Volume 71, Number 1, IN PRESS

Review
Rafael Brito-Aguilar
Dementia Around the World and the Latin America and Mexican Scenarios
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.

Short Communication
Hyunjin Jo, Minkyeong Kim, Seongbeom Park, Jong Eun Park, Soo Hyun Cho, Seung Joo Kim, Hyemin Jang, Yong Hee Jung, Junpyo Kim, Duk L. Na, Sang Won Seo, Jin Whan Cho, Hee Jin Kim (Handling Associate Editor: Amalia Bruni)
Dopa Responsive Parkinsonism in an Early Onset Alzheimer’s Disease Patient with a Presenilin 1 Mutation (A434T)
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.

Short Communication
Nicolaas A. Verwey, Charlotte E. Teunissen, Jeroen J.M. Hoozemans, Annemieke J.M. Rozemuller, Philip Scheltens, Yolande A.L. Pijnenburg
Cerebrospinal Fluid Amyloid-β Subtypes in Confirmed Frontotemporal Lobar Degeneration Cases: A Pilot Study
Abstract: To investigate amyloid-β (Aβ) in frontotemporal dementia (FTD), cerebrospinal fluid (CSF) Aβ38, Aβ40, and Aβ42 in frontotemporal lobar degeneration (FTLD; N=18 genetically and/or pathologically confirmed and N=8 FTD with concomitant amyotrophic lateral sclerosis) were compared with Alzheimer’s disease (AD; pathological or Pittsburgh-compound-B Positron-emission-tomography (PIB-PET) positive; N=25) and controls (N=24). For all thee Aβ subtypes, group difference was seen and post-hoc analysis revealed lower levels in FTLD compared to controls (p≤0.05). Aβ42/40 ratio showed no difference between FTLD and controls; however, a difference was seen between AD versus FTLD (p<0.01). This is an intriguing finding, suggesting a possible role of Aβ in FTLD pathogenesis.

Myuri Ruthirakuhan, Nathan Herrmann, Ana C. Andreazza, Nicolaas Paul L.G. Verhoeff, Damien Gallagher, Sandra E. Black, Alex Kiss, Krista L. Lanctôt
24S-Hydroxycholesterol Is Associated with Agitation Severity in Patients with Moderate-to-Severe Alzheimer’s Disease: Analyses from a Clinical Trial with Nabilone
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.

Kelly N.H. Nudelman, Jue Lin, Kathleen A. Lane, Kwangsik Nho, Sungeun Kim, Kelley M. Faber, Shannon L. Risacher, Tatiana M. Foroud, Sujuan Gao, Justin W. Davis, Michael W. Weiner, Andrew J. Saykin, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Simon Laws)
Telomere Shortening in the Alzheimer’s Disease Neuroimaging Initiative Cohort
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.

Alissa Bernstein, Krista L. Harrison, Sarah Dulaney, Jennifer Merrilees, Angela Bowhay, Julia Heunis, Jeff Choi, Julie E. Feuer, Amy M. Clark, Winston Chiong, Kirby Lee, Tamara L. Braley, Stephen J. Bonasera, Christine Ritchie, Dan Dohan, Bruce L. Miller, Katherine L. Possin (Handling Associate Editor: Joshua Grill)
The Role of Care Navigators Working with People with Dementia and Their Caregivers
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.

Tuan Anh Nguyen, Julia Gilmartin-Thomas, Edwin Chin Kang Tan, Lisa Kalisch-Ellett, Tesfahun Eshetie, Marianne Gillam, Emily Reeve
The Impact of Pharmacist Interventions on Quality Use of Medicines, Quality of Life, and Health Outcomes in People with Dementia and/or Cognitive Impairment: A Systematic Review
Abstract: Background: Medication use in people with dementia and/or cognitive impairment (PWD/CI) is challenging. As medication experts, pharmacists have an important role in improving care of this vulnerable population. Objective: Systematically review evidence for the effectiveness of pharmacist-led interventions on quality use of medicines, quality of life, and health outcomes of PWD/CI. Methods: A systematic review was conducted using MEDLINE, EMBASE, PsycINFO, Allied and Complementary Medicine (AMED) and Cumulative index to Nursing and Allied Health Literature (CINAHL) databases from conception to 20 March 2017. Full articles published in English were included. Data were synthesized using a narrative approach. Results: Nine studies were eligible for inclusion. All studies were from high-income countries and assessed pharmacist-led medication management services. There was great variability in the content and focus of services described and outcomes reported. Pharmacists were found to provide a number of cognitive services including medication reconciliation, medication review, and medication adherence services. These services were generally effective with regards to improving quality use of medicines and health outcomes for PWD/CI and their caregivers, and for saving costs to the healthcare system. Pharmacist-led medication and dementia consultation services may also improve caregiver understanding of dementia and the different aspects of pharmacotherapy, thus improving medication adherence. Conclusion: Emerging evidence suggests that pharmacist-led medication management services for PWD/CI may improve outcomes. Future research should confirm these findings using more robust study designs and explore additional roles that pharmacists could undertake in the pursuit of supporting PWD/CI.

