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

Authors: Goto, Tetsuya | Kuramoto, Eriko | Dhar, Ashis | Wang, Rachel P.-H. | Seki, Haruka | Iwai, Haruki | Yamanaka, Atsushi | Matsumoto, Shin-Ei | Hara, Hiromitsu | Michikawa, Makoto | Ohyagi, Yasumasa | Leung, Wai K. | Chang, Raymond C.-C.

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 Aβ 42 was found in granules in Vmes neurons. Neuronal death in the Vmes occurred after tooth extraction, resulting in the release of cytotoxic Aβ 42 and an increase in CD86 immunoreactive microglia. Released Aβ 42 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. 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. Pre-press, no. Pre-press, pp. 1-17, 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 here in 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. Pre-press, no. Pre-press, pp. 1-11, 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. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Joa, Kyung-Lim | Mankhong, Sakulrat | Kim, Sujin | Moon, Sohee | Lee, Kyoung-Hee | Yoo, Young-Hwan | Hwang, Byeong-Hun | Beak, 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. Pre-press, no. Pre-press, pp. 1-12, 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. Pre-press, no. Pre-press, pp. 1-19, 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. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Schaefer, Sydney Y. | Hooyman, Andrew | Duff, Kevin

Article Type: Short Communication

Abstract: Affordable, noninvasive methods of predicting functional decline are needed for individuals at risk for Alzheimer’s disease. This study tested whether a timed upper-extremity motor task predicted functional decline over one year in 79 adults diagnosed with amnestic mild cognitive impairment. Participants completed subjective and objective measures of daily functioning at baseline and one year later. Motor task performance and delayed memory were also evaluated at baseline. Motor task performance was a significant predictor of one-year follow-up daily functioning, improving model fits by 18– 35%. Thus, motor behavior has potential to be an affordable enrichment strategy that is sensitive to functional …decline. Show more

Keywords: Activities of daily living, functional decline, mild cognitive impairment, motor behavior

DOI: 10.3233/JAD-200518

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Singh, Pradeep K. | Chen, Zu-Lin | Strickland, Sidney | Norris, Erin H.

Article Type: Short Communication

Abstract: An activated plasma contact system is an abnormality observed in many Alzheimer’s disease (AD) patients. Since mild cognitive impairment (MCI) patients often develop AD, we analyzed the status of contact system activation in MCI patients. We found that kallikrein activity, high molecular weight kininogen cleavage, and bradykinin levels— measures of contact system activation— were significantly elevated in MCI patient plasma compared to plasma from age- and education-matched healthy individuals. Changes were more pronounced in MCI patients with impaired short-term recall memory, indicating the possible role of the contact system in early cognitive changes.

Keywords: Alzheimer’s disease, bradykinin, contact activation, high molecular weight kininogen, memory impairment, mild cognitive impairment, plasma kallikrein

DOI: 10.3233/JAD-200343

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Tousi, Babak

Article Type: Article Commentary

Abstract: Patients with dementia are particularly vulnerable during the COVID-19 pandemic. The initial response to COVID-19 promoted behavioral changes in both society and healthcare, while a long-term solution is sought by prioritizing societal values. In addition, there has been disruption to clinical care and clinical research. This pandemic might have significantly changed the care for our patients with dementia toward increased acceptance of telemedicine by the patients and providers, and its utilization in both clinical care and research.

Keywords: Access, Alzheimer’s disease, caregivers, clinical trial, coronavirus, COVID-19, dementia, health care, pandemic, telehealth, telemedicine

DOI: 10.3233/JAD-200461

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Capozzo, Rosa | Zoccolella, Stefano | Frisullo, Maria Elisa | Barone, Roberta | Dell’Abate, Maria Teresa | Barulli, Maria Rosaria | Musio, Marco | Accogli, Miriam | Logroscino, Giancarlo

Article Type: Research Article

Abstract: Background: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. Objective: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. Methods: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)–FTD were used by the neurologist with …patients and/or caregivers. Index symptoms of COVID-19 infection were searched. Results: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p  = 0.01) and language functions (p  = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. Conclusion: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency. Show more

Keywords: COVID-19, frontotemporal lobar dementia, multidisciplinary care, pandemic, quality life, telemedicine

DOI: 10.3233/JAD-200589

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Calfio, Camila | Gonzalez, Andrea | Singh, Sandeep Kumar | Rojo, Leonel E. | Maccioni, Ricardo B.

Article Type: Review Article

Abstract: One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants …that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence. Show more

Keywords: Alzheimer’s disease, anti-tau molecules, disease prevention and treatment, mechanisms, multitarget approaches, nutraceutical compounds

DOI: 10.3233/JAD-200443

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Bakulski, Kelly M. | Seo, Young Ah | Hickman, Ruby C. | Brandt, Daniel | Vadari, Harita S. | Hu, Howard | KyunPark, Sung

Article Type: Review Article

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. Show more

Keywords: Cadmium, epidemiology, heavy metal, lead, manganese, toxicant, window of susceptibility

DOI: 10.3233/JAD-200282

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-28, 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. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Hakim, 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. Pre-press, no. Pre-press, pp. 1-20, 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. Pre-press, no. Pre-press, pp. 1-10, 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. Pre-press, no. Pre-press, pp. 1-15, 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. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Xiao, Jinzhong | Katsumata, Noriko | Bernier, Francois | Ohno, Kazuya | Yamauchi, Yuki | Odamaki, Toshitaka | Yoshikawa, Kenji | Ito, Kumie | Kaneko, Toshiyuki

Article Type: Research Article

Abstract: Background: Probiotics use has been associated with modulation of inflammation and considered as a possible intervention for CNS diseases such as mild cognitive impairment (MCI) and dementia. Objective: We aimed to test the effect of the probiotic strain, Bifidobacterium breve A1 (MCC1274), to restore cognition in a physically healthy, suspected MCI population. Methods: In this randomized, double-blind, placebo-controlled trial, 80 healthy older adults suffering from MCI were divided into two even groups to receive once daily either probiotic (B. breve A1, 2×1010 CFU) or placebo for 16 weeks using a computer-generated algorithm. Cognitive …functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Japanese version of the MCI Screen (JMCIS) tests before and after the study as primary and secondary endpoints, respectively. Results: 79 participants completed the study, and no adverse events were observed. RBANS total score was significantly improved in probiotic group compared with placebo (mean between-group difference 11.3 [95% CI 6.7 to 15.8]; p  < 0.0001) after 16 weeks of consumption, in particular with significant improvement in domain scores of immediate memory, visuospatial/constructional, and delayed memory (p  < 0.0001), in both intention-to-treat (ITT) analysis and per-protocol (PP) analysis. JMCIS score was also improved versus placebo in ITT analysis (p  = 0.052) and PP analysis (p  = 0.036). Conclusion: Study results indicate B. breve A1 is a safe and effective approach for improving memory functions of suspected MCI subjects. Show more

Keywords: Bifidobacterium, clinical trial, dementia, memory, mild cognitive impairment, probiotics

DOI: 10.3233/JAD-200488

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 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. 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. 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. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Waragai, Masaaki | Ho, Gilbert | Takamatsu, Yoshiki | Wada, Ryoko | Sugama, Shuei | Takenouchi, Takato | Masliah, Eliezer | Hashimoto, Makoto

Article Type: Article Commentary

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.

Keywords: Aβ immunotherapy, adiponectin, adiponectin paradox, Alzheimer’s disease, amyloid-β, amyloidogenic evolvability, antagonistic pleiotropy

DOI: 10.3233/JAD-200416

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2020

Authors: Pekkala, Timo | Hall, Anette | Mangialasche, Francesca | Kemppainen, Nina | Mecocci, Patrizia | Ngandu, Tiia | Rinne, Juha O. | Soininen, Hilkka | Tuomilehto, Jaakko | Kivipelto, Miia | Solomon, Alina

Article Type: Short Communication

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 with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE ɛ 4 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.

Keywords: Amyloid-β, apolipoprotein E, plasminogen activator, positron emission tomography, type 2 diabetes

DOI: 10.3233/JAD-200145

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Assogna, Martina | Casula, Elias Paolo | Borghi, Ilaria | Bonnì, Sonia | Samà, Domenico | Motta, Caterina | Di Lorenzo, Francesco | D’Acunto, Alessia | Porrazzini, Francesco | Minei, Marilena | Caltagirone, Carlo | Martorana, Alessandro | Koch, Giacomo

Article Type: Research Article

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 mg×2/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. Show more

Keywords: Brain inflammation, behavioral symptoms, EEG, executive functions, frontotemporal dementia, GABA activity, transcranial magnetic stimulation

DOI: 10.3233/JAD-200426

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Hayashi, Kentaro | Gonzales, Tina K. | Kapoor, Amita | Ziegler, Toni E. | Meethal, Sivan Vadakkadath | Atwood, Craig S.

Article Type: Research Article

Abstract: Background: While sex hormones are essential for normal cognitive health, those individuals with greater endocrine dyscrasia around menopause and with andropause are more likely to develop cognitive loss and Alzheimer’s disease (AD). Objective: To assess whether circulating sex hormones may provide an etiologically significant, surrogate biomarker, for cognitive decline. Methods: Plasma (n  = 152) and serum (n  = 107) samples from age- and gender-matched AD and control subjects from the Wisconsin Alzheimer’s Disease Research Center (ADRC) were analyzed for11 steroids and follicle-stimulating hormone. Logistic regression (LR), correlation analyses, and recursive partitioning (RP) were used to examine the interactions …of hormones and hormone ratios and their association with AD. Models generated were then tested on an additional 43 ADRC samples. Results: The wide variation and substantial overlap in the concentrations of all circulating sex steroids across control and AD groups precluded their use for predicting AD. Classification tree analyses (RP) revealed interactions among single hormones and hormone ratios that associated with AD status, the most predictive including only the hormone ratios identified by LR. The strongest associations were observed between cortisol, cortisone, and androstenedione with AD, with contributions from progesterone and 17β-estradiol. Utilizing this model, we correctly predicted 81% of AD test cases and 64% of control test cases. Conclusion: We have developed a diagnostic model for AD, the Wisconsin Hormone Algorithm Test for Cognition (WHAT-Cog), that utilizes classification tree analyses of hormone ratios. Further refinement of this technology could provide a quick and cheap diagnostic method for screening those with AD. Show more

Keywords: Alzheimer’s disease, blood, classification tree, diagnostic, follicle-stimulating hormone, hormone ratio, model, prediction, recursive partitioning, steroids

DOI: 10.3233/JAD-200418

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Kaur, Harpreet | Golovko, Svetlana | Golovko, Mikhail Y. | Singh, Surjeet | Darland, Diane C. | Combs, Colin K.

Article Type: Research Article

Abstract: Background: The intestinal microbiota and its metabolites, particularly short-chain fatty acids (SCFAs), have been implicated in immune function, host metabolism, and even behavior. Objective: This study was performed to investigate whether probiotic administration influences levels of intestinal microbiota and their metabolites in a fashion that may attenuate brain changes in a mouse model of Alzheimer’s disease (AD). Methods: C57BL/6 wild-type (WT) mice were compared to AppNL -G -F mice. The animals were treated with either vehicle or probiotic (VSL#3) for 8 weeks. Fecal microbiome analysis along with Aβ, GFAP, Iba-1, c-Fos, and Ki-67 immunohistochemistry …was done. SCFAs were analyzed in serum and brains using UPLC-MS/MS. Results: Probiotic (VSL#3) supplementation for 2 months resulted in altered microbiota in both WT and AppNL -G -F mice. An increase in serum SCFAs acetate, butyrate, and lactate were found in both genotypes following VSL#3 treatment. Propionate and isobutyrate were only increased in AppNL -G -F mice. Surprisingly, VSL#3 only increased lactate and acetate in brains of AppNL -G -F mice. No significant differences were observed between vehicle and VSL#3 fed AppNL -G -F hippocampal immunore activities of Aβ, GFAP, Iba-1, and Ki-67. However, hippocampal c-Fos staining increased in VSL#3 fed AppNL -G -F mice. Conclusion: These data demonstrate intestinal dysbiosis in the AppNL -G -F mouse model of AD. Probiotic VSL#3 feeding altered both serum and brain levels of lactate and acetate in AppNL -G -F mice correlating with increased expression of the neuronal activity marker, c-Fos. Show more

Keywords: Alzheimer’s disease, butyrate, gliosis, microbiota, plaques, probiotics, short chain fatty acids

DOI: 10.3233/JAD-200436

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 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 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. 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. Pre-press, no. Pre-press, pp. 1-7, 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. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Kim, Dong Yeol | Choi, Sung Hyun | Lee, Jee Sun | Kim, Hyoung Jun | Kim, Ha Na | Lee, Ji Eun | Shin, Jin Young | Lee, Phil Hyu

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, autophagy, intra-arterial injection, mesenchymal stem cell, protection

DOI: 10.3233/JAD-200026

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Naude, James P. | Gill, Sascha | Hu, Sophie | McGirr, Alexander | Forkert, Nils D. | Monchi, Oury | Stys, Peter K. | Smith, Eric E. | Ismail, Zahinoor | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Assessing neuropsychiatric symptoms (NPS) in older adults is important for determining dementia risk. Mild behavioral impairment (MBI) is an at-risk state for cognitive decline and dementia, characterized by emergent NPS in later life. MBI has significantly higher dementia incidence than late life psychiatric conditions. However, its utility as a proxy for neurodegeneration has not been demonstrated. Plasma neurofilament light (NfL) is a validated biomarker of axonal damage, and has been shown to associate with hallmarks of neurodegeneration. Objective: The purpose of this investigation was to identify associations between NfL rate of change and the presence of MBI …symptomatology. Methods: We evaluated the association of MBI with changes in NfL in a cohort (n  = 584; MBI + n = 190, MBI– n  = 394) of non-demented participants from the Alzheimer’s Disease Neuroimaging Initiative. MBI was determined by transforming neuropsychiatric questionnaire items using a published algorithm. Change in NfL was calculated over 2 years. Results: Time*MBI status was the only significant interaction to predict change in NfL concentrations (F (1,574) = 4.59, p  = 0.032), even after controlling for age, mild cognitive impairment, and demographics. Analyses reclassifying 64 participants with new onset MBI over 2 years similarly demonstrated greater increases in NfL (F (1,574) = 5.82, p  = 0.016). Conclusion: These findings suggest MBI is a clinical proxy of early phase neurodegeneration with putative utility in identifying those at dementia risk. MBI can be used as a case ascertainment approach to capture those at high risk for cognitive decline and dementia, and is an important construct for clinicians dealing with cognitive and neuropsychiatric symptomatology in older adults. Show more

