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

Authors: Hack, Erica E. | Dubin, Joel A. | Fernandes, Myra A. | Costa, Sanduni M. | Tyas, Suzanne L.

Article Type: Research Article

Abstract: Background: Multilingualism is associated with enhanced executive function and may thus prevent cognitive decline and reduce the risk of dementia. Objective: To determine whether multilingualism is associated with delayed onset or reduced risk of dementia. Methods: Dementia was diagnosed according to DSM-IV criteria in the Nun Study, a longitudinal study of religious sisters aged 75+ years. Multilingualism was self-reported. Dementia likelihood was determined in 325 participants using discrete-time survival analysis; sensitivity analyses (n  = 106) incorporated additional linguistic measures (idea density and grammatical complexity). Results: Multilingualism did not delay the onset of dementia. However, participants …speaking four or more languages (but not two or three) were significantly less likely to develop dementia than monolinguals (OR = 0.13; 95% CI = 0.01, 0.65, adjusted for age, apolipoprotein E, and transition period). This significant protective effect of speaking four or more languages weakened (OR = 0.53; 95% CI = 0.06, 4.91) in the presence of idea density in models adjusted for education and apolipoprotein E. Conclusion: Linguistic ability broadly was a significant predictor of dementia, although it was written linguistic ability (specifically idea density) rather than multilingualism that was the strongest predictor. The impact of language on dementia may extend beyond number of languages spoken to encompass other indicators of linguistic ability. Further research to identify the characteristics of multilingualism most salient for risk of dementia could clarify the value, target audience, and design of interventions to promote multilingualism and other linguistic training as a strategy to reduce the risk of dementia and its individual and societal impacts. Show more

Keywords: Cognitive reserve, cohort studies, dementia, epidemiology, language, multilingualism, risk, survival analysis

DOI: 10.3233/JAD-181302

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Nudelman, Kelly N.H. | Lin, Jue | Lane, Kathleen A. | Nho, Kwangsik | Kim, Sungeun | Faber, Kelley M. | Risacher, Shannon L. | Foroud, Tatiana M. | Gao, Sujuan | Davis, Justin W. | Weiner, Michael W. | Saykin, Andrew J. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Although shorter telomeres have been associated with Alzheimer’s disease (AD), it is unclear whether longitudinal change in telomere length is associated with AD progression. Objective: To investigate the association of telomere length change with AD diagnosis and progression. Methods: In 653 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort, T/S ratio (telomere versus single copy gene), a proxy of telomere length, was measured for up to five visits per participant (N = 1918 samples post-QC) using quantitative PCR (qPCR). T/S ratio was adjusted for batch effects and DNA storage time. A mixed effects model was used …to evaluate association of telomere length with AD diagnostic group and interaction of age and diagnosis. Another mixed effects model was used to compare T/S ratio changes pre- to post-conversion to MCI or AD to telomere change in participants with stable diagnoses. Results: Shorter telomeres were associated with older age (Effect Size (ES) = –0.23) and male sex (ES = –0.26). Neither baseline T/S ratio (ES = –0.036) nor T/S ratio change (ES = 0.046) differed significantly between AD diagnostic groups. MCI/AD converters showed greater, but non-significant, telomere shortening compared to non-converters (ES = –0.186). Conclusions: Although AD compared to controls showed small, non-significant effects for baseline T/S ratio and T/S ratio shortening, we did observe a larger, though still non-significant effect for greater telomere shortening in converters compared to non-converters. Although our results do not support telomere shortening as a robust biomarker of AD progression, further investigation in larger samples and for subgroups of participants may be informative. Show more

Keywords: Alzheimer’s disease, longitudinal, progression, shortening, telomere

DOI: 10.3233/JAD-190010

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Jo, Hyunjin | Kim, Minkyeong | Park, Seongbeom | Park, Jong Eun | Cho, Soo Hyun | Kim, Seung Joo | Jang, Hyemin | Jung, Yong Hee | Kim, Junpyo | Na, Duk L. | Seo, Sang Won | Cho, Jin Whan | Kim, Hee Jin

Article Type: Short Communication

Abstract: Alzheimer’s disease patients with presenilin 1 (PSEN1 ) mutations commonly show parkinsonism in addition to dementia. Yet, whether these patients show dopaminergic deficit and response to L-dopa is largely unknown. We report a 43-year-old woman with a PSEN1 mutation (A434T) who showed right side dominant parkinsonism. As disease progressed, she developed bilateral parkinsonism which was markedly relieved by L-dopa. Amyloid (Florbetaben) positron-emission tomography (PET) showed cortical florbetaben uptake, relatively sparing the striatum. Initial dopamine transporter (FP-CIT) PET showed asymmetrically decreased FP-CIT uptake in the left striatum. We suggest that in Alzheimer’s disease patients with PSEN1 mutation, parkinsonism may …be relieved by L-dopa when it is associated with presynaptic dopaminergic deficit. Show more

Keywords: Alzheimer’s disease, FP-CIT PET, L-dopa, parkinsonism, presenilin 1

DOI: 10.3233/JAD-190469

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-6, 2019

Authors: Cullen, Stephanie | Borrie, Michael | Carroll, Susan | Sarquis-Adamson, Yanina | Pieruccini-Faria, Frederico | McKay, Scott | Montero-Odasso, Manuel

Article Type: Research Article

Abstract: Background: Poor dual-task gait (walking while performing a cognitively demanding task) has been linked to progression to dementia in older adults with mild cognitive impairment (MCI). However, many of these findings come from research environments; gait performance across the cognitive spectrum has not previously been studied in a clinical setting. Objective: To examine whether patients from a memory clinic show differences in usual and dual-task gait speed and dual-task cost (DTC) based on cognitive diagnosis. Methods: Patients in the Aging Brain Memory clinic (London, ON) performed a usual gait walk and three dual-task gait walks: counting …backwards by ones, naming animals, and counting backwards by seven (serial sevens) out loud. Patients were timed with a stopwatch over a six-meter path marked on the floor. One-way ANOVA was performed to evaluate associations between gait speed and DTC (% ) across groups. Results: One hundred ninety-four patients with subjective cognitive impairment (SCI; n  = 46), MCI (n  = 77), or dementia (n  = 71) were assessed. Performance in usual (p  <  0.001) and dual-task gait speed (counting gait p  <  0.001; naming animals p  <  0.001; serial sevens p  = 0.004) decreased across the spectrum of cognitive impairment. Patients with dementia had significantly higher DTC in both counting gait (p  = 0.02) and naming animals (p  = 0.04) conditions compared with patients with SCI and MCI, who had statistically similar DTC in all conditions. Conclusion: Dual-task gait performance significantly declines across the cognitive spectrum in a clinical setting. Dual-task gait testing may be used in conjunction with traditional assessments for diagnosing cognitive impairments. Show more

Keywords: Aging, cognition, dual-task gait, gait

DOI: 10.3233/JAD-181196

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Calderón-Garcidueñas, Lilian | Kulesza, Randy J. | Mansour, Yusra | Aiello-Mora, Mario | Mukherjee, Partha S. | González-González, Luis Oscar

Article Type: Research Article

Abstract: A major impediment in early diagnosis of Alzheimer’s disease (AD) is the lack of robust non-invasive biomarkers of early brain dysfunction. Metropolitan Mexico City (MMC) children and young adults show hyperphosphorylated tau, amyloid-β, and α -synuclein within auditory and vestibular nuclei and marked dysmorphology in the ventral cochlear nucleus and superior olivary complex. Based on early involvement of auditory brainstem centers, we believe brainstem auditory evoked potentials can provide early AD biomarkers in MMC young residents. We measured brainstem auditory evoked potentials in MMC clinically healthy children (8.52±3.3 years) and adults (21.08±3.0 years, 42.48±8.5 years, and 71.2±6.4 years) compared to …clean air controls (6.5±0.7 years) and used multivariate analysis adjusting for age, gender, and residency. MMC children had decreased latency to wave I, delays in waves III and V, and longer latencies for interwave intervals, consistent with delayed central conduction time of brainstem neural transmission. In sharp contrast, young adults have significantly shortened interwave intervals I–III and I–V. By the 5th decade, wave V and interval I–V were significantly shorter, while the elderly cohort had significant delay in mean latencies and interwave intervals. Compensatory plasticity, increased auditory gain, cochlear synaptopathy, neuroinflammation, and AD continuum likely play a role in the evolving distinct auditory pathology in megacity urbanites. Understanding auditory central and peripheral dysfunction in the AD continuum evolving and progressing in pediatric and young adult populations may shed light on the complex mechanisms of AD development and help identify strong noninvasive biomarkers. AD evolving from childhood in air pollution environments ought to be preventable. Show more

Keywords: Air pollution, alpha synuclein, Alzheimer’s disease continuum, auditory nuclei, auditory plasticity, auditory gain, brainstem auditory evoked potentials, children, hyperphosphorylated tau, combustion and friction-derived nanoparticles

DOI: 10.3233/JAD-190405

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Nocera, Joe R. | Arsik, Idil | Keskinocak, Pinar | Lepley-Flood, Amy | Lah, James J. | Levey, Allan I. | Esper, Greg J.

Article Type: Short Communication

Abstract: There is increasing interest in gait evaluations in clinical settings given the associations between gait and health outcomes. However, efforts examining implementation of gait evaluation in neurological clinics are lacking. Herein, gait implementation within a cognitive neurology clinic is presented. Over a 21-month period, a gait evaluation was collected on 81% of eligible patients (n  = 2,622; mean age 73.2±9.5; age range 49–94 years; 47% female). Patients and staff reported being satisfied with the gait assessment. These finding have implications for gait evaluations in clinical settings and for clinical research aimed at understanding the impact of cognitive symptomatology on gait.

Keywords: Cognition, dementia, gait, implementation

DOI: 10.3233/JAD-190106

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Mattos, Meghan K. | Sereika, Susan M. | Beach, Scott R. | Kim, Hyejin | Klunk, William E. | Knox, Melissa | Nadkarni, Neelesh K. | Parker, Lisa S. | Roberts, J. Scott | Schulz, Richard | Tamres, Lisa | Lingler, Jennifer H.