Si Guo*, Jing-Jing Xu*, Na Wei, Jun-Ya Han, Rui Xue, Po-Shi Xu, Chuan-Yu Gao (Handling Associate Editor: Ling-Qiang Zhu) *These authors have contributed equally to this work.
Honokiol Attenuates the Memory Impairments, Oxidative Stress, Neuroinflammation, and GSK-3β Activation in Vascular Dementia Rats
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.

Emilie T. Reas, Gail A. Laughlin, Jaclyn Bergstrom, Donna Kritz-Silverstein, Linda K. McEvoy
Physical Activity and Trajectories of Cognitive Change in Community-Dwelling Older Adults: The Rancho Bernardo Study
Abstract: Background: Although physical activity has been associated with better cognitive function and reduced dementia risk, its association with cognitive decline in normal aging remains uncertain. Objective: To determine whether physical activity in youth and older age are associated with age-related cognitive change. Methods: Over a period of 27 years, 2,027 community-dwelling adults (mean age 73.5; 60% women) of the Rancho Bernardo Study of Healthy Aging completed up to seven cognitive assessments, including tests of global cognitive function, executive function, verbal fluency, and episodic memory. At each visit, participants reported concurrent physical activity. At baseline (1988-1992), participants additionally reported physical activity as a teenager and at age 30. For each age period, participants were classified as regularly active (3+ times/week) or inactive. Results: Associations between concurrent physical activity and better cognitive function were stronger with advancing age on all tests, even after accounting for education, health, and lifestyle factors, as well as survival differences (ps < 0.05). Baseline physical activity did not predict rates of cognitive decline (ps > 0.40). Individuals who were physically active at age 30 and older age maintained the highest global cognitive function with advancing age (p = 0.002). Conclusion: Regular physical activity is associated with better cognitive function with advancing age. Physical activity in young adulthood may contribute to cognitive reserve, which together with physical activity in later years, may act to preserve cognitive function with age.

Yue Dong, Gregory J. Brewer
Global Metabolic Shifts in Age and Alzheimer’s Disease Mouse Brains Pivot at NAD+/NADH Redox Sites
Abstract: Age and Alzheimer’s disease (AD) share some common features such as cognitive impairments, memory loss, metabolic disturbances, bioenergetic deficits, and inflammation. Yet little is known on how systematic shifts in metabolic networks depend on age and AD. In this work, we investigated the global metabolomic alterations in non-transgenic (NTg) and triple-transgenic (3xTg-AD) mouse brain hippocampus as a function of age by using untargeted Ultrahigh Performance Liquid Chromatography-tandem Mass Spectroscopy (UPLC-MS/MS). We observed common metabolic patterns with aging in both NTg and 3xTg-AD brains involved in energy-generating pathways, fatty acids oxidation, glutamate, and sphingolipid metabolism. We found age-related downregulation of metabolites from reactions in glycolysis that consumed ATP and in the TCA cycle, especially at NAD+/NADH-dependent redox sites, where age- and AD-associated limitations in the free NADH may alter reactions. Conversely, metabolites increased in glycolytic reactions in which ATP is produced. With age, inputs to the TCA cycle were increased including fatty acid &beta;-oxidation and glutamine. Overall age- and AD-related changes were >2-fold when comparing the declines of upstream metabolites of NAD+/NADH-dependent reactions to the increases of downstream metabolites (p=10-5, n=8 redox reactions). Inflammatory metabolites such as ceramides and sphingosine-1-phosphate also increased with age. Age-related decreases in glutamate, GABA, and sphingolipid were seen which worsened with AD genetic load in 3xTg-AD brains, possibly contributing to synaptic, learning- and memory-related deficits. The data support the novel hypothesis that age- and AD-associated metabolic shifts respond to NAD(P)+/NAD(P)H redox-dependent reactions, which may contribute to decreased energetic capacity.