Keywords: Alzheimer’s disease, mild behavioral impairment, mild cognitive impairment, neurodegeneration, neurofilament light, neuropsychiatric symptoms

DOI: 10.3233/JAD-200011

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Muurling, Marijn | Rhodius-Meester, Hanneke F.M. | Pärkkä, Juha | van Gils, Mark | Frederiksen, Kristian S. | Bruun, Marie | Hasselbalch, Steen G. | Soininen, Hilkka | Herukka, Sanna-Kaisa | Hallikainen, Merja | Teunissen, Charlotte E. | Visser, Pieter Jelle | Scheltens, Philip | van der Flier, Wiesje M. | Mattila, Jussi | Lötjönen, Jyrki | de Boer, Casper

Article Type: Research Article

Abstract: Background: Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology. Objective: In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline. Methods: Gait was measured using tri-axial accelerometers attached …to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group. Results: Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p  < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE. Conclusion: These findings suggest that gait—particularly measures related to pace and rhythm—are altered in dementia and have a direct link with measures of neurodegeneration. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, gait analysis, tau proteins

DOI: 10.3233/JAD-200225

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Liang, Yingxia | Raven, Frank | Ward, Joseph F. | Zhen, Sherri | Zhang, Siyi | Sun, Haoqi | Miller, Sean J. | Choi, Se Hoon | Tanzi, Rudolph E. | Zhang, Can

Article Type: Research Article

Abstract: Background: The amyloid cascade hypothesis of Alzheimer’s disease (AD) posits that amyloid-β (Aβ) protein accumulation underlies the pathogenesis of the disease by leading to the formation of amyloid plaques, a pathologic hallmark of AD. Aβ is a proteolytic product of amyloid-β protein precursor (AβPP; APP), which is expressed in both neurons and astrocytes. Although considerable evidence shows that astrocytes may play critical roles in the pathogenesis of AD, the longitudinal changes of amyloid plaques in relationship to AβPP expression in astrocytes and cellular consequences are largely unknown. Objective: Here, we aimed to investigate astrocyte-related pathological changes of Aβ …and AβPP using immunohistochemistry and biochemical studies in both animal and cell models. Methods/Results: Weutilized 5XFAD transgenic mice and found age-dependent upregulation of AβPP in astrocytes demonstrated with astrocytic reactive properties, which followed appearance of amyloid plaques in the brain. We also observed that AβPP proteins presented well-defined punctate immuno reactivity in young animals, whereas AβPP staining showed disrupted structures surrounding amyloid plaques in older mice. Moreover, we utilized astrocyte cell models and showed that pretreatment of Aβ42 resulted in downstream astrocyte autonomous changes, including up regulation in AβPP and BACE1 levels, as well as prolonged amyloidogenesis that could be reduced by pharmacological inhibition of BACE1. Conclusion: Collectively, our results show that age-dependent AβPP up regulation in astrocytes is a key feature in AD, which will not only provide novel insights for understanding AD progression, but also may offer new therapeutic strategies for treating AD. Show more

Keywords: Alzheimer’s disease, amyloid pathology, amyloid-β , amyloid-β protein precursor, amyloidogenesis, astrocyte, autonomous

DOI: 10.3233/JAD-200128

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Wan, Xinkun | Ma, Bin | Wang, Xiaoxuan | Guo, Chenjia | Sun, Jing | Cui, Jing | Li, Liang

Article Type: Research Article

Abstract: Background: Glutathione (GSH) is an important endogenous antioxidant protecting cells from oxidative injury. Cysteine (Cys), the substrate limiting the production of GSH, is mainly generated from the trans-sulfuration pathway. S-adenosylmethionine (SAM) is a critical molecule produced in the methionine cycle and can be utilized by the trans-sulfuration pathway. Reductions in GSH and SAM as well as dysfunction in the trans-sulfuration pathway have been documented in the brains of Alzheimer’s disease (AD) patients. Our previous in vivo study revealed that SAM administration attenuated oxidative stress induced by amyloid-β (Aβ ) through the enhancement of GSH. Objective: To …investigate the effect of Aβ -induced oxidative stress on the trans-sulfuration pathway in astrocytes and neurons, respectively, and the protective effect of SAM on neurons. Methods: APP/PS1 transgenic mice and the primary cultured astrocytes, neurons, and HT22 cells were used in the current study. Results: SAM could rescue the low trans-sulfuration pathway activity induced by Aβ only in astrocytes, accompanying with increasing levels of Cys and GSH. The decrease of cellular viability of neurons caused by Aβ was greatly reversed when co-cultured with astrocytes with SAM intervention. Meanwhile, SAM improved cognitive performance in APP/PS1 mice. Conclusion: In terms of astrocyte protection from oxidative stress, SAM might be a potent antioxidant in the therapy of AD patients. Show more

Keywords: Amyloid-β , astrocytes, glutathione, S-adenosylmethionine, trans-sulfuration pathway

DOI: 10.3233/JAD-200103

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Duan, Wenna | Sehrawat, Parshant | Balachandrasekaran, Arvind | Bhumkar, Ashish B. | Boraste, Paresh B. | Becker, James T. | Kuller, Lewis H. | Lopez, Oscar L. | Gach, H. Michael | Dai, Weiying

Article Type: Research Article

Abstract: Background: Reliable cerebral blood flow (CBF) biomarkers using a noninvasive imaging technique are sought to facilitate early diagnosis and intervention in early Alzheimer’s disease (AD). Objective: We aim to identify brain regions in which CBF values are affected and related to cognitive decline in early AD using a large cohort. Methods: Perfusion MRIs using continuous arterial spin labeling were acquired at 1.5 T in 58 normal controls (NC), 50 mild cognitive impairments (MCI), and 40 AD subjects from the Cardiovascular Health Study cognition study. Regional absolute CBF and normalized CBF (nCBF) values, without and with correction …of partial volume effects, were compared across three groups. Association between regional CBF values and Modified Mini-Mental State Examination (3MSE) were investigated by multiple linear regression analyses adjusted for cardiovascular risk factors. Results: After correcting for partial volume effects and cardiovascular risk factors, ADs exhibited decreased nCBF with the strongest reduction in the bilateral posterior cingulate & precuneus region (p  < 0.001) compared to NCs, and the strongest reduction in the bilateral superior medial frontal region (p  < 0.001) compared to MCIs. MCIs exhibited the strongest nCBF decrease in the left hippocampus and nCBF increase in the right inferior frontal and insular region. The 3MSE scores within the symptomatic subjects were significantly associated with nCBFin the bilateral posterior and middle cingulate & parietal (p  < 0.001), bilateral superior medial frontal (p  < 0.001), bilateral temporoparietal (p  < 0.02), and right hippocampus (p  = 0.02) regions. Conclusion: Noninvasive perfusion MRI can detect functional changes across diagnostic class and serve as staging biomarker of cognitive status. Show more

Keywords: Alzheimer’s disease, arterial spin labeling, cerebral blood flow, cognition

DOI: 10.3233/JAD-200034

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Fuentes, Manuel | Klostermann, Arne | Kleineidam, Luca | Bauer, Chris | Schuchhardt, Johannes | Maier, Wolfgang | Jessen, Frank | Frölich, Lutz | Wiltfang, Jens | Kornhuber, Johannes | Klöppel, Stefan | Schieting, Vera | Teipel, Stefan J. | Wagner, Michael | Peters, Oliver

Article Type: Research Article

Abstract: Background: Cognitive functions and activities of daily living (ADL) become increasingly impaired with progressing Alzheimer’s disease. However, the temporal dynamics of this decline are inconsistent. Objective: To gain insight into the classical temporal cascade of specific cognitive and ADL changes, which may aid in improving detection of an impending clinical deterioration in patients, and to select ADL items and tests most sensitive to change in a specific disease stage. Methods: Patients with mild Alzheimer’s dementia (AD; MMSE = 23.9±2.88) were followed at 12 and 24 months. Lead-lag analysis of changes in cognitive and functional outcome measures (CDR-SOB, 12 …neuropsychological subtest scores from the CERAD + test battery, 25 Bayer-ADL items) was applied to rank the temporal sequence of changes on an ordinal scale. Results: Of 164 patients with mild AD, moderate disease progression was identified in 84 patients over 24 months (Δ MMSE 5.8±8.64; Δ CDR-SOB 4.32±4.03). Ten Bayer-ADL item measures were altered early in moderate progressors and included in a new ADL composite score. Accordingly, the new ADL score surpassed all neuropsychological measures in repeated lead-lag analysis. The Bayer-ADL total score, TMT-A, and MMSE were lagging variables in all lead-lag analyses. Conclusion: Short-term clinical deterioration in mild AD is initially preceded by changes (i.e., decline) in a well-defined set of ADL and not in classical cognitive measures. Show more

Keywords: Alzheimer’s disease, bayer activities of daily living scale, cognitive changes, disease progression, functional changes, lead and lag analysis

DOI: 10.3233/JAD-200230

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Solis, Jr. , Ernesto | Hascup, Kevin N. | Hascup, Erin R.

Article Type: Review Article

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. Show more

Keywords: Amyloid-β peptide, amyloid cascade hypothesis, blood-brain barrier, cerebral amyloid angiopathy, chronic cerebral hypoperfusion, functional hyperemia, in vivo mouse model, in vivo rat model, neurovascular coupling, vascular hypothesis

DOI: 10.3233/JAD-200473

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-20, 2020

Authors: Maccioni, Ricardo B. | Navarrete, Leonardo P. | González, Andrea | González-Canacer, Alejandra | Guzmán-Martínez, Leonardo | Cortés, Nicole

Article Type: Review Article

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 neuroimmuno modulation 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 multi targeting compounds appear to provide a new pathway for Alzheimer’s disease treatment. Show more

Keywords: Alzheimer’s disease, astrocytes, mediators, microglial cells, neuroinflammation, proinflammatory tau pathology

DOI: 10.3233/JAD-191014

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2020

Authors: Angehrn, Zuzanna | Sostar, Jelena | Nordon, Clementine | Turner, Andrew | Gove, Dianne | Karcher, Helene | Keenan, Alexander | Mittelstadt, Brent | de Reydet-de Vulpillieres, Frederic

Article Type: Research Article

Abstract: Background: The therapeutic paradigm in Alzheimer’s disease (AD) is shifting from symptoms management toward prevention goals. Secondary prevention requires the identification of individuals without clinical symptoms, yet “at-risk” of developing AD dementia in the future, and thus, the use of predictive modeling. Objective: The objective of this study was to review the ethical concerns and social implications generated by this new approach. Methods: We conducted a systematic literature review in Medline, Embase, PsycInfo, and Scopus, and complemented it with a gray literature search between March and July 2018. Then we analyzed data qualitatively using a thematic …analysis technique. Results: We identified thirty-one ethical issues and social concerns corresponding to eight ethical principles: (i) respect for autonomy, (ii) beneficence, (iii) non-maleficence, (iv) equality, justice, and diversity, (v) identity and stigma, (vi) privacy, (vii) accountability, transparency, and professionalism, and (viii) uncertainty avoidance. Much of the literature sees the discovery of disease-modifying treatment as a necessary and sufficient condition to justify AD risk assessment, overlooking future challenges in providing equitable access to it, establishing long-term treatment outcomes and social consequences of this approach, e.g., medicalization. The ethical/social issues associated specifically with predictive models, such as the adequate predictive power and reliability, infrastructural requirements, data privacy, potential for personalized medicine in AD, and limiting access to future AD treatment based on risk stratification, were covered scarcely. Conclusion: The ethical discussion needs to advance to reflect recent scientific developments and guide clinical practice now and in the future, so that necessary safeguards are implemented for large-scale AD secondary prevention. Show more

Keywords: Biomedical ethics, dementia, early diagnosis, early intervention, prodromal symptoms, qualitative research, secondary prevention

DOI: 10.3233/JAD-191159

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Habiba, Umma | Merlin, Sam | Lim, Jeremiah K.H. | Wong, Vickie H.Y. | Nguyen, Christine T.O. | Morley, John W. | Bui, Bang V. | Tayebi, Mourad

Article Type: Research Article

Abstract: Background: Amyloid-β soluble oligomers (Aβo) are believed to be the cause of the pathophysiology underlying Alzheimer’s disease (AD) and are normally detected some two decades before clinical onset of the disease. Retinal pathology associated with AD pathogenesis has previously been reported, including ganglion cell loss, accumulation of Aβ deposits in the retina, and reduction of nerve fiber layer thickness as well as abnormalities of the microvasculature. Objective: This study’s aim is to better understand the relationship between brain and retinal Aβo deposition and in particular to quantify levels of the toxic Aβo as a function of age in …the retina of a rodent model of AD. Methods: Retinas and brain tissue from 5×FAD mice were stained with Congo red, Thioflavin-T (Th-T), and Aβ plaque-specific and Aβo-specific antibodies. Results: We show that retinas displayed an age-dependent increase of Th-T-specific amyloid fibrils. Staining with anti-Aβ antibody confirmed the presence of the Aβ plaques in all 5×FAD retinas tested. In contrast, staining with anti-Aβo antibody showed an age-dependent decrease of retinal Aβo. Of note, Aβo was observed mainly in the retinal nuclear layers. Finally, we confirmed the localization of Aβo to neurons, typically accumulating in late endosomes, indicating possible impairment of the endocytic pathway. Conclusion: Our results demonstrate the presence of intraneuronal Aβo in the retina and its accumulation inversely correlated with retinal Aβ plaque deposition, indicating an age-related conversion in this animal model. These results support the development of an early AD diagnostic test targeting Aβo in the eye. Show more