Article Type: Review Article

Abstract: As calls for transparency in human subjects research grow, investigators conducting Alzheimer’s disease (AD) biomarker research are increasingly required to consider their ethical obligations regarding the return of AD biomarker test results to research participants. When disclosing these test results to potentially vulnerable participants, investigators may face unique challenges to identify adverse events, particularly psychological events. The purpose of this paper is to describe our research team’s experience with developing and implementing a process for enhanced adverse event monitoring following the return of amyloid-β (Aβ) imaging results to research participants with mild cognitive impairment (MCI). Ethical and logistical considerations are …presented along with preliminary findings from an ongoing randomized controlled trial of Aβ imaging results disclosure in MCI. Following receipt of amyloid imaging results, participants underwent 14 days of adverse event monitoring using ecological momentary assessment (EMA), a strategy to capture health, behaviors, and mood as they occur in participants’ natural settings in real time. EMA telephone calls were placed at random during waking hours to screen for mood changes. Investigators were alerted for positive depression, anxiety, suicidal ideation screenings, or for two days of failed call attempts. Preliminary feasibility of twenty-four participants with MCI who participated in EMA mood assessments was successfully completed 83% (SD = 0.4) of the time over 14 days with no alerts for anxiety or depression screening items. EMA, when used with standard adverse event monitoring, is a promising and novel approach to maximize early detection of negative psychological reactions following AD biomarker results disclosed in research settings. Show more

Keywords: Amyloid, cognitive dysfunction, ecological momentary assessment, ethics, research subjects

DOI: 10.3233/JAD-190091

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Brito-Aguilar, Rafael

Article Type: Review Article

Abstract:  Dementia has become a major public health concern around the world. Dementia risk factors are significantly different among countries. The number of new cases of dementia anticipated each year worldwide is almost 7.7 million, one new case every four seconds. There are 3.6 million (46%) new cases per year in Asia, 2.3 million (31%) in Europe, 1.2 million (16%) in the Americas, and 0.5 million (7%) in Africa. Latin American and Caribbean low and middle-income countries are at high risk. Air pollution is an important risk modifiable factor for dementia across the world, and the recent report of the Alzheimer’s …disease continuum in children and young adults residing in Metropolitan Mexico City along with the presence of cognitive impairment in 55% of the young adult population residing in Mexican cities with fine particulate matter concentrations above the current USEPA annual standard of 12 μg/m3 makes this a severe public health problem in progress. It is imperative to keep generating epidemiological data on dementia worldwide and their relationship with air pollutants to improve the strategies to face all the challenges associated with dementia and Alzheimer’s disease in particular. Alzheimer’s disease is a fatal disease, we have no cure, and we ought to invest in protecting our citizens by intervening in modifiable environmental factors. Show more

Keywords: Air pollution, Alzheimer’s disease, Alzheimer’s disease continuum, dementia, fine particulate matter, Latin America, Mexico, nanoparticles, prevalence

DOI: 10.3233/JAD-190177

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-5, 2019

Authors: Bernstein, Alissa | Harrison, Krista L. | Dulaney, Sarah | Merrilees, Jennifer | Bowhay, Angela | Heunis, Julia | Choi, Jeff | Feuer, Julie E. | Clark, Amy M. | Chiong, Winston | Lee, Kirby | Braley, Tamara L. | Bonasera, Stephen J. | Ritchie, Christine | Dohan, Dan | Miller, Bruce L. | Possin, Katherine L.

Article Type: Research Article

Abstract: Background: Care navigation is an approach to personalized care management and care coordination that can help overcome barriers to care. Care navigation has not been extensively studied in dementia, where health care workforce innovations are needed as a result of increasing disease prevalence and resulting costs to the health care system. Objective: To identify facilitators and barriers to care navigation in dementia and to assess dementia caregiver satisfaction with care navigation. Methods: Methods include qualitative research (interviews, focus groups, observations) with “Care Team Navigators” (CTNs) who were part of a dementia care navigation program, the Care …Ecosystem, and a quantitative survey with caregivers about their experiences with CTNs. Transcripts were analyzed to identify themes within the data. Results: CTNs identified the following facilitators to care navigation in dementia: working closely with caregivers; providing emotional support; tailoring education and resources; and coordinating with a clinical team around issues ranging from clinical questions to financial and legal decision-making. The barriers CTNS identified included burn-out, the progressive nature of the disease; coordinating with primary care providers; and identifying resources for dyads who are low-income, do not speak English, or live in rural areas. Caregivers across both sites highly rated CTNs, though satisfaction was higher among those in Nebraska and Iowa. Conclusions: Innovative approaches to care delivery in dementia are crucial. Care navigation offers a feasible model to train unlicensed people to deliver care as a way to deliver larger-scale support for the growing population of adults living with dementia and their caregivers. Show more

Keywords: Care navigation, caregivers, dementia, health care workforce

DOI: 10.3233/JAD-180957

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Guo, Si | Xu, Jing-Jing | Wei, Na | Han, Jun-Ya | Xue, Rui | Xu, Po-Shi | Gao, Chuan-Yu

Article Type: Research Article

Abstract: Vascular dementia (VaD) is caused by chronic decreases in brain blood flow and accounts for 15–20% of dementia cases worldwide. In contrast to Alzheimer’s disease (AD), no effective drug treatments are currently available for VaD. Previous studies have suggested that oxidative stress and neuroinflammation in the brain play important roles in the pathogenesis of VaD. Honokiol (HKL) is a well-known bioactive and nutraceutical compound that can act as an antioxidant and anti-inflammatory molecule. HKL can protect against memory impairments in AD mouse models. In this study, we explored whether the application of HKL was also protective against the insult of …chronic cerebral hypoperfusion (CCH) in rats. We found that HKL supplementation prevented the memory impairments in the inhibitory avoidance step-down and Morris water maze tasks in CCH rats. HKL also suppressed the levels of oxidative stress and inflammation in CCH rats. Moreover, HKL prevented dendritic spines abnormalities in CCH rats. We also found that HKL inhibited the activity of GSK-3β , which may be critical for the neuroprotective activity of HKL. Thus, our study demonstrated the protective role of HKL in VaD. Show more

Keywords: GSK-3β, Honokiol, inflammation, memory impairments, oxidative stress, vascular dementia

DOI: 10.3233/JAD-190324

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Ruthirakuhan, Myuri | Herrmann, Nathan | C. Andreazza, Ana | Verhoeff, Nicolaas Paul L.G. | Gallagher, Damien | Black, Sandra E. | Kiss, Alex | Lanctôt, Krista L.

Article Type: Research Article

Abstract: Background: Agitation is a prevalent and difficult-to-treat symptom of Alzheimer’s disease (AD). The endocannabinoid system (ECS) has been a target of interest for the treatment of agitation. However, ECS signaling may interact with AD-related changes in brain cholesterol metabolism. Elevated brain cholesterol, reflected by reduced serum 24-S-hydroxycholesterol (24S-OHC), is associated with reduced membrane fluidity, preventing ligand binding to cannabinoid receptor 1. Objective: To assess whether 24S-OHC was associated with agitation severity and response to nabilone. Methods: 24S-OHC was collected from AD patients enrolled in a clinical trial on nabilone at the start and end of each …phase. This allowed for the cross-sectional and longitudinal investigation between 24S-OHC and agitation (Cohen Mansfield Agitation Inventory, CMAI). Post-hoc analyses included adjustments for baseline standardized Mini-Mental Status Exam (sMMSE), and analyses with CMAI subtotals consistent with the International Psychogeriatric Association (IPA) definition for agitation (physical aggression and nonaggression, and verbal aggression). Results: 24S-OHC was not associated with CMAI scores cross-sectionally or longitudinally, before and after adjusting for baseline sMMSE. However, 24S-OHC was associated with greater CMAI IPA scores at baseline (F(1,36) = 4.95, p  = 0.03). In the placebo phase only, lower 24S-OHC at baseline was associated with increases in CMAI IPA scores (b = –35.2, 95% CI –65.6 to –5.0, p  = 0.02), and decreases in 24S-OHC were associated with increases in CMAI IPA scores (b = –20.94, 95% CI –57.9 to –4.01, p  = 0.03). Conclusion: 24S-OHC was associated with agitation severity cross-sectionally, and longitudinally in patients with AD. However, 24S-OHC did not predict treatment response, and does not change over time with nabilone. Show more

Keywords: Alzheimer’s disease, behavioral symptoms, biomarkers, geriatric psychiatry

DOI: 10.3233/JAD-190202

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Pérez-Ros, Pilar | Martínez-Arnau, Francisco Miguel | Baixauli-Alacreu, Susana | Caballero-Pérez, Mireia | García-Gollarte, José Fermín | Tarazona-Santabalbina, Francisco

Article Type: Research Article

Abstract: Background: Delirium is a common geriatric syndrome, with a prevalence of between 15–70% among older long-term care residents. It is associated with adverse outcomes, and its onset may prove imperceptible to health professionals. Few studies in institutionalized older people have analyzed the predictors of delirium. Objective: The aim of the present study was to identify delirium predisposing and triggering factors, and develop a predictive model. Methods: A cohort trial-nested case-control study covering a period of 12 consecutive months (April 2015 – March 2016) was carried out. Predisposing and triggering episodes of delirium were recorded. …Results: A total of 443 older persons were recruited, with a mean age of 85.73 (6.72) years and female predominance (78.3%; n  = 374). The incidence of older people with delirium was 18.7% (n  = 83). Dementia was the predisposing factor with the highest predictive capacity (OR = 2.74 [1.49–5.04]). In the presence of dementia, falls (OR = 2.45 [1.49–3.69]), neuroleptics (OR = 2.39 [1.23–4.65]) and anticholinergic drug use (OR = 1.87 [0.95–3.69]) were identified as triggering factors. The area under the curve (AUC) was 0.72 (95% CI: 0.66–0.78). Conclusions: Our findings suggest that interventions targeted to potentially preventable triggering factors could avoid the onset of delirium in older people with dementia. Knowledge of the predictive factors of delirium facilitates the screening of older people at increased risk, thereby allowing mental health service providers to prevent and identify the onset of a delirium episode. The decrease in delirium predictive factors should lead to a direct reduction in the occurrence of delirium and its consequences. Show more