Hazel I. Zonneveld*, Gennady V. Roshchupkin*, Hieab H.H. Adams, Boris A. Gutman, Aad van der Lugt, Wiro J. Niessen, Meike W. Vernooij, M. Arfan Ikram (Handling Associate Editor: Long Xie) * These authors contributed equally to this work.
High-Dimensional Mapping of Cognition to the Brain Using Voxel-Based Morphometry and Subcortical Shape Analysis
Abstract: Background: It is increasingly recognized that the complex functions of human cognition are not accurately represented by arbitrarily-defined anatomical brain regions. Given the considerable functional specialization within such regions, more fine-grained studies of brain structure could capture such localized associations. However, such analyses/studies in a large community-dwelling population are lacking. Objective: To perform a fine-mapping of cognitive ability to cortical and subcortical grey matter on magnetic resonance imaging (MRI). Methods: In 3,813 stroke-free and non-demented persons from the Rotterdam Study (mean age 69.1 (±8.8) years; 55.8% women) with cognitive assessments and brain MRI, we performed voxel-based morphometry and subcortical shape analysis on global cognition and separate tests that tapped into memory, information processing speed, fine motor speed, and executive function domains. Results: We found that the different cognitive tests significantly associated with grey matter density in differential but also overlapping brain regions, primarily in the left hemisphere. Clusters of significantly associated voxels with global cognition were located within multiple anatomic regions: left amygdala, hippocampus, parietal lobule, superior temporal gyrus, insula and posterior temporal lobe. Subcortical shape analysis revealed associations primarily within the head and tail of the caudate nucleus, putamen, ventral part of the thalamus, and nucleus accumbens, more equally distributed among the left and right hemisphere. Within the caudate nucleus both positive (head) as well as negative (tail) associations were observed with global cognition. Conclusions: In a large population-based sample, we mapped cognitive performance to cortical and subcortical grey matter density using a hypothesis-free approach with high-dimensional neuroimaging. Leveraging the power of our large sample size, we confirmed well-known associations as well as identified novel brain regions related to cognition.

Irene Martínez de Toda, Lara Miguélez, Carmen Vida, Eva Carro, Mónica De la Fuente
Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease
Abstract: Oxidative stress plays an essential and early role in the pathophysiology of Alzheimer’s disease (AD). Alterations in the redox state in AD and in mild cognitive impairment (MCI) patients appear in the brain and at peripheral level. Given that it is easier to study the latter, most of the research has been focused on plasma. However, the analysis of redox parameters in whole blood cells (including erythrocytes and leukocytes) has not really been investigated. Moreover, the association of these parameters with Mini-Mental State Examination (MMSE) clinical scores, has scarcely been studied. Therefore, the aim of the present work was to analyze several redox markers in whole blood cells from male and female MCI and AD patients. Antioxidant (superoxide dismutase, catalase (CAT), glutathione peroxidase (GPx), and reductase (GR) activities, and reduced glutathione (GSH) concentration) together with oxidant parameters (oxidized glutathione (GSSG) and thiobarbituric acid-reactive substances (TBARS)) were investigated using MCI and AD (10 women and 10 men in each group) and their age-matched control groups (15 women and 15 men). The results show an altered redox state in whole blood cells from AD patients (higher CAT, GSSG/GSH, TBARS and lower GPx, GR, GSH). Some of these redox parameters are already affected in MCI patients (higher TBARS and lower GPx and GR activities) in both sexes and, consequently, they could be used as markers of prodromal AD. Since GR, GSH, GSSG, and GSSG/GSH were found to be associated with MMSE scores, they seem to be useful clinically to monitor cognitive decline in AD progression.

Nicholas J. Tustison, Andrew J. Holbrook, Brian B. Avants, Jared M. Roberts, Philip A. Cook, Zachariah M. Reagh, Jeffrey T. Duda, James R. Stone, Daniel L. Gillen, Michael A. Yassa for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Joon-Kyung Seong)
Longitudinal Mapping of Cortical Thickness Measurements: An Alzheimer’s Disease Neuroimaging Initiative-Based Evaluation Study
Abstract: Longitudinal studies of development and disease in the human brain have motivated the acquisition of large neuroimaging data sets and the concomitant development of robust methodological and statistical tools for quantifying neurostructural changes. Longitudinal-specific strategies for acquisition and processing have potentially significant benefits including more consistent estimates of intra-subject measurements while retaining predictive power. Using the first phase of the Alzheimer’s Disease Neuroimaging Initiative (ADNI-1) data, comprising over 600 subjects with multiple time points from baseline to 36 months, we evaluate the utility of longitudinal FreeSurfer and Advanced Normalization Tools (ANTs) surrogate thickness values in the context of a linear mixed-effects (LME) modeling strategy. Specifically, we estimate the residual variability and between-subject variability associated with each processing stream as it is known from the statistical literature that minimizing the former while simultaneously maximizing the latter leads to greater scientific interpretability in terms of tighter confidence intervals in calculated mean trends, smaller prediction intervals, and narrower confidence intervals for determining cross-sectional effects. This strategy is evaluated over the entire cortex, as defined by the Desikan-Killiany-Tourville labeling protocol, where comparisons are made with the cross-sectional and longitudinal FreeSurfer processing streams. Subsequent linear mixed effects modeling for identifying diagnostic groupings within the ADNI cohort is provided as supporting evidence for the utility of the proposed ANTs longitudinal framework which provides unbiased structural neuroimage processing and competitive to superior power for longitudinal structural change detection.

