Volume 70, Number 4, 2019

Pages 965-981

Kylie H. Alm, Arnold Bakker (Handling Associate Editor: Juan Zhou)
Relationships between Diffusion Tensor Imaging and Cerebrospinal Fluid Metrics in Early Stages of the Alzheimer’s Disease Continuum
Abstract: Recently, the field of Alzheimer’s disease (AD) research has adopted a new framework that places the progression of AD 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.

Pages 983-993
Christin Nance, Aaron Ritter, Justin B. Miller, Brittany Lapin, Sarah J. Banks
The Pathology of Rapid Cognitive Decline in Clinically Diagnosed Alzheimer’s Disease
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 (χ2=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.

Pages 995-1004
Michelle R. Caunca, Marialaura Simonetto, Noam Alperin, Mitchell S.V. Elkind, Ralph L. Sacco, Clinton B. Wrightg, Tatjana Rundek (Handling Associate Editor: Vijay Ramanan)
Measures of Adiposity and Alzheimer’s Disease-Related MRI Markers: The Northern Manhattan Study
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 ε4 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 ε4 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.

Pages 1005-1023
Ian M. McDonough, Sarah K. Letang, Elizabeth (Ashley) Stinson
Dementia Risk Elevates Brain Activity During Memory Retrieval: A Functional MRI Analysis of Middle Aged and Older Adults
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.

Pages 1025-1040
Qini Gan*, Hongbo Yao*, Hana Na, Heather Ballance, Qiushan Tao, Lorene Leung, Hua Tian, Haihao Zhu, Benjamin Wolozin, Wei Qiao Qiu *These authors contributed equally to this work.
Effects of Amylin Against Amyloid-β-Induced Tauopathy and Synapse Loss in Primary Neurons
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.

Pages 1041-1049
Håkon Ihle-Hansen, Thea Vigen, Trygve Berge, Guri Hagberg, Knut Engedal, Ole Morten Rønning, Bente Thommessen, Magnus N. Lyngbakken, Ståle Nygård, Helge Røsjø, Arnljot Tveit, Hege Ihle-Hansen (Handling Associate Editor: Behnam Sabayan)
Carotid Atherosclerosis and Cognitive Function in a General Population Aged 63-65 Years: Data from the Akershus Cardiac Examination (ACE) 1950 Study
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.

Pages 1051-1058
Jagan A. Pillai, Aaron Bonner-Jackson, Lynn M. Bekris, Jiri Safar, Jim Bena, James B. Leverenz
Highly Elevated Cerebrospinal Fluid Total Tau Level Reflects Higher Likelihood of Non-Amnestic Subtype of Alzheimer’s Disease
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 ε4 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 ε4, 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.

Pages 1059-1068
Amber Watts, Heather M. Wilkins, Elias Michaelis, Russell H. Swerdlow
TOMM40 ‘523 Associations with Baseline and Longitudinal Cognition in APOE ε3 Homozygotes
Abstract: TOMM40 ‘523 is associated with Alzheimer’s disease (AD), but APOE linkage disequilibrium confounds this association. In 170 APOE ε3 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 ε3 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 ε3 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.

Pages 1069-1091
Gisela Esquerda-Canals, Alejandro R. Roda, Joaquim Martí-Clúa, Laia Montoliu-Gaya, Geovanny Rivera-Hernández, Sandra Villegas
Treatment with scFv-h3D6 Prevented Neuronal Loss and Improved Spatial Memory in Young 3xTg-AD Mice by Reducing the Intracellular Amyloid-β Burden
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.

Pages 1093-1102
Jianlan Gu, Dandan Chu, Nana Jin, Feng Chen, Fei Liu
Cyclic AMP-Dependent Protein Kinase Phosphorylates TDP-43 and Modulates Its Function in Tau mRNA Processing
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.

Pages 1103-1111
Tiago Mendes, Sandra Cardoso, Manuela Guerreiro, João Maroco, Dina Silva, Luísa Alves, Ben Schmand, Bianca Gerardo, Marisa Lima, Isabel Santana, Alexandre de Mendonça
Can Subjective Memory Complaints Identify Aβ Positive and Aβ Negative Amnestic Mild Cognitive Impairment Patients?
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.

Pages 1113-1122
Pilar Pérez-Ro*, Francisco Miguel Martínez-Arnau*, Susana Baixauli-Alacreu, Mireia Caballero-Pérez, José Fermín García-Gollarte, Francisco Tarazona-Santabalbina *These authors contributed equally to this work.
Delirium Predisposing and Triggering Factors in Nursing Home Residents: A Cohort Trial-Nested Case-Control Study
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.

Pages 1123-1132
Seung Wan Suh, Ji Won Han, Ju Ri Lee, Seonjeong Byun, Kyung Phil Kwak, Bong-Jo Kim, Shin Gyeom Kim, Jeong Lan Kim, Tae Hui Kim, Seung-Ho Ryu, Seok Woo Moon, Joon Hyuk Park, Jiyeong Seo, Jong Chul Youn, Dong Young Lee, Dong Woo Lee, Seok Bum Lee, Jung Jae Lee, Jin Hyeong Jhoo, In Young Yoon, Ki Woong Kim (Handling Associate Editor: Gemma Lombardi)
Short Average Duration of NREM/REM Cycle Is Related to Cognitive Decline in an Elderly Cohort: An Exploratory Investigation
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.