Keywords: Aged, delirium, incidence, nursing home, risk factors

DOI: 10.3233/JAD-190391

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Suh, Seung Wan | Han, Ji Won | Lee, Ju Ri | Byun, Seonjeong | Kwak, Kyung Phil | Kim, Bong-Jo | Kim, Shin Gyeom | Kim, Jeong Lan | Kim, Tae Hui | Ryu, Seung-Ho | Moon, Seok Woo | Park, Joon Hyuk | Seo, Jiyeong | Youn, Jong Chul | Lee, Dong Young | Lee, Dong Woo | Lee, Seok Bum | Lee, Jung Jae | Jhoo, Jin Hyeong | Yoon, In Young | Kim, Ki Woong

Article Type: Research Article

Abstract: Prospective studies concerning sleep architecture and cognitive function have focused on individual sleep measures per se , without considering the complementary role of non-REM (NREM) and REM sleep. We explored the association between NREM/REM cycle-related sleep architecture and cognitive decline. Community-dwelling elderly people in Korea from the Korean Longitudinal Study on Cognitive Aging and Dementia were enrolled. They were cognitively normal and underwent an overnight polysomnography at baseline. A NREM/REM cycle is a sequence of NREM and REM sleep, uninterrupted by a waking period of >2 min. After 4 years, the development of mild cognitive impairment (MCI) or dementia was related …to the measures of sleep architecture, including NREM/REM cycle parameters by logistic regression analyses. Of 235 participants (mean [SD] age 68 [5] years; 60% female) at baseline, 14 (5.9%) developed MCI/dementia at follow-up. A short average cycle length (OR, 0.97 [95% CI, 0.94–0.99]; p  = 0.02) was significantly associated with cognitive decline. When its substructure and NREM and REM sleep outside of cycles were considered simultaneously, the average REM sleep duration per cycle (OR, 0.87 [95% CI, 0.76–0.98]; p  = 0.03) was significantly related to the outcome. In conclusion, a short average duration of NREM/REM cycles, especially average REM sleep duration in each cycle, in cognitively normal elderly might be used as an early marker of cognitive decline. Show more

Keywords: Dementia, mild cognitive impairment, sequential hypothesis, sleep

DOI: 10.3233/JAD-190399

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Manji, Zahra | Rojas, Asheebo | Wang, Wenyi | Dingledine, Raymond | Varvel, Nicholas H. | Ganesh, Nicholas

Article Type: Research Article

Abstract: Alzheimer’s disease (AD) pathology consists of extracellular deposits of amyloid-β peptides (Aβ ) and intracellular neurofibrillary tangles. These pathological alterations are accompanied by a neuroinflammatory response consisting of increased expression of inflammatory mediators. An anti-inflammatory strategy designed to prevent or delay the development of AD would benefit from knowing when neuroinflammation appears in the transgenic models during prodromal disease stages relative to Aβ pathology. We investigated the expression patterns of inflammatory mediators in the brain of 5xFAD mice in comparison to development of Aβ deposition. Expression changes in inflammatory mediators and glial markers are more robust in …female mice starting at three months of age, in contrast to males in which there is no clear trend through five months. Female and male 5xFAD mice also displayed an age-dependent increase in cortical Aβ deposition congruent with neuroinflammation. Thus, in the 5xFAD mouse model of AD, administration of an anti-inflammatory agent would be most efficacious when administered before three months of age. Show more

Keywords: Alzheimer’s disease, amyloid, chemokines, cytokines, inflammation

DOI: 10.3233/JAD-180678

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: Watts, Amber | Wilkins, Heather M. | Michaelis, Elias | Swerdlow, Russell H.

Article Type: Research Article

Abstract: TOMM40 ‘523 is associated with Alzheimer’s disease (AD), but APOE linkage disequilibrium confounds this association. In 170 APOE ɛ 3 homozygotes, we evaluated relationships between short and very long TOMM40 alleles and longitudinal declines in three cognitive domains (attention, verbal memory, and executive function). We used factor analysis to create composite scores from 10 individual cognitive tests, and latent growth curve modeling adjusting for clinical status (normal, amnestic mild cognitive impairment, or AD) to summarize initial performance and change over three years. Relative to individuals with two very long TOMM40 alleles, APOE ɛ 3 homozygotes with …one or two short alleles showed lower baseline cognitive performance regardless of clinical status. The number of short or very long TOMM40 alleles was not associated with longitudinal cognitive changes. In APOE ɛ 3 homozygotes from the University of Kansas Alzheimer’s Disease Center cohort, an association between TOMM40 ‘523 and cognition is consistent with the possibility that TOMM40 influences cognition independent of APOE . Show more

Keywords: APOE , cognition, factor analysis, longitudinal, TOMM40

DOI: 10.3233/JAD-190293

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Gan, Qini | Yao, Hongbo | Na, Hana | Ballance, Heather | Tao, Qiushan | Leung, Lorene | Tian, Hua | Zhu, Haihao | Wolozin, Benjamin | Qiu, Wei Qiao

Article Type: Research Article

Abstract:  Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer’s disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ)-induced AD pathology in neurons with a dose-dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone …induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ-induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ-induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg), it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis. Show more

Keywords: Alzheimer’s disease, amylin, amyloid-β peptide, pramlintide, synapse, tauopathy, U-shape

DOI: 10.3233/JAD-190161

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-16, 2019

Authors: McGrath, Ryan | Robinson-Lane, Sheria G. | Cook, Summer | Clark, Brian C. | Herrmann, Stephen | O’Connor, Melissa Lunsman | Hackney, Kyle J.

Article Type: Research Article

Abstract: Background: Measures of handgrip strength may show promise for detecting cognitive erosion during aging. Objective: To determine the associations between lower handgrip strength and poorer cognitive functioning for aging Americans. Methods: There were 13,828 participants aged at least 50 years from the 2006 wave of the Health and Retirement Study included and followed biennially for 8 years. Handgrip strength was assessed with a hand-held dynamometer and cognitive functioning was assessed with a modified version of the Mini-Mental State Examination. Participants aged <65 years with scores 7– 11 had a mild cognitive impairment, ≤6 had a severe …cognitive impairment, and ≤11 had any cognitive impairment. Respondents aged ≥65 years with scores 8– 10 had a mild cognitive impairment, ≤7 had a severe cognitive impairment, and ≤10 had any cognitive impairment Separate covariate-adjusted multilevel logistic models examined the associations between lower handgrip strength and any or severe cognitive impairment. A multilevel ordered logit model analyzed the association between lower handgrip strength and poorer cognitive functioning. Results: Every 5-kg lower handgrip strength was associated with 1.10 (95% confidence interval (CI): 1.04, 1.15) and 1.18 (CI: 1.04, 1.32) greater odds for any and severe cognitive impairment, respectively. Similarly, every 5-kg lower handgrip strength was associated with 1.10 (CI: 1.05, 1.14) greater odds for poorer cognitive functioning. Conclusions: Measurement of handgrip strength is a simple, risk-stratifying method for helping healthcare providers determine poorer cognitive functioning. Interventions aiming to prevent or delay cognitive dysfunction should also implement measures of handgrip strength as an assessment tool for determining efficacy. Show more

Keywords: Alzheimer’s disease, cognition, dementia, frailty, geriatrics, muscle strength, muscle weakness

DOI: 10.3233/JAD-190042

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Khosravi, Mohsen | Peter, Jonah | Wintering, Nancy A. | Serruya, Mijail | Shamchi, Sara Pourhassan | Werner, Thomas J. | Alavi, Abass | Newberg, Andrew B.

Article Type: Research Article

Abstract: Background: 18 F-Fluorodeoxyglucose (18 F-FDG) positron emission tomography (PET) and 18 F-florbetapir PET are approved neuroimaging biomarkers for the Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objectives: This study aims to compare the efficacy of 18 F-FDG and 18 F-florbetapir PET at evaluating the cognitive performance of patients with AD, MCI, and normal controls (NCs). Methods: 63 subjects (36 male/27 female, mean age = 68.3) including 19 AD, 23 MCI, and 21 NCs underwent 18 F-FDG and 18 F-florbetapir PET imaging. A global quantification approach was applied on supra-tentorial, frontal, parieto-occipital, temporal, and cerebellar brain regions by …calculating the global SUVmean ratios (GSUVr) as the weighted average of all regional SUVmean. 18 F-FDG and 18 F-florbetapir GSUVr of each region were subsequently correlated with the Mini-Mental Status Examination (MMSE). Results: Subjects were studied in five categories as NC, MCI patients, AD patients, MCI and AD patients grouped together (MCI/AD), and a group including all the subjects (NC/MCI/AD). Both 18 F-FDG and 18 F-florbetapir could successfully detect subjects with dementia (p  <  0.001). Studied in all regions and groups, the correlation analysis of 18 F-FDG GSUVr with MMSE scores was significant in more regions and groups compared to that of 18 F-florbetapir. We also demonstrated that the correlation of 18 F-FDG GSUVr with MMSE is stronger than that of 18 F-florbetapir in the supra-tentorial and temporal regions. Conclusions: This study reveals how 18 F-FDG-PET global quantification is a superior indicator of cognitive performance in AD and MCI patients compared to 18 F-florbetapir PET. Accordingly, we still recommend 18 F-FDG-PET over amyloid imaging in the evaluation for AD and MCI. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, 18F-FDG, florbetapir, mild cognitive impairment, Mini-Mental Status Examination, positron emission tomography

DOI: 10.3233/JAD-190220

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Jensen-Dahm, Christina | Kbstrup Zakarias, Johanne | Gasse, Christiane | Waldemar, Gunhild

Article Type: Research Article

Abstract: Background: We recently reported frequent use of opioids among elderly with dementia. Discrepancies in clinical practice may in part explain the higher use of opioids in elderly with dementia, which geographical variation may be able to clarify. Objective: To investigate geographical variation in opioid use in elderly with dementia compared to elderly without dementia. Methods: Register-based cross-sectional study in the entire elderly (≥65 years) population of Denmark in 2015. Data included place of residence, prescriptions, and discharge diagnoses from hospital contacts. Prevalence of opioid use among elderly with (n  = 36,014) and without dementia (n  = 1,011,787) was …compared nationwide across the five Danish regions using logistic regression analysis and for the 98 municipalities using age and sex standardization. Results: 32.5% of elderly with dementia and 16.9% without were treated with an opioid in 2015. For home-living elderly with dementia, there was a 4-fold difference in opioid use (9.4 to 36.8% ) between municipalities compared to a 1.6-fold (12.7 to 20.2% ) difference for elderly without. In nursing home residents there was a 2-fold difference (dementia: 26.5 to 55.2% ; no dementia: 31.8 to 60.4% ). Differences between the five regions were minor. Conclusion: Opioid use in elderly with dementia was frequent and almost twice as high compared to elderly without dementia, which may challenge patient safety. The pronounced geographical variations at municipality level, particularly among elderly with dementia, indicate differences in the approach to treatment of chronic pain in primary care. Our study suggests that more guidance on treatment of pain in elderly with dementia is needed. Show more