Hao He, Pengfei Xu, Tingting Wu, Yiqi Chen, Jing Wang, Yuehong Qiu, Jin Fan, Qing Guan, Yuejia Luo (Handling Associate Editor: Andreas Tales)
Reduced Capacity of Cognitive Control in Older Adults with Mild Cognitive Impairment
Abstract: Cognitive control for the coordination of mental operations is essential in normal cognitive functioning in daily life. Although the decline in cognitive control in older adults with mild cognitive impairment (MCI) has been demonstrated, whether this decline serves as a core deficit in MCI remains unclear. In this study, we employed a perceptual decision-making task to estimate the capacity of cognitive control (CCC) in older adults with MCI (n = 55) and the age-, sex-, and education-matched healthy controls (HC, n = 55) selected based on a commonly used battery of ten neuropsychological tests in five cognitive domains. We found that the CCC was significantly correlated to the neuropsychological measures of the battery. The mean CCC was significantly lower in the MCI group (3.06 bps) than in the HC group (3.59 bps) and significantly lower in the amnestic MCI subgroup (2.90 bps) than in the nonamnestic MCI subgroup (3.22 bps). In detecting and classifying MCI in machine learning, the classifier with the CCC as the input feature outperformed the overall classification with neuropsychological measures in a single cognitive domain. The classification performance was significantly increased when the CCC was included as a feature in addition to measures in a single domain, and the CCC served as a key feature in optimal classifiers with inputs from multiple domains. These results support the hypothesis that the decline in cognitive control is a core deficit in MCI and suggest that the CCC may serve as a key index in the diagnosis of MCI.

Erica E. Hack, Joel A. Dubin, Myra A. Fernandes, Sanduni M. Costa, Suzanne L. Tyas
Multilingualism and Dementia Risk: Longitudinal Analysis of the Nun Study
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.

Scott H. Deibel, Bryant Young, Majid H. Mohajerani, Robert J. McDonald (Handling Associate Editor: Ira Driscoll)
Activity Rhythms Are Largely Intact in APPNL-G-F Alzheimer’s Disease Mice
Abstract: Circadian rhythm dysfunction is present in Alzheimer’s disease. Animal models of Alzheimer’s disease have been employed to investigate whether this dysfunction is a risk factor or symptom of the disease. The circadian phenotype in mouse models of Alzheimer’s disease is very disparate in terms of the degree and timing of the dysfunction. This is likely a result of some models elevating amyloid-β protein precursor instead of just the amyloid-β fragment present in human Alzheimer’s disease. We characterized activity rhythms in a novel knock-in mouse model (APPNL-G-F) of Alzheimer’s disease that elevates amyloid-β without overexpressing amyloid-β protein precursor. Despite increased rhythm amplitude, total activity, and a shortening of free-running period at 15 months of age, all other aspects of the activity rhythm were similar to controls from three to fifteen months of age. At two months of age, these mice were also able to entrain to a light-dark cycle with a period right on the edge of entrainment, which further suggests a healthy functioning circadian system. These data open the possibility that circadian rhythm disruptions in transgenic models of Alzheimer’s disease could be a result of these models having an artificial phenotype caused by overexpression of amyloid-β protein precursor.

Morgane Lacour, Olivier Quenez, Anne Rovelet-Lecrux, Bruno Salomon, Stephane Rousseau, Anne-Claire Richard, Muriel Quillard-Muraine Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Aline Zarea, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Eloi Magnin, Mathide Sauvée, Cecilia Marelli, Audrey Gabelle, Jeremie Pariente, Claire Paquet, Anne Boland, Jean-François Deleuze, the collaborators of the CNR-MAJ, Dominique Campion, Didier Hannequin, Gael Nicolas*, David Wallon* *These authors contributed equally to this work.
Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years
Abstract: Background: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. Objective: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p<0.0001) and associated neurologic symptoms more frequently (p<0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. Conclusion: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages.