Keywords: Anti-oligomer antibody, Alzheimer’s disease, amyloid-β oligomers, retina, retinal immunodetection, 5×FAD mice

DOI: 10.3233/JAD-191346

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Wing, Jeffrey J. | Levine, Deborah A. | Ramamurthy, Arun | Reider, Carson

Article Type: Research Article

Abstract: Background: Areas within the Appalachian region may have a greater burden of under diagnosed 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. Show more

Keywords: Alzheimer’s disease, Appalachian region, epidemiology, health disparities, medicare

DOI: 10.3233/JAD-200491

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

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 -retro in verso 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 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. Pre-press, no. Pre-press, pp. 1-21, 2020

Authors: Chatzistavraki, Maria | Papazafiri, Panagiota | Efthimiopoulos, Spiros

Article Type: Research Article

Abstract: Background: Coordinated calcium influx upon neuronal depolarization activates pathways that phosphorylate CaMKII, ERKs, and the transcription factor CREB and, therefore, expression of pro-survival and neuroprotective genes. Recent evidence indicates that amyloid-β protein precursor (AβPP) is trafficked to synapses and promotes their formation. At the synapse, AβPP interacts with synaptic proteins involved in vesicle exocytosis and affects calcium channel function. Objective: Herein, we examined the role of AβPP in depolarization-induced calcium-mediated signaling using acute cerebral slices from wild-type C57bl/6 mice and AβPP– /– C57bl/6 mice. Methods: Depolarization of acute cerebral slices from wild-type C57bl/6 and AβPP– /– …C57bl/6 mice was used to induce synaptic signaling. Protein levels were examined by western blot and calcium dynamics were assessed using primary neuronal cultures. Results: In the absence of AβPP, decreased pCaMKII and pERKs levels were observed. This decrease was sensitive to the inhibition of N- and P/Q-type Voltage Gated Calcium Channels (N- and P/Q-VGCCs) by ω -conotoxin GVIA and ω -conotoxin MVIIC, respectively, but not to inhibition of L-type VGCCs by nifedipine. However, the absence of AβPP did not result in a statistically significant decrease of pCREB, which is a known substrate of pERKs. Finally, using calcium imaging, we found that down regulation of AβPP in cortical neurons results in a decreased response to depolarization and altered kinetics of calcium response. Conclusion: AβPP regulates synaptic activity-mediated neuronal signaling by affecting N- and P/Q-VGCCs. Show more

Keywords: Alzheimer’s disease, amyloid-β protein precursor, AβPP, calcium, neuronal signaling, synapse

DOI: 10.3233/JAD-200290

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Griswold, Anthony J. | Sivasankaran, Sathesh K. | Van Booven, Derek | Gardner, Olivia K. | Rajabli, Farid | Whitehead, Patrice L. | Hamilton-Nelson, Kara L. | Adams, Larry D. | Scott, Aja M. | Hofmann, Natalia K. | Vance, Jeffery M. | Cuccaro, Michael L. | Bush, William S. | Martin, Eden R. | Byrd, Goldie S. | Haines, Jonathan L. | Pericak-Vance, Margaret A. | Beecham, Gary W.

Article Type: Research Article

Abstract: Background: Significant work has identified genetic variants conferring risk and protection for Alzheimer’s disease (AD), but functional effects of these variants is lacking, particularly in under-represented ancestral populations. Expression studies performed in easily accessible tissue, such as whole blood, can recapitulate some transcriptional changes occurring in brain and help to identify mechanisms underlying neurodegenerative processes. Objective: We aimed to identify transcriptional differences between AD cases and controls in a cohort of diverse ancestry. Methods: We analyzed the protein coding transcriptome using RNA sequencing from peripheral blood collected from 234 African American (AA) (115 AD, 119 controls) …and 240 non-Hispanic Whites (NHW) (121 AD, 119 controls). To identify case-control differentially expressed genes and pathways, we performed stratified, joint, and interaction analyses using linear regression models within and across ancestral groups followed by pathway and gene set enrichment analyses. Results: Overall, we identified 418 (291 upregulated, 127 downregulated) and 488 genes (352 upregulated, 136 downregulated) differentially expressed in the AA and NHW datasets, respectively, with only 16 genes commonly differentially expressed in both ancestral groups. Joint analyses provided greater power to detect case-control differences and identified 1,102 differentially expressed genes between cases and controls (812 upregulated, 290 downregulated). Interaction analysis identified only 27 genes with different effects in AA compared to NHW. Pathway and gene-set enrichment analyses revealed differences in immune response-related pathways that were enriched across the analyses despite different underlying gene sets. Conclusion: These results support the hypothesis of converging underlying pathophysiological processes in AD across ancestral groups. Show more

Keywords: Gene expression profiling, population characteristics, RNA, transcriptome

DOI: 10.3233/JAD-190855

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Vergouw, Leonie J. M. | Geut, Hanneke | Breedveld, Guido | Kuipers, Demy J. S. | Quadri, Marialuisa | Netherlands Brain Bank | Rozemuller, Annemieke J. M. | van Swieten, John C. | de Jong, Frank Jan | van de Berg, Wilma D. J. | Bonifati, Vincenzo

Article Type: Research Article

Abstract: Background: Rare variants in the low-density lipoprotein receptor related protein 10 gene (LRP10 ) have recently been implicated in the etiology of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Objective: We searched for LRP10 variants in a new series of brain donors with dementia and Lewy pathology (LP) at autopsy, or dementia and parkinsonism without LP but with various other neurodegenerative pathologies. Methods: Sanger sequencing of LRP10 was performed in 233 donors collected by the Netherlands Brain Bank. Results: Rare, possibly pathogenic heterozygous LRP10 variants were present in …three patients: p.Gly453Serin a patient with mixed Alzheimer’s disease (AD)/Lewy body disease (LBD), p.Arg151Cys in a DLB patient, and p.Gly326Asp in an AD patient without LP. All three patients had a positive family history for dementia or PD. Conclusion: Rare LRP10 variants are present in some patients with dementia and different brain pathologies including DLB, mixed AD/LBD, and AD. These findings suggest a role for LRP10 across a broad neurodegenerative spectrum. Show more

Keywords: Genetic predisposition to disease, genotype, LRP10, neuropathology, phenotype

DOI: 10.3233/JAD-200318

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Sy, Marie Charmaine C. | Espiritu, Adrian I. | Sy, Matthew Samuel C. | Jamora, Roland Dominic G. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: Scientific output in Southeast Asia (SEA) on the topic of dementia is postulated to be low in quality and quantity. It is also speculated that certain socioeconomic variables and measures of disease burden for dementia may play a significant role in driving the research output of a particular country. Objective: This study aimed to determine the research impact of published journal articles on dementia in SEA and its association with country-level socioeconomic factors and measures of disease burden for dementia. Methods: A systematic search was conducted using electronic healthcare databases. We included articles published on …dementia until August 2019 with at least 1 author affiliated with any SEA institution. We obtained bibliometric indices, relevant socioeconomic factors, and measures of disease burden for dementia from published sources. Results: One thousand six articles fulfilled the inclusion criteria. The majority of publications were related to Alzheimer’s disease (n  = 775, 77.0%). Singapore contributed the highest number of publications (n  = 457, 45.4%). Gross domestic product (GDP) per capita, % GDP for research and development, and total neurologists significantly correlated with several bibliometric indices. On the other hand, the measures of disease burden for dementia in SEA countries were not significantly associated with research productivity. Conclusion: Research productivity in SEA on dementia has substantially increased in recent years. Augmenting GDP per capita and expanding the apportionment of resources to research and development (R&D) may have a significant role in the advancement of dementia research in SEA. Show more

Keywords: Bibliometric analysis, burden of disease, dementia, scientometrics, socioeconomic factors, Southeast Asia

DOI: 10.3233/JAD-200355

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Sancesario, Giulia Maria | Di Lazzaro, Giulia | Alwardat, Mohammad | Biticchi, Benedetta | Basile, Valerio | Salimei, Chiara | Colona, Vito Luigi | Sinibaldi Salimei, Paola | Bernardini, Sergio | Mercuri, Nicola Biagio | Pisani, Antonio | Schirinzi, Tommaso

Article Type: Research Article

Abstract: Background: Synaptopathy is critical in pathophysiology of Parkinson’s disease (PD). Cerebrospinal fluid (CSF) levels of neurogranin (NG) and amyloid-β42 (Aβ42 ) are considered markers of synaptic dysfunction in neurodegenerative diseases. Objective: To evaluate the CSF synaptopathy-related biomarkers, especially the novel Aβ42 /NG ratio, in PD, establishing possible associations with cognitive level and other clinical parameters. Methods: Levels of NG, Aβ42 , amyloid-β40 , total and phosphorylated tau, and Aβ42 /NG ratio were measured in 30 PD patients and 30 controls and correlated with cognitive and motor parameters. The accuracy in distinguishing the cognitive status was …determined. Results: NG and Aβ42 were significantly reduced in PD, with higher NG levels in patients with worse cognition. The Aβ42 /NG ratio showed a direct correlation with Mini-Mental State Examination, independently from age and sex, and differentiated cognitively impaired patients with 92% sensitivity and 71.4% specificity, accuracy higher than NG alone. No correlations resulted with motor disturbances or therapy. Conclusions: The novel Aβ42 /NG ratio couples either presynaptic or postsynaptic markers of synaptic dysfunction, representing a potential global index of synaptopathy, useful to track cognitive functions in PD. Show more

Keywords: Cerebrospinal fluid biomarkers, cognitive, neurogranin, Parkinson’s disease

DOI: 10.3233/JAD-200344

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Sugimoto, Taiki | Ono, Rei | Kimura, Ai | Saji, Naoki | Niida, Shumpei | Sakai, Toshihiro | Rakugi, Hiromi | Toba, Kenji | Sakurai, Takashi

Article Type: Research Article

Abstract: Background: Very few studies have investigated the impact of cognitive frailty in clinical settings, especially in memory clinic populations. Objective: To examine the impact of cognitive frailty on activities of daily living (ADL), cognitive function, and conversion to dementia among memory clinic patients with mild cognitive impairment (MCI). Methods: The subjects of this retrospective study were 248 MCI patients (mean age, 76.3±5.4 years; females, 60.9%). All subjects completed a comprehensive geriatric assessment at baseline and at least one assessment during 3-year follow-up. Frailty was defined by generating a frailty index (FI), and MCI patients with frailty …(FI≥0.25) were considered to represent cognitive frailty. As primary outcomes, the Barthel Index, Mini-Mental State Examination, and incident dementia were evaluated during follow-up. At baseline, patients were assessed for apolipoprotein E (APOE ) phenotype. A linear mixed model, as well as a Cox proportional hazards regression model with adjustment for confounding variables, was performed. Results: Of these patients, 75 (30.2%) were classified as cognitive frail. APOE ɛ 4 carriers accounted for 26.7% of those with cognitive frailty and 44.5% of those without (p  = 0.008). Cognitive frail patients showed a faster ADL decline (estimate, –1.04; standard error, 0.38; p  = 0.007) than patients without cognitive frailty. Cognitive frailty was not associated with cognitive decline and incident dementia. Conclusion: Our findings demonstrated cognitive frailty increases the risk of dependence but not cognitive outcomes. Cognitive frailty may have heterogeneous conditions, including APOE ɛ 4-related pathologies, which may affect the cognitive trajectories of patients with MCI. Show more

Keywords: Cognitive frailty, disability, frailty, memory clinic, mild cognitive impairment, older persons

DOI: 10.3233/JAD-191135

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Narukawa, Masataka | Takahashi, Suzuka | Saito, Takashi | Saido, Takaomi C. | Misaka, Takumi

Article Type: Research Article

Abstract: Background: Some studies have reported a decline in taste sensitivities in patients with Alzheimer’s disease. However, the detail remains unknown. Objective: We investigated the effect of cognitive impairment on taste sensitivity using an App knock-in mouse model of Alzheimer’s disease. Methods: Behavioral assays, a brief access test, and a 48 h two-bottle preference test, to assess taste sensitivities were started from 12 months of age in mice that were confirmed to have impaired cognition. Results: In the assays, there was no significant difference in taste sensitivities between wild type and App knock-in mice. …Additionally, no apparent difference was observed in the expression of taste markers in their taste bud cells. Conclusion: We concluded that cognitive impairment might not greatly affect taste sensitivity. Show more

Keywords: Aging, App knock-in mice, donepezil, taste sensitivity

DOI: 10.3233/JAD-200284

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Thordardottir, Steinunn | Almkvist, Ove | Johansson, Charlotte | Zetterberg, Henrik | Blennow, Kaj | Graff, Caroline

Article Type: Research Article

Abstract: Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) which reflect different underlying disease mechanisms. Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. Methods: YKL-40 and neurogranin, as well as Aβ 42 , total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe …(p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, chitinases, genetics, mutation, neurogranin

DOI: 10.3233/JAD-191261

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Hu, Yueming | Meuret, Cristiana | Go, Scholastica | Yassine, Hussein N. | Nedelkov, Dobrin

Article Type: Research Article

Abstract: Background: The mechanisms of how APOE ɛ 4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated. Objective: To determine the impact of APOE genotype on the relative abundance of apoE protein isoforms and their specific glycosylation patterns in CSF and plasma via a newly developed mass spectrometric immunoassay (MSIA) assay. Methods: Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of non-demented older individuals (n  = 22), consisting of homozygous ɛ 3 and ɛ 4 …or heterozygous ɛ 3/ɛ 4, ɛ 2/ɛ 3, or ɛ 2/ɛ 4 carriers. The glycan structures were further confirmed after treatment with sialidase. Results: In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. For all individuals, a single O -linked glycan was observed in plasma, while two glycans (of the same type) per apoE were observed in CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In plasma and CSF, a trend of decreasing glycosylation was observed from apoE2>apoE3>apoE4. The difference in the percentage of secondary glycosylation in CSF was significantly greater in apoE4compared to the other isoforms. Conclusion: The new MSIA apoE as say robustly distinguishes among apoE isoforms and glycoformsin plasma and CSF. ApoE4 is the predominant isoform and least glycosylated in CSF. Assessing apoE isoform-specific glycosylation by MSIA may help clarifybrain apoE metabolism and AD risk. Show more