Pages 1133-1142
Xin Lv, Dongtao Zhou, Baojin Ge, Hui Chen, Yue Du, Shuai Liu, Yong Ji, Changqing Sun, Guangshun Wang, Yuxia Gao, Wen Li, Guowei Huang
Association of Folate Metabolites and Mitochondrial Function in Peripheral Blood Cells in Alzheimer’s Disease: A Matched Case-Control Study
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.

Pages 1143-1152
Leoni C. Menzel, Philipp W. Kramer, David A. Groneberg, Michael H.K. Bendels
Gender Disparities in Authorships of Alzheimer’s Disease and Dementia Research Articles
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.

Pages 1153-1161
Chuanying Huang, Shuqin Sun, Weijing Wang, Yujie Li, Wenjing Feng, Yili Wu (Handling Associate Editor: Manuel Montero-Odasso)
Cognition Mediates the Relationship Between Sensory Function and Gait Speed in Older Adults: Evidence from the English Longitudinal Study of Ageing
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.

Pages 1163-1174
Zhiqiang Guo, Zhenhua Ling, Yunxia Li (Handling Associate Editor: Jordi Peña-Casanova)
Detecting Alzheimer’s Disease from Continuous Speech Using Language Models
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.

Pages 1175-1185
Lin Lin*, Aiyi Liu*, Hanqin Li*, Jian Feng, Zhen Yan *These authors contributed equally to this work.
Inhibition of Histone Methyltransferases EHMT1/2 Reverses Amyloid-β-Induced Loss of AMPAR Currents in Human Stem Cell-Derived Cortical Neurons
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.

Pages 1187-1196
Ryan McGrath, Sheria G. Robinson-Lane, Summer Cook, Brian C. Clark, Stephen Herrmann, Melissa Lunsman O’Connor, Kyle J. Hackney
Handgrip Strength Is Associated with Poorer Cognitive Functioning in Aging Americans
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.

Pages 1197-1207
Mohsen Khosravi, Jonah Peter, Nancy A. Wintering, Mijail Serruya, Sara Pourhassan Shamchi, Thomas J. Werner, Abass Alavi, Andrew B. Newberg
18F-FDG Is a Superior Indicator of Cognitive Performance Compared to 18F-Florbetapir in Alzheimer’s Disease and Mild Cognitive Impairment Evaluation: A Global Quantitative Analysis
Abstract: Background: 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) and 18F-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 18F-FDG and 18F-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 18F-FDG and 18F-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. 18F-FDG and 18F-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 18F-FDG and 18F-florbetapir could successfully detect subjects with dementia (p < 0.001). Studied in all regions and groups, the correlation analysis of 18F-FDG GSUVr with MMSE scores was significant in more regions and groups compared to that of 18F-florbetapir. We also demonstrated that the correlation of 18F-FDG GSUVr with MMSE is stronger than that of 18F-florbetapir in the supra-tentorial and temporal regions. Conclusions: This study reveals how 18F-FDG-PET global quantification is a superior indicator of cognitive performance in AD and MCI patients compared to 18F-florbetapir PET. Accordingly, we still recommend 18F-FDG-PET over amyloid imaging in the evaluation for AD and MCI.

Pages 1209-1216
Christina Jensen-Dahm, Johanne Købstrup Zakarias, Christiane Gasse, Gunhild Waldemar (Handling Associate Editor: Alba Malara)
Geographical Variation in Opioid Use in Elderly Patients with Dementia: A Nationwide Study
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.

Pages 1217-1224
Mohamad El Haj, Abdelhalim Boudoukha, Pascal Antoine, Ahmed A. Moustafa, Karim Gallouj, Philippe Allain
Memories Supporting Myself: Autobiographical Memory Supports Self-Continuity in Alzheimer’s Disease
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.

Pages 1225-1239
Angélique A.A. Gruters, Inez H.G.B. Ramakers, Frans R.J. Verhey, Sebastian Köhler, Roy P.C. Kessels, Marjolein E. de Vugt (Handling Associate Editor: Katherine Gifford)
Association Between Proxy- or Self-Reported Cognitive Decline and Cognitive Performance in Memory Clinic Visitors
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.

Pages 1241-1257
Fabio Raman, Sameera Grandhi, Charles F. Murchison, Richard E. Kennedy, Susan Landau, Erik D. Roberson, Jonathan McConathy, and Alzheimer’s Disease Neuroimaging Initiative
Biomarker Localization, Analysis, Visualization, Extraction, and Registration (BLAzER) Methodology for Research and Clinical Brain PET Applications
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.

Pages 1259-1274
Zahra Manji, Asheebo Rojas, Wenyi Wang, Raymond Dingledine, Nicholas H. Varvel, Thota Ganesh (Handling Associate Editor: Colin Combs)
5xFAD Mice Display Sex-Dependent Inflammatory Gene Induction During the Prodromal Stage of Alzheimer’s Disease
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.

Pages 1275-1286
Lilian Calderón-Garcidueñas, Randy J. Kulesza, Yusra Mansour, Mario Aiello-Mora, Partha S. Mukherjee, Luis Oscar González-González
Increased Gain in the Auditory Pathway, Alzheimer’s Disease Continuum, and Air Pollution: Peripheral and Central Auditory System Dysfunction Evolves Across Pediatric and Adult Urbanites
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.