Arvey Camilo Villalba, Jenny García, Claudia Ramos, Amanda Rosario Cuastumal, David Aguillón, Daniel Camilo Aguirre-Acevedo, Lucia Madrigal, Francisco Lopera
Mental Disorders in Young Adults from Families with the Presenilin-1 Gene Mutation E280A in the Preclinical Stage of Alzheimer’s Disease
Abstract: Background: There are forms of Alzheimer's disease (AD) that have an autosomal dominant inheritance pattern; one of them is caused by the E280A mutation in the gene that codes for Presenilin-1 (PSEN1). Studying families of people with this mutation allows the evaluation of characteristics of the subjects before cognitive decline begins. Objective: To determine whether having the mutation E280A in PSEN1 increases the risk of presenting mental disorders in adults under 30 years old who are in the preclinical stage of AD and may be eligible for primary prevention studies of AD. Methods: A psychiatric evaluation was made to 120 people belonging to families with a history of early onset AD. Of these, 62 carried the E280A mutation in PSEN1. The occurrence of mental disorders between carriers and non-carriers of the mutation was compared. Results: No statistically significant differences were found in the frequency of any mental disorder between the group of carriers and non-carriers of the mutation (Hazard Ratio: 0.80, 95% CI 0.49 to 1.31); nor were differences observed when evaluating specific disorders. Conclusion: The E280A mutation does not increase the risk of mental disorders before the age of 30 in the relatives of people affected by familial AD. Studies with larger sample sizes are required to assess the risk of low incidence mental disorders.

Emilio Werden, Mohamed Salah Khlif, Laura J. Bird, Toby Cumming, Jennifer Bradshaw, Wasim Khan, Matthew Pase, Carolina Restrepo, Michele Veldsman, Natalia Egorova, Sheila K. Patel, Elie Gottlieb, Amy Brodtmann
APOE ε4 Carriers Show Delayed Recovery of Verbal Memory and Smaller Entorhinal Volume in the First Year After Ischemic Stroke
Abstract: Background: The apolipoprotein E (APOE) gene ε4 allele is a risk factor for Alzheimer’s disease and cardiovascular disease. However, its relationship with cognition and brain volume after stroke is not clear. Objective: We compared cognition and medial temporal lobe volumes in APOE ε4 carriers and non-carriers in the first year after ischemic stroke. Methods: We sampled 20 APOE ε4 carriers and 20 non-carriers from a larger cohort of 135 ischemic stroke participants in the longitudinal CANVAS study. Participants were matched on a range of demographic and stroke characteristics. We used linear mixed-effect models to compare cognitive domain z-scores (attention, processing speed, executive function, verbal and visual memory, language, visuospatial function) and regional medial temporal lobe volumes (hippocampal, entorhinal cortex) between groups at each time-point (three, 12-months post-stroke), and within groups across time-points. APOE gene single nucleotide polymorphisms (SNPs; rs7412, rs429358) were genotyped on venous blood. Results: APOE ε4 carriers and non-carriers did not differ on any demographic, clinical, or stroke variable. Carriers performed worse than non-carriers in verbal memory at three months post-stroke (p=0.046), but were better in executive function at 12 months (p=0.035). Carriers demonstrated a significant improvement in verbal memory (p=0.012) and executive function (p=0.015) between time-points. Non-carriers demonstrated a significant improvement in visual memory (p=0.0005). Carriers had smaller bilateral entorhinal cortex volumes (p<0.05), and larger-right-sided and contralesional hippocampal volumes, at both time-points (p<0.05). Conclusion: APOE ε4 is associated with delayed recovery of verbal memory function and reduced entorhinal cortex volumes in the first year after ischemic stroke.

Naoto Takenoshita, Soichiro Shimizu, Hidekazu Kanetaka, Hirofumi Sakurai, Ryo Suzuki, Takashi Miwa, Masato Odawara, Kenji Ishii, Hitoshi Shimada, Makoto Higuchi, Tetsuya Suhara, Haruo Hanyu
Classification of Clinically Diagnosed Alzheimer’s Disease Associated with Diabetes Based on Amyloid and Tau PET Results
Abstract: Background/Objective: Although type 2 diabetes mellitus (DM) is a risk factor for the development of dementia, the underlying brain pathologies and mechanisms vary among patients. In this study, we classified patients with clinically diagnosed Alzheimer’s disease (AD) associated with DM into subgroups based on their amyloid and tau accumulation patterns on positron emission tomography (PET), and analyzed the differences in clinical features and brain imaging findings between the subgroups. Methods: Sixty-four patients with probable or possible AD associated with DM were classified using PiB (detects amyloid, A) and PBB3 (detects tau, T) PET studies. Patients were classified into the A+/T+ group (n = 35, AD pathology), the A−/T+ group (n = 19, tauopathy), and the A−/T− group (n = 10, non-amyloid/non-tau neuronal damage). Results: Compared with the A+/T+ group, the A−/T+ group showed less-well controlled glycemia, longer duration of diabetes, more glucose variability, higher frequency of insulin therapy and biochemical hypoglycemia, and greater impairment of frontal lobe function, slower progression of cognitive decline, fewer APOE4 carriers, less severe medial temporal lobe atrophy, and lower frequency of posterior cerebral hypoperfusion. This subgroup showed different clinical and radiological features from AD. Conclusion: Among patients with clinically diagnosed AD with DM, there are subgroups with neuronal damage independent of AD pathology. A subgroup of dementia patients suspected of having tauopathy is strongly associated with DM-related metabolic abnormalities. This study highlights the identification of a novel dementia subgroup (diabetes-related dementia), which is important for considering appropriate therapies and care in clinical practice.