Keywords: Alzheimer’s disease, Apolipoprotein E, glycan, isoform, mass spectrometry

DOI: 10.3233/JAD-200203

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Thomas, Jason A. | Burkhardt, Hannah A. | Chaudhry, Safina | Ngo, Anthony D. | Sharma, Saransh | Zhang, Larry | Au, Rhoda | Hosseini Ghomi, Reza

Article Type: Research Article

Abstract: Background: There is a need for fast, accessible, low-cost, and accurate diagnostic methods for early detection of cognitive decline. Dementia diagnoses are usually made years after symptom onset, missing a window of opportunity for early intervention. Objective: To evaluate the use of recorded voice features as proxies for cognitive function by using neuropsychological test measures and existing dementia diagnoses. Methods: This study analyzed 170 audio recordings, transcripts, and paired neuropsychological test results from 135 participants selected from the Framingham Heart Study (FHS), which includes 97 recordings of cognitively normal participants and 73 recordings of cognitively impaired …participants. Acoustic and linguistic features of the voice samples were correlated with cognitive performance measures to verify their association. Results: Language and voice features, when combined with demographic variables, performed with an AUC of 0.942 (95% CI 0.929–0.983) in predicting cognitive status. Features with good predictive power included the acoustic features mean spectral slope in the 500–1500 Hz band, variation in the F2 bandwidth, and variation in the Mel-Frequency Cepstral Coefficient (MFCC) 1;the demographic features employment, education, and age; and the text features of number of words, number of compound words, number of unique nouns, and number of proper names. Conclusion: Several linguistic and acoustic biomarkers show correlations and predictive power with regard to neuropsychological testing results and cognitive impairment diagnoses, including dementia. This initial study paves the way for a follow-up comprehensive study incorporating the entire FHS cohort. Show more

Keywords: Alzheimer’s disease, artificial intelligence, biomarkers, cognitive dysfunction, data collection, dementia, early diagnosis, language, neuropsychological tests, voice

DOI: 10.3233/JAD-190783

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Luukkainen, Laura | Huttula, Samuli | Väyrynen, Henri | Helisalmi, Seppo | Kytövuori, Laura | Haapasalo, Annakaisa | Hiltunen, Mikko | Remes, Anne M. | Krüger, Johanna

Article Type: Research Article

Abstract: Background: Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson’s disease (PD) overlap in clinical characteristics, neuropathology, and genetics. Objective: The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. Methods: Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1 , ATP13A2, UCHL1, HTRA2, GBA , and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 …years) dementia patients presenting with atypical features (e.g., myocloniaor spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n  = 279, mean AAO 57, range 36–65) patients. Results: No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). Discussion: Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD. Show more

Keywords: Alzheimer’s disease, dementia, dementia with Lewy bodies, frontotemporal dementia, frontotemporal lobar degeneration, gene, mutation, neurodegenerative disease, Parkinson’s disease, single nucleotide polymorphism

DOI: 10.3233/JAD-200069

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Guthrie, Heather | Honig, Lawrence S. | Lin, Helen | Sink, Kaycee M. | Blondeau, Kathleen | Quartino, Angelica | Dolton, Michael | Carrasco-Triguero, Montserrat | Lian, Qinshu | Bittner, Tobias | Clayton, David | Smith, Jillian | Ostrowitzki, Susanne

Article Type: Research Article

Abstract: Background: Crenezumab is a fully humanized, monoclonal anti-amyloid-β immunoglobulin G4 antibody. Objective: This Phase Ib study (NCT02353598) evaluated the safety, tolerability, and pharmacokinetics of crenezumabat doses of ≤120 mg/kg administered intravenously every 4 weeks (q4w). Immunogenicity and exploratory biomarkers were also evaluated. Methods: In this multicenter, double-blind study, participants (aged 50–90 years) with mild-to-moderate Alzheimer’s disease (AD) and amyloid-positive PET scan were randomized to receive crenezumab 30 or 45 mg/kg (Cohort 1, n  = 21), 60 mg/kg (Cohort 2, n  = 21), or 120 mg/kg (Cohort 3, n  = 19) or corresponding placebo (n  = 14) intravenously q4wfor 13 weeks. Seventy-one participants were subsequently …enrolled in an optional open-label extension (OLE) and received crenezumab at the originally assigned dose level, except for Cohort 3 (crenezumab 60 mg/kg during OLE). Participants received regular brain MRIs to assess amyloid-related imaging abnormalities (ARIA). Results up to Week 133 are reported. Results: Approximately 94% of participants experienced ≥1 adverse event (AE). Most AEs were mild or moderate; 15.5% experienced a Grade ≥3 AE. No ARIA-edema/effusion (ARIA-E) events were observed. New ARIA-micro hemorrhages and hemosiderosis (ARIA-H) were reported in 4.9% (double-blind treatment period) and 9.9% (combined double-blind treatment and OLE periods) of participants. Steady-state trough concentrations of crenezumab were dose proportional and maintained for each dose level. Conclusion: Crenezumab doses of ≤120 mg/kg intravenously q4w were well tolerated. The observed safety profile for ≤133 weeks of treatment in a mild-to-moderate AD population was similar to that seen in previous trials. Show more

Keywords: Alzheimer’s disease, amyloid positron emission tomography, amyloid-β peptide, crenezumab, humanized monoclonal antibody, infusion site adverse event, magnetic resonance imaging, safety

DOI: 10.3233/JAD-200134

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Robillard, Julie M. | Kabacińska, Katarzyna

Article Type: Review Article

Abstract: Socially assistive robots have the potential to improve aged care by providing assistance through social interaction. While some evidence suggests a positive impact of social robots on measures of well-being, the adoption of robotic technology remains slow. One approach to improve technology adoption is involving all stakeholders in the process of technology development using co-creation methods. To capture relevant stake holders’ priorities and perceptions on the ethics of robotic companions, we conducted an interactive co-creation workshop at the 2019 Geriatric Services Conference in Vancouver, BC. The participants were presented with different portrayals of robotic companions in popular culture and answered …questions about perceptions, expectations, and ethical concerns about the implementation of robotic technology. Our results reveal that the most pressing ethical concerns with robotic technology, such as issues related to privacy, are critical potential barriers to technology adoption. We also found that most participants agree on the types of tasks that robots should help with, such as domestic chores, communication, and medication reminders. Activities that robots should not help with, according to the stakeholders, included bathing, toileting, and managing finances. The perspectives that were captured contribute to a preliminary outline of the areas of importance for geriatric care stake holders in the process of ethical technology design and development. Show more

Keywords: Aging, engagement, ethics, technology

DOI: 10.3233/JAD-200214

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2020

Authors: Wang, Si-Yu | Gong, Peng-Yu | Yan, E | Zhang, Ying-Dong | Jiang, Teng

Article Type: Review Article

Abstract: Late-onset Alzheimer’s disease (AD) accounts for most of all AD casesand is currently considered a complex disorder caused by a combination of environmental and genetic factors. As an important family member of triggering receptor expressed on myeloid cells (TREM ), TREM-like transcript 2 gene (TREML2 ) locates on human chromosome 6p21.1, a newly-identified hot zone for AD susceptibility, and encodes atransmembrane immune receptor. Emerging evidence implied a potential role of TREML2 in the susceptibility and pathogenesis of AD. Here, we review the recent literature about the association of TREML2 variants with AD risk and disease endophenotypes. Moreover, we …summarize the latest findings regarding cellular localization and biological functions of TREML2 and speculate its possible role in AD pathogenesis. In addition, we discuss future research directions of TREML2 and AD. Show more

Keywords: Alzheimer’s disease, amyloid-β , genetics, microglia, TREML2

DOI: 10.3233/JAD-200406

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Robillard, Julie M. | Goldman, Ian P. | Prescott, Tony J. | Michaud, François

Article Type: Research Article

Abstract: Portacolone et al.’s Ethics Review highlights the ethical challenges associated with the implementation of telepresence devices and applications in the context of aging and dementia. In this response, we review ethical considerations as they relate to specific modalities of telepresence, with an emphasis on the continuum of potential interaction agents, from known individuals to fully automated and intelligent interlocutors. We further discuss areas in need of empirical evidence to inform regulatory efforts in telepresence. We close with a call for meaningful end-user engagement at all stages of technology development.

Keywords: Alzheimer’s disease, ethics, patient engagement, robotics, telepresence

DOI: 10.3233/JAD-200154

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Rajji, Tarek K. | Bowie, Christopher R. | Herrmann, Nathan | Pollock, Bruce G. | Bikson, Marom | Blumberger, Daniel M. | Butters, Meryl A. | Daskalakis, Zafiris J. | Fischer, Corinne E. | Flint, Alastair J. | Golas, Angela C. | Graff-Guerrero, Ariel | Kumar, Sanjeev | Lourenco, Lillian | Mah, Linda | Ovaysikia, Shima | Thorpe, Kevin E. | Voineskos, Aristotle N. | Mulsant, Benoit H. | for the PACt-MD Study Group

Article Type: Research Article

Abstract: Background: By the time Alzheimer’s disease and related disorders (ADRD) are diagnosed, efficacy of treatments is limited. Preventive interventions are urgently needed. Objective: To design a randomized controlled trial to assess a novel intervention that aims to prevent ADRD in high-risk groups. Methods: We report on the rationale and describe the design of a multisite randomized controlled trial that aims to prevent ADRD in older persons with: (1) mild cognitive impairment (MCI); (2) remitted major depressive disorder (MDD) without MCI; or (3) remitted MDD with MCI. Results: PACt-MD (Prevention of Alzheimer’s dementia with Cognitive …remediation plus transcranial direct current stimulation in Mild cognitive impairment and Depression) is a trial that randomized 375 older participants with MCI, MDD, or MCI + MDD to cognitive remediation (CR) and transcranial direct current stimulation (tDCS) or sham-CR + sham-tDCS for 5 days/week for 8 weeks followed by boosters for 5 days/week once every 6 months until participants progress to MCI or ADRD, or the end of the study. Between boosters, participants are asked to train on CR daily. At baseline, end of 8 weeks, and yearly from baseline, participants undergo clinical, cognitive, and functional assessments. Primary aims are to compare the efficacy of CR + tDCS versus sham + sham in preventing: 1) long-term cognitive decline; and 2) incidence of ADRD or MCI. Secondary aim is to assess for cognitive improvement after the 8-week course. We will also explore the moderating and mediating effects of biomarkers collected from the participants. Conclusion: PACt-MD is unique in combining brain stimulation and psychosocial intervention to prevent ADRD. PACt-MD is also a platform for studying multi-domain biomarkers that will advance our understanding of the relationships among MCI, MDD, and ADRD. Show more

Keywords: Alzheimer’s disease and related disorders, cognitive remediation, major depressive disorder, mild cognitive disorder, PACt-MD, prevention, transcranial direct current stimulation, NCT02386670

DOI: 10.3233/JAD-200141

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Lakey-Beitia, Johant | Burillo, Andrea M. | La Penna, Giovanni | Hegde, Muralidhar L. | Rao, K.S.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multi factorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-βprotein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing …its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, copper, iron, metal chelation therapy, metalloproteins, polyphenols, zinc

DOI: 10.3233/JAD-200185

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2020

Authors: van der Willik, Kimberly D. | Schagen, Sanne B. | Ikram, M. Arfan

Article Type: Short Communication

Abstract: There is an ongoing debate about how cancer and dementia relate to each other, and whether their relation is biologically determined or caused by surveillance and survival bias. We aimed to circumvent these biases by determining the relation between the tumor marker carcinoembryonic antigen (CEA) and the risk of dementia in 6,692 participants from the population-based Rotterdam Study. We found that higher levels of CEA were associated with a higher risk of dementia (HR per standard deviation increase in CEA = 1.11, 95% CI 1.04;1.18). This finding may indicate that cancer and dementia are positively associated, but the mechanisms underlying the relation …between CEA and dementia warrant further investigation. Show more

Keywords: Carcinoembryonic antigen, cohort studies, dementia, epidemiology

DOI: 10.3233/JAD-200440

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Attademo, Luigi | Bernardini, Francesco

Article Type: Research Article

Abstract: As a global problem that has increasingly been causing worldwide concern, air pollution poses a significant and serious environmental risk to health. Risks of cardiovascular and respiratory diseases, as well as various types of cancer, have been consistently associated with the exposure to air pollutants. More recently, various studies have also shown that the central nervous system is also attacked by air pollution. Air pollution appears to be strongly associated with a higher risk of cognitive defects, neuro developmental (e.g., schizophrenia) and neurodegenerative (e.g., Alzheimer’s disease) disorders. Subjects with schizophrenia, as well as subjects with Alzheimer’s disease, experience a variety …of neuropsychological deficits and cognitive impairments. This determines an adverse effect on social and professional functioning, and it contributes to the long-term disease burden. However, no final conclusions have been drawn on the matter of the direct relationship between schizophrenia and Alzheimer’s disease. In recent years, the topic of urbanicity and mental health has become increasingly important. Urban exposure to environmental toxins and pollution is currently described as a reliable risk factor for schizophrenia and other psychoses, and it has been demonstrated more and more how exposure to air pollutants is associated with increased risk of dementia. Pathways by which air pollution can target and damage the brain, leading to an increased risk for developing schizophrenia and Alzheimer’s disease, are multiple and complex. Results from epidemiological studies suggest potential associations, but are still insufficient to confirm causality. Further studies are needed in order to verify this hypothesis. And if confirmed, the clinical implications could be of substantial relevance for both public and mental health. Show more

Keywords: Air pollution, Alzheimer’s disease, public health, schizophrenia

DOI: 10.3233/JAD-200289

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Si, Zizhen | Kang, Yuchun | Wang, Xidi | Wang, Xue | Sun, Changhui | Li, Yuanxin | Xu, Jiakun | Wu, Jiajia | Zhang, Zhujun | Li, Ling | Peng, Yahui | Li, Jihong | Sun, Chongran | Hui, Yang | Gao, Xu