Keywords: Analgesics, dementia, elderly, opioid, pain

DOI: 10.3233/JAD-190413

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Raman, Fabio | Grandhi, Sameera | Murchison, Charles F. | Kennedy, Richard E. | Landau, Susan | Roberson, Erik D. | McConathy, Jonathan | Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Tools for efficient evaluation of amyloid- and tau-PET images are needed in both clinical and research settings. Objective: This study was designed to validate a semi-automated image analysis methodology, called Biomarker Localization, Analysis, Visualization, Extraction, and Registration (BLAzER). We tested BLAzER using two different segmentation platforms, FreeSurfer (FS) and Neuroreader (NR), for regional brain PET quantification in participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset. Methods: 127 amyloid-PET and 55 tau-PET studies with volumetric MRIs were obtained from ADNI. The BLAzER methodology utilizes segmentation of MR images by FS or NR, then visualizes and …quantifies regional brain PET data using FDA-cleared software (MIM), enabling quality control to ensure optimal registration and detect segmentation errors. Results: BLAzER analysis required ∼5 min plus segmentation time. BLAzER using FS segmentation showed strong agreement with ADNI for global amyloid-PET standardized uptake value ratios (SUVRs) (r = 0.9922, p  <  0.001) and regional tau-PET SUVRs across all Braak staging regions (r >  0.97, p  <  0.001) with high inter-operator reproducibility (ICC >  0.97) and nearly identical dichotomization as amyloid-positive or -negative (2 discrepant cases out of 127). Comparing FS versus NR segmentation with BLAzER, global SUVRs were strongly correlated for amyloid-PET (r = 0.9841, p  <  0.001), but were systematically higher (4% on average) with NR, likely due to more inclusion of white matter with NR-defined regions. Conclusions: BLAzER provides an efficient methodology for regional brain PET quantification. FDA-cleared components and visualization of registration reduce barriers between research and clinical applications. Show more

Keywords: [18F]AV-45, [18F]AV-1451, amyloid-β , brain segmentation, neuroimaging, positron emission tomography, tau

DOI: 10.3233/JAD-190329

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Guo, Zhiqiang | Ling, Zhenhua | Li, Yunxia

Article Type: Research Article

Abstract: Background: Recently, many studies have been carried out to detect Alzheimer’s disease (AD) from continuous speech by linguistic analysis and modeling. However, few of them utilize language models (LMs) to extract linguistic features and to investigate the lexical-level differences between AD and healthy speech. Objective: Our goals include obtaining state-of-art performance of automatic AD detection, emphasizing N -gram LMs as powerful tools for distinguishing AD patients’ narratives from those of healthy controls, and discovering the differences of lexical usages between AD patients and healthy people. Method: We utilize a subset of the DementiaBank corpus, including 240 …control samples from 98 control participants and 256 AD samples from 194 “PossibleAD” or “ProbableAD” participants. Baseline models are built through area under curve-based feature selection and using five machine learning algorithms for comparison. Perplexity features are extracted using LMs to build enhanced detection models. Finally, the differences of lexical usages between AD patients and healthy people are investigated by a proportion test based on unigram probabilities. Results: Our baseline model obtains a detection accuracy of 80.7% . This accuracy increases to 85.4% after integrating the perplexity features derived from LMs. Further investigations show that AD patients tend to use more general, less informative, and less accurate words to describe characters and actions than healthy controls. Conclusion: The perplexity features extracted by LMs can benefit the automatic AD detection from continuous speech. There exist lexical-level differences between AD and healthy speech that can be captured by statistical N -gram LMs. Show more

Keywords: Geriatric assessment, language, machine learning, statistical

DOI: 10.3233/JAD-190452

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Lin, Lin | Liu, Aiyi | Li, Hanqin | Feng, Jian | Yan, Zhen

Article Type: Research Article

Abstract: Emerging evidence suggests that epigenetic dysregulation of gene expression is one of the key molecular mechanisms of neurodegeneration and Alzheimer’s disease (AD). However, little is known about the role of epigenetic dysregulation on synaptic dysfunction in humans, because of the difficulties of obtaining live human neurons. Here we generated mature human cortical neurons differentiated from human embryonic stem cells, and exposed them to amyloid-β (Aβ ). We found that the histone methyltransferase, EHMT1, which catalyzes histone lysine 9 dimethylation (H3K9me2, a mark for gene repression), was significantly elevated in Aβ -treated human stem cell-derived neurons. Aβ treatment led …to a significant reduction of AMPAR-mediated whole-cell current and excitatory postsynaptic current. Application of BIX01294, a selective inhibitor of EHMT1/2, restored AMPAR currents and glutamatergic synaptic transmission in Aβ -treated human cortical neurons. These results suggest that inhibition of the aberrant histone methylation is a novel approach to reverse Aβ -induced synaptic deficits in human neurons. Show more

Keywords: Alzheimer’s disease, AMPA receptor, amyloid-β, EHMT1, epigenetics, histone dimethylation, histone methyltransferase, human stem cell-derived neurons

DOI: 10.3233/JAD-190190

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: El Haj, Mohamad | Boudoukha, Abdelhalim | Antoine, Pascal | Moustafa, Ahmed A. | Gallouj, Karim | Allain, Philippe

Article Type: Research Article

Abstract: We investigated, for the first time, how people with mild Alzheimer’s disease (AD) reflect on continuity of their self (i.e., whether they are the same person they were before). We invited people with mild AD and control participants to conduct The Thinking about Life Experiences (TALE) Scale. More specifically, we invited participants to indicate whether they think about their life story: when they want to feel that they are the same person that they were before (Item 1), when they are concerned about whether they are still the same type of person that they were earlier (Item 2), when they …are concerned about whether their values have changed over time (Item 3), when they are concerned about whether their beliefs have changed over time (Item 4), and when they want to understand how they have changed from who they were before (Item 5). The scores of people with AD and control participants on the items of the TALE scale were similar, except for the first item on which people with AD provided higher scores than did control participants. As demonstrated by scores on Item 1, people with mild AD can retrieve autobiographical memories to reflect on situations in which they want to feel that they are the same person that they were before. In other words, people with mild AD can draw on their personal and meaningful events to maintain a continuous sense of self or even to reflect on situations in which they are concerned about their self-continuity. Show more

Keywords: Alzheimer’s disease, autobiographical memory, self, self-continuity

DOI: 10.3233/JAD-190440

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Gruters, Angélique A.A. | Ramakers, Inez H.G.B. | Verhey, Frans R.J. | Köhler, Sebastian | Kessels, Roy P.C. | de Vugt, Marjolein E.

Article Type: Research Article

Abstract: Background: It is uncertain whether self- and proxy-reported cognitive decline in older adults reflect an actual objective cognitive dysfunction in the clinical sense, and if these are predictive for developing dementia. Objective: The aim of the present study is to investigate the cross-sectional and longitudinal relation between subjective cognitive decline and objective cognitive performance, depressive symptoms, and to determine the predictive value for development of dementia. Methods: We included 405 patients without dementia at first visit from the Maastricht memory clinic participating in a longitudinal cohort study. Subjective cognitive decline was measured using a self- and …proxy-report questionnaire. All patients underwent a standardized neuropsychological assessment. Follow-up assessments were performed yearly for three consecutive years, and once after five years. Results: Subjective cognitive decline was associated with lower cognitive performance and more depressive symptoms. When comparing self- (n  = 342, 84% ) and proxy-reported decline (n  = 110, 27% ), it was shown that proxy reports were associated with a more widespread pattern of lower cognitive performance. In participants without cognitive impairment proxy-reported decline was not associated with depressive symptoms. In contrast, self-reported decline was associated with a stable course of depressive symptoms at follow-up. Proxy-reported cognitive decline (HR = 1.76, 95% CI = 1.12– 2.78), and mutual complaints (HR = 1.73, CI:1.09– 2.76) predicted incident dementia while self-reported decline did not reach statistical significance (HR = 1.26, 95% CI = 0.65– 2.43). Conclusion: Proxy-reported cognitive decline was consistently associated with lower cognitive performance and conversion to dementia over 5 years. Self-reported cognitive decline in patients without cognitive impairment might indicate underlying depressive symptoms and thus deserve clinical attention as well. Show more

Keywords: Cognition, dementia, depressive symptoms, mild cognitive impairment, proxy-report, subjective cognitive decline

DOI: 10.3233/JAD-180857

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Esquerda-Canals, Gisela | Roda, Alejandro R. | Martí-Clúa, Joaquim | Montoliu-Gaya, Laia | Rivera-Hernández, Geovanny | Villegas, Sandra

Article Type: Research Article

Abstract: The intracellular deposition of amyloid-β (Aβ ) peptides has been described in the brains of both Alzheimer’s disease (AD) patients and animal models. A correlation between the intracellular amyloid burden and neurodegeneration has recently been reported in a triple-transgenic AD (3xTg-AD) murine model. In the present study, we assessed the effect of scFv-h3D6, an anti-Aβ single-chain variable fragment (scFv) derived from the antibody bapineuzumab, on amyloid pathology in 5-month-old 3xTg-AD female mice, focusing on intracellular Aβ clearance, neuronal survival, and functional abilities. We also examined neuroinflammation and the histology of peripheral organ samples to detect any adverse …effects. A single intraperitoneal injection of scFv-h3D6 dramatically reduced intracellular Aβ burden in the deep layers of the cerebral cortex, pyramidal cells layer of the hippocampus, and basolateral amygdalar nucleus. The treatment prevented neuronal loss in the hippocampus and amygdala, while neither astrogliosis nor microgliosis was induced. Instead, an increase in the size of the white pulp after the treatment indicated that the spleen could be involved in the clearance mechanism. Although the treatment did not ameliorate behavioral and psychological symptoms of dementia-like symptoms, the results of cognitive testing pointed to a noticeable improvement in spatial memory. These findings indicated that the mechanism underlying the therapeutic effect of scFv-h3D6 was the clearance of intracellular Aβ , with subsequent prevention of neuronal loss and amelioration of cognitive disabilities. The treatment was safe in terms of neuroinflammation and kidney and liver function, whereas some effects on the spleen were observed. Show more