Yutaka Hatada, Mamoru Hashimoto, Shinya Shiraishi, Tomohisa Ishikawa, Ryuji Fukuhara, Seiji Yuki, Hibiki Tanaka, Yusuke Miyagawa, Mika Kitajima, Hiroyuki Uetani, Naoko Tsunoda, Asuka Koyama, Manabu Ikeda
Cerebral Microbleeds Are Associated with Cerebral Hypoperfusion in Patients with Alzheimer’s Disease
Abstract: Background: Although cerebral microbleeds (CMBs) are commonly observed in patients with Alzheimer’s disease (AD), their clinical relevance for AD remains unclear. Objective: We investigated the significance of CMBs in AD by examining the relationship between CMBs and cerebral blood flow (CBF) in patients with AD. Methods: Thirty-four patients (aged 77.9 ± 7.6 years; 17 men) with probable AD and multiple (≥ 8) CMBs were selected from 394 consecutive patients. For each lobe of the brain, the correlation between the number of CMBs observed on susceptibility-weighted images and the decrease in CBF observed on single-photon emission computed tomography was assessed. Results: The number of microbleeds was significantly correlated with the severity of decrease in the occipital lobe (Spearman’s r = 0.531, p < 0.001) and temporal lobe (r = 0.437, p < 0.001) but not in the frontal lobe (r = 0.201, p = 0.101) and parietal lobe (r = 0.178, p = 0.146). These results were unchanged in the partial correlational analysis after controlling the effect of other small vessel disease such as lacunars and white matter hyperintensities. Conclusion: Multiple CMBs are associated with cerebral hypoperfusion in AD. The effects of CMBs on CBF differed according to brain location, possibly reflecting different distributions of the underlying cerebral amyloid angiopathy and AD-related histopathology, such as neurofibrillary tangles.

Katie E. Osborn, Jonathan M. Alverio, Logan Dumitrescu, Kimberly R. Pechman, Alzheimer’s Disease Neuroimaging Initiative, Katherine A. Gifford, Timothy J. Hohman, Kaj Blennow, Henrik Zetterberg, Angela L. Jefferson
Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer’s Disease Pathology
Abstract: Background: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer’s disease pathology influences the brain’s vulnerability in this regard is not well understood. Objective: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer’s disease. Methods: Among Alzheimer’s Disease Neuroimaging Initiative participants with normal cognition (n=117), mild cognitive impairment (n=190), and Alzheimer’s disease (n=95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of Aβ42, hyperphosphorylated tau, and total tau. Results: Vascular risk and neurofilament light were not related in the main effect model (p=0.08). However, interactions emerged for total tau (p=0.01) and hyperphosphorylated tau (p=0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer’s disease biomarker profiles (p=0.046) where in comparison to the referent ‘normal’ biomarker group, individuals with abnormal levels of both Aβ42 and total tau showed stronger associations between vascular risk and neurofilament light. Conclusion: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer’s disease pathology.

Beibei Wu*, Yujing Wang*, Chenggang Shi, Yao Chen, Lexiang Yu, Juan Li, Weiwei Li, Yan Wei, Rongqiao He *These authors contributed equally to this work.
Ribosylation-Derived Advanced Glycation End Products Induce Tau Hyperphosphorylation Through Brain-Derived Neurotrophic Factor Reduction
Abstract: Advanced glycation end products (AGEs) have been implicated in the disease process of diabetes mellitus. They have also been found in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease patients. Furthermore, abnormally high levels of D-ribose and D-glucose were found in the urine of patients with type 2 diabetes mellitus, suggesting that diabetic patients suffer from dysmetabolism of not only D-glucose but also D-ribose. In the present study, intravenous tail injections of ribosylated rat serum albumin (RRSA) were found to impair memory in rats, but they did not markedly impair learning, as measured by the Morris water maze test. Injections of RRSA were found to trigger tau hyperphosphorylation in the rat hippocampus via GSK-3β activation. Tau hyperphosphorylation and GSK-3β activation were also observed in N2a cells in the presence of ribosylation-derived AGEs. Furthermore, the administration of ribosylation-derived AGEs induced the suppression of brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B (TrkB). Both GSK-3β inhibition and BDNF treatment decreased the levels of phosphorylated Tau in N2a cells. In particular, the administration of BDNF could rescue memory failure in ribosylated AGE-injected rats. Ribosylation-derived AGEs downregulated the BDNF-TrkB pathway in rat brains and N2a cells, leading to GSK-3β activation-mediated tau hyperphosphorylation, which was involved in the observed rat memory loss. Targeting ribosylation may be a promising therapeutic strategy to prevent Alzheimer’s disease and diabetic encephalopathies.