Article Type: Research Article

Abstract: Background: Adult hippocampal neurogenesis is critical for renewing hippocampal neural circuits and maintaining hippocampal cognitive function and is closely associated with age-related neurodegenerative diseases. Heme oxygenase 1 (HO-1) is a stress protein that catalyzes the degradation of heme into free iron, biliverdin, and carbon monoxide. Elevated HO-1 level constitutes a pathological feature of Alzheimer’s disease, Parkinson’s disease, and many other age-related neurodegenerative diseases. Objective: Here we research the precise role of HO-1 in adult hippocampal neurogenesis. Methods: To explore the effect of HO-1 overexpression on adult neural stem cells (aNSCs) and elucidate its mechanisms, Tg(HO-1) was …constructed. The transgenic mice and aNSCs were subjected to neurosphereing assay, clonal analysis, and BrdU labelling to detect the proliferation and self-renewal ability. LiCl, MG132, CHX, and IGF-1 treatment were used to research the signaling pathways which regulated by HO-1. Results: HO-1 overexpression decreased proliferation ability and induced apoptosis of aNSCs in subgranular zoon (SGZ) in vivo and in vitro . Furthermore, HO-1 overexpression inactivated canonical WNT/β-catenin pathway. Re-activate canonical WNT/β-catenin pathway rescued aNSCs proliferation and survival upon HO-1 overexpression. More importantly, phosphorylation of AKTS473 and GSK3βS9 was found to be significantly decreased in HO-1 overexpressed aNSCs. Re-activation of AKT signaling proved that HO-1 inhibited Wnt/β-catenin signaling pathway via AKT/GSK3β signaling pathway. Conclusion: These results demonstrated a critical role of HO-1 in regulating aNSCs survival and proliferation by inhibiting Wnt/β-catenin pathway through repression of AKT/GSK3β, which provide a novel insight into the role of HO-1 in Alzheimer’s disease pathogenesis. Show more

Keywords: Adult hippocampal neurogenesis, age-related neurodegenerative diseases, canonical Wnt/β-catenin pathway, heme oxygenase 1, neural stem cell

DOI: 10.3233/JAD-200114

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Takemoto, Mami | Ohta, Yasuyuki | Hishikawa, Nozomi | Yamashita, Toru | Nomura, Emi | Tsunoda, Keiichiro | Sasaki, Ryo | Tadokoro, Koh | Matsumoto, Namiko | Omote, Yoshio | Abe, Koji

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms of dementia such as depression and apathy in patients with Alzheimer’s disease (AD) are associated with a lower quality of life. Objective: We aimed to determine the efficacy of two antidepressants and one antipathy drug in the treatment of depression and apathy in AD patients. Methods: In the present study, we evaluated the efficacy of sertraline (n  = 11; average dose = 31.8 mg), escitalopram (n  = 13; average dose = 7.3 mg), and nicergoline (n  = 9; average dose = 14.5 mg) in treating depression and apathy over a period of 3 months (M).The 33 patients with AD demonstrated high Geriatric Depression Scale (GDS) …(>5) or a high Apathy Scale (AS) (>16) scores. Results: The patients receiving escitalopram treatment showed a significant improvement in GDS score from baseline (8.2±3.5) to 3 M (5.7±2.6, p  = 0.04), and the patients receiving sertraline treatment showed a significant improvement in AS score from baseline (20.8±5.2) to 3 M (16.8±6.1, p  = 0.05); however, no significant changes were noted in patients receiving nicergoline. Conclusion: These results provide novel information on the efficacy of sertraline and escitalopram in the treatment of apathy and depression, respectively, in patients with AD. Show more

Keywords: Alzheimer’s disease, apathy, depression, escitalopram, nicergoline, sertraline

DOI: 10.3233/JAD-200247

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2020

Authors: Mantovani, Elisa | Zucchella, Chiara | Schena, Federico | Romanelli, Maria Grazia | Venturelli, Massimo | Tamburin, Stefano

Article Type: Research Article

Abstract: Background: The progressive aging of the population will dramatically increase the burden of dementia related to Alzheimer’s disease (AD) and other neurodegenerative disorders in the future. Because of the absence of drugs that can modify the neuropathological substrate of AD, research is focusing on the application of preemptive and disease-modifying strategies in the pre-symptomatic period of the disease. In this perspective, the identification of people with cognitive frailty (CF), i.e., those individuals with higher risk of developing dementia, on solid pathophysiological bases and with clear operational clinical criteria is of paramount importance. Objective/Methods: This hypothesis paper reviews the …current definitions of CF, presents and discusses some of their limitations, and proposes a framework for updating and improving the conceptual and operational definition of the CF construct. Results: The potential for reversibility of CF should be supported by the assessment of amyloid, tau, and neuronal damage biomarkers, especially in younger patients. Physical and cognitive components of frailty should be considered as separate entities, instead of part of a single macro-phenotype. CF should not be limited to the geriatric population, because trajectories of amyloid accumulation are supposed to start earlier than 65 years in AD. Operational criteria are needed to standardize assessment of CF. Conclusion: Based on the limitations of current CF definitions, we propose a revised one according to a multidimensional sub typing. This new definition might help stratifying CF patients for future trials to explore new lifestyle interventions or disease-modifying pharmacological strategies for AD and dementia. Show more

Keywords: Biomarkers, cognitive frailty, dementia, frailty, mild cognitive impairment, neuropathology, subjective cognitive impairment

DOI: 10.3233/JAD-200137

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Liu, Rui-Ming | Chong, Zechen | Chen, Jiu-Chiuan

Article Type: Review Article

Abstract: Alzheimer’s disease (AD), an aging-related neurodegenerative disease, is a major cause of dementia in the elderly. Although the early-onset (familial) AD is attributed to mutations in the genes coding for amyloid-β protein precursor (AβPP) and presenilin1/presenilin 2 (PS1/PS2), the cause for the late-onset AD (LOAD), which accounts for more than 95% of AD cases, remains unclear. Aging is the greatest risk factor for LOAD, whereas the apolipo protein E4 allele (APOE ɛ 4) is believed to be a major genetic risk factor in acquiring LOAD, with female APOE ɛ 4 carriers at highest risk. Nonetheless, not all the elderly, …even older female APOE ɛ 4 carriers, develop LOAD, suggesting that other factors, including environmental exposure, must play a role. This review summarizes recent studies that show a potential role of environmental exposure, especially ozone and particulate matter exposure, in the development of AD. Interactions between environmental exposure, genetic risk factor (APOE ɛ 4), and sex in AD pathophysiology are also discussed briefly. Identification of environmental risk factor(s) and elucidation of the complex interactions between genetic and environmental risk factors plus aging and female sex in the onset of AD will be a key to our understanding of the etiology and pathogenesis of AD and the development of the strategies for its prevention and treatment. Show more

Keywords: Alzheimer’s disease, animal models, epidemiology, ozone, particulate matters

DOI: 10.3233/JAD-200435

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-18, 2020

Authors: Cuttler, Katelyn | Bignoux, Monique J. | Otgaar, Tyrone C. | Chigumba, Stephanie | Ferreira, Eloise | Weiss, Stefan F.T.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaque and neurofibrillary tangle formation, respectively. Neurofibrillary tangles form as a result of the intracellular accumulation of hyperphosphorylated tau. Telomerase activity and levels of the human reverse transcriptase (hTERT) subunit of telomerase are significantly decreased in AD. Recently, it has been demonstrated that the 37 kDa/67 kDa laminin receptor (LRP/LR) interacts with telomerase and is implicated in Aβ pathology. Since both LRP/LR and telomerase are known to play a role in the Aβ facet of AD, we hypothesized that they might also play a role in tauopathy. Objective: This study aimed …to determine if LRP/LR has a relationship with tau and whether overexpression of LRP::FLAG has an effect on tauopathy-related proteins. Methods: We employed confocal microscopy and FRET to determine whether LRP/LR and tau co-localize and interact. LRP::FLAG overexpression in HEK-293 and SH-S5Y cells as well as analysis of tauopathy-related proteins was assessed by western blotting. Results: We demonstrate that LRP/LR co-localizes with tau in the perinuclear cell compartment and confirmed a direct interaction between LRP/LR and tau in HEK-293 cells. Over expression of LRP::FLAG in HEK-293 and SH-SY5Y cells decreased total and phosphorylated tau levels with a concomitant decrease in PrPc levels, a tauopathy-related protein. LRP::FLAG overexpression also resulted in increased hTERT levels. Conclusion: This data suggest that LRP/LR extends its role in AD through a direct interaction with tau, and recommend LRP::FLAG as a possible alternative AD therapeutic via decreasing phosphorylated tau levels. Show more

Keywords: Alzheimer’s disease, 37 kDa/67 kDa laminin receptor (LRP/LR), PrPc , tau, telomerase

DOI: 10.3233/JAD-200244

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2020

Authors: Reyes-Pablo, Aldelmo Emmanuel | Campa-Córdoba, B. Berenice | Luna-Viramontes, Nabil Itzi | Ontiveros-Torres, Miguel Ángel | Villanueva-Fierro, Ignacio | Bravo-Muñoz, Marely | Sáenz-Ibarra, Bárbara | Barbosa, Oralia | Guadarrama-Ortíz, Parménides | Garcés-Ramírez, Linda | de la Cruz, Fidel | Harrington, Charles R. | Martínez-Robles, Sandra | González-Ballesteros, Erik | Perry, George | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: We recently developed the National Dementia Biobank in México (BioBanco Nacional de Demencias, BND) as a unit for diagnosis, research, and tissue transfer for researcher purposes. BND is associated with the Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de Mexico (UNAM), Mexico. The donation of fluids, brain, and other organs of deceased donors is crucial for understanding the underlying mechanisms of neurodegenerative diseases and for the development of successful treatment. Our laboratory research focuses on 1) analysis of the molecular processing of the proteins involved in neurodegenerative diseases named tauopathies and 2) the search for biomarkers for the non-invasive …early diagnosis of Alzheimer’s disease. Show more

Keywords: Alzheimer’s disease, amyloid-β , BioBank, brain tissue, neurodegenerative disease, tau protein, tauopathies

DOI: 10.3233/JAD-191015

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Roy, Maggie | Rheault, François | Croteau, Etienne | Castellano, Christian-Alexandre | Fortier, Mélanie | St-Pierre, Valérie | Houde, Jean-Christophe | Turcotte, Éric E. | Bocti, Christian | Fulop, Tamas | Cunnane, Stephen C. | Descoteaux, Maxime

Article Type: Research Article

Abstract: Background: White matter energy supply to oligodendrocytes and the axonal compartment is crucial for normal axonal function. Although gray matter glucose hypometabolism is extensively reported in Alzheimer’s disease (AD), glucose and ketones, the brain’s two main fuels, are rarely quantified in white matter in AD. Objective: Using adual-tracer PET method combined with a fascicle-specific diffusion MRI approach, robust to white matter hyper intensities and crossing fibers, we aimed to quantify both glucose and ketone metabolismin specific white matter fascicles associated with mild cognitive impairment (MCI; n  = 51) and AD (n  = 13) compared to cognitively healthy age-matched controls (Controls; …n  = 14). Methods: Eight white matter fascicles of the limbic lobe and corpus callosum were extracted and analyzed into fascicle profiles of five sections. Glucose (18 F-fluorodeoxyglucose) and ketone (11 C-acetoacetate) uptake rates, corrected for partial volume effect, were calculated along each fascicle. Results: The only fascicle with significantly lower glucose uptake in AD compared to Controls was the left posterior cingulate segment of the cingulum (–22%; p  = 0.016). Non-significantly lower glucose uptake in this fascicle was also observed in MCI. In contrast to glucose, ketone uptake was either unchanged or higher in sections of the fornix and parahippocampal segment of the cingulum in AD. Conclusion: To our knowledge, this is the first report of brain fuel uptake calculated along white matter fascicles in humans. Energetic deterioration in white matter in AD appears to be specific to glucose and occurs first in the posterior cingulum. Show more

Keywords: Alzheimer’s disease, diffusion MRI, FDG, ketones, PET, white matter

DOI: 10.3233/JAD-200213

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2020

Authors: Liu, Yi | Bian, Huijie | Xu, Siyi | Shu, Shu | Jia, Junqiu | Chen, Jian | Cao, Xiang | Bao, Xinyu | Gu, Yue | Xia, Shengnan | Yang, Hui | Yu, Linjie | Xu, Yun | Zhu, Xiaolei

Article Type: Research Article

Abstract: Background: Dysfunction of synaptic plasticity leads to memory impairment in Alzheimer’s disease (AD). Muscone (Mus) has shown neuroprotective effects in cerebral ischemic models. However, little is known of Mus effects on AD. Objective: To investigate the effects of Mus on memory functions and synaptic plasticity in 6-month-old APP/PS1 double-transgenic mice and explore the potential mechanisms. Methods: Mus was intraperitoneally injected into APP/PS1 or wild-type mice, and cognitive function was assessed by Novel object recognition and Morris water maze tests. The levels of amyloid-β (Aβ) were evaluated by immunofluorescence staining and ELISA. Synaptic morphology and plasticity were …evaluated by Golgi staining and long-term potentiation. Cell viability was examined by Cell Counting Kit-8 assay. The protein levels of histone deacetylase 2 (HDAC2) were accessed by western blotting and Immunofluorescence staining. The protein levels of microtubule associated protein 2 and synaptophysin were analyzed by immunofluorescence staining. The ubiquitination of HDAC2 was examined by co-immunoprecipitation. The interaction of Mus with HDAC2 was predicted by molecular docking analysis. Results: Mus treatment attenuated memory dysfunction, reduced Aβ level, and enhanced synaptic plasticity in APP/PS1 mice. In addition, Mus treatment decreased the level of HDAC2 in the hippocampus of APP/PS1 mice and Aβ1–42 -induced primary neurons, which might be associated with increased HDAC2 ubiquitination induced by HDAC2 and Mus interaction. Conclusion: Mus protected against synaptic plasticity and memory impairment in APP/PS1 mice, and enhanced HDAC2 degradation via ubiquitination, indicating that Mus was a potential drug for AD treatment. Show more