Keywords: 3xTg-AD, Alzheimer’s disease, amyloid-β , immunotherapy, scFv

DOI: 10.3233/JAD-190484

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-23, 2019

Authors: Huang, Chuanying | Sun, Shuqin | Wang, Weijing | Li, Yujie | Feng, Wenjing | Wu, Yili

Article Type: Research Article

Abstract: Background/Objective: Gait speed is an important indicator for assessing overall health status. Previous studies have reported the important role of sensory function in gait speed; however, the underlying mechanism is still unclear. This study aimed to examine whether cognition mediates the association of sensory function with gait speed among English older adults. Methods: Gait speed was assessed by “timed walking test”. Hearing was measured by using a hearing screening device. Vision was self-reported. Cognition was assessed by questionnaire. Baron and Kenny’s causal steps method and Sobel test were used to examine the mediating effect. …Results: Among 4,197 participants aged 60 years and older, 13.5% had poor hearing and 12.6% had poor vision, 2.6% had both poor hearing and poor vision. Multiple linear regression models suggested that poor hearing (β = – 1.905, p  <  0.001), poor vision (β = – 1.309, p  = 0.004), and poor dual sensory function (β = – 2.442, p  = 0.013) was associated with worse cognition. Cognition was correlated with gait speed (β = 0.004, p  <  0.001). Poor hearing (β = – 0.072, p  <  0.001), poor vision (β = – 0.031, p  = 0.029), and poor dual sensory function (β = – 0.081, p  = 0.011) was associated with slower gait speed. After introducing cognition into the models, regression coefficients between sensory function and gait speed decreased (β = – 0.066, p  <  0.001 for hearing; β = – 0.027, p  = 0.054 for vision; β = – 0.073, p  = 0.020 for combine hearing and vision). Sobel test identified the significant mediating effect of cognition on the association between sensory function and gait speed. Conclusion: Cognition partially mediates the association between sensory function and gait speed. Efforts to maintain mobility performance in older adults should consider protecting both sensory function and cognition. Show more

Keywords: Cognition, gait speed, hearing, mediating effect, vision

DOI: 10.3233/JAD-190364

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Lv, Xin | Zhou, Dongtao | Ge, Baojin | Chen, Hui | Du, Yue | Liu, Shuai | Ji, Yong | Sun, Changqing | Wang, Guangshun | Gao, Yuxia | Li, Wen | Huang, Guowei

Article Type: Research Article

Abstract: Background: The nutrition state plays an important role in the progress of aging. Folate may play a role in protecting mitochondrial (mt) DNA by reducing oxidative stress. Objective: The primary aim of this study was to examine the association of mitochondrial oxidative damage with risk of Alzheimer’s disease (AD), and to explore the possible role of folate metabolites in this association in a matched case-control study. Methods: Serum folate metabolites and mitochondrial function in peripheral blood cells were determined in 82 AD cases and 82 healthy controls, individually matched by age, gender, and education. …Results: AD patients had lower serum levels of folate and higher homocysteine (Hcy) concentration. AD patients had a reduced mtDNA copy number, higher mtDNA deletions, and increased 8-OHdG content in mtDNA indicative of reduced mitochondrial function. The highest level of mtDNA copy number would decrease the risk of AD (OR  = 0.157, 95% CI : 0.058–0.422) compared to the lowest level, independently of serum folate, and Hcy levels. Serum folate levels correlated with low 8-OHdG content in mtDNA both in AD patients and controls, independently of serum Hcy level. Moreover, serum Hcy levels correlated with low copy number in mtDNA both in AD patients and controls, independently of serum folate levels. Conclusion: In conclusion, mitochondrial function in peripheral blood cells could be associated with risk of AD independent of multiple covariates. AD patients with a folate deficiency or hyperhomocysteinemia had low mitochondrial function in peripheral blood cells. However, further randomized controlled trials are need to determine a causal effect. Show more

Keywords: Alzheimer’s disease, China, folate metabolites, mitochondrial function, peripheral blood cells

DOI: 10.3233/JAD-190477

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Menzel, Leoni C. | Kramer, Philipp W. | A. Groneberg, David | Bendels, Michael H.K.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease and dementia are an increasing burden affecting more than 50 million patients worldwide. Hence, research has increased significantly in recent decades. It is recognized that female authors are systematically underrepresented in research in general. Objective: In this article, we examine gender disparities in academic research on dementia and Alzheimer’s disease in the last decade. Methods: 104,858 male and female authorships from 37,961 original research articles were analyzed. The global and country-specific distribution of women across first, co, and last authorships was determined with the inclusion of a citation and productivity …analysis. Results: 42.1% of all authorships and 50.2% of the first, 42.2% of the co, and 32.8% of the last authorships were held by women. Women were less commonly cited, published fewer articles and were also less likely to secure prestigious authorships in articles with multiple authors compared with men. Distinct differences were observed among the countries. Conclusion: Substantial growth in the number of prestigious female authorships has been observed to date and is predicted to continue in the future, with an emphasis on the progressive representation of women and a diminishing gender gap. Show more

Keywords: Citation, gender gap, odds ratio, Prestige Index, productivity

DOI: 10.3233/JAD-190216

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Mendes, Tiago | Cardoso, Sandra | Guerreiro, Manuela | Maroco, João | Silva, Dina | Alves, Luísa | Schmand, Ben | Gerardo, Bianca | Lima, Marisa | Santana, Isabel | de Mendonça, Alexandre

Article Type: Research Article

Abstract: Background: The use of biomarkers, in particular amyloid-β (Aβ) changes, has allowed the possibility to identify patients with subjective memory complaints (SMCs) and amnestic mild cognitive impairment (aMCI) who suffer from Alzheimer’s disease (AD). Since it is unfeasible that all patients with aMCI could presently undergo biomarkers assessment, it would be important that SMCs might contribute to identify the aMCI patients who have AD amyloid pathology. Objectives: To know whether aMCI patients with amyloid biomarkers (Aβ+ ) present greater SMCs as compared to those without amyloid biomarkers (Aβ- ). Methods: Participants were selected from a cohort …of nondemented patients with cognitive complaints and a comprehensive neuropsychological evaluation, on the basis of 1) diagnosis of aMCI; 2) detailed assessment of memory difficulties with the SMC Scale; and 3) known amyloid status. The amyloid status was determined on the basis of either CSF Aβ1–42 concentration or amyloid PET imaging. Results: Of the 176 patients with aMCI studied, 90 were Aβ+ and 86 were Aβ- . The two groups did not differ in terms of age, gender, and education. The SMC total score was not significantly different in the Aβ+ aMCI patients (9.48±4.18) when compared to the Aβ- aMCI patients (10.52±4.57). The Aβ+ aMCI patients had lower scores on the MMSE and memory/learning tests, but not on the Geriatric Depression Scale, when comparing to the Aβ- aMCI patients. Conclusions: Evaluating SMCs does not seem helpful to identify, among patients with aMCI, those who have AD. Show more

Keywords: Alzheimer’s disease, amnestic, amyloid-β, anosognosia, depressive symptoms, mild cognitive impairment, subjective memory complaints

DOI: 10.3233/JAD-190414

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Pillai, Jagan A. | Bonner-Jackson, Aaron | Bekris, Lynn M. | Safar, Jiri | Bena, Jim | Leverenz, James B.

Article Type: Research Article

Abstract: Background: Cerebrospinal fluid (CSF) levels of total tau (t-tau) protein are thought to reflect the intensity of the neuronal damage in neurodegeneration, including Alzheimer’s disease (AD). The recent link of CSF t-tau to rapidly progressive AD raises the question among other AD clinical variants regarding CSF t-tau. We investigated the clinical phenotypes of AD patients with varying CSF t-tau levels. Objective: We tested the hypothesis that highly elevated CSF t-tau level would have a higher likelihood of presenting with atypical non-amnestic variants of AD. Methods: Retrospective comparative case study of 97 patients evaluated in a memory …clinic with clinical presentation and CSF biomarkers consistent with AD. We compared the age, sex, education, APOE ɛ 4 status, Montreal Cognitive Assessment (MoCA) score, clinical phenotype, and MRI volumetric measures by CSF t-tau quartile at baseline. Multivariable logistic regression models were used to evaluate if CSF t-tau levels predict non-amnestic presentations controlling for covariates. Results: Non-amnestic AD had a higher median CSF t-tau level compared to amnestic-AD (p  = 0.014). Each 50 pg/ml increase in CSF t-tau was associated with an increase in the odds of having a non-amnestic presentation (7.4%) and aphasia (10.6 %) as the initial presenting symptom even after taking into account; age, sex, education, APOE ɛ 4 , MoCA, and CSF Aβ42 . Logopenic AD had higher t-tau and p-tau levels compared to other variants. Conclusions: Highly elevated CSF t-tau levels could indicate more cortical involvement presenting with early non-amnestic symptoms in atypical AD subtypes, particularly in the logopenic variant. Show more

Keywords: Alzheimer’s disease, atypical variant, biomarkers, cerebrospinal fluid, cortical atrophy, hippocampal atrophy, mild cognitive impairment, tau

DOI: 10.3233/JAD-190519

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Gu, Jianlan | Chu, Dandan | Jin, Nana | Chen, Feng | Liu, Fei

Article Type: Research Article

Abstract: Trans-active response DNA-binding protein of 43 kDa (TDP-43) is a highly conserved and ubiquitously expressed nuclear protein. As a member of heterogeneous ribonucleoproteins, TDP-43 plays pivotal roles in mRNA processing. We recently found that TDP-43 promoted tau mRNA instability via acting on the 3’-untranslated region of its mRNA and enhanced tau exon 10 inclusion. TDP-43 is a phospho-protein. The function and the pathological aggregation of TDP-43 are regulated by the phosphorylation. In the present study, we determined phosphorylation of TDP-43 by cyclic AMP-dependent protein kinase (PKA). We found that TDP-43 was co-immunoprecipitated by and co-localized with PKA in the nucleus. …PKA phosphorylated TDP-43 at Ser379, Ser403/404, and Ser409/410 in vitro and in cultured cells. Phosphorylation of TDP-43 at these sites enhanced mutually their phosphorylation by PKA in vitro and in cultured cells. Overexpression of PKA suppressed TDP-43’s activity in promoting tau mRNA instability and tau exon 10 inclusion. These findings shed light on the role of PKA in phosphorylation and function of TDP-43. Downregulation of PKA signaling in AD brain may attenuate the impact of TDP-43 pathology in tau pathogenesis. Show more