Matthew J. Lennon, Steve R. Makkar, John D. Crawford, Perminder S. Sachdev
Midlife Hypertension and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background: Hypertension is an established risk factor for stroke and vascular dementia but recent meta-analyses examining the association between Alzheimer’s disease (AD) and hypertension have found no significant association. These meta-analyses included short term studies starting in late life which may have obscured the real effect of midlife hypertension. Objective: To examine the association of AD with midlife hypertension, by including only studies with a sufficiently long follow up duration. Methods: Relevant studies were found by searches of MEDLINE, EMBASE, and PubMed. Study outcomes were grouped by measures of blood pressure and definition of hypertension (e.g., systolic hypertension >140 mmHg or >160 mmHg). We assessed pooled effect estimates using random effects models and heterogeneity of pooled estimates through the I2 statistic. Results: Literature search found 3,426 publications of which 7 were eligible studies. There was a significant association between systolic hypertension (>160 mm Hg) and AD (HR 1.25, 95CI 1.06 – 1.47, p=0.0065). Similarly, for systolic hypertension >140 mm Hg, there was a smaller but still significant association (HR 1.18, 95CI 1.02 – 1.35, p=0.021). For diastolic hypertension, all four studies found no significant associations between diastolic hypertension and AD, and these data could not be pooled due to heterogeneity in reporting. Conclusions: Our study found that midlife stage 1 and stage 2 systolic hypertension is associated with increased risk of AD by 18 and 25%, respectively, although no association was found for diastolic hypertension. It is likely that assertive control of systolic hypertension starting in midlife is important to preventing AD.

Emma E.F. Kleipool, Marijke C. Trappenburg, Hannke F.M. Rhodius-Meester, Afina W. Lemstra, Wiesje M. van der Flier, Mike J.L. Peters, Majon Muller
Orthostatic Hypotension: An Important Risk Factor for Clinical Progression to Mild Cognitive Impairment or Dementia. The Amsterdam Dementia Cohort
Abstract: Background: Orthostatic hypotension (OH) has been cross-sectionally and longitudinally related to dementia in the general population. Whether OH contributes to clinical progression to mild cognitive impairment (MCI) or dementia is less certain. Also, differences in risk of progression between patients with early OH (EOH) versus delayed and/or prolonged OH (DPOH) are unclear. Objective: Assess the prevalence of EOH and DPOH, investigate the longitudinal association between EOH and DPOH and incident MCI or dementia. Methods: 1,882 patients from the Amsterdam Dementia Cohort [64±8 years; 43% female; n=500 with subjective cognitive decline (SCD), n=341 MCI, n=758 Alzheimer’s disease (AD), n=49 vascular dementia (VaD), n=146 frontotemporal dementia (FTD), n=88 Lewy body dementia (DLB)]. Definition OH: systolic blood pressure (BP) drop ≥20 mmHg and/or a diastolic BP drop ≥10 mmHg at 1 and/or 3 minutes after standing. EOH: OH only at 1 minute, DPOH: OH at (1 and) 3 minutes. Results: Prevalence OH: 19% SCD, 28% MCI, 41% dementia. Compared to SCD, odds of having OH were highest in patients with VaD and DLB; ORs (95%CI) were 2.6 (1.4-4.7) and 5.1 (3.1-8.4). After a mean (SD) follow-up of 2.2 (1.4) years, 105 (22%) of SCD or MCI patients showed clinical progression. Compared to patients without OH, those with DPOH had an increased risk of progression; hazard ratio (95%CI) was 1.7 (1.1-2.7), and those with EOH not; 0.8 (0.3-1.9). Conclusion: Compared to SCD, prevalence of OH was higher in MCI and highest in dementia, particularly in VaD and DLB. DPOH, more likely associated with autonomic dysfunction, is a risk factor for incident MCI or dementia.