Keywords: Alzheimer’s disease, amyloid-β, HDAC2, muscone, synaptic plasticity

DOI: 10.3233/JAD-200188

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: He, Yating | Zhang, Haihua | Wang, Tao | Han, Zhifa | Ni, Qing-bin | Wang, Kun | Wang, Longcai | Zhang, Yan | Hu, Yang | Jin, Shuilin | Sun, Bao-liang | Liu, Guiyou

Article Type: Research Article

Abstract: Background: Altered calcium homeostasis is hypothesized to underlie Alzheimer’s disease (AD). However, it remains unclear whether serum calcium levels are genetically associated with AD risk. Objective: To develop effective therapies, we should establish the causal link between serum calcium levels and AD. Methods: Here, we performed a Mendelian randomization study to investigate the causal association of increased serum calcium levels with AD risk using the genetic variants from a large-scale serum calcium genome-wide association study (GWAS) dataset (61,079 individuals of European descent) and a large-scale AD GWAS dataset (54,162 individuals including 17,008 AD cases and 37,154 …controls of European descent). Here, we selected the inverse-variance weighted (IVW) as the main analysis method. Meanwhile, we selected other three sensitivity analysis methods to examine the robustness of the IVW estimate. Results: IVW analysis showed that the increased serum calcium level (per 1 standard deviation (SD) increase 0.5 mg/dL) was significantly associated with a reduced AD risk (OR = 0.57, 95% CI 0.35–0.95, p  = 0.031). Meanwhile, all the estimates from other sensitivity analysis methods were consistent with the IVW estimate in terms of direction and magnitude. Conclusion: In summary, we provided evidence that increased serum calcium levels could reduce the risk of AD. Meanwhile, randomized controlled study should be conducted to clarify whether diet calcium intake or calcium supplement, or both could reduce the risk of AD. Show more

Keywords: Alzheimer’s disease, genome-wide association study, inverse-variance weighted, Mendelian randomization, serum calcium

DOI: 10.3233/JAD-191249

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Makino, Keitaro | Lee, Sangyoon | Bae, Seongryu | Shinkai, Yohei | Chiba, Ippei | Shimada, Hiroyuki

Article Type: Research Article

Abstract: Background: Both pain interference and depressive symptoms have certain effects on dementia, and these are reciprocally related. However, comorbid effects of pain interference and depressive symptoms on dementia have not been examined in detail. Objective: This longitudinal study aimed to examine the combined effects of pain interference and depressive symptoms on the incidence of dementia in community-dwelling elderly individuals. Methods: This prospective cohort study with a 36-month follow-up period included 4,326 community-dwelling elderly individuals without dementia at baseline. Pain interference and depressive symptoms were assessed for every participant at baseline. We collected medical records in the …Japanese public health insurance system to identify the incidence of dementia for 36 months. Results: The incidence rates of dementia during the follow-up period in the control, pain-interference, depressive-symptoms, and comorbid group were 3.2%, 6.2%, 7.9%, and 11.3%, respectively. A Cox regression analysis showed that the hazard ratios for the incidence of dementia were 1.85 (95% CI: 1.13–3.03) in the pain interference group, 1.87 (95% CI: 1.27–2.76) in the depressive symptoms group, and 2.20 (95% CI: 1.26–3.84) in the comorbid group, after adjusting for covariates. Conclusion: The coexistence of pain interference and depressive symptoms had a greater effect on the incidence of dementia than either condition alone in community-dwelling elderly individuals. Pain interference and depressive symptoms are known as common comorbid conditions and often form a negative cycle that accelerates the worsening of the individual symptoms of both. Thus, the comorbidity of these conditions may require monitoring for the prevention of dementia. Show more

Keywords: Activity limitation, community, dementia, depression, pain, prevention

DOI: 10.3233/JAD-191139

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Xiao, Zhenxu | Wu, Wanqing | Zhao, Qianhua | Liang, Xiaoniu | Luo, Jianfeng | Ding, Ding

Article Type: Research Article

Abstract: Background: Growing evidence has shown the association between ophthalmic disorders and the risk of cognitive decline, but the conclusions were inconsistent. Objective: This study aimed to verify the hypothesis that glaucoma or cataract or their combination is associated with incident dementia in Chinese older adults. Methods: We followed up 1,659 non-demented community residents aged ≥60 years for an average of 5.2 years in the Shanghai Aging Study. Histories of glaucoma and cataract were collected based on self-report and medical record confirmation. Consensus diagnoses of incident dementia and Alzheimer’s disease (AD) were made based on neurological and …neuropsychological assessments. Results: During the follow-up, 168 cases (10.1%) of incident dementia and 124 cases (7.5%) of incident AD were identified. Participants with glaucoma at baseline had a significant risk of incident dementia (hazard ratio [HR] = 2.38, 95% confidence interval [CI] 1.08–5.23) and incident AD (HR = 2.77, 95% CI 1.17–6.56) after adjusting for confounders. There was no association between cataract and incident dementia (HR = 1.23, 95% CI 0.85–1.79) or AD (HR = 1.14, 95% CI 0.73–1.77). Those who had both glaucoma and cataract were more likely to develop dementia (HR = 3.08, 95% CI 1.29–7.37) and AD (HR = 3.72, 95% CI 1.52–9.14), compared to those without ophthalmic conditions. Conclusion: Glaucoma is an independent risk factor of incident dementia and AD. The comorbidity of glaucoma and cataract may significantly increase the risk of dementia and AD. Show more

Keywords: Alzheimer’s disease, cohort studies, cataract, dementia, glaucoma, ophthalmology

DOI: 10.3233/JAD-200295

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Lu, Hanna | for the Open Access Series of Imaging Studies

Article Type: Research Article

Abstract: Background: Cortical complexity plays a central role in the diagnosis and prognosis of age-related diseases. However, little is known about the regional cortical complexity in the context of brain atrophy. Objective: We aimed to systematically examine the age-related changes of the cortical complexity of left dorsolateral prefrontal cortex (DLPFC) and its subregions. Methods: Two hundred and fourteen cognitively normal adults drawn from the Open Access Series of Imaging Studies (OASIS) were divided into four age groups: young, middle-aged, young-old, and old-old. Based on structural magnetic resonance imaging (sMRI) scans, the multiscale measures of cortical complexity included …cortical thickness (mm), surface area (mm2 ), grey matter volume (mm3 ), density, gyrification index (GI), and fractal dimension (FD). Results: Advancing age was associated with reduced grey matter volume, pial surface area, density, and FD of left DLPFC, but correlated with increased cortical thickness and GI. Volumetric measures, cerebrospinal fluid volume in particular, showed better performance to discriminate young-old adults from old-old adults, while FD was more sensitive than the volumetric measures to discriminate young adults and middle-aged adults than the other measures. Conclusion: This is the first demonstration that chronological age has a pronounced and differential effect on the cortical complexity of left DLPFC. Our findings suggest that surface-based measures of cortical region, thickness, and gyrification in particular, could be considered as valuable imaging markers for the studies of aging brain and neurodegenerative diseases. Show more

Keywords: Cortical complexity, cortical thickness, dorsolateral prefrontal cortex, folding, fractal dimension, grey matter, gyrification

DOI: 10.3233/JAD-200102

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Marston, Louise | Livingston, Gill | Laybourne, Anne | Cooper, Claudia

Article Type: Short Communication

Abstract: Care home residents with dementia often have accompanying agitation. We investigated agitation’s course at 5 time-points in 1,424 people with dementia over 16 months in 86 English care homes. We categorized baseline agitation symptoms on the Cohen-Mansfield Agitation Inventory (CMAI) into none (CMAI = 29; 15%), subclinical (CMAI = 30–45; 45%), or clinically-significant (CMAI > 45; 40%). 88% of those with no agitation at baseline remained free of clinically-significant agitation at all follow-ups. Seventy percent of those exhibiting clinically-significant agitation at baseline had clinically-significant agitation at some follow-ups. Over a 16-month observation period, this study finds many care home residents with dementia never develop clinically significant …agitation and interventions should be for treatment not prevention. Show more

Keywords: Agitation, dementia, neuropsychiatric symptoms, nursing homes

DOI: 10.3233/JAD-191195

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Motta, Caterina | Finardi, Annamaria | Toniolo, Sofia | Di Lorenzo, Francesco | Scaricamazza, Eugenia | Loizzo, Stefano | Mercuri, Nicola Biagio | Furlan, Roberto | Koch, Giacomo | Martorana, Alessandro

Article Type: Research Article

Abstract: Background: Neuroinflammatory cytokines can play a pivotal role in Alzheimer’s disease (AD) contributing to the evolution of degenerative processes. Objective: We aimed at evaluating the levels of cerebrospinal fluid (CSF) inflammatory cytokines, chemokines, and growth factors in subjects with diagnosis of amnestic mild cognitive impairment and mild AD. Methods: We evaluated CSF contents of inflammatory cytokines in 66 patients divided according to the NIA-AA research framework and the APOE genotype. CSF of a group of cognitively unimpaired individuals (n  = 23) was evaluated as control. All patients were evaluated for 24 months using Mini-Mental State Examination …(MMSE). Results: We found significant increased levels of IL-4, IL-6, IL-8, and G-CSF in the CSF of A+/T–APOE4 carriers, respect to A+/T–patients homozygous for APOE3 , respect to A+/T+ patients, regardless the APOE status, and respect to controls. Over a period of 24 months, A+/T–APOE4 carriers, with increased levels of cytokines, showed a preserved cognitive evaluation when compared to the other subgroups of patients (delta MMSE at 24 months respect to baseline: 0.10±0.35; p  < 0.05). Conclusion: Our data suggest that during early phases of AD, in APOE4 carriers, Aβ pathology likely induces a specific cytokines pattern synthesis associated to cognitive preservation. These data highlight the different role that neuroinflammation can play in AD pathology based on the presence of specific CSF biomarkers and on the APOE status. Show more

Keywords: Amyloid-β 42, APOE , cognitive decline, G-CSF, interleukins, tau

DOI: 10.3233/JAD-191250

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Cerami, Chiara | Dodich, Alessandra | Iannaccone, Sandro | Magnani, Giuseppe | Marcone, Alessandra | Guglielmo, Priscilla | Vanoli, Giovanna | Cappa, Stefano F. | Perani, Daniela

Article Type: Research Article

Abstract: Background: Corticobasal syndrome (CBS) is the usual clinical presentation of patients with corticobasal degeneration pathology. Nevertheless, there are CBS individuals with postmortem neuropathology typical of Alzheimer’s disease (AD). Objective: In this study, we aim to detect FDG-PET metabolic signatures at the single-subject level in a CBS sample, also evaluated with cerebrospinal fluid (CSF) markers for AD pathology. Methods: 21 patients (68.9±6.4 years; MMSE score = 21.7±6.3) fulfilling current criteria for CBS were enrolled. All underwent a clinical-neuropsychological assessment and an instrumental evaluation for biomarkers of neurodegeneration, amyloid and tau pathology (i.e., FDG-PET imaging and CSF Aβ42 and …tau levels) at close intervals. CBS subjects were classified according to the presence or absence of CSF markers of AD pathology (i.e., low Aβ42 and high phosphorylated tau levels). Optimized voxel-based SPM procedures provided FDG-PET metabolic patterns at the single-subject and group levels. Results: Eight CBS had an AD-like CSF profile (CBS-AD), while thirteen were negative (CBS-noAD). The two subgroups did not differ in demographic characteristics or global cognitive impairment. FDG-PET SPM t-maps identified different metabolic signatures. Namely, all CBS-AD patients showed the typical AD-like hypometabolic pattern involving posterior cingulate cortex, precuneus and temporo-parietal cortex, whereas CBS-noAD cases showed bilateral hypometabolism in fronto-insular cortex and basal ganglia that is typical of the frontotemporal lobar degeneration spectrum. Discussion: These results strongly suggest the inclusion of FDG-PET imaging in the diagnostic algorithm of individuals with CBS clinical phenotype in order to early identify functional metabolic signatures due to different neuropathological substrates, thus improving the diagnostic accuracy. Show more

Keywords: Alzheimer’s disease, corticobasal degeneration, corticobasal syndrome, FDG-PET, positron emission tomography

DOI: 10.3233/JAD-200153

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2020

Authors: Wood, Ryan M. | Garcia, Zacnite | Daniels, Nathan | Landon, Shannon M. | Humayun, Saima | Lee, Hyoung-gon | Macpherson, Lindsey J.