Keywords: mRNA processing, phosphorylation, PKA, tau, TDP-43

DOI: 10.3233/JAD-190368

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Ihle-Hansen, Håkon | Vigen, Thea | Berge, Trygve | Hagberg, Guri | Engedal, Knut | Rønning, Ole Morten | Thommessen, Bente | Lyngbakken, Magnus N. | Nygård, Ståle | Røsjø, Helge | Tveit, Arnljot | Ihle-Hansen, Hege

Article Type: Research Article

Abstract: Background: Studies on the relationship between carotid atherosclerosis and cognitive function in subjects from the general population are few and results have been inconsistent. Objective: We aimed to investigate the association between carotid atherosclerotic burden and cognitive function in a cross-sectional analysis of a population-based cohort aged 63–65 years. Methods: All habitants born in 1950 from Akershus County, Norway were invited to participate. A linear regression model was used to assess the association between carotid atherosclerosis and cognitive function. We used carotid plaque score as a measure of carotid atherosclerotic burden and the Montreal Cognitive Assessment …(MoCA) for global cognitive function. Results: We analyzed 3,413 individuals aged 63–65 with mean MoCA score 25.3±2.9 and 87% visible carotid plaques. We found a negative correlation between carotid plaque score and MoCA score (r = –0.14, p  < 0.001), but this association was lost in multivariable analysis. In contrast, diameter or area of the thickest plaque was independently associated with MoCA score. Lower educational level, male sex, current smoking, and diabetes were also associated with lower MoCA score in multivariable analysis. Conclusion: Carotid atherosclerotic burden was, unlike other measures of advanced carotid atherosclerosis, not independently associated with global cognitive function. Show more

Keywords: Atherosclerosis, cardiovascular risk factors, carotid plaque, cognition, cognitive function, Montreal Cognitive Assessment, http://www.clinicaltrials.gov, NCT01555411

DOI: 10.3233/JAD-190327

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Parodi-Rullán, Rebecca | Sone, Je Yeong | Fossati, Silvia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most prevalent form of dementia. Cerebrovascular dysfunction is one of the earliest events in the pathogenesis of AD, as well as in vascular and mixed dementias. Cerebral amyloid angiopathy (CAA), the deposition of amyloid around cerebral vessels, is observed in up to 90% of AD patients and in approximately 50% of elderly individuals over 80 years of age. CAA is a strong contributor to vascular dysfunction in AD. CAA-laden brain vessels are characterized by dysfunctional hemodynamics and leaky blood-brain barrier (BBB), contributing to clearance failure and further accumulation of amyloid-β (Aβ) in the cerebrovasculature and …brain parenchyma. Mitochondrial dysfunction is increasingly recognized as an important early initiator of the pathogenesis of AD and CAA. The objective of this review is to discuss the effects of Aβ on cerebral microvascular cell function, focusing on its impact on endothelial mitochondria. After introducing CAA and its etiology and genetic risk factors, we describe the pathological relationship between cerebrovascular amyloidosis and brain microvascular endothelial cell dysfunction, critically analyzing its roles in disease progression, hypoperfusion, and BBB integrity. Then, we focus on discussing the effect of Aβ challenge on endothelial mitochondrial dysfunction pathways, and their contribution to the progression of neurovascular dysfunction in AD and dementia. Finally, we report potential pharmacological and non-pharmacological mitochondria-targeted therapeutic strategies which may help prevent or delay cerebrovascular failure. Show more

Keywords: Alzheimer’s disease, amyloid, apoptosis, blood-brain barrier, cerebral amyloid angiopathy, endothelial cells, mitochondria, neurodegeneration, reactive nitrogen species, reactive oxygen species

DOI: 10.3233/JAD-190357

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2019

Authors: Caunca, Michelle R. | Simonetto, Marialaura | Alperin, Noam | Elkind, Mitchell S.V. | Sacco, Ralph L. | Wright, Clinton B. | Rundek, Tatjana

Article Type: Research Article

Abstract: Background: Adiposity may increase risk for dementia and Alzheimer’s disease (AD), but mechanisms are unclear. Objective: To examine associations between measures of adiposity with AD-signature region cortical thickness and hippocampal volume. Methods: We used data from the Northern Manhattan Study, a clinically stroke-free cohort of mostly Hispanic participants. Exposures of interest included body mass index (BMI), waist-hip-ratio (WHR), waist circumference (WC), and adiponectin concentration, measured at study entry. AD-signature region cortical thickness and hippocampal volume were obtained using Freesurfer. We estimated associations using multivariable linear regression, adjusting for sociodemographics and health behaviors. We re-examined estimates after …adjustment for APOE ɛ 4 allele status or carotid intima-media thickness (cIMT), among those cognitively unimpaired, and after weighting for inverse probability of selection into the MRI sub-study. We also repeated analyses for cortical thickness in non-AD signature regions. Results: The sample (N  = 947, 63% women, 66% Hispanic/Latino, 26% obese) had a mean (SD) age = 63 (8) years. Greater BMI and WC (both z-scored) were associated with thinner AD-signature region cortex (also z-scored) (BMI: β [95% CI] = –0.09 [–0.18, –0.01], WC: β [95% CI] = –0.11 [–0.20, –0.02]). We did not find evidence that adiposity was related to hippocampal volume. Results were consistent after adjustment for APOE ɛ 4 allele status or cIMT, after weighting for selection, among those cognitively unimpaired, and for non-AD signature region cortical thickness. Conclusion: Greater BMI and WC were related to cortical thinning within and outside the AD-signature region, suggesting a global effect not specific to AD. Show more

Keywords: Adiposity, brain aging, epidemiology, neuroimaging, structural MRI

DOI: 10.3233/JAD-190092

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: McDonough, Ian M. | Letang, Sarah K. | Stinson, Elizabeth (Ashley)

Article Type: Research Article

Abstract: Longitudinal research suggests that genetic, lifestyle, and environmental factors enhance one’s risk for developing Alzheimer’s disease and related dementias (ADRD). However, it is not known how an accumulation of such factors impact brain functioning. One barrier to this research is that increased risk for ADRD affects the cerebrovascular system and, therefore, alters the link between neural activity and the fMRI BOLD signal. To better interpret fMRI findings, several steps were taken to adjust fMRI activity thereby reducing such cerebrovascular effects. We hypothesized that as the number of ADRD risk factors increase, brain regions within the medial temporal lobes and the …default mode network would exhibit altered brain activity during an episodic memory retrieval task. Middle-aged and older adults (aged 50–74) free of dementia were recruited with varying levels of risk and underwent a neuropsychological battery and fMRI. In the memory task, participants viewed a pair of pictures. In an alternative-forced-choice test, participants viewed a picture cue and had to determine which of four pictures was paired with the cue. Increased dementia risk was positively associated with brain activity in regions of interest within the default mode network, the hippocampus, and the entorhinal cortex during memory retrieval. Whole-brain analyses revealed additional positive associations in prefrontal and occipito-temporal cortices. Risk factors most contributing to these elevated levels of brain activity included hypertension, diabetes, obesity, and cholesterol. We also ruled out confounds due to in-scanner performance and premorbid ability. Cumulative risk might represent early signs of burnout in brain regions underlying episodic memory. Show more

Keywords: Alzheimer’s disease, default mode network, dementia, episodic memory, functional magnetic resonance imaging, medial temporal lobe, minority health, risk factors

DOI: 10.3233/JAD-190035

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-19, 2019

Authors: Nance, Christin | Ritter, Aaron | Miller, Justin B. | Lapin, Brittany | Banks, Sarah J.

Article Type: Research Article

Abstract: Background: Variable rate of cognitive decline among individuals with Alzheimer’s disease (AD) is an important consideration for disease management, but risk factors for rapid cognitive decline (RCD) are without consensus. Objective: To investigate demographic, clinical, and pathological differences between RCD and normal rates of cognitive decline (NCD) in AD. Methods: Neuropsychology test and autopsy data was pulled from the National Alzheimer’s Coordinating Center database from individuals with a clinical diagnosis of AD. Individuals with average decline of 3 or more points on the Mini-Mental Status Examination (MMSE) per year over 3 years were labeled RCD; all …others were NCD. Results: Sixty individuals identified as RCD; 230 as NCD. These neuropsychology tests differed at baseline (RCD versus NCD): WMS-LM Immediate Recall (4.35[3.39] versus 6.31[3.97], p  < 0.001), Animal Naming (12.1[4.83] versus 13.9[4.83], p  = 0.007), TMT Part B (187[86.1] versus 159[79.0], p  = 0.02), WAIS-Digit Symbol (29.5[11.3] versus 29.5[11.3], p  = 0.04), and the BNT (21.5[7.05] versus 23.6[5.09], p  = 0.04). RCD had more thyroid disease (30% versus 16%, p  = 0.01) and greater usage of AD medication at baseline (80% versus 62%, p  = 0.01). RCD had more severe cerebral amyloid angiopathy (1.62(1.0) versus1.13(1.0), p  = 0.002), more neocortical Lewy bodies (20% versus 10%, p  = 0.04), and more atrophy (1.54[0.92] versus 1.17[0.83], p  = 0.04). A model combining select variables was significant above chance (χ 2  = 25.8, p  = 0.002), but not to clinical utility (AUC < 0.70; 95% CI). Conclusion: Individuals with RCD have more severe pathology, more comorbidities, and lower baseline neuropsychology test scores of language and executive function. Show more

Keywords: Alzheimer’s disease, cognitive decline, dementia, neuropathology, neuropsychological tests

DOI: 10.3233/JAD-190302

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Anstey, Kaarin J. | Ee, Nicole | Eramudugolla, Ranmalee | Jagger, Carol | Peters, Ruth