Tian Feng, Toru Yamashita, Jingwei Shang, Xiaowen Shi, Yumiko Nakano, Ryuta Morihara, Keiichiro Tsunoda, Emi Nomura, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe
Clinical and Pathological Benefits of Edaravone for Alzheimer’s Disease with Chronic Cerebral Hypoperfusion in a Novel Mouse Model
Abstract: Alzheimer’s disease (AD) and chronic cerebral hypoperfusion (CCH) often coexist in dementia patients in aging societies. The hallmarks of AD including amyloid-β (Aβ)/phosphorylated tau (pTau) and pathology-related events such as neural oxidative stress and neuroinflammation play critical roles in pathogenesis of AD with CCH. A large number of lessons from failures of drugs targeting a single target or pathway on this so complicated disease indicate that disease-modifying therapies targeting multiple key pathways hold potent potential in therapy of the disease. In the present study, we used a novel mouse model of AD with CCH to investigate a potential therapeutic effect of a free radical scavenger, Edaravone (EDA) on AD with CCH via examining motor and cognitive capacity, AD hallmarks, neural oxidative stress, and neuroinflammation. Compared with AD with CCH mice at 12 months of age, EDA significantly improved motor and cognitive deficits, attenuated neuronal loss, reduced Aβ/pTau accumulation, and alleviated neural oxidative stress and neuroinflammation. These findings suggest that EDA possesses clinical and pathological benefits for AD with CCH in the present mouse model and has a potential as a therapeutic agent for AD with CCH via targeting multiple key pathways of the disease pathogenesis.

Mark Yu Zheng Wong, Chuen Seng Tan, Narayanaswamy Venketasubramanian, Christopher Chen, M. Kamran Ikram, Ching-Yu Cheng, Saima Hilal (Handling Associate Editor: Masafumi Ihara)
Prevalence and Risk Factors for Cognitive Impairment and Dementia in Indians: A Multiethnic Perspective from a Singaporean Study
Abstract: Background: Dementia is the leading cause of dependency and disability among older persons worldwide. There remains, however, limited studies on dementia rates within the Asia-Pacific region, with little data on differences across major Asian ethnic groups. Objective: To study the prevalence of cognitive impairment (CI) and dementia in community-dwelling Indians from Singapore and to examine interethnic differences among Chinese, Malays, and Indians. Methods: Participants (>60 years) drawn from the Indian component of the multiethnic Epidemiology of Dementia in Singapore (EDIS) study were screened using the locally validated Abbreviated Mental Test and Progressive Forgetfulness Questionnaire. Screen-positive participants underwent further detailed neuropsychological assessments. CI was classified into Cognitive impairment no dementia (CIND)-mild, CIND-moderate, and dementia. Results: Of 961 Indian adults, 120 (12.5%) had CIND-mild, 101 (10.5%) CIND-moderate, and 12 (1.2%) dementia. The overall age-standardized prevalence of any CI was 24.6%. The prevalence of any CI increased with age (15.7% in ages 60-64 years to 30.1% in ages ≥ 80 years), and was higher in women than men. Multivariate analysis showed that age, lower education, and hypertension were independently associated with CI. Even after demographic and cardiovascular risk factor adjustment, Indians were more likely to be cognitively impaired compared to Chinese (odds ratio [OR], 95% CI:1.37 [1.01-1.86]) but not Malays (0.89 [0.72-1.10]). Conclusions: Among elderly Indians, the overall prevalence of any CI was 24.6%. Despite similar assessment protocols and risk factor adjustments, the prevalence of CI was higher in Indians compared to Chinese but similar to Malays. Further research is needed to unravel other factors that may underlie these ethnic differences.

Karel Kostev, Jens Bohlken, Louis Jacob
Association Between Migraine Headaches and Dementia in More than 7,400 Patients Followed in General Practices in the United Kingdom
Abstract: Background: Most previous studies focusing on the migraine headache-dementia relationship have failed to simultaneously adjust for several common comorbidities. Objective: The goal of this retrospective cohort study was to investigate the association between migraine headaches and dementia in general practices in the UK. Methods: The current study sample included patients who received a migraine diagnosis in one of 67 general practices in the UK between January 1997 and December 2016 (index date). Patients without migraine diagnoses were matched 1:1 to patients with migraine diagnoses based on propensity scores using a greedy algorithm and derived from the logistic regression using age, sex, index year, and co-diagnoses. The main outcome of the study was the association between migraine headaches and the incidence of dementia within 10 years of the index date. Results: This study included 7,454 individuals with or without migraine diagnoses. Mean age was 67.7 years (SD=5.8 years), and 72.9% of patients were women. Within 10 years of the index date, 5.2% of participants with and 3.7% of those without migraine headaches were diagnosed with dementia (log-rank p<0.001). The respective figures were 5.8% and 3.6% in women (log-rank p<0.001) and 4.5% and 3.4% in men (log-rank p=0.722). We observed a positive association between migraine diagnoses and all-cause dementia (hazard-ratio [HR]=1.43) as well as Alzheimer’s disease (HR=1.87). Sensitivity analyses further revealed that these associations were only significant in women (all-cause dementia: HR=1.65; Alzheimer’s disease: HR=2.27). Conclusion: Migraine diagnoses were positively associated with all-cause dementia and Alzheimer’s disease in women.