Article Type: Research Article

Abstract: Background: Previous studies indicate that taste dysfunction occurs early in the development of Alzheimer’s disease. It is debatable whether the deficit in taste is due primarily to peripheral sensory mechanisms or to central processing, or a combination of the two. Objective: The aim of our current study is to combine behavior and histological data in APP/PS1 transgenic mice to determine whether APP/PS1 transgenic mice show deficits in unconditioned taste preference and avoidance behaviors and whether taste impairments are due to defects in the peripheral taste system and/or problems with central processing of taste information. Methods: The …APP/PS1 transgenic mutant mice were used as a model of Alzheimer’s disease. We employed a brief-access gustometer test to assess immediate orosensory taste responses of APP/PS1 mice. We used immunohistochemistry to examine tongue, gustatory ganglion, and brain tissues to determine a cytological basis for behavioral deficits. Results: There is a significant, selective reduction of bitter taste sensitivity in APP/PS1 mice. These mice also have a loss of TRPM5-expressing taste receptor cells in the circumvallate papillae of the tongue. While we observed no overt loss of neuron cell bodies within the primary gustatory sensory neurons, degeneration of the neurons’ peripheral axons innervating the taste bud may play a role in the observed loss of TRPM5-expressing taste receptor cells. Conclusion: This data supports a potential role for peripheral taste dysfunction in AD through the selective loss of taste receptor cells. Further study is necessary to delineate the mechanisms and pathological significance of this deficit in AD. Show more

Keywords: APP/PS1 mutant, taste dysfunction, taste receptor cells

DOI: 10.3233/JAD-200376

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Iriondo, Ane | García-Sebastian, Maite | Arrospide, Arantzazu | Arriba, Maria | Aurtenetxe, Sara | Barandiaran, Myriam | Clerigue, Montserrat | Ecay-Torres, Mirian | Estanga, Ainara | Gabilondo, Alazne | Izagirre, Andrea | Saldias, Jon | Tainta, Mikel | Villanua, Jorge | Blennow, Kaj | Zetterberg, Henrik | Mar, Javier | Abad-García, Beatriz | Dias, Irundika H.K. | Goñi, Felix M. | Martínez-Lage, Pablo

Article Type: Research Article

Abstract: Background: Abnormal cholesterol metabolism changes the neuronal membrane and may promote amyloidogenesis. Oxysterols in cerebrospinal fluid (CSF) are related to Alzheimer’s disease (AD) biomarkers in mild cognitive impairment and dementia. Cholesterol turnover is important for axonal and white matter (WM) microstructure maintenance. Objective: We aim to demonstrate that the association of oxysterols, AD biomarkers, and WM microstructure occurs early in asymptomatic individuals. Methods: We studied the association of inter-individual variability of CSF 24-hydroxycholesterol (24-OHC), 27-hydroxycholesterol (27-OHC), 7-ketocholesterol (7-KC), 7β-hydroxycholesterol (7β-OHC), amyloid-β42 (Aβ42 ), total-tau (t-tau), phosphorylated-tau (p-tau), neurofilament (NfL), and WM microstructure using diffusion tensor …imaging, generalized linear models and moderation/mediation analyses in 153 healthy adults. Results: Higher 7-KC levels were related to lower Aβ42 , indicative of greater AD pathology (p  = 0.041) .  Higher 7-KC levels were related to lower fractional anisotropy (FA) and higher mean (MD), axial (AxD), and radial (RD) diffusivity. 7-KC modulated the association between AxD and NfL in the corpus callosum splenium (B  = 39.39, p  = 0.017), genu (B  = 68.64, p  = 0.000), and fornix (B  = 10.97, p  = 0.000). Lower Aβ42 levels were associated to lower FA and higher MD, AxD, and RD in the fornix, corpus callosum, inferior longitudinal fasciculus, and hippocampus. The association between AxD and Aβ42 was moderated by 7K-C (p  = 0.048). Conclusion: This study adds clinical evidence to support the role of 7K-C on axonal integrity and the involvement of cholesterol metabolism in the Aβ42 generation process. Show more

Keywords: Amyloid-β , cerebrospinal fluid, diffusion tensor imaging, oxysterols, white matter

DOI: 10.3233/JAD-200105

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2020

Authors: Hernandes-Alejandro, Mario | Montaño, Sarita | Harrington, Charles R. | Wischik, Claude M. | Salas-Casas, Andrés | Cortes-Reynosa, Pedro | Pérez Salazar, Eduardo | Cazares-Apatiga, Javier | Apatiga-Perez, Ricardo | Ontiveros Torres, Miguel Ángel | Perry, George | Pacheco-Herrero, Mar | Luna-Muñoz, José

Article Type: Research Article

Abstract: Background: Neurofibrillary tangles (NFTs) and amyloid plaques are the neuropathological hallmarks in brains with Alzheimer’s disease (AD). Post-translational modifications of tau, such as phosphorylation and truncation, have been proposed as initiators in the assembly of the abnormal paired helical filaments that constitute the NFTs. Neurons and NFTs are sites of matrix metalloproteinases (MMPs). Objective: The aim of this study was to analyze the relationship of MMP-9 and tau protein in brain samples with AD. Methods: This study was performed on brain tissue samples from patients with early, moderate, and late AD. MMPs and tau levels were …analyzed by western blot and gelatin-substrate zymography. Immunofluorescence techniques and confocal microscopy were used to analyze the presence of both proteins in NFTs. Further, molecular dynamics simulations (MDS) and protein-protein docking were conducted to predict interaction between MMP-9 and tau protein. Results: MMP-9 expression was greatest in moderate and late AD, whereas MMP-2 expression was only increased in late-stage AD. Interestingly, confocal microscopy revealed NFTs in which there was co-localization of MMP-9 and tau protein. MDS and protein-protein docking predictions indicate that a high-affinity complex can be formed between MMP-9 and full-length tau protein. Conclusion: These observations provide preliminary evidence of an interaction between these two proteins. Post-translational modifications of tau protein, such as C-terminal truncation or phosphorylation of amino acid residues in the MMP-9 recognition site and conformational changes in the protein, such as folding of the N-terminal sequence over the three-repeat domain, could preclude the interaction between MMP-9 and tau protein during stages of NFT development. Show more

Keywords: Alzheimer’s disease, matrix metalloproteinase-9, molecular dynamics simulation, protein-protein docking, tau protein

DOI: 10.3233/JAD-200146

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2020

Authors: Isaacs-Trepanier, Cameron | Saleem, Mahwesh | Herrmann, Nathan | Swardfager, Walter | Oh, Paul I. | Goldstein, Benjamin I. | Mitchell, Jane | Sugamori, Kim S. | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Patients with coronary artery disease have an increased risk for developing vascular cognitive impairment. Endothelial function is often diminished and has been associated with lower cognitive performance in these patients. The link between endothelial function and cognition in coronary artery disease is not fully understood. Angiogenesis may play a role in mediating the association between endothelial function and cognition since angiogenic processes rely heavily on the endothelium. Objective: The aim of this study was to determine if markers of angiogenesis mediate the relationship between endothelial function and cognition in coronary artery disease patients. Methods: In …50 participants with coronary artery disease, endothelial function was assessed using peripheral arterial tonometry. Vascular endothelial growth factor (pro-angiogenic) and endostatin (anti-angiogenic) were measured in peripheral serum samples. Cognition was assessed using the Montreal Cognitive Assessment. A mediation analysis, using a bias corrected inferential bootstrapping method with 10,000 permutations, was used to determine if vascular endothelial growth factor or endostatin mediated an association between peripheral arterial tonometry measures and cognitive performance on the Montreal Cognitive Assessment. Results: Endostatin, but not vascular endothelial function, mediated a relationship between endothelial function and cognitive performance when controlling for total years of education, body mass index, coronary artery bypass graft, stent, diabetes, and diuretic use. This analysis was also significant when delayed recall was substituted for the overall score on the Montreal Cognitive Assessment. Conclusion: These results suggest that endostatin mediates an association between endothelial function and cognitive performance in coronary artery disease. Show more

Keywords: Cognition, cognitive dysfunction, coronary artery disease, endothelium, endostatin, vascular endothelial growth factor

DOI: 10.3233/JAD-200058

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Fowler, Mackenzie E. | Triebel, Kristen L. | Cutter, Gary R. | Schneider, Lon S. | Kennedy, Richard E. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Cross-sectional studies suggest self-reported cancer history is associated with decreased risk of Alzheimer’s disease (AD). However, little is known about how self-reported cancer affects longitudinal AD progression, the primary outcome in clinical trials and observational studies. Objective: To determine self-reported cancer history’s effect on longitudinal AD progression in an observational study. Methods: We utilized data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate progression to AD by self-reported all-cancer, breast, prostate, colorectal, or non-melanoma skin cancer history. Linear mixed effects models were used to examine baseline differences and rates of progression on the Alzheimer’s …Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) by self-reported cancer history. Age at AD onset was examined using consensus clinical diagnoses with Cox proportional hazards regression. Results: Among 1,271 participants, models revealed no significant differences in progression over time but did reveal significantly lower baseline ADAS-Cog score, indicating better cognition at a given age in those with self-reported cancer history. Cox models indicated those with self-reported cancer history had significantly later age of AD onset (HR: 0.67, 95% CI: 0.53–0.85) after adjustment for covariates. Conclusion: Participants with self-reported cancer history entered ADNI with better cognition and later age of AD onset, but progressed similarly to participants without such history, indicating differences in AD between those with and without self-reported cancer history emerge early in the disease course. Such differences in longitudinal progression by self-reported cancer history could affect AD trials and observational studies, given the current focus on early disease course. Further investigation is warranted with detailed longitudinal assessment of cancer and AD. Show more

Keywords: Alzheimer’s disease, cancer, cognitive impairment, disease progression, mild cognitive impairment

DOI: 10.3233/JAD-200108

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Piamonte, Bernadeth Lyn C. | Espiritu, Adrian I. | Anlacan, Veeda Michelle M.

Article Type: Research Article

Abstract: Background: A critical strategy in the management of Alzheimer’s disease (AD) is optimizing the effects of currently available pharmacologic therapies such as citicoline (CC). Objective: The purpose of this study was to determine the effects of CC as adjunct therapy to cholinesterase inhibitors (AChEI) in the treatment of AD. Methods: We identified relevant studies by electronic search until April 2020. We considered studies with a comparator group that enrolled elderly patients with a diagnosis of AD and employed CC as an adjunct therapy to AChEIs compared to AChEI monotherapy or comparisons of different AChEIs combined with …CC. Methodological quality assessment was done using the Newcastle-Ottawa Scale. Results: Out of 149 articles identified, two retrospective cohort studies involving 563 elderly patients affected with AD were included. After 3 months and 9 months, better Mini-Mental Status Examination scores were observed in the “AChEIs + CC” group versus “AChEIs alone” group. CC combined with donepezil may be better in improving cognition than when combined with rivastigmine. No significant difference was noted in terms of activities of daily living (ADL) and instrumental-ADL. Neuropsychiatric Inventory and Geriatric Depression Scale-short form scores appeared to be lower in the combination treatment versus monotherapy. The adverse events of combined treatment were self-limiting and included occasional excitability, gastric intolerance, and headache. Conclusion: Limited evidence from pooled data of two observational studies suggests that CC used in adjunct with AChEIs in the treatment of AD was well-tolerated and showed improvement in cognition, mood, and behavioral symptoms compared to treating with AChEIs alone. Show more

Keywords: Alzheimer’s disease, cholinesterase inhibitors, citicoline, systematic review

DOI: 10.3233/JAD-200378

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2020

Authors: Fazlollahi, Amir | Raniga, Parnesh | Bourgeat, Pierrick | Yates, Paul | Bush, Ashley I. | Salvado, Olivier | Ayton, Scott

Article Type: Research Article

Abstract: Background: Cortical iron accumulation has been reported as a pathological feature of Alzheimer’s disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. Objective: To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. Methods: 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI …technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. Results: 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. Conclusion: The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex. Show more

Keywords: Alzheimer’s disease, cerebral microbleeds, iron, magnetic resonance imaging, quantitative susceptibility mapping

DOI: 10.3233/JAD-200076

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2020

Authors: Staekenborg, Salka S. | Kelly, Naomi | Schuur, Jacqueline | Koster, Pieter | Scherder, Erik | Tielkes, Caroline E.M. | Scheltens, Philip | Claus, Jules J.

Article Type: Research Article

Abstract: Background: The role of cognitive reserve (CR) to explain individual differences in cognitive functioning is unclear in memory clinic patients. Objective: To examine the cross-sectional effect of CR on cognition in relation to levels of neurodegeneration in a large elderly single-center memory clinic population. Methods: We included patients with subjective cognitive impairment (SCI, n  = 481), mild cognitive impairment (MCI, n  = 628) or Alzheimer’s disease (AD, n  = 1,099). Education was used as proxy for CR and visually rated medial temporal lobe atrophy (MTA) on CT was used as parameter of neurodegeneration. Relations between CR, cognition, and MTA …were analyzed with multiple linear regression adjusted for age, sex, and cerebral atrophy. In addition, we examined if education affects the relation between MTA and cognition using an interaction variable. Results: Education was significantly related to all measures of cognition including subtests with an explained variance of education as a determinant of cognition of 11%. More highly educated patients had more advanced levels of MTA at the same level of cognition. All these results were stronger or only present in demented compared to non-demented patients but appeared no longer significant in those with lowest overall cognition. The interaction effect was significant indicating that with more advanced MTA, less cognitive decline was shown in higher educated patients. Conclusion: Education is a very strong determinant of cognition in an elderly memory clinic population. The positive effect of education was stronger in demented than in non-demented patients but disappeared in those with the lowest cognitive scores indicating a “window of CR benefit”. Show more

Keywords: Cognitive reserve, dementia, education, medial temporal lobe atrophy, memory clinic

DOI: 10.3233/JAD-191332

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Barthold, Douglas | Joyce, Geoffrey | Ferido, Patricia | Drabo, Emmanuel F. | Marcum, Zachary A. | Gray, Shelly L. | Zissimopoulos, Julie

Article Type: Research Article

Abstract: Background: Four prescription drugs (donepezil, galantamine, memantine, and rivastigmine) are approved by the US FDA to treat symptoms of Alzheimer’s disease (AD). Even modest effectiveness could potentially reduce the population-level burden of AD and related dementias (ADRD), especially for women and racial/ethnic minorities who have higher incidence of ADRD. Objective: Describe the prevalence of antidementia drug use and timing of initiation relative to ADRD diagnosis among a nationally representative group of older Americans, and if there are disparities in prevalence and timing by sex and race/ethnicity. Methods: Descriptive analyses and logistic regressions of Medicare claims (2008–2016) …for beneficiaries who had an ADRD or dementia-related symptom diagnosis, or use of an FDA approved drug for AD. We investigate prevalence of use and timing of treatment initiation relative to ADRD diagnosis across time and beneficiary characteristics (age, sex, race/ethnicity, socioeconomic status, comorbidities). Results: Among persons diagnosed with ADRD or related symptoms, 33.3% used an approved drug over the study period. Odds of use was higher among Whites than non-Whites. Among ADRD drug users, 40% initiated use within 6 months of the initial ADRD or related symptoms diagnosis, and 16% initiated prior to a diagnosis. We observed disparities by race/ethnicity: 28% of Asians, 24% of Hispanics, 16% of Blacks, and 15% of Whites initiated prior to diagnosis. Conclusions: The use of antidementia drugs is relatively low and varies widely by race/ethnicity. Heterogeneity in timing of initiation and use may affect health and cost outcomes, but these effects merit further study. Show more

Keywords: Acetylcholinesterase inhibitors, Alzheimer’s disease and related dementias, disparities, donepezil, galantamine, memantine, rivastigmine

DOI: 10.3233/JAD-200133

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Haghani, Amin | Morgan, Todd E. | Forman, Henry Jay | Finch, Caleb E.