Article Type: Research Article

Abstract: Background: The translation of evidence on dementia risk factors into clinical advice requires careful evaluation of the methodology and scope of data from which risk estimates are obtained. Objective: To evaluate the quantity and quality and of evidence, we conducted a review of reviews of risk factors for Alzheimer’s disease (AD), Vascular dementia (VaD), and Any Dementia with the aim of evaluating the quantity, quality, and representativeness of evidence. Methods: PubMed, Cochrane library, and the Global Index Medicus were searched to identify meta-analyses of observational studies of risk factors for AD, VaD, and Any Dementia. PROSPERO …CRD42017053920. Results: Meta-analysis data were available for 34 risk factors for AD, 26 risk factors for Any Dementia, and eight for VaD. Quality of evidence varied greatly in terms of the number of contributing studies, whether data on mid-life exposure was available, and consistency of measures. The most evidence was available for cardiovascular risk factors. The most geographically representative evidence (five of six global regions) was available for alcohol, physical activity, diabetes, high midlife BMI, antihypertensives, and motor function. Evidence from Australia/Oceana or Africa was limited. With the exception of diabetes, evidence from Latin America/Caribbean was unavailable. Midlife specific data were only available for cholesterol and arthritis. Conclusion: There is a lack of mid-life specific data, limited data on VaD, and a lack of geographical representation for many risk factors for dementia. The quality, quantity, and representativeness of evidence needs to be considered before recommendations are made about the relevance of risk factors in mid or late life or for dementia subtypes. Show more

Keywords: Alzheimer’s disease, cohort studies, meta-analysis, prevention, risk factor, vascular dementia

DOI: 10.3233/JAD-190181

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-21, 2019

Authors: Simonovitch, Shira | Schmukler, Eran | Masliah, Eliezer | Pinkas-Kramarski, Ronit | Michaelson, Daniel M.

Article Type: Research Article

Abstract: This study examined the effects of apolipoprotein E4 (APOE4 ), the most prevalent genetic risk factor for Alzheimer’s disease (AD), on proteins involved in mitochondrial dynamics and autophagy, in the hippocampus of targeted replacement mice. Immunohistochemical measurements revealed that the levels of the mitochondrial fusion-mediating protein, MFN1, were higher, whereas those of corresponding fission-regulating protein, DRP-1, were lower in the hippocampus of ApoE4 mice than in the corresponding ApoE3 mice, indicating that APOE4 is associated with increased mitochondrial fusion and decreased fission. A similar ApoE4-driven decrease in DRP-1 was also observed in AD brains. The levels of the mitochondrial …proteins COX1 and Tom40, were higher in the ApoE4 mice, which is consistent with the increased fusion. Measurements of the levels of cleaved PINK1 and parkin, which mark and target mitochondria for mitophagic degradation, revealed lower levels of cleaved PINK1, suggesting reduced mitochondrial membrane potential, and higher levels of parkin in the hippocampus of ApoE4 compared with the ApoE3 mice, indicating altered mitophagy. The levels of the ubiquitin-binding scaffold protein, p62/SQSTM1, which directs selected cargo to the autophagosomes, were also higher in the ApoE4 mice. These findings suggest that APOE4 is associated with enhanced mitochondrial fusion and decreased fission. Additionally, the results indicate that the mitophagy/autophagy is reduced in ApoE4 mice, resulting in higher levels of proteins such as parkin and p62, which are normally degraded during this process. Taken together, these results suggest a novel mechanism that may underlie the pathological effects of APOE4 and indicate that use of APOE4 genotyping could pave the way for identification of novel APOE4 -related therapeutic targets. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, autophagy, mitochondrial dynamics, mitophagy

DOI: 10.3233/JAD-190074

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-15, 2019

Authors: Yu, Qian | Dai, Chun-ling | Zhang, Yongli | Chen, Yanxing | Wu, Zhe | Iqbal, Khalid | Liu, Fei | Gong, Cheng-Xin

Article Type: Research Article

Abstract: General anesthesia increases the risk for cognitive impairment and Alzheimer’s disease (AD) in vulnerable individuals such as the elderly. We previously reported that prior administration of insulin through intranasal delivery can prevent the anesthesia-induced cognitive impairment and biochemical changes in the brain. However, little is known about the underlying molecular mechanisms. Here, we report that general anesthesia resulted in downregulation of mammalian/mechanistic target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the brain along with reduction of presynaptic proteins and brain-derived neurotrophic factor and cognitive impairment in aged mice. Prior administration of intranasal insulin prevented these anesthesia-induced changes. …These results suggest the involvement of the mTOR-eEF2 signaling pathway in the anesthesia-induced brain changes and cognitive impairment and in the prevention of these changes with insulin. Correlation analyses and the use of eEF2 kinase inhibitor further support our conclusions. These studies shed light on the molecular mechanism by which anesthesia and insulin could act on synaptic proteins and cognitive function. Show more

Keywords: Anesthesia, cognitive impairment, eEF2, insulin, intranasal delivery, mTOR, synaptic proteins

DOI: 10.3233/JAD-190280

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019

Authors: Alm, Kylie H. | Bakker, Arnold

Article Type: Research Article

Abstract:  Recently, the field of Alzheimer’s disease (AD) research has adopted a new framework that places the progression of Alzheimer’s disease along a continuum consisting of a preclinical stage, followed by conversion to mild cognitive impairment, and ultimately dementia. Important neuropathological changes occur in the preclinical phase, necessitating the identification of metrics that can detect such early changes. While cerebrospinal fluid (CSF) measures of amyloid and tau are generally accepted as biomarkers of AD pathology, neuroimaging measures used to index white matter alterations throughout the brain remain less widely endorsed as candidate biomarkers. To explore the relationship between white matter alterations …and AD pathology, we review the literature on multimodal studies that assessed both CSF markers and white matter indices, derived from diffusion tensor imaging (DTI) methods, across cohorts primarily in the early phases of AD. Our review indicates that abnormal CSF measures of Aβ42 and tau are associated with widespread alterations in white matter microstructure throughout the brain. Furthermore, white matter variability is related to individual differences in behavior and can aid in tracking longitudinal changes in cognition. Our review advocates for the utilization of DTI metrics in investigations of early AD and suggests that the combined use of DTI and CSF markers may better explain individual differences in cognition and disease progression. However, further research is needed to resolve certain mixed findings. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, diffusion tensor imaging, mild cognitive impairment

DOI: 10.3233/JAD-181210

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-17, 2019

Authors: Pandey, Janardan P. | Kothera, Ronald T. | Liu, Shufeng | Costa, Andrea Saul | Mancuso, Roberta | Agostini, Simone

Article Type: Research Article

Abstract: Although genome-wide association studies (GWAS) of late-onset Alzheimer’s disease (AD) have identified numerous genes that influence the risk for disease, the majority of the genetic variance of AD remains uncharacterized. Furthermore, current GWAS, despite their name, do not evaluate all genes in the human genome. One such gene complex is immunoglobulin GM (γ marker) genes on chromosome 14. GM genes are excellent candidate genes for AD because they influence immunity to herpes simplex virus type 1 (HSV1), which has been implicated in AD pathology by an increasing number of reports. The aim of this investigation was to determine if …particular GM genotypes were associated with AD and mild cognitive impairment (MCI), and whether they contributed to the interindividual differences in the level of anti-HSV1 IgG antibodies. A total of 141 HSV1 seropositive individuals—56 AD patients, 48 MCI individuals, and 37 sex- and age-matched healthy controls—were characterized for GM alleles 3, 17, and 23. The homozygosity for the GM 3 allele was significantly associated with MCI (p  = 0.025). GM 3/17 heterozygous AD patients had significantly higher levels of anti-HSV1 antibodies than the healthy controls expressing the same genotype (p  = 0.0004). Among MCI subjects, the GM 3/17 genotype was associated with significantly higher level of anti-HSV1 antibodies as compared to the GM 17/17 homozygous genotype (pc  = 0.040). Among AD patients, the GM 23+/–genotype was significantly associated with anti-HSV1 antibody responses (pc  = 0.025). These results suggest that GM genes could act as potential unifiers of the genetic and viral etiology of AD. Show more

Keywords: Antibody dependent cellular cytotoxicity, APOE4, Fcγ receptor, γ marker (GM) allotypes, HSV1, immunoevasion

DOI: 10.3233/JAD-190265

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Kostev, Karel | Kurylo, Pawel | Kosik, Joanna | Jacob, Louis

Article Type: Research Article

Abstract: Background: Previous studies have suggested that there are substantial differences between countries in terms of persistence with antidementia drugs and that the management of dementia is likely to be population-specific. Objective: The aim of this study was to analyze the one-year persistence with donepezil, memantine, and rivastigmine in more than 66,000 elderly patients followed in Poland. Methods: This study included patients who were prescribed donepezil, memantine, or rivastigmine for the first time in general and neuropsychiatric practices in Poland between September 2016 and December 2017 (index date; N  = 66,030). The primary outcome of the study was …the one-year persistence with donepezil, memantine, and rivastigmine. Non-persistence was defined as a gap of at least 90 days without anti-dementia therapy. The secondary outcome was the identification of variables significantly associated with treatment non-persistence. Results: After 12 months of follow-up, 42.2% of donepezil users, 46.0% of rivastigmine users, and 65.9% of memantine users were persistent (log-rank p -value <0.001). Memantine (hazard ratio [HR] = 0.58) and rivastigmine users (HR = 0.92) were less likely to discontinue treatment one year after initiation than donepezil users. Furthermore, a younger age (60–64 years: HR = 1.32; 65–74 years: HR = 1.13) and therapy initiated by a neuropsychiatrist (HR = 1.11) were positively associated with therapy discontinuation, while we observed a negative association between the prescription of anti-psychotic drugs and non-persistence (HR = 0.81). Conclusion: One-year persistence with donepezil, memantine, and rivastigmine was low in elderly patients followed in Poland, and was influenced by age, physician specialty, and co-therapy. Show more

Keywords: Anti-dementia drugs, older adults, one-year persistence, Poland, predictors

DOI: 10.3233/JAD-190508

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-7, 2019

Authors: Brayne, Carol | Richard, Edo

Article Type: Editorial

DOI: 10.3233/JAD-190448

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: López-García, Sara | Jiménez-Bonilla, Julio | López Delgado, Anjana | Orizaola Balaguer, Pedro | Infante Ceberio, Jon | Banzo Marraco, Ignacio | Rodríguez Rodríguez, Eloy | Sánchez-Juan, Pascual

Article Type: Short Communication

Abstract: Dementia is not just a disease of old age. Early-onset dementia affects people younger than 65 and its differential diagnosis is broader than in older people. Nevertheless, although young people are considerably more liable to develop a rare form of dementia, Alzheimer’s disease (AD) remains the most common diagnosis. The aim of this article is to report on an early-onset AD patient associated with the rare pathogenic variant PSEN1 (Leu85Pro) presenting as a possible corticobasal syndrome with asymmetric limb apraxia, parkinsonian signs, and myoclonus.

