Mauger, Sophie Quernet, Axel Dewald, Odile Letortu, Béatrice Desgranges, Mathilde Groussard*, Hervé Platel* *These authors contributed equally to this work.
New Long-Term Encoding in Severely Amnesic Alzheimer’s Disease Patients Revealed Through Repeated Exposure to Artistic Items
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.

Pages 1581-1594
Juraj Secnik, Hong Xu, Emilia Schwertner, Niklas Hammar, Michael Alvarsson, Bengt Winblad, Maria Eriksdotter, Sara Garcia-Ptacek, Dorota Religa
Dementia Diagnosis Is Associated with Changes in Antidiabetic Drug Prescription: An Open-Cohort Study of ~130,000 Swedish Subjects over 14 Years
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.

Pages 1595-1608
Anna Laura Luiu, Nicolas Favez, Mireille Betrancourt, Nicolas Szilas, Frederic Ehrler (Handling Associate Editor: Carlo Abbate)
Family Relationships and Alzheimer’s Disease: A Systematic Review
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.

Pages 1609-1626
Rutendo Muzambi, Krishnan Bhaskaran, Carol Brayne, Jennifer A Davidson, Liam Smeeth, Charlotte Warren-Gash
Common Bacterial Infections and Risk of Dementia or Cognitive Decline: A Systematic Review
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.

Pages 1627-1636
Xinchun Mei*, Hai-Lin Zheng*, Cheng Li, Xin Ma, Hui Zheng, Edward Marcantonio, Zhongcong Xie, Yuan Shen (Handling Associate Editor: Xuemin Xu) *These authors contributed equally to this work.
The Effects of Propofol and Sevoflurane on Postoperative Delirium in Older Patients: A Randomized Clinical Trial Study
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.

Pages 1637-1650
Qing Guan, Xiaohui Hu, Ning Ma, Hao He, Feiyan Duan, Xin Li, Yuejia Luo, Haobo Zhang
Sleep Quality, Depression, and Cognitive Function in Non-Demented Older Adults
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.