Article Type: Research Article

Abstract: Epidemiological studies are associating elevated exposure to air pollution with increased risk of Alzheimer’s disease and other neurodegenerative disorders. In effect, air pollution accelerates many aging conditions that promote cognitive declines of aging. The underlying mechanisms and scale of effects remain largely unknown due to its chemical and physical complexity. Moreover, individual responses to air pollution are shaped by an intricate interface of pollutant mixture with the biological features of the exposed individual such as age, sex, genetic background, underlying diseases, and nutrition, but also other environmental factors including exposure to cigarette smoke. Resolving this complex manifold requires more detailed …environmental and lifestyle data on diverse populations, and a systematic experimental approach. Our review aims to summarize the modest existing literature on experimental studies on air pollution neurotoxicity for adult rodents and identify key gaps and emerging challenges as we go forward. It is timely for experimental biologists to critically understand prior findings and develop innovative approaches to this urgent global problem. We hope to increase recognition of the importance of air pollution on brain aging by our colleagues in the neurosciences and in biomedical gerontology, and to support the immediate translation of the findings into public health guidelines for the regulation of remedial environmental factors that accelerate aging processes. Show more

Keywords: Air pollution, Alzheimer’s disease, rodent models, O3 , particulate matter

DOI: 10.3233/JAD-200377

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-25, 2020

Authors: Beam, Christopher R. | Kaneshiro, Cody | Jang, Jung Yun | Reynolds, Chandra A. | Pedersen, Nancy L. | Gatz, Margaret

Article Type: Research Article

Abstract: Background: While sex differences in incidence of Alzheimer’s disease (AD) and potential explanations have received considerable attention, less attention has been paid to possible sex differences in genetic risk for AD. Objective: We examined sex differences in genetic and environmental influences on disease risk and age at onset for All Dementia, AD Only, and Non-AD Dementia. Methods: Twin pairs were drawn from the Swedish Twin Registry. All Dementia analysis included 9,467 pairs; AD only, 8,696 pairs; and non-AD dementia, 8,195 pairs. APOE analyses included 1,923 individual twins with measured ɛ 4 alleles. Dementia diagnoses were …based on clinical workup and national health registry linkage. Results: Although within-pair correlations for All Dementia and AD Only were higher for women than for men, sex differences did not statistically differ for genetic or environmental etiology of All Dementia, AD Only, and Non-AD dementia. Similar results were observed when looking at specific genetic effects (APOE ɛ 4). Co-twin control analyses indicated that among twin pairs discordant for dementia, female twins without dementia had approximately 40% greater risk of developing dementia, compared with their male counterparts, in the 2–5 years following the first twin’s diagnosis. Conclusion: For All Dementia, AD Only, and Non-AD Dementia, genetic influences could be equated across sex. Co-twin analyses, however, suggest greater risk to female than to male co-twins of dementia cases even though sex differences in either genetic or shared environmental influences on the risk of dementia could not be differentiated. Show more

Keywords: Alzheimer’s disease, ApoE ɛ4, sex differences, twin studies

DOI: 10.3233/JAD-191192

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Lv, Ling-Li | Liu, Bo | Liu, Jing | Li, Li-Sheng | Jin, Feng | Xu, Yun-Yan | Wu, Qin | Liu, Jie | Shi, Jing-Shan

Article Type: Research Article

Abstract: Background: Dendrobium nobile is a well-known traditional Chinese herbal medicine used for age-related diseases. Dendrobium nobile Lindl alkaloid (DNLA) is the active ingredient to improve learning and memory deficits in laboratory animals. Objective: The aim of the present study was to examine the anti-aging effects of long-term administration of DNLA and metformin during the aging process in senescence-accelerated mouse-prone 8 (SAMP8) mice. Methods: SAMP8 mice were orally given DNLA (20 and 40 mg/kg) or metformin (80 mg/kg) starting at 6 months of age until 12 months of age. Age-matched SAMR1 mice were used as controls. DNLA …and metformin treatments ameliorated behavioral deficits of 12-month-old SAMP8 mice, as determined by Rotarod, Y-maze, and Open-field tests. Results: DNLA and metformin treatments prevented brain atrophy and improved morphological changes in the hippocampus and cortex, as evidenced by Nissl and H&E staining for neuron damage and loss, and by SA-β -gal staining for aging cells. DNLA and metformin treatments decreased amyloid-β 1–42 , Aβ PP, PS1, and BACE1, while increasing IDE and neprilysin for Aβ clearance. Furthermore, DNLA and metformin enhanced autophagy activity by increasing LC3-II, Beclin1, and Klotho, and by decreasing p62 in the hippocampus and cortex. Conclusion: The beneficial effects of DNLA were comparable to metformin in protecting against aging-related cognitive deficits, neuron aging, damage, and loss in SAMP8 mice. The mechanisms could be attributed to increased Aβ clearance, activation of autophagy activity, and upregulation of Klotho. Show more

Keywords: Aging, amyloid-β , autophagy, Dendrobium nobile Lindl alkaloid (DNLA), metformin, senescence accelerated mouse prone 8 (SAMP8)

DOI: 10.3233/JAD-200308

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-13, 2020

Authors: Prieto, Sarah | Valerio, Kate E. | Moody, Jena N. | Hayes, Scott M. | Hayes, Jasmeet P. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: A complex set of interactions between biological, genetic, and environmental factors likely underlies the development of Alzheimer’s disease (AD). Identifying which of these factors is most associated with AD is important for early diagnosis and treatment. Objective: We sought to examine genetic risk and structural brain volume on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD. Methods: 686 adults (55–91 years old) completed a 3T MRI scan, baseline cognitive assessments, and biospecimen collection through the Alzheimer’s Disease Neuroimaging Initiative. Hierarchical linear regression analyses examined main and …interaction effects of medial temporal lobe (MTL) volume and polygenic hazard score (PHS), indicating genetic risk for AD, on a validated episodic memory composite score. Results: Genetic risk moderated the relationship between MTL volume and memory, such that individuals with high PHS and lower hippocampal and entorhinal volume had lower memory composite scores [Δ F (1,677) = 4.057, p  = 0.044, Δ R2  = 0.002]. Further analyses showed this effect was driven by the left hippocampus [Δ F (1,677) = 5.256, p  = 0.022, Δ R 2  = 0.003] and right entorhinal cortex [Δ F (1,677) = 6.078, p  = 0.014, Δ R 2  = 0.003]. Conclusions: Among those with high genetic risk for AD, lower volume was associated with poorer memory. Results suggest that the interaction between AD genetic risk and MTL volume increases the likelihood for memory impairment among older adults. Results from this study suggest that genetic risk and brain volume should be considered key factors in tracking cognitive decline. Show more

Keywords: Alzheimer’s disease, atrophy, entorhinal cortex, episodic memory, hippocampus, medial temporal lobe, polygenic risk

DOI: 10.3233/JAD-191312

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2020

Authors: Panzarella, Vera | Mauceri, Rodolfo | Baschi, Roberta | Maniscalco, Laura | Campisi, Giuseppina | Monastero, Roberto

Article Type: Research Article

Abstract: Background: The relationship between Alzheimer’s disease (AD) and periodontitis has been recently investigated with heterogenous results. Objective: This study aims to evaluate the oral health status and its relationship with cognitive impairment of participants, enrolled in the Zabút Aging Project, a community-based cohort study performed in rural community in Sicily, Italy. Methods: A case-control study (20 subjects with AD, 20 with amnestic mild cognitive impairment (aMCI), and 20 controls) was conducted. The protocol included a comprehensive medical and cognitive-behavioral examination. Full-mouth evaluation, microbial analysis of subgingival plaque samples (by RT-PCR analysis), and oral health-related quality …of life (OHR-QoL) were evaluated. Results: The decayed, missing, and filled teeth (DMFT) total score of AD subjects was significantly higher than for aMCI (p  = 0.009) and controls (p  = 0.001). Furthermore, the “M” component of DMFT (i.e., the number of missing teeth) was significantly higher in AD than in aMCI (p  < 0.001) and controls (p  < 0.001). A Poisson regression model revealed that age (p  < 0.001), male gender (p  = 0.001), and AD (p  = 0.001) were positively correlated with DMFT. Concerning oral microbial load, the presence of Fusobacterium nucleatum was significantly higher in AD than in controls (p  = 0.02), and a higher load of Treponema denticola was found in aMCI than with AD (p  = 0.004). OHR-QoL scores did not differ among the groups. Conclusion: The current research suggests that AD is associated with chronic periodontitis, which is capable of determining tooth loss due to the pathogenicity of Fusobacterium nucleatum . These data remain to be confirmed in larger population-based cohorts. Show more

Keywords: Alzheimer’s disease, cognitive impairment, epidemiology, oral health, periodontitis, tooth loss

DOI: 10.3233/JAD-200385

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Cai, Hong-Bin | Fan, Zhen-Zhen | Tian, Ting | Li, Zi-Chao | Zhao, Chon-Chon | Guo, Wen-Ting | Ge, Zhao-Ming

Article Type: Research Article

Abstract: The connection between diabetes and Alzheimer’s disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and normal diet-fed, the STZ + HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation …of H3K9 histone on CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter. Show more

Keywords: Alzheimer’s disease, cyclin-dependent kinase-5, diabetes, GCN5, H3K9 hyperacetylation, tau

DOI: 10.3233/JAD-200163

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-1, 2020

Authors: Li, Naiyan | Wang, Gang | Lu, Huarong

Article Type: Research Article

Abstract: Many cardiovascular disorders are predisposing factors for Alzheimer’s disease (AD), but the effects of early myocardial infarction (MI) on future development of AD are not well determined. Here, we performed MI on two different AD models in mice, APP/PS1 and rTg4510, which mimicked the plaque formation by amyloid-β peptide aggregates (Aβ) and neurofibrillary tangle formation by phosphorylated Tau (pTau), respectively. In both strains, we detected increased deposit of Aβ or formation of pTau, increased loss of neurons, and poorer performance in behavior tests including a Morris water maze test for spatial reference memory and a locomotion test for motor activity …in mice that had received MI, compared to mice that had been sham operated. Moreover, in a cohort of selected patients, we found that patients with previous MI had more chances to develop AD in the future. Together, our data suggest that the chances to develop AD may increase after MI. Show more

Keywords: Key words: Alzheimer’s disease, amyloid-β peptide aggregates, myocardial infarction, phosphorylated tau

DOI: 10.3233/JAD-200068

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2020

Authors: Jin, Jing | Guo, Jia | Cai, Hongbin | Zhao, Chongchong | Wang, Huan | Liu, Zhiyan | Ge, Zhao-Ming

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, microglia polarization, neuropathic pain, shDNMT1

DOI: 10.3233/JAD-200099

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Portacolone, Elena | Halpern, Jodi | Luxenberg, Jay | Harrison, Krista L. | Covinsky, Kenneth E.

Article Type: Review Article

Abstract: Due to the high costs of providing long-term care to older adults with cognitive impairment, artificial companions are increasingly considered as a cost-efficient way to provide support. Artificial companions can comfort, entertain, and inform, and even induce a sense of being in a close relationship. Sensors and algorithms are increasingly leading to applications that exude a life-like feel. We focus on a case study of an artificial companion for people with cognitive impairment. This companion is an avatar on an electronic tablet that is displayed as a dog or a cat. Whereas artificial intelligence guides most artificial companions, this application …also relies on technicians “behind” the on-screen avatar, who via surveillance, interact with users. This case is notable because it particularly illustrates the tension between the endless opportunities offered by technology and the ethical issues stemming from limited regulations. Reviewing the case through the lens of biomedical ethics, concerns of deception, monitoring and tracking, as well as informed consent and social isolation are raised by the introduction of this technology to users with cognitive impairment. We provide a detailed description of the case, review the main ethical issues and present two theoretical frameworks, the “human-driven technology” platform and the emancipatory gerontology framework, to inform the design of future applications. Show more

Keywords: Dementia, ethics, robots, technology

DOI: 10.3233/JAD-190952

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2020

Authors: Marino Gammazza, Antonella | Restivo, Vincenzo | Baschi, Roberta | Caruso Bavisotto, Celeste | Cefalù, Angelo B. | Accardi, Giulia | Conway de Macario, Everly | Macario, Alberto J.L. | Cappello, Francesco | Monastero, Roberto

Article Type: Research Article

Abstract: Molecular chaperones play essential roles in many processes such as cell differentiation, tissue homeostasis, and organ remodeling. Recent data indicate that chaperones can act as cytoprotectants for brain cells during the progression of neurodegenerative diseases, including Alzheimer’s disease (AD). However, very few data on the levels of chaperones in dementia, including its prodromal phases, have been reported. In this study, we used biological samples and epidemiological data collected during the Zabùt Aging Project (a prospective, community-based, cohort study of normal/pathological aging conducted in Sicily, Italy, with a follow-up of ten years) to determine if there is an association between plasma …levels of the chaperones Hsp60, Hsp70, and Hsp90 with amnestic mild cognitive impairment (aMCI) and AD. Twenty-six aMCI individuals, 26 AD and 26 controls, matched for age and sex, were enrolled. After adjustment for education subjects with AD showed significantly higher levels of Hsp60 than aMCI (OR = 1.16, 95% CI 1.04–1.30) and controls (OR = 1.12, 95% CI 1.03–1.22), while Hsp70 was significantly higher only in AD (OR = 1.84, 95% CI 1.09–3.10) than controls. In contrast, circulating levels of Hsp90 were significantly diminished in aMCI (OR = 0.69, 95% CI 0.52–0.91) and AD (OR = 0.51, 95% CI 0.35–0.75) compared to controls. However, these results were no longer significant after adjustment for multiple comparisons. Although the results lost significance after adjustment for multiple comparisons, they are encouraging despite the smallness of the sample and new studies should be carried out with larger populations to determine to what extent sequential measurement of serum chaperones in aMCI and AD can be trusted as indicators of disease status and progression. Show more

Keywords: Alzheimer’s disease, cognitive impairment, Hsp60, Hsp70, Hsp90, molecular chaperones, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-180825

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