Keywords: Alzheimer’s disease, amyloid PET, corticobasal syndrome, presenilin-1

DOI: 10.3233/JAD-190107

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-4, 2019

Authors: Molad, Jeremy | Hallevi, Hen | Korczyn, Amos D. | Kliper, Efrat | Auriel, Eitan | Bornstein, Natan M. | Ben Assayag, Einor

Article Type: Research Article

Abstract: Background: Stroke is a major cause of cognitive impairment and dementia. However, the underlying mechanisms beyond post-stroke cognitive impairment (PSCI) are not fully explained to date. Objective: We studied the contribution of vascular pathology measures to PSCI, separate from and in conjunction with pathologic markers associated with Alzheimer’s disease (AD). Methods: Data from 397 cognitively intact ischemic stroke patients were available. All patients underwent 3T MRI and evaluated for white matter hyperintensity volume (WMHV) and integrity, ischemic lesions, small vessel disease (SVD) markers and grey matter (GM), hippocampal and cerebrospinal fluid (CSF) volumes. Comprehensive cognitive tests …were performed on admission and after two years. We used multiple regression to evaluate the contributions of vascular pathology measures (Framingham risk score, WMHV, and existence of SVD) and AD-associated markers (apolipoprotein E4 status and hippocampal volume). Results: During two years follow-up, 80 participants (20.2%) developed PSCI. Low GM and cortex volume and high WMHV and CSF volume, but not the new lesion volume, predicted the development of PSCI in a dose-dependent relationship (p  = 0.001). Vascular related imaging markers and risk factors predicted PSCI better than AD related markers (p  <  0.001). Conclusions: Brain structural measures, including total GM volume, WMHV, and CSF volume were independently associated with PSCI and may serve as early biomarkers for risk prediction. In our sample, vascular pathology measures contributed significantly better to PSCI prediction than markers associated with AD. The newly detected ischemic lesion has not emerged as biomarker for PSCI risk, thus maybe a part of the ongoing vascular pathology. Show more

Keywords: Cognitive impairment, neuroimaging, predictors, stroke

DOI: 10.3233/JAD-190339

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-10, 2019

Authors: Schaeffer, Morgan J. | Callahan, Brandy L. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The percentage of verbal forgetting (VF%) measure of the Rey Auditory Verbal Learning Test (RAVLT) has been proposed to differentiate patients diagnosed clinically with Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB). Objective: To determine if VF% aligns with gold-standard biomarker and autopsy evidence of AD and DLB neuropathology. Methods: Clinical, cognitive, sociodemographic, and biomarker data were collected from 315 patients with baseline cognitive impairment and 485 normal controls from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). AD markers included reduced cerebrospinal fluid (CSF) amyloid-β, elevated total-tau and phosphorylated-tau, hippocampal atrophy, and the presence of …amyloid plaques and neurofibrillary tangles at autopsy. DLB markers included reduced CSF α -synuclein, preserved hippocampus, atrophied putamen, occipital glucose metabolism, and the presence of Lewy bodies at autopsy. Cognitively impaired participants were classified as ADVF% (n  = 190) or DLBVF% (n  = 125) based on their RAVLT VF% scores using a 75% cut-off (≥75%  = ADVF% , <75%  = DLBVF% ). Postmortem data were available for 13 ADVF% participants, 13 DLBVF% patients, and six healthy controls. Results: ADVF% and DLBVF% participants did not differ on CSF or neuroimaging biomarkers, with the exception of total tau levels which were higher in ADVF% . In the subset of participants with autopsy data, comorbid AD and DLB pathology was most frequent in ADVF% participants, and pure DLB pathology was most frequent in DLBVF% participants, however, these differences were not statistically significant. Conclusion: The RAVLT VF% measure does not reliably align with AD and DLB neuropathology in ADNI participants. Show more

Keywords: Alzheimer’s disease, biomarkers, cognitive assessment, Lewy body disease, memory, neuropathology

DOI: 10.3233/JAD-180962

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-11, 2019

Authors: Gagliardi, Geoffroy | Epelbaum, Stéphane | Houot, Marion | Bakardjian, Hovagim | Boukadida, Laurie | Revillon, Marie | Dubois, Bruno | Dalla Barba, Gianfranco | La Corte, Valentina | INSIGHT-preAD study group

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology is found in the brain years before symptoms are usually detected. An episodic memory (EM) decline is considered to be the specific cognitive sign indicating a transition from the preclinical to the prodromal stage of AD. However, there is still no consensus on the most sensitive tool to detect it. Objective: The goal of our study was to determine which EM measures, among three clinically used EM tests and one research EM test, would be optimal to use for detection of early decline in elderly cognitive complainers. Methods: 318 healthy elderly …participants with subjective cognitive complaint were followed for two years. We applied generalized linear mixed models to investigate the effect of baseline brain amyloid and metabolism on the longitudinal evolution of four EM tests. Results: Our findings show that participants performed significantly worse in two out of four EM tests (i.e., the Memory Binding Test and the Delayed Matched Sample test 48 items) as their level of brain amyloid load increased. However, we did not find an association between EM measures and brain metabolism. An interaction of the two biomarkers was associated with the number of intrusions in the Memory Binding Test over two years. Conclusion: As most clinical trials in AD are now including patients at its early clinical stage, the precise delineation of the transition phase between the preclinical and prodromal stages of the disease is of crucial importance. Our study indicates that challenging EM tests and intrusions are valuable tools to identify this critical transition. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, episodic memory, preclinical

DOI: 10.3233/JAD-180966

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-14, 2019

Authors: Terry, Nickolas | Masliah, Alberto | Overk, Cassia | Masliah, Eliezer

Article Type: Research Article

Keywords: Aging, Alzheimer’s disease, cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-190518

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-8, 2019

Authors: Nazarian, Alireza | Kulminski, Alexander M.

Article Type: Research Article

Abstract: Heritability analysis of complex traits/diseases is commonly performed to obtain illustrative information about the potential contribution of the genetic factors to their phenotypic variances. In this study, we investigated the narrow-sense heritability (h 2 ) of Alzheimer’s disease (AD) using genome-wide single-nucleotide polymorphisms (SNPs) data from three independent studies in the linear mixed models framework. Our meta-analyses demonstrated that the estimated h 2 values (and their standard errors) of AD in liability scale were 0.280 (0.091), 0.348 (0.113), and 0.389 (0.126) assuming AD prevalence rates of 10%, 20%, or 30% at ages of 65+, 75+, and 85+ years, respectively. …We also found that chromosomal regions containing two or more AD-associated SNPs at p  < 5E-08 could collectively explain 37% of the additive genetic variance of AD in our samples. AD-associated regions in which at least one SNP had attained p  < 5E-08 explained 56% of the additive genetic variance of AD. These regions harbored 3% and 11% of SNPs in our analyses. Also, the chromosomal regions containing two or more and one or more AD-associated SNPs at p  < 5E-06 accounted for 72% and 94% of the additive genetic variance of AD, respectively. These regions harbored 27% and 44% of SNPs in our analyses. Our findings showed that the overall contribution of the additive genetic effects to the AD liability was moderate and age-dependent. Also, they supported the importance of focusing on known AD-associated chromosomal regions to investigate the genetic basis of AD, e.g., through haplotype analysis, analysis of heterogeneity, and functional studies. Show more

Keywords: Aging, complex disorders, dementia, missing heritability, narrow-sense heritability, neurodegenerative disorders, polygenic inheritance

DOI: 10.3233/JAD-190168

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-9, 2019

Authors: Low, Audrey | Ng, Kok Pin | Chander, Russell Jude | Wong, Benjamin | Kandiah, Nagaendran

Article Type: Research Article

Abstract: Background: Asymmetrical patterns of cerebral damage have been widely observed in a range of neurodegenerative diseases, including Alzheimer’s disease (AD). Objective: To elucidate the clinical associations of asymmetrical white matter hyperintensities (WMH) in mild cognitive impairment (MCI) and AD. Methods: Regional WMH asymmetry of 340 participants (90 healthy controls, 132 MCI, 118 AD) was calculated as the difference in normalized hemispheric WMH volume (WMH/ICV) adjusted for structural brain asymmetry of respective lobar regions and total WMH. WMH asymmetry was analyzed in relation to disease classification, cognition, and APOE4 status using ANCOVA and multiple regression analysis, …controlling for gender, age, ethnicity, and correcting for multiple comparisons using Bonferroni correction. Moderation analysis examined interaction effects of APOE4 on associations between cognition and WMH asymmetry. Results: Greater left-dominant occipital WMH asymmetry was observed in AD, compared to healthy controls and MCI, and was associated with poorer global cognition, memory, language, and executive functions among cognitively impaired participants (MCI and AD). Cognitively impaired APOE4 carriers displayed greater left-dominant WMH asymmetry in the whole brain and frontal lobe, compared to non-carriers. Importantly, effects were independent of structural brain asymmetry, global cerebral atrophy, and overall WMH burden. Moderation analysis demonstrated associations between left-dominant WMH asymmetry and cognition in cognitively impaired APOE4 non-carriers, but not APOE4 carriers. Conclusion: Leftward asymmetry of WMH may be more pathological in nature, compared to symmetrical WMH. Furthermore, the detrimental effects of WMH asymmetry was more relevant in APOE4 -negative cognitive impairment, compared to APOE4 -positive which may be driven primarily by AD pathology. Show more

Keywords: Alzheimer’s disease, apolipoprotein E4, cerebral small vessel diseases, cognitive aging, leukoaraiosis, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-190159

Citation: Journal of Alzheimer's Disease, vol. Pre-press, no. Pre-press, pp. 1-12, 2019